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TANDEM REACTIONS OF FUNCTIONALIZED SOUARATE ESTERS AND OTHER CYCLOBUTENEDIONES. METHODOLOGY AND APPLICATIONS TO THE SYNTHESIS OF POLYQUINANE NATURAL PRODUCTS
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
by
Tina M. Morwick, B.A.
The Ohio State University 1996
Dissertation Committee: Professor Leo A. Paquette, Advisor Approved by Professor David J. Hart Professor John S. Swenton
Adviser Department of Chemistry UMI Number: 9639312
UMI Microform 9639312 Copyright 1996, by UMI Company. All rights reserved.
This microform edition is protected against unauthorized copying under Title 17, United States Code.
UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT
A novel cascade rearrangement generating poiyquinane structures on addition of two unsaturated anions to squarate esters has been investigated.
Utilizing a single laboratory operation, the electrocyclic^/aldol reaction is capable of the installation of up to five new chiral centers in a stereocontrolled fashion. It will accommodate both carbocyclic and heterocyclic nucleophiles, with either sp2 or sp hybridization. Relief of strain and possible anionic acceleration initiate the process under relatively mild conditions.
Initial mechanism studies focusing on the isolation and characterization of reaction intermediates have revealed the mode of bond reorganization for both major and minor products. The major products occur as a result of initial trans addition of two vinyl anions, followed by 4 k electrocyclic ring opening of the highly strained cyclobutene dioxolate. This process necessarily occurs with the appropriate torquoselectivity to deliver an acyclic tetraene whose intemal double bonds have a cis configuration. The tetraene undergoes a second 8 tc electrocyclic event, establishing a cyclooctatriene dienolate. On protonation, transannular aldolization ensues providing the poiyquinane substrates. Other pathways include cis addition followed by [3,3] sigmatropy and aldol reaction, as well as second-stage conjugate addition, pericyclic bond reorganization and vinylogous transannular aldol reaction. The particular pathway is orchestrated by the mode of second-stage addition. Structure-reactivity studies have revealed that both electrocyclic events fall under substituent control, and the effects of a variety of functionality have been investigated. Several methods for controlling regio and stereoselectivity have also been developed.
Incorporation of an allene into the current methodology has provided a means for investigating the "allene effect" with respect to periselectivity for the second electrocyclic event. The allene is apparently capable of significant transition state stabilization for the 6 k disrotatory option, leading exclusively to hexadienone substrates. Finally, attempts to utilize the newly discovered process as a key step for synthesis of the natural product crinipellin B have been carried out. Model studies addressing both the feasibility of a particular reaction sequence, as well as the reactivity of the y-hydroxy-a,p-bisalkoxy enone products derived from the electrocyclic^ aldol reaction were pursued to a successful conclusion. It was found that the trimethylsilyl group provides excellent diastereoselectivity and promotes reaction efficiency to a significant degree.
Ill To my husband, Ken, our children, Chrissy, Greg, Joe and Matt, and in memory of our parents, Oscar and Julia Pickard and Lloyd and Orpha Morwick
IV ACKNOWLEDGMENTS
I would like to thank the many individuals whose contributions have made this work possible. I must first thank my family for their patience and encouragement, and especially my husband, Ken, for all the extra responsibilities he has assumed over the last few years. His constant support has made this impossible task a reality. I must also thank my advisor. Dr. Leo Paquette, for giving me the opportunity to work in his research group. Contributing his blend of wisdom and practical experience, he has both guided and encouraged me throughout this study. The substance of the project has provided many avenues for growth, and
I have thoroughly enjoyed developing the various aspects involved. His shared enthusiasm and his very accessible nature has aided the work immeasurably. I would also like to thank the other members of my Dissertation
Committee; Dr. John Swenton, not only for serving on the committee, but for his many helpful discussions, and Dr. David Hart, who also served as my temporary advisor when I first came to Ohio State. Additionally, I would like to thank Dr. Gideon Fraenkel for the opportunity to work in his laboratory my first summer, and Dr. Kevin Martin for his help in getting started. My former supervisor from Eli Lilly & Co., Dr. Charles Paget, has given me a great deal of practical advice and help over the years, and I acknowledge him for his assistance in a variety of situations. There is one group member, whether she considers herself as such or not, that I must single out as someone who has unselfishly contributed a great deal of her time and talent to making it all work. Donna Rothe has helped in ways too numerous to express. I have truly enjoyed her friendship and support over the past five years. In similar vein, I would also like to thank Barbara
Cassity for her help in a variety of areas.
I would like to acknowledge Dr. Robin Rogers and Dr. Judith Gallucci for solving several crystal structures, and Dr. Kurt Loaning for his timely assistance in deriving names for the various structures.
Finally, one of the distinct advantages to working in a group of this size is the exposure one has to a vast array of unique backgrounds and experiences.
Many people have shared with me their particular wisdom and expertise, as well as their friendship, making my time at Ohio State a very enjoyable and rewarding experience. I would like to especially thank Dr. Dirk Friedrich who was responsible for the NMR studies and initial structural assignments, and who taught me how to run and interpret many of the special experiments required for the success of this project, and also Jeff Johnston for his contributions to the
NMR work, as well as many helpful discussions and ideas. Dr. Gene Hickey was a willing mentor in many areas. He taught me how to use the relevant computer software programs, day to day operations in the laboratory, and shared his unique chemistry expertise and creativity as well as his friendship. Gene, along with Scott Edmondson and Jim Lanter were also responsible for the computational chemistry involved in this study. Dr. Tim Lowinger shared his experience and many of his skills soon after I began working in the laboratory. I would like to thank Stephana Borrelly, Todd Heidelbaugh, Zhong-Li Gao and
Ralf Braun for helpful discussions and the use of many of their reagents as I
vi embarked on the natural product work. Finally, I would like to thank Steven
Paget and Ashton Hamme, whose friendships I have profited from immeasurably. Always willing to help and always good listeners, I wish both of them success in their future endeavors.
VII VITA
June 16, 1950 Bom-lndianapolis, IN.
June, 1972 Bachelor of Arts The University of Indianapolis Indianapolis, IN
January, 1973-November, 1979 Organic Chemist, Eli Lilly & Co.
September, 1990-August 1996 Graduate Fellow, The Ohio State University
PUBLICATIONS
1. Morwick, T.; Paquette, L. “Preparation of Polyquinanes by Double Addition of Vinyl Anions to Squarate Esters: 4,5,6,6a-Tetrahydro-3a-Hydroxy- 2,3-Diisopropoxy-4,6a-1(3aH)-Pentalenone”, Org.Synth., ^996, 74, 169.
2. Morwick, T.; Paquette, L. "Mapping the Chemical Reactivity of Polyquinanes Produced by Twofold Addition of Vinyl Anions to Squarate Esters. A Bicyclic Case Study", J. Org. Chem., 1996, 61, 146.
3. Paquette, L.; Monwick, T.; Negri, J. "Addition of 2,3-Dihydro-5- furanyllithium to Diisopropyl Squarate as a Means for the Rapid Generation of Structurally Complex Oxygen-Containing Tetraquinane Networks", Tetrahedron 1998, 52, 3075.
4. Paquette, L; Morwick, T. "The Squarate Ester -1 ,3,5,7-Octatetraene - Poiyquinane Cascade: Reaction Efficiency is Intimately Linked to the Locus of Substitution Within the Vinyl Anion", J. Am. Chem. Sac., 1995, 117, 1451-1452.
VIII 5. Morwick, T.; Doyen, J.; Paquette, L. "Acetylide Anions Exert Complete Control Over Aldolization During the Direct Conversion of Squarate Esters Into Polyquinanes", Tetrahedron Lett., 1995, 36, 2369-2372.
6. Negri, J.; Monwick, T.; Doyon, J.; Wilson, P.; Hickey, E.; Paquette, L "Direct Elaboration of Complex Polyquinanes through 2-Fold Addition of Vinyl Anions to Squarate Esters", J. Am. Chem. Sac., 1993, 115, 12189-12190.
7. "Squarate Ester Cascades. Methodology and Application to Natural Product Synthesis." Tina M. Morwick and Leo A. Paquette, 210th National ACS Meeting, Chicago, Illinois, August 20-24, 1995, Abstract No. 289.
8. Morwick, T.; Wikel, J. "Process for Removing Sulfonyl Groups from Benzimidazole Isomers", US Patent Number 4,463,181, 1984.
9. Morwick, T.; Paget, C.; Wikel, J. "Olefinic Benzimidazoles, Formulations, and Antiviral Methods", US Patent Number 4,420,479, 1983.
10. Morwick, T. "Lithiation of Trimethylsilyl Substituted Acetamide Derivatives. Addition to Carbonyl Compounds", Tetrahedron Lett., 1980, 21, 3227-3230.
FIELDS OF STUDY
Major Field: Chemistry
Studies in Organic Synthesis and Methodology
IX TABLE OF CONTENTS
ABSTRACT...... il
DEDICATION...... iv
ACKNOWLEDGMENTS...... v
VITA...... vlii
LIST OF TABLES...... xlii
LIST OF SCHEMES...... xvi
LIST OF FIGURES...... xxi
CHAPTER PAGE
1. INTRODUCTION...... 1
A. Squaric Acid and its Derivatives ...... 1 B. The Squarate-Polyquinane Connection ...... 6 C. Scope of the Dissertation Project ...... 8 D. List of References...... 14
2. THE ELECTR0CYCLIC2/ALD0L REARRANGEMENT OF SQUARATE ESTERS: INITIAL DISCOVERY AND MECH- ANISTIIC INVESTIGATION...... 16
A. Initial Discovery...... 16 B. Mechanism Studies ...... 20 C. List of References...... 42
3. QUINANE PRODUCTS PRODUCED BY TWOFOLD ADDITION OF ACHIRAL UNSATURATED ANIONS TO SQUARATE ESTERS AND OTHER CYCLOBUTENEDIONES...... 45
A. Introduction ...... 45 B. Twofold Addition of a Single Alkenyllithium Reagent ...... 46 C. Addition of Non-Identical Pairs of Alkenyllithium Reagents 53 D. Mixed Additions Combining Alkenyllithium Reagents with Vinylmagnesium Bromide ...... 59 E. Mixed Additions of Acetylenic and Alkenyl Reagents ...... 61 F. Rearrangements of Semi-Squarates and Other Cyclobutenediones ...... 66 G. List of References...... 74
4. REACTION EFFICIENCY: A FUNCTION OF SUBSTITUENT CONTROL...... 76
A. Introduction ...... 76 B. Nucleophilic Addition ...... 77 C. Electrocyclic Ring Opening of the Doubly Charged Cyclobutene Dioxolate...... 79 D. Electrocyclization of the Octatetraene ...... 82 E. List of References...... 91
5. AN ANALYSIS OF REGIO AND STEREOCHEMISTRY FOR THE ELECTROCYCLIC^ ALDOL REACTION...... 93
A. Introduction ...... 93 B. The Generation of Regio and Stereochemistry: A Summary 94 C. Control of 1,2 vs 1,4 Second Stage-Addition ...... 95 D. The Regiochemistry of Protonation ...... 96 E. Stereochemical Relationship at the Bond-Forming Centers 101 F. Stereochemical Consequences of Protonation and Transannular Aldol Reaction ...... 102 G. Diastereoselective Electrocyclization ...... 108 H. List of References...... 110
6. SQUARATE REARRANGEMENTS OF ALLENE ADDUCTS: CONTROL OF PERISELECTIVITY FOR THE ELECTRONIC REORGANIZATION OF 1,2,4,6,8 CUMULENIC PENTAENES 111
A. Introduction ...... 111 B. Reaction of Diisopropyl Squarate with a Combination of Alkenyl and Allenic Anions ...... 112 C. Mechanistic Rationalization ...... 119 D. A Contribution by the "Allene Effect" to the Periselection for Pentaene Electrocyclization...... 124 E. List of References...... 130
7. DEVELOPMENT OF A SYNTHETIC APPROACH TO CRINIPELLIN B BY INCORPORATION OF TANDEM ELECTR0CYCLIC2/ALD0L METHODOLOGY...... 132
A. Introduction ...... 132
xi B. Model Studies ...... 134 C. Synthesis of the Requisite Vinyl Bromide and Its Utilization in the Electrocyclic2/Aldol Reaction ...... 144 D. Summary of the Synthetic Proposal for Crinipellin B and Conclusions...... 152 E. List of References...... 156
8. EXPERIMENTAL...... 158
A. General Methods ...... 158 B. Experimental Procedures ...... 160 C. List of References...... 270
APPENDIX A...... 271
APPENDIX B...... 386
BIBLIOGRAPHY...... 439
XII LIST OF TABLES
TABLE PAGE 2.1 Rates and products of pyrolyses of cis-1,2-dialkenyi- cyclobutanes...... 26
2.2 Global minimum energy conformations of 1,3,5 cyclo octatriene dienolates as determined by molecular mechanics calculations (Chem 3-D output) ...... 32
3.1 Polyquinanes resulting from use of acetylide anions ...... 63
6.1 Reaction of diisopropyl squarate with methoxyallene and alkenyllithium reagents ...... 113
6.2 Reaction of diisopropyl squarate with an alkenyllithium followed by 1-methoxyallene ...... 114
6.3 Calculated and observed values for Xmax using Woodward's rules ...... 118
6.4 Activation parameters for the parent polyene CH2=CH-(CH=CH)n-CH3 (p), and the associated allene CH2=C=CH-(CH=CH)n-CH3 (a)...... 127
B.1 Crystal data and summary of intensity data collection and structure refinement for 52...... 388
B.2 Final fractional coordinates for 52...... 389
B.3 Bond distances (A) and angles (deg) for 5 2 ...... 391
B.4 Thermal parameters for 5 2 ...... 392
B.5 Crystal data and summary of intensity data collection and stmcture refinement for 57...... 394
B.6 Final fractional coordinates for 57 ...... 395
XIII B.7 Bond distances (A) and angles (deg) for 5 7 ...... 397
B.8 Observed and calculated structure factors for 57 ...... 398
B.9 Crystal data and summary of intensity data collection and structure refinement for 63...... 400
B.10 Final fractional coordinates for 63 ...... 401
B.11 Bond distances (A) and angles (deg) for 6 3 ...... 403
B.12 Thermal parameters for 63 ...... 404
B.13 Crystallographic details for 67 ...... 406
B.14 Bond lengths (A) for 6 7 ...... 407
B.15 Bond angles (deg) for 67 ...... 408
B.16 Bond angles (deg) involving the hydrogen atoms for 67 ...... 409
B.17 Positional parameters and B(eq) values for 67 ...... 410
B.18 Calculated and positional parameters for the hydrogen atoms for 67...... 411
B.19 Anisotropic displacement parameters for 6 7 ...... 413
B.20 Observed and calculated structure factors for 67 ...... 415
B.21 Crystal data and summary of intensity data collection and structure refinement for 103...... 426
B.22 Final fractional coordinates for 103 ...... 427
B.23 Bond distances (A) and angles (deg) for 103 ...... 429
B.24 Thermal parameters for 103 ...... 430
B.25 Crystal data and structure refinement for 199 ...... 432
B.26 Atomic coordinates ( x 10"^) and equivalent isotropic displacement parameters (A x 10^) for 199 ...... 433
B.27 Bond distances (A) and angles (deg) for 199 ...... 434
B.28 Anisotropic displacement parameters for 199 ...... 435
XIV B.29 H y d r o g e n coordinates ( X 104) and isotropic displacement parameters (Â2 x 10^) 199 ...... 436
XV LIST OF SCHEMES
SCHEME PAGE
1.1 Typical syntheses of squarate compounds ...... 3
1.2. Proposed biogenesis of monlllformln ...... 4
1.3 Examples of squarate rearrangements ...... 5
1.4 Derivatlzatlon of squarate esters ...... 6
1.5 Squarate-derlved route to linear triqulnanes ...... 8
1.6 Initial discovery of the squarate rearrangement ...... 9
1.7 Boat and chair conformations for the Cope rearrangement ...... 10
2.1 PInacol-type ring expansion of cyclobutanols to splrofurans ...... 16
2.2 Reaction of dllsopropyl squarate with 2,3-dlhydro-5- furanylllthlum or 1-llthlocyclopentene ...... 18
2.3 Reaction of 3,4-dlphenylcyclobut-3-ene-1,2-dlone with phenyl acetylide anion ...... 19
2.4 Oxy-Cope rearrangement of tricarbonyl(T|®-1,2- dloxobenzocyclobutene)chromlum(O) ...... 20
2.5 Squarate rearrangement via dianlonic oxy-Cope methodology 21
2.6 Heterocyclic squarate rearrangement via oxy-Cope methodology ...... 22
2.7 Reaction of dllsopropyl squarate with 2,3-dlhydro-5- furanylllthlum followed by 1-llthlocyclopentene ...... 23
2.8 Reaction of dllsopropyl squarate with 1-llthlocyclopentene followed by 2,3-dlhydro-5-furanylllthlum ...... 24
2.9 Radical-mediated conversion of squarate derivatives Into substituted furanones...... 28
2.10 Proposed electrocyclic mechanism ...... 29
xvl 2.11 Trapping the intermediate cyclooctatriene dienolates as silyl enol ethers (carbocyclic reaction) ...... 34
2.12 Trapping the intermediate cyclooctatriene dienolates as silyl enol ethers (carbocyclic reaction) ...... 35
2.13 Trapping the intermediate cyclooctatriene dienolates as silyl enol ethers (heterocyclic reaction) ...... 37
2.14 Dienolate regeneration with methyllithium (heterocyclic reaction) ...... 38
2.15 Conformational equilibration of the dienolate ...... 40
2.16 Trapping the intermediate of a reaction of diisopropyl squarate with 2-lithiopropene ...... 40
3.1 Squarate rearrangement with vinyllithium or 2-propenyllithium 48
3.2 Squarate rearrangement with c/s-2-butenyllithium ...... 49
3.3 Squarate rearrangement with frans-2-butenyllithium ...... 50
3.4 Squarate rearrangement with (E)-1 -propenyllithium ...... 52
3.5 Squarate rearrangement with a-bromostyrene ...... 53
3.6 Squarate rearrangement with 2-propenyllithium and 1 -lithiocyclopentene ...... 54
3.7 Squarate rearrangement with (E)-1-propenyllithium and 1-lithiocyclopentene 55
3.8 Squarate rearrangement with vinyllithium and 1 -lithiocyclopenetene ...... 56
3.9 Squarate rearrangement with 2-propenyllithium and frans-2-butenyllithium...... 57
3.10 Squarate rearrangement with 2-propenyllithium and 1 -lithio(trimethylsiiyl)ethylene ...... 59
3.11 Squarate rearrangement with 2-propenyllithium and vinylmagnesium bromide ...... 60
XVII 3.12 Squarate rearrangement with 1 -llthlocyclopentene and 1-llthlopropyn e ...... 62
3.13 Proposed route to 101 ...... 65
3.14 Reaction of 3,4-dlethylcyclobutene-1,2-dlone with 1 -llthlocyclopentene ...... 66
3.15 Reaction of 3,4-dlethylcyclobutene-1,2-dlone with 2,3-dlhydro-5-furanylllthlum 67
3.16 Failed ring expansion of a splrofuran cyclopentenedlone ...... 68
3.17 Condensation of acetylenic seml-squarates with 2-propenylllthlu m ...... 70
3.18 Proposed pathway for electrocyclic rearrangement of acetylenic semlsquarates...... 71
3.19 By-product formation with acetylenic seml-squarates...... 72
3.20 Rearrangement using 3,4-dlphenylcyclobutene-1,2-dlone ...... 73
4.1 By-products from reaction of dllsopropyl squarate with 1 -llthlocyclopentene and (£)-1-propenyllithium ...... 78
4.2 Tandem electrocyclic, [2+2] reaction of a substituted cyclobutenone...... 80
4.3 Alkoxy-activated bond cleavage...... 81
4.4 Pericyclic consequences of lithium chelation ...... 81
4.5 P-effect for 8;c electrocyclization ...... 86
4.6 Altemate conformation for 8 îï electrocyclization...... 88
4.7 Quenching the intermediate with methyl Iodide ...... 89
5.1 Reglocontrol of aldolization via p-ellmlnatlon ...... 101
5.2 Diastereoselective electrocyclization...... 109
6.1 Ring expansion of the allene mono-adduct of a squarate derivative ...... 112
XVIII 6.2 Electrocyclic and oxy-Cope pathways for cis and trans bis-adducts in the allene series ...... 120
6.3 Electrocyclic pathway for the 1,4 adducts ...... 122
6.4 By-product resulting from 6 tc electrocyclization from reaction of diisopropyl squarate with (£)-1-propenyllithium ...... 125
6.5 Tandem [1,5] hydrogen migration, 6 k electrocyclization...... 125
7.1 Proposed route to crinipellin B ...... 133
7.2 Key step for the synthesis of crinipellin B via squarate rearrangement to a triquinane ...... 134
7.3 Model study ...... 135
7.4 Reduction of initial adduct with lithium aluminum hydride ...... 136
7.5 Reduction of initial adduct with lithium aluminum hydride in the presence of TMEDA...... 138
7.6 Reduction of the intermediate halide ...... 139
7.7 Reduction of the extended enone and attempted carbonyl transposition ...... 140
7.8 Deconjugative protonation and alkylation ...... 142
7.9 Potential proton removal within the five-membered ring ...... 143
7.10 Preparation of 192 ...... 144
7.11 Squarate rearrangement with 192 and vinyllithium ...... 145
7.12 Squarate rearrangement with 192 and 2-propenyllithium ...... 145
7.13 Squarate rearrangement with 192 and 1 -lithio(trimethylsilyl)ethylene or 1 -lithiopropyne ...... 146
7.14 Preparation of 1 9 8 ...... 147
7.15 Squarate rearrangement with 198 and vinyllithium ...... 148
7.16 Diastereotopic coils of the helical intermediate ...... 148
7.17 Squarate rearrangement with 198 and
xix 1 -lithio(trimethylsilyi)ethylene ...... 150
7.18 Reaction of 200, 202, and 203 with methanesulfonyl chloride, triethylamine, lithium chloride and lithium carbonate ...... 151
7.19 Synthetic plan for crinipellin B from 200 ...... 153
XX LIST OF FIGURES
FIGURE PAGE
1.1 Squaric acid ...... 1
1.2 Resonance stabilization of the dianion of squaric acid ...... 2
1.3 Four isomeric triquinanes...... 7
1.4 Crinipellin B ...... 13
2.1 Intermediates for the squarate rearrangement ...... 30
3.1 Yields for the heterocyclic squarate rearrangement using various reaction conditions ...... 47
3.2 Diastereotopic faces of the pre-aldol intermediate ...... 58
3.3 By-products from acetylene rearrangements ...... 64
4.1 a and p positions of the vinyl anion ...... 84
4.2 Effect of a-substituents on 8% helical conformation ...... 85
4.3 Steric constraints of terminal cis methyl substituents ...... 87
4.4 Activation parameters for electrocyclization of isomeric decatetraenes ...... 87
5.1 The generation of regio and stereochemistry in the squarate rearrangement ...... 94
5.2 Global minimum energy conformations of protonated trans- and cis-fused 1,3,5-cyclooctatriene dienolates ...... 97
5.3 Global minimum energy conformations of protonated dienolates from addition of vinyllithium and cyclopentenyllithium ...... 99
5.4 Monoprotonated intermediates from conjugate addition of Grignard reagents ...... 100
5.5 Pre-aldol conformera for minimally substituted intermediates 103
XXI 5.6 Global minimum energy conformations of protonated trans fused 1,3,5-cyclooctatriene dienolates ...... 104
5.7 Global minimum energy conformations of protonated trans- and cis-fused 1,3,5-cyclooctatriene dienolates ...... 105
5.8 Transannular steric interaction for the boat conformation ...... 106
5.9 Pre-aldol boat intermediates ...... 107
6.1 Allylic coupling (*J) for cyclohexadienone systems ...... 116
6.2 UV spectra of 148 and 150 ...... 117
6.3 Potential regioisomers resulting from protonation of an extended enolate at the two non-terminal positions ...... 123
6.4 Intermediates resulting from 6jt and 8k electrocyclization...... 128
6.5 Orbital diagram for 87t electrocyclization of a 1,2,4,6,8 pentaene and 6k electrocyclization of a 1,2,4,6 tetraene ...... 129
A.1 NMR spectrum of 13 ...... 272
A.2 1H NMR spectrum of 14 ...... 273
A.3 NMR spectrum of 15 ...... 274
A.4 1H NMR spectrum of 16 ...... 275
A.5 1H NMR spectrum of 18 ...... 276
A.6 NMR spectrum of 19 ...... 277
A.7 1H NMR spectrum of 20 ...... 278
A.8 NMR spectrum of 31 ...... 279
A.9 1H NMR spectrum of 32 ...... 280
A.10 NMR spectrum of 33 ...... 281
A.11 1R NMR spectrum of 34 ...... 282
A.12 iH NMR spectrum of..35...... 283
A. 13 NMR spectrum of43 (rt)...... 284
xxii A.14 1H
A.15 1H
A.16
A.17 1H
A.18 1H
A.19 1H
A.20
A.21
A.22 1H
A.23 1H
A.24 1H
A.25 1H
A.26 1H
A.27 1H
A.28 1H
A.29 1H
A.30 1H
A.31 1H
A.32 1H
A.33 1H
A.34 1H
A.35 1H
A.36 1H
A.37 1H
XXIII A.38 m NMR spectrum of 75 ...... 309
A.39 NMR spectrum of 76 ...... 310
A.40 NMR spectrum of 77 ...... 311
A.41 NMR spectrum of 79 ...... 312
A.42 NMR spectrum of 80 ...... 313
A.43 NMR spectrum of 81 ...... 314
A.44 NMR spectrum of 83 ...... 315
A.45 NMR spectrum of 87 ...... 316
A.46 NMR spectrum of 88 ...... 317
A.47 NMR spectrum of 89 ...... 318
A.48 NMR spectrum of 90 ...... 319
A.49 1R NMR spectrum of 91 ...... 320
A.50 NMR spectrum of 92 ...... 321
A.51 NMR spectrum of 93 ...... 322
A.52 NMR spectrum of 94 ...... 323
A.53 NMR spectrum of 95 ...... 324
A.54 1R NMR spectrum of 96 ...... 325
A.55 1H NMR spectrum of 98 ...... 326
A.56 1H NMR spectrum of 101...... 327
A.57 1R NMR spectrum of 103...... 328
A.58 1H NMR spectrum of 104 ...... 329
A.59 NMR spectrum of 105 ...... 330
A.60 1R NMR spectrum of 106...... 331
A.61 1H NMR spectrum of 109 ...... 332 xxiv A.62 1H NIVIR spectrum of 111...... 333
A.63...... NMR spectrum of 112...... 334
A.64...... 1H NMR spectrum of 113...... 335
A.65...... NMR spectrum of 114...... 336
A.66...... 1H NMR spectrum of 115...... 337
A.67...... IH NMR spectrum of 116...... 338
A.68 ...... 1H NMR spectrum of 117...... 339
A.69 ...... 1H NMR spectrum of 118 ...... 340
A.70 NMR spectrum of 119 ...... 341
A.71 m NMR spectrum of 122...... 342
A.72 1R NMR spectrum of 123...... 343
A.73 NMR spectrum of 132...... 344
A.74 1R NMR spectrum of 138 ...... 345
A.75 1R NMR spectrum of 139 ...... 346
A.76 NMR spectrum of 140...... 347
A.77 NMR spectrum of 141...... 348
A.78 NMR spectrum of 143 ...... 349
A.79 NMR spectrum of 144 ...... 350
A.80 NMR spectrum of 145 ...... 351
A.81 NMR spectrum of 148 ...... 352
A.82 1R NMR spectrum of 149 ...... 353
A.83 NMR spectrum of 150 ...... 354
A.84 NMR spectrum of 153 ...... 355
A.85 NMR spectrum of 166 ...... 356
XXV A.86 NMR spectrum of 167 ...... 357
A.87 ...... NMR spectrum of 168 ...... 358
A.88 ...... NMR spectrum of 170...... 359
A.89 m NMR spectrum of 171a ...... 360
A.90 NMR spectrum of 171b ...... 361
A.91 ...... 1H NMR spectrum of 172...... 362
A.92 ...... NMR spectrum of 173...... 363
A.93 ...... NMR spectrum of 174...... 364
A.94 ...... NMR spectrum of 175...... 365
A.95 ...... m NMR spectrum of 176...... 366
A.96 NMR spectrum of 179 ...... 367
A.97 NMR spectrum of 180 ...... 368
A.98 1H NMR spectrum of 181 ...... 369
A.99 NMR spectrum of 183 ...... 370
A. 100 1H NMR spectrum of 184 ...... 371
A.101 NMR spectrum of 185 ...... 372
A. 102 NMR spectrum of 186 ...... 373
A. 103 NMR spectrum of 190 ...... 374
A. 104 1H NMR spectrum of 192 ...... 375
A. 105 NMR spectrum of 193 ...... 376
A. 106 NMR spectrum of 199 ...... 377
A. 107 1H NMR spectrum of 200...... 378
A.108 1R NMR spectrum of 202, 203 ...... 379
A. 109 1H NMR spectrum of 204 ...... 380 xxvi A.110 1H NMR spectrum of 205...... 381
A.111 1H NMR spectrum of 206...... 382
A.112 NMR spectrum of 208 ...... 383
A.113 NMR spectrum of 209 ...... 384
A.114 NMR spectrum of 210...... 385
B.1 Final X-ray model of 52...... 387
B.2 Final X-ray model of 57...... 393
B.3 Final X-ray model of 63...... 399
B.4 Final X-ray model of 67...... 405
B.5 Final X-ray model of 1 0 3 ...... 425
B.6 Final X-ray model of 1 9 9 ...... 431
B.7 Preliminary ORTEP of 70...... 437
XXVII CHAPTER 1
INTRODUCTION
A. Squaric Acid and its Derivatives
Squaric acid (1) was first synthesized by Cohen in 1959J Formally a
representative of the cyclobutadienoquinone system, the synthesis and properties of dihydroxycyclobutenedione (squaric acid) and its derivatives were studied in the sixties and seventies, and this chemistry was reviewed in 1978.2
HO^ _ ^ 0
H O ' “ ^ 0
Figure 1.1. Squaric acid.
Much of this research was inspired by the many unique characteristics of these systems. They are thermally stable compounds having the same formal degree of strain as the cyclobutadiene framework. The cyclobutenediones, examples of a 2n aromatic system (resonance energy of 31-60 kcal. per mole)^ exist in sharp contrast to the unstable 4 k anti-aromatic cyclobutadiene.
Squaric acid is a very strong dibasic acid (p /<2 = 2.2) due to the resonance stabilization of its dianion (Figure 1.2).^ Alkoxy, amino and halide derivatives react as vinylogous esters, amides, and acid halides, respectively.
O".___^ 0 o ^ _ ^ o
o ' 0
Figure 1.2. Resonance stabilization of the dianion of squaric acid.
Medicinally, squaric acid derivatives have been reported to act as bioisosteres of carboxylic acids,^ and squaramides as amino acid bioisosteres.6 The latter have also been used as binding subunits for molecular recognition.^
Synthesis of these systems typically proceeds via photochemical
(alkyne + alkene) or thermal (alkyne + ketene or tetrahaloethylene) [ 2 +2 ] cycloaddition, or ring expansion of cyclopropane derivatives. Squaric acid itself can be prepared in kilogram quantities from hexachlorobutadiene
(Scheme 1.1). R R
hv HgO^ 1^= R Z ~ - -R + 0 0 n 0 0
A H2SO4 22a ^>==<^ + = -R F F F F 0 ^ 0
Cl H2SO4 32a R = R + ) = 0 Cl Cl 0 0 '0 Cl
R \ R' OR'
H - 0 0 ^0
Cl HO OH Cl Cl 1. morpholine :1b Cl •Cl 2.
Cl
Scheme 1.1. Typical syntheses of squarate compounds.
Related structures are also derived biosynthetically. For example, the
mycotoxin, moniliformin (2 ), is produced as a secondary metabolite by the moki Fusarium monilifomne from acetate via malonyl coenityme A (Scheme
1.2).8 0
2 CH3CO2H 2 H02CCH2C(0)SC oA Ox
0
HO, f -H2O ^
HO
Scheme 1.2. Proposed biogenesis of moniliformin.
While these highly strained carbocycles were studied as chemical novelties for several years, recently they have been employed in a number of synthetic transformations and cascade sequences as well as natural product synthesis.^ The burgeoning interest in these substrates as precursors to a variety of carbocyclic and heterocyclic systems stems from the potential strain energy pent into the small ring. While the squarates and associated cyclobutenediones exist as stablized aromatic systems, the destruction of aromaticity initiated by addition of an appropriate nucleophile liberates a highly energized intermediate capable of undergoing a variety of ring expansions and rearrangements under relatively mild conditions. Some examples are shown in Scheme 1.3. OAc
0 RO RO^ OCH 3 0 Liebeskind RO 0 Moore Moore
RO // RO' 0 Ph. OAc R
RO 0 Eguchi Liebeskind RO
RO
Paquette
Scheme 1.3. Examples of squarate rearrangements, a^d; b^c; c^b; ; e^®; f9a.
Exploitation of the strain energy associated with these four-membered rings has also proliferated as a result of the ready availability of squarate esters and the numerous techniques which have been recently developed for derivatization of the cyclobutenedione framework.Acid-catalyzed rearrangements and Stille coupling are exemplary (Scheme 1.4). RO. 0 1. TFAA RO. :0 10a R'Li 2. HzO RO' R" ■0
RO. ;0 RO, R'SnBu 3 ,10b cat. RCIPd(PPh 3)2 0
Scheme 1.4. Derivatization of squarate esters.
B. The Squarate-Poiyquinane Connection
The development of yet another paradigm in the arsenal of squarate
derived transformations has been achieved. A novel cascade process
initiated by the addition of a pair of alkenyl anions to squarate derivatives has
provided entry into the forum of polyquinane chemistry. The polyquinanes
have enjoyed long-standing attention in synthetic organic chemistry. These
substrates, which occur naturally in a variety of structural frameworks, have
provided the synthetic chemist with a plethora of target molecules around which a variety of unique and interesting synthetic methodologies have been
developed.^ Three basic arrangements of the triquinane system are found
in nature. The angular, as depicted by the antibiotic fungal metabolite, pentalenene and linear, exemplified by hirsutene also a fungal metabolite are the most common. The [3.3.3] propellane framework is present in the novel sesquiterpene, modhephene An additional isomeric arrangement is exemplified by the unusual tricyclic construction found in triquinacene (6)J1® The present methodology offers potential for preparation of the more typical linear and angular systems.
Figure 1.3. Four compounds representing structurally isomeric forms of the triquinane nucleus.
Recently, a squarate-derived route to the linear triquinane 9 via the intermediate bicyclo[3.2.0]heptenone 8^2 was described by Moore (Scheme 1.5).2f Tandem oxy-Cope/transannular ring closure complete the synthesis, which uses dimethyl squarate as starting material. MeO. ,0
MeO^ ^ 0 TMSO 2 NaHCO 3 TMSO
8
0 OH
9
Scheme 1.5. Squarate-derived route to linear triquinanes.
C. Scope of the Dissertation Project
The new squarate cascade reported herein was discovered serendipitously in the Paquette laboratories in 1991.13 The initial reactions are shown in Scheme 1. 6 .
8 , , (3eq) U ------/-PrO f-PrO^ ^ 0 THF -78 "Cto 20 X ,-PrO O' 0 OH 0 10 2. NaHCO 3, H2O 13 (26%) 14 (14%)
(3 eq) 12 + /-Pro /-PrO^ ^ 0 THF -78 °C to 20 "C /.pro' OH 10 2. NaHCOs, H2O 1 5 (46%) 16 (25%)
Scheme 1.6. Initial discovery of the squarate rearrangement.
The research described in the ensuing chapters has developed along four directions. At the outset, the intention was to delineate the mechanisms by which the various products are formed. This work is described in Chapter
2. The proposed oxy-Cope (boat transition-state)/(chair transition-state) initiated pathways'll left many unresolved questions. For example, while Cope rearrangements in most systems are known to proceed predominantly through the lower energy chair transition state, the divinyl cyclobutanes are a striking exception to this trend as the boat conformation is now preferred and often the exclusive conformation through which these reactions proceed. This is due in part to the significantly enhanced strain energy associated with the chair product, a c/s,frans-cycloocta-1,5-diene.i5 Cope rearrangement of c/s-1,2-frar7s,frans-dipropenylcyclobutane is shown in Scheme 1.7. The stereochemical consequences of the boat and chair options within the ring and at the bond-forming centers are to be noted.
BOAT CONFORMATION
CH: CH:
CHAIR CONFORMATION NOT OBSERVED
Scheme 1.7. Cope rearrangement of 1,2-frans,frans-dipropenyi cyclobutane through the boat and chair transition states.
Notwithstanding, in the present case formation of 13,14, and 15 from a cis-substituted divinylcyclobutene via a concerted Cope rearrangement must necessarily proceed through the chair transition state.
The mixed additions described in Chapter 2 provided new questions.
It was found that when diisopropyl squarate was subjected to treatment with one equivalent of the anion of dihydrofuran, followed by exposure to excess cyclopentenyl anion, three isomeric products similar to those in Scheme 6 were isolated. Reversing the order of addition, however, gave different results. At this point, it became necessary to develop a rationale for the observation that product structure was dependent on the order of addition of the two anions. The newly proposed mechanisms described herein provide
10 answers to these questions and rationally account for the observations noted throughout the course of these investigations. Current wisdom ascribes a trans addition and subsequent valence isomerization via two electrocyclic events for production of substrates such as 13,14, and 15.
Polycycle 16, in which cis stereochemistry at the bond forming centers is noted, is expected to arise from initial Cope rearrangement through a boat transition state.
Following the mechanistic work, an investigation into the various parameters which were necessary for efficient conversion of the squarates into a polyquinane framework was undertaken. In order to assess the fundamental requirements for this chemistry to function effectively, it was necessary to carry out a systematic study of substituent effects with respect to product formation. Variously substituted unsaturated anions and cyclobutenediones were subjected to the reaction protocol. Chapter 3 is a compilation of the results of this investigation.
In Chapter 4, attempts have been made to integrate these findings and draw conclusions concerning which step of the tandem sequence of events is influenced by the particular adjustments of functionality. While the oxy-Cope pathway that operates to a limited extent is easily facilitated under the present conditions, the proposed electrocyclic sequence is much more substituent selective for both concerted steps of the tandem process.
Literature precedent for many of the observed substituent requirements is provided. The various cascading events which unfold during the course of bond construction and molecular reorganization deliver products with a substantial increase in complexity. In the fully substituted cases, five
11 stereogenic centers can be observed. Combining this with two events requiring regiochemical differentiation, the potential number of distinct isomeric products resulting from these squarate rearrangements exceeds
100! The third facet probed in this project was the origin of the various regio and stereoselectivies, and the development of methodology by which these processes could be controlled. Chapter 5 summarizes this research. Much control is provided by systematic requirements imposed by conformational, steric and electronic constraints. However, the production of a single isomer to the exclusion of the myriad of possible products required the development of new methodology. While achievement of this lofty goal is still elusive in many systems, various techniques have been developed which offer solutions to the lack of selectivity in the several steps.
Incorporation of allene anions into the current procedure provided some interesting results. The aliénés afforded significant input into the periselectivity of bond reorganization. Products arising from 6tc valence isomerization were observed to the exclusion of the 8tc option under certain circumstances. While 8 jt electrocyclization of an acyclic octatetraene is generally favored over 6 k periselection due to the reduced activation energy requirements, 16 the aliénés apparently provide significantly greater stabilization to the latter process. The so-called "allene effect" has been documented in the case of [1,5] and [1,7] sigmatropy, and both empirical and theoretical investigations have provided some insight as to the nature of this phenomenon.17 Chapter 6 describes this possible extension of the allene effect.
12 Finally, the natural course of events has led to the application of this synthetic methodology to natural product synthesis. The target structure was the tetraquinane crinipellin B (17).
<
OH 17
Figure 1.4. Crinipellin B.
Initially, model studies were carried out. The purpose of these studies was twofold. The potential for modification of the initial product of a rearrangement into a substrate which was properly appended for conversion into the crinipellin nucleus was investigated. Concurrently, a study of the reactivity of the y-hydroxy-a.p-bisalkoxyenone derivatives produced from the squarate ester-initiated reaction was probed. These model studies were pursued to a successful conclusion. The various strategies for employing the squarate rearrangement as the key step for generation of either a tetraquinane or a triquinane framework associated with the natural product are described. Utilization of a trimethylsilyl moiety to direct diastereoselectivity and regioselectivity has been found to be quite profitable. These results are reported in Chapter 7.
13 LIST OF REFERENCES
1 (a) Cohen, S.; Lâcher, J.; Park, J. J. Am. Chem. Soc. 1959, 81, 3480. (b) Paine, A.J. Tetrahedron Lett. 1984, 25, 135. Squaric acid can be purchased on a kilogram scale from Aldrich Chemical Company.
2 (a) Schmidt, A.H.; Ried, W. Synthesis 1978, 1. (b) Knorr, H.; Ried, W. Synthesis 1976, 649. (c) Schmidt, A.H.; Ried, W. Synthesis 1978, 869.
3 Park, J.D.; Cohen, S.; Lâcher, J.R. J. Am. Chem. Soc. 1962, 84, 2919.
4 Cohen, S.; Cohen, S.G. J. Am. Chem. Soc. 1966, 88, 1533.
5 Campbell, E.F.; Park, A.K.; Kinney, W.A.; Fengl, R.W.; Liebeskind, LS. J. Org. Chem. 1995, 60, 1470.
6 Kinney, W.A.; Leen N.E.; Garrison, D.T.; Podlesny, E.J.; Simmonds, J.T.; Bramlett, D.; Notvest, R.R.; Kowal, D.M.; Tasse, R.P. J. Med. Chem. 1992, 35, 4720.
7 Tomas, S.; Rotger, M.C.; Gonzalez, J.F.; Deya, P.M.; Ballester, P.; Costa, A. Tetrahedron Lett.. 1995, 36, 2523.
8 Franck, B. Angew. Chem., Int. Ed. Eng. 1984, 23, 493.
9 (a) Xu, S.L.; Xia, H.; Moore, H.W. J. Org. Chem. 1991, 56, 6094. (b) Yamamoto, Y.; Ohno, M.; Eguchi, S. J. Org. Chem. 1994, 59, 4707. (c) Moore, H.W.; Decker, O.H.W. Chem. Rev. 1986, 86, 821. (d) Liebeskind, L.S.; Birchler, A.G.; Liu, F. J. Org. Chem. 1994, 59, 7737. (e) Liebeskind, L.S. Tetrahedron 1989, 45, 3053. (f) Paquette, L.A.; Sturino, C.; Doussot, P. Submitted for publication, (g) Santora, V.J.; Moore, H.W. J. Am. Chem. Soc. 1995, 117, 8486. (h) Winters, M.P.; Stranberg, M.; Moore, H.W. J. Org. Chem. 1994, 59, 7572.
10 (a) Reed, M.W.; Pollart, D.J.; Perri, S.T.; Poland, L.D.; Moore, H.W. J. Org. Chem. 1988, 53, 2477. (b) Liebeskind, L.S.; Wang, J. Tetrahedron Lett. 1990, 31, 4293. (c) Liebeskind, L.S.; Fengl, R.W. J. Org. Chem. 1990, 55, 5359. (d) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Org. Chem. 1988, 53, 2482. (e) Sidduri, A.; Budries, N.; Laine, R.M.; Knochel, P.
14 Tetrahedron Lett. 1992, 33, 7515. (f) Mehta, P.G. Synthetic Comm. 1994, 24, 2497.
(a) Paquette, LA.; Doherty, A.M. Polyquinane Chemistry, Springer- Veriag: Berlin Heidelberg, 1987. (b) Ibid. 195-197. (c) Ibid. 169-173. (d) Ibid. 206-208. (e) Ibid. 85-88.
12 Compound 8 was prepared in 10 steps from dimethyl squarate (40% overall).
13 Reaction of diisopropyl squarate with an excess of two equivalents of the anion of dihydrofuran or cyclopentenyllithium was carried out by Joanna Negri, a post-doctoral student under the supervision of Dr. Leo Paquette. Her products and yields are shown in Scheme 5. Structural verification was accomplished by X-ray crystallography.
14 Transition state pathways were predicted on the basis of stereochemical markers at the bond-forming centers. See Chapter 2 for details. Following the initial bond reorganization, protonation and transannular aldol chemistry ensue, leading to the observed products.
15 Berson, J.A.; Dervan, P.B.; Jenkins, J.A. J. Am. Chem. Soc. 1972, 94, 7598.
15 Huisgen, R.; Dahmen, A.; Huber, H. J. Am. Chem. Soc. 1967, 89, 7130.
17 (a) Shen, G.Y.; Tapia, R.; Okamura, W.H. J. Am. Chem. Soc. 1987, 109, 7499. (b) Skattebol, L. Tetrahedron 1BS9, 25, 4933. (c) Jensen, F. J. Am. Chem. Soc. 1995, 117, 7487.
18 Anke, T.; Heim, J.; Knoch, F.; Mocek, U.; Steffan, B.; Steglich, W.; Angew. Chem., Int. Ed. Engl. 1985, 24, 709.
15 CHAPTER 2
THE ELECTR0CYCLIC2/ALD0L REARRANGEMENT OF
SQUARATE ESTERS: INITIAL DISCOVERY AND MECHANISTIC
INVESTIGATION
A. Initial Discovery
This project was spawned from an area of research which has been
actively pursued for several years by a number of students working in the
Paquette laboratories. The generation of spirocyclic architecture by ring expansion of modified cyclobutanone and cyclopentanone substrates has found utility in the preparation of compounds for host/guest chemistry and in
natural product synthesis.^ The prototype reaction for generation of spirofuran functionality by pinacol type ring expansion is shown in Scheme 2.1.
O h r j° “'Ô 2. H+ [ i f e O'
Scheme 2.1. Pinacol-type ring expansion of a cyclobutanol adduct to the spirofuran derivative.
16 In an attempt to carry out a double ring expansion, two equivalents of 2,3- dihydro-5-furanyllithium were added concurrently to a carbocycle containing two carbonyl groups within the ring. The chosen substrate was a squarate ester and the unexpected results are shown in Scheme 2.2. It should be pointed out that the nucleophile used in this reaction is readily available by the direct metalation of the parent heterocycle^ or via transmétalation of stannylated precursors.^ Subsequently, a reaction utilizing the cyclopentenyl anion 12 was carried out in similar fashion, providing 15 and
16. 1-Lithiocyclopentene was readily generated by lithium-halogen exchange of the vinyl iodide^ with fert-butyllithium.
It was at this stage that my involvement commenced. Initially, these two preliminary reactions were repeated. Some additional products 18,19, and 20 were isolated in low yield (Scheme 2.2). Structural assignments for the major products 13,14,15, and 16 were based on X-ray crystalographic data. Structures of the minor isomers 18,19, and 20 were determined by a combination of 2D, nOe, semi selective DEPT and INVREC analyses.
17 /-PrO /-Pro (3 eq) U /-PrO + /-PrO THF /-Pro 0 -78 °C -> 20 °C /-PrO OH O' 0 OH O' 2. H2O 10 13 (38%) 14 ( 15%)
Li H ^ (3eq) + /-PrO + /-PrO THF -78 °C 20 °C H 2. H2O 18 (3%) 19 (2%)
H
+ /-PrO
/-PrO OH 15 (40%) 16 (26%) 20 (4%)
Scheme 2.2. Reaction of diisopropyl squarate with excess 2,3-dihydro-5- furanyllithium or 1-lithiocyclopentene.
While studies on the cyclobutene-1,2-diones as highly electrophilic building blocks have been quite extensive, only a limited number of examples have been reported in which two equivalents of an unsaturated anion have been appended. Several years ago, Müller, Hambrecht and
Straub reported the addition of two equivalents of acetylide anions to variously substituted cyclobutenediones.^ In the case of 3,4- diphenylcyclobut-3-ene-1,2-dione, a product of retroelectrocyclic ring opening/tautomerization was observed (Scheme 2.3).
18 Ph 0 1 .Ph-^-MgBr 'OH // R = ■Ph Ph OH 2. H2O
Ph
P h ^ O R
Scheme 2.3. Ring opening of 3,4-diphenylcyclobut-3-ene- 1,2-dione on addition of 2 equiv of phenyl acetylide anion.
More recently, Butenschon, et al.6 have reported in a series of papers that the chromiumtricarbonyl complex of 1,2-dioxobenzocyclobutene experiences dianionic oxy-Cope rearrangement^ under very mild conditions following double addition of a vinyllithium species (Scheme 2.4). Both additions must necessarily occur anti to the Cr(C0)3 moiety for obvious steric reasons. Transfer of the electron-withdrawing effect of the metal carbonyl to the keto groups reportedly enhances the electrophilicity of the substrate and also facilitates the ring-opening process.
19 CH 3 - '-CHs Li J À J IL 0 (> 2 equiv) I 0~ (0 C)3Cr (OOsCr
CH 3
H2O
(OOsCr HO (OOsCr (OOsCr
Scheme 2.4. Oxy-Cope rearrangement of tricarbonyl(Ti6-1,2- dioxobenzocyclobutene)chromium(O)
Therefore, the latent potential of squarate compounds on sequential exposure to a pair of vinyl anions is only recently unfolding. Valuable features of the current methodology include a rapid buildup of structural complexity, the installation of several stereogenic centers in tandem fashion, and the exploitation of highly strained starting materials which initiate the cascade sequence under relatively mild conditions. Additionally, the potential for controlling regie and stereoselectivity can be quite significant.
B. Mechanism Studies
Preliminary mechanistic detail for the major products in the reaction utilizing the carbocyclic nucleophile 12 attributed initial bond reorganization to competing dianionic oxy-Cope rearrangements, providing 22 and 24
(Scheme 2.5). Stereochemistry at the bond-forming centers is predictive of 20 the transition state conformation. Following this event, aqueous quench
delivers 23 and 25. These intermediates are extremely labile to
transannular aldol chemistry completing the sequence to deliver the
observed products 15 and 16.
/-Pro H
21a 22 23 10
;-PrO /-Pro /-Pro
/-Pro
21b 24 25
Scheme 2.5. Squarate rearrangement via dianionic oxy-Cope reaction. Dienolate 22 derives from the chair transition state conformation, while 24 is a boat conformation product.
Competition between 1,2 and 1,4 addition was expected to differentiate the major products 13 and 14 in the heterocyclic reaction (Scheme 2.6). Ensuing oxy-Cope rearrangement proceeds exclusively through the chair transition state affording 27 and 29, which following aqueous quench, liberates the pre-aldol intermediates. The transannular event provides the a- and p-hydroxyketo aldol products.
21 ° f o - 0 ^ ® 0 /-PrO^^^/=rC \ /-PrO 13
0 ^ /-PrO /-PrO 27 28 10 " I l y,-r.0/-Pr /-PrO ,-r.v.Q- .0- /-PrO^jLU^O /-PrO^^/=< \ /-Pro 14
0" 0 ^ O' ^ 0 26b 29 30
Scheme 2.6. Original reaction paths suggested for the heterocyclic squarate rearrangement. Dialkoxide 26a is a product of 1,2 addition of both nucleophiles, while 26b has experienced conjugate addition of one of the nucleophiles.
In an effort to test these mechanistic proposals, the stepwise introduction of 11 and 12 to diisopropyl squarate was carried out. Utilizing both possible addition sequences, it was found that the product mix was highly dependant on the order of addition. Schemes 14 and 15 summarize these results. When addition of the carbocyclic nucleophile is preceded by exposure to a slight excess of 11, products 31, 32, and 33 were isolated following flash chromatography and final purification by medium pressure liquid chromatography (Scheme 2.7).
22 /-Pro /-PrO— /-Pro /-Pro OH O' 10 31 (9%)
+ + /-PrO
/-Pro OH /-PrO OH 32 (12%) 33 (26%)
Scheme 2.7. Squarate rearrangement products following addition of one equivalent of the anion of dihydrofuran and one equivalent of cyclopentenyl anion.
Products 31 and 32 must necessarily proceed through the chair transition state if oxy-Cope chemistry is operative. Isomeric differentiation of these two products occurs at the time of protonation. It should be appreciated that when different vinyl anions are incorporated into the tandem process, the dienolate resulting from preliminary valence isomerization is unsymmetrical. Protonation of the "oxy" enolate ultimately leads to 31, while quench at the altemate site is responsible for the formation of 32. Product 33 is a Cope boat-derived isomer that has experienced exclusive protonation on the carbocyclic enolate. Reversal of the order of addition of the two nucleophiles alters the course of events. While 31 and 32 appear consistently in both sequences, two new isomers 34 and 35 now complete the mix (Scheme 2.8).
23 /•-Pro
/-PrO^ ^ 0 2.LÎ. 0 /-Pro OH 0 10 31 (12%)
/-PrO 0
+ /-Pro + /-Pro
/-Pro OH 32 (21%) 34 (3% ) 35 (8%)
Scheme 2.8. Squarate rearrangement products resulting from addition of one equivalent of cyclopentenyl anion followed by one equivalent of the anion of dihydrofuran.
In the current case, all products must necessarily derive from exclusive utilization of the chair transition state if oxy-Cope chemistry is operative. Second stage 1,4 addition of the heterocyclic nucleophile is expected to induce the squarate derivative to production of 34 and 35, both having the altered regiochemistry of the enone. Differentiation of the new pair of isomers occurs as a result of variable diastereofacial protonation of the enolate again exclusive to the carbocyclic direction.
The major implication provided by these unexpected results was that the different reaction pathways responsible for the ultimate isomeric distribution of products were initiated by competing events which took place during the second stage of addition. It became immediately obvious that 1,4 addition occurs only with the stablized anion of the vinyl ether, and only during the second addition event. 1,4-Addition of lithium acetylides® as well as Grignard reagents® to squarate esters has been reported.
24 What was unclear at this time was the nature of the event which
differentiated the isomers such as 15 and 16 having variable
stereochemistry at the bond-forming centers. The oxy-Cope argument was
insufficient. It would be expected that once the pair of nucleophiles was in
place (by necessity in a stereoproximal fashion), the order of addition would
become inconsequential. Yet it was observed that the order of addition was
directly responsible for controlling the overall course of events. Other
aspects of the Cope methodology were equally inconsistent. For instance, it
is known that c/s-divinylcyclobutanes undergo Cope rearrangement through
the boat transition state."'o Only when significant steric constraints are
introduced (i.e. incorporation of cis-substituted functionality on the
cyclobutane ring) does the stereochemical outcome reverse, accompanied
by a significant rate reduction. Table 2.1 compares Cope rearrangement of
a simple c/s-divinylcyclobutane and three c/s-propenylcyclobutanes of variable alkene stereochemistry. Rate constants for formation of the boat
products (kb) and the crossover products (kb) are included. It was suggested that the crossover products arose from Cope rearrangement of the sterically constrained system through the chair transition state followed by double bond isomerization.
25 Boat Crossover _Vv_ , ______A ______^ Reactant ^Product ^b T rin ' Product ^b. rel '
181,000
cDV
41,800
cTT
435 24
cCT
200
cCC
Table 2.1. Rates and products of pyrolyses of c/s-1,2-dlalkenylcyclobutanes.
Thus, while not being fully aware of the consequences of dianionic acceleration7.li in these systems, it seemed appropriate to investigate altemate methods for the initial bond reorganization. Differentiation during second stage addition could occur as a result of variable stereochemical approach of the nucleophile. Synthesis of products such as 16 likely proceeds through the cis addition/Cope boat pathway, while introduction of trans stereochemistry during bond reconstruction may occur as a result of
26 initial trans addition of the second nucleophile. The resultant stereodistal relationship of the pair of vinyl anions obviates the possibility for Cope rearrangement. Both DeBoer^ 2 and Berson^^ have reported that trans- divinylcyclobutanes do not undergo Cope rearrangement as do their cis counterparts. Salaun has studied the anionic version with divinylcyclobutanols and found that while the stereoproximal isomers undergo anionically accelerated oxy-Cope rearrangement, the corresponding stereodistal adducts undergo exclusive retro-ene reactions. Hemolytic bond cleavage and the associated radical-mediated processes were considered, but not expected, as the stereoselectivity indicated a more concerted process. While thermally induced cleavage of frans-divinylcyclobutanes to the allylic radicals has been proposed as the pathway to cyclooctadiene formation, these rearrangements require much higher temperatures than for the corresponding cis isomers which can undergo Cope rearrangement. Eguchi has also reported radical-mediated ring opening of cyclobutenones prepared from nucleophilic addition to squarate esters for the synthesis of substituted furanones. However, in these examples, generation of the radical intermediate was carried out by exposure to an equivalent of lead tetraacetate (Scheme 2 .9 ).
27 OH 0 • EtO 0 E t O . / 1. PhLi Pb(0 Ac )4 2 Z ^ P h EtO"^ ^ 0 2. H2O hn^ ^ r \ E tO " ^ ^ 0 36 Ph AcO Ph E tO . ^ 0 EtO E tO ^ r ^ 0 E t O - ^ E tO ^ ^ ' EtO 0 0 (77%)
Scheme 2.9. Radical-mediated oxidative rearrangement of squarate derivatives to substituted furanones.
A mechanistically more attractive proposal for concerted bond reorganization of the trans isomers incorporated two consecutive electrocyclic events. Conrotatory electrocyclic ring opening of the cyclobutene delivers an acyclic octatetraene. The torquoselectivity of this event has been studied theoretically by Houkjs and verified experimentally to favor outward splaying of the more highly electron-donating oxido f u n c t i o n s . Subsequent Brr electrocyclization to a cyclooctatriene dienolate is now possible due to the cis stereochemistry of the internal double bonds.
The conrotatory nature of both concerted events is allowed by orbital symmetry,18 and in cases whereby both of the appended nucleophiles are stereochemically equivalent, bond cleavage and reconstruction are necessarily restricted to formation of the anti isomer. The overall transformation is depicted in Scheme 2.10 for product 15.
28 /-Pro. 0/-P r
/-Pro
37 38
/-Pro
/-Pro /-Pro OH 39 40
Scheme 2.10. Proposed electrocyclic route to the major products.
4jc-Electrocyclic ring opening of squarate esters following nucleophilic addition has extensive literature precedent.While the number of examples of Btc electrocyclization of conjugated acyclic octatetraenes is more limited, the reaction has been studied by Huisgen^^ and Marve|20 and, more recently by Houk^i using molecular mechanics. 8jc-
Electrocyclizations have also been observed biosynthetically .22
At this point, an investigation was initiated in an attempt to decipher the pathway for initial bond reorganization in these systems. A study of the proposed intermediates both empirically and theoretically was carried out. Significantly, it can be appreciated that the stereochemical and positional markers present in the hypothetical 1,3,5-cyclooctatriene dienolates can be directly linked to mechanistic origin. In particular, the all cis arrangement of the triene in 39 clearly distinguishes it from the Cope/chair intermediate 22.
Therefore, assuming double bond isomerization does not interfere, trapping experiments should provide direct evidence for the preceding events.
29 Figure 2.1 summarizes the potential intermediates (carbocyclic framework) to be considered as products of concerted bond reorganization, and the preliminary events leading to their formation. Only 1,2 addition is considered. Dienolates 41 and 42 result from valence isomerization via an altemate conformational option.
o’ 0" (-Pro
/-PrO /-Pro 24 cis addition cis addition Cope/boat TS Cope/boat TS
/-Pro
/-Pro
39 42 cis addition trans addition trans addition Cope/chair TS electrocyclic ^ electrocyclic ^
Figure 2.1. Potential intermediates for the squarate rearrangements. Mode of addition and concerted reorganization pathway are listed for each example. Dienolates 24 and 41 precede formation of products such as 16, while 22, 39, and 42 would lead to the companion product, 15.
It should be noted that one can readily distinguish between the cis addition/Cope chair pathway leading to 22 and the trans addition/electrocyclic2 course preceding formation of 39 by trapping the hypothetical intermediate and investigating its symmetry aspects by NMR.
30 While the former has no elements of symmetry, the latter involves a C2 axis
which can be realized by virtue of rapid conformational interchange of the
nearly planar 39 with respect to the NMR time scale. In the case of optimum
interconversion, this should result in a corresponding reduction to the
number of signals by 50%. Other structural aspects can be examined by
comparison of coupling constants and nOe effects. Specific orientation at
the stereogenic centers can be unequivocally established by subsequent
conversion into the quinane products of known stereochemistry.
At the outset, molecular mechanics calculations involving closely
related analogues of 22, 24, 39, 41, and 42 provided insight into the thermodynamic stability of the various intermediates. For this purpose, the
neutral form of each relevant diastereomer was minimized in either the
MODEL KS 2.96 or KS 2.99 program.23 The anionic forms of 22, 24, and
42 were also investigated for comparison. Furthermore, the isopropyl
groups were replaced by methyl in order to reduce the number of possible sidechain rotamers. The data compiled in Table 2.2 reveal a correlation
between the neutral and oxido species. As expected, results show that total energy values increase with a corresponding increase in the number of trans-fused double bonds incorporated into the medium ring framework.
31 MeO MeO
MeO MeO
^ E Strain 99.643 36.651 ^H, -52.670 -97.993 ^ E Total 108.68 45.69
MeO MeO
MeO MeO
^ Estrain 66.270 AHf -78.085 A Erotai 75.31
MeO MeO^-.^^z/zr
MeO MeO
A Estrain 116.659 52.372 A Hf 33.645 -79.583 A EtouI 125.70 61.41 OH MeO MeO.
MeO MeO
0 - OH D DO ^ ^Strain 39.67 AH, -91.13 ^ ^Total 48.71
HO MeO MeO
OH MeO MeO
^ ^Strain 117.844 61.557 A H, -40.623 -78.245 ^ ^Tctal 126.88 70.60
Table 2.2. Global minimum energy conformations of 1,3,5 cyclooctatriene dienolates as determined by molecular mechanics calculations (Chem 3-D output). All energies are in units of kcal/mol.
32 These results corroborate the newly proposed mechanistic pathways
for 15 (37-40) and for 16 (21 b-25) in that the expected intermediates
represent the lowest energy channels for electronic reorganization.
Trapping experiments were subsequently undertaken. The addition of
excess chlorotrimethylsilane after treatment of 10 with 3 equiv of cyclo-
pentenyllithium provided a chromatographically separable mixture of 43 (43%),
44 (24%), and 48 (5%) (Schemes 2.11 and 2.12). The two major products 43
and 44 (Scheme 2.11) were readily distinguished from the third isomer 48
(Scheme 2 .12) on the basis of their symmetry. While 44 gave evidence of being a relatively rigid symmetrical structure, 43 is clearly a conformationally dynamic molecule. Peak broadening at room temperature was considered to be diagnostic of the indicated stereochemistry. Time-averaged symmetry which reduces the signal count by 50% became more apparent on heating, but decomposition was incurred before a fully resolved spectrum could be achieved
(See Figures A.13, A.14, and A.15 for variable temperature NMR spectra).
Complete structural confirmation of 44 was accomplished by nOe, semi- selective DEPT and INEPT24 and 2D NMR experimentation, corroborating the operation of the Cope/boat pathway. Structural differentiation between 43 and 44 was made possible by chemical correlation. To this end, the three bissilyl enol ethers were individually exposed to excess methyllithium in order to liberate the enolate anions. An ensuing aqueous quench returned 15 (99%),
16 (93%), and 24 (43%)/50 (43%), respectively. The obvious loss of stereocontrol during the protonation of 47 may be the result of the dissimilarity in reaction conditions. Altematively, the very minor amount of 48 produced from the squarate condensation could be cause for the non-detection of the epimer 50 in the original reaction (Scheme 2.2).
33 A. Electrocyclic Option
MesSIQ MesSICI
/-Pro CHgLi Q- MesSiO 39 43
/-Pro /-PrO
40 15
B. Sigmatropic Option
MesSiO : Me 3 SIC!
’ CHsLi
/-Pro H /-PrO OH 25
Scheme 2.11. Trapping the intermediate cyclooctatriene dienolates as silyl ethers. The two major intermediates shown here are regenerated with MeLi and converted to the final products by protonation/transannular aldol. Events preceding formation of the dienolates 24 and 39 can be seen in Scheme 2.5 via 21b and Scheme 2.10.
34 /-Pro. 0 1,4- /•-Pro addition /-PrO
45
/-Pro
/-Pro /-Pro
46 MesSiCI 47
TEA
/-Pro /-Pro /-Pro 48 49
(a only)
/-Pro
0 HO
20, a-H 50, p-H
Scheme 2.12. Trapping the Intermediate cyclooctatriene dienolate as a silyl ether. The minor intermediate shown here is regenerated with MeLi and converted to the final products by protonation/transannular aldol.
35 The 1H NMR spectrum of 48 shows it also to be a conformationally
dynamic molecule whose sluggish rate of interconversion again gives rise to
peak broadening. Unlike 43, however, there is no indication of symmetry.
These data show that cyclopentenyllithium exhibits an unusually high
propensity for cis 1,2-addition. Although trans-dialkoxide formation is
indeed favored by approximately 2 :1, this ratio falls considerably below the
customarily high kinetic preference for anti addition. The incursion of 1,4-
addition to generate 45 is very modest (Scheme 2.12). Subsequent isomerization via 46 leads to the doubly-charged cyclooctatriene 47,
characteristic of the electrocyclic option. It will be noted that advancement
along this reaction channel has the incontrovertible consequence of delivering an a-hydroxy substituted polyquinane as product.
The conformational rigidity imposed by the third vicinal stereogenic carbon
in 25, 40 and 49 so limits the conformational freedom of these
cyclooctadienones that the final transannular aldolization proceeds in a
single, well-defined stereochemical direction. As anticipated, the initial
protonation of doubly-charged intermediates 39 and 47 proceeds with
installation of a cis ring fusion, since considerable torsional deformation of the medium-ring framework would accompany proton delivery from the
opposite face. By comparison, the initial protonaton of 24 occurs in trans fashion to afford 16. More complete details of the stereochemistry of
protonation can be found in Chapter 5. In similar fashion, treatment of 10 with three equivalents of 11 followed by excess chlorotrimethylsilane afforded a chromatographically
separable mixture of three disilylated compounds. The first two were identified as 51 (51%) and 52 ( 24%) (Scheme 2.13). A third minor isomer,
36 assumed to be 53 (3%), proved to be highly sensitive and decomposed too
rapidly to permit its full characterization.
1. 3 equiv MesSiQ /-PrO 1 1 ,THF / i-PrO^ ^ 0 2. MesSiCi, (C2H5)sN MesSiO O' 10 51
MesSIQ, /-Pro Me 3 SIC. MesSIO \
MesSiO
53
Scheme 2.13. Trapping the intermediate cyclooctatriene dienolates as silyl ethers. Intervening events are analogous to those shown in Schemes 2.5 (via 21b), 2.10, and 2.12.
Peak broadening in the NMR spectra was again considered as evidence for the unique architectural arrangement in these medium-ring compounds. In the current case, this conclusion was confirmed. The high crystallinity of 52 made possible direct scrutiny of its solid-state three- dimensional structural features by X-ray crystallography (Figure B.1, Table B.1). The refinement of structure, successfully accomplished in the centric
P1 space group defines the vicinal relationship of the pairs of isopropoxy and trimethylsilyloxy substituents. This pattem distinguishes 51 from 52. The all cis arrangement of the triene present in 52 was unequivocally identified, thereby establishing the mechanistic pathway. X-ray confirmation
37 of this intermediate was ultimately used to verify the operation of the
electrocyclic process for other examples.
Individual exposure of 51 and 52 to methyllithium in order to
regenerate the corresponding diene diolates and subsequent quenching with water resulted in high-yield conversion to 13 (100%) and 14 ( 8 6 %),
respectively (Scheme 2.14). The interrelationship between intermediate and end-product was consequently unambiguous. The inability to isolate the minor product 19 (Scheme 2.2) which should derive from 52 was possibly a result of differing reaction conditions. Ketone 18 would be the product from the unstable 53.
MesSiQ
1. CHsLI 2. HzO MesSiO /-PrO OH 0 13
MesSiQ MesSiQ 1. CHsLi i-PrO 2. HzO
14
Scheme 2.14. Dienolate regeneration and diastereofacial proton quench as with 39 (Scheme 2.11) and 47 (Scheme 2.12) precedes the transannular aldol reaction providing 13 and 14.
Thus it can be seen in Schemes 2.13 and 2.14 that 2,3-dihydro-5- furanyllithium (11) adds twice to 10 in three different ways. Following formation of the monoadduct, the major reaction channel involves 1 ,2 - 38 addition from the opposite face to generate the trans dialkoxide. A minor route takes advantage of the anti 1,4 option. Judging from isolated yields, trans addition operates to the near exclusion of the cis alternative. A cascade of chemical events ensues involving conrotatory 47t electrocyclization, conrotatory 8n ring closure,and diastereoselective protonation/transannular aldol reaction.
The results of these experiments clearly define the operation of the proposed pathways. Many systems studied during the course of this project do not contain enough stereochemical markers to verify the actual reaction channel. However, due to the overwhelming predominance for the anti addition option in those systems which have fully substituted vinyl anions, we necessarily assume this protocol to be consistently preferred. One point of interest which should be mentioned before leaving this section concerns the conformational flexibility allowed when intermediates such as 39 are not subjected to the constraints imposed by the presence of the fused carbocycles. Molecular models indicate that conversion of one of the cyclopentanoids (A or B) to the acyclic variant allows the electrocyclic intermediate to slip to the boat conformation (Scheme 2.15). Depending on the substitution at the bond-forming centers, the latter may be more stable.
This phenomenon was investigated by trapping adduct 54 as the TMS enol ether 55 in 70% yield (Scheme 2.16). In this system it is impossible to be certain of the events leading to the cyclooctatriene intermediate due to insufficient substitution of the vinyl anion. However, on the basis of precedent and experimental results to be mentioned in Chapter
3 , it is expected that the electrocyclic version is operative.
39 /-Pro /-Pro H /-Pro /-Pro O' 0 " 39 39' 24'
Scheme 2.15. Unlocking the electrocyclic conformation by cleavage of one of the bonds of a fused cyclopentanoid allows the all cis octatriene access to the boat conformation.
/-Pro JL /-P rO ^^ "-'0 3 equiv
10 54a
OSIMe 3 MesSiO I > TMSCI TEA /-PrO /-PrO 54b 55
Scheme 2.16. Trapping the intermediate from reaction of diisopropyl squarate and 3 equiv of 2 -lithiopropene.
1H and NMR are clearly indicative of a conformationally rigid, symmetrical boat structure. Repercussions of this flexibility in more complex systems become evident during protonation/proton transfer, as the electrocyclic intermediates preferentially protonate cis to the adjacent chiral center, while the boat intermediates have shown a distinct preference for the
40 anti alternative. A more thorough treatment of the stereochemical consequences of protonation is presented in Chapter 5.
41 LIST OF REFERENCES
1 (a) Paquette, L.A.; Lawhom, D.E.; Teleha, C.A. Heterocycles ^9B0, 30, 765. (b) Paquette, L.A.; Lanter, J.C.; Wang, H-L. J. Org. Chem. 1996, 61, 1119. (c) Paquette, L.A.; Wang, H-L. Tetrahedron Lett. 1995, 36, 6005. (d) Negri, J.T.; Rogers, R.D.; Paquette, L.A. J. Am. Chem. Soc. 1991, 113, 5073. (e) Paquette, L.A.; Negri, J.T.; Rogers, R.D. J. Org. Chem. 1992, 57, 3947. (f) Paquette, L.A.; Branan, B.M.; Friedrich, D.; Edmondson, S.D.; Rogers, R.D. J. Am. Chem. Soc. 1994, 116, 506. (g) Paquette, L.A.; Branan, B.M. Heterocycles“\995, 60, 1852. (h) Paquette, L.A.; Branan, B.M.; Rogers, R.D.; Bond, A.M.; Lange, H.; Gleiter, R. J. Am. Chem. Soc. 1995, 117, 5992. (I) Paquette, L.A.; Lord, M.D.; Negri, J.T. Tetrahedron Lett. 1993, 34, 5693. (j) Lord, M.D.; Negri, J.T.; Paquette, L.A. J. Org. Chem. 1995, 60,191. (k) Paquette, L.A.; Doussot, P. Research Chem. Intermed, submitted for publication. (I) Paquette, L.A.; Sturino, 0.; Doussot, P. submitted for publication.
2 Boeckman, R.K., Jr.; Bruza, K.J. Tetrahedron Lett. 1977, 4187.
3 See, for example: (a) Paquette, LA.; Opiinger, J.A. Tetrahedron 1989, 4 5 , 107. (b) Paquette, L.A.; Dullweber, U.; Cowgill, L.D. Tetrahedron Lett. 1993, 34, 8019 and relevant references cited therein.
^ (a) Barton, D.H.R.; Bashiardes, G.; Fourrey, J. Tetrahedron Lett. 1983, 24, 1605. (b) Barton, D.H.R.; Bashiardes, G.; Fourrey, J. Tetrahedron 1988, 44, 147.
5 (a) Hambrecht, J.; Straub, H. Tetrahedron Lett. 1976,1079. (b) Hambrecht, J.; Straub, H.; Müller, E. Chem. Ber. 1974, 107, 3962.
6 Brands, M.; Wey, H.; Bruckmann, J.; Kruger, C; Butenschon, H. Chem. Eur. J. 1996, 2, 182 and relevant references cited therein.
7 For reviews of the oxy-Cope reaction: (a) Paquette, L.A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609. (b) Lutz, R.P. Chem. Rev. 1984, 84, 206.
8 Liebeskind, L.S.; Wirtz, K.R. J. Org. Chem. 1990, 55, 5350.
42 9 (a) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Org. Chem. 1988, 53, 2482. (b) Dehmlow, E.V.; Schell, H.G. Chem. Ber. 1980, 7 73, 1. (c) Kraus, J.L. Tetrahedron Lett. 1985, 26, 1867.
10 Berson, J.A.; Dervan, P.B.; Jenkins, J.A. J. Am. Chem. Soc. 1972, 94, 7598.
11 Anionic acceleration of oxy-Cope rearrangements was originally described by Evans. Evans, D.A.; Golob, A.M.; J. Am. Chem. Soc. 1975, 97, 4765.
12 Hammond, G.S.; DeBoer, C.D. J. Am. Chem. Soc. 1964, 86, 899.
13 Berson, J.A.; Dervan, P.B. J. Am. Chem. Soc. 1972, 94, 8949.
14 Bamier, J.P.; Ollivier, J.; Salaun, J. Tetrahedron Lett. 1989, 30, 2525.
15 Yamamoto, Y.; Ohno, M.; Eguchi, S. J. Am. Chem. Soc. 1995, 7 77, 9653 and relevant references cited therein.
16 (a) Nakamura, K.; Houk, K.N. J. Crg. Chem. 1995, 60, 6 8 6 . (b) Rudolf, K.; Spellmeyer, D.; Houk, K.N. J. Crg. Chem. 1987, 52, 3708. (c) Rondan, N.; Houk, K.N. J. Am. Chem. Soc. 1985, 107, 2099.
17 Piers, E.; Ellis, K.A.; Tetrahedron Lett. 1993, 34, 1875. The reversal of torquoselectivity with Lewis acids has been reported: (a) Niwayama, S. J. Crg. Chem. 1996, 61, 640. (b) Niwayama, S.; Houk, K.N. Tetrahedron Lett. 1993, 34, 1251. See also Chapter 1, ref 9a, c-e, g, h.
18 (a) Die Erhaltung der Orbitaisymmetrie; Veriag Chemie, Weinheim 1970; (b) The Conservation of Orbital Symmetry, Veriag Chemie, Weinheim/Academic Press, New York 1970; (c) Angew. Chem. 1969, 81, 797; (d) Angew. Chem., Int. Ed. Engl. 1969, 8, 781.
19 (a) Huisgen, R.; Boche, G.; Dahmen, A.; HechtI, W. Tetrahedron Lett. 1968, 5215, (b) Huisgen, R.; Dahmen, A.; Huber, H. Tetrahedron Lett. 1969, 1461. (c) See also Chapter 1, Ref. 16.
20 (a) Man/ell, E.N.; Seubert, J.; Vogt, G.; Zimmer, G.; Moy, G.; Siegmann, J.R. Tetrahedron 'ÏQIQ, 34, 1323, (b) Review: Marvell, E.N. Thermal Electrocyclic Reactions, Academic Press, New York, 1980, Chapter 8 .
21 Thomas, B.E. IV; Evanseck, J.D.; Houk, K.N. J. Am. Chem. Soc. 1993, 115, 4165.
43 22 (a) Pohnert, G.; Boland, W. Tetrahedron 1994, 5 0 ,10235. (b) Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E.; UenishI, J. J. Am. Chem. Soc. 1982, 104, 5555, and relevant references cited therein.
23 Still, W.C.; Steliou, K. private communication. Through use of the Grid Search function within MODEL, a multiconformer run was performed within each molecule incorporating the appropriately stereodisposed bond construction. In each case, over 300 conformers were generated and minimized to ensure arrival at the global minimum energy conformer. The MMX software program was then used to optimize the lowest energy conformer in each instance.
24 (a) Bax, A. J. Magn. Reson. 1984, 57, 314. (b) Bax, A.; Nin, C.H. J. Am. Chem. Soc. 1984, 106, 1150. (c) Miiler, N.; Bauer, A. J. Magn. Reson. 1989, 82, 400.
44 CHAPTER 3
QUINANE PRODUCTS PRODUCED BY TWOFOLD ADDITION OF
ACHIRAL UNSATURATED ANIONS TO SQUARATE ESTERS AND
OTHER CYCLOBUTENEDIONES
A. Introduction
In order to develop a full appreciation of the synthetic potential which can be extracted from this new methodology, a systematic investigation of the effects of various substituents was undertaken. Due to the variety of underlying mechanistic events which must converge in tandem fashion, seemingly minor adjustments in functionality often have far-reaching consequences. This chapter is a summary of the various substrates which have been brought together during this investigation. The subsequent chapters will utilize these results to draw conclusions concerning efficiency and selectivity. The information in this chapter is organized into five sections. The first four examine the nucleophiles which have been added to the squarate esters. The final section is a digression from the ester substrates to other electrophilic cyclobutenediones. Throughout this summary, reference will be made to two sets of reaction conditions, A and B. A seemingly minor factor differentiates them.
45 However, depending on the locus of substitution of the nucleophilic reactants, the results can be significantly different. Conditions A involve sequential addition of the carbanions at -78 °C, with or without additives to enhance nucleophilicity, followed by variable time and temperature conditions, quenching with an aqueous solution of NH 4CI or water, and immediate work-up. Alternatively, conditions B involve an analogous sequence of events to the point of quench. The quenching solutions are deoxygenated prior to their introduction into the reaction mixture, which is subsequently maintained for a number of hours under an inert atmosphere before workup. In many cases, the latter modification has boosted yields significantly. For reactions carried out under each set of conditions, both will be reported.
Exclusive recourse has been made to diisopropyl squarate as the ester of choice. Ease of preparation, 1 lessened irritant properties with respect to the lower dimethyl and diethyl homologs, 1 and enhanced stability all contribute to this selection.
B. Twofold Addition of a Single Alkenyllithium Reagent
Use of a common nucleophile in both addition steps has the distinct characteristic of maintaining symmetry as long as possible during the course of the rearrangement. The reactions in Scheme 2.2 fall into this category, and the reported yields result from conditions A. The heterocyclic reaction was repeated using anhydrous CeCIs,^ (conditions A), and again with the lithium anion under conditions B (Figure 3.1).
46 /-PrO o'
Reaction /•-Pro /-Pro Conditions /-Pro 13 14 1 A (Lithium) 38% 15% 2 A (Cerium) 44% 0% 3 B (Lithium) 52% 18%
/•-PrO 0
/-Pro /•-Pro
18 19 1 A (Lithium) 3% 2% 2 A (Cerium) 0% 0% 3 8 (Lithium) 6% 4%
Figure 3.1. Yields for reaction of diisopropyl squarate with two equivalents of 11 utilizing different sets of reaction conditions.
Regioselective addition was observed with the cerate, a result of the greater oxophilicity of these reagents, and the expected improvement in efficiency was noted with the alternate conditions B. When 10 was treated with an excess of two equiv of either vinyllithium^ or 2 -propenyllithium, comparable yields were observed under both sets of conditions. However, for vinyllithium best results were achieved when the temperature was maintained at -78 °C until workup was initiated
(Scheme 3.1).
47 ü CH=CH2 10 (> 2 equiv) THF i-PrO OH 56 (45%)
Li /-PrO CH 3 >=C H ; HgC 10 /-PrO (> 2 equiv) THF /-PrO OH CH 3 0 OH CH 3
57 (90% ) 58 (2.5%)
Scheme 3.1. Squarate rearrangement with vinyllithium or 2 -propenyllithium.
Structural assignment to 56 rests reliably on semi-selective DEPT studies at 300 MHz. A cis stereochemical relationship is a necessary consequence of the transannular aldol. For 57, X-ray crystallographic analysis provided unequivocal structural proof (Figure B.2, Tables B.5-8). Semi-selective DEPT revealed the regiochemistry of the enone in 58 to be a consequence of second-stage conjugate addition. Direct comparison of the spectroscopic characteristics of 58 with its regioisomer 57 made possible accurate definition of the relative stereochemistry at the chiral centers.
The level of substitution resident in 56 to 58 is inadequate to reveal the nature of bond construction. However, use of the c/s- and trans-2- butenyllithiums'^ provides a degree of structural complexity which is informative with respect to these issues. Consequently, these reagents were individually generated and added in excess of two equiv to 10 (Schemes 3.2 and 3.3). Yields are for conditions B.
48 Li X 10 59 3 eq
/-Pro
/-Pro /-Pro
/-Pro H /-Pro
H+ 61 (4%)
60a R = H (73%) b R = 3,5-C0C6h3(N0 2)2
Scheme 3.2. Squarate rearrangement with c/s-2-butenyllithium.
49 Li
10 62 /-PrO-"^— 3 eq
1,4- addition
/-PrO 1 1
/-Pro 0/-Pr /-PrO O ’
H" H+ H +
/-Pro H 61 (1.5%) /-Pro
0 -
60a (3%)
63 (3.5%)
Scheme 3.3. Squarate rearrangement with frans-2-butenyllithium.
50 The cis isomer 59 was found to engage readily in reaction and to generate efficiently (77%) a 19:1 mixture of 60a and 61. On the basis of spectroscopic data, 61 was clearly a product of 1,2 addition in a stereoproximal orientation giving rise to Cope chemistry. In order to derive comparable structural information from the major diquinane, it was necessary to prepare the 3,5-dinitrobenzoate derivative 60b. The stereochemistry determined for 60b is consistent with a stereodistal bis 1 ,2 adduct having undergone two conrotatory electrocyclic events.
The inefficiency associated with the addition of frans-2-butenyllithium to
10 (Scheme 3.3) contrasts strikingly with the cis version. While the Cope product 61 is consistently low in both sequences (4%, 1.5%), a significant loss of efficiency for production of the electrocyclic product 60a is observed for the latter (73%, 3%). Furthermore, 63 (3.5%: see Figure B.3, for X-ray crystal structure), a product of 1,4 addition, shows unusual stereoselectivity for the aldol reaction, a possible indication that the pre-aldol intermediate may arise from electrocyclization through an alternate conformation or possibly from a
Cope crossover to the chair transition state.
(£)-1-Propenyllithium,5 another homolog of vinyllithium, also has the resident functionality adequate to examine mechanistic details. This case, however, represents somewhat of an anomaly (Scheme 3.4). When conditions A were utilized, no quinane products were isolated. Adoption of conditions B also produced no quinane products after stirring the reaction mixture following quench for 92 hours under argon. If, however, the quenched reaction mixture was subsequently refluxed for eight hours a 10% yield of 64 could be isolated, along with 2 1 % of a cyclohexadienone derivative, a product of 071 electrocyclization.
51 The stereochemistry of 64 was determined by nOe analysis to be a
product of Cope rearrangement. Consideration of the conditions employed,
however, suggests this is not likely. Additionally, engagement of this nucleophile in other systems has led to predominant trans addition. Perhaps
double bond isomerization or an intervening pericyclic event was responsible.
A discussion of substituent effects with respect to the efficiency of the
electrocyclization reaction can be found in Chapter 4.
Li /-Pro 10 CH; 3 eq ??
H+
Conditions A (0%) Conditions B (10%)
Scheme 3.4. Squarate rearrangement with (E )-1 -propenyllithium.
The effect of aromatic stabilization at the anionic carbon was next investigated. To this end, a-bromostyrene was subjected to lithium/halogen exchange and added to 10 in excess of two equiv (Scheme 3 .5 ).sb
52 Ph i-PrO^ ,0 Li /-Pro /-Pro ^ 0
65 Conditions A (15%) Conditions B (20%)
Scheme 3.5. Squarate rearrangement with a-lithlostyrene.
The only isolable quinane product 65 can be seen to arise from exclusive 1,4 addition of the second nucleophile in relatively poor yield. Only minor improvement was observed by making recourse to the alternate reaction conditions. Stereochemistry of the phenyl at C -8 could not be unequivocally determined by nOe studies. However, the small enhancement for OH to H-8 (0.9%) and H -8 to OH (0.3%) was indicative of a cis relationship for the phenyl and hydroxy substituents.
C. Addition of Non-Identical Pairs of Alkenyllithium Reagents
The addition of two different alkenyl anions to 10 provides an opportunity to extend our appreciation of several facets of this cascade reaction. For example, generation of an unsymmetrical cyclooctatriene dienolate offers the potential for synthesis of either a linear or angular triquinane framework,® if site selective protonation can be achieved. Exposure of 10 sequentially to 2-propenyllithium and cyclopentenyllithium provided the appropriate functionality to examine this phenomenon (Scheme
53 3.6). Both enolate sites were found to undergo protonation providing a 1:2.3 mixture of an angular triquinane 6 6 and the linear counterpart 67 (see Figure
B.4, Tables B. 13-20 for X-ray data) in 8 8 % yield (conditions A). Protonation at the five-membered ring may be kinetically favored due to strain associated with the exocyclic double bond. However, the lack of selectivity is a critical point that requires additional study. Surprisingly, an issue as fundamental as the competitive reactivity of two enolate anions in comparable structural environments has been very infrequently examined.^
i-P rO ^ > = =a 10 ! . U - 0 /-PrO O ' CH3
0, / Ï H ÇH3
/-Pro + '-PrO
/■-PrO Oh 'CHs /-PrO OH
66 (27%) 67 (61%
Scheme 3.6. Squarate rearrangement with 2 -propenyllithium and cyclopentenyllithium.
In addition to the issue of regioselective protonation, the sequence of addition also becomes a factor in cases where the terminal positions of both vinyl anions are substituted. This was seen earlier during the mechanism studies. Another case in point is provided by the sequential introduction of
54 (£)-1-propenyllithium to 10 followed by an excess of cyclopentenyllithium
(Scheme 3.7).
0 * CH3
APrO-V/
69
+ /-PrO + /-PrO •CH3
/•-PrO OH /-Pro OH /-Pro OH
70 71 72 Conditions A 12% Conditions A 0% Conditions A 32% Conditions B 40% Conditions B 12% Conditions B 22%
70 71 72 10 Conditions A 20% Conditions A 0% Conditions A 0% Conditions B 62% Conditions B 0% Conditions B 4%
Scheme 3.7. Squarate rearrangement of (E)-1-propenyllithium and cyclopentenyllithium.
Examination of results from conditions B reveals that if cyclopentenyllithium is added subsequent to 1-propenyllithium, the yield of products 71 and 72 resulting from cis addition is enhanced. The deviation observed when 1 -propenyllithium is the second nucleophile has its origins in
55 the previously observed tendency for the cyclopentenyl anion to undergo a significant degree of cis 1,2-addition. While trans addition was nearly exclusive in the second experiment, the second-stage entry of cyclopentenyllithium results in the competitive formation of the stereoproximal adduct at an approximately equivalent level, providing the opportunity for [3,3] sigmatropy. The difference in the regioselectivity of protonation for 69 may result from the different conditions used to quench the dienolate. The example carried out under method A was quenched at room temperature with water and led to exclusive formation of 72. The companion reaction
(conditions B) was non-selectively protonated at 0 °C with an aqueous solution of NH4CI, providing a 1:2 ratio of 71 and 72. Additionally, it can once again be noted that the altemate conditions (B) enhanced the yield of electrocyclic product 70 resulting from trans addition (see Figure B.7 for preliminary ORTEP diagram). Replacement of 1-propenyllithium with vinyllithium excludes the potential for differentiation by order of addition, as one of the bond-forming centers is no longer chiral (Scheme 3.8). However, yield optimization as a function of conditions® and regioselectivity of protonation was observed in this reaction.
/•-Pro 1.1-' 10 2. L i - O 73 Conditions A 20% Conditions B 67%
Scheme 3.8. Squarate rearrangement with vinyllithium and cyclopentenyllithium.
56 The example presented in Scheme 3.9 holds interest for yet other
reasons. When direct comparison is made with Scheme 3.3, it is seen that a
significant recouping of efficiency is possible if the second anion is 2-
propenyllithium and recourse is made to the modified reaction conditions (B).
Diquinanes 74 (30%) and 75 (28%) are recognized to arise via the
electrocyclic pathway and the common monoprotonated intermediate 78
(Figure 3.2). In this instance, the conversion to 78 is accompanied by the capability for conformational equilibration represented by 78a^78b. This
singular ring inversion, which probably borders on being an isoenergetic
process, opens the way for transannular aldolization to occur from diastereotopic 7t-faces of the carbonyl group.^ The near-equal distribution of
74 and 75 indicates the cyclization rates for the two species to be closely comparable.
0, CHs
10 ------" /-Pro-4 >-CH 3 +/-PrO — ■CHs 2."3Cs.ru_ Li /-PrO OH CHs OH CH3 74 (30%) 75 (28%)
0. S""yH3
/-PrO OH OH 3 0 OH CH3 76 (22%) 77 (4%)
Scheme 3.9. Squarate rearrangement with 2-propenyllithium and trans-2- butenyllithium.
57 . C H 3 ^ 0 .CH3-3
78b
Figure 3.2. Diastereotopic faces of the pre-aldol intermediate.
Product 76 arises from the second possible pre-aldol regioisomer, formed by protonation of the bisenolate at the second reactive site. In this
instance, conformational interconversion, if operative, is of little significance since transannular cyclization proceeds to deliver only that isomer having the vicinal methyl groups both (3-oriented. The minor constituent 77 is the obvious end result of 1,4 addition by the 2-lithiopropene. The use of 1-lithio(trimethylsilyl)ethyleneio as a first-stage reactant ultimately leads to generation of a dianionic intermediate having electronically disparate enolate centers (Scheme 3.10). In this experiment, 79 was isolated as a single epimer of unknown configuration at C-8 in 72% yield. Consequently, protonation was directed exclusively to the silicon-substituted carbon.
58 /-Pro 10 /-Pro 2.H3C > C H ; Li
0 CH 3 H +
/-PrO OH SiMe 3
79 (72%)
Scheme 3.10. Squarate rearrangement with 2-propenyllithium and 1 lithio(trimethylsilyl)ethylene.
D. Mixed Additions Combining Alkenyllithium Reagents with
Vinylmagnesium Bromide
It has been reported that Grignard reagents undergo conjugate addition with squarate esters, the extent of which is likely controlled by the size of the alkoxide.'*'* Because the 1,4 addition mode offers some unique opportunities for regiocontrol, the use of Grignard reagents was investigated. When excess vinylmagnesium bromide was added subsequent to one equivalent of 2-lithiopropene, three isomeric products were formed (Scheme 3.11). Diquinanes 80 and 81 are products of second-stage 1,4 addition of the Grignard reagent, while 82 is produced by sequential 1,2 addition of both species. The major products are differentiated by opposing diastereofacial aldol reactions. For the minor product, only a single epimer
59 is possible, as a cis relationship between the angular methyl and hydroxyl
groups is a necessary consequence of the transannular aldol reaction.
/-Pro
/-Pro i r ^ 0 ” 2. CH2=CHMgBr - t o 0 OH /-PrO ÔH
80 - a (23%) 82 (6%) 81 - p (13%)
a . '-Pro
ru. I. ^1 I \-»i Ii*iyui ^ /L P r O - V ^ f^
^ ^ 0 2. jl^ '-Pro OH 0 OH
^^3 82 (14%) 83 (13%)
Scheme 3.11. Squarate rearrangement with 2-propenyllithium and vinylmagnesium bromide.
Reversal of the order of addition of the two nucleophiles produced five distinct products, three of which resulted from over-addition of the vinylmagnesium bromide. In each case, initial 1,2 addition was established, however. The two remaining products from mixed addition are shown. While 82 derives from 1,2 addition of both nucleophiles, 83 results from conjugate addition of the lithium reagent which is added in the second step. Structural proof for 80 and 81 rests reliably on a combination of semi- selective DEPT and nOe enhancements. For 82 and 83, 3J coupling from the angular methyl to the carbonyl carbon (82) or p carbon of the enone
60 (83) was sufficient for structural analysis. Therefore, while the Grignard undergoes almost exclusive 1,4 addition when added subsequent to another nucleophilic species, initial addition of this substrate occurs strictly in a 1,2 sense to diisopropyl squarate. The poor yields and lack of selectivity in subsequent stages of the tandem sequence discouraged continued investigation of the Grignard chemistry.
E. Mixed Additions of Acetylenic and Alkenyl Reagents
The possibility of using more highly unsaturated nucleophiles to effect bond reorganization was also investigated. The addition of two equivalents of an acetylenic anion to a squarate ester has been reported to lead to an acyclic diketone (see Scheme 2.3). Addition of a single alkynyl nucleophile on the other hand, in combination with a vinyllithium species follows a different course. First to be examined was the addition to diisopropyl squarate of 1 equiv of cyclopentenyllithium followed by propynyllithium in modest excess (Scheme 3.12). The expectation was that dianion 84 would be formed. Its adoption of the coiled conformation followed by Sit electrocyclization produces the strained 1,2,4,6-cyclooctatetraene intermediate. We are unaware of any direct precedence for this step. However, a doubly allenic cyclooctapentaene has previously been suggested as a transient intermediate for the conversion of c/s,c/s-3,5- octadiene-1,7-diyne to benzocyclobutadiene d im e r .^ 2 Following the formation of 85, protonation of the cumulenic enolate anion can be anticipated to be rapid since the relief of ring strain is maximized when
61 proceeding to 86. The isolation of 87 in 54% yield conforms to this
mechanistic proposal and provided the impetus to explore this molecular
scaffolding process in greater depth.
OPr- / /-Pro /-Pro // /•-Pro CHs 84 85
proton
/• CHs source
86 87
Scheme 3.12. Squarate rearrangement of cyclopentenyllithium and propynyllithium.
As seen from the typical results compiled in Table 3.1, the fundamental constitutional features of the hypothetical reaction pathway can be accommodated by a variety of monosubstituted acetylenes.
62 Expt. First Second no. anion anion Product Yield, %
Ü—^ Li /-Pro 27
FPrO OH
2 U — U - S 3 - CHzOCH 3 /-PrO—^ ^ ^ C H z O C H 3 25
/-PrO OH gg
3 L i - ^ Li-^CHs ^PrO-^J^^CHa> R . 71 CH3 /-Pro OH 90 CHs
4 u - f u -^-çy /-Pro- 25 CHs /■PrO OH 91
^OCgHs i^rO CHs
0 18 CHs
93 CHs
Li—= ■ EDA /-PrO - 18 CHs /-PrO OH 94
CHs Pro 39
Table 3.1. Polyquinanes resulting from use of acetylide anions.
63 In most cases it was found that the reactions progressed with fewer side products when the acetylenic component was added in the second step. This was most evident in cases where propargylic protons were present. Several reactions were carried out under both sets of conditions (A and B), and only minor improvement was observed with the single exception of experiment 8. In this case the 11% yield of 95 using conditions A was improved to 39% with the optional protocol. This is expected due to the non ideal substitution pattern of the vinylic component.
When the reaction efficiency is low, it is sometimes due to the operation of alternative reaction pathways which are kinetically competitive.
Several of these have been identified. For example, experiment 1 and allied reactions involving 1 -lithiocyclopentene also lead to 96. This product stems from the well known isomerization/oxidationi3 of the cyclopentenyl monoadduct and seemingly materializes because the second stage phenylacetylide addition proceeds quite slowly. The reduced nucleophilicity of the acetylenes with respect to the vinyl anions could be compensated for in some cases by the addition of ionophores to chelate the lithium cation.
Most effective in this regard was the macrocyclic [12]crow n-4.i4
OJ ÇcHz i-PrO^ I -OH /•-Pro /-PrO^ 0 OC2H5 OC2H5 96 97
Figure 3.3. By-products from reactions of acetylenes.
64 Experiment 5 eventuates as well in the formation of the heavily
functionalized cyclopentenone 98 (36%). This product quite possibly arises
by means of isomerization of 97 as shown. The unexpected persistence of
the dialkoxide of 97 may be a consequence of stereochemistry (cis addition
> trans addition) and/or stereoelectronic effects. Experiment 6 also gives
rise to the analogous phenyl derivative of 98 in 22% yield.
Most interesting was the concurrent production of 101 in experiment
6. This product presumably arises from initial conjugate addition of the
acetylene which, following valence isomerization, leads to 99 (Scheme 3.13). The ability of the strained allenic enolate to induce protonation in an
Sn' fashion was unprecedented. It has been observed throughout these
investigations that in cases whereby second stage addition occurs with 1,4
regioselectivity, initial protonation occurs exclusively on the enolate resulting from the initial 1,2 addition (Scheme 3.11). See Chapter 5 for a complete discussion of regioselective protonations.
/-Pro 0 1- L i - ( proton // source /-Pro O 2- LiC^Ph '-Pro Ph /-PrO ^ H+ 99
Ph /-Pro 0/-Pr 100
Scheme 3.13. Proposed route to the by-product 101 resulting from sequential addition of 2-propenyllithium and lithiumphenylacetylide.
65 F. Rearrangements of Semi-Squarates and Other Cyclobutene diones
The isopropoxy groups in 10 are amenable to ready replacement by a variety of substituents. The electronic character of the resultant cyclobutenedione is often significantly altered during such chemical changes. At issue in the present context is the extent to which these perturbations impact on the operability of the two principal mechanistic pathways. The results of condensing the diethyl derivative 102^5 with an excess of cyclopentenyl anion proved to be immediately diagnostic of significant differences. The cerium derivative was used to avoid deprotonation of the acidic methylene protons (Scheme 3.14).
HsC ^ Q (3 equiv) OH CeCls.THF 102 103 (23%)
Scheme 3.14. Reaction of 3,4-diethylcyclobutene-1,2-dione with three equivalents of cyclopentenyl anion.
In this instance, 103 was found to be the only isolable tetraquinane product. Its stereochemical features, verified by means of X-ray diffraction
(Figure B.5, Tables B.21-24), reveal that the dianionic oxy-Cope process
66 continues to operate satisfactorily. Since it is highly unlikely that the second- stage addition occurs exclusively in cis fashion, it would appear that the pendant alkyl substitution interferes with the efficiency of the electrocyclic alternative. The nature of the effect is not currently understood. However, the expectation Is that this modification directly influences the efficiency of the first step in the electrocyclic cascade. The reaction of 102 with the heterocyclic anion 11 holds significance in this regard (Scheme 3.15).
H3C ^ Q (3 equiv)
CeCb 104 ( 6 %
0
OH HO
105 (24%) 106 (32% )
Scheme 3.15. Reaction of 3,4-diethylcyclobutene-1,2-dione with three equivalents of 2,3-dihydro-5-furanyllithium.
Again it was observed that the oxy-Cope product was the only isolable tetraquinane, and It was produced to a similar extent as In the squarate reaction (Figure 3.1). When the organocerate was used, ring expansion chemistry of the pinacol variety depicted in Scheme 2.1 was apparently favored over 4 k pericyclic bond reorganization. Splrofuran 105 occurs as a consequence of monoaddition/ring expansion. The bis adduct
67 leading to 106 is apparently incapable of the second ring expansion, and instead undergoes simple hydrolysis of the appended vinyl ether. This particular finding is noteworthy in that discovery of the squarate chemistry detailed herein came about as a direct consequence of a failed attempt to form the bis spirofuran adduct for a derivative similar to 105 on addition of the anion of dihydrofuran (Scheme 3.16). The inability to induce a second ring expansion on sequential addition of 11 to diisopropyl squarate prompted the experiments in Scheme 1.6. Characterization of 106 was in fact verified by direct comparison to the corresponding squarate analogue
107.16
° 2. Proton Observed 107
/-Pro
0 Desired
Scheme 3.16. Failed attempt at ring expansion of the spirofuran cyclopentenedione.
The intolerance of dialkylcyclobutenedione 102 for the electrocyclic sequence on addition of two olefinic anions was used in an attempt to decipher the mechanistic pathway for the reaction of diisopropyl squarate
68 with 2-propenyllithium (Scheme 3.1). In this case, the lack of substitution at the terminal position of the vinyl anion made it impossible to determine the pathway for diquinane formation. While a 90% yield of diquinane product was isolated from reaction of 2-propenyllithium with diisopropyl squarate, no quinane products could be found in a similar reaction with 102. This implies that 57 occurs as a direct consequence of trans addition and electrocyclic chemistry.
Next to be investigated was a series of semisquarate derivatives in which one of the alkoxy groups of the squarate ester was replaced by an acetylenic moiety. These derivatives can be prepared directly from diisopropyl squarate by condensation with the acetylenic nucleophile, followed by acid-catalyzed rearrangement (see Scheme 1.4). The results of the condensation reactions of the acetylenic systems 108,^^-^®® 109 and 11018 with excess 2-propenyllithium are shown in Scheme 3.17. It was obsen/ed that in the presence of only a slight excess of 2 equiv of the nucleophile, reaction of the silicon derivative 108 was uneventful. However if a larger excess was used (> 4 equiv) complete removal of the silicon group was incurred.
69 " ^ ' > ch2 Li
/-PrO (> 2 equiv) THF 0 OHCH3
108, R = SiMe 3 111 , R = SiMe 3 ( 1 1 %) 109, R = CM 3 112,R=H(24%) 110,R = C 6 H 5 113 , R = CH 3 (28% ) 114, R = C6Hs (8%)
ÇH 3
0 OH CH 3 /-Pro OH CH3
115, R = SiMe 3 (21% ) 119(7%) 116,R=H(16%) 117, R = C H 3 (12% ) 118, R = C 6Hs (17% )
Scheme 3.17. Condensation of acetylenic semi-squarates with 2- propenyllithium.
Scheme 3.18 depicts the expected pathway for formation of the quinane products, initial 1,2 addition should occur exclusively at the more reactive carbonyl followed by 1,4 addition which is seen to operate nearly exclusively with these substrates without concem for the nature of the R group. Apparently, the direct connection of a triple bond to an isopropoxycyclobutene-1,2-dione plays an unmistakable role in guiding entry of the second nucleophile. The only isolated product of bis 1,2 addition was 119 in relatively minor amount. Regioselective protonation of the unsymmetrical dienolate resulting from second-stage 1,4 addition is expected, followed by the transannular event. Poor selectivity for the aldol
70 reaction, a characteristic of the 1,4 adducts, was also a factor in the acetylenic series.
0 (2 equiv) 0 (-^3
O’^yT%.0i-Pr
/■-Pro CH3 '-PrOv CH3
0 OH CH3 0 OH CH3
113(28%) 117(12%)
Scheme 3.18. Proposed pathway for eiectrocyclic rearrangements of acetylenic semisquarates.
Relative regiochemistry of the alkoxy and alkynyl groups could not be unequivocally determined by semi-selective DEPT studies. However, the indicated relationship was assigned on the basis of the presumed mechanism and absorption frequencies at 75 MHz. Regiochemistry of the enone was rigorously determined by coupling from the angular methyl. Stereochemistry was generally assigned on the basis of direct
71 comparison of NMR to similar derivatives. This was confirmed in a couple of cases by nOe analysis.
The formation of by-products was again responsible for the observed loss of reaction efficiency. In the current case, competitive side reactions occur as a result of the 1,4 regiochemistry of addition. The typical by-product found in yields as great as 34%, and the proposed route to its formation are shown in Scheme 3.19.
Li CHg
(2 equiv)
r CH3
Scheme 3.19. By-product formation in acetylenic semi-squarates.
Diphenylcyclobutenedione^s has also been found to undergo nucleophile-induced conversion into a diquinane (Scheme 3.20). Regio and stereochemistry was verified analogously to the acetylenic semisquarates. Exclusive conjugate addition of the second nucleophile was again observed.
72 A y - ^ ° Li ch3
0 0 ÔH CH3 121 122 (61%)
Scheme 3.20. Rearrangement using diphenylcyclobutenedione.
In summary, substantial characterization of the versatility for the electrocyclic2/aldol reaction has been carried out by functional group analysis. The several conclusions concerning reaction efficiency and selectivity which can be drawn from these observations are detailed in subsequent chapters.
73 LIST OF REFERENCES
1 See Chapter 1, ref lOd.
2 Drying procedure for CeCIs 7 H2O can be found in The Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A. Ed., John Wiley & Sons, New York, 1995, Vol. 2, 1031. (b) Review of lanthanide reagents in organic synthesis: Molander, G.A. Tetrahedron, 1986, 42, 6573.
3 Vinyllithium was generated from vinylstannane by treatment with n- butyllithium or directly from vinyl bromide: Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 4839.
4 (a) Dreiding, A.S.; Pratt, R.J. J. Am. Chem. Soc. 1954, 76,1902. The isomerically pure bromides are currently available from Aldrich Chemical Company.
5 (a) Hayashi, T.; Konishi, M.; Ocamoto, V.; Kabeta, K.; Kumuda, M. J. Org. Chem. 1986, 51, 3772. (b) Miller, S.A.; Gadwood, R.C. J. Org. Chem. 1988, 53, 2214. For the exchange with f-butyllithium in this case, temperature must be strictly maintained at -78°C to avoid formation of 1-propynyllithium.
6 See Chapter 2, ref 11 a.
7 (a) Paquette, L.A.; Temansky, R.J.; Balogh, D.W. J. Am. Chem. Soc. 1982, 104, 4502. (b) Paquette, LA.; Temansky, R.J.; Balogh, D.W.; Taylor, W.J. J. Am. Chem. Soc. 1983, 105, 5441. (c) Paquette, L.A.; Balogh, D.W.; Temansky, R.J.; Begley, W.J.; Banwell, M.G. J. Org. Chem. 1983, 48, 3282.
8 The reaction using conditions A was carried out by Pete Wilson, a post doctoral student working in the Paquette group.
9 Strictly speaking, 75 is drawn in an enantiomeric relationship to the formal cyclization product of 78b for the purpose of showing its structural relationship to 74 more clearly.
10 (a) Boeckman, R.K., Jr.; Blum, D.M.; Ganem, B.-T.; Halvey, N. Org. Synth. 1978, 58, 152. (b) Grobel, B.-T.; Seebach, D. Angew. Chem., Int. Ed.
74 Engl. 1974, 13, 83. (c) Zweifel, G.; Lewis, W. J. Org. Chem. 1978, 43, 2739. (d) The Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A., Ed. John Wiley & Sons, New York, 1995, Vol. 7, 5322.
11 Kraus, J.L. Tetrahedron Lett. 1985, 26, 1867. See also Chapter 1, ref lOd.
12 Mitchell, G.H.; Sondheimer, F. J. Am. Chem. Soc. 1969, 91, 7520.
13 (a) Moore, H.W.; Yerxa, B.R. Chemtracts: Org. Chem. 1992, 5, 273. See also Chapter 1, ref 9c.
14 (a) Cook, F.L.; Caruso, T.C.; Byrne, M.P.; Bowers, C.W.; Speck, D.H.; Liotta, C.L. Tetrahedron Lett. 1974, 4029. (b) Gokel, G.W. Crown Ethers and Cryptands, The Royal Society of Chemistry, Cambridge, 1991. (c) Gokel, G.W.; Durst, H.D. Synthesis 1976, 168.
13 (a) Birchler, A.G.; Liu, F.; Liebeskind, L.A. J. Org. Chem. 1994, 59, 7737. (b) Edwards, J.P.; Krysan, D.J.; Liebeskind, L.A. J. Org. Chem. 1993, 58, 3942. (c) Danheiser, R.L. Org. Synth. 1990, 68, 32. (d) Zhao, D-C.; Tidwell, T.T. J. Am. Chem. Soc. 1992, 114, 10980.
16 The experimental and spectroscopic data for this reaction can be found in Joanna Negri's notebook, ll-JN-194.
17 (a) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Org. Chem. 1988, 53, 2482. (b) Liebeskind, L.S.; Wang, J. Tetrahedron Lett. 1990, 31 4293.
18 Liebeskind, L.S. Tetrahedron 1969, 45, 3053.
13 (a) Schmidt, A.H.; Kircher, G.; Maus, S.; Bach, H. J. Org. Chem. 1996, 61, 2085. (b) Maahs, G.; Hegenberg, P. Angew. Chem., int. Ed. Engl. 1966, 5, 888. (c) DeSelms, R.C.; Fox, C.J.; Riordan, R.C. Tetrahedron Lett. 1970, 781. (d) Green, B.R.; Neuse, E.W. Synfries/s 1974, 46. (e) Neuse, E.W.; Green, B. J. Org. Chem. 1974, 39, 1585.
75 CHAPTER 4
REACTION EFFICIENCY: A FUNCTION OF SUBSTITUENT
CONTROL
A. Introduction
In order to evaluate the Impact of the various substituents examined In
Chapter 3, It Is necessary to consider each of the sequential reactions which make up the tandem process. Minor revisions to either the electrophlllc component or the carbanlonic coupling partners can potentially Influence the outcome of one or several of the various steps. Initially, two sequential nucleophlllc additions must occur to form the the doubly charged cyclobutene dioxolate. A subsequent concerted bond reorganization transpires. As the stereodlstal Intermediate predominates, the eiectrocyclic pathway Is of primary consideration. Perlcycllc ring opening of the highly strained Intermediate necessarily occurs at a relatively low temperature. While this particular reaction has extensive literature documentation,i It generally occurs at temperatures well above those observed In the present context. Anionic acceleration may be crucial. Additionally, lithium chelation effects may Influence reactivity. The second eiectrocyclic event Is one that Is known to have a relatively low energy of activation,^ but the equilibrium
76 position can vary significantly between the carbocyciic and open forms in direct relationship to the resident functionality. A major part of this chapter deals with the impact of nucleophilic substitution on this reaction. Direct observation of the acyclic octatetraene has provided the means for examination of this phase of the rearangement in greater detail. The remaining components which complete the overall sequence are the protonation and transannular aldol ring closure. While it has been documented that protonation necessarily occurs prior to the eiectrocyclic event in certain cases, the altemate scenario has also been observed. Whatever the nature of these two final events, they apparently occur with great facility regardless of the resident functionality. Therefore, once arrival at the cyclooctatriene dienolate
(dienol) has been achieved, the final conversion is uneventful.
The substance of this chapter is devoted to a consideration of the interdependency of functionalization and efficiency for three phases of the rearrangement process, initial nucleophilic coupling and the pair of eiectrocyclic events. Relevant reference to Cope chemistry will be included to a limited extent. Reference to the variety of by-products which have been isolated and characterized throughout this investigation will be made. This information was crucial to the analysis of structure-reactivity relationships.
B. Nucleophilic Addition
First-stage addition to the electrophilic cyclobutenedione always occurs with great facility. The singular consideration at this point is whether complete mono addition is accomplished before second stage addition is initiated in cases where different nucleophiles are involved. In most instances, there is
77 only minor competition, and as a result, the doubly electrophilic squarate is generally added to a solution of the first nucleophile. In cases where second- stage addition at -78 °C was competitive (see aliéné chemistry. Chapter 6), recourse was made to reversing the stepwise sequence.
Problems associated with nucleophilic addition of the second component were more conspicuous. In some cases, only monoaddition could be accomplished. Isolation of the monoadduct, if stable, or a rearranged product was predictive. The poor yield associated with the weaker a-styrenyl anion (Scheme 3.5) is believed to result from difficulty with second-stage coupling. Additionally, it was found that for the reaction shown in Scheme 3.10, reversing the order of addition such that the weaker a-silyl anion was added last reduced the overall yield by more than 50%, an expected consequence of inefficient second stage addition. In certain cases, competition between second-stage addition and eiectrocyclic ring opening was observed. This phenomenon was subject to temperature control (Scheme 4.1).
1. 0/-Pr 10 + 3
70 96 123 ( 1) 5% 20% 26% (2) 20% 0% 23%
Scheme 4.1. Reaction of diisopropyl squarate with cyclopentenyllithium followed by frans-propenyllithium. After the second addition, the reaction mixture was maintained at room temperature (1) or 0 °C (2) for at least 3 1/2 h. Reaction conditions A were used. •
78 Quinone 96, a product derived from rearrangement/oxidation of the cyclopentenyl monoadduct, is produced concurrent with the desired 70 as a result of competition between 4n electrocyclization and second-stage coupling. Maintaining the temperature at -20 °C to 0 °C for a period of 3 1/2 to 16 h following addition promotes the latter. A significant improvement in the production of 70 was seen in Scheme 3.7 when recourse was made to the alternative reaction conditions B. Implications surrounding the formation of 123 will be discussed subsequently. lonophores such as TMEDA and the polyether [12]crown-4 were also used in some cases to enhance second stage addition of weaker nucleophiles. Significant improvement was observed for addition of the acetylides (Chapter 3.E).
0. Eiectrocyclic Ring Opening of the Doubly Charged
Cyclobutene Dioxolate
The efficiency of this event is believed to be associated with functionalization on the electrophile. The effects of a variety of substituents have been demonstrated.^ In the current case, incorporation of groups other than alkoxy on the cyclobutenedione have had a major impact on the efficiency of this step. Schemes 3.14 and 3.15 demonstrate the failure of the eiectrocyclic process when alkyl substituents are used. On the other hand, dianionic oxy-Cope rearrangement apparently operates irrespective of the nature of the electrophilic component. While the stage at which these modifications become involved is not known with certainty, they are believed to reduce the efficiency of the primary eiectrocyclic event. The expected
79 Instability of the dioxolate intermediate has precluded isolation of the cyclobutene bis-adduct. However, the competitive ring expansion observed in the heterocyclic reaction (Scheme 3.15) was indicative of the lessened capability for the initial pericyclic bond construction.
The interrelationship of eiectrocyclic ring opening efficiency with respect to substitution on the cyclobutene has been reported by EguchP
(Scheme 4.2). In this case, it was observed that electrocyclization for X =
OMe occurred at a lower temperature than when X = Cl. For X = NMe 2, no ring opening was observed at any temperature.
AcO
OAc
X = OMe > Cl » NEt2
Scheme 4.2. Eiectrocyclic ring opening followed by [2+2] cycloaddition.
Valence isomerization of the cyclobutene in the current context occurs well below the typical temperatures required for this concerted process in other systems. This is quite possibly due to anionic acceleration."^ Electron push and resonance energy of the enolate anion, which are suggested as being responsible for anionic promotion of the oxy-Cope reaction, may factor into the current situation. The interplay between this hypothetical effect and the electronic nature of the cyclobutene functionality is not understood.
80 Electron donation modulated by the enol ether may help to provide the "push-pull" necessary to carry out bond construction (Scheme 4.3, path a). Conversely, the inductive effect of oxygen may provide stabilization for the incipient anion (Scheme 4.3, path b). Lithium chelation may enhance the inductive effect of the alkoxy substituent.
0 " O' RO. RO RO, C £ RO RO RO RO' 0 - 1 0 "
Scheme 4.3. Alkoxy activated bond cleavage.
Alternatively, chelation of lithium ions to the hetero atoms may also raise the energy content of the cyclobutene and facilitate bond cleavage
(Scheme 4.4).
RO
Li
Scheme 4.4. Pericyclic consequences of lithium chelation.
81 Substitution of alkoxy by aikyne compromises the efficiency to some
extent due to competing processes, but pericyclic chemistry is still operative
(Scheme 3.17). The diphenyl derivative 121 is apparently easily coerced into valence isomerization to the open form with respect to the dialkyl
derivative.5 Surprisingly, attempts to carry out the cascade rearrangement
on this system with mixed nucleophiles provided no quinane products,
possibly a result of competition between electrocyclization and second-
stage addition.
D. 8n Electrocyclization of the Octatetraene
Efficiency of the second concerted event has been found to be strongly interdependent on functionality resident on the nucleophilic component. In this case, direct observation of a derivative of the acyclic intermediate was possible.® Trienedione 123 (Scheme 4.1), a product of air oxidation of the acyclic intermediate, has been isolated and characterized. While the stereochemistry of the intemal double bond was not rigorously determined, this information is of no consequence. In situations where the acyclic octatetraene dienolate was apparently highly favored at equilibrium, protonation provided a diol which was found to be prone to rapid air oxidation. Herein lies the significance of the altemate reaction conditions.
In reactions where electrocyclization of the dianionic species was slow or non-existant at room temperature, significant recouping of efficiency could be attained by quenching the reaction mixture with an aqueous solution of
NH4 CI under strictly anaerobic conditions and allowing extended time for
82 electrocyclization of the putative dienol. In many cases, this process
apparently occurred more readily in the neutral form.^ For example, careful monitoring of the reaction in Scheme 3.9 by TLC demonstrated that while no electrocyclization of the acyclic dienolate could be detected after 16 hours at room temperature, the appearance of 74 to 77 was followed to completion over the course of 8 hours following aqueous quench (argon atmosphere).
The ability to observe the acyclic octatetraene intermediates, and the apparent disparity of efficiency of this step allowed the qualitative correlation of substituent effects for this process. The interconversion of c/s,c/s-1,3,5,7- octatetraene and c/s,c/s,c/s-1,3,5-cyclooctatriene is a conrotatory process which occurs rapidly at room temperature, having a measured activation energy of 17.0 kcal/mol.® By comparison, the corresponding interconversion of c/s-1,3,5-hexatriene and c/s,c/s-1,3-cyclohexadiene has an activation energy of 29.9 kcal/mol and an activation entropy of -5 eu.® The transition structure for the tetraene has helical geometry, which has been suggested by Schleyer as having Mobius aromatic character based on geometrical, energetic and magnetic criteria.R elative stabilities of the open and closed form in these reactions are often quite similar and, depending on substituents and reaction conditions, equilibrium constants can be quite variable. For the current case, it was observed that substituents at both the a- and p-positions of the vinyl anion have direct relevance to the overall efficiency of S/c electrocyclization.
83 >=<:
Figure 4.1. a- and ^-positions of the vinyl anion.
For the a-position, substituents larger than H promote a favorable outcome (compare 56 and 57, Scheme 3.1 as well as Schemes 3.2 and
3.4). It was observed that 57 was formed twice as efficiently as 56, presumably due to the presence of the a-methyl substituent on the vinyl anion. While no apparent product of electrocyclization is observed in Scheme 3.4, utilization of the a-methyl homologue of the nucleophilic reactant leads to a 73% yield of 60a (Scheme 3.2). Cases where only one of the nucleophiles was without the a- substituent were intermediate. Conditions A generally gave very low yields of the quinane product resulting from electrocyclization/aldol chemistry.
However, efficiency was recaptured by making recourse to the diol via the altemate conditions (compare Schemes 3.7, 3.8, and 4.1).
These observations can be rationalized by consideration of the transition state conformation necessary for electrocyclization (Figure 4.2). As X gets larger, the population of the helical conformer F' should be enhanced, a potential entropie contribution to the rate of reaction. Additional conformational control is also expected to result from lithium chelation to the acyclic dioxolate or diol seen in Scheme 4.4.
84 /-Pro. OPr- / /-Pro OPr- /
T X=CH 3
H H HH F"
Figure 4.2. Effect of a-substituents on 8 jc helical conformations.
A similar observation has been made for the related case of hexatriene-cyclohexadiene isomerizations.i^ These electrocyclizations progress through a boat-like transition state in a disrotatory fashion. Alkyl and vinyl substitution at the 3-position of hexatriene have been found to lower the activation energy for this process by 3-5 kcal/mol. An enhancement of the s-cis conformation by substituents at this position has been suggested by Spangler as one of the reasons for rate enhancement. Substituent effects at the p-position are also significant. Scheme 4.5 compares reactions in Schemes 3.1, 3.2 and 3.3. It can be seen that for 2- propenyllithium with no p-substituent, a 92% overall yield of product expected to originate primarily from the eiectrocyclic sequence is isolated.
While the homologous c/s-1-butenyllithium still provides 73% of an electrocyclic-derived product, reaction efficiency drops precipitously when the trans isomer is used.
85 jj 0 , CH3 i-PrO^ CH 3 Li CH 3 f-PrO —<\ 10 4.
/-PrO OH CH 3 0 OH CH3 57 (90%) 58 (2.5%)
H3 C CHs Q, Ç H 3C H 3
10 CH3 ^ /-PrO — CH3
/-Pro OH CH3 /-Pro OH CH3 60a (73%) 61 (4%)
H3 C /-PrO CH 3 .CH 3 L i^ ^ C H g /-PrO—^^ ^ ^ ^ C H 3 + 60a + 61 10 0 OH CH3 (3%) (1.5%) 63 (3.5%)
Scheme 4.5. p-effect for Bn electrocyclization.
Again, consideration of the helical transition state conformation is informative (Figure 4.3). The degree of steric constraint is expected to increase in going from 124 to 125 to 126, accompanied by a significant increase in activation energy. As before, however, utilization of the altered reaction conditions can overcome the constraints brought on by the presence of a single cis substituent (Scheme 3.9).
86 OPr-/ OPr-/ OPr- /
H 3C" Yxsz>Vr CH 3
H H CH3 CH 3 124 125 126
Figure 4.3. Steric constraints of terminal cis methyl substituents.
The classical studies by H u i s g e n ^ z on the conrotatory electrocyclization of three isomeric decatetraenes corroborate these observations (Figure 4.4). Activation enthalpies and entropies for the valence isomerization of 127,128, and 129 to the related eight-membered carbocycle were measured. It was observed that as terminal methyl substituents changed from trans to cis, the activation energy increased by
2.7 (127->128) and 4.0 (128->129) kcal/mol.
^ ^ C H 3
/CH 3
CH 3 CH3 H 127 128 129
a H kcal/mol 15.1 17.8 2 1 . 8 A S * Clausius -19 -17 - 1 2
Figure 4.4. Activation parameters for electrocyclization of isomeric decatetraenes.
87 It is also noteworthy that the presence of cis substituents on the vinyl anions significantly raises the activation energy for the Cope rearrangement through the boat transition state as was shown in Table 2.1. This may be the reason for the loss of efficiency for the minor boat product 63.
Finally, the promotional effects of protonation of the dienolate on the conrotatory electrocyclization warrants discussion. 8 k electrocyclization is an equilibrium process. While the cyclic form is often favored, slight alterations in functionality can cause the acyclic form to predominate at equilibrium. While the the relative stabilities of acyclic and cyclic tautomers for the anionic and neutral species is not obvious, a poor equilibrium can certainly be compensated by the ability of the neutral form to progress forward to the transannular aldol reaction. Additionally, a short-lived cyclooctatriene intermediate may allow electrocyclization to occur through the other possible conformation in which the terminal cis methyl groups no
longer overlap with the tetraene. While this produces a highly strained trans,cis,trans dienolate in the anionic form, rapid tautomerization to the more stable all-cis arrangement 131b is an option for the neutral species
(Scheme 4.6).
HO. CHs HO CH;
CH 3 /-Pro \ ---- HO CHs
Scheme 4.6. Altemate conformation for 8 k electrocyclization.
88 Whatever the nature of this effect, an obvious question to be considered was whether or not any degree of electrocyclization occurred in the anionic form. For cases which were efficient using conditions A, did the observed products come about exclusively as a consequence of rapid electrocyclic/aldol following aqueous quench? In order to investigate this possibility, methyl iodide was added to the reaction of 2-lithiopropene and diisopropyl squarate following storage of the dianionic intermediate at room temperature for a period of 4 hours. (Scheme 4.7).
0-? /•-PrO^\^=<ÇH: 59. + 0-alkylated
54b OH CH, HsC ^ or Mel 132 (36%) 10 (> 2 equiv) THF
/•-Pro " A
Scheme 4.7. Quench of cyclic or acyclic intermediate with methyl iodide.
Reaction of the hypothetical intermediate (54b or 124) with methyl iodide led to a 36% yield of 132 along with varying amounts of 59 and O- alkylated products. Diketone 133 was not observed. Diquinane 59 is
89 believed to arise from incomplete reaction with methyl iodide. However, its isolation, along with the lack of a total mass balance, does not preclude the presence of the acyclic form 124 immediately prior to quench. Nevertheless, the isolation of 132 confirms that a significant degree of electrocyclization can occur with the dianionic intermediate in cases where the nucleophilic components are ideally substituted.
In conclusion, a variety of substituent effects for both the electrophilic and nucleophilic components of the electrocyclic2/aldol reaction have been identified. An investigation of these effects has provided an understanding of the synthetic potential for this chemistry, and has also advanced prevailing wisdom for the pericyclic processes of which the squarate rearrangement is composed.
90 LIST OF REFERENCES
1 Review on cyclobutene ring opening reactions: (a) Durst, T.; Breau, L. in Comprehensive Organic Synthesis’, Trost, B.M.; Fleming, I., Eds.; Pergamon Press, Oxford, 1991, Vol. 5, Chapter 6.1. (b) Marvell, E.N. Thermal Eiectrocyclic Reactions, Academic Press, New York, 1980, 124. (c) See also Chapter 1, ref. 9; Chapter 2, ref. 16, 17.
2 See Chapter 2, refs 19 to 22.
3 Yamomoto, Y.; Ohno, M.; Eguchi, S. Tetrahedron 1994, 50, 7783.
4 While eiectrocyclic ring opening of cyclobutenes has been thououghly studied, the anionic version has limited literature precedent. See: (a) Organic Reactions, John Wiley & Sons, New York, 1993, Chapter 2, 143. (b) Kametani, T.; Tsubuki, M.; Nemoto, H.; Suzuki, K.J. Am. Chem. Soc. 1981, 103, 1256. (c) Thies, R.W.; Shih, H-H.J. J. Org. Chem. 1977, 42, 280.
5 (a) Battiste, M.A.; Bums, M.E. Tetrahedron Lett. 1966, 523. (b) See Chapter 2, ref 5.
6 A recent example using reaction of two equiv of an alkyllithium with dialkyl squarates for the synthesis of acyclic 1,4-diketones: Varea, T.; Grancha, A.; Asensio, G. Tetrahedron, 1995, 45, 12373.
7 See for example Schemes 3.7, 3.8, and 3.9, Figure 3.1, and Table 3.1, Expt. no. 8.
8 Goldfarb, T.D.; Landquist, L.J. J. Am. Chem. Soc. 1967, 89, 4588.
9 Lewis, K.E.; Steiner, H. J. Chem. Soc. 1964, 3080.
10 Houk, K.N.; Li, Y.; Evanseck, J.D. Angew. 3.4 682.
11 Jiao, H.; Schleyer, P. v. R. J. Chem. Soc. Perkin Trans II 1994, 407.
12 See Chapter 2 ref 19.
91 13 (a) Evanseck, J.D.; Thomas, B.E., IV; Spellmeyer, D.C.; Houk, K.N. J. Org. Chem. 1995, 60, 7134, and relevant references cited therein, (b) Spangler, C.W.; Jondahl, T.P.; Spangler, B. J. Org. Chem. 1973, 38, 2478.
92 CHAPTER 5
AN ANALYSIS OF REGIO AND STEREOCHEMISTRY FOR THE
ELECTR0CYCLIC2 ALDOL REACTION
A. Introduction
Utilization of any newly discovered chemical process in synthesis
requires an understanding of regiochemical control elements as well as the potential for stereoinduction. The development of methods for regulating these variables is crucial. In the current methodology, the formation of five stereogenic centers from achiral reactants demonstrates the rapid installation of molecular complexity which can be achieved. The regiochemistry of the transannular event gives rise to isomeric triquinanes with either a linear or angular framework. Additionally, the consequences of
1,2 vs 1,4 addition impart regiochemical significance to the functionality on the highly oxidized carbocyciic portion of the final product.
Initially, this chapter provides a summary of the events responsible for stereoinduction at each of the chiral centers as well as the regiochemical impact on structural connectivity. Each event is subsequently examined with respect to control factors related to functionalization and reaction conditions.
93 B. The Generation of Regio and Stereochemistry: A Summary
B Ri
0 OH D Ri OH ° Rz OH
G' G"
Figure 5.1. Regio and stereoinduction for the squarate rearrangement: Stereogenic centers (A->OH); regiochemical consequences of 1,2 vs 1,4 second stage addition (G vs G'); and regiochemical consequences of enolate protonation/transannular aldol (G vs G").
The regiochemistry of the enone (G vs G') is introduced during second-stage addition (1,2 vs 1,4). Quinane framework (G vs G") is a function of the regiochemistry of protonation/transannular aldol. For non- symmetrical semisquarates, the regiochemistry of Ri and R 2 also results from competitive protonation/aldol condensation. The relative stereochemistry of B and C is set during initial bond reorganization, viz. Cope rearrangement or the eiectrocyclic^ sequence.
The preferred process is of course dependent on the stereochemical approach of the second nucleophile, and ultimately, is a direct consequence of the cis/trans nature of the pair of vinyl anions utilized. For Structure G, the configuration of D with respect to B and 0 emerges during protonation or proton transfer. As the resulting enol(s) are potentially subject to thermodynamic equilibration, the epimeric relationship of D may be a consequence of kinetic protonation or thermodynamic control.
94 Finally, the stereorelationship of A and OH (Structure G) with respect to B, C, and D is established during the aldol reaction. The transannular nature of this event necessitates the cis orientation of A and OH.
C. Control of 1,2 vs 1,4 Second-Stage Addition
While first-stage addition apparently occurs exclusively with 1,2 selectivity, it has been observed that the degree of conjugate addition for the second nucleophile is related to the choice of the metal counterion. Use of lithium reagents typically leads to the 1,2 adduct when the squarate ester is employed (see for example Schemes 3.1, 3.2, 3.6, and 3.7), while the
Grignard reagents prefer a 1,4 approach in the second step (Scheme 3.11).
While it has been reported that the size of the ester function may regulate this event to a degree,^ we have not studied this element of control. "Softer" anions also tend to have some degree of selectivity for conjugate addition. The a-styryl anion (Scheme 3.5) gave exclusively a product of 1,4 addition, while the anion of dihydrofuran (Scheme 2.12) as well as lithium phenylacetylide (Scheme 3.13) gave varying degrees of 1,4 products. The provision for regiochemical control alloted by the 1,4 alternative brings significance to the development of methods for accommodating this option. While cuprate chemistry is an obvious choice, this latent potential has not yet been developed. Apparently, functionality resident on the cyclobutenedione also controls the regiochemistry of addition (Schemes 3.18 and 3.20). This is most likely an electronic effect affording enhanced electrophilic character to the conjugate site.
95 D. The Regiochemistry of Protonation
Assembly of the molecular framework Is guided by the regiochemistry
of protonation of an unsymmetrical dienolate. This event is thereby directly
responsible for the connectivity observed in the final products. While it is not
known with certainty the degree of interplay between kinetic protonation and
thermodynamic equilibration of the resulting carbonyl components, a
number of control elements have been identified.
Initially, the unsymmetrical intermediates provided by the mixed addition of heterocyclic and carbocyclic nucleophiles were examined
(Figure 5.2). Molecular mechanics calculations involving closely related analogs provided some insight into whether or not the regiochemistry of protonation conformed to the thermodynamic bias of the system.
96 HO MeO MeO
MeO MeO
H HH A Egtnain 45.985 26.972 AH( -135.799 -160.409 AEjotal 59.17 40.16 HO
MeO MeO
MeO MeO
AEstrain 50.438 30.356 AH, -131.899 -174.468 AEjotal 61.87 41.79 HO
MeO MeO
MeO MeO
J JJ ^Strain 43.534 AH, -137.929 -160.420 AETotal 56.72 39.44
MeO MeO
MeO MeO
K KK ^^Strain 45.800 28.692 AH, -136.240 -176.100 AETotal 57.23 40.12
Figure 5.2, Global minimum energy conformations of protonated trans- and cis-fused 1,3,5-cyclooctatriene dienolates from 1,2 addition as determined by molecular mechanics calculations (Chem 3-D output). All energies are in units of kcal/mol.
97 Figure 5.2 examines the protonation of dienolate intermediates
leading to 31,3 2, and 33. In Scheme 2.7, it can be seen that the ratio of products resulting from protonation on the heterocyclic enolate/carbocyclic enolate for 31 and 32 is 1:1.33. The data in Figure 5.2 reveal a close correlation between the neutral and oxido species, both of which are biased in favor of protonation on the heterocyclic enolate, in direct contrast to the observed ratios. Likewise, quinane 3 3, resulting from exclusive protonation on the carbocyclic site, exists in opposition to the predicted thermodynamic bias for J,JJ.
Therefore for this sequence of reactions, it is possible that kinetic factors outweigh the influence of thermodynamic effects. Alternatively, assuming equilibration is faster than the rate of aldolization, the relative proportion of products observed may reflect the differing activation energies for the two processes, which is not necessarily consistent with the position of equilibrium for the separate regioisomeric intermediates, a situation similar to what has been postulated by the Curtin-Hammett Principle.^ In situations where the degree of substitution at the two enolate sites varies, nearly exclusive protonation at the less highly substituted enolate is observed (Schemes 3.7 and 3.8). Molecular mechanics calculations for the pre-aldol regioisomers for the reaction in Scheme 3.8 show that this preference for the less sterically congested site conforms with thermodynamic prediction (Figure 5.3).
98 MeO OH M e O ^
H O ^ M Restrain 22.96 21.51 -130.78 -121.58
AExotal 31.18 29.31
Figure 5.3. Global minimum energy conformations of protonated 1,3,5- cyclooctatriene dienolates from mixed addition of vinyllithium and cyclopentenyllithium as determined by molecular mechanics calculations (Chem 3-D output). All energies are in units of kcal/mol.
An obvious ploy for fostering regioselective protonation would be to increase the latent energy content and reactivity of one enolate center significantly over the other. The potential for achieving reliable regioselectivity in this manner was realized by incorporation of an acetylide anion in place of one of the vinyls. As can be seen in Scheme 3.12, protonation of the highly energized cumulenic enolate occurs to the complete exclusion of the alternate site, thereby providing a single isomer. Consideration of the examples in Table 3.1 demonstrates the consistency of this method for regioselective protonation.
An altemative means for controlling this element of regiochemistry was realized by the use of 1-lithio(trimethylsilyl)ethylene as a first-stage reactant. The electronic disparity in the unsymmetrical enolate (Scheme
3.10) leads to exclusive protonation at the silicon substituted site. Use of this method for the natural product work will be detailed in Chapter 7. An obvious extension can be found in the corresponding (phenyldimethylsilyl)-
99 ethylene anion.3 Introduction of this functionality provides a means for site- directed oxidation at this position via Fleming methodology/
Use of the 1,4 addition mode offers another method for attaining selectivity. As can be seen in Scheme 3.11, reversal of the tendency for protonation of the less highly substituted enolate can be realized when the alkenyl anion used to generate that enolate site is introduced at the conjugate position. Figure 5.4 shows the two potential monoprotonated enolates (a-protonation only). Obviously, only 134 is capable of subsequent vinylogous aldolization.
/ - P r O - \ / / i- P r O ^ \ _ y
134 135
Figure 5.4. Monoprotonated intermediates from 1,2 addition of 2- lithiopropene and 1,4 addition of vinylmagnesium bromide to diisopropyl squarate.
Temperature may also have some regiochemical consequences with respect to protonation. This was suggested as a possible reason for the variable results observed for protonation of dienolate 69 in Scheme 3.7. In this case, quenching at room temperature gave selective protonation leading to 72, while introduction of the aqueous NH 4CI at 0 °C resulted in the appearance of 71 in a 1 :2 ratio with 72. The effects of temperature on regioselective protonation are more pronounced in the allene-derived intermediates described in Chapter 6 .
100 Finally, some companion chemistry involving generation of the pre- aldol intermediate via p-elimination has been described (Scheme 5.1 ).s This
procedure provides another method for controlling regioselectivity of the transannular aldol.
OCH3
/■-Pro 0 /-PrO.^ / = f // /-Pro 0 /-Pro 2 . Li CH-
'-Pro OH
/-Pro
0 CH3
Scheme 5.1. Regiocontrol of aldolization via p-elimination.
E. Stereochemical Relationship at the Bond-Forming Centers
The steric relationship of functionality at the bond forming centers is a direct consequence of the direction of approach of the second nucleophile
which initiates the subsequent pericyclic event. As a result, the cis/trans nature of the nucleophilic reaction partners bears ultimate responsibility for the observed spatial relationship at these centers (B and C; Figure 5.1). In general, nearly exclusive trans addition is observed, setting the stage for the
101 pair of eiectrocyclic events. However in some cases, a significant degree of cis addition can complicate the process. Most notable has been the tendency for cyclopentenyllithium to approach from a stereoproximal position. When this situation occurs, it is often beneficial to simply reverse the order of addition so that the nucleophile which is not predisposed to syn attack is added second (Scheme 3.7 and the aliénés. Chapter 6).
F. Stereochemical Consequences of Protonation and
Transannular Aldol Reaction
Section D dealt with the regioselectivity of protonation. In this section the stereochemical consequences of protonation are examined. Two basic situations will be discussed. The first involves intermediates in which both p- positions are unsubstituted as in Scheme 3.1. In these cases, the stereochemistry of position D (Figure 5.1) must necessarily rest entirely on the diastereoselectivity of the aldol reaction, as the dienolate intermediate prior to protonation is achiral. The second type of situation to be examined involves intermediates in which protonation generates a pair of diastereomers. In this case, the relative contributions of kinetics and thermodynamics with respect to both protonation and aldolization become relevant. An investigation of the two boat-shaped pre-aldol conformations for the minimally substituted cases N (Figure 5.5) reveals that steric interaction between the R groups may be responsible for the favoritism shown for N' as the apparently preferred transition-state conformation.
102 /-Pro m
N'
Figure 5.5. Pre-aldol conformers for minimally substituted intermediates.
As the level of substitution increases, the situation becomes more complex. The chiral, racemic cyclooctatriene dienolate can be protonated from either of two faces, generating a pair of diastereomers. Selectivity for this step, as well as the subsequent aldolization, may be a consequence of thermodynamic equilibration or each event may be kinetically controlled. This is further complicated by the degree of elecytrocyclization which takes place after protonation. For the mixed additions of hetero and carbocyclic anions (Schemes 2.7 and 2.8), molecular mechanics calculations again provided information concerning relative stabilities of the protonated intermediates (Figures 5.6 and 5.7).
103 HO MeO
MeO 0 0 H HH ^^Strain 45.985 26.972 AHf -135.799 -160.409 AETotal 59.17 40.16 o “ ^ M e O ^ y ^ M e 0 ^ y = \i
MeO MeO O H 0 OHO 0
^^Strain 46.956 26.991 AHf -135.477 -158.370 AETotal 60.15 40.18 O" 0 HO Me0..^y=^ MeO
MeO MeO
I II ^^Strain 50.438 30.356 AHf -131.899 -174.468 ^ E jo ta l 61.87 41.79 HO M e O ^ y ^ MeO
MeO MeO O H PP AEgiran 47.374 27.688 AHf 135.439 -174.946 AETotal 58.80 39.12
Figure 5.6. Global minimum energy conformations of trans-fused protonated 1,3,5-cyclooctatriene dienolates resulting from 1,2 addition as determined by molecular mechanics calculations (Chem 3-D output). All energies are in units of kcal/mol.
104 HO MeO
MeO O H QQ 49.794 29.015 -132.682 -174.734 61.22 40.45 HO MeO
MeO 0 ^ K KK
AEstrain 45.800 28.692 AHf -136.240 -176.100 AEjotal 57.23 40.12 MeO O- MeO MeO
HO
RR 60.634 29.949 -118.675 -174.697 AExotal 72.06 41.38 MeO O- MeO MeO
HO O H ss AEstrain 58.114 29.710 AHf -120.903 -174.896 AEjotal 69.54 41.14
Figure 5.7. Global minimum energy conformations of cis- and trans-fused protonated 1,3,5-cyclooctatriene dienolates resulting from 1,2 and 1,4 addition as determined by molecular mechanics calculations (Chem 3-D output). All energies are in units of kcal/mol.
105 From these data, it can be seen that, irrespective of whether the
medium-ring fusion is trans or cis, and whether the intermediate dienolate
results from 1,2 or 1,4 addition, trans proton delivery leads to a more stable
product with but one exception (H, HH). What is generally observed,
however, is that for conformationally-locked intermediates, when the stereochemistry at the bond-forming centers is trans, proton delivery occurs cis to the adjacent position providing a cis-fused quinane ring. On the other
hand, when the medium-ring fusion is cis, protonation generally occurs from the opposite side. Inspection of the trienediolate reveals that when this intermediate can attain a stable boat conformation, protonation occurs from inside the most stable boat as was seen in Figure 5.5 for N’. The most stable boat will be the one in which transannular steric interactions for T are minimized (T", Figure 5.8).
/-Pro ^ L /-Pro
Figure 5.8. Transannular steric interaction for the boat conformation.
Conversely, if the intermediate is protonated from the eiectrocyclic conformation, cis proton delivery is favored. In both cases, subsequent aldolization proceeds via a boat conformation in which the substituent a to
106 the carbonyl is oriented to the outside as seen for N’ (Figure 5.5). The boat conformation presumably positions the reactive centers in greatest proximity.
As an example, both products in Scheme 3.6 can be seen to arise from protonation of the more stable boat-shaped trienediolate from the inside, and subsequent aldolization from the conformations depicted in
Figure 5.9. Enolate 136 leads to 66, and 137 provides 67.6
/-Pro n L
136 137
Figure 5.9. The more stable boat-shaped pre-aldol intermediates for 66 and 67, respectively.
Finally, when the enolate is exocyclic to a fused quinane, the aldol reaction is also necessarily limited to a single conformation. This includes all pre-aldol intermediates leading to angular quinanes. This arrangement places even greater conformational control on the transannular reaction. For reactions in which protonation occurs prior to electrocyclization or those partially cyclized at the time of quench, generation of the pre-aldol intermediate occurs via tautomerization. For these cases, the number of examples is too limited to draw conclusions. However, it can be noted that the single exception to the above discussion involves the formation of 74 and 75 (Scheme 3.9). These diastereomers result from utilization of both conformations for the aldol reaction. For this case, electrocyclization was
107 observed to occur exclusively following treatment of the dienolate with
aqueous NH4CI.
The above discussion is relevant only to intermediates resulting from
second-stage 1,2 addition. When 1,4 addition occurs, protonation and/or
aldolization is generally non-selective. It is possible that enhanced
instability resulting from the proximal relationship of the oxido anions leads
to non-selective kinetic control of these events (see, for example 47,
Scheme 2 .1 2 ).
G. Diastereoselective electrocyclization
The examples described in the preceding sections involve the use of achiral reaction partners. Therefore, all products are necessarily racemic in
nature. If chirality is resident in one of the vinyl anions, it is now possible to
distinguish between the two coils of the helical conformation through which electrocyclization progresses. Scheme 5.2 examines the sequence of events from addition through electrocyclization. Initial non-selective trans addition of the two vinyl anions produces a pair of diastereomers U and V. Eiectrocyclic ring opening of the cyclobutene destroys the chirality introduced in the initial step, converting the pair of diastereomers back into a single enantiomer W (drawn as two opposing helical conformations W and W"). The acyclic octatetraene then undergoes electrocyclization via the less sterically hindered coiled transition state conformation W , generating dienolate X. The relative stereochemistry of R with respect to the adjacent chiral centers in the final product is thereby established. Subsequent events are as previously described.
108 ;-PrO /-Pro +
R 10
/-Pro 0-/-Pr RO
RO 0"
w W"
Scheme 5.2. Diastereoselectivity of electrocyclization induced by chirality on the vinyl anion.
An investigation of chiral induction in the electrocyclicz/aldol reaction has been carried out simultaneously to the current work.^ The relevance of diastereoselective electrocyclization will be examined in greater detail in
Chapter 7.
109 LIST OF REFERENCES
1 See Chapter 1, ref 10d.
2 Curtin, D.Y.; Rec. Chem. Prog. 1954, 15, 111. (b) Carey, F.A. Sundberg, R.J. Advanced Organic Chemistry, Part A, Plenum Press, New York, 1990, 215.
3 Ryu, I.; Hayama, Y.; Harai, A.; Sonoda, N.; Orita, A.; Ohe, K.; Mural, S. J. Am. Chem. Sac. 1990, 112, 7061.
4 Fleming, I.; Henning, R.; Plaut, H. J. Chem. Sac. Chem. Commun. 1984, 29.
5 Paquette, L.A.; Doyon, J. J. Am. Chem. Soc. 1995, 117, 6799.
6 Enolate 137 Is drawn In an enantiomeric relationship to 67 for purposes of comparison to 136.
7 Paquette, L.A.; Kuo, L.H.; Hamme, A.I. II; Kreuzholz, R.; Doyon, J. Submitted for publication.
110 CHAPTER 6
SQUARATE REARRANGEMENTS OF ALLENE ADDUCTS:
CONTROL OF PERISELECTIVITY FOR THE ELECTRONIC
REORGANIZATION OF 1,2,4,6,8 CUMULENIC PENTAENES.
A. Introduction
The appearance of the aliéné moiety in organic synthesis has become much more apparent over the past few decades, and a variety of synthetic methods for the preparation and use of these unique substrates has been developed/ It was considered that the cumulenic arrangement of the allene nucleophile might extend the utility of the present process, and also provide an interesting variation for the squarate rearrangement. While the use of nucleophilic aliénés is often complicated by their isomerization to the propargyl anion,2 adding yet another degree of complexity to the problem of selectivity, the alkoxyallenes are known to add regioselectively. These versatile building blocks have been used in both chiral and achiral form for natural product synthesis.^ The parent methoxyallene,^ which is easily prepared by isomerization of methylpropargyl ether with potassium fe/t-butoxide, can be metallated by n-butyllithium at -78°C and added to a variety of ketones and aldehydes to produce allenic alcohols.
I l l The addition of aliénas to squarate derivatives has been reported by
Moore for the synthesis of o-qulnone methldes. It was found that this nucleophile adds readily to dimethyl squarate and undergoes conventional, thermally Induced ring expansion via the proposed 4 tc,67c eiectrocyclic sequence (Scheme 6.1).5
OH RO RO OR OR OR OH OH
Scheme 6.1 . Ring expansion of the allene mono-adduct of a squarate derivative.
B. Reaction of Dilsopropyi Squarate with a Combination of
Alkenyl and Allenic Anions
In our hands, the addition to dilsopropyi squarate of an allenic anion, specifically 1-methoxyallenylllthlum, In conjunction with an alkenyl nucleophile has prompted an unexpected diversion from the normal progression of events. Tables 6.1 and 6.2 summarize the results of these experiments. In Table 6.1, the cumulative vinyl ether anion Is the first stage reactant. The order of addition Is reversed for the second series. On Inspection of the data compiled In these summaries. It Is
Immediately obvious that, once again, the order of addition Is critical to the subsequent mode of rearrangement. While products 138,143, and 148 are
112 common to both reaction sequences, the remaining derivatives make their appearance as a direct consequence of the specific second-stage reactant.
Reactant 1 Reactant 2 Products
OhPr 0 QCH3 Li MeO^ 1 ^C=C=CH 2 r Li C H 3 0 V t . . CHg/ f-PrO HO CH3 138(20%) 139(17%)
0 ÇH3
140 (15%)
OhPr 0 ÇH3 CH3 0 ^ ^ _OAPr U _ MeO. OH '■PrO-^J^^CH 3 2 r=C=CH2 CH 3O U' X CM3 / \ ^PrO HO 143 (26% ) 1 4 4 (38%)
Q OCH 3
f-PrO HO CH3
147 ( 8%)
OAPr 0 qCH 3
MeO. CH 3O 3 ^,C=C=CH2 CH3, /-Pro HO
148 (20%) 149 (22%) Table 6.1. Reaction of diisopropyl squarate with methoxyallene and alkenyllithium reagents.
113 Reactant 1 Reactant 2 Products
OhPr
MeO. ,C=C=CH2 4 V / CH30% LI CH3/ 138 (36%)
Of-Pr Of-Pr HO HO OCH OCH 3 CH CH 141 (10%) 142 (15%)
MeO^ 0=C=CH2 U 143 (29%)
OhPr H Or-Pr 0 , 0 HO. HO OCH3 CH3
145 (27%) 146 (14%)
MeO^ ):=C=CH2 Li 148 (34%)
OhPr H. OhPr 0 ^^A ^ O h P r 0 OhPr HO. HO. T ^ 0 CH3 / ) c S CH3 1 50 (34%) Table 6.2. Reaction of dilsopropyi squarate with an alkenyllithium followed by 1-methoxyallenyllithium.
114 Overall yields ranged from 42% for reaction 3 to 74% for the companion reaction 6. Unlike the rearrangements described in Chapter 3, the allene systems tended to undergo significant decomposition in the dianionic form if the temperature of the reaction mixture was allowed to warm above 0 °G. Additionally, maintaining the temperature within the range of -20 °C to 0 °C for an extended length of time reduced the overall yield significantly. For example, while the maximum temperatures reached in reactions 2, 5 and 6 (dianionic intermediate) were -10 °G, -15 °G and -30 °G for periods of 1 to 4 h giving combined product yields of 72%, 70%, and
74%, the higher temperature allowance for reactions 1 and 3 (0 °G to rt; 9-15 h) caused a significant reduction in overall yields (42% and 52%).
Reactions in which the allene was used as the initial anion were also complicated by the fact that some second-stage addition occurred at -78 °G.
Therefore, it was necessary to combine the initial reactants such that the anion was added to a solution of the electrophile at -78 °G, in contrast to the usual conditions. In fact, the entire sequence of events appeared to progress more rapidly and at lower temperatures than had been previously observed for the examples in Ghapters 2 and 3. For reaction 6, following introduction of the second nucleophile, the mixture was stirred at -78 °G (1 h) and -15 °G (2 h) for a total reaction time of only 3 h before quench. Furthermore, during an additional 3 h allotment following quench, TLG revealed no obvious changes. Various spectroscopic methods were employed for structure identification. The typical semi-selective DEPT experiments used to identify connectivity in the previous examples by the generation of and carbon sub-spectra, were a valuable source of information for 138 through 151.
115 Additionally, advantage was taken of the ability to observe weak coupling for allylic systems when pulsing was carried out for an extended time period.
Regiochemical differentiation between 148 and 150 are exemplary.
Irradiation of H-10 (148) for at least 24 h provided a spectrum in which C-3 and C-5 were observed J allylic coupling), as well as C-4, C-9 and two of
C-11, 12 or 13 (2J and 3J coupling). In a similar vein for 150, C-1 (^J), C-6,
C-9, and 2 of 0-11, 12 and 13 {^J and 3J) were noted on irradiation of H-10 for a similar time period (Figure 6.1). The lack of observable polarization transfer to 0-5 (V ) (150) may result from a non-ideal geometric arrangement of the four bond unit in this molecule.
0/-Pr 0/-Pr 0/-Pr
150
C-3 (allylic) C-1 (allylic)
10 10 H H \- C-5 (allylic)
Figure 6.1. Allylic coupling (^J) for cyclohexadienone systems.
The regiochemistry of these adducts was further verified by UV analysis. It was expected that the extended conjugation present in 141,
116 145, and 150 would exhibit ultraviolet absorption at longer wavelength than the cross conjugated 148, and corresponding adducts. Figure 6.2
compares the UV spectrum of 148 with that of 150. It was observed that ^max was indeed shifted to longer wavelength for isomer 150.
Woodward has derived empirical generalizations for the effects of various functionality on these transitions for conjugated enones.®
Using these generalizations, one can calculate the expected Xm^x for the two
systems (Table 6.3)
‘ .* : 5 •• t I I i’ I 148
far J I
V O.OOW4—
0.7297? 4 {
Figure 6.2. UV spectra of 148 and 150.
117 0/-Pr 0/-Pr 0 ^ ^ ^ 0 /-Pr O ^ J ^ O i - P r 6-membered, cyclic, a,p- h o T J unsaturated R - / ^ r OCH3 ketone H3C R R > CH3 R
base value (nm) 215 215
a-polar group (OR) 35 35 p-polar group 30 30 Y-polar group 17
p-ring residue 12 5-ring residue 18 (2X) homocyclic diene 39 Double bond 30 extending conluqation Total (calc, nm) 292 402
Observed (nm) 320 (138) 354 (141 ) 320 (143) 352 (145) 318 (148) 350 (150)
Table 6.3. Calculated and observed values for kmax using Woodward's rules.
It can be seen that these highly functionalized systems do not correlate quantitatively with what would be expected from theory. However, each system has provided consistent absorption data showing the expected shift to higher wavelength as a consequence of extended conjugation.
118 c. Mechanistic Rationalization
As before, an explanation for the results observed during the series of mixed additions with methoxyallene relies on the premise that reaction channels leading to the various substrates are established as a direct consequence of regio- and stereo-differentiation during second-stage addition. Again, recourse is made to the argument of cis addition, dianionic oxy-Cope rearrangement vs trans addition, eiectrocyclic^ ring expansion.
This time, however, electronic reorganization via electrocyclization chemistry progresses through a disrotatory 6 tz periselection rather than the conventional 8 k altemative.
Scheme 6.2 shows the proposed mechanism for the formation of
138,139, and 140. It is rationalized that when 1 -lithiomethoxyallene is added in advance of the alkenyllithium anion, both stereoproximal and stereodistal adducts result from a non-selective approach of the second nucleophile. For the stereoproximal adducts, rapid dianionic oxy-Cope rearrangement ensues, delivering quinane products such as 139 and 140. For those intermediates having undergone trans addition, 4tc eiectrocyclic ring opening transpires, producing the acyclic 1,2,4,6,8 pentaene. For the cumulenic pentaene, activation energy for 6tc valence isomerization is apparently suppressed with respect to the 6 k option, as the former is the exclusive reaction channel, leading to the formation of cross-conjugated cyclohexadienone 138. For these reactions, the vinyl anion is observed to undergo regioselective addition to the carbonyl carbon. No products resulting from conjugate addition were observed.
119 /-Pro MeO
-f-
OCH 3 OCH3
oxy-Cope 4ti
0 /-Pro /-Pro
/-Pro /-Pro 3 OCH 3
,+
/-Pro OH CH 3 /-Pro /-Pro /-Pro ^
/-Pro 0 OCH 3 OCH 3
,+
OH /-Pro /-Pro
/-PrO OH OCH 3 /-PrO OCH 3
140 138
Scheme 6.2. Eiectrocyclic and oxy-Cope pathways for cis and trans bis- adducts in the allene series.
Unexpectedly, the degree of cis addition is much greater when the lithioalkene is exposed to an allene-substituted mono-adduct. Whether this
120 results from steric or electronic factors is not known. However, the extent of involvement of the oxy-Cope rearrangement is thereby enhanced. Allenic oxy-Cope rearrangements have been reported in the literature.^ Recently, Rajagopalan has described the anionic version.8 It was reported that substitution of vinyl functionality by an allene apparently enhances the reactivity of these systems toward the [3,3] sigmatropic process, a result which is suggestive of potential weakening of the k bond due to the strain of the cumulated diene. In the current examples, the oxy-Cope rearrangement is apparently rapid and progresses efficiently at relatively low temperatures. The single concem to be addressed involves the regioselectivity of protonation of the intermediate dienolate. In the simplest case (Scheme 6.2), the near equal distribution of 139 and 140 results from an apparent inability to differentiate the relative stabilities of the two enolate sites under the reaction conditions. The added degree of strain afforded by the exocyclic double bond may be responsible for a more rapid processing of the final sequence of events, leading to a lack of selectivity. In reaction 2 (Table 6.1), nearly complete selectivity for protonation of the allenic enolate (y position) is observed, while the intermediate of reaction
3 experiences protonation exclusively at the vinylic site. The temperature at which quench was carried out may bear some responsibility for the observed results. The non-selective case (reaction 1 ) was quenched at 0 °C, while the intermediate for reaction 2 was quenched at -10 °C, and water was introduced to reaction 3 at rt. One attempt to investigate the results of protonation at -78 °C was foiled by the appearance of a complex mixture of products which could not be separated by conventional means.
121 /-Pro 1 . " r i- P r O ^ /-Pro 10 2. MeO. 0/-Pr ..C=C=CH2 Li OCH3
OH /-Pro
/■-Pro OCH 3 /•-Pro
138
OCH 3 H'^ 0/-Pr
H3O+
/-Pro OCH 3
Scheme 6.3. Mechanism for formation of 141 and 142 and associated products.
The suggested route for preparation of the cyclohexadiene isomers 141 and 142 is shown in Scheme 6.3. It is expected that formation of these substrates in conjunction with 138 to the complete exclusion of the quinane products 139 and 140 would be a consequence of stereoselective trans
122 addition of the allenic anion, setting the stage for the electrocyclic sequence, which progresses exclusively through the disrotatory process. Both 1,2 and
1,4 addition are accommodated by the electrophile, and the stablized enol ether carbanion is found to exercise the 1,4 option to a significant extent when added as the second stage reactant. The isomeric 141 and 142 resulting from the conjugate addition mode were isolated as an inseparable mixture. Compound 142 and associated derivatives could, however, be converted into their conjugated regio isomers by treatment with triethylamine. Structural identification of these products was derived in part by their ability to undergo this isomerization. In order to distinguish between these adducts and related structures resulting from protonation of the extended enolate at the y position
(152, Figure 6.3), recourse was again made to semi-selective DEPT studies at 300 MHz. While an upfield shift of the isopropoxy methine heptet (146, H- 14) to 3.70 ppm was indicative of its attachment to a saturated ring position, additional verification was acquired by selective irradiation of this proton and observation of its coupling to 0-2. Coupling between H-2 and C-1 was also noted in a separate experiment.
H 0/-Pr G/-Pr 0/-Pr HO OCH 3 OCH 3
152
Figure 6.3. Potential regioisomers resulting from protonation of an extended enolate at the two non-terminal positions.
123 The relative proportion of 141 to 142 was also influenced to a
degree by the temperature of the reaction mixture at the time of quench. While a 2:3 ratio was observed at 0 °C, quenching at -40 °C resulted in an
even greater preference for the kinetic product 142, which under these
conditions was present to an extent of 75 % of the isomeric mixture.
D. A Contribution by the "Ailene Effect" to the Periselection for
Pentaene Eiectrocyclization
The unexpected results for pericyclic bond reorganization of the acyclic pentaene apparently came about as a result of the pendant 1,2 diene. In all previous cases, exclusive eiectrocyclization of the bis-adducts via the Srt process was observed with but one exception. In Scheme 3.4 the reaction mixture was maintained at room temperature for 96 h and then refluxed for 8 h following quench. By-product 153 was isolated in 21% yield in addition to quinane 64. Adduct 153 derives from 6 tc eiectrocyclization followed by air oxidation. As was discussed in Chapter 5, conversion of this acyclic intermediate to the cyclooctatriene was hindered by the lack of substitution at positions 2 and 7 (Scheme 6.4). To our knowledge, the kinetic effect on 6tc eiectrocyclization associated with substitution of an allene into an acyclic hexatriene has not been studied. The examples by MooreS incorporate the 6n event into a tandem squarate reaction without isolation of the acyclic intermediate.
124 HO i-PrO. CH3 i-PrO
. P K , y f-PrO i-PrO O 153
Scheme 6.4. Formation of a by-product of Btt eiectrocyclization upon addition of 2 equiv of frans-propenylllthium to diisopropyl squarate.
The associated [1,5] sigmatropic hydrogen shift has, however, been studied kinetically, and Skattebel has reported the activation energy for [1,5] sigmatropy for 5-methyl-1,2,4-hexatriene to be 24.6 kcal/mol (Scheme 6.5).9 This is in contrast to conventional activation parameters, which generally range from 30-36 kcal/mol.i°
? ? 154 155 156
Scheme 6.5. Pericyclic [1,5] hydrogen migration of 154 followed by 6tt eiectrocyclization. The formation of 1 55 was measured kinetically in the gas phase.
Okamura has studied both [1,5] and [1,7] sigmatropic hydrogen migrations in systems where the terminal vinyl group was substituted by an allene moiety. This work was done in conjunction with related studies on the 125 [1,7] hydrogen shift which transforms previtamin D to the physiologically
active formJi He observed that incorporation of the allene lowers the
activation energy for the [1,5] event by 10-12 kcal/mol, but has a negligible effect on the [1,7] shift. It should be noted that the activation energy for
typical [1,7] hydrogen migrations in simple systems is approximately 20
kcal/mol. 10' 12
Transition state structures for [1,7] hydrogen migration and 8 tc
eiectrocyclization are quite similar. 13 Both progress through a highly
ordered Mobius type structure, and have relatively low energies of activation. Schleyer has studied the two systems theoretically, and found that both benefit from Mobius aromatic stabilization.
While the similarities between transition state structures for [1,5] hydrogen migration and 6tc eiectrocyclization are not as obvious, both are 6
electron processes having similar activation energies, and apparently both are subject to stabilization by the pendant allene. Conversely, the transition
state structure for8 k eiectrocyclization is not privy to the stabilizing effects of
the allene unit, as was the case for [1,7] sigmatropy. To our knowledge, the allene effect on competitive 6n: vs 8tc
eiectrocyclization has not been studied. Okamura, however, has observed the pericyclic events associated with an allene system capable of either [1,7]
hydrogen migration or 6ti eiectrocyclization. 11® In this work, it was
discovered that while [1,7] shifts are typically the preferred pericyclic channel, substitution by the allene results in bond reorganization via the eiectrocyclization alternative. Jensen has recently published the results of a theoretical study of the allene effect in [1,n] hydrogen migrations.is This work confirms Okamura's
126 empirical observations that allene substitution significantly enhances the rate of [1,5] migration, but affects the [1,7] variant only minimally. The results of his calculations are shown in Table 6.4. Jensen rationalizes this phenomenon by consideration of the electronic structure of the transition state for these conversions as two interacting radical fragments. He suggests that for the parent reaction, the activation energy results from a combination of strain factors associated with acquiring proper transition state geometry and stabilization between the two radical fragments. The terminal double bond of the allene can stabilize the incipient radical by conjugation when orbital overlap is possible. The geometry of the [1,5] migration is conducive to significant overlap, while in the case of the [1,7] reaction overlap is poor.
reaction a£^
[l,5 ]p 37.6 -8.2 [1,5]a 28.2 -9.1 [1.7]p 22.1 -13.9 [1,7]s 20.3 -12.5
Table 6.4. Activation parameters for the parent polyene
CH2 =CH-(CH=CH)n-CH 3 (p), and the associated allene
CH2 =C=CH-(CH=CH)n-CH 3 (a). Energies are in kcal/mol.
Skattebol used a similar argument to explain his observations seen in Figure 6.3. He suggests that if the transition state is product-like, additional
127 conjugation by k electrons from the terminal double bond of the allene
should provide a stabilizing contribution.
If, in the current case, a product-like transition state structure is considered, ring strain and a lack of planarity characteristic of intermediate
158 could account for the preferential formation of the more planar 157, which should benefit from resonance stabilization associated with the
exocyclic double bond (Figure 6.4).
OCH 3
0/-Pr /-Pro OCH 3 O' 0/-Pr 157 158
Figure 6.4. Intermediates resulting from 6 k and Btc eiectrocyclization.
Additionally, an inspection of the acyclic pentaene (Btc) and tetraene
(071) shows that as the transition state is approached, the 6 k system
undergoes a significant degree of twisting in the disrotatory sense (Figure 6.5). As bond a rotates to allow orbital overlap for new bond construction, the terminal allene orbitals (grey) also rotate. This twisting affords the opportunity for additional orbital overlap and transition state stabilization.
On the other hand, the Mobius transition state (Btc) requires no degree of twisting for con rotatory bond construction. As a result, conjugative overlap with the terminal p lobes of the allene is not a factor.
12B Figure 6.5. Orbital diagram for 8jt conrotatory eiectrocyclization of a
1,2,4,6,8 pentaene and 6 tz disrotatroy eiectrocyclization of a 1,2,4,6 tetraene.
In conclusion, the ability of a squarate ester to undergo sequential pericyclic events on mixed addition of allenic and alkenyl anions has been investigated. The conventional Cope rearrangement resulting from stereoproximal adducts and electrocyclic^ process resulting from the stereodistal components is apparently operative. Valence isomerization for the second electrocyclic event is, however, diverted from the usual 8 k preference to the 6tc option as a result of the presence of the allene. This represents a further documentation for the "allene effect" in pericyclic chemistry.
129 LIST OF REFERENCES
1 (a) The Chemistry of Ketenes, Aliénés and Related Compounds, Patai, S., Ed., John Wiley, New York, 1980. (b) The Chemistry of the Aliénés, Landor, S.R., Ed., Academic Press, London, 1982. (c) Schuster, H.F.; Coppola, G.M. Aliénés in Organic Synthesis; John Wiley, New York, 1984.
2 (a) Balme, G.; Doutheau, A.; Gore J; Malacria, M. Synthesis 1979, 508. (b) Kobayashi, S., Nishio, K. J. Am. Chem. Soc. 1995, 177, 6392. (c) Creary, X. J. Am. Chem. Soc. 1977, 93, 7632.
3 (a) Zimmer, R. Synthesis, 1992,165. (b) Rochet, P.; Vatéle, J-M.; Gore, J. Syniett, 1993, 105.
^ (a) Encyclopedia of Reagents in Organic Synthesis, Paquette, L.A., Ed., John Wiley, New York, Volume 5, 3316. (b) Hoff, 8; Brandsma, L.; Arens, J.F. Reel. Trav. Chim. Pays-Bas ^968, 87, 916.
5 (a) Taing, M.; Moore, H. W. J. Org. Chem. 1996, 61, 329. (b) Ezcurra, J.; Moore, H.W. Tetrahedron Lett. 1993, 6177.
6 Spectrometric Identification of Organic Compounds, Silverstein, R.M.; Bassler, G.C.; Morrill, T.C., John Wiley, New York, 1991, 302.
7 (a) Cookson, R.C.; Singh, P. J Chem. Soc. (C)'\97^, 1477. (b) Douthean, A.; Balme, G.; Malacria, M.; Gore, J. Tetrahedron, Lett. 1978, 1803.
® (a) Balakumar, A.; Janardhanam, S.; Rajagopalan, K. J. Org. Chem. 1993, 58, 5482. (b) Janardhanam, S.; Devan, B.; Rajagopalan, K. Tetrahedron Leff 1993, 34, 6761.
9 Skattebol, L. Tetrahedron 1969, 25, 4933.
10 Spangler, C.W. Chem. Rev. 1976, 76, 187.
130 (a) Hoeger, C.A.; Johnston, A.D.; Okamura, W.H. J. Am. Chem. Soc. 1987, 109, 4690. (b) Shen, G.-Y.; Tapai, K.; Okamura, W.H. J. Am. Chem. Soc. 1987, 109, 7499. (c) Palenzuale, J.A.; Elnagar, H.Y.; Okamura, W.H. J. Am. Chem. Soc. 1989, 111, 1770. (d) Barrack, S.A.; Okamura, W.H. J. Org. Chem. 1986, 51, 3201. (e) Elnagar, H.Y.; Okamura, W.H. J. Org. Chem. 1988, 53, 3060. (f) Curtin, M.L.; Okamura, W.H. J. Am. Chem. Soc. 1991, 113, 6958. (g) Okamura, W.H.; Elnagar, H.Y.; Ruther, M.; Dobreff, S. J. Org. Chem. 1993, 58, 600. (h) Okamura, W.H. Acc. Chem. Res. 1983, 16, 81.
12 Baldwin, J.E.; Reddy, V.P. J. Am. Chem. Soc. 1987, 109, 8051.
12 See Chapter 4, ref 10.
14 Jiao, H.; Schleyer, P.v.R. Angew. Chem., Int. Ed. Engl., 1993, 32, 1763. See also Chapter 4, ref 11.
15 Jensen, F. J. Am. Chem Soc. 1995, 117, 7487.
131 CHAPTER 7
DEVELOPMENT OF A SYNTHETIC APPROACH TO CRINIPELLIN
B BY INCORPORATION OF TANDEM ELECTR0CYCLIC2/ALD0L
METHODOLOGY
A. Introduction
Crinipellin B is one of a family of five crinipeliins, first isolated and
characterized by Anke in 1985/ These novel diterpene antibiotic
compounds were the first examples of natural products with the tetraquinane
framework. Since their discovery, a variety of strategies aimed toward the
synthesis of the crinipellin skeleton have been described .2 Crinipellin B has been successfully synthesized in racemic form from 2-
methylcyclopentenone, in a linear approach consisting of sequential
annulation of each of the quinane rings.2e With an appropriate framework and a degree of complexity which provides a challenging opportunity for implementation of the electrocyclic^/aldol reaction, our attention was focused toward utilization of this strategy for the synthesis of crinipellin B. Initially, a convergent scheme in which the current methodology would be used to generate the tetraquinane in a single step from diisopropyl squarate and diquinane 1593 was envisioned. Scheme 7.1 shows the key
132 step for this synthesis, providing the highly functionalized 160, and its subsequent conversion into crinipellin B. Use of phenylthiomethyllithium^ as a means of carbonyl transposition and, ultimately, for generation of the exo methylene, and a final oxidation achieving the direct conversion of the more reactive epoxide to the a-ketol^ are relevant features of this synthetic proposal.
i-PrO ' ■ t o 0 H -Pro V / 7 = CH3I i-PrO 159 (1 equiv); i-PrO 0 2. CHz=CHU NH4CI hPrO 160
SPh 1. NaBH 4, SPh 1 PhSCHzU CeCl3
2 H3O+ i-PrO ^ ^ O^equlv), l-PrO py 3. KOt-Bu.THF
/ CF3SO3H. 1. H3O; \ DMSO; 2. Nal0 4 O (/-POzNEt'. 3. CH3CN, HOOH CH2CI2
Scheme 7.1. Proposed route to crinipellin B via the diquinane anion 159, diisopropyl squarate, and vinyllithium.
While this strategy offered the advantage of maximum convergency, there were some obvious hurdles to overcome if it were to be used successfully. Efficiency of eiectrocyclization was potentially problematic due to the cis-methyl located at the p-position of the vinyl anion. However, use of the alternate conditions B had previously shown that the detrimental effects
133 of a single cis-methyl could be overcome (Scheme 3.9). The stereochemistry of alkylation with methyl iodide was not consistent with what has been observed for protononation. The several uncharted features present in this model, however, could alter selectivity. Most importantly, the regiochemistry of the alkylation step, requiring the introduction of methyl at the more highly substituted enolate site, was a pressing concem. Chapter 3 described a variety of methods developed for the control of regiochemistry.
Unfortunately, none provided a workable solution to the current problem. For these reasons, an altemate proposal was developed. Scheme 7.2 shows the key step. While this approach was not as convergent as the first, it did not require modification of regioselectivity for the transannular event.
A
0 ' 9 : /-P ro . Li 161 /-P ro
/-P ro /-P ro I /-P ro OH 2. CH2=CHLi
Scheme 7.2. Key step for synthesis of crinipellin B via initial formation of a triquinane framework.
B. Model Studies
In order to examine the potential for this approach, model studies were carried out. The goal was to develop methodology for functionalization of the y-hydroxy-a,P-bisalkoxyenone. To our knowledge, the reactivity of this
134 highly oxygenated system has not been described In the literature. As the
utilization of squarate esters for a variety of strain-induced ring expansions
increases, a working knowledge of the chemical potential of this motif becomes important on its own merit. For our purposes, chemical manipulation has been selectively directed toward provision of an appropriately functionalized triquinane precursor which can be readily annulated and modified for the preparation of the crinipellin nucleus. Scheme 7.3 outlines the objective.
10
/-Pro /-Pro
/-Pro OH 'CH3 0 CH 3 CH 3 OH
5 7
Scheme 7.3. Model study.
Installation of the angular methyl at C-4, generation of the double bond in the saturated ring, and transposition of the enone were the goals for this study. The newly-formed unsaturation would be used for construction of the a-hydroxy ketone, and the transposed enone was necessary for annulation of the fourth ring. Adduct 57, formed selectively in 90% yield from squarate chemistry was chosen because of its easily identifiable angular methyl and methine protons (H-8,10). It was expected that selective irradiation of these sites would provide a very time-efficient means for
135 establishing carbon-carbon connectivity of the various derivatives via semi-
selective DEPT studies at 300 MHz.
The reduction of 57 with lithium aluminum hydride was examined first. Stirring of the two reactants in THF at 0-20 °C for a short time led to the isolation of 166 (56%) and 167 (16%) (Scheme 7.4).
Qv Me Q, Me M-0 Me i- P r O - \ /-Pro — /-Pro- /•-Pro OH Me OM Me h OM Me
r 2 I Me H3O+ H0.„, i- P r O ~ \ /•-Pro— + /-Pro—^ OM Me 3 OH Me ÔH Me 165a, R ’ = H, =0M 166 (56%) 167 (16%) b.R^ = 0M, R^ = H
Dess-Martin (40%)
0 Me /-P rO -^
ÔH Me 168
Scheme 7.4. Reduction of 57 with lithium aluminum hydride.
The unique features inherent to 166 and 167 provided similar electronic environments to positions 1 and 3, precluding a reliable identification of these absorptions in the NMR spectra. The identity of the
136 major alcohol as the product of initial 1,4 addition was eventually secured by oxidation to 168 with the Dess-Martin reagent® and NMR analysis of this
ketone by means of semi-selective DEPT studies. Alcohol 167 was shown to be epimeric to 166 by comparison of its related spectroscopic characteristics. The substitution pattern in 166 and 167 presumably reflects the fact that LiAIH^ adds to 57 in kinetically-controlled 1,4-fashion, perhaps via complexation to the angular hydroxyl and p-alkoxy substituents to deliver the enolate anion, which finds it possible to eject the allylic isopropoxy group by means of conventional ^-elimination. Reduction of ketone 164 proceeds in the 1,2 mode, with attack from the P-face predominating for obvious steric reasons. The salient feature of the two-step conversion of 57 to 168 is that removal of the P-alkoxy substituent can be readily achieved in a fully controlled manner. In an attempt to divert the regioselectivity of the initial reduction away from the 1,4-mode, chelating reagents were introduced in order to saturate the chelation sites on lithium (Scheme 7.5). With the inclusion of 1 equiv of tetramethylethylenediamine, 1,2-reduction was indeed accommodated as seen by the formation of 170, but only to the 18% level. The predominant pathway continued to be that depicted in Scheme 4, producing 171a and
171b in 37% and 4% yield, respectively, after hydrolysis with IN hydrochloric acid.
137 HO. /-P rO -O •/-Pro
MezCHO) ÔH Me 0 OH Me 1 LiAIH 4 169 170 (18%) 1 eg 57 2 1N HCI % (pH Me Me H+ 171a , Ri =H R2 = OH (37%) 1 6 6 /1 6 7 b, Ri = 0 H R2 = H (4%)
Scheme 7.5. Reduction of 57 with lithium aluminum hydride in the presence of tetramethylethylenediamine.
Attention was next turned to the dehydration of 57 in order to extend conjugation into the adjacent ring. To this end, 57 was treated with methanesulfonyl chloride and triethylamine in CH 2CI2 as solvent (Scheme 7.6). It was anticipated that direct conversion to 173 would ensue. Instead, the corresponding chloride 172 resulted. The tertiary nature of this chloride would implicate the intervention of a carbocationic intermediate y to the carbonyl of the enone. Indeed, the substitution pattem in this putative cation allows for stabilization to materialize by electron donation through the double bond from the isopropoxy oxygen positioned a to the carbonyl.
138 Me LiCI, Q\ Me U 2 C O 3 . 57 /-Pro DMF /-Pro 150 °C Me -P r T I Me (87%) /-Pro 172 173
Me HO... + /-Pro
Me 174 (39%) 175 (49% )
Scheme 7.6. Formation of an a,p,Y,S unsaturated ketone, and reduction of the intermediate halide.
Chloride 172 was routinely converted without purification to 173 by heating with lithium chloride and lithium carbonate in DMF.^ The overall yield was 87%. Consequently, the introduction of added unsaturation does not appear to be problematic. The reduction of chloride 172 with UAIH 4 in ether proceeds in an interesting manner. Evidently, chloride ion is first displaced by Sn' attack of hydride at the position a to the carbonyl to give a
P,y-unsaturated enone which experiences second-stage reduction from the p-face to deliver 174 (35%) and 175 (49%). Operation of the Sn' mechanism indicates that the site of nucleophilic attack is more electron- deficient than usual, thereby lending credence to the concept advanced above that the carbocation precursor to 172 may well be stabilized by charge delocalization from the attached oxygen. The «-position is more
139 distant from the site of the ring fusion and consequently hydride attack on the double bond is no longer stereoselective.
The next phase of the effort involved probing the chemistry associated with dienone 173. Scheme 7.7 outlines some of these results.
HO.... LiAIH 4 IN HCI 173 /-PrO EtzO /-Pr2 (96%) 176
KOH, DMSO; CH3I
Me Me MeO H-rCH
H Me /-Pro Me
180 178
IN HCI (50% for 3 steps)
Me MeO
/-Pro
/-Pro Me /-Pro Me 181 179
Scheme 7.7. Reduction of the extended enone 173, followed by attempted carbonyl transposition.
140 Derivative 173 was treated with UAIH 4 in ether, the logic being that arrival at carbinol 176 would constitute the first stage of producing the transposed a-alkoxy enone. While 176 was indeed produced in essentially quantitative yield, the subsequent acidic hydrolysis of this unstable product triggered a more deep-seated series of events than originally projected
(Scheme 7.7). Instead of protonation at hydroxyl oxygen and ionization with loss of water, the conjugation afforded by the diene provides for kinetically relevant protonation at the methyl-substituted terminus and generation of oxonium ion 177. Once this has occurred, formation of dienol 178 can be envisioned by loss of a proton. The latter on reprotonation gave rise to 179 as an 8:1 mixture of epimers.
If the timing of events in this mechanistic cascade has been accurately portrayed, then the possibility appeared open for redirecting events merely by 0-alkylation of the hydroxyl group in 176. The conversion to 180 could be implemented without difficulty. Since the ensuing protonation should position positive charge on one of the isopropoxy oxygens as reflected in 177 and proton loss from an enol is no longer possible, dealkylation could operate to provide a route to distinctively different enone 181. Indeed, 181 was obtained in 50% overall yield from
173 as a 2:1 mixture of diastereomers. Notwithstanding the opportunities offered by the acquisition of 181, a means for effecting 1,3-carbonyl transposition had not yet been secured.
We came to favor a route wherein 173 would be deprotonated to generate the extended enolate 182, protonation or alkylation of which should be directed to a site closer to the carbonyl. Once the structural change of this type had been accomplished (Scheme 7.8), the expectation was that the
141 isolated a,P-dialkoxy enone chromophore should exhibit conventional reactivity.
LDA 173 THF, (97%) HMPA /-Pro GHz 182 183
1. LIAIH 4 CH3 I (80%) 2. 1 N HCI (85%)
9, Me Me
/-Pro Me cHz CHz 185 184
1. LiAIH 4 2. 1N HCI (84%)
Me
Me CH2 186
Scheme 7.8. Deconjugative protonation and alkylation of 173.
At the experimental level, the deconjugative protonation to give 183 (97%) and méthylation to afford 185 (80%) proved to be highly efficient and regioselective processes in the presence of HMPA. Without the inclusion of this chelating solvent, the deconjugative protonation occurred only to the 142 level of 20%, and no alkylation could be achieved. This was believed to be a consequence of what Seebach has described as internal proton return
(IPR), whereby lithium chelation to the protonated amine (from LDA) is responsible for proton transfer, presumably to oxygen, on addition of an electrophile. When this occurs, simple ketonization regenerates the starting, conjugated enone.s Use of an equivalent of n-butyllithium to deprotonate the amine has been shown to overcome the effect. In our case, incorporation of the chelating solvent to a level of 10% also proved efficacious.
When this pair of intermediates was subjected in turn to hydride reduction and work-up with 1N HCI, smooth conversion to 184 (85%) and
186 (84%) was noted. With deprotonation of 173 occurring at the exo methyl, the relevant issue became whether proton removal would occur as readily within the unsubstituted five-membered ring and permit equally convenient access to the delocalized anion 188 (Scheme 7.9). The answer to this question would be delayed until the requisite vinyl anion needed to generate the crinipellin framework was prepared and reacted with diisopropyl squarate in conjunction with vinyllithium.
LDA Pro
187 188
Scheme 7.9. Methylene deprotonation to generate anion 188.
143 c. Synthesis of the Requisite Vinyl Bromide and Its Utilization in the Electrocyclic^/Aldol Reaction
In continuation of our efforts to investigate the efficacy of the reaction in Scheme 7.2 as a candidate for the crinipellin project, synthesis of the vinyl bromide needed for the generation of 161 was undertaken. Scheme 7.10 outlines the racemic synthesis from 2-methylcyclopentenone.9
0 OSiMe 3 OTf CHg '-PrMgCI, CuCN, 1 • MeU
H TMSCI, HMPA, THF \_7 2. PhN(Tf) 2 / ^'■-Pr THF '-Pr 189 (61%) 190 (94%)
SnBu 3 Br (/-PPzNH, n-BuU CH3 Brz A ^ C H 3
BU3 SnH, CuCN, THF \—[ \—Z ^/■-Pr ^ i-Pr 191 192 (58%- 2 steps)
Scheme 7.10. Preparation of 192 from 2-methylcyclopentenone.
Cuprate addition of the isopropyl group accelerated by the presence of TMSCI and HMPA^o generated the silyl enol ether 189, which underwent regeneration of the enolate by treatment with methyllithium. Trapping the enolate with N-phenyltriflimideii delivered the enol triflate 190 in 94% yield.12 Coupling of 190 with a stannylcuprate via a method described by Wulffi3 provided the vinylstannane. Isolation of 191 free of tin by-products proved to be difficult,^^ and it was therefore converted to the vinyl bromide directly.
144 Several attempts to incorporate the vinyl bromide into a squarate
rearrangement were subsequently undertaken. Initially, the addition of vinyl
lithium (generated in situ from vinylstannane) followed by the anion derived
from 192 to diisopropyl squarate produced no isolable quinane products.
1 SnBu 3 n-BuLI No desired product Isolable
, 0 ° - 192
Scheme 7.11. Reaction of diisopropyl squarate with vinyllithium and the anion of 192.
It was believed that the terminal cis-methyl group was problematic, to the extent that it posed a significant constraint to eiectrocyclization.
Therefore, a partnership of the chiral anion with 2-lithiopropene, a
nucleophile which undergoes the pericyclic reaction more effectively , was
expected to be more profitable. In this case, a single quinane product was
isolated in poor yield (Scheme 7.12).
, t-BuLI
10 Br 2 , t-BuLI /-Pro OH 193 - 14%
Scheme 7.12. Reaction of diisopropyl squarate with 2-propenyllithium and the anion of 192.
145 While the desired diastereoselectivity of electrocyciization was
realized, the formation of linear triquinane 193, resulting from protonation of
the unsymmetrical enolate at the wrong site, was not a serviceable solution
to the problem. The example shown in Scheme 3.6 demonstrated the same
preference for protonation of a similar dienolate.
More futile attempts engaged two additional coupling partners which
had previously shown success (Scheme 7.13).
Br
1 100 p No desired product , t-BuLI
, t-BuLi
No desired product 1 2 H Me n-BuLi, [12]cr-4
Scheme 7.13. Reaction of diisopropyl squarate with 1- lithio(trimethylsilyl)ethylene (Scheme 3.10) or 1-lithiopropyne (Table 3.1) and the anion of 192.
The expectation that the failure of this nucleophile to engage profitably in the squarate rearangement resulted from a significant barrier to electrocyciization afforded by the presence of the methyl group prompted the decision to abandon this reagent for the lower homologue. To this end, the synthesis of 198 was carried out. Preparation of the enantiomer of 198 has
146 literature precedence (Scheme 7 .13)/s The final step in this sequence,
recently reported by Barton,^6 was a modification of that which was used in
the original method.
1. H2, PtOz ^ 0 ^ 0 1. HBr/EtOH ► 2. O3, NaBH4 , NaOH 2 . NaOEt, (EtOzQzCHz 3. NaOEt 3. H+ i-Pr S-carvone 194
EtOzQ COzEt COzMe
1. H2 SO4 1. SOzClz V 2. (MeOzCO 2. NaCOs /■-Pr 3. KOH, MeOH, H + 195
COzH 1. ( CICO) z Br
NaO 2.3% overall
AIBN, BrCCIa /-Pr 197 X) 198
Scheme 7.14. Preparation of the chiral vinyl bromide 198.
With 198 in hand, its reaction with diisopropyl squarate in conjunction with vinyllithium was carried out. Scheme 7.15 shows the results.
147 A 1. 98 ' /-Pro 10 /-Pro OH /■-Pro OH 2. CH 2 =CHSnBu 3 , n-BuLi 199 (19%) 200 ( 14%)
Scheme 7.15. Reaction of diisopropyl squarate with vinyllithium and the anion of 198.
Products 199 and 200 (see Figure B.6, Tables B.25-29 for X-ray confirmation) result from a non-diastereoselective electrocyciization.
Desired isomer 200 derives from the expected coil of the helix in which the terminal vinyl unit approaches opposite to the isopropyl group, as in 201 '
(Scheme 7.16). However, the major diastereomer occurs as a result of approach from the more sterically hindered direction 201".
/-Pro 0-/-Pr /•-Pro 0-/-Pr
H-
' 201 201 '
Scheme 7.16. Representation of the diastereotopic approaches in the electrocyciization of intermediate 201.
148 It was not understood why the apparently more hindered approach was favored. However, the thought was that the presence of the tetraalkylstannane resulting from exchange of the vinyltin derivative with n- butyllithium may bear responsibility for both the unexpected selectivity and the poor yield. Therefore a second experiment in which vinyllithium was generated directly from vinylbromide was undertaken. In this case no selectivity was observed as 199 and 200 were produced in identical quantities. The overall yield improved (199 - 25%, 200 - 25%), but not significantly. In a further effort to improve the production of 200, the acyclic intermediate was trapped with TMSCI, and the resultant bis-silyl enol ether was subjected to a variety of conditions to induce pericyclic bond construction. Unusually, no electrocyciization was found to occur unless the diol was regenerated, and in these cases, only to the extent previously noted. The lack of success in these endeavors prompted an investigation of other, more suitable coupling partners for 198. A remarkable improvement in the efficiency of this chemistry was realized when 1-lithio(trimethylsilyl)ethylene was added to diisopropyl squarate in advance of the anion of 198 (Scheme 7.17). In this case, excellent yield coupled with an equally favorable diastereoselectivity was realized.
149 Br I- ^ S iM e s
10 +
2. ^ /-Pro ÔH SiMes i-PrO ÔH 'SiMe 3
r . o a . t-BuLi 202 (72%) 203 (9%) Br
Scheme 7.17. Reaction of diisopropyl squarate with 1- iithio(trimethylsilyl)ethyiene and the anion of 198.
Triquinanes 202 and 203 were isolated as an inseparable mixture.
However, subsequent conversions yielded derivatives which could be separated, and eventual complete identification was afforded by the characterization of these secondary adducts. For 202, the regiochemistry of both second-stage addition and protonation of the unsymmetrical dienolate was determined by semi-selective DEPT studies, and was found to be consistent with what had been previously obsen/ed in a similar reaction (Scheme 3.10).
Subsequently, 200 and the mixture of 202 and 203 were separately subjected to the model study reactions (Scheme 7.18). For 200, the intermediate halide was formed uncontaminated with the elimination product 205. As before, stereochemistry at C-4 was not determined, but was presumed to be p. The unstable 205 underwent elimination in 95% yield.
150 A LiCI, CH3 SO2 CI, U 2CO3, 200 DMF EtsN, CH2CI 2 /-PrO 150 X 80% (95%) /-Pro Cl 204 205
/-Pro
SiMe 3 202,203 206 DMF Et3N, CH 2CI2 2 steps 150 X
/-PrO
/-Pro Cl SiMe 3 SiMe 3 209 8.3% 2 steps
Scheme 7.18. Reactions of 200, 202, and 203 with methanesulfonyl chloride, triethylamine, lithium chloride, and lithium carbonate.
In the case of the mixture of diastereomers 202 and 203, formation of the halide was more difficult due to enhanced steric congestion afforded by the trimethylsilyl functionality. As a consequence, more strenuous reaction conditions were required, resulting in the formation of 206 and 207 contaminated with the elimination products 208 and 209. Therefore, these diastereomers were routinely carried on to the next step. A pure sample of 206 was, however isolated and characterized. Stereochemistry at C-4 was not rigorously determined, but was expected to be |3. For 207, isolation of a pure sample was not accomplished. Both 208 and 209 were isolated and
151 studied spectroscopically. For 209, as a result of the elimination of chirality at C-8 and semi-selective DEPT studies at 300 MHz, its expected regio- and stereochemical constitution became unambiguous.
With 205 and 209 in hand, each was engaged in the alkylation reaction depicted in Scheme 7.8. After several attempts, it became obvious that deprotonation within the 5-membered ring, providing access to a delocalized anion such as 188 (Scheme 7.9) was not to be tolerated.
D. Summary of the Synthetic Proposal for Crinipellin B and
Conclusions
Scheme 7.19 outlines the approach envisioned for the synthesis of crinipellin B from intermediate 200. It was initially expected that access to
2 1 0 would be secured via the model study reactions.
152 1. MsCI, EtaN lalH U»H 2. LiCI, LICOa, DMF APrO 3. LDA, Mel. THF, HMPA 4. LAH, HaO+ o 210 200
1. NaBH4, 1. TBDMSCI, Imidazole [.«»H CeCIa UH 2. PhaPCHa o 3. TBAF 2. H3O+ HO HO 212 211 A 1. LDA c“H 1. m-CPBA 1. CHaC(OEt)a Propanoic Acid 2. CH2 I2, ZnCu 2. H2NNHT0 S ► "O 3. TsCI, TEA 2. PPA 3. NaCNBHa 214 213
2. PPTS O OTs 216 217 215
1. H2O2, NaHCOa
2. CFaSOaH, DMSO 2. (MeaSi)2NLi (APOaNEt (H2CNMe2)+r O OH "O "O 218 219
Scheme 7.19. Synthetic plan for crinipellin B from 200.
153 Luche reduction 17 of 210 followed by hydrolysis of the enol ether would deliver 211. Alcohol protection, Wittig olefination and deprotection would generate 212 which, following Claisen rearrangement and cyclodehydrationi 8 would beget 213 housing the tetraquinane framework.
Adduct 214 should be accessible via stereoselective epoxidation from the less hindered direction and Sn' reduction of the hydrazone. Subsequent base-promoted epoxide isomerizationi^ and hydroxy-directed Simmons- Smith cyclopropanation^o followed by radical-induced ring opening constitutes a potential method for stereospecific introduction of the angular methyl substituent. Alternatively, oxidation of the intermediate alcohol followed by the same radical reaction would preserve oxygen substitution within the central ring of the original triquinane. Allylic oxidation of 216 with Collins' reagent and subsequent acid-catalyzed isomerization of the y- hydrogen would produce the enone which will be used to install the remaining functionality on the annulated ring. With arrival at 217, base- catalyzed epoxidation of the enone and installation of the exo-methylene group with Eschenmoseris salt were used by Piers on a similar intermediate to crinipellin. 2e Finally, peroxyimidic acid epoxidation^i and direct generation of the a-ketol from the resultant epoxide® complete the sequence. Under the current state of affairs, it would appear that 210 or its silicon derivative are not accessible via the model study chemistry. Notwithstanding the lost opportunity resulting from an apparent inability to generate the delocalized anion of either 205 or 208, new channels contingent upon the sillicon functionality can be envisioned. If the same expediency realized for the trimethylsilyl enhanced rearrangement can be
154 afforded by a phenyldimethylsilyl derivative, introduction of oxygenation into the central ring might be possible via Fleming methodology.22 Epoxidation of vinylsilane 208 or a derivative of this compound, followed by acid- catalysed rearrangement of the resultant a,p-epoxysilane would deliver a carbonyl at the position originally substituted by silicon, thereby constituting an alternative ploy for incorporating oxygenation in the central ring. Finally, an allylsilane available via some of the chemistry developed during the model studies; e.g. Schemes 7.5 (following ketone reduction or protection) or 7.6, is potentially amenable to desilylative electrophilic substitution at position 3 (typical o r d e r in g ).23 Such reactivity could be useful for introducing functionality for annulation of the final ring.
In conclusion, the development of a synthetic plan for preparation of crinipellin B, contingent upon generation of the angular triquinane portion via electrocyclic2/aldol methodology, has been described. Model studies examining the feasibility of this process and elaborating the potential chemistry of the y-hydroxy-a,p-bisalkoxyenone functionality were carried out. A highly efficient and diastereoselective rearangement was discovered, which, while apparently not explicitly amenable to the full extent of the model chemistry, may open new avenues for the subsequent synthetic endeavor.
155 LIST OF REFERENCES
* See Chapter 1 , ref 18.
2 Mehta, G.; Rao, K.S.; Reddy, M.S. J. Chem. Soc., Perkin Trans. 1 1991, 693. (b) Mehta, G.; Rao, K.S. J. Chem. Soc., Chem. Commun 1987, 1578. (c) Schwartz, G.E.; Curran, D.P.; J. Am. Chem. Soc. 1990, 112, 9272. (d) Mehta, G.; Rao, K.S.; Reffy, M.S. Tetrahedron Lett. 1988, 29, 5025. (e) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.
3 Work toward the synthesis of the requisite vinyl bromide (racemic) was done by Pete Wilson, Paquette research group, unpublished results.
4 Corey, E.J.; Seebach, D. J. Org. Chem. 1966, 31, 4097.
5 Trost, B.M.; Fray, M.J. Tetrahedron Lett. 1988, 27, 2163.
6 (a) Dess, D.B.; Martin, J.C. J. Org. Chem. 1983, 48, 4155. (b) Ireland, R.E.; Liu, L.J. Org. Chem. 1993, 58, 2899.
7 This method has been used for the bromide, (a) Joly, R.; Wamant, J.; Nomine', G.; Bertin, D. Bull. Ch/m. Soc. Fr. 1958, 366. (b) Hanna, R. Tetrahedron Lett. 1968, 2105. (c) Branan, B.M.; Paquette, L.A. J. Am. Chem Soc. 1994, 116, 7658.
8 Seebach, D. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624.
9 For a potential enantioselective addition of the cuprate see: (a) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275, . (b) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 35, 895. (c) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4273. (d) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 895. (e) Kanai, M.; Koga, K.; Tomioka, K. Tetrahedron Lett. 1992, 33, 7193.
10 (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025. (b) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4029.
156 (a) McMurry, J.E.; Scott, W J. Tetrahedron Lett. 1983, 24, 979. For a more reactive triflating reagent see: Comins, D.L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
12 For reviews, see: (a) Stang, P.J. Acc. Chem. Res. 1978, 11, 107. (b) Stang, P.J.; Hanack, M.; Subramanian, L.R. Synthesis, 1982, 85.
13 Gilbertson, S.R.; Challener, C.A.; Bos, M.E.; Wulff, W.D. Tetrahedron Lett. 1988, 29, 4795.
1^ For methods of removal of tin by-products see: (a) Leibner, J.E.; Jacobus, J. J. Org. Chem. 1979, 44, 449. (b) Curran, D.; Chang, V. H-T. J. Org. Chem. 1989, 54, 3152.
15 Paquette, L.A.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.; Friedrich, D. J. Org. Chem. 1991, 56, 6199.
16 Barton, D.H.R.; Lâcher, B.; Zard, S.Z. Tetrahedron, 1987, 43, 4321.
17 (a) Tanaka, K.; Kishigami, S.; Toda, F. J. Org. Chem. 1991, 56, 4333. (b) Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50. 910.
18 Dorsch, M.; Jàger, V.; Spôniein, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 798.
19 (a) Crandall, J.; Apparu, M. in Organic Reactions, Dauben, W.G., Ed., John Wiley & Sons, New York, 1983, Vol. 29, Chapter 3. Morgan, K.M.; Gajewski, J.J. J. Org. Chem. 1996, 61, 820.
20 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
21 This reagent is useful for oxidation of double bonds in the presence of ketones. For a more reactive perimidic acid reagent (Cl 3CC(NH)0 0 H), see Arias, L.A.; Adkins, S.; Nagel, C.J.; Bach, R.D. J. Org. Chem. 1983, 48, 8 8 8 . This reagent is also capable of epoxidizing enones.
22 See Chapter 5, ref 4.
23 For reactions of epoxysilanes and allylsilanes see Silicon In Organic Synthesis, Colvin, E.W., Butterworths, Boston, 1989, Chapters 8 , 9.
157 CHAPTER 8
EXPERIMENTAL SECTION
A. General Methods
All reactions were carried out under an Inert atmosphere of argon. Glassware was generally oven-dried or flame-dried in vacuo and purged with argon. All solvents were reagent grade. Benzene, diethyl ether (ether), dimethoxyethane (DME), hexane, pentane, tetrahydrofuran (THF), and toluene were distilled from sodium or sodium/benzophenone ketyl.
Chlorotrimethylsilane (TMSCI), dichloromethane (CH 2CI2), diisopropylamine, hexamethylphosphoric triamide (HMPA), methyl iodide , tetramethylethylene diamine (TMEDA), and triethylamine (TEA) were distilled from CaH 2. n-Butanol, cyclopentanol, methanol, and 2-propanol were used directly or distilled from CaH 2. Ethanol was used directly or refluxed over Mg prior to distillation. The Trapp solvent mixture was made up of THF; ether; pentane (4:1:1). Tetramethylguanidine was distilled immediately prior to use. Mesitylene was dried by removal of approximately
10% of the solvent volume by atmospheric distillation prior to use. [12]Crown-4 was purchased from Aldrich Chemical Company and purified by two sequential distillations (b.p. 67-70 °C @ 0.5 torr) from CaH 2, followed
158 by storage over 4 Â molecular sieves. All reagents were reagent grade and purified where necessary. Titrations of alkyllithium reagents were carried out by the procedure of Kofron.^ All lithium reagents were prepared by exchange of the bromide with f-butyllithium unless otherwise noted.
Diisopropyl squarate was prepared according to the procedure of Liebeskind.2 Cyclopentenyllithium was prepared by exchange of 1- iodocyclopentene prepared according to the procedure of Barton.3
CeCl3"7 H2 0 was dried according to the procedure described in the
Encyclopedia of Reagents for Organic Synthesis^ All reactions were monitored by thin-layer chromatography or VPC. Development of chromatography plates was accomplished by the use of one of the following stains: p-anisaldehyde (7 ml of concentrated H 2SO4; 180 ml of abs. ethanol;
2 mL of glacial acetic acid; 5 mL of p-anisaldehyde; H 2SO4 and ethanol are mixed slowly at 0 °C followed by the remaining ingredients.); phosphomolybdic acid ( 8 % in abs. ethanol); potassium permanganate (3 g of KMn0 4 , 20 g of K 2CO3, 300 mL of 5% aqueous NaOH); ninhydrin (2.2% in abs. ethanol). Samples analyzed by VPC were run on a Varian 3300 analytical gas chromatograph. Unless otherwise noted, programmed temperatures were: 70 °C (1 min) - 250 °C, 10 °C/min. Melting points were measured on a Thomas Hoover (Uni-Melt) capillary melting point apparatus and are uncorrected. The column chromatographic separations were performed with Woelm silica gel (230- 400 mesh). For medium pressure liquid chromatographic (MPLC) separations, Merck LiChroprep Si60 (40-63|im) columns were used, unless otherwise noted. Infrared spectra were recorded with a Perkin-Elmer 1320 or 1600 FT IR spectrometer. Proton magnetic resonance spectra (^H NMR)
159 and carbon-13 magnetic resonance spectra NMR) were recorded on a
Broker AC 300 FT NMR spectrometer, Broker AC 250 FT NMR spectrometer or Broker AC 200 FT NMR. Coopling constants {J) are reported in Hz. For the long-range DEPT (distortionless enhancement by polarization transfer) and INEPT (insensitive noclei enhanced by polarization transfer) experiments osed for determining connectivity, cooplings are reported as either 2 -bond (2J ), 3-bond (3J), or 4-bond (allylic) (4J ). Intensities, which are often a fonction of stereochemistry (3 J cooplings are a function of the dihedral angle), are not reported, bot are sometimes mentioned for stereochemical porposes. The high-resolotion and fast-atom-bombardment mass spectra were obtained at The Ohio State University Campos Chemical
Instromentation Center. Elemental analyses were performed at the Scandinavian Microanalytical Laboratory, Herlev. Denmark.
8. Experimental Procedures
1-lcdocyciopentene. A solotion of cyclopentanone (5 g, 60 mmol), hydrazine hydrate (150 mL), and triethylamine (30 mL) in ethanol (90 mL) was heated at the reflox temperatore for 16 h, cooled, poo red into ice water
(500 mL), and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water, dried and evaporated at room temperatore to provide the hydrazone, which was osed directly.
To a solotion of tetramethylgoanidine (69 g, 600 mmol) in anhydroos ether (600 mL) was added dropwise over a 2 h period a solotion of iodine
(15.24 g, 120 mmol) in the same solvent. Sobseqoently a solotion of the hydrazone in dry ether (150 mL) was introdoced slowly over 2 h. The dark
160 reaction mixture was stirred at room temperature for 30 min and freed of
ether by distillation under slight vacuum. An additional 50 mL of
tetramethylguanidine was added, and the black mixture was heated at 80-90
°C for 2 h, cooled to room temperature, diluted with ether (100 mL) and
washed with 2 N hydrochloric acid (2 x 100 mL), dilute sodium bisulfite
solution (2 X 100 mL), and brine (100 mL). The solvent was removed by
distillation at or below room temperature, and the residue was distilled to
give 6.0 g (52 %) of a colorless liquid, bp 75-78 °C at approximately 50 - 60 Torr): VPC Rt = 3.66 min (initial temperature = 50 °C); IR (neat cm-"') 2960,
1610; 1R NMR (200 MHz, CDCI3 ) 6 6.12-6.05 (m, IN), 2.63-2.52 (m, 2 H),
2.37-2.26 (m, 2 H), 2.00-1.82 (m, 2 H); i3C (50 MHz, CDGI3 ) ppm 139.9, 92.6, 43.7, 33.9, 23.8. (£)- and (Z)-2-Bromo-2-butene. Three sequential distillations of
a commercial isomeric mixture through a 30-cm glass bead-packed column
afforded material containing greater than 97% of the Z- isomer, bp 82-83 °C
(lits bp 85.5 °C).
The residue from the first distillation, which was now richer in the E- isomer {E/Z = 80:20, VPC analysis), was taken in 4 g lots, combined with 290
mg of NaOH in cyclopentanol (15 mL) and heated to 90 °C. After 10 h, volatile material was distilled from the reaction vessel. Four fractions were collected (total 2 g), the isomeric content of which varied from 1.4% Zto 0%
Z These were combined, redistilled from CaHa through a short Vigreux column to furnish the E-isomer containing less than 1% of the Z- contaminant, bp 90-91 °C (lifS bp 93.9 °C). While the pure isomers appear to be stable to heat, they are very prone to equilibration when exposed to light. Therefore, all handling of
161 these materials was performed with the exclusion of light to the maximum extent possible. Prototypical Procedure for Double Addition of a Single
Alkenyl Anion. Method A. All apparatus was either flame-dried under vacuum and purged with argon, or flame-dried under argon immediately prior to use. An argon atmosphere was maintained throughout the reaction until quench. An alkenyl halide (2.25-4.0 equiv) was dissolved in dry THF
(10-25 mL), cooled to -78 °C, and treated dropwise with fe/t-butyllithium (4.5- 8.0 equiv, 1.7 M in hexanes) via syringe. The reaction mixture was stirred at
-78 °C for 30 min, treated with a cold (-78 °C) solution of diisopropyl squarate (150-594 mg, 0.75-3.0 mmol) in THF (5 mL) via cannula, and allowed to stir at -78 °C (1 h), 0 °C (0-16 h), and rt (16 h). Subsequently, the contents were opened to the atmosphere, quenched with saturated NH 4CI solution (6 mL), and diluted with ether (25 mL) and water (25 mL). The separated aqueous phase was extracted with ether (2 x 25 mL), and the combined organic phases were washed with water (25 mL) and brine (25 mL), dried, and concentrated. Product separation and purification were customarily accomplished by MPLC on silica gel. Method B. In glassware dried as described above was placed a vinyl halide or tributylvinylstannane (3.0-4.0 equiv) dissolved in dry THF (10-
15 mL). After cooling to -78 °C, ferf-butyllithium ( 6 -8 equiv) or n-butyllithium
(3-4 equiv, 1.6 M in ether) was introduced dropwise. After 30 min, a cold (-
78 °C) solution of diisopropyl squarate (198 mg, 1.0 mmol) in dry THF (5 mL) was added via cannula and the resultant mixture was stirred at -78 °C (0-24 h), 0 °C (0-36 hr), and rt (0-16 h). The reaction mixture was quenched under argon with saturated NH 4CI solution (6 mL, previously deoxygenated by
162 bubbling argon through for 20 min prior to use) and stirred at 2 0 °C for an additional 1-92 h under the inert atmosphere. The remainder of the workup parallels very closely that described under Method A. Prototypical Procedure for Mixed Alkenyllithium Additions.
Method C. All apparatus was flame-dried under argon, an atmosphere of which was maintained until quenching was effected. A solution of the first vinyl halide (1.1-1.25 equiv) in dry THF (5-10 mL) was cooled to -78 °C, treated dropwise with terf-butyllithium (2.2-2.5 equiv), and stirred at -78 °C for 30 min. During this time, the second alkenyllithium was similarly generated from 1.1-4 equiv of a second vinyl halide and a proportionate amount of fert-butyllithium and THF. A solution of diisopropyl squarate (198-
990 mg, 1.0-5 mmol) in dry THF (5-25 mL) was cooled to -78 °C and cannulated into the solution of the first anion. After 30 min, the second anion was similarly introduced and the temperature of the reaction mixture was maintained at -78 °C for 1 h, at 0 °C for 0 - 2 h, and at rt for 12 - 24 h before being retumed to 0 °C for quenching with water (6 mL). After 0-2 h of stirring open to the atmosphere, ether (25 mL) and water (25 mL) were added and the separated aqueous phase was extracted with ether (2x10 mL). The combined organic phases were washed with water (25 mL) and brine (25 mL), dried, and evaporated. The residue was purified by flash chromatography on silica gel and by further MPLC and/or recrystallization if necessary. Method D. This procedure differs from Method C in that 1.07-1.5 equiv of the first vinyl halide or tributylvinylstannane was treated with fe/t- butyllithium (2.14-3.0 equiv) or n-butyllithium (1.07-1.5 equiv). Also, after addition of the second alkenyllithium (2.0-2.5 equiv of the vinyl halide and a
163 proportionate amount of fe/t-butylllthium in THF), the reaction mixture was
stirred at -78 °C for 0.5-1 hr, at 0 °C for 0-20 h, and at rt for 0-20 h. Finally,
the reaction mixture was allowed to warm to rt after quenching at 0 °C with
deoxygenated saturated NH 4CI solution with continued stirring for 1-24 h
under argon prior to workup. In this method, quenching and the subsequent
storage period were carried out under an inert atmosphere.
/-PrO /-PrO,
/-Pro /-Pro /•-Pro
13 14 18
(3aA?*,6afl*,6bfl*,9a/?*,9bfl*)-1,2,6a,6b,8,9,9a,9b-
Octahydro-6a-hydroxy-5,6-diisopropoxy-4H-pentaleno[1,2-
b:3a,3b']difuran-4-one (13), (3a/?*,6aS*,6b/T*,9a/î*,9b/î*)-
1,2,6a,6b,8,9,9a,9b-Octahydro-6a-hydroxy-4,5-diisopropoxy-6/y-
pentaleno[1,2-b:3a,3d']difuran-6-one (14), (3aR*,6aS*,6bS*,
9aS*,9b/?*)-1,2,6a,6b,8,9,9a,9b-Octahydro-6a-hydroxy-4,5- diisopropoxy-6H-pentaleno[1,2-b:3a,3b']difuran-6-one (18), and (3afl*,6aS*,6b/?*,9aS*,9bfl*)-1,2,6a,6b,8,9,9a,9b-Octahydro-6a-
hydroxy-4,5-dilsopropoxy-6H-pentaleno[1,2-b:3a,3b']difuran-6-
one (19). Generation of the anion was accomplished by treatment of 2,3- dihydrofuran (0.23 mL, 3.07 mmol) in anhydrous THF (15 mL) with tert- butyllithium (1.76 mL of 1.7 M, 3.0 mmol). The reaction mixture was allowed to warm to 0 °C, maintained at this temperature for 20 min, and subsequently
retumed to -78 °C. At this time a cold (-78 °C) solution of 10 (198 mg, 1.0
mmol) in dry THF (10 mL) was introduced via cannula. After 10 min at -78
164 °C, the reaction mixture was allowed to warm to rt and stirred for 15 h,
refluxed for 4 h, cooled to 20 °C, and quenched by dropwise addition of water (5 mL). After further dilution with brine (20 mL), the products were extracted into ethyl acetate (3 x 25 mL), and the combined organic phases were washed with brine (40 mL), dried, and evaporated to a volume of 5-10 mL. On standing, 91 mg of 13 crystallized and was separated by filtration. A second batch of crystals recovered from the filtrate proved to be pure 14 (33 mg). The remaining oil was purified by flash chromatography on silica gel
(elution with 60:35:5 petroleum ether-ethyl acetate-acetonitrile) to give an additional 37 mg of 13 (total 38%), more 14 (17 mg, total 15%), 9.3 mg (3%) of 18, and 5 mg (2%) of 19.
For 13: colorless rhombic crystals, mp 116-117 °C; IR (CHCI 3, cm'1)
3660, 3475, 1765, 1695, 1600, 1380, 1310; NMR (300 MHz, CDCI 3) Ô
5.29 (heptet, J = 6 Hz, 1 H), 4.82 (heptet, J = 6 Hz, 1 H), 4.30 (d, J = 5.7 Hz, 1
H), 4.18 (m, 1 H), 3.94 (m, 1 H), 3.85-3.75 (m, 2 H), 2.68 (m, 1 H), 2.47 (td, J =
7.5, 3.5 Hz, 1 H), 2.26 (ddd, J = 16,12, 8 Hz, 1 H), 1.98 (m, 1 H), 1.78 (m, 2
H), 1.35 (d, J = 6 Hz, 6 H), 1.20 (d, J = 6 Hz, 6 H); 1^0 NMR (75 MHz, CDCI3) ppm 195.7, 168.9, 133.7, 93.6, 89.9, 82.2, 75.3, 72.2, 70.9, 68.1,49.7, 48.8, 33.5, 31.6, 22.8, 22.6, 22.4, 22.2; MS m/z(M+) calcd 338.1729, obsd
338.1743. Anal. Calcd forCisHaeOe: C, 63.89; H, 7.74. Found: 0, 63.59; H,
7.76. For 14: colorless rhombic crystals, mp 136-138 °C (from ether/hexanes); IR (CHCI 3, cm-i) 3500, 1700, 1610, 1380, 1310, 1195,
1100, 1070; 1H NMR (300 MHz, CDCI3) 5 5.34 (heptet, J = 6 Hz, 1 H), 5.15
(heptet, J = 6 Hz, 1 H), 4.30 (d, J= 5.1 Hz, 1 H), 4.10 (m, 1 H), 3.95 (m, 1 H),
165 3.82 (m, 2 H), 2.74 (m, 1 H), 2.53 (m, 1 H), 2.22 (m, 1 H), 2.05 (m, 1 H), 1.80
(m, 2 H), 1.31-1.15 (series of d, J = 6 Hz, 12 H); 1% NMR (75 MHz, CDCI3) ppm 196.5, 163.5, 133.4, 94.3, 90.2, 82.1, 73.9, 71.5, 70.4, 68.1, 49.65, 49.60, 33.8, 31.8, 22.7 (2 C), 22.6, 22.0; MS m/z (M+) calcd 338.1729, obsd
338.1760.
/4na/. Calcd for C 18 H26O6: 0, 63.89; H, 7.74. Found: C, 63.82; H,
7.79.
For 18: colorless crystals, mp 109-110 °C; IR (CHCI 3, cm*'') 3550,
1715, 1620, 1390, 1320, 1110; ^H NMR (300 MHz, CDCI 3) ô 5.34 (heptet, J
= 6 Hz, 1 H), 5.06 (heptet, J = 6 Hz, 1 H), 4.19-3.98 (m, 4 H), 3.90-3.80 (m, 1
H), 3.22 (s, 1 H), 2.90-2.81 (m, 1 H), 2.61-2.53 (m, 1 H), 2.16-1.81 (m, 4 H),
1.34(d, J=6Hz,3H), 1.30 (d, J= 6 Hz, 3 H), 1.22 (d, J= 6 Hz, 3 H), 1.21 (d,
J= 6 Hz, 3 H); 130 NMR (75 MHz, CDCI3) ppm 196.0, 166.6, 132.8, 92.6,
86.0, 79.2, 74.3, 72.2, 71.7, 69.5, 47.2, 41.5, 30.5, 28.8, 22.8, 22.7 (2 C), 22.4; MS m/z(M+) calcd 338.1729, obsd 338.1730.
Anal. Calcd for C 18 H26O6: C, 63.89; H, 7.74. Found: C, 63.98; H,
7.88.
Semi-selective INEPT from H-8 (5 2.86): 166.5 (C-3, 3J), 92.6 and
79.3 (C-4, C-5, 2J, 3j), and 86.1 (C- 6 , 3J).
Irradiate Observe % NOE
H-7 H-6 9.4 H-8 8.6 H-6 H-7 7.4 OH H-6 1.6
For 19: colorless crystals, mp 105-107 °C; IR (CHCI 3, cm*i) 3550,
1705, 1615, 1385, 1310, 1 1 0 0 ; 1H NMR (300 MHz, CDCI3) ô 5.27 (heptet, J
= 6 Hz, 1 H), 5.06 (heptet, J = 6 Hz, 1 H), 4.34-4.21 (m, 3 H). 3.99 (m, 1 H),
166 3.45 (d, J = 11 Hz, 1 H), 2.49-2.32 (m, 2 H), 2.15-1.98 (m, 1 H), 1.98-1.88 (m,
1 H), 1.84-1.76 (m, 1 H), 1.75-1.60 (m, 1 H), 1.30 (d, J = 6 Hz, 3 H). 1.28 (d, J
= 6 Hz, 3 H), 1.22 (d, J= 6 Hz, 3 H), 1.19 (d, J= 6 Hz, 3 H) (OH not seen);
13C NMR (75 MHz, CDCI3) ppm 197.2, 163.9, 131.1, 98.8, 89.1, 75.2, 74.8,
74.1, 72.0, 70.3, 50.4, 42.7, 30.3, 26.4, 22.9, 22.6; MS m/z{M+) calcd
338.1729, obsd 338.1730.
Irradiate Observe % NOE
H-7 H-10P 4 H-8 H-6 5 H-9a 2 H-9a H-8 4
Semi-selective INEPT from H-6 (6 3.45); 197.2 (C-1, 3J) and 75.2 (C-
4, 3^. A second reaction performed on an identical scale was stirred at -78
°C for 30 min, maintained at 0 °C for 5 h, and at room temperature for 15 h.
The mixture was subsequently cooled to 0 °C, quenched as in method B with saturated NH 4CI solution (previously deoxygenated, 6 mL), and stirred at rt under argon for an additional 16 h before being diluted with brine (2 0 mL) and extracted with ether (3 x 25 mL). Workup in the predescribed manner afforded 174 mg (52%) of 13, 60 mg (18%) of 14, 19 mg ( 6%) of 18, and 14 mg (4%) of 19.
A third reaction was carried out by generation of the anion as described above from 2,3-dihydrofuran (0.23 mL, 3.07 mmol) in anhydrous THF (15 mL) and fert-butyllithium (1.76 mL of 1.7 M, 3.0 mmol). The solution of the lithium anion was subsequently cannulated into a slurry of anhydrous
CeCIa (from 1.12 g (3 mmol) of the heptahydrate) in 10 mL THF at -78 °C.
After 3 h, a cold (-78 °C) solution of 198 mg (1 mmol) of diisopropyl squarate
167 in 5 mL of THF was cannulated into the organocerate. The remaining
procedure paralleled method A, 1 h, 1 h, 16 h until quench was enacted with
a saturated solution of NaHCOa (5 mL). After 30 min, the reaction mixture
was diluted with 10 mL of H 2O and 10 mL of ethyl acetate, and filtered
through Celite. Following extraction with ethyl acetate, the combined organic extracts were washed with brine, dried and evaporated to leave an
oil which was purified by flash column chromatography (elution with 2 0 % ethyl acetate in petroleum ether) and subsequent MPLC (elution with 5% acetonitrile and 30% ethyl acetate in petroleum ether) to yield 155 mg 13
(44%) as a single product.
/-Pro •
/■-Pro' OH 15 16
(3aff*,6a/?*,6bS*,9aS*,9bS*)-1,2,3,6a,6b,7,8,9,9a,9b- Decahydro-6a-hydroxy-5,6-diisopropoxy-4H-dicyclopenta[a,b]- pentalen-4-one (15), (3aff*,6afl*,6bS*,9a/?*,9bS*)-
1,2,3,6a,6b,7,8,9,9a,9b-Oecahydro-6a-hydroxy-5,6- diisopropoxy-4H-dicyclopenta[a,b]pentalen-4-one (16), and (3aff*,6a/î*,6b/?*,9aS*,9bS*)-1,2,3,6a,6b,7,8,9,9a,9b-
Decahydro-6a-hydroxy-4,5-diisopropoxy-6H-dicyclopenta- [a,b]pentalen-6-one (20). From 1.57 g (8.0 mmol) of cyclopentenyl iodide, 9.4 mL (16 mmol) of terf-butyllithium, and 594 mg (3.0 mmol) of diisopropyl squarate according to Method A for the following time periods 1, 0, and 16 h, there was obtained in the order of elution 37 mg (4%) of 20, 276
168 mg (28%) of 15, and 217 mg (22%) of 16. In a second run, involving 400
mg (2.04 mmol) of cyclopentenyl iodide, 2.4 mL (4.08 mmol) of tert-
butyllithium, and 150 mg (0.75 mmol) of diisopropyl squarate and the
following time periods 1, 0, and 16 h, there was isolated 100 mg (40%) of 15
and 64 mg (26%) of 16.
For 15; colorless crystals, mp 125-126 °C; IR (CHCI 3, cm*'') 3575,
1680, 1610, 1375, 1300, 1 1 0 0 ; NMR (250 MHz, CDCI3) Ô 5.30 (heptet, J
= 6.1 Hz, 1 H), 4.86 (heptet, J= 6.1 Hz, 1 H), 2.37 (m, 2 H), 2.20-2.00 (m, 3
H), 1.80-1.51 (m, 6 H), 1.51-1.38 (m, 5 H), 1.30 (d,J= 6.1 Hz, 6 H), 1.20 (d, J
= 6.1 Hz, 3 H), 1.15 (d, J= 6.1 Hz, 3 H); 1% NMR (75 MHz, CDCI 3) ppm 204.5, 166.1, 130.1, 85.4, 73.9, 71.7, 68.4, 57.1, 52.9, 52.5, 33.3, 33.2, 30.7,
28.2, 26.6, 24.9, 23.0, 22.8, 22.7, 22.3; MS m/z{M+) calcd 334.2144, obsd
334.2148.
Anal. Calcd for C 20H30O4: 0, 71.82; H, 9.04. Found: 0, 71.75; H,
9.05.
For 16: colorless crystals, mp 87-89 °G; IR (CHCI 3, cm*'') 3580, 1685,
1610, 1380, 1305, 1100; ^H NMR (250 MHz, CDCI 3) Ô 5.36 (heptet, J = 6.1
Hz, 1 H), 4.98 (heptet, J= 6.1 Hz, 1 H), 2.19 (m, 1 H), 2.05-1.55 (m, 3 H),
1.55-1.25 (series of m, 4 H), 1.30 (d,J= 6.1 Hz, 6 H), 1.20 (d,J = 6.1 Hz, 3
H), 1.18 (d, J = 6.1 Hz, 3 H); ^30 NMR (75 MHz, CDCI 3) ppm 203.5, 165.2, 133.3, 78.6, 73.7, 73.0, 71.5, 48.11, 48.09, 30.0, 28.6, 27.6, 26.4, 23.0, 22.7, 22.4, 22.1, 21.9; MS m/z(M+) calcd 334.2144, obsd 334.2149.
y4na/. Calcd for C 20H30O4: C, 71.82; H, 9.04. Found: C, 71.92; H, 9.08.
For 20: white solid, mp 171-172 °C; IR (CHCI 3, cm*'') 3550, 1690,
1600, 1470, 1315, 1100; 1H NMR (300 MHz, CeDe) ô 5.34 (heptet, J = 6 Hz,
169 1 H), 5.22 (heptet, J = 6 Hz, 1 H), 2.96 (s, 1 H), 2.26-2.20 (m, 1 H), 2.16-2.10
(m, 1 H), 2.06-1.90 (m, 1 H), 1.88-1.41 (m, 11 H), 1.14-1.07 (m, 12 H), 0.99-
0.84 (m, 1 H); 13C NMR (75 MHz, CeDe) ppm 200.8, 172.4, 127.0, 79.8, 73.3,
72.0, 71.4, 60.3, 56.3, 49.0, 31.7 (2 C), 28.0, 27.0, 26.0, 22.8, 22.7, 22.6,
22.5, 19.9; MS m/z(M+) calcd 334.2144, obsd 334.2144.
>4na/. Calcd for C 20H30O4: C, 71.81; H, 9.05. Found: C, 71.40; H,
9.27.
Long-range DEPT from H -1 2 (Ô 2.23): 172.4 (C-1, 3j), 79.8 (C-4, 3j),
49.0 (C- 6 , 3J), and 31.7 (C-13, 3j).
Long-range DEPT from H -6 (ô 2.13): 172.4 (3j), 72.0 (C-5, 2j), 56.3
(C-7, 2J), and 26.0 (C- 8 , 3j).
irradiate Observe % NOE
H-11a(5 0.91) H-6 3 H-8 7 H -lip 20 H-7 (5 1.99) H-8 1 H-6 (5 2.13) H-8 3 H-11a 2 OH (5 3.0) H-8 1 H -llp 1
12 12
10 1 11 10 31
(3afl*,6aS*,6bS*,9aS*,9bS*)-2,3,6a,6b,8,9,9a,9b-
OctahydrO'6a-hydroxy-5,6-diisopropoxycyclopenta[3,3a]-
170 pentaleno[1,2-6]furan-4(1 H)-one (31), (3a/?*,6afl*,6bfl*,9aS*,
9bff*)-1,6a,6b,7,8,9,9a,9b-Octahydro-6a-hydroxy-5,6- diisopropoxycyclopenta[2,3]pentaleno[2,1-b]furan-4(2H)-one
(32), and (3a/?*,6a/?*,6bf?*,9af?*,9bfl*)-1,6a,6b,7,8,9,9a,9b-
Octahydro-6a-hydroxy-5,6-diisopropoxycyclopenta[2,3]- pentaleno[2,1-b]furan-4(2H)-one (33). 2,3-Dihydrofuran (0.55 mL,
7.5 mmol) dissolved in cold (-78 °C) THF (5 mL) under argon was metalated with tert-butyllithium (3.10 mL of 1.7 M, 5.27 mmol) as before. Subsequently, method C was followed with 1.0 g, (5.0 mmol) of 10, 1.0 g (5.1 mmol) of cyclopentenyl iodide, and 6.0 mL of 1.7 M fe/t-butyllithium (10.2 mmol), for 1 h, 0 h, and 24 h. The reaction mixture was then cooled to 0 °C and quenched with 20 mL of H 2O. Flash chromatography on silica gel of the orange oil recovered from a typical work-up (elution with 40% ether in petroleum ether) led to the isolation of three fractions. MPLC (elution with
40% ether in petroleum ether) of fraction B gave 152 mg (9%) of pure 31 and 198 mg ( 12%) of pure 32. MPLC of fraction C (elution with 35% ethyl acetate in petroleum ether) afforded 436 mg (26%) of 33. Fraction A contained no relevant products.
For 31: colorless solid, mp 139-141 °C; IR (CHCI 3, cm*"') 3590, 1695,
1625, 1390, 1315; NMR (300 MHz, CDCI 3) Ô 5.33 (heptet, J = 6 Hz, 1 H),
4.88 (heptet, J = 6 Hz, 1 H), 4.04 (d, J = 4.7 Hz, 1 H), 3.86-3.72 (m, 2 H),
2.56-2.50 (m, 1 H), 2.33 (s, 1 H), 2.24-2.19 (m, 1 H), 2.08-1.39 (series of m, 8
H), 1.35 (d, J=6Hz,3 H), 1.30 (d, J= 6 Hz, 3 H), 1.23 (d, J = 6 Hz, 3 H), 1.19
(d, J = 6 Hz, 3 H); i^C NMR (75 MHz, GDCI3) ppm 203.4, 165.0, 131.1, 91.4,
85.4, 74.2, 71.9, 6 8 .1 , 52.1, 50.9, 34.0, 33.5, 32.1, 26.9, 22.9, 2 2 .6 , 22.4; MS m/z(M+) calcd 336.1937, obsd 336.1940.
171 Anal. Calcd for C 19 H28 O5: C, 67.82; H, 8.39. Found: 0, 68.15; H, 8.66.
Irradiate Observe % NOE
H-6 H-7 1.9 H-8 H-7 6.7 OH 4.6 H-7 H-6 2.4 H-8 11
Semi-selective INEPT from H-6 (Ô 2.22): 203.4 (0-1, 3J).
Semi-selective INEPT from H-8 (8 4.04): no effect at 165.0 (0-3, ^J) because of an approximate 90° dihedral angle.
For 32: colorless solid, mp 67-69 °0; IR (OHOI 3, cm-i) 3470, 1680,
1585, 1317, 1295, 1080, 1 0 0 0 , 970; 1H NMR (300 MHz, ODOI 3) 8 5.32
(heptet, J = 6 Hz, 1 H), 4.91 (heptet, J= 6 Hz, 1 H), 4.23-4.17 (m, 1 H), 4.00- 3.92 (m, 1 H), 3.27 (s, 1 H), 2.64-2.46 (m, 2 H), 2.41-2.33 (m, 1 H), 2.28-2.14
(m, 1H), 1.86-1 .66 (m, 4 H). 1.65-1.47 (m, 2 H), 1.37 (d, V = 6 Hz, 3 H), 1.35
(d, J = 6 Hz, 3 H), 1.30-1.20 (m, 1 H), 1.24 (d, J = 6 Hz, 3 H), 1.20 (d, J = 6 Hz,
3 H); 130 NMR (75 MHz, ODOI3) ppm 196.8, 169.1, 132.7, 94.1, 82.5, 74.9,
72.1, 70.6, 54.7, 50.5, 50.3, 32.9, 30.5, 28.0, 25.2, 23.0, 22.8 (2 0), 22.3; MS m/z(M+) calcd 336.1937, obsd 336.1947.
Anal. Oalcd for O 19 H28 O5: 0, 67.82; H, 8.39. Found: 0, 68.00; H, 8.52.
Irradiate Observe % NOE
H-7 H-12P 2.9 H-8 H-12P 1.1 H-12P H-7 5.0 OH 4.1 H-12a H-6 2.6
Semi-selective INEPT from H-6 (8 2.37): 196.8 (0-1, 3J).
172 Semi-selective INEPT from H-8 (62.59): no effect at 169.1 (C-3, 3J) because of an approximate 90° dihedral angle.
For 33: colorless oil; IR (CHCI3, cm'i) 3500 (br), 1695, 1610, 1390,
1305, 1 1 0 0 , 1015; NMR (300 MHz, CDCI3) 6 5.32 (heptet, J = 6 Hz, 1 H),
5.00 (heptet, J= 6 Hz, 1 H), 4.21-4.12 (m, 2 H), 3.0 (br, 1 H), 2.60-2.51 (m, 1
H), 2.05-1.85 (m, 4 H), 1.83-1.38 (series of m, 5 H), 1.34 (d, J = 6 Hz, 3 H),
1.33 (d, J = 6 Hz, 3H), 1.23 (d, J= 6 Hz, 3 H), 1.20 (d, J= 6 Hz, 3 H), 1.2-1.1
(m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 197.6, 166.6, 134.9, 97.7, 75.6,
74.7, 72.9, 71.8, 55.1, 46.1,44.6, 27.1, 26.2, 22.9, 22.6, 22.5 (2 C), 22.0 (2
C); MS m/z (M+) calcd 336.1937, obsd 336.1935.
Anal. Calcd for C 19 H28 O5: 0, 67.82; H, 8.39. Found: 0, 67.81; H,
8.53.
Irradiate Observe % NOE
H-6 H-7 6.7 H-13a 5.9 OH H-8 2.5
Semi-selective INEPT from H-6 (5 2.56): 197.6 (0-1, 3J).
(3afl*,6aS*,6bS*,9aS*,9b /-Pro. Q R*)-1,6a,6b,7,8,9,9a,9b- /-Pro 11 OHO ^ 1 0 Octahydro-6a-hydroxy-4,5- 0 HO H 9 35 diisopropoxycyclopenta[2, 3]pentaleno[2,1 -b]f uran- 6(2W)-one (34) and (3a/?*,6aS*,6bfl*,9aS*,9b/?*)-1,6a,6b,7,8, 9,9a,9b-Octahydro-6a-hydroxy-4,5-diisopropoxycyclopenta[2,3]- pentaleno[2,1-b]furan-6(2H)-one (35). Adaptation of the same
173 procedure and quantities as the previous reaction, except that cyclopentenyl anion was the leading nucleophile, led to isolation of an oil which was subjected to flash chromatography on silica gel (elution with 1:1 ether/petroleum ether) to give a purified four-component mixture. Through a combination of MPLC on silica gel (elution with 40% ether in petroleum ether) or alumina (elution with 6:3:1 petroleum ether/ether/acetone), there was isolated 207 mg (12%) of 31, 374 mg (21%) of 32, 50 mg (3%) of 34, and 142 mg ( 8 %) of 35.
For 34: colorless solid, mp 139-141 °C: IR (CHCI 3, cm-i) 3510 (br),
1700, 1610, 1380, 1370, 1305, 1 1 0 0 ; NMR (300 MHz, CDCI3) 5 5.26
(heptet, J = 6 Hz, 1 H), 5.02 (heptet, J = 6 Hz, 1 H), 4.21 (ddd, J= 8.3, 8.3, 1.4
Hz, 1 H), 3.96-3.90 (m, 1 H), 2.70 (br, 1 H), 2.30-2.24 (m, 1 H), 2.06-1.92 (m,
4H), 1.77-1.52 (m, 5 H), 1.30 (d, J= 6 Hz, 3 H), 1.28 (d, J= 6 Hz, 3 H), 1.21
(d, J = 6 Hz, 3 H), 1.19 (d, J = 6 Hz, 3 H), 1.13-1.05 (m, 1 H); 13C NMR (75
MHz, CDCI3) ppm 199.0, 164.0, 130.7, 100.4, 76.2, 73.9, 71.9,70.6, 57.9,
53.6, 47.0, 30.9, 26.9, 25.2, 22.8, 22.7 (2 0), 22.6, 19.4; MS m/z(M+) calcd
336.1937, obsd 336.1933.
Anal. Calcd for C 19 H28 O5: C, 67.82; H, 8.39. Found: C, 67.76; H,
8.53.
Irradiate Observe % NOE
H-6 H-13P 0.9 H-8 3.5 H-12P H-7 5.5 H-13P 3.0 OH 0.8
Semi-selective INEPT (in CeDe solution) from H-6 (5 2.13): observe
163.0 (C-1,3J).
174 For 35: colorless solid, mp 79-81 °C; IR (CHCI 3, cm*i) 3500 (br),
1700, 1610, 1380, 1370, 1300, 1290; NMR (300 MHz, CDCI 3) 5 5.29
(heptet, J = 6 Hz, 1 H), 5.05 (heptet, J = 6 Hz, 1 H), 4.13-4.06 (m, 1 H), 3.98-
3.90 (m, 1 H), 3.12 (br, 1 H), 2.64-2.41 (m, 3 H), 2.18-2.06 (m, 1 H), 1.81-1.43
(m, 6 H), 1.34-1.20 (m, 1 H), 1.31 (d, J = 6 Hz, 3 H), 1.29 (d, J = 6 Hz, 3 H),
1.22 (d, J = 6 Hz, 3 H), 1.20 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 198.6, 165.1, 132.8, 94.7, 82.6, 73.9, 72.0, 70.2, 54.1, 50.6, 50.1, 33.3,
30.9, 27.7, 25.6, 22.8, 22.7, 22.6 (2 C); MS m/z(M+) calcd 336.1937, obsd
336.1940.
Anal. Calcd for C 19 H28 O5: 0, 67.82; H, 8.39. Found: 0, 67.89; H,
8.43.
Irradiate Observe % NOE
H-7 H-8 5.4 H-8 H-7 5.0 H-6 H-8 < 1
Semi-selective INEPT from H-6 (Ô 2.45): 165.1 (C-1, 3J).
Semi-selective INEPT from H-8 (Ô 2.61): no effect at 198.6 (0-3, 3J) because of an approximate 90° dihedral angle.
MesSIQ MegSiC^ MesSiOv
/-Pro Me^zSiO oSiMes Me 3 SIC 43 44 48
[[(1GaR%1GbR*)-1,2,3,8,9,1G,10a,10b-Octahydro-5,8- dlisopropoxy-dicyclopenta[a,c]cycloocten-4,7-ylene]dioxy]- bis[trimethylsilane] (43), [[(IGa/7%1 GbS*)-1,2,3,8,9,10,1 Ga,1 Gb- Octahydro-5,6-diisopropoxy-dicyc[openta[a,c]cycloocten-4,7-
175 ylene]dioxy]bis[trimethylsilane] (44), and [[(10a/?*,10bR'^- 1,2,3,8,9,10,1 Oa,1 Ob-Octahydro-6,7-diisopropoxy-dicyclopenta-
[a,c]cycloocte^-4,5-ylene]dioxy]bis[trimethylsilane] (48). A vacuum-dried flask was purged with argon, an atmosphere of which was maintained throughout the reaction. A solution of cyclopentenyl iodide (1.17 g, 6.0 mmol) in dry THF (20 mL) was cooled to -78 °C, treated sequentially with fe/t-butyllithium (7.06 mL of 1.7 M in hexanes, 12 mmol) and then 396 mg ( 2 .0 mmol) of diisopropyl squarate according to the general procedure
(0.5, 0.75, and 16 h). The reaction mixture was cooled to 0 °C, treated with triethylamine (20 drops) and chlorotrimethylsilane ( 0 .6 8 mL, 6 .0 mmol), and stirred for 1 h. The solvent was evaporated and the residue was flashed through a short column of silica gel that had been pretreated with 2 % triethylamine in petroleum ether. Separation of the isomers was effected with 0.5% triethylamine and 2 % ether in petroleum ether as eluant. There was isolated in order of elution 231 mg (24%) of 44, 50 mg (5%) of 48, and
409 mg (43%) of 43.
For 43: colorless crystalline solid, mp 88-90 °C; IR (CHCI 3, cm-i) 1255, 1110, 880, 850; NMR (300 MHz, CeDe, 400 °K) Ô 4.32 (heptet, J =
7.5 Hz, 2 H), 2.59-2.49 (m, 4 H), 2.43-2.30 (m, 2 H), 1.83-1.57 (m, 5 H), 1.51-
1.32 (m, 3 H), 1.28 (d, J = 7.5 Hz, 6 H), 1.25 (d, J = 7.5 Hz, 6 H), 0.28 (s, 18 H); 13C NMR (75 MHz, CeDe, 350 K) ppm 135.7, 70.6, 31.1,28.5, 23.3, 23.2,
22.4, 0.99 (3 C's not obsen/ed due to slow conformational equilibration); MS m/z (M+) calcd 478.2934, obsd 478.2964.
For 44: colorless oil; IR (CHCI3, cm-i) 1250, 1 1 1 0 , 870, 850; iH NMR
(300 MHz, CeDe) 5 4.42 (heptet, J = 6 Hz, 2 H), 3.03 (m, 2 H), 2.67-2.57 (m, 2
H), 2.37-2.25 (m, 2 H), 1.77-1.64 (m, 4 H), 1.51-1.12 (m, 4 H), 1.27 (d, J = 6
176 Hz, 6 H), 1.19 (d, J = 6 Hz, 6 H), 0.32 (s, 18 H); 1^0 NMR (75 MHz, CeDe) ppm 137.7,137.6, 130.5, 70.8, 47.6, 31.5, 30.0, 23.9, 23.3, 23.1, 1 .1; MS m/z
(M+) calcd 478.2934, obsd 478.2934.
Irradiate Observe % NOE
H-7a (52.63) H-7b 27 H-7b (52.31) H-7a 26 H-8 4 H-8 (5 0.30) H-7b 2 H-7a 1 H-9 2
For 48: colorless oil; IR (CHCI3, cm*i) 1255, 1105, 880, 850; 1R NMR
(300 MHz, CeDe. 350 K) 6 4.33 (heptet, J = 7 Hz, 1 H), 4.19 (heptet, J = 7 Hz,
1 H), 2.67-2.19 (m, 6 H), 1.81-1.25 (m, 8 H), 1.23-1.19 (m, 12 H), 0.31 (s, 9
H), 0.24 (s, 9 H) (poorly resolved spectrum resulting from slow conformational equilibration); "'^C NMR (50 MHz, CeDe) ppm 70.2, 23.4, 1.4,
0 .6 (other peaks are not observed because of conformational dynamics); MS
m/z(M+) calcd 478.2934, obsd 478.2939.
MegSiQ [[(lOaR*. 10bH*)-1,2,9,10, 10a,10b-Hexahydro-5,6-
MesSiO diisopropoxycycloocta[1,2- b:4,3-6']difuran-4,7-diyl]-
dioxy]bis[trimethylsilane] (51) and [[(10a/?*, 10b/?*)-1,2,9,10,
10a,10b-Hexahydro-6,7-dlisopropoxycycloocta[1,2-b:4,3-
b']difuran-4,5-diyi]dioxy]bis[trlmethyisilane] (52). A vacuum-dried
flask was purged with argon, an atmosphere of which was maintained
177 throughout the reaction. Vinyl anion 11 was generated as before from 0.45
mL (6.0 mmol) of 2,3-dihydrofuran in dry THF (20 mL) and 3.53 mL of fe/t-
butyllithium (6.0 mmol). This cold (-78 °C) solution was treated dropwise with an equally cold solution of 10 (396 mg, 2.0 mmol) according to the
previous procedure (1.0, 1.0, and 16 h). The reaction mixture was cooled to
0 °C, treated with triethylamine (20 drops) and chlorotrimethylsilane (0.68 mL, 6.0 mmol), and stirred for 1 h. The solvent was evaporated and the residue was flashed through a short column of silica gel which had been pretreated with 2% triethylamine in petroleum ether. Separation of the isomers was effected with 1 % triethylamine and 2 0 % ethyl acetate in petroleum ether as eluant. There was isolated 490 mg (51%) of 51, 230 mg
(24%) of 52, and 3% of a third isomer which decomposed before characterization.
For 51: colorless crystals, mp 64-67 °C; IR (CHCI 3, cm-'') 1240, 1165,
1 1 0 0 , 1060, 1020, 865, 835; NMR (300 MHz, CeDe) S 4.52-4.40 (br m, 2
H), 3.79-3.67 (m, 4 H), 2.72-2.67 (br m, 2 H), 1.53-1.38 (br m, 2 H), 1.36-1.16
(m, total 11 H), 1.25 (d, J = 6 Hz, 3H), 0.35 (s, 18 H) (spectrum was poorly resolved as above); NMR (75 MHz, CeDe) the only well resolved peaks are seen at 71.0, 67.9, 23.5, 22.4, and 0.96 ppm; MS m/z(M+) calcd 482.2519, obsd 482.2534.
For 52: colorless crystals, mp 147-150 °C; IR (CHCI 3, cm-'') 1245,
1170, 1110, 1070, 1035, 840; 1R NMR (300 MHz, CeDe) 6 4.36-4.31 (br m, 1
H), 4.19 (heptet, J= 6 Hz, 1 H), 3.77-3.68 (m, 4 H), 2.69 (br m, 2 H), 1.31-
1.06 (m, total 13 H), 1.30 (d, J = 6 Hz, 3H), 0.41 (s, 9 H), 0.35 (s, 9 H) (again, poorly resolved spectrum); ''^C NMR (75 MHz, CeDe) the only well resolved
178 peaks are seen at 71.0, 23.2,1.4, and 1.3 ppm; MS m/z(M+) calcd
482.2519, obsd 482.2530.
General Procedure for DIenolate Generation from 43, 44,
48, 51, and 52. A flame-dried flask was purged with argon, an atmosphere of which was maintained throughout the course of reaction. A solution of 43
(27 mg, 0.057 mmol) in dry THF (2 mL) was cooled to -78 °C, treated dropwise with methyllithium (0.16 mL of 1.4 M in ether, 0.23 mmol), and allowed to warm to rt after 15 min. The reaction mixture was quenched with water (3 mL) and extracted with ether (3x). The combined organic phases were dried and evaporated to leave 20 mg (100%) of 15. Alternatively, when 43 (24 mg, 0.05 mmol) was similarly treated with tetrabutylammonium fluoride at room temperature (0.25 mL of 1 M in THF, 5 equiv) in place of methyllithium, and quenched with water, after 30 min 18 mg (100%) of 15 was isolated.
(3a/?*,6a/?*,6bf?*,9afl*,9bS*)-1,2,3,6a,6b,7,
8,9,9a,9b-Decahydro-6a-hydroxy-5,6-
/•-Pro OH dlisopropoxy-4H-dlcyclopenta[a,b]pentalen-4-
one (220). Comparable treatment of 44 (2 2 mg,
0.046 mmol) with an equal amount of MeLi fumished 14.3 mg (93%) of 16.
If tetrabutylammonium fluoride was used analogously to the above, a 3:1 mixture of 14/220 was isolated. These isomers were separated by MPLC with 28% ether in petroleum ether.
For 220: white solid, mp 59-60 °C; IR (CHCI 3, cm-i) 3580, 2950, 1670,
1610; 1H NMR (300 MHz, CDCI3) 55.35 (heptet, J= 6 Hz, IH), 4.93 (heptet, J =
179 6 Hz, IH), 2.68-2.59 (m, 1H), 2.49-2.37 (m, 2H), 1.98-1.12 (m, 12H), 1.32 (d, J =
6 Hz, 3H), 1.31, (d, J = 6 Hz,3H), 1.21 (d, J = 6 Hz, 3H), 1.19 (d, J= 6 Hz, 3H),
0.93-0.84 (m, 1H); 13C NMR (75 MHz, CDCI3) ppm 204.6, 168.0, 130.3, 82.1,
73.7, 71.7, 68.1, 53.8, 51.9, 44.4, 31.7, 31.3, 28.5, 27.6, 27.5, 26.7, 22.7 (2C),
22.6 (2C): MS m/z(m+) calcd 334.2144, obsd 334.2144.
Anal. Calcd for C 20H30O4: C, 71.81; H, 9.05. Found: C, 72.27, H, 9.16.
(3a/?*,6a/?*,6bS*9aS*9bS*)-1,2,3,6a,6b,7,8,9,
/ ^ 9a,9b-Decahydro-6a-hydroxy-4,5-diisopropoxy-
0 ÔH ' 6H-dicyclopenta[a,b]pentalen-6-one (50). When 50 48 (12.8 mg, 0.027 mmol) was subjected to similar treatment with MeLi, 7.8 mg (87%) of a 1:1 mixture of 20 and 50 was recovered. Altematively, when 48 (19 mg, 0.04 mmol) was similarly treated with tetrabutylammonium fluoride, 10 mg (75%) of 50 was isolated as a single diastereomer; colorless oil; IR (CHCI 3, cm*i) 3550, 1685, 1590, 1380, 1370,
1310, 1095; 1H NMR (300 MHz, CDCI 3) Ô 5.41 (heptet, J = 6 Hz, 1 H), 4.87
(heptet, J = 6 Hz, 1 H), 2.77 (br s, 1 H), 2.43-2.30 (m, 2 H), 2.19-2.15 (m, 1 H),
2.05-1.99 (m, 1 H), 1.79-1.32 (m, 9 H), 1.29 (d, J = 6 Hz, 6 H), 1.23 (d, J = 6 Hz, 3
H), 1.21 (d, J= 6 Hz, 3 H), 0.98-0.83 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm
200.9, 175.0, 128.6, 86.0, 73.6, 71.9, 65.0, 57.2, 52.9, 52.5, 33.5, 32.4, 31.2, 28.0, 26.3, 25.5, 22.7 (3 0), 22.5; MS m/z (M+) calcd 334.2144, obsd 334.2144.
Anal. Calcd for C 20H30O6: C, 71.81; H, 9.05. Found: C, 72.04; H,
9.35. Utilizing the procedure of methyllithium, 20 mg (0.057 mm) of 51 was converted into 20 mg (100%) of 13.
180 By means of an identical procedure, 20 mg (0.057 mmol) of 52 was transformed into 12 mg ( 8 6 %) of 14.
MesSiO I i [(2,3-Dlisopropoxy-5,8-dimethyl-1(8),2,4- /-PrO^ cyclooctatrien-1,4-ylene)dioxy]bis[trimethyl-
5 5 sHane] (55). A vacuum-dried flask was purged with argon, an atmosphere of which was maintained throughout the reaction. A solution of 2-bromopropene (0.26 mL, 3.0 mmol) in dry THF (10 mL) was cooled to -78 °C, treated sequentially with tert- butyllithium (3.53 mL of 1.7 M in hexanes, 6 mmol) and then 198 mg (1.0 mmol) of diisopropyl squarate according to the general procedure (0.5, 0.75, and 16 h). The reaction mixture was cooled to 0 °C, treated with triethylamine (10 drops) and chlorotrimethylsilane (0.34 mL, 3.0 mmol), and stirred for 1 h. The solvent was evaporated and the residue was flashed through a short column of silica gel with 1% triethylamine and 5% ethyl acetate in hexanes as eluant. There was isolated 300 mg (70%) 55 as a colorless oil; IR (neat, cm*i) 2970, 1664, 1628; NMR (300 MHz, CeDe) 5
4.42 (heptet, J = 6 Hz, 2H), 2.71-2.61 (m, 2H), 1.97-1.87 (m, 2H), 1.71 (s,
6 H), 0.30 (s, 18 H); 13C NMR (75 MHz, CeDe) ppm 139.7, 136.7, 118.9, 70.7,
32.6, 22.3, 23.0, 17.5, .7; MS m/z (M+) calcd 426.2621, obsd 426.2635.
(3afl*,6afl*)-4,5,6,6a-Tetrahydro-3a-hydroxy-
^ 2,3-dlisopropoxy-1(3aH)-pentalenone (56). Method B was utilized with tributylvinylstannane (1.77 mL, 4.0 mmol) and n-butyllithium (2.5 mL, 4.0 mmol) for the following time periods: 24, 0, 0, and 16 h. There was isolated 111 mg
181 (44%) of 56 as a colorless oil; IR (neat, cm-'') 3418, 1693, 1608; "'H NMR
(300 MHz, CeDe) Ô 5.32 (heptet, J = 6 Hz, 1 H), 5.20 (heptet, J = 6 Hz, 1 H),
2.91 (brs, 1 H), 2.61 (d, J = 9 Hz, 1 H), 2.04 (dd, J = 13, 6 Hz, 1 H), 1.94-1.87
(m, 1 H), 1.81-1.68 (m, 1 H), 1.64-1.43 (m, 2 H), 1.28-1.14 (m, 1 H), 1.16 (d, J
= 6 Hz, 3 H), 1.13 (d, J = 6 Hz, 3 H), 1.11 (d, J = 6 Hz, 6 H); 13C NMR (75
MHz, CeDe) pm 199.7, 167.4, 133.2, 82.2, 73.4, 71.6, 55.8, 37.3, 28.3, 25.0,
22.7 (4 C); MS m/z(M+) calcd 254.1518, obsd 254.1519.
Anal. Calcd for C 14H22O4 : C, 66.12; H, 8.72. Found: C, 66.01; H,
8.78.
Long-range DEPT from H -6 (8 1.90): 199.7 (C-1, 3J), 82.2 (C-4, 3j),
5 5 .8 (C-5 , 2J), 37.3, 25.0 (C-7,8; 2j, 3j).
Long-range DEPT from H -6 (5 1.74): 199.7 (3j), 55.8 (2J), 37.3, 25.0
(2J, 3J). Another example in which identical quantities were used under conditions B for 0, 2, 8 , and 14 h yielded only 69 mg (27%) of 56.
When conditions A were utilized, again with identical quantities for 0,
2, and 8 h, only 18 mg (7%) 56 was recovered.
Using identical quantities with conditions A for 24, 0, 0 h provided 8 8 mg (35%) 56.
If vinyllithium was generated directly from vinyl bromide (6 mL of 1M in THF, 6 mmol) and fert-butyllithium (7.1 mL of 1.7M in hexanes, 12 mmol) at -120 °C in the Trapp-mixture (THF/ether/pentane 4:1:1) using the method described by Seebach,^ and treated with a cold (-78 °C) solution of 198 mg
(Immol) of 10 in 10 mL THF under method B for 1, 16, 0, 8 h, 97 mg (38%) of the diquinane 56 was recovered as well as the more polar component 56a (this could not be isolated previously due to the fact that it was copolar with
182 the tetraalkylstannane by-product), which was unstable and therefore characterized only by NMR. and NMR was consistent with the following structure: ^ 1H NMR (300 MHz, CeDe) ô 6.33 (dd, J = 17, 11 Hz 2H), /-Pro 5.91 (dd, J = 17, 2 Hz, 2H), 5.11 (dd, J = 11, 2 Hz, 2H), 3.96 f - P r O - \ ^ ) — (heptet, J = 6 Hz, 2H) 0.91 (d, J = 6 Hz, 3 H); 13C NMR (75 56a MHz, CeDe) ppm 143.3, 127.9, 127.3, 113.9, 71.0, 22.7. Unusually, this intermediate was not prone to air oxidation as readily as the homologous examples, nor was it observed to undergo additional electrocyclization, in spite of its apparent tautomeric preference for the enol form in solution.
10 CHs /-Pro cHs (3a/?*,4S*,6afl*)-4,5,6,6a- Tetrahydro-3a-hydroxy-2,3-
/ - P r o ^ OH "CHs 0^ 0 h " c h 3 diisopropoxy.4,6a-dimethyl- 1(3a//)-pentalenone (57) and
(3a/7*,6S*,6a/7*)-4,5,6,6a-Tetrahydro-6a-hydroxy-2,3- diisopropoxy-3a,6-dimethyl-1(3aH)-pentalenone (58). Method A was employed with 2-bromopropene (0.33 mL, 3.75 mmol) and tert- butyllithium (4.4 mL, 7.5 mmol) for the following time periods: 1,16, and 16 h. There was isolated 253 mg (90%) of 57 and 7 mg (2.5%) of 58.
For 57: white solid, mp 51-52 °C; IR (CHCI 3) 3589, 1697, 1616, 1381, 1311; 1H NMR (300 MHz, CeDe) 5 5.38-5.24 (m, 2 H), 2.24-2.18 (m, 2
H), 1.94-1.86 (m, 1 H), 1.43-1.23 (m, 2 H), 1.28 (s, 3 H), 1.11 (d, J = 6 Hz, 3
H), 1.10(d, J=6Hz,3H), 1.09 (d, J= 6 Hz, 3 H), 1.07 (d, J= 6 Hz, 3 H), 1.01
(d, J = 7 Hz, 3 H), 0.98-0.84 (m, 1 H); 13C NMR (75 MHz, CeDe) ppm 202.7,
183 165.4, 132.5, 83.1, 73.6, 71.2, 56.7, 46.9, 35.0, 31.3, 22.9, 22.6 (2 C), 22.5,
19.6, 15.5; MS m/z(M+) calcd 282.1831, obsd 282.1831.
Anal. Calcd for C 16H26O4: 0, 68.06; H, 9.28. Found: C, 68.35; H,
9.34.
For 58: white solid, mp 109-110 °C; IR (CHCI 3, cm*i) 3560, 1650,
1600, 1385; 1R NMR (300 MHz, CDCI 3) 6 5.40 (heptet, J = 6 Hz, 1 H), 4.89
(heptet, J = 6 Hz, 1 H), 2.85 (s, 1 H), 2.01-1.91 (m, 2 H), 1.72-1.64 (m, 1 H),
1.45-1.34 (m, 1 H), 1.30 (d, J = 6 Hz, 3 H), 1.29 (d, J = 6 Hz, 3 H), 1.27 (d, J =
6 Hz, 3 H), 1.19(d, J= 6 H z,3 H ), 1.13 (s, 3 H), 1.07-0.96 (m, 1 H), 0.97 (d, J
= 7 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 199.9, 171.9, 131.4, 83.9, 73.4,
71.1,52.8, 46.6, 34.3, 30.8, 22.8, 22.6, 22.3 (2 C), 19.9, 15.3; MS m/z{m+) calcd 282.1831, obsd 282.1830. Long-range DEPT from H-10 (5 1.26): 171.9 (C-1, 3J), 83.9 (C-4, 3j),
52.8 (C-5, 2J), and 34.3 (C- 6 , 3J).
Stereochemistry of methyl-9 was determined by comparison of coupling patterns (^H NMR) to similar derivatives.
An analogous reaction using conditions B with a final 16 h period following quench gave similar results.
0 12 (3afl*,4S*,5S‘,6S*,
'10 6a/?*)-4,5,6,6a-Tetra-
/-PrO ÔH 'g hydro-3a-hydroxy-2,3-
61 diisopropoxy>4,5,6,6a- tetramethyl-1(3aH)-pentalenone (60a) and (3aR*,4S*,5/?*,6S*, 6a/?*)-4,5,6,6a-Tetrahydro-3a-hydroxy-2,3-dilsopropoxy- 4,5,6,6a-tetramethyi-1(3aH)-pentalenone (61). Method A was
184 employed with (£)-2-bromo-2-butene (506 mg, 3.75 mmol) and tert- butyllithium (4.4 mL, 7.5 mmol) for the following time periods; 1,16, and 16 h. There was isolated 226 mg (73%) of 60a and 1 1.5 mg (4%) of 61. For 60a: white solid, mp 53-54 °C; IR (film, cm‘i) 3445, 1695, 1615,
1380, 1302; 1H NMR (300 MHz, CDCI 3) 5 5.32 (heptet, J = 6 Hz, 1 H), 4.90
(heptet, J = 6 Hz, 1 H), 2.10 (s, 1 H), 2.10-1.95 (m, 2 H), 1.74-1.68 (m, 1 H),
1.34 (d, J = 6 Hz, 3 H), 1.30 (d, J = 6 Hz, 3 H), 1.20 (d, J = 6 Hz, 3 H), 1.18 (d,
J = 6 Hz, 3 H), 1.00 (s, 3 H), 0.95 (d, J = 7 Hz, 3 H), 0.82 (d, J = 6 Hz, 3 H),
0.75 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 204.6, 165.6, 129.8,
85.5, 73.9, 71.7, 57.1,47.9, 43.1,40.9, 23.0, 22.7 (2 C), 22.4, 15.1, 14.0,
13.5, 10.5; MS m/z(M+) calcd 310.2144, obsd 310.2152.
Anal. Calcd for C 18 H30O4: C, 69.64; H, 9.74. Found: 0, 69.38; H,
9.79.
The 3 ,5 -dinitrobenzoate ester 60b was prepared conventionally and isolated as a yellowish oil: IR (CHCI 3, cm*’’) 1730, 1690, 1620, 1540, 1340,
1310; iH NMR (300 MHz, CDCI3) 5 9.22 (t, J = 2 Hz, 1 H), 9.08 (d, J = 2 Hz, 2
H), 5.40 (heptet, J = 6 Hz, 1 H), 5.07 (heptet, J = 6 Hz, 1 H), 2.61 (dq, J= 7.5,
7.5 Hz, 1 H), 2.17-2.09 (m, 1 H), 1.90-1.80 (m, 1 H), 1.35 (d, J = 6 Hz, 3 H),
1.31 (d, J=6Hz,3H), 1.27(d, J=6Hz,3H), 1.21 (d, J= 6 Hz, 3 H), 1.09 (s,
3 H), 1.02 (d, J= 6.9 Hz, 3 H), 0.95 (d, J = 6 Hz, 3 H), 0.94 (d, J= 7.6 Hz, 3
H); 13C NMR (75 MHz, CDCI3) ppm 201.5, 163.0, 161.0, 148.7, 134.6, 131.0, 129.2, 122.3, 97.2, 74.6, 72.2, 57.7, 45.7, 43.5, 42.0, 23.1,22.9, 22.8, 22.6,
13.9, 13.8, 13.6, 9.9; MS m/z(M+) calcd 504.2107, obsd 504.2111. Long-range DEPT from H-12 (5 1.09): 201.5 (0-1, 3J), 97.2 (0-4, 3J),
57.7 (0-5, 2J), and 42.0 (0-6, 3J).
185 Irradiate Observe % NOE H-8 (5 2.61) H-13 6 5 6 \7 H-7 8.5 H-6 (5 1.85) H-10 7 NOg H-7 1 H-12 1 H-7 (5 2.13) H-8 10 NOg H-6 1 H-11 2.5 H-12 1 H-13 2.5
For 61: colorless oil; IR (CHCI3, cm-i) 3590, 1690, 1620, 1450, 1380,
1300; 1H NMR (300 MHz, CeDe) 5 5.35 (heptet, J = 6 Hz, 1 H), 5.27 (heptet, J
= 6 Hz, 1 H), 2.44 (dq, J = 7.5, 7.5 Hz, 1 H), 2.05 (s, 1 H), 1.77 (dq, J = 12, 7
Hz, 1 H), 1.35-1.27 (m, 1 H), 1.20 (s, 3 H), 1 .12 (d, J = 6 Hz, 6 H), 1.10 (d, J =
6 Hz, 3 H), 1.05 (d, J = 6 Hz, 3 H), 0.94 (d, J = 7 Hz, 3 H), 0.82 (d, J = 7 Hz, 3
H), 0.71 (d, J = 7 Hz, 3 H); 130 NMR (75 MHz, CeDe) ppm 202.9, 164.9,
131.3, 84.0, 73.4, 71.0, 59.1,49.4, 40.7, 40.2, 22.7, 22.4, 22.3 (2 C), 16.1, 13.7, 13.3, 9.6; MS m/z(M+) calcd 310.2144, obsd 310.2146. Long-range DEPT from H-12 (5 1.20): 202.9 (C-1, 84.0 (C-4, 3j),
59.1 (C-5, 2J), and 40.7 (C- 6 , 3j).
Long-range DEPT from H -8 (5 1.77): 164.9 (C-3, 3j) and 84.0 (C-4,
2J).
186 Irradiate Observe % NOE Irradiate Observe % NOE
H-6 (5 2.45) H-7 7.5 H-10 (5 0.72) H-7 14
H-11 4 H-8 4.5
H-8 (5 1.77) H-7 1 H-6 1.5
H-9 3.5 H-11 (5 0.84) H-6 15
H-10 2.5 H-8 10 H-11 3.5 H-12 5
H-9 (5 0.95) H-7 4 H-12(51.20) H-6 3
H-8 8 OH 2 H-11 5
OH (52.44) H-8 2.5
/-Pro (3a/?*,4fl*,5fl*,6/?*,6a/?*)-4,5,6,6a-Tetrahydro- /-Pro 6a-hydroxy-2,3-diisopropoxy-3a,4,5,6-
OH tetramethyl-1(3aH)-pentalenone (63). Method 63 B was utilized with (2)-2-bromo-2-butene (506 mg,
3.75 mmol) and ferf-butyllithium (4.4 mL, 7.5 mmol) for the following time periods: 1, 36, 6 , and 1 h. There was obtained 25 mg of a mixture of 60a (3%), 61 (1.5%), and 63 (3.5%) (estimated by NMR integration). A pure sample of 63 was obtained following chromatography of several runs.
For 63: white solid, mp 105-106 °C; IR (CHCI 3, cm-i) 3560, 1690,
1595, 1450, 1370, 1310; 1R NMR (300 MHz, CeDe) Ô 5.40 (heptet, J = 6 Hz,
1 H), 5.31 (heptet, J = 6 Hz, 1 H), 2.87 (s, 1 H), 2.42-2.36 (m, 1 H), 1.52-1.36
(m, 2 H), 1.34 (s, 3 H), 1.20 (d, J = 6 Hz, 3 H), 1.15 (d, J= 6 Hz, 3 H), 1.14 (d,
J = 6 Hz, 3 H), 1.10 (d, J = 6 Hz, 3 H), 0.95 (d, J = 6 Hz, 3 H), 0.94 (d, J= 6.5
Hz, 3 H), 0.79 (d, J = 6.5 Hz, 3 H); 1% NMR (75 MHz, CeDe) Ppm 2 0 2 .2 ,
187 173.1, 131.0, 82.5, 73.7, 71.1, 52.7, 46.8, 42.2, 39.4, 22.9, 22.7, 22.6, 22.5,
19.3, 14.3,13.3, 9.1; MS m/z(M+) calcd 310.2144, obsd 310.2143.
CH o ^ (3afl*,5S*,6S*,6afl*)-4,5,6,6a-
Tetrahydro-3a-hydroxy>2,3-
dilsopropoxy-5,6-dimethyl- /-Pro OH 1(3aH)-pentalenone (64) and
(±)-4-Hydroxy-2,3- diisopropoxy-5-methyl-4-[(E)-1-propenyl]-2,5-cyclohexadien-1- one (153). Combining 198 mg (Immol) of 10, 0.26 mL (3mmol) of (£)-1- bromopropene, and 3.5 mL (6 mmol) of tert-butyllithium according to method
B, the following reaction times were used: 30 min, 20 h, 0 h, and 92 h. TLC indicated that the reaction mixture still contained almost exclusively the acyclic octatetraene. A subsequent 8 h reflux period destroyed the intermediate, leading to significant decomposition, and the production of 64 and 153. Purification by column chromatography produced 21% of cyclohexadienone by-product (from 6 rc electrocyclization ) 153, as well as
28 mg (10%) of 64 as a colorless oil; IR (neat, cm-i) 3394, 2965, 1693, 1612;
1H NMR (300 MHz, CeDe) 6 5.31 (heptet, J = 6 Hz, 1H), 5.30, (heptet, J = 6
Hz, IH), 2.36 (d, J= 1.8 Hz, IH), 2.33-2.24 (m, IH), 2.14 (s, IH), 2.06 (dd, J =
12.6, 6 Hz, IH), 1.83-1.72 (m, IH), 1.57 (dd, J=12, 12 Hz, IH). 1.14(d, J = 6
Hz, 3H), 1.13 (d, J = 6 Hz, 3H), 1.12 (d, J = 6 Hz, 3H), 1.11 (d, J = 6 Hz, 3H),
0.96 (d, J= 7.3 Hz, 3H), 0.74 (d, J = 7 Hz, 3H); 13C NMR (75 MHz, CeDe) ppm 198.8, 167.0, 132.8, 81.6, 73.3, 71.5, 63.8, 42.1, 39.3, 36.0, 22.8, 22.65
(2C), 22.60, 14.7, 14.6; MS m/z(M+) calcd 282.1831, obsd 282.1829.
Anal. Calcd for CieH 2e0 4 : C, 68.06; H, 9.28. Found: C, 67.69; H, 9.41.
188 Long-range DEPT from H-SP (S 1.57): 167.0 (C-3, 3J), 81.6 (C-4, 2J),
36.0 (C-6 or 7), 14.6 (C-9, 3J);
Long-range DEPT from H-6 (8 2.28): 198.9 (C-1, 3J), 81.6 (C-4 2J), 42.1
(C-8. 3J). nOe: CeDe +1 drop DMSO cfe
Irradiate Observe % NOE Irradiate Observe % NOE Irradiate Observe % NOE H-9 (5.79) H-8a 2.6 OH (5 3.45) H-5 5.0 H-10 (51.01 : H-5 11.7 H-8P 6.5 H-9 1.3 H-6 11.3 H-5 3.0 H-10 1.5 H-9 5.5 H-6 2.7 H-5 (5 2.46) OH 5.5 H-8b 2.9 H-10 4.7 H-10 3.7 H-7 1.3 H-7 10.9 H-6 2.3 H-8a(51.20 H-8p 24 H-6 (5 2.31) H-9 2.0 H-8p 1.8 H-7 11.9 H-5 4.9 H-8p H-9 3.2 H-7 (51.85) H-8a 6.1 H-8p 1.6 H-10 3.0 H-6 6.2 H-7 8.8 H-5 5.6 H-9 5.1
For 153: colorless oil; IR (neat, cm-i) 3400, 2977, 1670, 1600; NMR (300 MHz, CeDe) 8 6.67 (q, J = 7.5, Hz, 1 H), 5.83 (dq, J= 15, 7, Hz, 1
H), 5.56 (dq, J= 15, 1.5, Hz, 1 H), 5.39-5.28 (m, 2H), 3.07 (s, 1 H), 1.80 (d, J = 7.5 Hz, 3 H), 1.51 (dd, J= 7 , 1.5 Hz, 3 H), 1.18 (d, J= 6 Hz, 3 H), 1.16 (d, J
= 6 Hz, 3 H), 1.14 (d, J = 6 Hz, 3 H), 1.13 (d, J = 6 Hz, 3 H); 13C NMR (75
MHz, CeDe) ppm 187.4, 167.4, 139.0, 134.3, 131.6, 129.2, 125.9, 75.1, 74.0,
71.9, 22.9, 22.73, 22.68 (2C), 17.6, 13.8; MS m/z(M+) calcd 280.1675, obsd
280.1678.
10 /-PrO Dh (3aS*,6a/?*)-4,5,6,6a-Tetrahydro-6a-hydroxy-
/-Pro 2,3-diisopropoxy-3a,6-diphenyl-1(3aA/)- pentalenone (65). Using method B with 198 mg (1 mmol) of 10, 640 mg (3.5 mmol) of a-bromostyrene, and
4.2 mL (7.0 mmol) of fert-butyllithium for 1,8, 10, and 24 189 h, 80 mg (20%) of 65 was isolated as a yellow solid; mp 133-5 °C; IR (CHCI 3, cm-1) 3560, 3000, 1710, 1615; 1R NMR (300 MHz, CDCI3) 7.38-7.23 (m, 10H),
5.48 (heptet, J= 6 Hz, IH), 5.11 (heptet, J= 6 Hz, IH), 3.34-3.28 (m, IH), 2.69-
2.54 (m, 2H), 2.38-2.22 (m, 2H), 1.96 (br s, 1H), 1.38 (d, J = 6 Hz, 3H), 1.37 (d,
J = 6 Hz, 3H), 1.35 (d, J = 6 Hz, 3H), 1.31 (d, J = 6 Hz, 3H); 13C NMR (75 MHz,
CDCI3) ppm 2 0 0 .0 , 171.0, 139.9, 137.5, 129.5 ( 2 C), 129.1 ( 2 C), 128.0 ( 2 C),
127.9 ( 2 C), 127.5, 127.1, 126.8, 84.4, 74.3, 71.7, 61.6, 54.3, 34.3, 33.0, 22.8,
22.7 (2C), 22.5; MS m/z (M+) calcd 406.2144, obsd 406.2155.
Long-range DEPT from H -6 (Ô 3.24): 200.0 (C-3, 3J), 137.5 (C-Ph 9, 2J),
129.5 (-Ph 9, 3J), 84.4 (0-4, 2J), 34.3, 33.1 (0-6,7, 2.3j).
Irradiate Observe % NOE
H- 8 (5 3.25) Ph 12.5 OH 0.3 OH (61.95) Ph 5.1
H-8 0.8
In a previous experiment following method A with 1, 3.5, 16 h, 60 mg (15%) of 65 was isolated.
(3aR%4S*,5aS*,8a/7*)-
/-Pro 4,5,5a,6,7,8-Hexahydro-3a-
/-Pro OH hydroxy-2,3-diisopropoxy-4- methylcyclopenta[c]pentalen- 1(3aH)-one (66) and (3aR*,3bS*,6aR*,7aA*)-3a,3b,4,5,6,6a,7,7a^0ctahydro-3a- hydroxy-2,3-diisopropoxy-7a-methyj-1H-cyciopenta[a]penta!en- 1-one (67). Method 0 was adopted with 2-bromopropene (0.11 mL, 1.25
190 mmol), ferf-butyliithium (1.5 mL, 2.5 mmol), cyclopentenyl iodide (784 mg,
4.0 mmol), and terf-butyllithium (4.7 mL, 8.0 mmol). There was obtained 83 mg (27%) of 22 and 188 mg (61%) of 23.
For 6 6 : colorless oil; IR (neat, cm'i) 3460, 1700, 1620; ‘*H NMR (300
MHz, CeDe) 6 5.31-5.18 (m, 2 H), 2.67 (s, 1 H), 2.45-2.38 (m, 1 H), 2.12-1.94
(m, 3 H), 1.89-1.71 (m, 3 H), 1.50-1.43 (m, 1 H), 1.34-1.18 (m, 2 H), 1.14 (d, J
= 6 Hz, 6 H), 1.12 (d, J = 6 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 1.05 (d, J = 7 Hz,
3 H); 13C NMR (75 MHz, CeDe) ppm 202.9, 165.5, 132.6, 83.7, 73.5, 71.1, 66.3, 47.4, 42.7, 37.1, 33.9, 31.4, 28.3, 23.0, 22.8, 22.7, 22.4, 15.4; MS m/z
(M+) calcd 308.1987, obsd 308.1977.
Anal. Calcd for C 18 H28 O4 : C, 70.10; H, 9.15. Found: C, 69.81; H, 9.20.
Long-range DEPT from H -6 (6 2.45-2.40): 202.9 (C-1, 3J), 83.7 (C-4,
3J), 66.3 (C-5, 2J), 42.7 (C-8 , 3 j), 37.1 (C-7, 2J), 33.9 (C-12, 2 j), and 28.3 (C-
11. 3J). nOe: CeDe nOe: CDCI3 + 1 drop DMSO cte
Irradiate Observe % NOE Irradiate Observe % NOE
OH (5 2.13) H-8 , H-1 op 6.5 H-9 (5 0.90) H-8 9 H-7P(51.47) H-S, H-1 Op 7.5 OH 1.5
H-6 1.5 H-7P 2
H-6 (5 2.42) H-7p 1.5 H-8 (5 1.97) H-9 4 H-1 la , H-12a 10 OH 2.5 H-7a, H-12P 6.5 H-7p 3
For 67: white crystals, mp 127-128 °C; IR (CHCI 3 , cm-"*) 3590, 1694, 1618, 1382, 1310; ^H NMR (300 MHz, CeDe) Ô 5.39-5.24 (m, 2 H), 2.24 (dd,
J = 11.2, 4.4 Hz, 1 H), 1.99 (s, 1 H), 1.94-1.59 (m, 5 H), 1.45-1.23 (m, 2 H), 1.31 (s, 3 H), 1.20-0.86 (m, 14 H); 13C NMR (75 MHz, CeDe) ppm 203.0,
191 164.5, 133.4, 78.7, 73.4, 71.3, 62.7, 62.0, 46.2, 38.8, 28.0, 25.7, 23.0, 22.9,
22.7, 22.6, 22.5, 19.4; MS m/z(M+) calcd 308.1987, obsd 308.1987.
Anal. Calcd for C 18 H28 O4: C, 70.10; H, 9.15. Found: 0, 70.12; H, 9.18.
11 (3aff*,5A?*,5aS,8a/?*)- 0 /10 g 4,5,5a,6,7,8-Hexahydro- /-Pro \5 >...... 9 /-PrO 3a-hydroxy-2,3- /-Pro OH /-Pro OH 70 dilsopropoxy-5- methylcyclopenta[c]pen- talen-1(3aH)-one (70) and (3a/?*,5S*,5aS*,8a/?*)-4,5,5a,6,7,8-
Hexahydro-3a-hydroxy*2,3-diisopropoxy-5-methylcyclopenta- [c]pentalen-1(3aH)-one (72). Method D was employed with cyclopentenyl iodide (210 mg, 1.07 mmol), fert-butyllithium (1.26 mL, 2.14 mmol), (E)-1 -bromopropene (0.18 mL, 2.0 mmol), and fert-butyllithium (2.36 mL, 4.0 mmol) for the following time periods: 0.5, 20, and 0 h. After quenching, stirring was continued for 16 h. There was isolated 190 mg (62%) of 70 and 12 mg (4%) of 72.
For 70: white solid, mp 101-102 °C; IR (CHCI 3, cm-i) 3590, 1680,
1620, 1300, 1 1 0 0 ; 1H NMR (300 MHz, CDCI3) 6 5.33 (heptet, J = 6 Hz, 1 H),
4.89 (heptet, J = 6 Hz, 1 H), 2.04-1.39 (series of m, 11 H), 1.33 (d, J = 6 Hz, 3
H), 1.32 (d, J= 6 H z,3 H ), 1.22 (d, J= 6 Hz, 3 H), 1.17 (d, J= 6 Hz, 3 H), 0.94
(d, J = 6.5 Hz, 3 H); 130 NMR (75 MHz, CDCI 3) ppm 204.2, 168.2, 128.8, 82.4, 73.7, 71.8, 67.1, 55.5, 48.0, 40.0, 32.1, 31.9, 26.8, 22.8, 22.7, 22.6,
22.2, 18.8; MS m/z(M+) calcd 308.1987, obsd 308.1988.
192 A nal. Calcd for G 18 H28 O4: C, 70.10; H, 9.15. Found: C, 70.04; H,
9.12. A preliminary ORTEP diagram of 70 can be seen in Figure B.7.
Long-range DEPT from H -6 (Ô 2.10): 203.4 (C-1, 3J), 32.5, 27.2 (C-8 ,
1 0 , 11, or 12) and 19.0 (C-9, 3J). The strong coupling of H -6 to the C-9 methyl is particularly informative of stereochemistry. For 72: colorless oil; IR (neat, cm*i) 3440, 1700, 1640, 1390, 1310;
1H NMR (300 MHz, CeDe) 8 5.36-5.27 (m, 2 H), 2.38-2.30 (m, 2 H), 2.17 (dd,
J= 13, 6 Hz, 1 H), 2.12-2.06 (m, 2 H), 1.85-1.72 (m, 3 H), 1.58-1.48 (m, 1 H),
1.41 (dd, J=13, 13 Hz, 1 H), 1.32-1.19 (m, 1 H), 1.15 (d, J = 6 Hz, 6 H), 1.12
(d, J = 6 Hz, 3 H), 1.11 (d, J = 6 Hz, 3 H), 0.79 (d, J= 6.8 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 203.1, 166.3, 133.1, 81.8, 73.2, 71.3, 65.5, 54.9, 40.8,
31.8, 30.2, 28.2, 27.7, 22.8 (2 C), 22.7 (2 C), 15.2; MS m/z(M+) calcd
308.1987, obsd 308.1984.
Ana/. Calcd for C 18 H28 O4: C, 70.10; H, 9.15. Found: C, 70.46; H,
9.35.
Long-range DEPT from H -6 (8 2.33): 203.1 (C-1, 3J), 81.8 (C-4, 3j),
65.5 (C-5, 2J), 40.8 (C- 8 , 3j), 30.2 (C-10, 3j), and 27.7 (C-11 or C- 12). The lack of polarization transfer to C-9 (15.2) indicates the existence of a trans configuration (dihedral angle = ca 90°).
Long-range DEPT from H- 8 a (8 2.17): 166.3 (C-3, 3J), 81.8 (C-4, 2j),
65.5 (C-5, 3J), and 54.9 (C- 6 , 3j).
Long-range DEPT from H-10 (8 2.09): 203.1 (C-1, 3j), 81.8 (C-4, 3J),
65.5 (C-5, 3J), 54.9 (C- 6 , 3j), and 28.2, 27.7 (C-1 1, 12).
193 Long-range DEPT from H-SP (5 1.41): 166.3 (C-3, 3J), 81.8 (C-4, 2j),
31.8 (C-7, 2J), and 15.2 (C-9, 3J).
Irradiate Observe % NOE
H-9 (50.79) H-6 2 H-8ot 1 H-7 12 H-12a 1 H-8P 3 H-12P 5 H-8P (51.41) H-8a 21 H-9 2 H-8a(52.17) H-7 5 H-8P 24 H-9 1
(3afl*,3bS*,6af?*,7S*,7afl*)-
/-PrO 3a,3b,4,5,5a,6,8a,7,a-Octahydro-3a-
/-PrO " OH g hydroxy-2,3-diisopropoxy-7-methyl-1H- 71 cyclopenta[a]pentalen-1-one (71). Method D was utilized with (£)-1-bromopropene (0.10 mL, 1.1 mmol), fe/t-butyllithium
(1.3 mL, 2.2 mmol), cyclopentenyl iodide (392 mg, 2.0 mmol), and fe/t- butyllithium (2.4 mL, 4.0 mmol) for the following time periods: 0.5, 8 , and 8 h. Stirring was continued for 16 h after quenching. There was produced 124.4 mg (40%) of 70, 38.2 mg (12%) of 71, and 6 6 .8 mg (22%) of 72.
For 71: colorless oil; IR (CHCI3, cm-l) 3600, 1693, 1617, 1382, 1307;
1H NMR (300 MHz, CeDe) ô 5.313 (heptet, J = 6 Hz, 1 H), 5.308 (heptet, J = 6
Hz, 1 H), 2.67 (d, J= 0.6 Hz, 1 H), 2.43 (s, 1 H), 2.42-2.30 (m, 1 H), 2.26 (ddd,
J=12.5, 12, 6 Hz, 1 H), 1.81-1.62 (m, 4 H), 1.24-0.99 (m, 3 H), 1.14(d, J = 6
Hz, 9 H), 1.13 (d, J = 6 Hz, 3 H), 1.00 (d, J=7.5 Hz, 3 H); i^C NMR (75 MHz,
194 CeDe) ppm 199.4. 165.2, 134.1, 78.1, 73.5, 71.5, 70.5, 55.8, 52.2, 33.5, 27.8,
23.0, 22.9, 22.70, 22.67 (2 0), 21.2, 14.9; MS m/z (M+) calcd 308.1986, obsd
308.1987. Long-range DEPT from H-5 (Ô 2.73): 199.4 (C-1, 2j), 165.2 (C-3, 3J),
78.1 (C-4, 2J), 52.2 (C-7, 3J), 33.5 (C- 6 , 2j), and 14.9 (C-12, 3j).
Long-range DEPT from H -6 (Ô 2.37): 199.4 (3j), 78.1 (3J), 55.8 (C- 8 ,
2J), and 14.9 (2J). The lack of polarization transfer to C-11 indicates that H-7 is a (dihedral angle approx. 90°).
Long-range DEPT from H -8 (Ô 2.26): 165.2 (3j), 78.1 (2J), and 52.2
(2J). The lack of polarization transfer to C-5 and C -6 indicates that H -8 is p
(dihedral angle approx. 90°). nOe: CgOg + 1 drop DMSO cfe
irradiate Observe % NOE
OH (53.37) H-5 5.5 H-8 3.2 H-5 (5 2.72) H-6 ,8 4.5 H-12 4.4
OH 2 .0 H-12(51.04) OH .9 H-5 9.9 H-6 ,8 24.1
In a previous example, method C was used with 400 mg (2.06 mmol) of cyclopentenyl iodide and 2.35 mL (4 mmol) of ferf-butyllithium for the first nucleophile, 396 mg (2mmol) of 10, and (E)-bromopropene (0.23 mL, 2.7 mmol), fe/t-butyllithium (3.2 mL, 5.4 mmol) for the second nucleophile. Reaction times of 2, 0, and 16 h provided 30 mg (5%) of 70, 106 mg (20%) of 96 and 160 mg (26%) of 123.
195 0 For 96: orange solid, mp 50-51 °C; IR (CHCI 3, cm-i)
Y i T ^ 2990, 1660, 1580; NMR (300 MHz, CDCI 3) 6 4.71
" n t Z (heptet, J = 6 Hz, 2H), 2.73 (t, J = 7.5 Hz, 4H), 2.70 0 (quintet, J = 7.5 Hz, 2H), 1.26, (d, J = 6 Hz, 12 H); i3C
NMR (75 MHz, CDCI3) ppm 183.1, 146.7, 146.3, 75.9, 30.3, 2 2 .6 , 21.5; MS m/z(M+) calcd 264.1361, obsd 264.1362.
Anal. Calcd. for C 15H20O4: 0, 68.16; H, 7.63. Found: C, 68.19; H, 7.67.
2 0 For 123: yellow solid, mp 51-2 °C; IR (neat, cm-^)
T 4 T 6 T 8 " ; 2960. 1650, 1620, 1560; ^H NMR (300 MHz, ^/-PrO 0 123 CeDe) 5 6.93 (dq, J = 15.4, 6.7 Hz, 1H), 6.77 (dq, J
= 15.4, 1.5 Hz, 1H), 6.52 (m, 1H), 4.30 (heptet, J =
6 Hz, 1H), 4.20 (heptet. J = 6 Hz, 1H), 2.80 (m, 2H), 2.11 (m, 2H),1.62 (t J =
7.5 Hz, 2H), 1.42 (dd,J= 6.7, 1.5 Hz, 3H), 1.19 (d, J = 6 Hz, 6 H). 1.11 (d, J =
6 Hz, 6 H); 13C NMR (75 MHz, CeDe) 188.0, 187.7, 151.6, 147.0, 143.1,
142.8, 139.7, 127.9, 74.8, 73.4, 33.9, 31.2, 22.9 (30), 22.7 (02), 18.0; MS m/z(M+) calcd 306.1831, obsd 306.1834.
Anal. Oalcd. forO i 8 H2e0 4 : 0, 70.56; H, 8.55. Found: 0, 70.22; H, 8.59.
Long-range DEPT from H-2 (S 6.93): 188.0 (0-4, 3J), 127.9 (0-3, 2 J),
18.0 ( 0 -1, 2J).
Long-range DEPT from H-3 (Ô 6.77): 188.0 (04, 2J), 142.8 (0-2, 2J),
18.0 (0-1, 3J).
Long-range DEPT from H-9 (Ô 6.52): 187.7 (0-7, 3J), 146.9 (0-8, 2J),
33.9(0-12, 3J), 31.2 (0-10, 2J), 22.9 (0-11, 3J).
Long-range DEPT from H-10 (Ô 2.81): 146.9 (0-8, 3J), 143.1 (0-9, 2J),
33.9 (0-12, 3J), 22.9 ( 0 -1 1 , 2J).
196 Long-range DEPT from H-12 (5 2.11): 187.7 (C-7, 3J), 146.9 (C- 8 , 2J),
143.1 (C-9, 3J ), 33.9 (C-10, 3J ), 22.9 (C- 1 1 , 2J),
In a similar experiment also using method C with 210 mg (1.07 mmol) of cyclopentenyl iodide, 1.26 mL (2.14 mmol) of ferf-butyllithium, 198 mg (1 mmol) of 10, 0.71 mL (8.2 mmol) of (E)-1 -bromopropene, and 9.6 mL (16.4 mmol) of tert-butyllithium for 0.5, 3.5, and 16 h, 61 mg (20%) of 70 and 71 mg (23%) of 123 was isolated. A final example in which 0.10 mL (1.1 mmol) of (£)-1-bromopropene and 1.3 mL (2.2 mmol) of fe/t-butyllithium were used for the first nucleophile, with 198 mg (1 mmol) of 10 followed by 392 mg (2 mmol) of cyclopentenyl iodide and 2.4 mL (4 mmol) of ferf-butyllithium for the second nucleophile was carried out for the following reaction times (method C): 1, 0, 16 h. This reaction mixture was quenched at room temperature with H 2O to provide 36.3 mg (12%) of 70, 100 mg (32%) of 72 and 57 mg (18%) of 123 following flash column and MPLC with 15% ethyl acetate in petroleum ether as eluant.
(3a/?*,5aS,8a/?*)-4,5,5a,6,7,8-Hexahydro-3a- 6 hydroxy-2,3-diisopropoxycyclopenta[c]pentalen-
1(3aH)-one (73). Method D was adopted with
tributylvinylstannane (0.38 mL, 1.3 mmol), n-butyllithium (0.82 mL, 1.3 mmol), cyclopentenyl iodide (408 mg, 2.08 mmol), and ferf- butyllithium (2.5 mL, 4.25 mmol) for the following time periods: 1, 2, and 10 h. After quenching, stirring was continued for 11 h. There was isolated 198 mg (67%) of 73 as a colorless oil; IR (neat, cm*"') 3417, 1692, 1608; NMR
(300 MHz, CeDe) 5 5.34-5.23 (m, 2 H), 2.57 (s, 1 H), 2.43-2.37 (m, 1 H), 2.09-
197 2.03 (m, 3 H), 1.88-1.61 (m, 5 H), 1.47-1.30 (m, 2 H), 1.15 (d, J= 6 Hz, 3 H).
1.14(d, J=6Hz, 3H), 1.11 (d, J=6Hz,3H), 1.09 (d, J= 6 Hz. 3 H); 1%
NMR (75 MHz, CeDe) ppm 203.2, 166.3, 132.4, 83.0, 73.3, 71.3, 65.3, 50.0,
34.2, 33.8, 30.6, 28.4, 28.0, 22.8, 22.7 (2 G), 22.6; MS m/z(M+) calcd
294.1831, obsd 294.1830.
Anal. Calcd for C i 7H2e0 4 : C, 69.36; H, 8.90. Found: C, 68.99; H,
8.84. Long-range DEPT from H-6 (Ô 2.39): 203.2 (C-1, 3J), 83.0 (C-4, 3J), and 65.3 (C-5, 2j).
0 11 9\ 0 11 .10 APrO. 1 9*^3 W IV W ■ X X I I c
10 1-PrO 2 i-PrO 7 APrO
/-PrO OH À-PrO OH /-PrO OH O OH CH3 76
(3aR*,4fl*,5R*,6afî*)-4,5,6,6a-Tetrahydro-3a-hydroxy-2,3- dlisopropoxy-4,5,6a-trimethyl-1 (3aH)-pentalenone (74), (3afl*,4S*,5S*,6afl*)-4,5,6,6a-Tetrahydro-3a-hydroxy-2,3- dlisopropoxy-4,5,6a-trimethyl-1 (3aH)-pentalenone (75), (3afl*,4S*,6S*,6aR*)-4,5,6,6a-Tetrahydro-3a-hydroxy-2,3- diisopropoxy-4,6,6a-trimethyl-1(3a//)-pentalenone (76), and (3a/?*,5fl*,6fl*,6a/?*)-4,5,6,6a-Tetrahydro-6a-hydroxy-2,3- diisopropoxy-3a,5,6-trlmethyl-1(3aH)-pentalenone (77). Method D was utilized with (2)-2-bromo-2-butene (150 mg, 1.1 mmol), ferf-butyllithium
(1.3 mL, 2.2 mmol), 2-bromopropene (0.22 mL, 2.5 mmol), and ferf- butyllithium (3.0 mL, 5.0 mmol) for the following time periods: 1,10, and 10 h. Stirring was continued for 16 h after quenching. There was isolated 89
198 mg (30%) of 74, 84 mg (28%) of 75, 64 mg (22%) of 76, and 11 mg (4%) of
77. For 74: colorless oil; IR (neat, cm*'') 3440, 1694, 1613, 1380, 1304; 1H NMR (300 MHz, CeDe) 5 5.32 (heptet, J = 6 Hz, 2 H), 2.23 (dq, J = 7, 7 Hz,
1 H), 2.02 (dd, J= 13, 7 Hz, 1 H), 1.83-1.73 (m, 1 H), 1.29 (s, 3 H), 1.27-1.16
(m, 1 H), 1.14-1.08 (m, 12 H), 0.82 (d, J = 7 Hz, 3 H), 0.73 (d, J = 7 Hz, 3 H)
(OH not observed); 13C NMR (75 MHz, CeDe) ppm 203.3, 166.8, 132.4, 83.6,
73.3, 71.4, 54.5, 42.7, 42.1,33.2, 22.8, 22.7, 22.6 (2 C), 19.5, 15.0, 8 .6 ; MS m/z(M+) calcd 296.1987, obsd 296.1985.
Anal. Calcd for C 17H28 O4: C, 68.89; H, 9.52. Found: C, 68.59; H,
9.57. Long-range DEPT from H-11 (5 1.30): 203.3 (C-1, 3J), 83.6 (C-4, 3J),
54.5 (C-5, 2J), and 42.1 (C- 6 , 3j). Long-range DEPT from H-9 (Ô 0.87): 83.6 (C-4, 3j) and 42.7, 33.2 (C-
7/C-8, 2j,3j). nOe in CgDe ht-1 drop DMSOcfe
Irradiate Observe % NOE Irradiate Observe % NOE
OH (5 3.54) H-11 3 H-9 (50.87) OH 6
H-8 1.5 H-8 11.5 H-9 3 H-11 1.5
H-6a(5 2.10: H-6 p 20.5 H-10 (5 0.78) OH 4.5 H-7 4.5 H-7 13 H-10 0.5 H-9 5
H-7 (51.80) H-10 4 H-8 2.5
H-6 a 2.5 H-11 1.6
H-8 7 H-63 2
H-6 a 0.7
199 For 75: colorless oil; IR (neat, cm-i) 3437, 1692, 1611, 1380, 1303; 1H NMR (300 MHz, CeDe) Ô 5.B-5.2 (m, 2 H), 2.31-2.19 (m, 1 H), 2.01 (dq, J=
7.2 Hz, 1 H), 1.89 (dd, J = 13, 8 Hz, 1 H), 1.59 (dd, J = 13, 6 .8 Hz, 1 H), 1.32
(s,3H), 1.16(d, J = 6 Hz, 3H), 1.14 (d, J= 6 Hz, 3 H), 1.11 (d, J = 6 Hz, 3 H),
1.09 (d, J = 6 Hz, 3 H), 0.80 (d, J= 8.0 Hz, 3 H), 0.74 (d, J = 7 Hz, 3 H) (OH not observed); 1% NMR (75 MHz, CeDe) ppm 203.6, 165.7, 131.1, 85.3,
73.6, 71.4, 55.9, 48.9, 40.9, 36.0, 23.1, 23.0, 22.6, 22.5, 21.2, 14.9, 10.8; MS m/z(M+) calcd 296.1987, obsd 296.1988.
Anal. Calcd forCigH 2 8 0 4 : C, 68.89; H, 9.52. Found: C, 68.85; H,
9.57. Long-range DEPT from H-11 (5 1.32): 203.6 (C-1, 3J), 85.3 (C-4, 3J),
55.9 (C- 5 , 2J), and 40.9 (C- 6 , 3j). nOe in CeDe hh 1 drop DMSOde
Irradiate Observe % NOE Irradiate Observe % NOE
OH (5 3.54) H-11 3 H-9 (5 0.87) OH 6
H-8 1.5 H-8 11.5 H-9 3 H-11 1.5
H-6a (5 2.10; H-6 p 20.5 H-10 (5 0.78) OH 4.5 H-7 4.5 H-7 13 H-10 0.5 H-9 5
H-7 (5 1.80) H-10 4 H-8 2.5
H-6 a 2.5 H-11 1.6
H-8 7 H-6 p 2
H-6 a 0.7
For 76: colorless oil; IR (neat, cm-i) 3404, 1693, 1614, 1380, 1306;
1H NMR (300 MHz, CeDe) ô 5.29 (heptet, J = 6 Hz, 2 H), 2.50-2.44 (m, 1 H),
2.40-2.30 (brs, 1 H), 2.32-2.20 (m, 1 H), 1.34-1.16 (m, 2 H), 1.19 (s, 3 H),
1.12 (d, J = 6 Hz, 3 H), 1.11 (d, J = 6 Hz, 3 H), 1.10 (d, J=6 Hz, 3 H), 1.07 (d.
2 0 0 J = 6 Hz, 3 H), 0.98 (d, J = 7 Hz, 3 H), 0.95 (d, J = 7 Hz, 3 H); 1% NMR (75
MHz, CeDe) ppm 203.4, 165.0, 131.4, 84.1, 73.7, 71.2, 60.2, 43.9, 39.4, 36.4,
23.0, 22.62 (2 C), 22.59, 16.2 (2 C), 15.9; MS m/z (M+) calcd 296.1987, obsd
296.1985.
Anal. Calcd for C 17H28 O4: C, 68.89; H, 9.52. Found: C, 68.74; H, 9.62.
Long-range DEPT from H -8 (52.37): 165.9 (C-3, 3J), 84.1 (C-4, 2j),
39.4 (C-7, 2J), 16.1 (C-9, 2j). Long-range DEPT from H-11 (5 1.25): 203.4 (C-1, 3J), 84.1 (C-4, 3j),
60.2 (C-5, 2J), 26.4 (C-6 , 3j). nOe in CeDe + 1 drop DMSOofe
Irradiate Observe % NOE Irradiate Observe % NOE
OH (5 3.05) H-8 4 H-8 (52.37) H-9 3 H-11 3 H-10 2.5 H-9 1.5 H-11 (51.23) H-10 3.5
H-10 1 OH 1
For 77: colorless solid, mp 90-91 °C; IR (CHCI 3, cm*l) 3554, 1691,
1597, 1383, 1308; ^H NMR (300 MHz, CeDe) Ô 5.33 (heptet, J = 6 Hz, 1 H),
5.18 (heptet, J = 6 Hz, 1 H), 2.68 (s, 1 H), 1.97-1.83 (m, 1 H), 1.65 (dd, J = 13,
6.5 Hz, 1 H), 1.44 (dd, J= 13, 13 Hz, 1 H). 1.34 (s, 3 H), 1.42-1.32 (m, 1 H),
1.14 (d, J = 6 Hz, 3 H), 1.09 (d, J = 6 Hz, 9 H), 1.05 (d, J = 6 Hz, 3 H), 0.77 (d,
J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 201.0, 174.3, 126.6, 84.2, 73.4, 71.4, 51.9, 50.3, 45.1,41.4, 22.7 (2 C), 22.6, 22.4, 21.4, 17.2, 10.7; MS m/z(M+) calcd 296.1987, obsd 296.1985.
Anal. Calcd for C 17H28 O4: C, 68.89; H, 9.52. Found: C, 68.54; H,
9.86.
2 0 1 Long-range DEPT from H-11 (Ô 1.34): 174.3 (C-1, 3j), 84.2 (0-4, 3J),
51.9 (C-5, 2J), 45.1 (C-6, 3J).
(3aff*,6a/?*)-4,5,6,6a-Tetrahydro-3a-
hydroxy-2,3-diisopropoxy>6a-methyl-4-
/-PrO " ÔH "siMe 3 (trlmethylsllyl)-1(3aH)-pentalenone (79). 79 Method D. From 179 mg (1.5 mmol) of (1- bromovinyl)trimethylsilane, fe/t-butyllithium (1.5 mL, 2.6 mmol), 2- bromopropene (0.18 mL, 2.0 mmol) and fe/t-butyllithium (2.35 mL, 4.0 mmol) for 1,3, 16, and 3 h, there was isolated 245 mg (72%) of 79 as a colorless solid, mp 73-74 °C; IR (CHCI 3 , cm-i) 3590, 1690, 1620; NMR (300 MHz, CeDe) 5 5.25 (heptet, J = 6 Hz, 1 H), 5.17 (heptet, J = 6 Hz, 1 H), 2.90 (s, 1
H),2.18(dd, J=12,5Hz, 1 H), 1.42 (ddd, J= 11, 5, 5 Hz, 1 H), 1.31-0.83 (m,
3H), 1.22 (s, 3 H), 1.18(d, J=6Hz,3H), 1.14 (d, J= 6 Hz, 3 H), 1.12 (d, J =
6 Hz, 3 H), 1.04 (d, J= 6 Hz, 3 H), 0.06 (s, 9 H); 13C NMR (75 MHz, CeDe) ppm 203.2, 166.6, 133.0, 84.3, 74.3, 71.3, 57.3, 40.2, 38.0, 25.3, 22.9, 22.8, 22.7, 22.6, 19.6, -1.2; MS m/z{M+) calcd 340.2070, obsd 340.2086.
Anal. Calcd for CigH 2 2 0 4 Si: C, 63.49; H, 9.47. Found: C, 63.65; H,
9.39.
Long-range DEPT from H-9 (Ô 1.22): 203.2 (C-1, 3J), 84.3 (C-4, 3J),
57.3 (C-5, 2J), and 38.0 (C-6, 3 j)
/-Pro. 1 /-PrO 1 /-Pro,
0 OH OH 80 81 82
2 0 2 (3a/7*,6S*,6a/7*)-4,5,6,6a-Tetrahydro-6a-hydroxy-2,3- diisopropoxy-3a-methyl-1 (3aH)-pentalenone (80),
(3a/?*,6/?*,6a/?*)-4,5,6,6a-Tetrahydro-6a-hydroxy-2,3- diisopropoxy-3a-methyl-1(3aW)-pentalenone (81), {3aR*,SaR*)-
4,5,6,6a-Tetrahydro-3a-hydroxy-2,3-diisopropoxy-6a-methyl- 1 (3aH)-pentalenone (82). The first nucleophile was generated as before from 0.10 mL of 2-bromopropene and 1.3 mL (2.2 mmol) of fe/t-butyllithium at
-78 °C, and after 30 min a solution of diisopropyl squarate (198 mg, Immol) in 5 mL of THF (pre-cooled to -78 °C) was added. After an additional 30 min, 5 mL vinylmagnesium bromide (0.6M in THF, 3 mmol) was added, and the temperature of the reaction mixture was allowed to rise to 25 °C. After 16 h, the reaction mixture was quenched with a solution of deoxygenated NH 4 CI and stirred for an additional 24 h following quench. Typical work-up provided
61 mg (23%) of 80, 35 mg (13%) of 81 and 17 mg ( 6 %) of 82.
For 80: colorless oil; IR (neat, cm-i) 3417, 2973,1697, 1603; ^H NMR
(300 MHz, CDCI3) Ô 5.26 (heptet, J = 6 Hz, 1H), 4.84 (heptet, J = 6 Hz, 1H),
2.77 (dd, J= 5.4, 2 Hz, 1H), 2.05-1.92 (m, 1H), 1.82-1.70 (m, 4H), 1.29 (d, J = 6
Hz, 3H), 1.24 (d, J = 6 Hz, 3H), 1.21 (d, J = 6 Hz, 3H), 1.15 (d, J = 6 Hz, 3H),
0.94 (d, J = 7 Hz, 3H); 13C NMR (75 MHz, CDCI 3) ppm 200.1, 170.1, 132.0,
83.5, 73.7, 71.5, 50.6, 45.5, 32.0, 26.0, 22.7, 2 2 .6 , 22.5, 2 2 .2 , 14.4; MS m/z (M+) calcd 268.1675, obsd 268.1667.
Long-range DEPT from H -8 (5 1.99): 200.1 (C-3, 3J), 83.5 (0-4, 2J),
32.0, 26.0 (0-6,7, 2J, 3j)_ 14,3 (C-9, 2J).
Irradiate Observe % NOE
OH (5 3.37) H-8 2 .6
H-9 0.1
203 For 81: white solid, mp 80-81 °C; IR (neat, cm*i) 3556, 2977, 1693,
1597; 1H NMR (300 MHz, CDCI 3) 5 5.19 (heptet, J = 6 Hz, 1H), 4.80 (heptet, J
= 6 Hz, 1H),2.87 (dd J=9, 5Hz, 1H),2.65 (s, 1H), 2.06-1.94 (m, 1H), 1.94-
1.82 (m, 1H), 1.77-1.70 (m, 1H), 1.66-1.40 (m, 2H), 1.33 (d, J = 6 Hz, 3H), 1.28
(d J = 6 Hz, 3H), 1.22 (d J = 6 Hz, 3H), 1.19(d J = 6 Hz, 3H), 1.03 (d J=7Hz,
3H); 13C NMR (75 MHz, CDCI3) ppm 2 0 1 .0 , 171.8, 129.1, 83.1, 73.9, 71.9,
50.0, 39.9, 34.1, 26.5, 22.72, 22.69, 22.52, 22.48, 12.8; MS m/z(M+) calcd
268.1675, obsd 268.1643.
Long-range DEPT from H -8 (d 1.89): 201.0 (C-3, 3J), 12.7 (C-9, 2J).
Irradiate Observe % NOE
OH (5 2.65) H-9 2.8 H-5 1.5 H-9 (5 1.03) OH 7.5 H-5 0.7
For 82: colorless oil, IR (neat, cm*i) 3415, 2970, 1690, 1610; ^H NMR
(300 MHz, CeDe) 5 5.31 (heptet, J = 6 Hz, 1H), 5.28 (heptet, J = 6 Hz, 1H),
2.19-2.09 (m, 3H), 1.50 (ddd, J = 13, 13, 6 Hz, 1H), 1.37-1.24 (m, 2H), 1.27 (s,
3H), 1.12(d, J = 6 Hz, 3H), 1.10 (d, J= 6 Hz, 6 H), 1.09 (d, J = 6 Hz, 3H), 1.15-
1.00 (m, 1H); i^C NMR (75 MHz, CeDe) ppm 202.2, 165.6, 132.3, 81.9, 73.0,
71.1,54.3, 37.4, 36.7, 22.4 (2C), 22.3 (2C), 22.2, 18.7; MS m/z(M+) calcd
268.1675, obsd 268.1669.
Long-range DEPT from H-9 (5 1.27): 202.3 (C-1, 3J), 81.9 (C-4, 3J),
54,3 (C-5, 2J), 36.7(C-6 or 7).
204 i-P ro 9 (3a/?*,6afl*)-4,5,6,6a-Tetrahydro-6a-hyclroxy-2,3-
APro- 2.5 mL (4.25 mmol) of fe/t-butyllithium was cannulated into the reaction mixture. The temperature was maintained at -40 to -55 °C for a period of 5 h, and at 0 °C for 16 h, after which time the reaction mixture was quenched with deoxygenated saturated NH 4 CI solution, and stored at room temperature with stirring under argon for 24 h. Typical work-up afforded 37 mg (14%) of 82 and 34 mg (13%) of 83 along with 100 mg (40%) of three compounds resulting from double addition of vinylmagnesium bromide. For 83; colorless oil; IR (neat, cm-"') 3411, 2975, 1696, 1602; ^H NMR (300 MHz CeDe) S 5.32 (heptet, J = 6 Hz, 1H), 5.20 (heptet, J = 6 Hz, 1H), 3.90 (s, 1H), 2.19 (ddd, J= 13. 6, 1 Hz, 1H), 1.91 (ddd, J = 11.5, 6, 1 Hz, 1H), 1.75 (ddd, J = 13, 7, 7 Hz, 1H), 1.42-1.26 (m, 3H), 1.33 (s, 3H), 1.11 (d, J = 6 Hz, 3H), 1.05 (d, J = 6 Hz, 6H), 1.02 (d, J = 6 Hz. 3H); 13C NMR (75 MHz, CeDe) ppm 200.1, 170.1, 132.0, 83.5, 73.7, 71.5, 50.6, 45.5, 32.0, 26.0, 22.7, 22.6, 22.5, 22.2, 14.4; MS m/z (M+) calcd 268.1675, obsd 268.1668. Long range DEPT from H-9 (S 1.33): 172.6 (C-1, 3J) 82.4 (C-4, 3J) 51.6 (C-5, 2J) 35.4 (C-6 or 7). General Procedure for Acetylide Anion Additions. The apparatus was flame-dried under argon, an atmosphere of which was 205 maintained until quench. The vinyl halide (1.07 - 1.25 equiv) was dissolved in anhydrous THF (10 mL), cooled to -78 °C, treated dropwise with ferf- butyllithium (2.14 -1.50 equiv), and stirred for 30 min. In a separate flask, a monosubstituted acetylene (2-5 equiv) was dissolved in THF at -78 °C, treated with n-butyllithium (2-5 equiv), and stirred at -78 °C for 30 min (one example used fe/t-butyllithium). A solution of diisopropyl squarate (198 mg, 1.0 mmol) in THF (4 mL) was cooled to -78 °C and cannulated into the solution of the first anion. After 30 min, the second anion was similarly introduced. In many cases, a chelating agent (a diamine or [12]crown-4) was pre-mixed with the acetylide. The reaction mixture was stirred at -78 °C for 0 - 20 h, 0 °C for 0 - 3 h, and at rt for 1.- j 6 h, quenched with deoxygenated saturated NH 4CI solution at 0 °C (6 mL), stirred for 0 -16 h under argon, and partitioned between water (25 mL) and ether (25 mL). The usual workup followed. (3aR\5aS\8aR*).5a,6,7,8-Tetrahydro-3a- ^2 ^ hydroxy-2,3-diisopropoxy-5-methyl- ;-PrO OH ^ cyclopenta[c]pentalen-1 (3aH)-one (87). Using the general procedure, 198 mg (Immol) of diisopropyl squarate in THF was added to a solution of the first anion generated from 210 mg (1.07 mmol) of 1 -iodocyclopentene and 1.26 mL (2.14mmol) of ferf-butyllithium. Excess propyne was condensed into a flask containing 10 mL of THF at -78 °C, and 3 mL (4.8 mmol) of rr-butyllithium was added dropwise. After 30 min, this anion was cannulated into the reaction mixture. The following reaction times were used: 1, 16, 0, 16 h. Typical work-up yielded 165 mg (54%) of 87 as a white solid, mp 106 °C; IR 206 (CHCIs, cm-1) 3580, 1690, 1615, 1380, 1305, 1260, 1100; NMR (300 MHz, CDCI3) Ô 5.41 (m, 1 H), 5.29 (heptet, J = 6 Hz, 1 H), 4.86 (heptet, J = 6 Hz, 1 H), 2.79 (m, 1 H), 2.29 (s, 1 H), 2.02-1.96 (m, 1 H), 1.80-1.70 (m, 3 H), 1.61 (d, J = 1 Hz, 3 H), 1.59-1.47 (m, 2 H), 1.29 (d, J = 6 Hz, 3 H), 1.25 (d, J = 6 Hz, 3 H), 1.16 (d, J = 6 Hz, 3 H), 1.15 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CDCI3 ) ppm 202.9, 169.1, 146.3, 130.7, 126.3, 85.2, 73.7, 71.8, 63.9, 57.3, 31.0, 30.3, 26.7, 22.6, 22.5 (2 C), 22.4, 15.3; MS m/z{M+) calcd 306.1831, obsd 306.1831. Anal. Calcd for C 18 H26O4: 0, 70.55; H, 8.56. Found: C, 70.73; H, 8.60. Long-range DEPT from H -6 (8 3.20): 202.9 (0-1, 3J), 146.3 (C-7, 2j), 126.3 (C-8 , 3J), 85.2 (C-4, 3J), 30.3, 26.7 (2 of C-9, 10, 11). In a similar example using TMEDA with work-up immediately following quench, a 40% yield of 87 was isolated. (3afl*,5aS*,8aff*)-5a,6,7,8-Tetrahydro- 3a-hydroxy-2,3-diisopropoxy-5- /■-Pro OH phenylcyclopenta[c]pentaien-1(3aH)- one (88). Using the general procedure, the following quantities of reagents were mixed: 198 mg (1 mmol) of diisopropyl squarate, 210 mg (1.07 mmol) of 1-iodocyclopentene, 1.26 mL (2.14 mmol) of ferf-butyllithium, 0.55 mL (5.0mmol) of phenylacetylene, and 2.94 mL (5 mmol) of ferf-butyllithium for the following reaction times: 1, 0 , 16, 0 h. Typical work-up yielded 101 mg (27%) of 88 as a white solid, mp 170-171 °C; IR (CHCI3, cm-1) 3585, 2980, 1675, 1605; 1R NMR (300 MHz, CDCI 3) 8 7.43-7.42 (m, 2H), 7.41-7.25 (m, 3H), 6.19 (s, 1H), 5.35 (heptet, J = 6 Hz, 207 1H), 4.96 (heptet, J= 6 Hz, 1H). 3.57-3.54 (m, 1H), 2.49 (s, 1H), 2.15-2.11 (m, 1H), 2.08-2.00 (m, 1H), 1.98-1.80 (m, 2H), 1.65-1.59 (m, 2H), 1.37 (d, J = 6 Hz, 3H), 1.30 (d, J = 6 Hz, 3H), 1.22 (d, J = 6 Hz, 3H), 1.18 (d, J = 6 Hz, 3H); 13C NMR (75 MHz, CDCI3) ppm 202.1, 168.8, 147.7, 134.6, 131.0, 128.4, 128.1, 126.7, 125.7, 85.0, 74.1, 72.0, 63.7, 53.9, 32.0, 31.4, 27.0, 22.7 (2C), 22.6, 22.5; MS m/z(M+) calcd 368.1987, obsd 368.1992. Anal. Calcd for C 23H28 O4: C, 74.96; H, 7.66. Found: 0, 74.80; H, 7.72. Long-range DEPT from H -6 (ô 3.56): 202.1 (0-1, 3J), 147.7 (C-7, 2J), 125.7 (C-8 , 3J), 134.5 (C-9, 3J), 85.0 (C-4, 3J), 63.7 (C-5, 2J). 1 ( H (3a/?*,5aS*,8a/?*)-5a,6,7,8-Tetrahydro- /-PrO 41^ ^ CH 2 OCH 3 3a-hydroxy-2,3-diisopropoxy-5- Q i-PrO ÔH (methoxymethyl)cyclopenta[c]pentalen- 89 1(3aH)-one (89): Using the general procedure, the following quantities of reagents were mixed: 198 mg (Immol) of diisopropyl squarate, 216 mg ( 1.1 mmol) of 1-iodocyclopentene, 1.29 mL (2.2 mmol) of fe/t-butyllithium, 140 mg (2.0 mmol) of methyl progargyl ether, 1.25 mL (2.0 mmol) of n-butyllithium, and 0.47 mL (3.1 mmol) of TMEDA for the following reaction times: 2, 0, 16, 0 h. Typical work up yielded 83 mg (25%) of 89 as a colorless oil; IR (neat, cm'"') 3420, 1690, 1600; 1H NMR (300 MHz, CDCI3) 5 5.71 (d, J= 1.2 Hz, 1 H), 5.29 (heptet, J = 6 Hz, 1 H), 4.88 (heptet, J = 6 Hz, 1 H), 3.86 (s, 2 H), 3.27 (s, 3 H), 2.95-2.93 (m, 1 H), 2.41 (s, 1 H), 2.03-1.97 (m, 1 H), 1.78-1.71 (m, 3 H), 1.63-1.51 (m, 2 H), 1.31 (d, J=6Hz,3H), 1.27 (d, J= 6 Hz, 3 H), 1.17 (d, J= 6 Hz, 3 H), 1.15 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 202.6, 168.7, 146.6, 208 130.8, 127.3, 84.9, 73.9, 71.9, 70.0, 63.8, 58.3, 54.0, 30.9, 30.8, 26.9, 22.6 (2 C), 22.5, 22.4; MS m/z(M+) Calcd 336.1937, obsd 336.1937. Anal. Calcd for C 19 H28 O5: G, 67.83; H, 8.39. Found: C, 67.98; H, 8.42. Long-range DEPT from H -6 (5 2.94): 202.6 (C-1, 3J), 146.6 (C-7, 2J), 127.3 (C-8 , 3J), 84.8 (C-4, 3J), 70.0 (C-12, 3J) 30.9, 30.8, 26.9 (C-9, 10, 11). Q. 9 CH (3afl*,6a/?*)-6,6a-Dihydro-3a-hydroxy-2,3- /-PrO diisopropoxy-5,6a-dimethyl-1(3aH)- 8 /-PrO ÔH pentalenone (90): Using the general 90 procedure, 336 mg (1.7 mmol) of diisopropyl squarate in THF was added to a solution of the first anion generated from 0.185 mL (2.1 mmol) of 2 -bromopropene and 2.5 mL (4.25 mmol) of fe/t- butyllithium. Excess propyne was condensed into a flask containing 10 mL of THF at -78 °C, and 2.1 mL (3.36 mmol) of n-butyllithium was added dropwise. After 15 min, [12]crown-4 (592 mg, 3.36 mmol) was also added. After 30 min, this anion was cannulated into the reaction mixture. The following reaction times were used: 0, 1, 1, 16 h. Typical work-up yielded 335 mg (71%) of 90 as a colorless oil; IR (neat, cm'i) 3430, 1690, 1610, 1380, 1110, 1030; ^H NMR (300 MHz, CDCI 3) 6 5.48 (m, 1 H), 5.33 (heptet, J = 6 Hz, 1 H), 4.86 (heptet, J = 6 Hz, 1 H), 2.56 (dm, J = 18 Hz, 1 H), 2.19 (dm, J = 18 Hz, 1 H), 2.16 (s, 1 H), 1.65 (m, 3 H), 1.33 (d, J = 6 Hz, 3 H), 1.29 (d, J = 6 Hz, 3 H), 1.22 (s, 3 H), 1.19 (d, J= 6 Hz, 3 H), 1.17 (d, J= 6 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 203.1, 168.2, 144.6, 130.4, 126.5, 86.2, 74.0, 71.9, 54.1,45.4, 22.7 (2 C), 22.3 (2 C), 19.3, 16.7; MS m/z(M+) calcd 280.1674, obsd 280.1679. 209 Anal. Calcd for C 16H24O4: C, 68.55; H, 8.63. Found: C, 68.63; H, 8.56. Two previous examples of this reaction were done without addition of the ionophore. In one case, work-up commenced immediately following quench (54% yield), while the second reaction was allowed to stir an additional 16 h after quench (56% yield). Q. 9CH3 (3afl*,6a/?*)-5-(1-Cyclohexen-1-yl)-6,6a- dihydro>3a-hydroxy-2,3-diisopropoxy-6a- 8 /-PrO OH methyl-1 (3aH)-pentalenone (91). Using 91 the general procedure, the following quantities of reagents were mixed: 198 mg (Immol) of diisopropyl squarate, 0.11 mL (1.25 mmol) of 2-bromopropene, 1.5 mL (2.5 mmol) of fe/t-butyllithium, 212 mg (2.0 mmol) of 1-ethynylcyclohexene, 1.25 mL (2.0 mmol) of n- butyllithium, and 352 mg (2.0 mmol) of [12] crown-4 for the following reaction times: 0, 3, 16, 16 h. Typical work-up yielded 86 mg (25%) of 91 as a colorless oil; IR (neat, cm-i) 3408, 1693, 1605; iR NMR (300 MHz, CeDe) 5 5.77 (s, 1 H), 5.57 (dd, J= 4, 4 Hz, 1 H), 5.32 (heptet, J = 6 Hz, 1 H), 5.23 (heptet, J = 6 Hz, 1 H), 3.06 (dd, J = 17, 1 Hz, 1 H), 2.38 (s, 1 H), 2.37 (dd, J = 16, 1.5 Hz, 1 H), 2.00-1.85 (m, 4 H), 1.45-1.32 (m, 4 H), 1.45 (s, 3 H), 1.18 (d, J=6Hz,3H), 1.14(d, J=6Hz,3H), 1.11 (d, J = 6 Hz, 3 H), 1.10(d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) Ppm 202.7, 168.0, 146.0, 133.0, 130.9, 128.1, 124.5, 86.2, 73.7, 71.6, 53.5, 41.5, 25.9, 22.9, 22.8 (2 C), 22.7, 22.5, 22.4, 20.0 (one C overlapped); MS m/z (M+) calcd 346.2144, obsd 346.2142. 210 0 (3a/?*,6a/î*)-5-Ethoxy-6,6a- ^ y-PrO\ ^ ^ diisopropoxy- 6 a-methyl- /-PrO OH 0C2H5 1(3aH)-pentalenone (92) and 4-(Ethoxyethynyl)-4- hydroxy-2,3-dilsopropoxy-5,5-dlmethyl-2-cyclopenten-1-one (98). Using the general procedure, the following quantities of reagents were mixed: 198 mg (1 mmol) of diisopropyl squarate, 0.11 mL (1.25 mmol) of 2-bromopropene, 1.5 mL (2.5 mmol) of fe/t-butyllithium, 280 mg (2.0 mmol) of ethyl ethynyl ether (50% in hexane), 1.25 mL (2.0 mmol) of n- butyllithium, and 352 mg (2.0 mmol) of [12]crown-4 for the following reaction times: 20, 1, 1, 16 h. Typical work-up yielded 114.5 mg (37%) of 92 and 110 mg (36%) of 98. For 92: white solid, mp 116-117 °C; IR (CHCI 3, cm-i) 3590, 1695, 1620; 1H NMR (300 MHz, CeDe) 5 5.35 (heptet, J = 6 Hz, 1 H), 5.20 (heptet, J = 6 Hz, 1 H), 4.71 (s, 1 H), 3.42-3.26 (m, 2 H), 2.97 (dd, J= 17, 1.2 Hz, 1 H), 2.35 (dd, J=17, 1.7 Hz, 1 H), 2.13(s, 1 H), 1.38 (s, 3 H), 1.19 (d, J = 6 Hz, 6 H), 1.13(d, J = 6 Hz, 3H), 1.09 (d, J= 6 Hz, 3 H), 0.95 (t, J= 7 Hz, 3 H); 130 NMR (75 MHz, GDCI3) ppm 201.1, 167.8, 160.8, 129.7, 97.7, 83.1, 72.6, 70.6, 64.0, 50.8, 40.2, 21.9, 21.8, 21.7, 21.5, 19.1, 13.3; MS /n/z(M+) calcd 310.1780, obsd 310.1791. Anal. Calcd for C 17H26O5: C, 65.78; H, 8.44. Found: C, 65.58; H, 8.44. For 98: colorless oil; IR (neat, cm-i) 3427, 1703, 1626; 1R NMR (300 MHz, CeDe) Ô 5.33 (heptet, J = 6 Hz, 1 H), 5.22 (heptet, J=6 Hz,1 H), 3.52 (q, J = 7 Hz, 2 H), 2.63 (s, 1 H), 1.47 (s, 3 H), 1.40 (s, 3 H), 1.19 (d, J = 6 Hz, 3 211 H), 1.16 (d, J = 6 Hz, 3 H), 1.11 (d, J= 6 Hz, 3 H), 1.10 (d, J= 6 Hz, 3 H), 0.87 (t, J= 7 Hz. 3 H): 13C NMR (75 MHz, CeDe) ppm 201.4, 164.0, 129.1, 94.8, 73.5, 73.2, 72.9, 70.7, 49.0, 37.5, 22.9, 21.8, 21.7, 21.6, 20.7, 13.0 (one C overlapped): MS m/z (M+) calcd 310.1780, obsd 310.1795. 0, 9CH3 Q. 9CH3 (3afl*,6afl*)-6,6a- /-PrO dihydro-3a-hydroxy- 8 /-PrO OH 93 0 % 101 2,3-diisopropoxy-6a- mèthyl-5-phenyl- 1(3aH)-pentalenone (93) and (3a/î*,6a/?*)-6,6a-dihydro-2- hydroxy-3,3a-diisopropoxy-6a-methyl-5-phenyl-1(3aH)- pentalenone (101). Using the general procedure, the following quantities of reagents were mixed: 198 mg (1 mmol) of diisopropyl squarate, 0.11 mL (1.25 mmol) of 2-bromopropene, 1.5 mL (2.5 mmol) of fe/t-butyllithium, 0.22 mL (2.0 mmol) of phenylacetylene, 1.25 mL (2.0 mmol) of n-butyllithium, and 352 mg (2.0 mmol) of [12]crown-4; for the following reaction times: 0, 3, 16, 0 h. Typical work-up yielded 60 mg (18%) of 93, 70 mg (20%) of 101, and 74 mg (22%) of the phenyl derivative of by-product 98 (see Chapter 3). In a similar run in which the reaction mixture was stirred for an additional 16 h under argon following quench, no improvement in efficiency was observed. For 93: colorless oil; IR (CHCI 3 , cm-i) 3580, 2990, 1695, 1620; 1R NMR (300 MHz, CeDe) 5 7.20-7.15 (m, 2H), 7.06-7.01 (m, 3H), 6.24 (dd, J = 1.7, 1.7 Hz, 1H), 5.32 (heptet, J = 6 Hz, 1H), 5.24 (heptet, J = 6 Hz, 1H), 3.21 (dd, J = 18, 1.7 Hz, 1H), 2.50 (dd, J = 18, 1.7 Hz, 1H), 2.24 (s, 1H), 1.44 (s, 3H), 1.18(d, J = 6 Hz, 3H), 1.13 (d, J= 6 Hz, 3H), 1.10 (d, J = 6 Hz, 6 H); 13C NMR (75 MHz, CeDe) ppm 202.0, 167.4, 144.1, 135.2, 130.9, 128.3, 128.1, 212 126.3, 126.1, 86.0, 73.6, 71.4, 53.6, 42.1, 22.6, 22.5, 22.4, 22.3, 19.5; MS m/z(M+) calcd 342.1832, obsd 342.1828. Long-range DEPT from H-9 (Ô 1.44): 202.0 (C-1, 86.0 (0-4, 3J), 53.6 (0-5, 2J), 42.1 (0-6, 3J). For 1 0 1 : colorless oil; IR (OHOI3, cm-i) 3 4 9 0 , 2981, 1710, 1626; 1H NMR (300 MHz, OeDe) ô 7.16-7.13 (m, 3H), 7.06-7.03 (m, 3H), 6.49 (s, 1H), 5.29 (heptet, J = 6 Hz, 1H), 3.92 (heptet, J = 6 Hz, 1H), 3.08 (dd, J = 18, 1.5 Hz, 1H), 2.42 (dd, J= 17, 2 Hz, 1H), 1.40 (s, 3H), 1.21 (d, J = 6 Hz, 3H), 1.19 (d, J = 6 Hz, 3H), 1.12 (d, J = 6 Hz, 3H), 1.07 (d, J = 6 Hz, 3H); 130 NMR (75 MHz, OeDe) ppm 202.9, 162.5, 144.9, 135.4, 130.4, 128.6, 128.4, 126.4, 124.3, 91.2, 74.5, 67.8, 54.3, 42.4, 24.9, 24.5, 22.9, 22.8, 20.5; MS m/z(M+) calcd 342.1832, obsd 342.1831. Long-range DEPT from H-9 (8 1.40): 202.9 (0-1, 3J), 9 1 .2 (0-4, 3J), 54.3 (0-5, 2J), 42.3 (0-6, 3J). INEPT from H-11 (0-methine) (8 5.29): 0-3 (162.6, 3J). INEPT fromH-10 (0-methine) (8 3.92): 0-4 (91.2,3J). 0 , SCHs (3afl*,6afl*)-6,6a-dlhydro-3a-hydroxy-2,3- ^ diisopropoxy-6a-methyl-1(3aH)-pentalenone 8 /■-PrO OH (9 4 ): Using the general procedure, the following 94 quantities of reagents were mixed: 198 mg (1 mmol) of diisopropyl squarate, 0.11 mL (1.25 mmol) of 2-bromopropene, 1.5 mL (2.5 mmol) of ferf-butyllithium, and 920 mg (10 mmol) of lithium acetylide ethylenediamine c o m p le x .^ The acetylide was weighed in a dry box. The reaction times were as follows: 0, 0, 3, 16 h. Typical work-up yielded 49 mg (18%) of 94 as a colorless oil; IR (neat, cm-i) 3420, 2975, 1693,1613; 213 1H NMR (300 MHz, CDCI3) ô 5.86-5.76 (m, 2 H), 5.33 (heptet, J = 6 Hz, 1H), 4.87 (heptet, J = 6 Hz, 1H), 2.66 (ddd, J= 20, 2, 2 Hz, 1H), 2.26 (ddd, J = 18, 2, 2 Hz, 1H), 2.29 (brs, 1H), 1.32 (d, J = 6 Hz, 3H). 1.29 (d, J = 6 Hz, 3H), 1.23 (s, 3H),1.19 (d, J = 6 Hz, 3H), 1.18 (d, J = 6 Hz, 3H); i^C NMR (75 MHz, CDCI3) ppm 203.0, 167.9, 134.0, 132.3, 130.5, 8 6 .0 , 74.1, 72.0, 53.2, 41.6, 22.6 (3C), 22.3, 19.0; MS m/z(M+) calcd 342.1832, obsd 342.1828. Long range DEPT from H-9 (ô 1.23): 203.0 (C-1, 3J). 86.0 (0-4, 3J), 53.2 (C-5, 2J), 41.6 (C-4, 3J). 1OCH3 g ^ (3a/?*,6fl*,6a/?*)-6,6a-Dihydro-3a-hydroxy- /-PrO—(\ a\ 2,3-dilsopropoxy-5,6-dimethyl-1(3aW)- 8 /■-PrO OH g g pentalenone (95): Using the general procedure, 198 mg (1 mmol) of diisopropyl squarate in THF was added to a solution of the first anion generated from 0.10 mL (1.15 mmol) of (£)-1-bromopropene and 1.35 mL (2.3 mmol) of fe/t-butyllithium. Excess propyne was condensed into a flask containing 10 mL of THF at -78 °C, and 3 mL (4.8 mmol) of n-butyllithium was added dropwise. After 30 min, this anion was cannulated into the reaction mixture. The following reaction times were used: 1, 16, 0, 16 h. Typical work-up yielded 1 10 mg (39%) of 95 as a colorless oil; IR (CHCI 3, cm-i) 3588, 1695, 1615, 1381, 1307, 1098; 1H NMR (300 MHz, CeDe) 6 5.49 (m, 1 H), 5.30 (heptet, J = 6 Hz, 1 H), 5.24 (heptet, J = 6 Hz, 1 H), 2.69-2.66 (m, 1 H), 2.62 (d, J = 3 Hz, 3 H), 2.53 (s, 1 H), 1.34-1.33 (m, 3 H), 1.31-1.27 (m, 1 H), 1.17-1.11 (m, 12 H); 13C NMR (75 MHz, CeDe) ppm 198.8, 168.6, 148.9, 128.3, 126.0, 84.9, 73.6, 71.7, 62.6, 44.6, 22.9, 22.8, 22.7, 22.6, 20.9, 14.7; MS m/z(M+) calcd 280.1675, obsd 280.1674. 214 Anal. Calcd for C 16H24O4: C, 68.55; H, 8.63. Found: 68.70; H, 8.69. (in acetone-c% solution) In’adiate Observe % NOE OH (5 2.89) H-5 1 H-5 (5 2.31) H-6 1 H-10 12 H-10 (5 1.20) H-5 5 In a similar reaction in which work-up immediately followed quench, only an 11% yield of product was isolated. (3afl*,6aS*,6bS*,9afl*,9bS*)-5,6-Diethyl- 1,2,3,6a,6b,7,8,9,9a,9b-decahydro-6a- H3C ^ _ H3C OH hydroxy-4//-dicyclopenta[a,b]pentalen-4-one 103 (103). Cyclopentenyllithium was generated from the iodide (588 mg, 3.0 mmol) and fe/t-butyllithium (3.52 mL of 1.7 M, 6.0 mmol) as previously described. This solution was cannulated into a slurry of dried cerium trichloride (from 1.12 g of the heptahydrate) in THF (10 mL) at -78 °C. After 2 h, a solution of 103 (138 mg, 1.0 mmol) in 5 mL of THF was added and the reaction mixture was stirred at -78 °C for 3 h and at rt overnight prior to quenching with saturated NH 4GI solution (6 mL). The usual workup gave 63 mg (23%) of 103 as colories crystals, mp 123-124 °C; IR (CHCI 3, cm-i) 3580, 1690, 1630, 1500, 1350; ^H NMR (300 MHz, CDGI 3) 52.55-1.34 (m, 2 H), 2.31-2.14 (m, 3 H). 2.07-1.88 (m, 3 H), 1.83-1.51 (m, 8 H), 1.46-1.36 (m, 2 H), 1.20-1.07 (m, 1 H), 1.17 (t, J = 8 Hz, 3 H), 1.01 (t, J = 8 Hz, 3 H) (OH signal not seen); 13G NMR (75 MHz, GDGI 3) ppm 211.3, 170.6, 145.2, 85.8, 74.9, 56.1,48.9, 47.8, 31.3, 28.5, 27.7, 26.1,23.3, 21.9, 21.7, 16.9, 14.2, 13.0; MS m/z(M+) calcd 274.1932, obsd 274.1931. 215 (3a/?*,6a/î*,6bS*,9aS*,9bfl*)-5,6-Diethyl- 1,2,6a,6b,8,9,9a,9b-Octahydro-6a-hydroxy- 4H-pentaleno[1,2-b:3a,3b"]difuran-4-one (13) 104 (104). The anion was generated from 0.23 mL (3 mmol) of of 2,3-dihydrofuran and 1.76 mL (3 mmol) of ferf-butyllithium as previously described. Subsequently, 138 mg (1 mmol) of 102 in 5 mL of THF was cannulated into the solution of the anion at -78 °C. Reaction was continued according to method A for 1, 4, 16 h. Typical work-up yielded 16 mg ( 6 %) of 104 as a colorless oilr IR (CHCI 3, cm*i) 3520, 2980, 1700, 1630, 1450, 1370, 1350; iR NMR (300 MHz, CeDe) 54.15-4.10 (m, 1 H), 3.93-3.86 (m, 1 H), 3.89 (d, J= 5 Hz, 1H), 3.70-3.63 (m, 1 H), 3.50-3.42 (m, 1H), 3.29 (s, 1H), 2.49-2.40 (m, 1 H), 2.31 (q, J = 8 Hz, 1H), 2.20 (q, J = 8 Hz, 1H), 2.18- 2.03 (m, 2H), 1.99-1.89 (m, 1H), 1.65-1.54 (m, 1H), 1.45-1.34 (m, 3H), 1.08 (t, J = 8 Hz, 3 H) 0.96 (t, J = 8 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 205.8, 170.1, 143.2, 94.1, 87.2, 84.1, 71.7, 69.0, 47.9, 42.2, 30.2, 28.6, 20.6, 16.7, 13.4, 12.6; MS m/z(M+) calcd 278.1518, obsd 278.1521. Long-range DEPT from H -6 (6 2.44): 205.8 (C-1, 3J), 87.2 (C- 8 , 3J), 84.1 (C-4, 3J), 30.2 (C-12, 2J), 28.6 (C-10, 3J). Long-range DEPT from H-7 (5 1.95): 68.9 (C-9, 3J), 47.9 (C- 6 , ^J) 30.2 (C-12, 3J), 28.6 (C-10, 2 J). 216 Irradiate Observe % NOE OH (53.28) H-8 2.1 H-7 (51.95) H-10 5.4 H-6 5.7 H-8 5.3 H-6 (5 2.44) H-7 4.5% H-12 3.5% A separate reaction using the same quantities and prior conversion of the lithium anion to the cerium compound as above for 1, 0 , 16 h provided after work-up 46 mg (24%) of 105 and 63 mg (32%) of 106. 0 For 105: colorless oil; IR (neat, cm'i) 3420, 2980, ^ 3C 1740, 1700; NMR (300 MHz, CDCI3) 5 4.16 (t,J = 105 6 .6 Hz, 2H), 2.55-2.37 (m, 4H), 2.25-2.13 (m, 2 H), 2.11- 1.93 (m, 2 H), 1.10 (t, J=7.6 Hz, 6 H) ; 13C NMR (75 MHz, CDCI3) ppm 2 0 2 .8 , 159.1, 79.2, 71.6, 32.5, 26.5, 17.4, 12.4; MS m/z (M+) calcd 208.1099, obsd 208.1104. Anal. Calcd for C 12H16O3: C, 69.21; H, 7.74. Found: 69.67; H, 8.09. For 106: colorless oil; IR (neat, cm*'') 3440, 2980, 1710, 1635; ^H NMR (300 MHz, CDCI 3) 5 OH HO 4.70 (s) 1H, 4.10-3.94 (m, 1H), 3.87-3.77 (m, 106 1H), 3.60-3.40 (m, 2H), 2.69-2.45 (m, 1H), 2.43- 1.61 (m, 12H), 1.05 (t, J= 11 Hz, 3H) .98 (t, J= 11 Hz, 3H); 130 NMR (75 MHz, CDCI3) ppm 209.1, 204.2, 167.2, 144.8, 93.4, 89.0, 71.0, 60.9, 33.8, 33.2, 30.2, 27.0, 20.0, 17.2, 12.8, 12.7; MS,m/z(M+- H 2O) calcd 278.1518, obsd 278.1499. 217 3-lsopropoxy-4-(1 -propynyl)-3>cyclobutene-1,2- ^ ^ ^ dione (109). Propyne (ca 2 mL) was condensed into a ' 0 flame-dried flask under argon at -78 °C. THF (25 mL) 109 was slowly introduced by syringe followed by the dropwise addition of n-butyllithium (8.0 mL of 1.36 M, 11 mmol). The reaction mixture was stirred at -78 °C for 30 min and treated with a precooled (-78 °C) solution of diisopropyl squarate (2.0 g, 10 mmol) in THF (25 mL) via cannula. Reaction was allowed to proceed for 1 h at -78 °C prior to the addition of trifluoroacetic anhydride (1.9 mL, 13.5 mmol). Stirring was maintained for 15 min, at which point saturated NH 4CI solution (30 mL) was added and the temperature allowed to warm to 20 °C. Brine (50 mL) was added and the product was extracted into ether (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried, and evaporated to give 1.75 g (97%) of 109 as yellow crystals, mp 99-100 °C (from ether- petroleum ether); IR (CHCI 3, cm-i) 2220, 1800, 1770, 1590, 1400; ^H NMR (200 MHz, CDCI3) S 5.38 (heptet, J = 6 Hz, 1 H), 2.27 (s, 3 H), 1.50 (d, J = 6 Hz, 6 H); 13C NMR (50 MHz, CDCI3) ppm 196.2, 195.4, 191.5, 162.3, 118.6, 80.6, 66.9, 22.5, 6.0; MS m/z(M+) calcd 178.0629, obsd 178.0631. /■-Pro /-Pro CH3 (3a/?*,6f?*,6afl*). MegSi 7 4,5,6,6a-Tetra- 11s " o ^ " c H 3 111 0^ o h \ h 3 hydro- 6 a-hydroxy- 3-isopropoxy-3a,6- dimethyl-2-[(trimethylsilyl)ethynyl]-1 (3aH)-pentalenone (111) and (3aff*,6S*,6a/?*)“4,5,6,6a-Tetrahydro-6a-hydroxy-3- isopropoxy-3a,6-dlmethyl-2-[(trlmethylsllyl)ethynyl]-1(3aH)- 218 pentalenone (115). According to method A, 236 mg (1.0 mmol) of 108, 0.20 mL (2.25 mmol) of 2 -bromopropene, and 2.65 mL (4.5 mmol) of ferf- butyllithium were combined and stirred for 1,16, and 4 h. The reaction mixture was subsequently cooled to -78 °C and quenched. Typical work-up provided 35 mg (11%) of 111 and 6 8 mg (21%) of 115. For 111: white solid, mp 113-115 °C; IR (CHCI 3, cm'i) 3570, 2160, 1700, 1580, 1320, 1110; 1H NMR (300 MHz, CeDe) 5 5.70 (heptet, J = 6 Hz, 1 H), 2.72 (s, 1 H), 1.95-1.88 (m, 1 H), 1.76-1.72 (m, 1 H), 1.70-1.42 (m, 1 H), 1.37-1.31 (m, 2 H), 1.22 (s, 3 H), 1.10 (d, J = 6 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 0.94 (d, J = 7 Hz, 3 H), 0.16 (s, 9 H); NMR (75 MHz, CDCI 3) ppm 204.2, 190.7, 100.0, 95.9, 95.3, 85.5, 75.3, 55.8, 41.5, 34.6, 32.1, 22.7, 22.5, 20.0, 13.2, -0.2; MS m/z(M+) calcd 320.1808, obsd 320.1810. Long-range DEPT from H-10 (Ô 1.22): 190.7 (C-1, 3J), 85.5 (0-4, 3J), 55.8 (C-5, 2J), 34.6 (C-6 , 3J). Long-range DEPT from H -8 (8 1.95-1.88): 204.2 (C-3, 3j), 34.6 (C- 6 , 3J). Irradiate Observe % NOE OH H-10 1 H-9 3 H-8 2 H-6a H-8 2 H-1 3 H-6P H-10 2 H-9 1 H-10 H-ep 3 OH 2 H-9 OH 0.6 H-7P 3 219 For 115: white crystals, mp 108-109 °C; IR (CHCI 3, cm'i) 3560, 2160, 1700, 1685; NMR (300 MHz, CDCI 3) 6 5.72 (heptet, J = 6 Hz, 1 H), 3.01 (s, 1 H), 2.02-1.91 (m, 2 H), 1.69-1.60 (m, 1 H), 1.50-1.39 (m, 1 H), 1.35 (d, J = 6 Hz, 6 H), 1.11 (s, 3 H), 0.94 (d, J = 7 Hz, 3 H), 0.98-0.83 (m, 1 H), 0.16 (s, 9 H); 13c NMR (75 MHz, CDCI 3) ppm 203.2, 189.5, 100.3, 99.2, 94.8, 86.3, 75.2, 56.0, 46.8, 34.8, 30.5, 22.6, 22.3, 19.0, 15.0, - 0 .2 ; MS m/z (M+) calcd 320.1808, obsd 320.1813. Long-range DEPT from H-10 (Ô 1.11): 189.5 (0-1, 3j), 86.3 (C-4, 3J), 55.8 (C-5, 2J), 34.2 (C-6 , 3J) Stereochemistry determined by comparison of coupling patterns in 1H NMR with similar samples. (3afl*,6/?*,6a/î*)-2- Ethynyl-4,5,6,6a- 8 \ 9 112 tetrahydro- 6 a- 0 OH CM 3 0 OH CHs hydroxy-3-isoprop- oxy-3a,6-dimethyl-1(3aH)-pentalenone (112) and (3a/?*, 6 S*, 6a/?*)-2-Ethynyl-4,5,6,6a-tetrahydro-6a-hydroxy-3-isopropoxy- 3a,6-dimethyl-1(3a//)-pentalenone (116). From 236 mg (1.0 mmol) of 108, 0.33 mL (3.75 mmol) of 2-bromopropene, and 4.4 mL (7.5 mmol) of fe/t-butyllithium, according to method A for 2, 15, 0 h, there was obtained 60 mg (24%) of 112 and 40 mg (16%) of 116. For 112: white solid, mp 112-113 °C; IR (CHCI 3, cm-i) 3550, 3300, 1690, 1580, 1450, 1380, 1320; ^H NMR (300 MHz, CDCI 3) 5 5.67 (heptet, J = 6 Hz, 1 H), 3.18 (s, 1 H), 2.58 (s, 1 H), 2.07-2.00 (m, 1 H), 1.89-1.79 (m, 1 H), 1.68-1.46 (m, 3 H), 1.38 (d, J= 6 Hz, 6 H), 1.18 (s, 3 H), 0.99 (d, J= 7 H z, 220 3 H): 13C NMR (75 MHz, CDCI3) ppm 204.5, 190.7, 94.7, 85.5, 82.7, 75.5, 74.3, 55.8, 41.4, 34.5, 31.9, 22.5, 22.2, 19.9, 13.2; MS m/z(M+) calcd 248.1412, obsd 248.1414. Long-range DEPT from H-10 (Ô 1.18): 190.7 (C-1, 3J), 85.5 (C-4, 3j), 55.8 (C-5, 2J), 34.5(C-6, 3j). Stereochemistry determined by comparison of coupling patterns In NMR with similar samples. For 116: white crystals, mp 107-108 °C; IR (CHCI 3, cm*i) 3550, 3310, 2 1 0 0 , 1700, 1570, 1450, 1380, 1320; 1R NMR (300 MHz, CDCI 3) 5 5.66 (heptet, J = 6 Hz, 1 H), 3.20 (s, 1 H), 3.02 (s, 1 H), 2.05-1.96 (m, 2 H), 1.71 -1.63 (m, 1 H), 1.52-1.42 (m, 1 H), 1.38 (d, J = 6 Hz, 3 H), 1.36 (d, J = 6 Hz, 3 H), 1.14 (s, 3 H), 0.94 (d, J = 7 Hz, 3 H), 0.98-0.83 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 203.4, 189.5, 97.9, 86.4, 83.1,75.4, 73.9, 56.1, 46.8, 34.7, 30.5, 22.5, 22.2, 19.0, 15.0; MS m/z(M+) calcd 248.1412, obsd 248.1415. Long-range DEPT from H -8 (S 2.05): 202.8 (C-3, 3j), 8 6 .6 (C-4, 2j), 30.8 (0-7, 2J). Long-range DEPT from H -6 (5 1.89): 188.7 (C- 1, 3j), 8 6 .6 (C-4, 3j), 56.5 (C-5, 2J), 47.2 (C-8 , 3j), 30.8 (C-7, 2j). Long-range DEPT from H -6 (8 1.25): 188.7 (C-1, 3 j), 56.1 (C-5, 2j), 30.8 (C-7, 2J). Long-range DEPT from H-9 (8 1.07): 86.6 (C-4, 3j), 47.2 (C-8 , 2j), 30.8 (C-7, 3j). Long-range DEPT from H-10 (81.20): 188.7 (C-1, 3J), 8 6 .6 (C-4, 3j), 56.1 (C-5, 3J), 35.1 (C-6 , 3j). 221 Irradiate Observe % NOE OH (5 3.55) H-8 2.5 H-9 1.5 H-ep (51.89) H-7p 9.5 H-8 (5 2.05) OH 1 H-7P 4 H-9 (51.07) H-7a 2 H-10 (5 1.20) H-6P 0.5 H-8 0.5 /-Pro /•-Pro H a C ^ ^ 117 8 \ 9 113 119 /-Pro OH CHs 0 OH CM 3 0 OH CH 3 9 (3afl*,6/?*,6a/?*)-4,5,6,6a-Tetrahydro-6a-hydroxy-3- isopropoxy-3a,6-dimethyl-2(1 -propynyl)-1 (3aA/)-pentaienone (113), (3af7*,6S*,6a/7*)-4,5,6,6a-Tetrahydro-6a-hydroxy-3- isopropoxy-3a,6-dimethyl-2(1 -propynyl)-1 (3aH)-pentalenone (117), and (3af7*,4S*,6a/7*)-4,5,6,6a-Tetrahydro-4,6a-dimethyi- 2(1-propynyl)-1(3aH)-pentalenone (119). From 180 mg (1.0 mmol) of 109, 0.35 mL (4.0 mmol) of 2-bromopropene, and 4.7 mL (8.0 mmol) of tert- butylllthium, according to method A for 3, 15, and 6 h, there was obtained 72 mg (28%) of 113, 33 mg (12% of 117, and 17 mg (7%) of 119. For 113: colorless oil, IR (CHCI3 , cm-i) 3555, 1692, 1586, 1384, 1319; 1H NMR (300 MHz, CeDe) 5 5.58 (heptet, J = 6 Hz, 1 H), 3.39 (s, 1 H), 2.03 (dd, J= 13.5, 7 Hz, 1 H), 1.81-1.72 (m, 1 H), 1.62 (s, 3 H), 1.56-1.46 (m, 1 H), 1.42-1.34 (m, 2 H), 1.28 (s, 3 H), 1.08 (d, J = 6 Hz, 3 H), 1.05 (d, J = 6 222 Hz, 3 H), 1.04 (d, J = 7 Hz, 3 H); NMR (75 MHz, CeDe) ppm 204.7, 188.2, 91.0, 85.7, 74.4, 71.0, 55.6, 41.8, 34.9, 32.1,22.3 (2 G), 22.2, 20.4, 13.7, 4.1; MS ah/ z (M + ) calcd 262.1569, obsd 262.1574. Long-range DEPT from H-10 (5 1.28): 188.2 (0-1, 3J), 85.7 (0-4, 3j), 55.6 (0-5, 2J), 34.9 (0-6, 3j). Stereochemistry determined by comparison of coupling patterns in i H NMR with similar samples. For 117: colorless oil; IR (OHOI3, cm'i) 3547, 1693, 1588, 1384, 1318; 1H NMR (300 MHz, OeDe) Ô 5.57 (heptet, J= 6 Hz, 1 H), 3.38 (s, 1 H), 2.06-1.99 (m, 1 H), 1.98-1.92 (m, 1 H), 1.60 (s, 3 H), 1.46-1.37 (m, 1 H), 1.33- 1.27 (m, 1 H), 1.23 (s, 3 H), 1.10 (d, J= 6 Hz, 3 H), 1.05 (d, J= 6 Hz, 3 H), 1.04 (d, J= 6 Hz, 3 H), 0.94-0.88 (m, 1 H); 13C NMR (75 MHz, OeDe) ppm 203.3, 186.8, 91.5, 86.5, 74.3, 70.7, 55.9, 47.2, 35.1, 30.9, 22.3 (2 0), 22.1, 19.4, 15.4, 4.1; MS m/z(M+) calcd 262.1569, obsd 262.1572. Long-range DEPT from H-10 (Ô 1.22): 186.8 ( 0 - 1 , 3j), 86.5 (0-4, 3j), 55.9 (0-5, 2J), 35.1 (0-6, 3j). Stereochemistry determined by comparison of coupling patterns in 1H NMR with similar samples. For 119: colorless oil; IR (OHOI3, cm'i) 3587, 1707, 1606; ^H NMR (300 MHz, OeDe) 5 5.46 (heptet, J = 6 Hz, 1 H), 2.12-2.06 (m, 1 H), 1.96-1.89 (m, 1 H), 1.71 (s, 1 H), 1.57 (s, 3 H), 1.37-1.21 (m, 2 H), 1.19 (s, 3 H), 1.18 (s, 3H), 1.16(d, J = 6 Hz, 3H), 1.10(s,3H), 1.02-0.77 (m, 1 H); 13C NMR (75 MHz, OeDe) ppm 205.8, 156.5, 130.3, 104.2, 85.2, 75.0, 72.2, 57.7, 46.7, 35.7, 30.9, 22.9, 22.6, 19.5, 15.5, 4.7; MS m/z(M+) calcd 262.1569, obsd 262.1547. 223 Long-range DEPT from H-10 (S 1.10): 205.8 (C-1, 3J), 85.2 (0-4, 3j), 57.7 (0-5, 2J), 35.7 (0-6, 3j). Long-range DEPT from H-11 (S 1.57): 156.5 (0-3, 5J), 130.3 (0-2, 4j), 104.1 (0-13, 3J), 74.9 (0-12, 2j). Stereochemistry determined by comparison of coupling patterns in ^ H NMR with similar samples. /-Pro /-Pro cH3g (3a/?*,6fl*,6afl*)- Ph = Ph—^ ^ 4,5,6,6a-Tetrahydro- 118 ^ } o H CH 3 111 0%^CH3 6a-hydroxy-3- isopropoxy-3a,6- dimethyl-2-(phenylethynyl)-1(3aH)-pentalenone (114) and (3a/?*,6S*,6a/?*)-4,5,6,6a-Tetrahydro-6a-hydroxy-3-isopropoxy- 3a,6-dimethyl-2-(phenylethynyl)-1(3aH)-pentalenone (118). From 240 mg (1.0 mmol) of 110, 0.35 mL (4.0 mmol) of 2-bromopropene, and 4.7 mL (8.0 mmol) of fe/t-butyllithium, according to method A for 1, 0, 16 h, there was isolated 26 mg ( 8 %) of 114 and 55 mg (17%) of 118. For 114: colorless solid, mp 126-128 °0; IR (OHOI 3, cm*'') 3557, 1695, 1604, 1579; NMR (300 MHz, OeDe) 6 7.45-7.41 (m, 2 H), 7.02-6.95 (m, 3 H), 5.63 (heptet, J= 6 Hz, 1 H), 3.15 (s, 1 H), 2.08-2.01 (m, 1 H), 1.82- 1.73 (m, 1 H), 1.57-1.50 (m, 1 H), 1.48-1.35 (m, 2 H), 1.29 (s, 3 H), 1.10 (d, J = 6 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 1.03 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, OeDe) ppm 203.7, 189.2, 131.7 (3 0), 128.7 (2 0), 123.9, 96.6, 94.6, 85.9, 81.3, 75.2, 56.0, 41.9, 35.1, 32.2, 22.4, 22.2, 20.4; 13.5; MS m/z(M+) calcd 324.1725, obsd 324.1725. 224 Long-range DEPT from H-10 (S 1.29): 189.2 (C-1, 3j), 85.9 (0-4, 3J), 56.0 (0-5, 2J), 35.1 (0-6, 3j). Stereochemistry determined by comparison of coupling patterns In ^ H NMR with similar samples. For 118: colorless solid, mp 118-119 °0; IR (OHOI 3, cm-"') 3550, 1697, 1605, 1582; NMR (300 MHz, OeDe) 5 7.44-7.36 (m, 2 H), 7.01-6.92 (m, 3 H), 5.61 (heptet, J = 6 Hz, 1 H), 3.64 (s, 1 H), 2.15-2.00 (m, 1 H), 1.99- 1.93 (m, 1 H), 1.50-1.40 (m, 1 H), 1.36-1.32 (m, 1 H), 1.29 (s, 3 H), 1.13 (d, J = 7 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 1.05 (d, J = 6 Hz, 3 H), 1.01 -0.85 (m, 1 H); 13C NMR (75 MHz, OeDe) ppm 202.8, 188.1, 131.6 (3 0), 128.7 (2 0), 123.9, 99.9, 95.0, 8 6 .8 , 80.9, 75.1, 56.2, 47.2, 35.2, 31.0, 22.4, 22.1, 19.5, 15.5; MS m/z(M+) calcd 324.1725, obsd 324.1723. Long-range DEPT from H-10 (5 1.29): 188.1 (0-1, 3j), 86.8 (0-4, 3j), 56.2 (0-5, 2J), 35.2 (0-6, 3j). Stereochemistry determined by comparison of coupling patterns In ^H NMR with similar samples. Ph CH3 (3aS*,4S*,6a/?*)-4,5,6,6a-Tetrahydro-6a- - 6 hydroxy-3a,6-dimethyl-2,3-diphenyl-1 {3aH)~ 0 'CH 3 pentalenone (122). From 234 mg (1.0 mmol) of 3,4- ^ dlphenylcyclobutene-1,2-dlone, 0.264 mL (3.0 mmol) of 2-bromopropene, and 3.5 mL (6.0 mmol) of tert-butylllthlum, according to method B for 0, 15, 0, and 3 h, there was Isolated 194 mg (61%) of 122 as a white, crystalline solid, mp 173-4 °0; IR (OHOI 3) 3545, 1701; ^H NMR (300 MHz, ODOI3) Ô 7.34-7.27 (m, 3 H), 7.21-7.07 (m, 7 H), 3.31 (s, 1H), 2.28-2.15 (m, 1H), 1.90-1.74 (m, 2H), 1.52 (ddd, J= 18, 12, 12 Hz, 1 H), 1.41 (s, 3H), 1.22-1.08 (m, 1H), 1.11 (d, J = 7 Hz, 3 H); 130 NMR (75 MHz, OeDe) ppm 225 208.3, 175.0, 139.1, 135.0, 130.7, 129.3, 128.5, 128.3, 128.0, 127.9, 127.8, 88.3, 58.6, 47.6, 34.3, 31.2, 20.4, 15.9; MS m/z(M+) calcd 318.1620, obsd 318.1615. Anal. Calcd for C 22H22O2: C, 82.99; H, 6.96. Found: 0, 82.83; H, 6.99. Long-range DEPT from H-10 (5 1.41): 175.0 (0-1, 3J). 88.3 (0-4, ^J), 58.6 (0-5, 2J), 34.3 (0-6, 3J). Long-range DEPT from H-8 (5 2.23): 208.3 (0-3, 3J), 88.3 (0-4, 2j), 31.2 (0-7, 2J), 15.9 (0-9, 2j). Irradiate Observe % NOE Irradiate Observe % NOE H10(81.41) OH 5.8 H-8 (5 2.23) OH 4.3 H-6p 1.2 H-7p 3.5 H-8 .6 H-6p 2.5 H6p(51.55) H-6 (3afl*,6af?*)-4,5,6,6a-Tetrahydro-3a-hydroxy- 2,3-diisopropoxy-4,4,6a-trimethyl-1(3aH)- l-PrO OH pentalenone (132). Method A was employed with 132 9 ^ 2-bromopropene (0.26 mL, 3 mmol), fert-butyllithium (3,5 mL, 6 mmol), and diisopropyl squarate (198 mg, Immol) for the following time periods: 0, 0, and 4 h. Subsequently, 5 mL of HMPA was added followed by 0.13 mL methyl iodide. After stirring the reaction mixture at room temperature for an additional 16 h, typical work-up provided 106 mg (36%) of 32 as a white solid, mp 70-71 °0; IR (neat) 3447, 1693, 1613; 1H NMR (300 MHz, OeDe) ô 5.31-5.22 (m, 2 H), 2.23 (brs, 1H), 2.10 (ddd, J = 13, 6.5, 4 Hz, 2 H), 1.55-1.45 (m, 1 H), 1.39-1.24 (m, 2 H), 1.30 (s, 3 H), 1.11 226 (d, J = 6 Hz, 3 H). 1.10 (d, J = 6 Hz, 3 H), 1.09 (d, J = 6 Hz, 3 H), 1.07 (d, J= 6 Hz, 3 H), 1.00 (s, 3 H), 0.98 (s, 3 H); 13C NMR (75 MHz, CeDe) ppm 203.2, 166.1, 131.6, 84.4, 73.7, 71.3, 57.1, 45.3, 38.9, 33.2, 25.8, 23.9, 22.9, 22.6 (2 C), 22.5, 20.6: MS m/z(M+) calcd 296.1988, obsd 26.1990. Anal. Calcd for C 17H28 O4: C, 68.89; H, 9.51. Found: C, 68.90; H, 9.48. Long-range DEPT from H-11 (ô 1.30): 203.2 (C-1, 3J), 84.4 (C-4, 3j), 57.1 (C-5, 2J), 33.2 (C-6 , 3j). Prototypical Procedure for Mixed Additions with 1- Lithiomethoxyaliene and an Alkenyllithium. Method E. All apparatus was flame-dried under argon, an atmosphere of which was maintained until quenching was effected. A solution of methoxyallene (77- 157.5 mg, 1.1-2.25 mmol) in dry THF (5-10 mL) was cooled to -78 °C and treated dropwise with n-butyllithium (0.65-1.34 mL of 1.68M in ether, 1.1 - 2.25 mmol). After 30 min at -78 ^C, the anion was cannulated into a solution of diisopropyl squarate (198-396 mg, 1-2 mmol) in 5-10 mL THF at -78 °C, and stirred at this temperature for 30 min. During this time, the alkenyllithium was generated from 3-5 mmol of a vinyl halide and 6-10 mmol of fert-butyllithium in 15 mL of THF. After 30 min, the alkenyllithium was similarly introduced and the temperature of the reaction mixture was maintained at -78 °C for 3-16 h, at -1 0 °C to 0 °C for 4-15 h, and at rt for 0-5 h, quenched at -10 °C to rt with a solution of deoxygenated NH4CI (argon was bubbled through solution for 20 min), and stirred at 0 °C to rt for 0-10 h. Subsequently, ether (25 mL) and water (25 mL) were added and the separated aqueous phase was extracted with ether (2x10 mL). The 227 combined organic phases were washed with water (25 mL) and brine (25 mL), dried, and evaporated. The residue was purified by flash chromatography on silica gel using 10-30% ethyl acetate and 0.5-1% TEA in petroleum ether and by further MPLC and/or recrystallization if necessary. Method F. All apparatus was flame-dried under argon, an atmosphere of which was maintained until quenching was effected. A solution of diisopropyl squarate (198-396 mg; 1 - 2 mm) in 5-10 mL of THF was cooled to -78 °C, cannulated into a solution of the alkenyllithium generated as above from 1.1-2.2 mmol of the vinyl halide and 2.2-4.4 mmol of fe/t-butyllithium in 10-15 mL of THF, and stirred for 30 min. During this time, a solution of methoxyallene (175-350 mg, 2.5-5 mmol) in dry THF (10- 15 mL) was cooled to -78 °C and treated dropwise with nbutyllithium (1.5-3.1 mL of 1.68M, 2.5-5 mmol). After 30 min at -78 °C, the anion was cannulated into the reaction mixture, which was stirred at -78 °C for 1-4 h, -40 °C to 0 °C for 1 -3 h, quenched as above at -40-0 °C, and stirred for an additional 0.5-3 h at 0 °C under argon. Subsequent work-up was carried out as in method E. 11 in 0 CHs :CH° ^ /-Pro So ^ 9 /-PrO^ HO 3 138" 139 140 (±)-4-Hydroxy-4-isopropenyl-2,3-diisopropoxy-6-methoxy- 5-methyl-2,5-cyclohexadien-1-one (138), (3aR*,6a/?*)-4,5,6,6a- Tetrahydro-3a-hydroxy-2,3-diisopropoxy-6a-methoxy-4-methyl-6- methylene-1 (3aH)-pentalenone (139), and (±)c/s- 6 ,6 a-Dihydro- 3a-hydroxy-2,3-dllsopropoxy-4-methoxy-5,6a-dlmethyl-1(3aAy)- 228 pentalenone (140). Method E was used with 157.5 mg (2.25 mmol) of methoxyallene, 1.34 mL (2.25 mmol) of n-butyllithium, 396 mg (2 mmol) of diisopropyl squarate, 0.45 mL (5 mmol) of 2-bromopropene, and 5.9 mL (10 mmol) of te/t-butyllithium, for 3 h (-78 °C) and 15 h (0 °C). The black reaction mixture was quenched at 0 °C and stirred for 1 h at rt. Typical work-up and flash chromatography with 20% ethyl acetate, 1 % TEA in petroleum ether yielded 230 mg (37%) of a mixture of 138 and 139 (54:46 ratio - estimated by GC) and 94 mg (15%) of 140. Following several recrystallizations from petroleum ether, 138 was isolated as a white solid, mp 105-7 °C; IR (CHCI 3, cm-1) 3565, 1649, 1618; NMR (300 MHz, CeDe) 5 5.46 (d, J = 0.4 Hz, 1 H), 5.26 (heptet, J = 6 Hz, 1 H), 5.01 (m, 1H), 4.66 (heptet, J = 6 Hz, 1 H), 3.65 (s, 3 H), 2.81 (s, 1H), 1.88 (s, 3H), 1.42 (d, 0.4 Hz, 3 H), 1.19 (d, J = 6 Hz, 3 H), 1.14(d, J=6Hz,3H), 1.05 (d, J= 6 Hz, 3 H), 1.03 (d, J= 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 180.5, 158.0, 148.8, 144.4, 136.5, 134.6, 113.6, 77.3, 74.7, 73.7, 59.7, 22.6, 22.51, 22.48 (2C), 18.1, 10.3; MS m/z (M+) calcd 310.1780, obsd 310.1786; UV (MeOH) ^max (nm) 320, Smax 3,031. Long-range DEPT from H-10 (5 5.46): 144.3 (C-9, 2J), 77.3 (C-4 3J), 18.0 (C-11, 3j). The experiment was not continued for a time period necessary to observe weak V allylic coupling. Combining the mother liquors from the several recrystallizations, evaporating solvent and flashing the resultant oil with 25% ether in petroleum ether provided a pure sample of 139 as a colorless oil; IR (neat, cm-1) 3482, 1706, 1613; 1H NMR (300 MHz, CeDe) 6 5.76 (dd, J= 3, 1.5 Hz, 1 H), 5.27(heptet, J = 6 Hz, 1 H), 5.21 (heptet, J = 6 Hz, 1 H), 5.12 (dd, J = 3, 1.5 Hz, 1 H) , 3.53 (s, 3 H), 3.06 (s, 1H), 2.18-2.03 (m, 3H), 1.14 (d, J= 6 Hz, 229 3 H). 1.11 (s,3H), 1.09 (d, J=6Hz,3H), 1.07 (d, J = 6 Hz, 3 H), 1.05 (d. J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 194.1, 168.8, 144.9, 131.8, 113.8, 82.6, 82.0, 74.0, 71.6, 54.1, 40.1, 39.6, 22.7 (20), 22.6 (20), 14.5; MS m/z (M+) calcd 310.1780, obsd 310.1778. Long-range DEPT from H-10 (5 5.76): 144.8 (0-6, 2J), 82.6 (0-5 3J), 40.1 (0-7, 3J) Long-range DEPT from H-11 (ô 3.53): 82.6 (0-5 3J). Lack of any nOe enhancement to 0-9 from 0-11 or OH indicates this methyl is a, which would be expected; however, methine 8 is buried with methylenes 7 so that stereo of 0-9 is inconclusive. For 140: colorless oil; IR (neat, cm*"') 3448, 1685, 1613; ^H NMR (300 MHz, OeDe) 5 5.32 (heptet, J = 6 Hz, 1 H), 5.23 (heptet, J = 6 Hz, 1 H), 3.54 (s, 3 H), 2.90 (s, 1H), 2.63 (dd, J= 16.5, 1 Hz, 1 H), 2.00 (dd, J = 16, 1 Hz, 1 H), 1.40 (s, 3H), 1.38 (s, 3H), 1.17 (d, J= 6 Hz, 3 H), 1.14 (d, J= 6 Hz, 3 H), 1.11 (d, J=6Hz,3H), 1.09 (d, J= 6 Hz, 3 H); 1^0 NMR (75 MHz, OeDe) ppm 202.3, 167.7, 152.9, 130.9, 117.5, 83.2, 74.0, 71.6, 59.9, 51.7, 41.9, 22.85, 22.78, 22.6, 22.5, 19.6, 12.5; MS m/z(M+) calcd 310.1780, obsd 310.1781. Long-range DEPT from H-9 (Ô 3.54): 152.9 (0-8, 3J). Long-range DEPT from H- 6 a (5 2.63): 202.3 (0-1, 3J), 152.9 (0-8, 3j), 117.5 (0-7 2J), 51.7 (0-5, 2j). Long-range DEPT from H- 6 b (Ô 1.99): 202.3 ( 0 -1 , 3j), 152.9 (0-8, 3j), 117.5 (0-7 2J), 51.7 (0-5, 2j), 19.6 (0-11, 3j). Long-range DEPT from H-11 (8 1.40): 202.3 (0-1, 3J), 83.1 (0-4, 3j), 51.7 (0-5 2J),41.9 (0-6, 3j). 230 Long-range DEPT from H-10 (Ô 1.38): 152.9 (C-8, 3J), 117.5 (0-7 2J), 41.9 (0-6, 3J). O ^ J ^ O i-P r 0 ^>^OWr (±)-6 -Hydroxy- 6 -lsopropenyl- HoZr T HO J Jl 2,3-diisopropoxy-4-methoxy-5- -Y T ^ O C H s - Y i r OCH3 ^ CH3 -1 4 1 ^ CH2 142 methyl-2,4-cyclohexadien-1- one (141) and (±)-6-Hydroxy- 6- isopropenyl-2,3-diisopropoxy-4-methoxy-5-methylene-3-cycfo- hexen-1-one (142). Method F was utilized with 198 mg (1 mmol) of diisopropyl squarate, 0.1 mL (1.1 mmol) of 2-bromopropene, 1.3 mL (2.2 mmol) of fe/t-butyllithium, 175 mg (2.5 mmol) of methoxyallene, and 1.5 mL (2.5 mmol) of 1.68 M />butyllithium for 4 h (-78 °0) and 30 min (0 °0). The yellow reaction mixture was quenched at 0 ° 0 and stirred for an additional 20 min at 0 °0. Typical work-up provided 77 mg (25%) of a mixture of 141 and 142 (2:3 ratio - estimated by NMR) and 111 mg (36%) 138 as a white solid. For 142: iH NMR (as a mixture) (300 MHz. OeDe) 5 5.67-5.63 (m, 2H), 5.10 (dd, J = 1.5, 0.8 Hz, 1 H) 4.89 (dd, J = 2.6, 1.3 Hz, 1 H), 4.66 (s, 1H), 4.39 (heptet, J = 6 Hz, 1 H), 4.19 (s, 1H), 3.69 (heptet, J = 6 Hz, 1 H), 3.50 (s, 3 H), 1.63 (dd, J= 1.3, 0.8 Hz, 3 H), 1.23 (d, J = 6 Hz, 3 H), 1.15 (d, J = 6 Hz, 3 H), 1.13(d, J = 6 Hz, 3H), 1.10 (d, J = 6 Hz, 3 H); I3c NMR (75 MHz, OeDe) ppm 205.1, 145.4, 140.6, 139.0, 115.8, 1 1 1 .8 , 83.6, 76.5, 73.2, 72.8, 59.2, 23.1, 22.9, 22.8, 22.3, 18.9 (one carbon overlaps); A pure sample of 141 was acquired by treating 54 mg of the mixture of 141 and 142 with 0.024 mL of TEA in 5 mL of THF and 1 mL of DMF for a period of 16 h under argon. Following a typical workup, 49 mg (91%) of 141 231 was isolated as a yellow oil; IR (neat, cm-i) 3466, 1650,1565; NMR (300 MHz, CeDe) 5 5.36 (d, J = 0.7 Hz, 1 H), 5.15 (heptet, J= 6 Hz, 1 H), 4.87 (dd, 1.4 Hz, 1 H), 4.58 (heptet, J = 6 Hz, 1 H), 4.00 (s, 1H), 3.35 (s, 3 H), 1.93 (s, 3H), 1.66 (dd,J= 1.4, 0.7 Hz, 3 H), 1.18 (d, J= 6 Hz, 3 H), 1.13(d, J = 6 Hz, 3 H), 1.12 (d, J = 6 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 198.6, 156.4, 145.6, 144.6, 134.8, 130.2, 112.5, 82.1, 75.7, 73.4, 59.9, 22.7 (3C), 22.5, 17.0, 10.7; MS m/z(M+) calcd 310.1780, obsd 310.1786. UV: (MeOH) A-max (nm) 354, £max 3,078. In a similar reaction using 2 mmol of diisopropyl squarate and a proportionate amount of the remaining reagents for 2 h (-78 °C) and 3 h (-40 °C), quenching at -40 °C and stirring an additional 15 h (0 °C) provided, after typical work-up, 16.4% of 141 and 142 (1:3 ratio - estimated by ^H NMR) and 45.5% of 138. 0 CHs CHs (±)-4-Hydroxy-2,3- OH /-Pro /T T s^ diisopropoxy-S-methoxy-S- /-Pro h o ^ O C H s methyl-4-[(Z)-1 -methyl-1 - 144 propenyi]-2,5-cyclohexadlen- 1-one (143) and (3a/?*,6S*,6a/?*)-6,6a-Dihydro-3a-hydroxy-2,3- dlisopropoxy-4-methcxy-5,6,8a-trimethyl-1(3aH)-pentalencne (144). Method E was used with 157.5 mg (2.25 mmol) of methoxyallene, 1.34 mL (2.25 mmol) of n-butyllithium, 396 mg (2 mmol) of diisopropyl squarate, 0.51 mL (5 mmol) of (E)-2-bromo-2-butene, and 5.9 mL (10 mmol) of fert-butyllithium, for 3 h (-78 °C) and 4 h (-10 ®C). The yellow reaction mixture was quenched at -10 °C and stirred 10 h at 0 °C. Typical work-up and flash chromatography with 18-30% ethyl acetate and 0.5% TEA in 232 petroleum ether yielded 165.5 mg (26%) of 143 and 249 mg (38%) of 144. A portion of 144 was obtained as a mix with 143 and what is believed to be 147 (relative amounts were estimated by NMR), the remaining 144 was still contaminated with what is believed to be 147 (approx 8 %). This by-product could not be removed by additional chromatography, nor was it separable by GC. For 143: white, crystalline solid, mp 133-4 °C; IR (CHCI 3, cm*'') 3563, 1649, 1617; 1H NMR (300 MHz, CeDe) 6 5.94 (qq, J= 7, 1.0 Hz, 1 H), 5.25 (heptet, J = 6 Hz, 1 H), 4.71 (heptet, J = 6 Hz, 1 H), 3.69 (s, 3 H), 2.52 (m, 1H), 1.87 (s, 3H), 1.47 (dd, J= 7, 1 Hz, 3H), 1.30 (d, J = 1 Hz, 3 H), 1.20 (d, J = 6 Hz, 3 H), 1.17 (d, J = 6 Hz, 3 H), 1.02 (d, J = 6 Hz, 3 H), 0.97 (d, J = 6 Hz, 3 H): 13C NMR (75 MHz, CeDe) Ppm 180.7, 158.3, 148.8, 137.1, 134.8, 134.3, 127.4, 77.5, 74.7, 73.7, 59.7, 22.6 (2C), 22.5 (2C), 13.5, 12.0, 10.4; MS m/z (M+) calcd 324.1937, obsd 324.1934; UV (MeOH) W (nm) 320, Emax 3,051. For 144: colorless oil; IR (neat, cm*l) 3444, 1683, 1614; 1H NMR (300 MHz, CeDe) ô 5.31 (heptet, J= 6 Hz, 1 H), 5.17 (heptet, J= 6 Hz, 1 H), 3.57 (s, 3 H), 3.12 (s, 1H), 2.80-2.73 (m, 1H), 1.40 (d, J=0.9 Hz, 3 H), 1.30 (s, 3H), 1.18(d, J=6Hz,3H), 1.15 (d, J= 6 Hz, 3 H), 1.11 (d, J= 6 Hz, 3 H), 1.08 (d, J = 6 Hz, 3 H), 1.01 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 203.0, 167.3, 153.4, 130.2, 122.6, 83.0, 74.0, 71.5, 59.9, 55.4, 42.4, 22.9, 22.8, 22.6, 22.5, 15.7, 15.0, 11.0; MS m/z(M+) calcd 324.1937, obsd 324.1940. Long-range DEPT from H- 12 (5 1.30): 203.0 (C-1, 3J), 83.0 (C- 4, 3J), 55.4 (C-5 2J), 42.3 (C-6 , 3j). 233 Long-range DEPT from H-11 (S .99): 122.6 (C-7, 3j), 55.4 (C-5, 3j), 42.3 (C-6 2J). Irradiate Observe % NOE irradiate Observe % NOE H-6 (52.76) H-12 1.0 H-11 (51.01) OH 1.5 H-10 3.8 H-6 20 OH 1.3 H-10 5.7 H-12(51.30) H-11 6.2 H-12 5.4 H-6 3.2 OH 5.8 0/-Pr H 0/-?r (±)-6-Hydroxy-2,3- 0 ^ J ^ O i - P r OcJ>WO/-Pr HOJ H O J i ||3 ^2 diisopropoxy-4-methoxy-5- T ^ O C H s OCH3 methyl-6-[(Z)-1-methyl-1- CHs ^9 CHz 146 145 propenyl]-2,4-cyclohexadien- 1-one (145) and (±)-6- Hydroxy-2,3-dlisopropoxy-4-methoxy-S-methylene-6-[(Z)-1- methyl-1 -propenyl]-3-cyclohexen-1 -one (146). Method F was utilized with 396 mg (2 mmol) of diisopropyl squarate, 0.23 mL (2.25 mmol) of (£)-2-bromo-2-butene, 2.65 mL (4.5 mmol) of fert-butyllithium, 350 mg (5 mmol) of methoxyallene, and 3.0 mL (5 mmol) of 1.68 M n-butyllithium for 3 h (-78 °C) and 1 h (-30 °C). The yellow reaction mixture was quenched at -30 °C and stirred for an additional 3 h at 0 °C. Typical work-up provided 265 mg (41%) of a mixture of 145 and 146 (2:1 ratio - estimated by NMR) and 189 mg (29%) of 143 as a white solid. For 146: NMR (as a mixture) (300 MHz, CeDe) S 5.73-5.65 (m, 3H), 4.62 (s, 1H), 4.56 (heptet, J = 6 Hz, 1 H), 3.70 (heptet, J = 6 Hz, 1 H), 3.52 (s, 3 H), 1.53 (d, J= 0.9 Hz, 3 H), 1.35 (dd, J= 7, 0.9 Hz, 3 H), 1.24 (d, J 234 = 6 Hz, 3 H), 1.08 (d, J = 6 Hz, 3 H), (6 protons from isopropoxy methyls overlap with those of 145; OH is not observed); NMR (75 MHz, CeDe) ppm 205.8, 143.7, 140.8, 138.6, 135.9, 125.1, 112.1, 84.6, 76.7, 73.1, 72.4, 59.3, 23.2, 22.6, 22.4, 22.3, 13.6, 11.9. Long-range DEPT from H-14 (6 3.70): 76.7 (0-2, 3J). Long-range DEPT from H-2 (5 4.62): 205.8 (0-1, 2j), 143.7, 138.6 (0- 3,4 2.3J), 73.0 (0-14, 3J). A pure sample of 145 was acquired by treating 156 mg of the mixture of 145 and 146 with 0.048 mL of TEA in 5 mL of THF and 1 mL of DMF for a period of 16 h under argon. Following the typical workup, 143 mg (92%) of 145 was isolated as a yellow oil; IR (neat, cm*"') 3466, 1648, 1567; ^H NMR (300 MHz, OeDe) 5 5.36 (qd, J = 7 , 1, Hz, 1 H), 5.14 (heptet, J = 6 Hz, 1 H), 4.57 (heptet, J = 6 Hz, 1 H), 3.97 (s, 1H), 3.38 (s, 3 H), 1.91 (s, 3H), 1 .54 (dd, J= 1, 1 Hz, 3 H), 1.42 (dd, J= 7, 1 Hz, 3 H),1.18 (d, J = 6 Hz, 3 H), 1.15 (d, J = 6 Hz, 3 H), 1.13 (d, J = 6 Hz, 3 H), 1.06 (d, J= 6 Hz, 3 H); 130 NMR (75 MHz, OeDe) ppm 199.1, 156.0, 145.7, 134.8, 134.6, 130.4, 1 2 0 .6 , 82.2, 75.5, 73.1,60.0, 22.75 (20), 22.72, 22.3, 13.5, 10.8, 10.7; MS nVz(M+) calcd 3324.1937, obsd 324.1936. UV (MeOH) ^ a x (nm) 352, Smax 3,850. 13 0 OCH112 (±)-4-(1 -Cyclopenten-1 -yl)-4- ; . P r n - i j 5^ ^ hydroxy-2,3-diisopropoxy-8- CHsO^^ « ^ 0 7 8 C 4 ^ 1 1 /-Pro HO 9 "^^° methoxy-5-methyl-2,5- 149 cyclohéxadien-1-one (148) and (3a/î*,3bfl*,6a/î*,7a/?*)- 3a,3b,4,5,6,6a,7,7a-Octahydro-3a-hydroxy-2,3-diisopropoxy-7a- 235 methoxy-7-methylene-1H-cyclopenta[a]pentalen-1-one (149). Method E was used with 77 mg (1.1 mmol) of methoxyallene, 0.66 mL (1.1 mmol) of n-butylllthlum, 198 mg (1 mmol) of dllsopropyl squarate, 588 mg (3 mmol) of 1-lodocyclopentene, and 3.53 mL (6 mmol) of fert-butylllthlum, for 16 h (-78 °C), 4 h (0 °C), and 5 h (rt). The black reaction mixture was quenched at rt. Typical work-up, flash chromatography with 30% ethyl acetate In petroleum ether, and further purification by MPLC (22% ethyl acetate In methylene chloride) yielded 66 mg (20%) of 148, 75 mg (22.3%) of 149, and 37 mg of 15 resulting from Incomplete addition of the first anion.. For 148: white solid, mp 97-98 °C; IR (CHCL3, cm 'i) 3569, 1692, 1649, 1614; 1H NMR (300 MHz, CeDe) 6 5.87 (dd, J= 2, 2 Hz, 1 H), 5.27(heptet, J = 6 Hz, 1 H), 4.66 (heptet, J = 6 Hz, 1 H),3.67 (s, 3 H), 2.99 (s, 1H), 2.20-2.15 (m, 2H), 2.06-1.98 (m, 1 H), 1.93 (s, 3 H), 1.93-1.87 (m, 1 H), 1.67-1.59 (m, 2 H), 1.18 (d, J= 6 Hz, 3 H), 1.17 (d, J= 6 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 1.00 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) Ppm 180.5, 158.2, 148.2, 145.2, 136.9, 134.2, 128.6, 75.5, 74.8, 73.6, 59.7, 32.8, 31.9, 24.0, 22.6 (2C), 22.5 (2C) 10.5; MS m/z(M+) calcd 336.1937, obsd 336.1938; UV (MeOH) W (nm) 318, Smax 3,007. >4na/. Calcd for C 19 H28 O5: C, 67.83; H, 8.39. Found: C, 67.87; H, 8.39. Long-range DEPT from H-10 (5 5.86): 158.3 (C-3, V , weak allylic coupling), 145.2 (C-9, 2j), 136.9 (C-5, ^J, weak allylic coupling), 75.5 (C-4 3J), 32.8, 24.0 (2 of C-11, 12, 13). Allylic coupling to C-3,5 distinguish this reglochemlstry from 150. 236 For 149: white solid, mp 67-8 °C; IR (neat, cm’"') 3460, 2990, 1710, 1615; 1H NMR (300 MHz, CeDe) 8 5.53 (dd. J = 0.8, 0.8, Hz, 1 H), 5.51-5.18 (m, 2H), 4.99 (dd, J = 2.3, 0.8 Hz, 1 H), 3.49 (s, 3 H), 2.90 (s, 1H), 2.07-1.95 (m, 1H), 1.89-1.81 (m, 1 H), 1.79-1.69 (m, 3 H), 1.56-1.37 (m, 2 H), 1.06-1.04 (m, 1 H), 1.15 (d, J = 6 Hz, 3 H), 1.14 (d, J = 6 Hz, 3 H), 1.12 (d, J = 6 Hz, 3 H), 1.05 (d, J= 6 Hz, 3 H); 1% NMR (75 MHz, CeDe) ppm 193.5, 166.0, 146.3, 135.0, 108.0, 92.1, 78.9, 74.4, 71.6, 60.0, 54.2, 49.1, 27.0, 23.4, 23.1 (2C), 22.8, 22.6 (2C); MS m/z(M+) calcd 336.1937, obsd 336.1934. Anal. Calcd for C 19 H28 O5: C, 67.83; H, 8.39. Found: C, 67.57; H, 8.40. Long-range DEPT from H -8 (6 1.85): 166.0 (C-3, 3J), 146.3 (C- 6 , 3J), 78.9 (C-4, 2J), 23.4, 2 2 .8 (2 of C-9, 10,11) Long-range DEPT from H-7 (8 1.99): 146.3 (2J), 108.0 (C-12, 3j), 78.9 (3J), 23.4, 22.8. Lack of polarization transfer from H -8 to C-5 is indicative of stereochemistry at C-7. For the epimer shown, this dihedral angle is 90°. If the stereochemistry at C-7 is inverted, the angle is approximately 180° and should show strong coupling. The lack of nOe enhancement from H-13, OH or H-8 to H-7 is also indicative. Irradiate Observe % NOE H-13 (53.49) OH 3.5 H-8 2.2 OH (52.90) H-8 3.6 H-13 6.1 H-8 (51.85) H-13 2.8 H-7 (5 2.00) H-11 6.8 237 15 (±)-6-(1-Cyclopenten-1-yl)-6- 0/-Pr H 0/-Pr 0,;JL2 o/-Pr hydroxy-2,3-diisopropoxy-4- , a l ^ ^ 0 CH3 methoxy-5-methyl-2.4- 1 2 ( ^ 1 0 CH3 ^ 2 1 5 T cyclohexadien-1-one (150), and (±)-6-(1 -Cyclopenten-1 - yl)-6-Hydroxy-2,3-diisopropoxy-4-methoxy-5-methylene-3-cyclo- hexen-1-one (151). Method F was utilized with 198 mg (1 mmol) of diisopropyl squarate, 216 mg (1.1 mmol) of 1-iodocyclopentene, 1.3 mL (2.2 mmol ) of fert-butyllithium, 175 mg (2.5 mmol) of methoxyallene, and 1.5 mL (2.5 mmol) of 1.68 M rr-butyllithium for 1 h (-78 °C) and 2 h (-15 °C). The yellow reaction mixture was quenched at -15 °C and stirred for an additional 3 h at 0 °C. Typical work-up provided 134 mg (40%) of a mixture of 150 and 151 (85:15 ratio - estimated by NMR) and 114 mg (34%) of 148 as a white solid. For 151 : NMR (as a mixture: due to low proportion of 151 not all peaks could be designated) 5.64-5.67 (m, 2H) H-6, 5.58 (d, J= 1.8, IN) H-9, 5.22 (heptet, J= 6, Hz, 1 H) methine 14, 4.66 (s, 1 H) H-2, 4.42 (heptet, J = 6 Hz, 1 H) methine 15, 3.52 (s, 3H) H-13. 10, 11, 12, and methyls from 14 and 15 are buried. 13C NMR (75 MHz, CeDe) ppm 204.7, 145.1, 143.2, 140.9, 138.9, 130.1, 110.6, 80.6, 76.6, 73.1,73.0, 59.1, 32.8, 31.5, 23.6, 23.0, 22.7, 22.6, 22.5. A pure sample of 150 was prepared in a reaction using identical quantities as the above for 10 h (-78 °C) and 6 h (0 °C). Quenching at 0 °C and typical work-up provided 80 mg (24%) of 150 uncontaminated with its regioisomer 151. On standing, the unstable 150 decomposes to a mixture of 150 and a new isomer which was separated by chromatography. The ^H 238 and 13C spectra of this compound indicate it to be of very similar constitution to 150, possibly resulting from a pinacol-type rearrangement. For 150: IR (neat, cm-l) 3460, 2960, 1720, 1640, 1610; NMR (300 MHz, CeDe) 5 5.82 (dd, J = 2, 2, Hz, 1 H), 5.13 (heptet, J = 6, Hz, 1 H), 4.62 (heptet, J= 6, Hz, 1 H), 4.18 (s, 1 H), 3.36 (s, 3H), 2.39-2.26 (m, 1H), 2.25- 2.09 (m, 3 H), 1.99 (s, 3 H), 1.71-1.61 (m, 2 H), 1.18 (d, J = 6 Hz, 3 H), 1.15 (d, J=6Hz, 3H), 1.14(d, J=6Hz,3H), 1.08 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 198.5, 156.1, 144.8, 144.7, 134.6, 130.6, 127.7, 80.7, 75.6, 73.2, 60.0, 32.6, 30.5, 23.9, 22.8 (2C), 22.3 (2C), 10.9; MS m/z(M+) calcd 336.1937, obsd 336.1924; UV (MeOH) W (nm) 350, Smax 3,827. Long-range DEPT from H-10 (5 5.82): 198.5 (C-1, ^J, weak allylic coupling), 144.8 (C-9, 2j), 80.7 (C-6, 3J), 32.6, 23.9 (2 of C-11, 12, 13). Allylic coupling to C-1 distinguishes this regioisomer from 148. 10 H (1fl*,3aS*,4S*,6aS*)- H O j 1 3 /C H —0 - ^ 7 i - P r O - : ^ }? 1,5,6,6a-Tetrahydro-2- Ms _ 3 OH Me OH Me isopropoxy-4,6a-dimethyl- 9 167 1,3a(4W)-pentalenediol (166) and (Iff*,3a/? *,4/?*, 6aff*)-1,5,6,6a-Tetrahydro-2-isopropoxy-4,6a-dimethyl-1,3a(4/?)- pentalenedioi (167). A cold (0 °C), magnetically stirred suspension of LiAIH4 (44 mg, 1.16 mmol) in 5 mL of dry THF was treated under argon via cannula with a solution of 57 (143 mg, 0.51 mmol) in THF (5 mL) also cooled to 0 °C. The reaction mixture was stirred at 0 °C for 45 min and at rt for 30 min before being returned to 0 °C and treated with methanol (3 drops) and 10% Rochelle's salt solution (10 mL). After 30 min of stirring, brine (25 239 mL) was added and the products were extracted into ether (2 x 25 mL). The combined organic phases were washed with brine, dried, and concentrated. The residue was subjected to flash chromatography on silica gel (elution with 30-50% ethyl acetate in hexanes) to give 65 mg (56%) of 166 and 19 mg (16%) of 167. For 166; colorless solid, mp 82-84 °C; IR (film, cm'i) 3410, 1650; NMR (300 MHz, CeDe) ô 4.34 (s, 1 H), 4.27 (s, 1 H), 3.93 (heptet, J = 6 Hz, 1 H), 2.54-2.47 (m, 1 H), 2.36 (s, 1 H), 1.90 (qd, J = 13, 6 .6 Hz, 1 H), 1.58-1.50 (m, 1 H), 1.24-1.09 (m, 2 H), 1.13 (s, 3 H), 1.07 (d, J= 6 Hz, 3 H), 1.06 (d, J = 7 Hz, 3 H), 1.02 (d, J = 6 Hz, 3 H) (OH signal not seen); 13C NMR (75 MHz, CeDe) ppm 160.7, 97.4, 90.9, 81.4, 71.6, 50.6, 44.3, 31.9, 31.2, 24.2, 21.7, 21.2, 14.0; MS m/z(M+) calcd 226.1569, obsd 226.1564. Irradiate Observe % NOE H-3 H-11 13.4 H-12,13 5.9 H-1 H-10 4.8 H-6 H-1 3.3 H-10 H-1 14.8 H-8 4.3 H-8 H-10 0.6 Long-range DEPT from H -8 (Ô 1.89): observe C-3 (97.4 ppm, 3J), C-4 (90.9 ppm, 2j), C-7 (31.2 ppm, 2j), and C-9 (14.0, ppm, 2J). Long-range DEPT from H-10 (d 1.13): observe C-4 (90.6 ppm, 3J), C- 1 (81.4 ppm, 3J), C-5 (50.3 ppm, 2j), and C -6 (31.6, ppm, 3J). For 167: colorless solid, mp 118-120 °C; IR (CHCI 3, cm*i) 3596, 1643; 1H NMR (300 MHz, CDCI3) 5 4.55 (s, 1 H), 4.24 (heptet, J = 6 Hz, 1 H), 3.96 (s, 1 H), 1.93-1.85 (m, 2 H), 1.66-1.51 (m, 4 H), 1.29 (d, J = 6 Hz. 3 H), 1.28 (d, J = 6 Hz, 3 H), 1.02 (s, 3 H), 0.98 (d, J = 7 Hz, 3 H), 0.99-0.87 (m, 1 240 H); 130 NMR (75 MHz, CDCI3) ppm 160.9, 99.3, 91.4, 82.6, 71.7, 50.8, 42.6, 38.9, 30.1,21.5, 21.3, 17.9, 14.7; MS m/z(M+) calcd 226.1569, obsd 226.1568. Long-range DEPT from H-10 (S 1.02): observe C-4 (91.4 ppm, 3j), 0 - 1 (82.6 ppm, 3j), C-5 (50.8 ppm, 2j), and C -6 (38.9, ppm, 3j). 0 Me ^ (3afl*,4fl*,6aS*)-4,5,6,6a-Tetrahydro-3a- vL I i-PrO 7 hydroxy-2-isopropoxy-4,6a-dimethyl-1 (3aH)- ^ OH Me pentalenone (168). To a solution of 166 (10 mg, 9 ^ 0.044 mmol) in CH2CI2 (3 mL, distilled from CaH 2) was added 75 mg (4 equiv) of thie Dess-Martin reagent in a single portion. The reaction mixture was stirred at rt for 3 h, diluted with ether (25 mL), washed with saturated NaHCOa (25 mL) and 10% NaHSOa solutions (25 mL), and brine (25 mL), then dried and evaporated. Flash chromatography (elution with 10% ethyl acetate in dichloromethane) fumished 4 mg (40%) of 168 as a colorless oil; IR (neat, cm-i) 3420,1712, 1622; 1R NMR (300 MHz, CDCI3) 5 6.00 (s, 1 H), 4.36 (hept, J = 6 Hz, 1 H), 2.01-1.93 (m, 2 H), 1.60 (ddd, J = 12, 6 ,6 Hz, 1 H), 1.50-1.40 (m, 2 H), 1.35 (d, J = 6 Hz, 3 H), 1.33 (d, J = 6 Hz, 3 H), 1.11 (s, 3 H), 1.07 (d, J = 7 Hz, 3 H), 0.88-0.75 (m, 1 H); NMR (75 MHz, CDCI3) ppm 206.4, 155.8. 124.7, 85.3, 72.8, 55.7, 44.3, 35.9, 30.1, 21.5, 21.1, 19.3, 14.1; MS m/z(M+) calcd 224.1412, obsd 224.1421. Long-range DEPT from H-10 (6 1.11): observe C-1 (206.4 ppm, 3J). 241 10 H H 10 ''J Me 6 HO^^ Me 6 / l > 7 0=< y 7 r 2 4 3 4 (3afl*,6fl*,6aS*)-4,5,6,6a-Tetrahydro-6a-hydroxy-2- isopropoxy-3a,6-dimethyl-1(3a//)-pentalenone (170) and (1 fl*/1 S*,4S*,6a/?*)-4,5,6,6a-Tetrahydro-1 -hydroxy-4,6a- dimethyl-2(1H)-pentalenone (171a and 171b). A magnetically stirred slurry of UAIH 4 (32 mg, 0.86 mmol) in dry THF (4 mL) was cooled to 0 °C and treated with TMEDA (0.15 mL, 1 mmol). After 30 min, a cold (0 °C) solution of 57 (105 mg, 0.38 mmol) in the same solvent (5 mL) was intro duced via cannula and the reaction mixture was stirred at 0 °C for 15 min and at rt for 30 min before being retumed to 0 °C and carefully quenched with IN HCI (1 mL). After 2 h of agitation at rt, the mixture was diluted with brine (15 mL) and extracted with ether (2x1 5 mL). The combined organic extracts were washed with brine, dried, and evaporated to leave an oil which was purified by MPLC on silica gel. Elution with 25% ethyl acetate in hexanes afforded 15 mg (18%) of 170, 23.5 mg (37%) of 171a, and 2.5 mg (4%) of 171b. The preferable way to produce pure 171a and 171b is to hydrolyze 166 and 167 independently. For 170: colorless crystals, mp 127-128 °C; IR (CHCI 3, cm*"') 3553, 1715, 1615; 1H NMR (300 MHz, CDCI3) 5 6.00 (s, 1 H), 4.32 (heptet, J = 6 Hz, 1 H), 2.70 (s, 1 H), 2.02 (m, 1 H), 1.68-1.60 (m, 3 H), 1.30 (d, J = 6 Hz, 3 H), 1.29 (d, J = 6 Hz, 3 H), 1.15 (s, 3 H), 1.13-0.98 (m, 1 H), 0.91 (d, J = 7 Hz, 3 H); 13Q NMR (75 MHz, GDCI3) ppm 204.1, 153.0, 135.7, 86.1, 71.9, 51.0, 242 ^'■ïTnT’-iTÉirr 'in 46.9, 36.9, 30.4, 2 2 .2 , 21.3, 21.2, 14.9; MS m/z{M+) calcd 224.1412, obsd 224.1414. Long-range DEPT from H-10 (Ô 1.15): observe C-1 (135.7 ppm, 3J), C-4 (86.1 ppm, 3J), C-5 (51.0 ppm, 2j), and C -6 (36.9, ppm, 3J). Long-range DEPT from H -8 (d 2.04): observe C-3 (204.1 ppm, 3j), C- 4 (2J), C-2 (30.4 ppm, 2j), and C-9 (14.8, ppm, 2j). For 171a: colorless solid, mp 72-73 °C; IR (film, cm*'') 3413, 1709, 1623; 1H NMR (300 MHz, CDCI3) Ô 5.71 (d, J = 2 Hz, 1 H), 3.84 (s, 1 H), 3.18 (s, 1 H), 3.04-2.95 (m, 1 H), 2.47-2.33 (m, 1 H), 2.09-1.95 (m, 1 H), 1.53-1.40 (m, 2 H), 1.196 (s, 3 H), 1.193 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, CDCI 3) ppm 210.5, 200.1, 118.8, 79.3, 53.5, 33.0, 31.5, 27.5, 26.2, 17.3; MS m/z (M+) calcd 166.0994, obsd 166.0999. Long-range DEPT from H -1 (5 3.84): observe C-4 (200.1 ppm, 3J) and C -1 0 (26.2, ppm, 3j). Long-range DEPT from H -8 (Ô 2.99): observe C-4 (2j), C-3 (118.8 ppm, 3J), C -6 or C-7 (31.5 ppm, 2j or 3J), and C-9 (17.3, ppm, 2j). Long-range DEPT from H-3 (5 5.71): observe C-2 (210.5 ppm, 2j), C- 4 (2J), C-1 (79.3 ppm, 3J), and C-5 (53.5, ppm, 3J). For 171b: colorless solid, mp 72-73 °C; IR (CHCI 3, cm*'') 3540, 1710, 1620; 1H NMR (300 MHz, CDCI3) d 5.83 (d, J = 2 Hz, 1 H), 3.94 (s, 1 H), 2.99-2.96 (m, 1 H), 2.46-2.35 (m, 1 H), 1.90 (ddd, J = 13, 8 , 4 Hz, 1 H), 1.67 (ddd, J= 13, 13, 8 Hz, 1 H), 1.53-1.42 (m, 1 H), 1.21 (d, J= 7 Hz, 3 H), 1.07 (s, 3 H) (OH signal not observed); ^^C NMR (75 MHz, CDCI 3) ppm 209.7, 196.5, 118.2, 84.6, 54.3, 34.9, 32.9, 32.3, 22.1, 17.7; MS m/z(M+) calcd 166.0994, obsd 166.0994. 243 (3a/?*,4S*,6aS*)-3a-Chloro-4,5,6,6a- tetrahydro-2,3-diisopropoxy-4,6a-dimethyl- 1(3aH)-pentalenone (172). An argon-blanketed solution of 57 (1.20 g, 4.25 mmol) and trlethylamine (3.5 mL, 25.6 mmol) in CH2CI2 (40 mL) was cooled to 0 °C and treated dropwise with 0.72 mL and 0.60 mL portions (2.4 eq) of methanesulfonyl chloride at an interval of 30 min. The reaction mixture was allowed to warm to rt between additions and stirred for an additional 30 min at rt following the second addition, then diluted with water (50 mL). The separated aqueous phase was extracted with CH 2CI2 (25 mL) and the combined organic layers were washed sequentially with water (25 mL), IN HCI (25 mL), saturated NaHCOs solution (25 mL), and brine (25 mL) prior to drying and solvent evaporation. Flash chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) yielded 172 containing a small amount of 173. This oily material was generally used directly. A pure sample of 172 could be acquired by flash chromatography on silica gel (elution with 3% ethyl acetate in CH 2CI2). For 172: IR (neat, cm-l) 1703, 1619; NMR (300 MHz, CeDe) ô 5.34-5.22 (m, 2 H), 2.16 (qdd, J= 5.6, 1.2, 19.5 Hz, 1 H), 2.08 (dd, J = 12, 6 Hz, 1 H), 1.36 (s, 3 H), 1.32-1.21 (m, 1 H), 1.19-1.10 (m, 1 H), 1.15(d, J = 6 Hz, 3 H), 1.13 (d, J = 6 Hz, 3 H), 1.10 (d, J = 7 Hz, 3 H), 1.06 (d, J = 6 Hz, 3 H), 1.05 (d, J = 6 Hz, 3 H), 0.92-0.78 (m, 1 H); 13C NMR (75 MHz, CeDe) PPm 199.8, 163.4, 133.8, 79.4, 73.9, 71.4, 56.9, 49.6, 35.3, 30.9, 22.6, 22.3 (2 C), 22.1, 14.8 (one methyl C masked); MS m/z(M+) calcd 300.1492, obsd 300.1513. 244 A nal. Calcd for C 16H25CIO3: C, 63.97; H, 8.39. Found: 0, 64.08; H, 8.43. Long-range DEPT from H-10 (6 1.36): observe C-1 (199.8 ppm, ^J), C-4 (79.4 ppm, 3J), C-5 (56.9 ppm, 2 j), and C -6 (35.3 ppm, 3J). 6,6a-Dihydro-2,3-diisopropoxy-4,6a-dimethyl- 1(H)-pentalenone (173). Lithium chloride (1.09 g, 7 g 25.7 mmol, dried by heating at 140 °C and 0.5 Torr for Me 173 3 h) and lithium carbonate (2.10 g, 28.4 mmol) were added to DMF (50 mL, freshly distilled from CaH 2 at 70 Torr) and the mixture was heated to 120 °C. A solution of impure 172 from the previous experiment dissolved in dry DMF (15 mL) was introduced and the stirred mixture was heated at 150 °C for 5 h, cooled to rt, diluted with ether (100 mL), and filtered through a pad of Celite. The filtrate was washed with brine (3 x 25 mL), dried, and evaporated to leave a solid which was purified by chromatography on silica gel (elution with 3% ethyl acetate in dichloromethane). There was isolated 978 mg (87% for two steps) of 173 as a colorless, crystalline solid, mp 90-91 °C (from ether/hexanes); IR (CHCI3, cm-1) 1682, 1568; 1H NMR (300 MHz, CDCI 3) Ô 5.26 (heptet, J = 6 Hz, 1 H), 4.91 (heptet, J = 6 Hz, 1 H), 2.88-2.77 (m, 1 H), 2.22 (ddd, J= 8.2, 7.5, 0.7 Hz, 1 H), 1.91 (dd, J=0.7, 1.8 Hz, 1 H), 1.84-1.73 (m, 1 H), 1.66 (dd, J = 1 2 , 6 Hz, 1 H), 1.36 (d, J = 6 Hz, 3 H), 1.31 (d, J = 6 Hz, 3 H), 1.26 (d, J = 6 Hz, 3 H), 1.23 (s, 3 H), 1.20 (d, J = 6 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 203.5, 159.5, 136.8, 135.1, 132.2, 73.3, 71.9, 56.5, 39.6, 31.4, 23.2, 22.8, 22.4, 14.7 (two methyl C masked); MS m/z(M+) calcd 264.1725, obsd 264.1712. 245 A nal. Calcd for C 16H24O3: C, 72.69; H, 9.15. Found: C, 72.98; H, 9.33. Long-range DEPT from H-10 (5 1.23): observe C-1 (203.5 ppm, 3j), C-4 (136.8 ppm, 3J), C-5 (56.5 ppm, 2j), and C -6 (31.4, ppm, 3J). Long-range DEPT from H-9 (5 1.91): observe C-3 (159.5 ppm, ^J), C- 4 (136.8 ppm, 3J), C -8 (132.2 ppm, 2j), and C-7 (39.6 ppm, 3J). (1R*,2/?*,4S*,6afl*)- 1,2,4,5,6,6a-Hexahydro-2,3- ,0 3 ^ 0 ^ 'Me i'TT ,0 ’ Me dilsopropoxy-4,6a-dlmethyl- 12' 1 74 12' 175 1-pentalenol (174) and (1A?*,2S*,4S*,6a/7*)- 1,2,4,5,6,6a-Hexahydro-2,3-diisopropoxy-4,6a-dimethyl-1 - pentalenol (175). A magnetically stirred slurry of UAIH 4 (4 mg, 0.1 mmol) in anhydrous ether (2 mL) was cooled to 0 °C, treated via cannula with a solution of 172 (17 mg, 0.057 mmol) in the same solvent (1 mL), stirred at 0 °C for 45 min, and treated sequentially with methanol (1 drop) and 10% Rochelle's salt solution (5 mL). After 30 min of additional stirring, the mixture was diluted with brine (5 mL) and ether (5 mL), and the separated aqueous phase was extracted with ether (10 mL). The combined organic layers were washed with brine (15 mL), dried, and evaporated. Flash chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) yielded 6.0 mg (39%) of 174 and 7.5 mg (49%) of 175. For 174: colorless oil; IR (CHCI3, cm-i) 3508, 1685, 1455; 1R NMR (300 MHz, CDCI3) Ô 4.18 (s, 1 H), 4.15 (heptet, J = 6 Hz, 1 H), 3.74 (heptet, J = 6 Hz, 1 H), 3.65 (s, 1 H), 2.63-2.52 (m, 1H), 2.37-2.23 (m, 1 H), 1.79-1.72 246 (m, 1 H), 1.60 (s, 1H), 1.52-1.43 (m, 1 H), , 1.24 (d, J = 6 Hz, 3 H), 1.18 (d,J = 6 Hz, 3 H), 1.17 (d, J = 6 Hz, 3 H), 1.66 (s, 3 H), 1.15 (d, J= 6 Hz, 3H), 1.13 (d, J = 7 Hz, 3 H) 1.27-1.09 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 143.4, 137.3, 90.3, 77.8, 71.2, 70.6, 56.2, 36.2, 29.7, 28.7, 26.2, 23.3, 22.7, 22.4, 22.1, 18.4; MS m/z(M+) calcd 268.2038, obsd 268.2036. Long-range DEPT from H-4 (ô 3.65): observe C-2 (143.4 ppm, 3J), C- 1 (137.3 ppm, 3J), C-10 (26.2 ppm, 3J). Long-range DEPT from H-3 (Ô 4.18): observe C-2 (2j), 0 -1 (3j), C-4 (77.8 ppm, 2J), C-11 (71.2 ppm, 3j), C-5 (56.2 ppm, 3j). Long-range DEPT from H -8 (ô 2.58): observe C-2 (3j), C-1 (2j), C-9 (18.4 ppm, 2j), Long-range DEPT from H -6 (6 1.74): observe C-4 (3j), C-5 (56.2 ppm, 2J), C-7 (36.2 ppm, 2J), C -8 (29.7 ppm, 3j), C-10 (26.2 ppm, 3 j). Long-range DEPT from H-7a (5 1.47): observe C-1 (3J), C-5 (3J), C -6 (28.7 ppm, 2J), C -8 (2j), C-9 (18.4 ppm, 3J). Irradiate Observe % NOE H-10 H-3 5.6 H-4 10.2 H-7p 3.5 H-9 H-7a 3.6 H-7a H-9 2.0 H-4 H-10 3.5 H-3 H-4 6.5 H-10 2.1 For 175: colorless oil; IR (CHCI3, cm-l) 3612, 1696, 1454; ^H NMR (300 MHz, CDCI3) ô 4.18 (s, 1 H), 4.15 (heptet, J= 6 Hz, 1 H), 3.74 (heptet, J = 6 Hz, 1 H), 3.65 (s, 1 H), 2.63-2.52 (m, 1 H), 2.37-2.23 (m, 1 H), 1.79-1.72 (m, 1 H), 1.60 (s, 1 H), 1.52-1.43 (m, 1 H), 1.24 (d, J = 6 Hz, 3 H), 1.27-1.09 (m, 1 H), 1.18(d, J = 6 Hz, 3H), 1.17 (d, J= 6 Hz, 3 H), 1.16 (s, 3 H), 1.15 (d, 247 J = 6 Hz, 3 H), 1.13 (d, J= 7 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 143.4, 137.3, 90.3, 77.8, 71.2, 70.6, 56.2, 36.2, 29.7, 28.7, 26.2, 23.3, 22.7, 22.4, 22.1, 18.4; MS m/z(M+) calcd 268.2038, obsd 268.2028. Long-range DEPT from H-4 (ô 3.87): obsen/e C-2 (142.4 ppm, 3j), C- 1 (134.6 ppm, 3J), 0-10 (24.7 ppm, 3j). Long-range DEPT from H-3 (ô 4.52): observe C-2 (2J), C-1 (3j), C-4 (76.5 ppm, 2J), C-11 (72.2 ppm, 3j). Long-range DEPT from H-7 (5 1.45): observe C-1 (3J), C-5 (3J), C -8 (2j), C-9 (19.0 ppm, 3j). Irradiate Observe % NOE H-3 H-4 6.5 H-10 H-3 5.6 H-4 10.2 Me (1 R*,6aR*)^^ ,5,6,6a-Tetrahydro-2,3- /-PrO diisopropoxy-4,6a-dimethyl-1-pentalenol (176). A 16 mg (0.033 mmol) sample of 173 in /-PrO Me 176 anhydrous ether (3 mL) was reduced with LiAIH 4 (1.25 mg, 0.033 mmol) in the manner described above. Flash chromatography of the crude product on silica gel (elution with 1 0 % ethyl acetate in hexanes) afforded 15.5 mg (96%) of 176 as a colorless oil; IR (neat, cm-i) 3486, 1630; ^H NMR (300 MHz, CDCI 3) 54.83 (heptet, J = 6 Hz, 1 H), 4.30 (s, 1 H), 4.28 (heptet, J = 6 Hz, 1 H), 2.73-2.61 (m. 1 H), 2.18 (ddd, J = 16, 8 , 0.7 Hz, 1 H), 1.88 (s, 1 H), 1.76 (dd, J=0.8, 0.8 Hz, 3 H), 1.78-1.60 (m, 2 H), 1.28 (d, J=6Hz,3H), 1.25 (d, J= 6 Hz, 6 H), 1.19 (d, J = 6 Hz, 3 H), 1.03 (s, 3 H); 13C NMR (75 MHz, CDCI3) ppm 144.5, 140.1, 133.1, 1 2 1 .0 , 248 79.6, 72.1, 71.8, 56.0, 40.1, 37.1, 22.9, 22.8, 22.6, 22.0,17.8, 14.5; MS m/z (M+) calcd 266.1882, obsd 266.1881. (3a/?*,6aS*)-4,5,6,6a-Tetrahydro-2,3- y diisopropoxy-4,6a-dimethyl-1 (3a//)- g pentalenone (179). An 82 mg (0.31 mmol) sample Me 179 9 of 173 was reduced with UAIH 4 (6.4 mg, 0.17 mmol) in anhydrous ether (6 mL) as before. The unpurified product was taken up in 4 mL of IN HCI, stirred overnight at rt, and diluted with brine (15 mL) and ether (15 mL). The separated aqueous layer was extracted with ether (25 mL), and the combined organic phases were dried and concentrated to leave 58 mg (70%) of 179 as a colorless oil; IR (CHCI 3, cm-i) 1690, 1606; 1H NMR (300 MHz, CeDe) 5 5.30 (heptet, J = 6 Hz, 1 H), 5.29 (heptet, J = 6 Hz, 1 H), 2.03 (d, J = 1.4 Hz, 1 H), 2.03-1.94 (m, 1 H), 1.60-1.49 (m, 1 H), 1.46-1.36 (m, 1 H), 1.21 (s, 3 H), 1.15 (d, J = 6 Hz, 3 H), 1.14 (d, J= 6 Hz, 3 H), 1.13(d, J = 6 Hz, 3H), 1.125 (d, J= 6 Hz, 3 H), 1.09 (d, J= 6 Hz, 3 H), 0.88 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, CeDe) ppm 204.1, 169.1, 130.9, 72.8, 71.0, 57.6. 52.1,37.2, 34.3, 32.4, 24.2, 22.8, 22.73, 22.67, 22.59, 20.6; MS m/z(M+) calcd 266.1882, obsd 266.1882. Long-range DEPT from H-10 (5 1.19): observe C-1 (205.5 ppm, 3j), C-4 (57.2 ppm, 3j), C-5 (51.8 ppm, 2j), C -6 (33.8 ppm, 3j). Long-range DEPT from H -8 (8 2.03): observe C-3 (170.9 ppm, 3j), C- 5 (3J), C-6 (3J), C-9 (20.5 ppm, 2j). Long-range DEPT from H-4 (8 2.10): observe C-1 (3J), C-3 (2J), C-2 (130.6 ppm, 3J), C-5 (2J), C -8 (36.6 ppm, 2J), C-7 (32.1 ppm, 3j), C-10 (23.8 ppm, 3J), C-9 (3J). 249 (1 f?*,6afl*)-1,5,6,6a-Tetrahydro-2,3- diisopropoxy-1 -methoxy-4,6a- /.pro Me dimethylpentaiene (180). A 40 mg (0.15 mmol) 180 sample of 173 was reduced with UAIH 4 in the predescribed manner. The resultant 176 was dissolved in DMSO (1 mL) and added to a slurry of finely ground KOH (34 mg, 4 equiv) in the same solvent (1 mL). After being stirred for 5 min at rt, this mixture was treated with methyl iodide (0.03 mL, 2 equiv), allowed to react for 30 min, poured into water (25 mL), and extracted with CH 2CI2 (3x15 mL). The combined organic phases were washed with water (25 mL) and brine (25 mL), dried, and evaporated to leave an oil, which was purified by chromatography on silica gel (elution with 10% ethyl acetate in hexanes). There was isolated 21 mg (50% for the two steps) of 180 as an unstable colorless oil; IR (neat, cm-1) 1628; NMR (300 MHz, CDCI 3) 5 4.68 (heptet, V = 6 Hz, 1 H), 4.33 (heptet, J = 6 Hz, 1 H), 3.90 (s, 1 H), 3.34 (s, 3 H), 2.75-2.64 (m, 1 H), 2.27- 2.15 (m, 1 H), 1.77 (s, 3 H), 1.77-1.67 (m, 2 H), 1.27 (d, J= 6 Hz, 3 H), 1.25 (d, J= 6 Hz, 3 H), 1.24 (d, J= 6 Hz, 3 H), 1.18 (d, 6 Hz, 3 H), 1.01 (s, 3 H); 13C NMR (75 MHz, CDCI3) ppm 144.0, 140.2, 134.6, 120.5, 89.1, 72.0, 71.8, 57.4, 55.3, 40.3, 38.1, 22.9, 22.8, 22.6, 22.1, 18.0, 14.3; MS mz (M+) calcd 280.2038, obsd 280.2040. 11 H 2 MeO,. f-Me (1R*,6afl*)-4,5,6,6a-Tetrahydro-3-isopropoxy- 1 •methoxy-4,6a-dimethyl-2(1 W)-pentalenone (181). A solution of 180 (8 mg, 0.028 mmol) in THF (2 mL) was treated with IN HCI (1 mL), stirred at rt for 2 250 h, diluted with brine (5 mL), and extracted with ether (3x5 mL). The combined organic layers were washed with brine (10 mL), dried, and evaporated to leave a residue which was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to give 181 (5 mg, 73%) as a 3:1 mixture of diastereomers: colorless oil; IR (neat, cm-i) 1716, 1651; NMR (300 MHz, CDCI3) Ô (major isomer) 4.89-4.78 (m, 1 H), 3.51 (s, 3 H), 3.47 (s, 1 H), 2.96-2.86 (m, 1 H), 2.20 (ddd, J= 8 , 8 , 13 Hz, 1 H), 1.95 (dd, J= 6.7, 12 Hz, 1 H), 1.87-1.38 (m, 2 H), 1.28 (d, J = 7 Hz, 3 H), 1.21 (d, J = 6 Hz, 3 H), 1.14 (d, J = 6 Hz, 3 H), 1.08 (s, 3 H); 5 (minor isomer) 4.89-4.78 (m, 1 H), 3.54 (s, 1 H), 3.51 (s, 3 H), 2.98-2.93 (m, 1 H), 2.41-2.34 (m, 1 H), 1.87-1.39 (m, 3 H), 1.25 (d, J = 6 Hz, 3 H), 1.23 (d, J = 7 Hz, 3 H), 1.11 (d, J = 6 Hz, 3 H), 1.02 (s, 3 H); 13C NMR (75 MHz, CDCI3) ppm (major isomer) 201.6, 167.2, 145.5, 91.0, 71.1, 58.7, 50.6, 38.4, 34.3, 32.5, 22.6 (2 C), 22.1, 20.4; (minor isomer) 202.0, 167.7, 145.1, 90.7, 71.3, 58.6, 51.3, 36.3, 33.7, 32.0, 22.7, 22.4, 22.0, 17.9; MS m/z{M+) calcd 238.1569, obsd 238.1569. Long-range DEPT (major isomer) from H -8 (5 2.90): obsen/e C-3 (167.2 ppm, 2J), C-9 (20.4 ppm, Long-range DEPT from H-10 (Ô 1.08): observe C -6 (38.4 ppm, 3J), C- 4 (50.6 ppm, 2J), C-5 (91.1 ppm, 3j),C-3 (3J). Long-range DEPT (minor isomer) from H-10 (Ô 1.02): observe C -6 (36.3 ppm, 3^, C-4 (51.3 ppm, 2j), C-5 (90.7 ppm, 3j), C-3 (167.7 ppm, 3j). Long-range DEPT from H-11 (5 3.51): observe C-5 (3J). 251 (3a/î*,6aS*)-4,5,6,6a-Tetrahydro-2,3- diisopropoxy-6a-methyl-4-methylene-1(3aW)- 8 ^ pentalenone (183). Diisopropylamine (0.4 mL, 2.3 mmol) was dissolved in dry THF (16 mL), cooled to -15 °C, treated dropwise with n-butyllithium ( 1.4 mL of 1.6 M in hexane, 2.3 mmol), stirred for 15 min, and cooled to -78 °C before being treated dropwise via cannula with a solution of 173 (124 mg, 0.47 mmol) in dry THF (4 mL). After 30 min, HMPA (1 mL) was introduced and stirring was maintained for 15 min, at which point saturated NH 4CI solution (6 mL) was added all at once. The reaction mixture was allowed to warm to rt, diluted with water (25 mL), and extracted with ether (2 x 25 mL). The combined organic phases were washed with IN HCI (25 mL), saturated NaHCOa solution (25 mL), and brine (25 mL) prior to solvent evaporation. Flash chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) furnished 120 mg (97%) of 183 as a colorless oil; IR (neat, cm-i) 1699, 1617; 1H NMR (300 MHz, CDCI 3) 5 5.29 (heptet, J = 6 Hz, 1 H), 4.96 (dd, J = 1, 1 Hz, 1 H), 4.92 (dd, J= 1, 1 Hz, 1 H), 4.83 (heptet, J = 6 Hz, 1 H), 2.83 (s, 1 H), 2.19-2.13 (m, 2 H), 2.03-1.96 (m, 1 H), 1.37-1.23 (m, 1 H), 1.30 (d, J=6Hz,3H), 1.19 (d, J= 6 Hz, 3 H), 1.18 (d, 6 Hz, 3 H), 1.18 (s, 3 H), 1.16 (d, J = 6 Hz, 3 H); 130 NMR (75 MHz, CDCI3) ppm 205.3, 168.9, 148.9, 130.9, 109.3, 73.3, 71.5, 54.5, 52.1, 34.7, 31.8, 23.0, 22.7, 22.5, 22.4, 22.3; MS m/z (M+) calcd 264.1725, obsd 264.1737. Ana/. Calcd for C 16H24O3: 0, 72.69; H, 9.15. Found: C, 72.67; H, 9.14. Long-range DEPT (CeDe solution) from H-9 (5 4.92): observe C-3 (168.9 ppm, 4J), C-4 (54.5 ppm, 3j), C-7 (31.8 ppm, 3J). 252 Long-range DEPT from H-9 (5 5.03): observe C-3 (^J), C -8 (148.9 ppm, 2 J ), C-4 (3 J ), C-7 (3J ). Long-range DEPT from H-4 (5 2.83): observe C-1 (205.3 ppm, 3 J ), C- 3 (2 J ), C-8 (2 J ), C-2 (130.9 ppm, ^J), C-5 (52.3 ppm, ^J), C-7 ( 3 j) , C-8 ( 2 j) , C-9 (109.3 ppm, 3 j ) , C-10 (23.0 ppm, 3 j) . 10 1 Me (3a/?*,6a/?*)-4,5,6,6a-Tetrahydro-2- 6 ,.Pro^^, ys y 7 isopropoxy-3a-methyl-6-methylene-1(3a/f)- // 4 \ \ pentalenone (184). A cold (0 °C), magnetically 0 CH2 9 1 8 4 stirred slurry of ÜAIH4 (6 mg, 0.16 mmol) in anhydrous ether (3 mL) was treated via cannula with a solution of 183 (69 mg, 0.26 mmol) in the same solvent (5 mL). After 30 min, the reaction mixture was carefully quenched with 1N HCI (4 mL) and stirring was maintained at rt for 9 h. After dilution with water (25 mL), the product was extracted into ether (2 x 25 mL) and the combined organic phases were dried and evaporated. The residue was subjected to flash chromatography on silica gel (elution with 10% ethyl acetate in hexanes) to give 45.5 mg (85%) of 184 as a colorless oil; IR (neat, cm’i) 1718, 1617; ^H NMR (300 MHz, CeDe) 5 5.56 (s, 1 H), 5.31 (d, J = 1 Hz, 1 H), 4.92 (ddd, J= 1, 1, 2.4 Hz, 1 H), 3.98 (heptet, J = 6 Hz, 1 H), 2.63 (dd, J = 1.6, 1.6 Hz, 1 H), 2.17-1.98 (m, 2 H), 1.40-1.23 (m, 2 H), 1.01 (d, J = 6 Hz, 3 H), 1.00 (d, V = 6 Hz, 3 H), 0.93 (s, 3 H); 13C NMR (75 MHz, CeDe) ppm 199.6, 153.8, 148.4, 134.3, 109.2, 71.7, 61.8, 46.9, 37.7, 32.8, 26.6, 21.4 (2 C); MS m/z (M+) calcd 206.1307; obsd 206.1328. Anal. Calcd for C 13H18 O2: C, 75.69; H, 8.80. Found: C, 75.58; H, 8.85. 253 Long-range DEPT from H-10 (Ô 0.93): observe C-1 (134.3 ppm, 3J), C-4 (61.8 ppm, 3J), C-5 (46.9 ppm, 2J), C-6 (37.7 ppm, 3J). (3afl*,6aS*)-4,5,6,6a-Tetrahydro-2,3- /-Pro—^ diisopropoxy-3a,6a-dimethyl-4-methylene- i-PrO' 'ch 2 1(3aH)-pentalenone (185). Diisopropylamine 185 (0.085 mL, 0.65 mmol) was dissolved in dry THF (10 mL), cooled to -15 °C, treated dropwise with n-butyllithium (0.31 mL of 1.6 M in hexane, 0.5 mmol), stirred for 15 min, and cooled to -78 °C before being treated dropwise via cannula with a solution of 173 (75 mg, 0.28 mmol) in dry THF (2 mL). After 30 min, HMPA (1 mL) was introduced and stirring was maintained for 15 min, at which point methyl iodide (6 mL) was added all at once. The reaction mixture was allowed to warm to rt, stirred for an additional 5 h, diluted with water (25 mL), and extracted with ether (2 x 25 mL). The combined organic phases were washed with IN HCI (25 mL), saturated NaHCOa solution (25 mL), and brine (25 mL) prior to drying and solvent evaporation. Flash chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) afforded 63 mg (80%) of 185 as a colorless oil; IR (neat, cm-i) 1698, 1615; ^H NMR (300 MHz, CDCI 3) ô 5.33 (heptet, J = 6 Hz, 1 H), 4.95 (s, 1 H), 4.92 (s, 1 H), 4.83 (heptet, ^ = 6 Hz, 1 H), 2.17-2.10 (m, 2 H), 2.06-1.99 (m, 1 H), 1.31-1.22 (m, 1 H), 1.28 (d, J = 6 Hz, 3 H), 1.19(d, J = 6 Hz, 6 H), 1.16 (d, J= 6 Hz, 3 H), 1.14 (s, 3 H), 1.05 (s, 3 H); 13C NMR (75 MHz, CDCI3) ppm 205.2, 171.8, 154.3, 130.4, 107.4, 73.2, 71.6, 55.0, 51.8, 34.2, 30.8, 22.59, 22.54, 22.3, 22.2, 19.9, 17.3; MS m/z(M+) calcd 278.1882, obsd 278.1885. 254 >Ana/. Calcd for C 17H26O3: 0, 73.35; H, 9.41. Found: C, 73.63; H, 9.42. Ms (3a/?*,6a/?*)-4,5,6,6a-Tetrahydro-2- isopropoxy-3a,6a-dimethyl-4-methylene- / Me % ^ ^ " 2 1 (3aH)-pentalenone (186). A 50.5 mg (0.18 186 mmol) sample of 185 was reduced with LIAIH 4 (4 mg, 0.106 mmol) in the usual manner. The reaction mixture was carefully quenched with 1N HCI (3 mL), stirred at 0 °C for 0.5 h and at rt for 2.5 h, diluted with water (20 mL), and extracted with ether (2 x 20 mL). The combined organic phases were washed with saturated NaHCOa solution (20 mL) and brine (25 mL), dried, and concentrated to leave a residue which was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in hexanes). There was isolated 33.4 mg (84%) of 186 as a colorless oil; IR (neat, cm-i) 1 7 2 I, 1621; 1H NMR (300 MHz, CDCI3) Ô 5.55 (s, 1 H) 5.19 (d, J= 2.5 Hz, 1 H), 4.91 (d, J=2.2 Hz, 1 H), 4.03 (heptet, J = 6 Hz, 1 H), 2.17-2.07 (m, 1 H), 2.03 (ddd, J= 15, 15, 7 Hz, 1 H), 1.38 (dd, J = 12, 7 Hz, 1 H), 1.25 (ddd, J = 12,12, 7 Hz, 1 H), 1.13 (s, 3 H), 1.01 (d, J = 6 Hz, 3 H), 1.00 (d, J = 6 Hz, 3 H), 0.85 (s, 3 H); 13C NMR (75 MHz, CeDe) ppm 201.4, 154.1, 153.5, 133.6, 108.6, 71.2, 58.5, 50.2, 36.0, 30.8, 23.5, 21.2 (2 C), 17.3; MS m/z(M+) calcd 220.1463, obsd 220.1456. Anal. Calcd for C 14H20O2: C, 76.33; H, 9.15. Found: C, 75.84; H, 9.18. 255 OSiMe 3 (±)-l -Methyl-3-(1 -methylethyl)-1 -(trimethylsiloxy)- cyclopentene (189). All apparatus was flame-dried under ^ argon, an atmosphere of which was maintained throughout the reaction. A 1 liter, 2-necked flask equipped with a gas inlet adapter was charged with 400 mL of THF. CuBr-Me 2S (2.1 g, 10.2 mmol) was added to form a slurry. The reaction-mixture was cooled to -78 °C, and HMPA (26.6 mL, 153 mmol) was added followed by isopropylmagnesium chloride (51 mL, 2.0M in THF, 102 mmol). This mixture was stirred at -78 °C for 30 min, during which time a second flask was charged with 100 mL of THF and 2 -methyl- 2 -cyclopentenone (5.0 mL, 51 mmol), cooled to 0 °C, charged with trimethylsilyl chloride (19.4 mL, 153 mmol), and further cooled to -78 °C. The second mixture was cannulated into the flask containing the Grignard reagent and the temperature of the resultant mixture was allowed to warm to 0 °C over 2 h. After an additional 2 h at 0 °C, the solvents were evaporated to leave an oil which was treated with 300 mL of hexane and mixed thoroughly. Most of the hexane was decanted, and the residue was treated similarly with 3 x 100 mL portions of hexane. The combined hexane washes were poured through a plug of glass wool, filtered through Celite, and evaporated to an oil which was distilled. There was isolated starting material (2 g, 21 mmol) and 6 .6 g (61%) of 189 as a colorless liquid; bp 134- 136 °C at 1 Torr; 1H NMR (200 MHz, CDCI3) Ô 2.52-2.38 (m, 1 H) 2.27-2.13 (m, 2 H), 1.93-1.43 (m, 3 H), 1.46 (s, 3H), 0.88 (d, J = 7 Hz, 3 H), 0.69 (d, J = 7 Hz, 3 H), 0.17 (s, 9 H); 13C NMR (50 MHz, CDCI 3) ppm 147.1, 115.6, 50.6, 33.0, 28.9, 20.6, 20.2, 15.8, 10.5, 0.6; VPC Rt: 8.68. 256 OTf (±)1 -(2-Methyl-3-(1 -methylethyl)cyclopenteny I) triflate (190) All apparatus was flame-dried under argon, an '■P’’ atmosphere of which was maintained throughout the reaction. 190 Product 189 (5.4 g, 25.5mmol) was dissolved in 150 mL of THF and the resultant solution was cooled to -40 °C. Methyllithium (19.1 mL, 26.8 mmol) was added dropwise while the temperature was maintained between -30 and -40 °C. After 1 h, N-phenyl triflimide (9.67 g, 27.1 mmol) dissolved in 100 mL of THF was cooled to 0 °C and added via cannula. The reaction mixture was stirred at -30 to -40 °C for 1 h, diluted with 500 mL of ether, and washed with three successive 100 mL portions of sodium hydroxide (10%), 100 mL of water, 100 mL of brine, dried and evaporated. Flash chromatography of the residue on silica gel (elution with 5% ethyl acetate and 0.5% triethylamine in hexanes) yielded 6.5 g (94%) of 190 as a colorless oil. This material could also be distilled bp 72-3 °C at 1.3 Torr; ^H NMR (300 MHz, CDCI3) Ô 2.58-2.50 (m, 3 H) 1.98-1.84 (m, 2 H), 1.77-1.66 (m, 1H), 1.66 (s, 3H), 0.92 (d, J= 7 Hz, 3 H), 0.74 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, CDCI3) ppm 143.3, 130.7, 50.0, 30.2, 28.5, 20.3, 20.0, 15.6, 10.7 (CF3 not seen); VPC Rt: 5.19. (±)-2-Methyl-3-(1-methylethyl)-1-(tributylstannyl)- \ __/ cyclopentene (191). All apparatus was flame-dried under ^ /-P r 191 argon, an atmosphere of which was maintained throughout the reaction. A solution of LDA was prepared from diisopropyl amine (6.75ml, 51.5mmol) in 400 mL of THF by addition of n-butyllithium (32 mL, 51.5 mmol) at -10 to -15 °C. After 15 min the temperature of the solution of LDA was cooled to -78 °C and tributyltin hydride (12.2 mL, 45.3 mmol) 257 dissolved in 100 mL of THF was added. The reaction mixture was stirred at -78 °C for 40 min, after which time CuCN (2.03 g, 22.7 mmol) was added as a solid. After 30 min of stirring at -50 °C, 190 (5.60 g, 20.6 mmol), dissolved in an equal portion of THF was added, and the resultant mixture was stirred at -45 to -55 °C for 2 h, warmed to rt, and the solvents were evaporated. The residue was taken up in hexane, filtered through a plug of glass wool, and filtered through Celite. The recovered hexanes were evaporated and the resultant oil was used directly in the next step. GO/MS Rt: 15, m/z (M+) 357, + tin by-products. Br I (±)-1-Bromo-2-methyl-3-(1-methylethyl)cyclopentene \__/ (192). The entire product 191 was dissolved in 200 mL of ^ /-P r 1 92 pentane, cooled to -60 °C, treated with a solution of bromine (1.27 mL, 24.7 mmol) in 30 mL of pentane, and stirred at -60 to -40 °C for 30 min, after which time an additional 0.2 mL of the bromine solution was added. After an additional 30 min, the reaction mixture was diluted with 250 mL of a 10% aqueous KF solution. The pentane was evaporated and 200 mL of ether was added. This mixture was stirred for 4 h, filtered, and separated into two phases. The ether layer was washed successively with 100 mL portions of aqueous KF, water, and brine, dried and evaporated to leave an oil. The product, still contaminated with a tin by product, was distilled, bp 110-115 °C at 65 Torr, and flashed through Florisil (pentane eluant) to yield 2.41 g (58%) 192 as a colorless oil; ‘•H NMR (300 MHz, CDGI3) 6 2.57-2.50 (m, 3 H) 1.99-1.80 (m, 3 H), 1.66 (dd, J= 2,1 Hz, 3 H), .91 (d, J = 7 Hz, 3 H), .69 (d, J = 7 Hz, 3 H); 13C NMR (75 MHz, CDCI 3) 258 ppm 139.2, 116.6, 53.2, 39.0, 28.7, 2 2 .1, 20.7, 15.7, 14.2; VPC Rt: 4.49; GO/MS Rt: 4.5, m/z(M+) 2 0 2 , 204. y (3aR*,3bS*,6R*,6aR*,7aR*)- 2/ \5 13 f-PrO-\ M 3a,3b,4,5,6,6a,7,7a-Octahydro-3a- /-PrO OH 9 hydroxy-2,3-diisopropoxy-6a,7a- ^ dimethyl-6-isopropyl-1 H-cyclo- penta[a]pentalen-1-one (193). Method D was adopted with 192 (223 mg, 1.1 mmol, flashed through a short column of Florisil with pentane immediately prior to use), fe/t-butyllithium (1.3 mL, 2.2 mmol), diisopropyl squarate (198 mg, 1.0 mmol), 2-bromopropene (0.18 mL, 2 mmol), and fe/t- butyllithium (2.35 mL, 4 mmol). The following time periods were utilized: 3, 12, and 3 h. After quenching, stirring was continued for 24 h. There was isolated 52 mg (14%) of 193 as a solid, mp 82-4 °C; IR (neat, cm*'') 3456, 1691, 1612; 1H NMR (300 MHz, CeDe) 55.82-5.25 (m, 2H), 2.27 (d, V= 12.6 Hz, 1H), 2.09 (dd, J = 6 .6 , 13 Hz, 1H), 1.97-1.87 (m, 1H), 1.68-1.40 (m, 3H), 1.33 (s, 3H), 1.27 (d, J= 12.6 Hz, 1H), 1.24-1.13 (m, 1H), 1.20 (d, J = 6 Hz, 3H). 1.17 (d, J = 6 Hz, 3H), 1.15 (d, J = 6 Hz, 3H), 1.10 (d, J = 6 Hz, 3H) 0.79- 0.67 (m, 1H), 0.72 (d, J = 6.5 Hz, 6 H), 0.72 (s, 3H), (OH not seen); 13C NMR (75 MHz, CeDe) ppm 203.9, 166.2, 133.0, 77.8, 73.4, 71.7, 63.6, 61.7, 56.4, 48.9, 48.4, 33.1, 30.0, 23.4, 23.3, 22.7, 22.5, 21.77, 21.75, 20.7, 19.1, 13.0; MS m/z (M+) calcd 364.2613, obsd 364.2614. Anal. Calcd for C 22H3e0 4 : 0, 72.49; H, 9.95. Found: C, 72.32; H, 9.93. Long-range DEPT from H -6 (Ô 2.27): 203.9 (C-1, 3J), 77.8 (C-4, 3j), 63.7 (C-1 1 , 3J), 48.4 (C-7, 2j), 13.0 (C-16, 3j). 259 Long-range DEPT from H-16 (5 1.33): 203.9 (C-1, 3J), 77.8 (0-4, 3j), 61.7 (C-5, 2J),48.9 (C- 6 , 3j). Long-range DEPT from H-1 1 (6 2.10): 166.2 (C-3, 3j), 77.8 (C-4, 2j), 48.4 (C-7, 2J). nOe in CDCI 3 Irradiate Observe % NOE H-15 H-13,14 4.5 H-6a 3.7 H-17,18 11.6 H-13,14 H-6a 2.8 H-16 H-6P 3.2 H-8 3.4 H-11 H-6p 1.7 H-13,14 2.7 H-8, lOp 8.5 Strong enhancement from H-15 to H-17, 18 is also Indicative of stereochemistry of H- 8 . (3aS,5aS,6/7,8aS)- 4,5,5a,6,7,8-Hexahydro-3a- /-Pro hydroxy-2,3-diisopropoxy-6- f-PrO OH /-Pro OH isopropylcyclopenta[c]penta 199 200 len-1(3aH)-one (199) and (3a/7,5a/7,6/?,8a/?)- 4,5,5a,6,7,8-Hexahydro-3a-hydroxy-2,3-diisopropoxy-6- lsopropylcyclcpenta[c]pentalen-1(3aH)-one (200). Method D was adopted with 198 (208 mg, 1.1 mmol, flashed through a short column of Florisil with pentane immediately prior to use), fert-butyllithium (1.3 mL, 2.2 mmol), diisopropyl squarate (198 mg, 1.0 mmol), and vinyl bromide (approx 260 600 mg, 5.6 mmol), fert-butyllithium (4.0 mL, 6.8 mmol). The second anion was generated at -120 °C in the Trapp solvent mixture. The following time periods were utilized: 1,16, and 0 h. After quenching, stirring was continued for 48 h. There was isolated 83 mg (25%) of 199 and 85 mg (25%) of 200. For 199: crystalline solid, mp 62-4 °C; IR (neat, cm*^) 3435, 1692, 1613; 1H NMR (300 MHz, CDCI3) 5 5.27 (heptet, J = 6 Hz, 1H), 4.82 (heptet, J = 6 Hz, 1H), 2.40 (s, 1H), 2.28-2.33 (m, 1H), 1.95 (dd, J= 6.4, 12.7 Hz, 1H), 1.78-1.51 (m, 7H), 1.44-1.32 (m, 1H), 1.26 (d, J = 6 Hz, 3H), 1.25 (d, J = 6 Hz, 3H), 1.27-1.10 (m, 1H), 1.14 (d, J= 6 Hz, 3H), 1.12 (d, J = 6 Hz, 3H), 0.84 (d, J= 6.5 Hz, 6 H); 1^0 NMR (75 MHz, CDCI3) ppm 203.8, 167.6. 129.0, 83.1, 73.5, 71.6, 66.1, 51.9, 50.2, 38.9, 30.7, 29.5, 29.0, 26.1,22.6, 22.5, 22.3, 2 2 .2 , 22.1, (1 C overlaps); MS m/z (M+) calcd 336.2301, obsd 336.2301. Long-range DEPT from H -6 (S 2.36): 203.8 (C-1, 3J), 83.1 (0-4, 3J), 66.1 (0-5, 2J ), 51.9 (0-11, 2J ), 29.0 (0-12, 3J). For 200: colorless oil; IR (neat, cm*i) 3424, 1693, 1613; 1H NMR (300 MHz, ODOI3) Ô 5.31 (heptet, J = 6 Hz, 1H), 4.91 (heptet, J = 6 Hz, 1H), 2.26 (s, 1H), 2.08-1.95 (m, 2H), 1.85-1.63 (m, 4H), 1.59-1.32 (m, 5H), 1.29 (d, J = 6 Hz, 3H). 1.27(d, J = 6 Hz, 3H), 1.19 (d, J = 6 Hz, 3H), 1.14(d, J = 6 Hz, 3H), 0.88 (d, J= 6 .6 Hz, 3H) 0.83 (d, J= 6 .6 Hz, 3H); 13C NMR (75 MHz, ODOI3) ppm 203.7, 165.8, 131.7, 82.6, 73.4, 71.5, 64.8, 53.8, 52.5, 33.1, 31.7, 31.3, 27.9, 26.7, 2 2 .6 , 22.5, 22.4, 22.0, 20.1 (1 0 not observed); MS m/z (M+) calcd 336.2301, obsd 336.2295. Anal. Oalcd for O 20H32O4: 0, 71.39; H, 9.59. Found: 0, 71.01 ; H, 9.63. 261 Long-range DEPT from H -6 (5 1.98): 203.7 (C-1, 3J), 82.6 (0-4, 3j), 64.8 (C-5, 2J), 52.5 (C-11, 2j), 31.7 (C-1 2 , 3j). Irradiate Observe % NOE H-6 H-13,14 3.1 H-12,10 3.7 H-13,14 H-6 3.6 X-ray structure for 199 also verifies the structure for 200 once the regiochemistry of the enone was established. L (3aA,5a/?,6A,8aA). 4,5,5a,6,7,8-Hexahydro-3a- /-Pro /-Pro j | b / 7 hydroxy-2,3-diisopropoxy-6- /-PrO ^OH SiMes ÔH SiMe 3 isopropyl-4-(trlmethylsilyl)- cyclopenta[c]pentaien- 1(3aH)-one (202) and (3aS,5aS,6/?,8aS)-4,5,5a,6,7,8-Hexa- hydro-3a-hydroxy-2,3-diisopropoxy-6-isopropyl-4-(trimethyl- silyl)cyclopenta[c]pentalen-1(3aH)-cne (203). Method D was adopted with 1 -bromo-1 -(trimethylsilyl)ethylene (224 mg, 1.25 mmol), fe/t- butyllithium (1.5 mL, 2.5 mmol), diisopropyl squarate (198 mg, 1.0 mmol), and 198 (472 mg, 2 mmol, freshly prepared), fert-butyllithium (2.35 mL, 4 mmol) for 4, 16, and 2 h. After quenching, stirring was continued for 30 min. There was isolated 330 mg (81%) of a mixture of 202 and 203 (89:11). For 202: colorless oil; IR (CHCI3, cm-"') 3598, 2958, 1695, 1623; NMR (300 MHz, CeDe) ô 5.27-5.18 (m, 2H), 2.24-2.19 (m, 1H), 2.13-1.87 (m, 4H), 1.80-1.65 (m, 1H). 1.57-1.30 (m, 5H), 1.19 (d. J = 6 Hz, 3H). 1.18 (d, J = 6 Hz, 3H), 1.10 (d, J = 6 Hz, 3H), 1.05 (d, J = 6 Hz, 3H), 0.90 (d, J = 7 Hz, 3H) 262 0.89 (d, J = 7 Hz, 3H), 0.16 (s, 9H); 13C NMR (75 MHz, CeDe) ppm 202.9, 165.3, 133.1, 84.9, 74.2, 71.3, 67.6, 54.8, 53.2, 34.9, 32.6, 32.0, 30.1, 29.1, 22.94, 22.89, 22.6, 22.5 (20), 20.7, -0.9; MS m/z (M+) calcd 408.2696, obsd 408.2693. Long-range DEPT from H -6 (5 2.22): 202.9 (0-1, 3J), 84.9 (0-4, 3j), 53.2 (0-11, 2J), 34.9 (0-8, 3j), 32.6 (0-12, 3j). Long-range DEPT from H-9 (6 2.06): 202.9 (0-1, 3j), 67.6 (0-5, 2j), 53.2 (0-11, 3J). Long-range DEPT from H-13 or 14 (8 0.9): 53.2 (0-11, 3j), 32.6 (0- 12, 2J), 20.7 (0-13 or 14, 3j). (5afî,6/?,8a/7)-4,5,5a,6,7,8-Hexahydro-3a- U h chloro-2,3-diisopropoxy-6-isopropylcyclo- /-PrO penta[c]pentalen-1(3aH)-one (204). An argon- /•-PrO Cl blanketed solution of 200 (70 mg, 0.208 mmol) and triethylamine (0.06 mL, .416 mmol) in OH 2OI2 (5 mL) was cooled to 0 °0 and treated dropwise with 0.024 mL (0.312 mmol) of methanesulfonyl chloride. After stirring for 30 min. at rt, the reaction mixture was again cooled to 0 ° 0 and treated with an identical amount of triethylamine and methanesulfonyl chloride. Following an additional interval of 30 min. at rt a final treatment with the same quantities was repeated, the reaction mixture was again stirred for 30 min at rt, then diluted with cold water (10 mL). The separated aqueous phase was extracted with OH 2OI2 (10 mL) and the combined organic layers were washed sequentially with water (10 mL), IN HOI (10 mL), saturated NaHOOa solution (10 mL), and brine (10 mL) prior to drying and solvent evaporation. Flash 263 chromatography of the residue on silica gel (elution with 15% ethyl acetate in hexanes) yielded 59 mg (80%) of 204 as a colorless oil; IR (neat, cm*"') 2966, 1704, 1627; NMR (300 MHz, CDCI 3) S5.35 (heptet, J = 6 Hz, 1H), 4.95 (heptet, J = 6 Hz, 1H), 2.39 (dd, J= 13.2, 5.6 Hz, 1H), 2.06-2.81 (m, 5H), 1.60-1.44 (m. 4H), 1.38-1.13 (m, 1H), 1.33 (d, J = 6 Hz, 3H). 1.30 (d, J = 6 Hz, 3H), 1.22 (d, J = 6 Hz, 3H), 1.17 (d, J = 6 Hz, 3H), 0.90 (d, J= 6.7 Hz, 3H) 0.86 (d, J = 6.7 Hz, 3H); 1^0 NMR (75 MHz, CDCI 3) ppm 201.5, 164.3, 132.1, 76.9, 73.8, 71.9, 65.7, 54.2, 53.0, 35.6, 31.9, 31.4, 31.1,27.5, 22.62, 22.56 (2C), 22.4, 22.0, 20.2; MS m/z(M+) calcd 408.2696, obsd 408.2693. (5a/î,6fl,8a/?)-5a,6,7,8-Tetrahydro-2,3- I'H diisopropoxy-6-isopropylcyclopenta- [c]pentalen-1(5H)-one (205). Lithium chloride i PrO 205 (3 4 mg, 0 .8 mmol, dried by heating at 140 °C and 0.5 Torr for 3 h) and lithium carbonate (65 mg, 0.87 mmol, dried at rt and 0.5 Torr for 3 h) were added to DMF (2 mL, freshly distilled from CaH 2 at 70 Torr) and the mixture was heated to 120 °C. A solution of 204 (49 mg 0.138 mmol) dissolved in dry DMF (2 mL) was introduced and the reaction mixture was heated at 150 °C for 1.5 h, cooled to rt, diluted with ether (15 mL), and filtered through a pad of Celite. The filtrate was washed with brine (3x5 mL), dried, and evaporated to leave 42 mg (95%) of 205 as a colorless oil. This unstable compound underwent minor decomposition during flash chromatography on silica gel (elution with 5% ethyl acetate and 0.5% triethylamine in petroleum ether). Product 205 was a colorless oil; IR (neat, cm*l) 1696, 1624, 1580; ^H NMR (300 MHz, CeDe) Ô 5.32 (dd, J= 2, 2 Hz, 1H), 5.24 (heptet, J = 6 Hz, 1H), 4.99 (heptet, J = 6 Hz, 1H), 2.58-2.46 (m. 264 2H), 2.93 (ddd, J = 10.5, 10.5, 2 Hz, IN), 2.01-1.64 (m, 5H), 1.37-1.29 (m, IN), 1.20 (d, J = 6 Hz, 3H). 1.14 (d, J= 6 Hz, 6 H), 1.11 (d, J = 6 Hz, 3H), 0.96 (d, J= 6.5 Hz, 3H) 0.88 (d, J= 6.5 Hz, 3H); 13C NMR (75 MHz, CeDe) ppm 200.3, 157.7, 142.9, 137.7, 117.6, 73.2, 72.1,68.5, 55.1,47.8, 45.4, 38.8, 31.4, 31.2, 23.1,22.9, 22.8, 22.7, 22.1, 21.3; MS m/z(M+) calcd 318.2194, obsd 318.2182. (5a/?,6f?,8a/?)-4,5,5a,6,7,8- Hexahydro-3a-chloro-2,3- diisopropoxy-6-isopropyl-4- /-PrO Cl SiMe 3 ^1 SiMe 3 (trimethylsilyl)cyclopenta- 206 207 , , . , [c]pentalen-1 (3aH)-one (206) and (5aS,6A,8aS)-4,5,5a,6,7,8-Hexa-hydro-3a-ehloro-2,3- diisopropoxy-6-isopropyl-4-(trimethylsilyl)cyclopenta[c]pentalen- 1(3aH)-one (207). An argon-blanketed solution of the mixture of 202 and 203 (133 mg, 0.33 mmol) and triethylamine (0.15 mL, 1 mmol) in CH2CI2 (5 mL) was cooled to 0 °C and treated dropwise with 0.04 mL (0.52 mmol) of methanesulfonyl chloride. The reaction mixture was allowed to warm to rt and stirred for 30 min. Subsequently, the reaction mixture was treated with 0.2 mL of triethylamine followed by 0.1 mL of methanesulfonyl chloride at 30 min intervals for a 4-hr period, then diluted with cold water (25 mL). The separated aqueous phase was extracted with CH 2CI2 (15 mL) and the combined organic layers were washed sequentially with water (15 mL), IN HCI (15 mL), saturated NaHCOg solution (15 mL), and brine (15 mL) prior to drying and solvent evaporation. Flash chromatography of the residue on silica gel (elution with 5% ethyl acetate and .5% triethylamine in 265 petroleum ether) yielded 90 mg (74%) of a mixture of 204, 205, and 206 (3.5:2.0:3.0 - estimated by NMR) plus, presumably, very minor amounts of similar derivatives resulting from 203. Compounds 204, 205, and 206 could be isolated separately by MPLC (elution with 5% ethyl acetate in petroleum ether). Products resulting from the minor diastereomer 203 eg. 207, could not be isolated. For 206. colorless oil; IR (neat, cm-i) 1705, 1628; 1R NMR (300 MHz, CeDe) 6 5.32 (heptet, J= 6 Hz, 1H), 5.26 (heptet, J = 6 Hz, 1H), 2.32 (ddd, J = 13.2, 7.1, 3.6 Hz, 1H), 2.22-2.17 (m, 1H), 2.11-2.01 (m, 1H), 1.87-1.75 (m, 1H), 1.73-1.59 (m, 2H), 1.51-1.39 (m, 3H), 1.22-1.18 (m, 1H), 1.21 (d, J = 6 Hz, 3H). 1.19 (d, J = 6 Hz, 3H), 1.12 (d, J = 6 Hz, 3H), 1.02 (d, J = 6 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H) 0.83 (d, J=6.7 Hz, 3H), .22 (s, 9H); 13C NMR (75 MHz, CeDe) ppm 200.4, 163.4, 133.7, 80.6, 74.9, 71.7, 6 8 .8 , 54.8, 53.6, 37.5, 32.6, 32.5, 32.0, 31.4, 22.84, 22.81, 22.4, 22.3, 22.1,20.6, - 0 .6 ; MS m/z{M+) calcd 426.2357, obsd 426.2364. Long-range DEPT from H -6 (5 2.20): 200.4 (C-1, 3J), 80.6 (C-4, 3j), 37.5 (C-8 , 3J), 32.6(C-13, 3J). Long-range DEPT from H-10 (6 2.33): 200.4 (C-1, 3J), 53.6 (C-13, 3 j). Long-range DEPT from H-13 or 14 (6 0.84): 53.6 (C-12, 3j), 32.6 (C- 13, 2J) Irradiate Observe % NOE H-9 H-12or15 6.1 H-6 H-14, 15 3.0 H-13, 7 8.1 H-14,15 H-6 3.6 The nOe data are inconclusive for determination of stereochemistry at C-8 . 266 Comparison of the NMR of adducts 204 and 205, which resulted from desilylation, with the same adducts prepared from 2 0 0 , was used to verify, in part, the stereochemistry of 2 0 2 and 206. In a separate reaction. An argon-blanketed solution of 202 and 203 (100 mg, 0.25 mmol) and triethylamine (1.3 mL, 9.5 mmol) in CH 2CI2 (5 mL) was treated dropwise at rt with 0.5 mL (6.5 mm) of methanesulfonyl chloride during which time the reaction mixture warms to a slight reflux. After stirring for 30 min, the reaction mixture was diluted with cold water (10 mL) and subjected to a similar work-up. Following flash chromatography of the residue on silica gel (elution with 5% ethyl acetate and 0.5% triethylamine in petroleum ether) and drying for 16 h at 1 Torr, 82 mg of a mixture of 206, 207, 208, and 209 was isolated. This mixture was taken on to the next step. (5aR,6f?,8aR)-5a,b,7,8- Tetrahydro-2,3- /-PrO^^CI SiMe 3 Cl SiMe 3 dilsopropoxy-6-lsopropyl-4- 15 20fi 207 (trimethyisilyl)cyciopenta[c] pentalen-1(5H)-one (208) and (5aS,6A,8aS)-5a,b,7,8- Tetrahydro-2,3-diisopropoxy-6-isopropyl-4- (trimethyisilyl)cyclopenta[c]pentalen-1(5H)-one (209). Lithium chloride (50 mg, 1.15 mmol, dried by heating at 140 °C and 0.5 Torr for 3 h) and lithium carbonate (100 mg, 1.34 mmol, dried at rt and 0.5 Torr for 3 h) were added to DMF (4 mL, freshly distilled from CaH 2 at 70 Torr), and the mixture was heated to 120 °C. A solution of the mixture of 206, 207, 208, 267 and 209 from the previous experiment dissolved in dry DMF (3 mL) was introduced and the reaction mixture was heated at 150 °C for 1.5 h, cooled to rt, diluted with ether (20 mL), and filtered through a pad of Celite. The filtrate was washed with brine (3x10 mL), dried, and evaporated to leave an oil, which was purified by chromatography on silica gel (elution with 5% ethyl acetate and 0.5% triethylamine in petroleum ether). There was isolated 53.5 mg (56% for two steps) of 208 and 6.5 mg (7% for two steps) of 209. For 208: white solid, mp 58-9 °C: IR (neat, cm 'i) 1690, 1600, 1575, 1382: 1H NMR (300 MHz, CeDe) S 5.37-5.26 (m, 2 H), 2.82 (dd, J = 19.6, 11.4 Hz, 1H), 2.57-2.48 (m, 2H), 1.99-1.68 (m, 5H), 1.44-1.35 (m, 1H), 1.21 (d, J = 6 Hz, 3H). 1.16(d, J = 6 Hz, 3H), 1.15 (d, J= 6 Hz, 3H), 1.08 (d, J = 6 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H) 0.90 (d, J= 6.5 Hz, 3H), .26 (s, 9H); 13C NMR (75 MHz, CeDe) ppm 200.5, 157.5, 151.7,136.9, 130.8, 73.1, 71.9, 70.7, 54.9, 51.2, 48.3, 39.1, 31.8, 31.6, 23.1,22.9, 2 2 .8 , 22.7, 2 2 .2 , 21.4, -0.04; MS m/z (M+) calcd 390.2590, obsd 390.2587. For 209: white solid, mp 66-67 °C; IR (CHCI 3. cm-i) 1678, 1612, 1568; 1H NMR (300 MHz, CeDe) 5 5.42 (heptet, J = 6 Hz, 1H), 5.37 (heptet, J = 6 Hz, 1H), 2.86-2.68 (m, 2H), 2.58-2.48 (m, 1H), 2.14-1.92 (m, 2H), 1.90- 1.69 (m, 2H), 1.41-1.20 (m, 2H), 1.22 (d, J = 6 Hz, 3H). 1.17 (d, J= 6 Hz, 3H), 1.16 (d, J = 6 Hz, 3H), 1.00 (d, J = 6 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H) 0.83 (d, J = 6.7 Hz, 3H), 0.29 (s, 9H); 13C NMR (75 MHz, CeDe) ppm 201.1, 157.6, 152.6, 137.4, 131.1, 73.2, 71.7, 69.2, 53.4, 47.0, 42.4, 40.1,31.0, 29.5, 23.0, 22.9, 22.8, 22.5. 22.3, 22.2, 0.0; MS m/z (M+) calcd 390.2590, obsd 390.2590. 268 Long-range DEPT from H -6 (6 2.83): 201.1 (C-1, 3j), 40.1, 29.5 (2 of C-7, 9, 10). Identification of the regiochemistry of this isomer which has lost the stereocenter at C-8 via semi-selective DEPT, in turn verifies the origin of the by-product 203, as arising from electrocyclization from the alternate helical arrangement. 269 LIST OF REFERENCES 1 Kofron, W.G.; Baclawski, L.M. J. Org. Chem. 1976, 41, 1879. 2 See Chapter 1, ref 10d. 3 See Chapter 2, ref 4. 4 See Chapter 3, ref 2. 5 See Chapter 3, ref 4. 6 See Chapter 3, ref 3. 7 (a) Schmidt, C. Can. J. Chem. 1976, 54, 2310. (b) Huffman, J.W.; Arapakos, P.G. J. Org Chem. 1965, 30, 1604, 270 APPENDIX A X-RAY DATA 271 CO Figure A .I. NMR spectrum of 13. 272 CO Figure A.2. NMR spectrum of 14. 273 Figure A3. NMR spectrum of 15. 274 « Figure A.4. iH NMR spectrum of 16. 275 CO Figure A.5. NMR spectrum of 18. 276 m Figure A.6. NMR spectrum of 19. 277 CO Q CO Ü Figure A.7. NMR spectrum of 20. 278 ff Figure A.8. NMR spectrum of 31. 2 7 9 CO 13 ss: ils A.9. 1H NMR spectrum of 32 280 CO 1H NMR spectrum of 33. 281 Figure A.11. NMR spectrum of 34. 282 J K Q ;ss 223:5% 85S28& 3**1 Figure A.12. NMR spectrum of 35. 283 to O to Ü g Figure A.13. NMR spectrum of 43 at rt. 284 to CD Figure A.14. NMR spectrum of 43 at 350 °K. 285 CO Figure A.15. ’ H NMR spectrum of 43 at 400 °K. 286 CO Q CO ü .8 - 8. Figure A.16. NMR spectrum of 44. 287 -t A.17. 1H NMR spectrum of 48. 288 CO Figure A.18. NMR spectrum of 50. 289 CO Q CO Ü Figure A.19. NMR spectrum of 51. 290 CO CO Figure A.20. NMR spectrum of 52. 291 CO CO ■A A A .8 .8 Figure A.21. ’ H NMR spectrum of 55. 292 CO CO -8 Figure A.22. NMR spectrum of 56. 293 CO D CO Ü -S -8 .8 Figure A.23. NMR spectrum of 57. 294 -8iII -S .8 Figure A.24. NMR spectrum of 58 295 .8 - 8 . Figure A.25. H4 NMR spectrum of 60a. 2 9 6 '•— _ep ü Q ü -* S Figure A.26. NMR spectrum of 60b. 2 9 7 .8 to to Figure A.27. NMR spectrum of 61. 298 s ■n .8 Figure A.28. NMR spectrum of 63. 299 .8 CO CO .8 .8 .8 Figure A.29. NMR spectrum of 64. 300 : Sîfc CO o o ü Figure A.30. NMR spectrum of 65. 301 CO CO Figure A.31. NMR spectrum of 66. 302 o ■ o 53322 CD CO 3 0 2 : to L (O Figure A.32. NMR spectrum of 67. 303 CO Figure A.33. NMR spectrum of 70. 304 CO Q oCO Ü Figure A.34. NMR spectrum of 71 305 CO CO Figure A.35. NMR spectrum of 72. 306 i CO Figure A.36. NMR spectrum of 73. 307 (O Q Figure A.37. ’ H NMR spectrum of 74. 308 CD Figure A.38. NMR spectrum of 75. 309 % Figure A.39. ‘’H NMR spectrum of 76. 310 (O (D - 8 . Figure A.40. NMR spectrum of 77. 311 Figure A.41. NMR spectrum of 79. 312 .g CO .8 Figure A.42. NMR spectrum of 80. 313 CO Figure A.43. NMR spectrum of 81. 314 (D CD Figure A.44. NMR spectrum of 83. 315 CO Figure A.45. NMR spectrum of 87. 316 CO CO Figure A.46. "'H NMR spectrum of 88. 317 CO . 8 - Figure A.47. NMR spectrum of 89. 318 : .8 CO ü a .8 ü 9s s -S Figure A.48. ‘'H NMR spectrum of 90. 319 CO Q CO ü Si I > “ . Figure A.49. ‘'H NMR spectrum of 91. 320 Figure A.50. NMR spectrum of 92. 321 -S a(D <£> O -Si .8 Figure A.51. m NMR spectrum of 93. 322 00 -S Figure A.52. NMR spectrum of 94. 323 Figure A.53. NMR spectrum of 95. 324 CO Figure A.54. NMR spectrum of 96. 325 (O Q (O ü .8 -% .8. Figure A.55. ’ H NMR spectrum of 9 8. 326 CO CO Figure A.56. NMR spectrum of 1 01. 327 m Figure A.57. ’ H NMR spectrum of 1 03. 328 CO ! 1H NMR spectrum of 104 329 CO % - 8. Figure A.59. NMR spectrum of 105. 330 ( J CO CO Figure A.60. "'H NMR spectrum of 106. 331 en ü D ü Figure A.61. NMR spectrum of 109. 332 .8 .8 CO -S. - 8 i Figure A.62. NMR spectrum of 111, 333 CO Figure A.63. NMR spectrum of 112. 334 _ CO CO Z 5 T I TW 931M IL Figure A.64. NMR spectrum of 113. 335 (O to -8 Figure A.65. NMR spectrum of 114. 336 CO Figure A.66. NMR spectrum of 115. 337 CO .8 Figure A.67. NMR spectrum of 116. 338 • o . o CO o Q (J CO ü o m O : STS' m nx o c ’ o . n o (O n (O o rs lO r* n « o *0J "mmaiNf Figure A.68. NMR spectrum of 117. 339 CO CO Figure A.69. NMR spectrum of 118. 340 CO CO -m M a iN X L . Figure A.70. NMR spectrum of 119. 341 g -H Figure A.71. NMR spectrum of 122. 342 CO CO Figure A.72. NMR spectrum of 123. 343 ■A «O Q CO ü .8 -S Figure A.73. NMR spectrum of 132. 344 CO Q CO ü J d L5 I » Figure A.74. NMR spectrum of 138. 345 CO Z Z ü & ix ■ Figure A.75. NMR spectrum of 139. 346 .8 CO Q CO o J .8 Figure A.76. NMR spectrum of 140. 347 and 2 H J i i Figure A.77. NMR spectrum of 141, 348 Figure A.78. ’ H NMR spectrum of 143. 349 a S E CO Q i CO f-: Ü J ^ S 5 F t : r : I r- i : s I Figure A.79. iH NMR spectrum of 144. 350 -8 1 “ i .8 Figure A.80. "'H NMR spectrum of 145. 351 (D CO .8 .8 Figure A.81. NMR spectrum of 148 352 Figure A.82. NMR spectrum of 149. 353 (O -8. .8 .8 .8 Figure A.83. NMR spectrum of 150 354 (O CO A .8 .8 A Figure A.84. iH NMR spectrum of 153. 355 (O .8 8 .8 1H NMR spectrum of 166. 356 en -8 .8. -S -8 -S .8 8 ■H .8 8 -8 g l8 Figure A.86. "'H NMR spectrum of 167. 357 _£? ü Û Ü .s .8 Figure A.87. NMR spectrum of 168. 358 ü Q ü rS .8 Figure A.88. NMR spectrum of 170. 359 CO Figure A.89. NMR spectrum of 171a. 360 m .8 .8 .8 Figure A.90. NMR spectrum of 171b. 361 oCO oCO -S. .8 Figure A.91. NMR spectrum of 172. 362 -8 . 8. CO -8 ■u -8 Figure A.92. m NMR spectrum of 173. 363 CO Figure A.93. NMR spectrum of 174. 364 CO Û CD ü Figure A.94. "'H NMR spectrum of 175. 365 3 1 .8 Figure A.95. "'H NMR spectrum of 176. 366 CO G CO ü 3 -S - 8 . Figure A.96. NMR spectrum of 179. 367 CO .8 .8 Figure A.97. NMR spectrum of 180. 368 CO ^ J .8 Figure A.98. NMR spectrum of 181. 369 CO .8 - 8 . 1H NMR spectrum of 183 370 (O CO Figure A.100. NMR spectrum of 184. 371 CO 1H NMR spectrum of 185. 372 CO CO Figure A.102. NMR spectrum of 186. 3 7 3 JE? O Û -S ü .8 Figure A.103. NMR spectrum of 190. 374 -S % .a Figure A.104. ’’H NMR spectrum of 192. 375 CO CO Figure A.105. NMR spectrum of 193. 376 CO .8 Figure A.106. NMR spectrum of 199 377 CO 1H NMR spectrum of 200 378 J ig Figure A.108. NMR spectrum of 202, 203. 379 g s -S Figure A.109. NMR spectrum of 204. 3 8 0 CO CO Figure A.110. NMR spectrum of 205. 381 (£> CO Figure A.111. NMR spectrum of 206. 382 CO CO .8 Figure A.112. NMR spectrum of 208. 383 CO CO I Figure A.113. '•H NMR spectrum of 209. 384 -S .8 .8 .8 .8 -8. ^8 Figure A.114. tH NMR spectrum of 220. 385 APPENDIX B X-RAY DATA 386 CIS C13 Sil C18 0 2 01 C14 S i2 C5 C4 C16 03 C17 C6 C2 C3 C 7 04, CIO C20 C23 C19 Oil 021 C22 05 C12 C24 Figure B.1. Computer-generated perspective drawing of the final X-ray model of 52. The methyl groups bonded to silicon and the isopropyl groups attached to oxygen are depicted only in line notation for clarity. 387 Formula; For. wt. ^24^42^6^*2; 482.77 Color/shape colorless/parallelepiped Space group P1 Temp., °C 20 Cell Constants® a,  10.962(9) b,A 11.488(4) c,A 12.284(4) a, deg 96.21(3) P, deg 106.47(5) Y, deg 100.47(5) Cell vol, A3 1437.7 Formula units/unit cell 2 Dcaic 9 cm-3 1.12 Hcaic> cm ^ 1.58 Diffractometer/scan Enraf-Nonius CAD-4/o)-2e Radiation, graphite monochromator MoKa(X= 0.71073) Max crystal dimmensions, mm 0.35 X 0.40 X 0.60 Scan width 0.80 +0.35tanq Standard reflections 500; 050; 006 Decay of standards ±2% Reflections measured 5052 20 range, deg 2 < 20 < 50 Range of h, k, I +13, ±13, ±14 Reflections observed [Fq > 5a(Fo)]^ 2866 Computer programs^ SHELX18 Structure solution SHELXS20 No. of parameters varied 319 Weights [a(Fo)2 + 0.0010 Fo2]-1 GOF 0.90 R = zllFol-IFcll/zlFol 0.047 Rw 0.060 Largest feature final diff. map 0.2e* A-3 Table B.1.1. Crystal data and summary of intensity data collection and structure refinement for 52. sLeast-squares refinement of (sin0/A.)2 values for25 reflections 0 > 20° ^Corrections: Lorentz-polarization. ^Neutral scattering factors and anomalous dispersion corrections from ref. 1. 388 Atom x/a y/b z/c B(eqv)a Si(l) 0.2933(1) 0.0469(1) 0.13860(9) 3.66 Si{2) 0.3154(1) -0.35304(9) 0.14335(9) 3.66 0(1) 0.3409(3) 0.1128(2) 0.3838(2) 4.15 0(2) 0.3114(3) -0.0631(2) 0.2142(2) 3.65 0(3) 0.3356(2) -0.2731(2) 0.2697(2) 2.88 0(4) 0.1415(2) -0.4158(2) 0.3094(2) 3.42 0(5) -0.0698(2) -0.3196(2) 0.3450(2) 3.33 0(6) 0.0068(2) -0.1477(2) 0.5347(2) 3.17 0(1) " 0.3852(5) 0.1890(3) 0.4945(3) 4.36 0(2) 0.3746(4) 0.1068(3) 0.5799(3) 3.70 0(3) 0.2603(3) 0.0070(3) 0.5070(3) 2.73 0(4) 0.2880(3) -0.0026(3) 0.3944(3) 2.57 0(5) 0.2748(3) -0.0906(3) 0.3092(3) 2.55 0(6) 0.2460(3) -0.2219(3) 0.3063(3) 2.46 0(7) 0.1528(3) -0.2932(3) 0.3344(3) 2.51 0(8) 0.0589(3) -0.2560(3) 0.3867(3) 2.51 0(9) 0.0963(3) -0.1776(3) 0.4833(3) 2.65 0(10) 0.2315(3) -0.1097(3) 0.5527(3) 2.72 0(11) 0.2159(4) -0.0888(4) 0.6731(3) 3.57 0(12) 0.0766(4) -0.0744(4) 0.6465(3) 3.86 0(13) 0.2698(6) -0.0231(5) -0.0107(3) 6.01 0(14) 0.1478(4) 0.1036(5) 0.1429(4) 5.27 0(15) 0.4436(5) 0.1670(4) 0.1837(4) 5.94 0(16) 0.3422(7) -0.5034(4) 0.1656(5) 7,20 0(17) 0.1510(4) -0.3600(5) 0.0447(4) 5.50 0(18) 0.4438(4) -0.2779(4) 0.0883(4) 4.74 0(19) 0.1377(5) -0.4820(4) 0.4009(4) 4.95 0(20) 0.2717(6) -0.4630(5) 0.4850(5) 8.08 0(21) 0.0820(7) -0.6093(4) 0.3494(5) 7.75 0(22) -0.1282(4) -0.3486(3) 0.2220(3) 3.44 0(23) -0.1461(5) -0.2379(4) 0.1719(4) 5.04 0(24) -0.2545(4) -0.4359(4) 0.2043(4) 5.04 a B(eqv) = b Isotropic refinement. Table B.2. Final fractional coordinates for 52. 389 Atom x/a y/b z/c H(l) C D] 0.473 0.231 0.510 H(2) C 1)] 0.332 0.245 0.498 H(l) C 2)] 0.451 0.075 0.603 H(2) C 2)] 0.360 0.145 0.646 H(l) C 3)] 0.180 0.028 0.505 H(l) C 10)] 0.301 -0.148 0.551 H(l) C 11) ] 0.275 -0.019 0.720 H(2) C 11)] 0.227 -0.156 0.711 H(l) C 12) ] 0.074 0,008 0.643 H(2) c 12)] 0.040 -0.101 0.703 H(l) c 13)] 0.259 0.036 -0.060 H(2) c 13)] 0.198 -0.090 -0.040 H(3) c 13)] 0.348 -0.049 -0.008 H(l) c 14)] 0.133 0.155 0.087 H(2) c 14)] 0.158 0.146 0.217 H(3) c 14)] 0.076 0.037 0.123 H(l) c 15)] 0.429 0.219 0.128 H(2) c 15)] 0.518 0.135 0.183 H(3) c 15)] 0.458 0.211 0.258 H(l) c 16)] 0.359 -0.542 0.101 H(2) c 16)] 0.266 -0.549 0.175 H(3) c 16)] 0.414 -0.498 0.233 H(l) c 17)] 0.144 -0.396 -0.031 H(2) c 17)] 0.132 -0.282 0.043 H(3) c 17)] 0.091 -0.409 0.073 H(l) c 18)] 0.434 -0.318 0.013 H(2) c 18) ] 0.525 -0.283 0.140 H(3) c 18)] 0.441 -0.196 0.086 H(l) c 19)] 0.090 -0.455 0.448 H(l) c 20)] 0.269 -0.507 0.546 H(2) c 20)] 0.309 -0.380 0.516 H(3) c 20)] 0.323 -0.493 0.443 H(l) c 21)] 0.075 -0.659 0.405 H(2) c 21)] 0.143 -0.630 0.314 H(3) c 21)] 0.000 -0.621 0.292 H(l) c 22)] -0.077 -0.384 0.184 H(l) c 23)] -0.187 -0.254 0.091 H(2) c 23)] -0.064 -0.185 0.189 H(3) c 23)] -0.199 -0.202 0.208 H(l) c 24)] -0.300 -0.454 0.124 H(2) c 24)] -0.306 -0.401 0.244 H(3) c 24)] -0.238 -0.508 0.232 Table B.2 (continued). Final fractional coordinates for 52. 390 o n o n n n o cr 1/1 ro f-»W00 (7> nonoooooooooowwww o o (D roH-*»-'Cs>cr»*p‘ U>Ma^ai>f*roM<^x->Nx--.x-s CO KO O ' w ' «—x «_x X ««x **-x ".MX *_x CO CO I—* h -* CD 1 1 1 1 1 1 1 1 1 1 i 1 i 1 L) I I I I I I I I I I I I I o n o n o o o o I i I I I i I I 1 I 1 I i i I 1 I B (/) CO I-» CO CO noonooooooooonooo 00 ro CO CDM o '■w-'fsjfsjro»—'MH-' 0 COCOI-'kO*^ ÜJ h-* ' h-' ' O **** •«—' w "s_x D > in4«U1U14»i««UIU1i(«4«<«WW(B00(%)00rt u>0'sjcnocooMComoooa>C7>u>MOoc\roMa^oNJMi-* 3 0'-4t-‘Ocri'-irov-'u>Ljtoa>oo*»4>-***» fp • •••••••••••••••••••*••••• iO OfNjfvJOOCD>f«CDOa)lX)CnMCT\t-'OQOO 3 h-»'«jOD-«j««jNjroœtnûnvû*-j-^ojtf*oocoaN~*40JcnH-'OOh-'o> x ^ «XM X“N x-s x-« x*« x—« X*«> X ^ X ^ X*S X"«> X—« X ^ X ^ X—« x-s n ;^W,fkCJWWWWWWWWWWWWWWWWhJN)N)fUN)hJ cnaNC/icn4>4^i^c/i.fk.^>^4^4^4ï«ifhcnifk m Atom Ull U22 U33 012 U13 023 0.0241(5 Si(l) 0.0694(7) 0.0643(7) 0.0499(6) 0.0240(6) 0.0335(6) Si(2) 0.0690(8) 0.0518(6) 0.0572(6) 0.0088(6) 0.0353(6) -0.0044(5 0.004(1: 0( 1) 0.104(2) 0.038(1) 0.056(2) 0. 000( 1 ) 0.037(2) 0 ( 2 ) 0.084(2) 0.051(1) 0.047(1) 0.016(1) 0.040(1) 0.015(1) 0. 001( 1) 0(3) 0.049(1) 0.043(1) 0.048(1) 0 . 010( 1 ) 0.024(1) 0.008(1) 0(4) 0.071(2) 0.036(1) 0.061(2) 0.009(1) 0.035(1) - 0 . 002( 1 ) 0(5) 0.049(2) 0.061(2) 0.047(1) -0.005(1) 0 . 020( 1 ) 0 . 002( 1 ) 0 ( 6 ) 0.052(2) 0.055(1) 0.048(1) 0 . 012( 1 ) 0.027(1) C(l) 0.087(3) 0.046(2) 0.071(3) -0.004(2) 0.029(2) -0.009(2) C(2) 0.060(3) 0.059(2) 0.053(2) -0.008(2) 0.017(2) -0.009(2) C(3) 0.045(2) 0.049(2) 0.037(2) 0.009(2) 0.016(2) -0.003(1) C(4) 0.047(2) 0.038(2) 0.039(2) 0.004(2) 0.016(2) 0.004(1) C(5) 0.046(2) 0.044(2) 0.033(2) 0.008(2) 0.017(2) 0 . 0 1 0 ( 1 ) C(6) 0.048(2) 0.039(2) 0.032(2) 0 . 012( 2 ) 0.016(1) 0. 002( 1 ) C(7) 0.050(2) 0.036(2) 0.036(2) 0.009(2) 0.017(2) 0.003(1) C(8) 0.043(2) 0.040(2) 0.039(2) 0.003(2) 0.017(2) 0.008(1) C(9) 0.045(2) 0.044(2) 0.043(2) 0 . 01 1 ( 2 ) 0.024(2) 0 . 0 1 1 ( 1 ) C(10) 0.047(2) 0.051(2) 0.033(2) 0 . 01 1 ( 2 ) 0.016(2) 0.004(1) C(ll) 0.066(3) 0.075(3) 0.032(2) 0.015(2) 0. 020( 2) 0.006(2) C(12) 0.073(3) 0.070(3) 0.046(2) 0.015(2) 0.035(2) - 0 . 002( 2 ) C(13) 0.133(5) 0.114(4) 0.056(3) 0.063(4) 0.047(3) 0.035(3) C(14) 0.082(3) 0.106(4) 0.072(3) 0.038(3) 0.033(3) 0.018(3) C(15) 0.098(4) 0.088(4) 0.110(4) 0.017(3) 0.059(3) 0.043(3) C(16) 0.173(6) 0.061(3) 0.127(4) 0.035(4) 0.099(4) 0.010(3) C(17) 0.082(3) 0.109(4) 0.064(3) -0.013(3) 0.028(3) -0.026(3) C(18) 0.076(3) 0.084(3) 0.076(3) 0.024(3) 0.046(3) 0 . 010( 2 ) C(19) 0.113(4) 0.053(3) 0.083(3) 0.025(3) 0.059(3) 0.028(2) C(20) 0.185(7) 0.104(5) 0.105(5) 0.048(5) 0.046(5) 0.055(4) C(21) 0.169(6) 0.052(3) 0.156(6) 0.009(4) 0.079(5) 0.038(3) C(22) 0.054(2) 0.058(2) 0.050(2) 0.005(2) 0.016(2) -0.004(2) C(23) 0.087(4) 0.081(3) 0.067(3) 0.009(3) 0.007(3) 0. 010( 2 ) C(24) 0.069(3) 0.083(3) 0.079(3) -0.011(3) 0.011(3) -0.005(3) Anisotropic thermal parameters are defined by exp[-2pi(pi)(hha*a*Ull + kkb*b*U22 + llc»c*U33 + 2hka*b*U12 + 2klb*c*U23 + 2hla*c*U13)]. Hydrogen atoms were given a fixed isotropic thermal parameter of B = 5.5 angstroms squared. Table B.4. Thermal parameters for 52. 392 Figure B.2. Computer-generated perspective drawing of the final X-ray model of 57. 393 Compd C16H26O4 Color/shape colorless/parallelepiped For. wt. 282.38 Space group P 2 i/C Temp., °C 21 Cell Constants^ a.A 17.596(11) b.A 8.818(2) C.A 10.888(10) p. deg 96.60(6) Cell vol. A3 1678 Formula units/unit cell 4 DcalC’ 9 ^ 1.12 Mcalc* cm ^ 0.85 Diffractometer/scan Enraf-Nonius CAD-4/d)-20 Radiation, graphite monochromator MoKa (1= 0.71073) Max crystal dimensions, mm 0.23 X 0.40 X 0.48 Scan width 0.80 + 0.35 tan0 Standard reflections 800; 021; 102 Decay of standards ±35% Reflections measured 3322 20 range, deg 2<20<5O Range of h. k. I ±20. +10. +12 Reflections observed [Fq > 5a{FQ)]^ 547 Computer programs^ SHELXl Structure solution S H E L X S 2 No. of parameters varied 99 Weights [o(Fo)2 + 0.0024 Fo2]-1 GOF 2.54 R = 21|Fol-|FcIIÆlFol 0.135 Rw 0.154 Largest feature final diff. map 0.5e* A'3 Table B.5. Crystal data and summary of intensity data collection and structure refinement for 57. ^Least-squares refinement of (sin0/X)2 values for 25 reflections 0 > 12° ^Corrections: Lorentz-polarization. cNeutral scattering factors and anomalous dispersion corrections from ref. 1. 394 Atom x/a y/b z/c H(l) 0(1)] 0.326 0.036 1.112 H(l) 0(6)1 0.417 0.171 0.692 H(2) 0(6)] 0.475 0.161 0.811 H(l) 0(7)] 0.467 -0.091 0.741 H{2) 0(7)] 0.379 -0.082 0.708 H(l) 0(8)] 0.459 -0.097 0.939 H(l) 0(9) ] 0.141 -0.120 0.928 H(l) 0(13)] 0.191 -0.376 0.936 H(2) 0(13)] 0.129 -0.341 1.021 H(3) 0(13)] 0.211 -0.381 1.077 H(l) 0(13)1 0.114 -0.155 1.094 H(2) 0(13) ] 0.164 -0.010 1.110 H(3) 0(13) ] 0.182 -0.147 1.198 H(l) 0(12)1 0.135 0.266 0.706 H(l) 0(13) ] 0.018 0.240 0.717 H(2) 0(13)1 0.021 0.070 0.753 H(3) 0(13)1 0.023 0.117 0.616 H(l) 0(14)] 0.063 0.320 0.862 H(2) 0(14)] 0.151 0.319 0.883 H(3) 0(14)1 0,105 0-195 0.943 H(l) 0(15)1 0.429 0.330 0.956 H(2) 0(15)1 0.344 0.296 0.976 H(3) 0(15)1 0.362 0.410 0.875 H(l) 0(16)1 0.367 -0.272 0.978 H{2) 0(16)1 0.433 -0.291 0.898 H(3Ï 0(16)1 0.350 -0.317 0.840 Table B.6. Final fractional coordinates for 57. 395 Atom x/a y/b z/c B(eqv)a 0(1) 0.3814(8) 0.052(2) 1.065(1) 4.0(4) b 0(2) 0.252(1) -0.117(2) 0.996(2) 6.4(5) b 0(3) 0.159(1) 0.051(2) 0.779(1) 5.0(4) b 0(4) 0.2736(9) 0.243(2) 0.677(2) 5.0(4) b C(l) 0.355(1) 0.025(2) 0.940(2) 2.5(5) b C(2) 0.269(1) -0.006(2) 0.910(2) 3.2(5) b C(3) 0.234(1) 0.070(2) 0.824(2) 3.0(5) b C(4) 0.288(1) 0.171(3) 0.774(2) 3.9(5) b C(5) 0.364(1) 0.169(3) 0.851(2) 2.5(5) b C(6) 0.427(1) 0.127(3) 0.772(2) 4.0(6) b 0(7) 0.421(1) -0.050(3) 0.765(2) 5.0(6) b 0(8) 0.410(1) -0.098(2) 0.891(2) 2.5(5) b 0(9) 0.175(2) -0.157(5) 0.995(4) 11(1) b 0(10) 0.182(2) -0.332(4) 1.011(4) 16(2) b 0(11) 0.164(3) -0.118(6) 1.115(4) 20(2) b 0(12) 0.114(2) 0.190(4) 0.755(3) 7.9(9) b 0(13) 0.039(1) 0.144(3) 0.700(3) 7.9(9) b 0(14) 0.107(2) 0.257(4) 0.872(3) 11(1) b 0(15) 0.378(1) 0.319(2) 0.916(2) 4.7(6) b 0(16) 0.382(1) -0.259(3) 0.898(2) 5.4(6) b a B(eqv) = (8*^/3)[a^Uu(a*)^ + + c^OjjCc*)* + ab(cos 7 )Ui2 a*b* + ac(cos^)Uj3a'c* + bc(cosa)U23b*c*) b Isotropic refinement. Table B.6. (continued). Final fractional coordinates for 57. 396 Atoms Distance Atoms Distance 0(1) — 0(1) 1.41(2) 0(2) — 0(2) 1.41(2) 0(2) — 0(9) 1.39(4) 0(3) — 0(3) 1.35(2) 0(3) — 0(12) 1.46(3) 0(4) — 0(4) 1.24(2) C(l) — 0(2) 1.54(3) 0(1) — 0(5) 1.61(3) 0(1) — 0(8) 1.58(3) 0(2) — 0(3) 1.25(3) 0(3) — 0(4) 1.45(3) 0(4) — 0(5) 1.49(3) 0(5) — 0(6) 1.53(2) 0(5) — 0(15) 1.51(2) 0(6) — 0(7) 1.56(3) 0(7) — 0(8) 1.47(2) 0(8) — 0(16) 1.50(3) 0(9) — 0(10) 1.55(5) 0(9) — 0(11) 1.39(5) 0(12) — 0(13) 1.45(3) 0(12) — 0(14) 1.43(3) Atoms Angle Atoms Angle 0(2) — 0(2) — 0(9) 117(2) 0(3) --- 0(3) 0(12) 116(2) 0(1) — 0(1) — 0(2) 116(2) 0(1) --- 0(1) — 0(5) 114(2) 0(2) — 0(1) — 0(5) 100(2) 0(1) --- 0(1) — 0(8) 107(2) 0(2) — 0(1) — 0(8) 115(2) 0(5) -- 0(1) — 0(8) 104(2) 0(2 ) — 0(2) — 0(1) 105(2) 0(2) --- 0(2) — 0(3) 137(2) 0(1) — 0(2) — 0(3) 117(2) 0(3) --- 0(3) — 0(2) 126(2) 0(3) — 0(3) — 0(4) 126(2) 0(2) --- 0(3) — 0(4) 108(2) 0(4) — 0(4) 0(3) 124(2) 0(4) -- 0(4) — 0(5) 125(2) 0(3) — 0(4) — 0(5) 112(2) 0(1) --- 0(5) — 0(4) 102(2) 0(1) — 0(5) — 0(6) 106(2) 0(4) --- 0(5) 0(6) 110(2) 0(1) — 0(5) — 0(15) 115(2) 0(4) --- 0(5) — 0(15) 110(2) 0(6) — 0(5) — 0(15) 113(2) 0(5) --- 0(6) — 0(7) 103(2) 0(6) — 0(7) — 0(8) 105(2) 0(1) --- 0(8) — 0(7) 105(2) 0(1) — 0(8) — 0(16) 115(2) 0(7) -- 0(8) — 0(16) 113(2) 0(2) — 0(9) — 0(10) 101(3) 0(2) -- 0(9) — 0(11) 100(4) 0(10) — 0(9) — 0(11) 99(4) 0(3) -- 0(12) — 0(13) 107(2) 0(3) — 0(12) — 0(14) 107(3) 0(13) — 0(12) — 0(14) 108(3) Table B.7. Bond distances (Â) and angles (deg) for 57. 397 ...... ** ■• « " FO ...... PC — " n " « " I . — PC'..... PC 'w' •• "'L ...... PO " r c — M —L—PC PC «'I * FO 0 » 7 9 3 1 1 Q s t 0 1 0 0 2S ... y 0 0 7 3 ...... SI 13 “ t C> 10 ' - ' - 7 ------3 - 3 ...... 4 2 4 2 “ - i s “ i " ' 2 12 — 14 5 I t - 1 7 " ' 0 0 10 9 4 3 • s s . ------j 24 " s “ " 0 5 2 “ '=■5 5 ' “ s ' c1 IS " * 3 - r 1 0 12 19 — - 2 3 12 " ' S ' ----- 17 ...... 1 7 ...... 1 0 1A - 2 0 12 1 1 0 2 13 2 7 • 2 7 1 0 2 2 5 2 0 ) 21 3 2 5 — 3 “ ' s r ' — T Ï 3 ------3 1------5 — 13'------Ï 2 ' — r r a — r j - — 1" “ 2------4 7 - 5 5" 0 S'" ------2 5 *~ ^ 2 3 4 2 > 2 2 12 11 2 2 S 21 « 7 ) IS 2 4 - 2 2 2 3 3 4 IS 3 7 2 ------r 31 — '2 7 01------i s ------* 2 " —:& lOT “ T ~ 2 ' - “ 3 5 " —SS------12 — -^11 2 2 9 0 - 3 - 1 9 3 2 9 5 2 0 0 7 2 S 2 7 - 2 - 2 6 2 S - 1 3 . 2 1 _ - i o ____2S p . - 2 6 _.i. 2 13 ...... 12.. ...4... t X 0 13 - 1 4 s 1 1 11 - s 2 1 14 i “ 2 ' 2 7 24 - s A 12 12 1 * - I S - 5 3 0 2 3 3 2 9 IS 2 2 3 2 3 13 10 5 1 0 4 2 1 4 - 2 0 Q- - 2 " - 3 2 " — i « - i'2 ■ ------3S- — 3? —=10 ■'“S' * ' r 11 ------7 —'- 1 2 “ 2 2 4 — - 2 6 " “ S " 14 ...... 1 6 ...... 3 f 1 2 s 5 2 5 2 5 2 34 35 10 6 2 < - s 1 2 s S 2 2 15 - 1 2 12 3------4 3 ------y 2 S9 “ i i * - - 1------S4 ■*'-47 ■— = 2 -'S ''" i — ; 7 “ 2 '“ "2 1 2 " 11 ' “ 7 “ ------1 6 “ T i l 4 0 3 S 2 2 - 3 22 s 2 2 - 2 ------s 2 0 - 1 2 "2 “0 •-!* " - 2 1 " ~ 1 ' I - 2 S " —- 3 2 “------1 7 ' s " ' i ...... 1 0 0 " 2 - 2 ““ 13 " 1 3 " ------2" ■■7 - '2 2 0 '•*1 3 1 3 S3 2 0 2 2 9 IS 2 9 2 19 ------32 - 2 ----- 15 3 ------, 3 ™o “ ^ 2 0 ” " 2 "1 ...... 11 - - - 1 I ------T4 ? - 1 11 - s ' ' 2"“ 2 ' ~ - s - ■ " t” 3 ------3 ------IS 1 2 2 - 5 3 25 - 2 5 0 - 1 4 2 3 2 3 2 2 9 - 2 4 0 - S ” 3 ... 7 9 o ' i 1 ■ s - 2 1 •“ 2Î • -24~ - r - i a " —o ' - 2 " — 1 2 " 11 '— 1 S “ - 2 • i s - 17 - ' : 3 ...... 14 ...... 21 IS 2 2 4 2 7 : s 3 9 12 0 13 2 7 2 7 2 2 4 0 - 2 2 3S - 3 7 0 2 13 0 0 IS -10' • 2-1 ~ 2S - 2 1 - — 0 “- 2 "- “ 2 0 — = 2 1 ' I s " 3 ' '2 “ 13 - 3 '" 1 "■ " 2 0 : i ? ...... 2 0 3 3 2 13 — 2 1 3 —'S'- - 0 2 9 — 2 5 - 2 - 1 ------s s 5 9 ------2 - p 2 I S “ - 2 0 “ 0 - 3 “ 2 IS - T i t - “ 2 “ 3 1 0 " 2 2 1 0 2 3 3 2 3 0 12 3 IS 0 2 5 2 2 2 - 2 7 2 19 -Jl.v.. 0 IS. --^5 IS 2y 0 2 10 1 • S 2 2 4 S' 0 2S ■ 2 ..... 1 I S - ■ " 1 7 " " 0 -2 '*'41--59 “12 ' 3 2 ■ 1 0 - . 7 -'“ -5 2 •• 3 “ '2 4 ' 2 4 ...... 2 3 # - 3 1 - 9 2 3 4 IS 2 0 2 4 3 s 29 -15 224 IS 26 31 _» -O. 14 .2.7 2 4 7 _ = 4 9 _ 2 ._—?«-_ - 2 3 _ 7 ...7S._ J 2 .____ PC — m " “ PO "t POPC M « PO PC“ m " ■ L w * I J Q 2 0 - 1 7 4 3 2 - 3 6 15 7 - 1 2 _ . a o . „ — 2 2 ______T l ... -72___I2. -A- _ 4 ___. . l a ____1 3 . ___ _ 6 _ 5 . . ___1 6 - . - 1 6 . . 1 _- 7 . io "* 15 2 6 12 5 1 0 • 1 0 - 1 0 5 12 — ..s .. _ 3 _ _ % 9 .. 4 2 1 . _ = 3 . _ 7 . . . 4 ...... - 1 6 . .0 ...S..-...11 ... .2 . .7 . . . 1 1 - H- 13 - " l i - 2 1 - 1 1 2 10 - 1 3 3 1 9 • 2 4 2 - 6 7 - 9 7 . _ . 1 0 . 3 ... .T .ÎÔ .. . . . - 5 .. I . . 1 3 _ . 6 . . 4 .. 14 . _ r 1 6 . - 7 . 6 . 2 J • 3 5 3 ..... - 15 - 1 6 1 11 6 0 2 5 2 5 3 3 3 6 - I S - 2 1 • 1 2 - 1 3 S 13 10 52 . 14 . . . T l 4 .. - 2 0 . 3 7 1C 3 ___t... . I . 2 7 . z l O . . .1 . . . s .... •JO - U ' •• 2 1 I S s 12 - 1 1 2 6 5 2 2 2 5 3 3 - 5 1 6 13 5 IS 2 5 _.3.__.iî _ _ 6 __.10 . I . - .1 4 .. _ T .1Z ____= 5 . - . 1... .30...-.-.30.____a . ....0 ....6 .— .1 3 _..-M...... I ..... 12 ...T.15 ...... IS 1 0 2 5 2 6 - 2 - 1 6 - 7 17 - 1 9 5 14 2 2 31 3 - 1 7 - 5 2 13 1 6 5 13 _.1.1______9 ... _ - 4 _- 2 . . . .37 .._r40 ____6 . - _ 1 ._ . 5 ___„ I 9 . . ^ 1 9 - . ___11 . 0 .. 6 - .1 1 . ..T l4 0 . . 6 - . 1 4 .. ...12 .—... 3 0 - 3 1 1 0 5 2 0 17 6 1 6 5 15 a 2 15 2 5 - 1 0 - 1 7 I 12 .^.4._ . 2 . _ jr2t . ...2....4 ..._ .3 6 as _ i l . . . . a . . . 5 ...... 2 1 ..___1 7 .. ..2 6 ...... 1 0 . 6 ...... Tl ... 0 .. .1 ... .2 5 ... ------3 2 4 - 6 2 5 - 9 24 10 - 5 2 5 2 6 1 2 3 11 2 - 1 2 - 1 2 5 2R 2 5 6 . . - 3 0 ______3.....5 _ 3 _ __ _ 1 6 _ .a ._ 4 - 1 3 .. ___l . l _ ___3 .. ..1 7 -_ - . 2 3 . .5 . 2 .6 .- 1 0 . ____1 4 .. . . 2 1 „ 5 5 10 - 6 3 1 0 5 2 5 13 S “ 17 ' - 9 5 2 0 5 1 1 6 12 5 13 -T .I 5 ...... ___2 . ...6. . . . 3 „ . . . : 3 4 ...... a.... 5 . . _ . 1 6 ... .1 3 16 ..... ^ .7 . 6 . 6 ; 3 13 • 1 3 ■ ! ; 3 9 3 • 1 0 3 4 6 -s 15 - 1 5 2 ___1 ...S....a._._ I 4 .. _ 1 0 .. . 4 ..... 1 3 _ ____ -._r3. ..a....5 ...... la . -,-■.15...... & .6 ...... 15 9 .... - I . 3 . 6 ... 12 .. - 1 3 . - 1 6 - 7 9 2 3 6 3 6 - 1 4 0 10 12 0 10 16 19 1 16 2 0 e 19 23 - . 0 , 4 __ .1 4 6 ___6 _ . a .._ 5 ._ . . 1 4 .___2 1 . ___r 3 . . . . 5 . ..6 - 1 2 . . - 1 2 „ . - 2 . . ..S.. 6 - .11 . . . 1 3 ______34 ~ ' l 2 13 • 1 3 S 3 5 - 1 3 S 16 IS 5 - 2 1 - 6 2 5 5 1 7 2 0 5 5 • 1 3 - 3 0 - 3 9 2 7 2 4 5 2 0 - 1 9 6 5 15 •1 2 11 . 6 . ___16 — ,.“ 1 6 . _ ...-.7... ..I.. ...20 .23...... _ 0 j " - —.ra . .4 .. „X 2 .... 1 S _ ___5 _.s....S ._ _t.l.._ .12.. ___ 4 6 ...„ 3 2 3 3 7 5 13 • 2 IS 2 7 - 2 1 5 14 1 IS 21 • 2 3 5 15 - 1 2 7 2 1 - 1 2 ___Sl ___ 11 5 - 7 . . .1 . - 7 ...... 1 3 - , . r l 4 . 3 9 . - . 1 7 .. ... 1 6 ...... 3 13 •IS -1 0 5 5 11 - 3 7 10 3 i f " 12 s s -2 2 IS 12 5 11 7 • 1 5 2 5 5 14 3 0 • 2 3 S 1 0 3 4 .21. 9 3 ..IT _ ...1 4 ...,...t S. . . . 6 .5 1 0 ____. 0 ... 2 . 1 . 1 ____9 • 3 0 - 1 3 . s 2 2 -1 2 10 12 Q 2 11 10 Table B.8. Observed and calculated structure factors for 57. 398 Figure B.3. Computer-generated perspective drawing of the final X-ray model of 63. 399 Compd C18 H30O4 Color/shape colorless/parallelepiped For. wt. 310.44 Space group P2i/n Temp., °C 22 Cell Constants^ a.A 9.485(5) b.A 20.378(9) C.A 10.400(9) p. deg 107.77(7) Cell vol, A^ 1914 Formula units/unit cell 4 Dcalc. 9 cm'3 1.08 McalC' ^ ^ 0.80 Diffractometer/scan Enraf-Nonius CAD~4/ci)-29 Radiation, graphite monochromator MoKa (k = 0.71073) Max crystal dimensions, mm 0.28 X 0.45 X 0.50 Scan width 0.80 + 0.35 tan0 Standard reflections 200; 060; 004 Decay of standards ±3% Reflections measured 3691 20 range, deg 2 <20 <50 Range of h, k, I +11, +24. ±12 Reflections observed [Fq > SoCFq)]^ 1320 Computer programs^ SHELXl Structure solution SHELXS2 No. of parameters varied 223 Weights (a(Fo)2 + 0.0004 Fo^j-I GOF 0.77 R = Z||FoHFcl|/Z|Fol 0.066 Rw 0.071 Largest feature final diff. map 0.2e- A-3 Table B.9. Crystal data and summary of intensity data collection and structure refinement for 63. sLeast-squares refinement of (sino/x)2 values for 25 reflections 0 > 12° ^Corrections: Lorentz-polarization. ^Neutral scattering factors and anomalous dispersion corrections from ref. 1. 400 Atom x/a y/b z/c B(eqv)a 0(1) 0.0470(4) 0.5845(2) 0.4102(4) 4.14 0(2) -0.1946(4) 0.5330(2) 0.5005(4) 4.83 0(3) -0.3823(4) 0.6496(2) 0.4800(4) 4.21 0(4) -0.3046(5) 0.7352(2) 0.2696(4) 5.67 C(l) -0.1036(6) 0.5814(2) 0.3295(5) 3.07 C(2) -0.2002(6) 0.5780(3) 0.4214(5) 3.19 C(3) -0.2913(6) 0.6351(3) 0.4040(5) 3.21 C(4) -0.2592(6) 0.6752(3) 0.3132(6) 3.50 C(5) -0.1491(6) 0.6468(3) 0.2493(5) 3.55 C(6) -0.2243(7) 0.6241(3) 0.1015(6) 4.95 C(7) -0.2692(6) 0.5536(3) 0.1138(6) 4.88 C(8) -0.1406(6) 0.5255(3) 0.2253(6) 4.04 C(9) -0.4960(7} 0.6010(3) 0.4763(6) 5.10 C(10) -0.562(1) 0.6180(4) 0.5824(9) 9.84 C(ll) -0.6063(8) 0.5959(5) 0.3400(8) 12.09 C(12) -0.4067(8) 0.7721(3) 0.3208(7) 6.43 C(13) -0.491(1) 0.8164(5) 0.207(1) 12.94 C(14) -0.325(1) 0.8069(5) 0.4415(9) 12.06 C(15) -0.0225(8) 0.6945(3) 0.2598(8) 6.26 C(16) -0.344(1) 0.6682(5) 0.0159(8) 9.84 C(17) -0.3157(8) 0.5149(4) -0.0202(7) 7.45 C(18) -0.0091(7) 0.5059(3) 0.1779(6) 5.41 a B(eqv) = b Isotropic refinement. Table B.10. Final fractional coordinates for 63. 401 Atom x/a y/b z/c H(l) 0(1)] 0.058 0.545 0.450 H(l) C(6)j -0.159 0.624 0.049 H(l) 0(7)1 -0.358 0.552 0.138 H(l) 0(8)] -0.163 0.485 0.261 H(l) 0(9)] -0.454 0.558 0.495 H(l) 0(10) ] -0.632 0.589 0.599 H(2) 0(10) ] -0.607 0.659 0.55: H{3) 0(10) ] -0.482 0.624 0.663 H(l) 0(11) ] -0.685 0.566 0.334 H(2) 0(11)] -0.581 0.595 0.259 H(3) 0(11)] -0.636 0.639 0.354 H(l) 0(12)] -0.477 0.747 0.349 H(l) 0(13)] -0.549 0.840 0.252 H(2) 0(13)) -0.538 0.818 0.113 H(3) 0(13)] -0.396 0.836 0.227 H(l) 0(14) ] -0.399 0.830 0.466 H(2) 0(14)] -0.271 0.837 0.404 H(3) 0(14)] -0.260 0.787 0.519 H(l) 0(15)] 0.052 0.674 0.231 H(2) 0(15)] 0.016 0.706 0.353 H(3) 0(15)] -0.055 0.733 0.208 H(l) 0(16)] -0.330 0.714 0.024 H{2) 0(16)] -0.430 0.657 0.039 H(3) 0(16)] -0.356 0.655 -0.074 H(l) 0(17)] -0.328 0.471 0.002 H(2) 0(17)] -0.241 0.517 -0.064 H{3) 0(17)] -0.406 0.531 -0.079 H(l) 0(18)] -0.048 0.472 0.114 H(2) 0(18)] 0.065 0.488 0.253 H(3) 0(18)] 0.032 0.540 0.137 Table B.10 (continued). Final fractional coordinates for 63. 402 s' o- onooooooooooooooooo X—^ o 43kH*tJH'09a\U>a>Mh-*0Ji^UJMN)N>N>H*U> noonoooooooo m MU)00'sja>cnUiH'»-'4^(xJM SmX S=X s«x «MX «MX *«pX «MX «MX«mX «mX «MX I I I I i I I I I I I t 1 I t I 1 noonnononoonnonoono OD nonnnnnnnnnn O X-«« X—« X—« x*«« x*v x*\ x-«« X"*« X—s x-« x-s D MH'M03*«.ja>if>»OON>ifkCJH* Q. ifk CO «kX ^X «MX ^X «MX ««MX «MX «MX I I I I I I I I I I I I I I I I I I I g . I I I 1 t i I I I I I I I I 1 1 I I I a oooooonnooonnnooooo B) «■*> <-S «—» #*»» %-» x-s <*-> <|>^ »|^ 3 h^H*H*MH*OOMH Q. nnonooooooo (D 1 I I > I I I I I I 1 I I I I I I i I MvO‘^a>ai*^fo»-'4ku>N> (O 1 I I I I I I I I I I I I I I I I t I > nnnnnnnnonnnoor>onoo r r x^ X—s x^ x^ x-^ X-» x"> X-*. x^ X^ X^ X—^ X^ X^ X-^ x^ I I I I I I I i O MMU30D00*^a>(T\(/1Uiai4hCJtJN)MMMi^ I I I i i I I I 3 (A o> oononoonoon W x-«« X^ X^ X-"« X—« x"«« I I I I I I i I I I I I I t I I I I I MMMH'MCnOJCnMvOfO I I I I I i i I I I 1 I I I I I I I I (a) o *«j o en —" «MX «MX fsj «MX «MX n n O O n n n n n n n o o n o n n n O 1 % M M M M «•«JMM M o 4k en 4k N) 00 00 00 en M 1 1^ t j M œ *«J m M 1 ««.X«mX«mX 1 D 1 M H * M M H* H* h- »-* H* M h-» I-» I-* »-» I-* h - 1—' 1—' h-* M h - ' »-» t-> h - H-* ►-» »-* 1 (A M O h-* H - O »-* h-* o I-» h-* O o N> fO O H* H* N> > 1 en 4 k en en en en 4k en 4k 4k ro r t W m M W ro 4k ü i 4k M N> ro ex) vo 4k 0(1) 0.036(2) 0.055(3) 0.057(3) 0.005(2) 0.003(2) 0.010(2 0(2) 0.061(3) 0.063(3) 0.057(3) 0.022(2) 0.028(2) 0.023(2. 0(3) 0.049(2) 0.051(3) 0.057(3) 0.003(2) 0.022(2) -0.011(2 0(4) 0.086(3) 0.041(3) 0.083(3) 0.018(3) 0.034(3) 0.011(2: C(l) 0.035(3) 0.038(3) 0.039(3) -0.001(3) 0.008(3) 0.004(3: C(2) 0.038(3) 0.038(3) 0.039(3) 0.003(3) 0.005(3) 0.003(3) C(3) 0.035(3) 0.036(4) 0.044(4) 0.002(3) 0.003(3) -0.007(3) C(4) 0.042(4) 0.029(3) 0.052(4) 0.003(3) 0.003(3) -0.002(3) C(5) 0.043(3) 0.040(3) 0.046(4) 0.003(3) 0.009(3) 0.006(3! C(6) 0.066(5) 0.076(5) 0.039(4) 0.019(4) 0.009(3) 0.008(3. C(7) 0.038(4) 0.092(5) 0.049(4) -0.005(4) 0.008(3) -0.027(4: C(8) 0.054(4) 0.043(4) 0.054(4) -0.003(3) 0.023(3) -0.005(3: C(9) 0.053(4) 0.060(5) 0.077(5) -0.001(4) 0.029(4) -0.007(4: C(10) 0.115(7) 0.152(9) 0.107(7) -0.046(7) 0.069(6) -0.026(6: C(ll) 0.088(6) 0.27(1) 0.096(7) -0.094(8) 0.042(6) -0.077(8) C(12) 0.087(6) 0.058(5) 0.091(6) 0.021(5) 0.029(5) 0.015(4: C(13) 0.17(1) 0.18(1) 0.113(8) 0.11(1) -0.015(7) 0.009(8: C(14) 0.17(1) 0.17(1) 0.104(9) 0.062(9) 0.024(8) -0.025(7: C(15) 0.076(5) 0.055(5) 0.101(5) -0.005(4) 0.036(5) 0.021(4: C(16) 0.147(9) 0.141(8) 0.061(6) 0.063(7) -0.010(6) 0.005(5: C(17) 0.065(5) 0.139(8) 0.069(5) -0.004(5) 0.012(4) -0.047(5: C(18) 0.061(5) 0.078(5) 0.062(5) 0.013(4) 0.023(4) -0.004(4: Anisotropic thermal parameters are defined by expC~2pi(pi) (hha*a*Ull + kkb*b*U22 + llc*c*U33 + 2hka*b*U12 + 2klb*c*U23 + 2hla*c*U13)]. Hydrogen atoms were given a fixed isotropic thermal parameter of B = 5.5 angstroms squared. Table B.12. Thermal parameters for 63. 404 04 C16 CIS C4 C18 C6 C3 C17 05 03 07 02 02 Oil 08 09 012 C14 010 013 Figure B.4. Computer-generated perspective drawing of the final X-ray model of 67. 405 Formula ^18^28^4 Formula wt. 308.42 Space group P2i/a a. A 11.076(2) b. À 8.758(2) c. 18.342(2) P. deg 100.52(1) Volume, A3 1749 Z 4 Density (calc), g/cm"3 1.17 Crystal size, mm 0.15x0.38x0.38 Radiation MoKa with graphite monochromator Linear abs. coeff., cm-i 0.76 Temperature 22 °C 29 limits 4° < 29 < 50° Scan speed 27min in œ (3 rescans) Background time/scan time 0.5 Scan range (1.20 + 0.35 tan9)° in m Data collected +h, +k, i l Scan type ci)-29 Unique data 4303 Unique data, with Fq2 > 1o(Fq2) 1399 Final number of variables 201 R(F)a 0.067 Rw(F)b 0.052 Error in observation of unit weight, e 2.60 Table B.13. Crystallographic details for 67. »R(F) = r||F„|-|Fe||/aFo| "R»(F) = [Iw(|Fo|-|Fd)2/i;w|Fo|2]<'2 with w = 1/o2(F^) 406 atom atom distance atom atom di stance 0(1) C(l) 1.414(5) C(5) C(18) 1.521(6) 0(2) C(2) 1.376(8) C(6) C(7) 1.494(6) 0(2) C(12) 1.486(10) C(7) C(8) 1.515(6) 0(3) C(3) 1.371(5) C(7) C(ll) 1.515(6) 0(3) C(15) 1.407(6) C(8) C(9) 1.533(7) 0(4) C(4 ) 1.225(5) C(9) C(10) 1.555(6) C( 1) C(2) 1.507(7) C(10) C(ll) 1.514(6) C(l) C(5) 1.581(5) C(12) C(13) 1.512(10) C(l) C(ll) 1.533(6) C(12) C(14) 1.513(11) C(2) C(3) 1.334(6) C(13) C(12A) 1.61(2) C(2) 0(2A) 1.451(12) C(15) C(16) 1.513(7) C(3) C{4) 1.428(6) C(15) C(17) 1.454(7) C(4) C(5) 1.520(6) C(12A) 0(2A) 1.44(2) C(5) C(6) 1.543(6) C(12A) C(14A) 1.43(2) Distances ate in angstroms. Estimated standard deviations in the least significant figure are given in parentheses. Table B.14. Bond lengths (A) for 67. 407 atom atom atom angle atom atom atom angle C(2) 0(2) 0(12) 115.8(8) 0(4) 0(5) 0(18) 108-8 ( 4 ) C(3) 0(3) 0(15) 115.4(4) 0(6) 0(5) 0(18) 113.0(4) 0(1) C(l) 0(2) 112.4(4) 0(5) 0(6) 0(7) 102.6(4) 0(1) C(1 ) 0(5) 114-7(4) 0(6) 0(7) 0(8) 127.1(5) 103.2(4 ) 0(1) C(1 ) 0(11) 108.1(4) 0(6) 0(7) 0(11 ) C(2) C(l) 0(5) 102.6(4) 0(8) 0(7) 0(11) 102.6(4) C(2) C(l) 0(11) 115.8(4) 0(7) 0(8) 0(9) 103.3(4) C(5) C(l) 0(11) 103.0(3) 0(8) 0(9) 0(10) 106.8(4) 0(2) C(2) 0(1) 137.3(6) 0(9) 0(10) 0(11) 102.7(4 ) 0(2) C(2) 0( 3) 108.9(6) 0(1) 0(11) 0(7) 105.7(4) C(l) C(2) 0(3) 113.7(4) 0(1) 0(11) 0(10) 128.9(5) C(l) C(2) 0(2A) 94.0(6) 0(7) 0(11) 0(10) 102.1(4) C(3) C(2) 0(2A) 152.3(7) 0(2) 0(12) 0(13) 102.3(6) 0(3) 0(3*) 0(2) 124.9(5) 0(2) 0(12) 0(14) 109.1(7 ) 0(3) 0(3) 0(4) 124.9(5) 0(13) 0(12) 0(14) 109.1(8) C(2) 0(3) 0(4) 109.8(5) 0(3) 0(15) 0(16) 106.6(6) 0(4) 0(4) 0( 3) 124.7(5) 0( 3) 0(15) 0(17) 114.2(5) 0( 4 ) 0(4) 0( 5) 125.5(4 ) 0(16) 0(15) 0(17) 113.2(5) C(3) 0(4) 0(5) 109.8(4) 0(13) 0(12A) 0(2A) 99(1) C(l) 0(5) 0(4) 102.9(4) 0(13) 0(12A) 0(14A) 117(2) C(l) 0(5) 0(6) 106.2(4 ) 0(2A) 0(12A) 0(14A) 108(1 ) C(l) 0(5) 0(18) 115.1(4) 0(2) 0( 2A) 0(12A) 112(1) C(4) 0(5) 0(6) 110.4(4 ) Angles are in degrees. Estimated standard deviations in the least significant figure are given in parentheses. Table B.15. Bond angles (deg) for 67. 408 a tom atom distance atom atom distance 0( 1 ) H( 12) 1.02 C( 14 ) H( 30) 0.97 C(6) H(l) 0.98 C(I4) H(31) 0.98 C(6) H(2) 0.98 C(14) H(32) 0.98 C(7) H(3) 0.98 C(15) H(ll) 0.98 C(8) H(4) 0.98 C(16) H(16) 0.98 C(8) H(5) 0.98 C(16) H(17) 0.98 C(9) H(6) 0.98 C( 16) H(18) 0.98 C(9) H(7) 0.98 C(17) H(21) 0.98 C(10) H(8) 0.98 C(17) H(22) 0.98 C(10) H(9) 0.98 C(17) H(23 1 0.98 C(ll) H(10) 0.98 C(18) H(13) 0.98 C(12) H(19) 0.98 C(18) H(14 ) 0.98 C(13) H(24) 0.98 C(18) H(15) 0.98 C(13) H(i5) 0.98 C(12A) H(20) 0.98 C(13) H(26) 0.98 C(14A) H(33) 0.97 C(13) H(27) 0.98 C(14A) H(34 ) 0.98 C(13) H( 28) 0.98 C(14A) H(35) 0.97 C( 131 H(29) 0.98 Table B.16. Bond lengths (Â) Involving the hydrogen atoms for 67. 409 atom Y z B(eq) 0(1) 0.4074(2) 0.0499(4) 0.6605(2) 5.8(2) 0(2) 0.5534(5) -0.1220(7) 0.8080(4) 4.5(3) 0(3) 0.7285(3) 0.0578(4) 0.8651(2) 6.5(2) 0(4) 0.7972(3) 0.2615(4) 0.7539(2) 6.0I2J C(l) 0.5357(4) 0.0268(5) 0.6785(3) 4.1(2) Cl 2) 0.5782(5) -0.0124(5) 0.7591(3) 4.8(3) C(3) 0.6695(5) 0.0758(6) 0.7931(3) -.4(3) C( 4 ) 0.7064(4) 0.1791(5) 0.7411(3) 3.9(2) CIS) 0.6156(41 0.1722(5) 0.6682(3) 3.6(2) C(6) 0.6828(4) 0.1347(6) 0.6038(3) 4.7(3) C(7) 0.6961(4) -0.0349(6) 0.6089(3) 4.9(3) C(8) 0.7200(4) -0.1430(7) 0.5486(3) 6.1(3) C(9) 0.6677(5) -0.2951(6) 0.5702(3) 6.6(31 C(10) 0.5888(5) -0.2582(6) 0.6299(3) 6.0(31 C(ll) 0.5717(4) -0.0870(5) 0.6226(3) 4.2(21 C(12) 0.4415(8) -0.215(1) 0.7828(6) 4.1(2) CI13) 0.4800(5) -0.3705(7) 0.8149(3) 7.3(1) CI14) 0.3382(9) -0.155(1) 0.8185(5) 6.1(3) Cl 151 0.7204(6) 0.1828(8) 0.9121(3) 6.9(4) Cl 161 0.8043(5) 0.1476(9) 0.9849(3) 9.6(4) Cl 17) 0.5959(6) 0.2206(9) 0.9205(4) 11.7(5) CI18) 0.5450(4) 0.3218(6) 0.6573(3) 5.9(3) CII2A) 0.486(2) -0.190(2) 0.832(1) 6.2(4) 01 2A) 0.490(1) -0.135(1) 0.7583(6) 5.2(5) CI14A) 0.302(2) -0.123(2) 0.856(1) 9.0(6) •Occupancy factor is 0.62 ••Occupancy factor is 0.38 The form of the equivalent isotropic displacement parameter is: B( eq I Table B.17. Positional parameters and B(eq) values for 67. 410 j2 atom X y z B, . H(l) 0.6339 0.1653 0.5560 5.6 H(2) 0.7632 0.1847 0.6106 5.6 H(3) 0.7563 -0.0579 0.6537 5.9 H(4) 0.6774 -0.1090 0.4998 7.3 H(5) 0.8081 -0.1515 0.5485 7.3 H{6) 0.6166 -0.3420 0.5268 7.9 H(7) 0.7347 -0.3647 0.5907 7.9 H(8) 0.5098 -0.3116 0.6194 7.2 H(9) 0.6322 -0.2861 0.6796 7.2 H(10) 0.5140 -0.0702 0.5760 5.0 H(ll) 0.7544 0.2717 0.8906 8.3 H(12) 0.3641 0.1030 0.6977 7.0 H(13) 0.6016 0.4052 0.6516 7.1 H(14) 0.5070 0.3417 0.7006 7.1 H(15) 0.4812 0.3152 0.6128 7.1 H(16) 0.8830 0.1091 0.9752 11.5 H(17) 0.7661 0.0703 1.0118 11.5 H(18) 0.8184 0.2410 1.0147 11.5 H(19) 0.4190 -0.2175 0.7285 5.0 H(20) 0.5624 -0 .1648 0.8658 7.7 H(21) 0.5988 0.2868 0.9639 14.1 H(22) 0.5545 0.2741 0.8761 14.1 H{23) 0.5513 0.1268 0.9273 14.1 H(24) 0.4228 -0.4474 0.7902 8.6 Table B.18. Calculated positional parameters for the hydrogen atoms for 67. 411 B. â2 atom X y = H(25) 0.4781 -0.3696 0.8681 8.6 - H(26) 0.5630 -0.3928 0.8071 8.6 • H(27) 0.4053 -0.3924 0.7786 8.6 •• H(28) 0.4776 -0.4257 0 .8608 8.6 •• H(29) 0.5521 -0.4009 0.7947 8.6 •• H(30) 0.3237 -0.0482 0.8049 7.2 * H(31) 0.3620 -0.1649 0.8723 7.2 • H( 32) 0.2645 -0.2154 0.8009 7.2 • H( 33) 0.3762 -0.0167 0 .8404 10.2 •• H(34) 0.3939 -0.1309 0.9096 10.2 •• H( 35) 0.3086 -0.1789 0.8330 10.2 •• •Occupancy factor is 0.62 ••Occupancy factor is 0.38 Table B.18 (continued). 412 04 rO m o m in lO CO 04 04 00 c 04 04 rn m rn m -cr TT =) VO rn CO o \ VO r** in CO in m 04 o 04 04 in 04 04 04 04 04 O o o o o o O o 04 04 m m 04 04 m m m 04 m TT m 04 1—< 3 O O' 04 04 m o O' O' m O 04 V m O o O o 1-4 m o o o o o O o O O o O o O o O o o o o O O o o o o o o o o o o 1 1 1 1 1 1 m cn "TT m m m TT m m V TT in V m O O' O' ▼H in 04 04 rn rn m m m rn TT IT in m m 04 o O' in VO 04 VO O' o in m O' 04 VO in CO cn m rn m VO O' o v VO V TP o o o o o o o o o o o o o o o o o o o o o o O O o o o o o o « « . «-4 04 V m 04 m "V Tf m m m TT in m 04 04 3 04 00 O' O in 04 o- o in ov in CO o O' in 04 04 m in o VO O' v o in r r in in VO -4 CO m in OV o o •-< o o O o o o o o O «-H o o o O o o o o o O o o o o o o O o o o O S o 0 4 o VO CO CV J— 1 < o o o o u V u o u u u u V o o o o Table B.19. Anisotropic displacement parameters for 67. 413 s ' cr ATOM Ull U22 U33 U12 U13 U23 (D C( 14) 0.078(3) * 00 Lk C(15) 0.084(5) 0.110(5) 0.070(4) 0.001(4) 0.013(4) -0.004(4) CO C(16) 0.108(5) 0.179(7) 0.073(5) 0.009(5) 0.004(4) 0.008(5) o o C(17) 0.116(6) 0.200(8) 0.122(6) 0.056(6) 0.003(5) -0.079(6) 3 C( 16) 0.085(4) 0.044(3) 0.092(4) -0.000(3) 0.010(3) 0.007(3) 5 ’ c *Re£ineci isotcoplcally The form of the anisotropic displacement parameter i s : exp(-2Tr^(U^^h^a*^ + U22>«^b*^ + Uj^l^c*^ + ZU^jhka^b* + Zu^^hla'c» + 2U23klb*c*)l k 1 Fo FC sigF k 1 Fo Fc sigF k 1 Fo FC si h = 0 ■ 3 3 164 156 3 9 2 56 49 5 3 7 247 229 6 11 -1 52 45 6 0 2 1143 1169 6 3 12 40 36 5 0 3 283 288 2 3 14 61 69 4 h = 1 0 4 639 641 3 4 -19 44 33 6 0 5 789 806 4 4 -13 77 80 3 1 -17 46 49 7 0 7 393 397 3 4 -12 83 69 3 1 -16 112 120 5 0 8 176 175 3 4 -11 129 133 4 1 -15 62 88 5 0 9 341 332 3 4 -9 91 88 3 1 -14 81 77 4 0 10 127 106 12 4 -8 173 177 9 1 -13 78 89 4 0 12 156 163 4 4 -6 235 223 2 1 -11 275 285 4 0 14 121 132 5 4 -3 263 262 2 1 -10 40 76 7 0 15 138 150 7 4 -1 47 48 3 1 -8 56 60 3 0 16 88 96 5 4 0 119 137 4 1 -6 106 116 3 0 17 112 111 5 4 2 161 167 2 1 -5 80 79 4 0 19 62 84 4 4 4 40 47 3 1 -4 95 110 3 1 -14 60 76 6 4 5 233 229 2 1 -3 123 121 2 1 -13 234 239 4 4 10 123 118 11 1 -2 604 600 3 1 -12 78 87 3 4 15 82 78 3 1 -1 1005 1018 5 1 -11 163 170 3 5 -7 204 197 3 1 0 1177 1179 6 1 -10 165 172 5 5 —6 178 175 6 1 1 400 405 2 1 -7 362 373 4 5 1 171 177 3 1 2 516 538 3 1 —6 136 154 8 5 2 405 391 3 1 3 566 563 3 1 -2 65 74 2 5 3 191 193 3 1 4 400 397 3 1 1 257 254 2 5 4 172 177 5 1 5 152 136 3 1 3 50 52 2 5 8 112 111 6 1 6 81 76 3 1 5 181 168 5 5 10 84 88 5 1 7 427 434 3 1 8 162 164 7 5 11 54 58 4 1 8 102 90 4 1 9 164 167 3 6 -12 167 161 4 1 9 181 170 3 1 15 48 72 5 6 -10 63 54 6 1 11 55 55 4 1 16 115 119 12 6 -9 41 50 6 1 12 59 58 4 2 -12 172 159 5 6 -8 106 114 5 1 16 169 163 5 2 -7 69 79 2 6 -7 81 76 3 2 -17 55 65 6 2 -6 430 437 10 6 -5 125 119 4 2 -15 114 109 5 2 -4 242 248 5 6 -4 86 89 5 2 -12 58 59 5 2 0 519 540 3 6 -3 95 86 5 2 -11 168 170 4 2 1 119 119 2 6 -1 41 44 5 2 -10 191 190 4 2 2 155 172 4 6 0 107 103 5 2 -9 140 154 4 2 10 98 93 4 6 14 69 80 4 2 -7 308 298 3 2 11 241 241 6 7 -8 116 111 6 2 -6 229 222 3 2 15 86 85 3 7 -7 124 121 4 2 -5 127 134 3 3 -15 111 120 4 7 -4 157 168 4 2 -4 122 113 3 3 -13 155 160 5 7 -2 120 122 4 2 -2 129 135 3 3 -11 72 72 7 7 -1 208 208 3 2 -1 537 538 3 3 -10 253 255 3 7 5 169 187 4 2 0 729 742 4 3 —6 73 74 2 8 -5 68 70 5 2 1 558 569 3 3 -5 382 364 10 8 -4 83 79 3 2 3 138 141 3 3 -4 142 138 4 8 -3 71 69 4 2 4 215 224 3 3 -1 82 76 2 8 0 61 47 5 2 5 139 136 3 3 2 232 230 2 9 1 51 61 8 2 6 48 39 4 Table B.20. Observed and calculated structure factors for 67. 415 k 1 Fo Fc SigF k 1 Fo Fc sigF k 1 Fo Fc si 2 7 48 52 4 4 2 96 96 5 7 -14 60 54 6 2 8 168 148 3 4 3 156 156 4 7 -10 64 57 5 2 9 121 125 4 4 5 121 135 4 7 -7 55 43 6 2 10 41 67 5 4 6 92 102 4 7 -5 91 105 4 2 11 47 35 5 4 7 94 84 4 7 -4 67 58 5 2 12 110 108 4 4 8 133 133 5 7 -2 109 107 4 2 14 100 91 5 4 9 75 63 4 7 -1 78 58 4 2 15 55 62 6 4 10 135 129 5 7 2 139 151 5 2 16 53 43 6 4 11 77 84 4 7 7 47 39 7 3 -16 93 96 4 4 12 157 152 5 7 11 63 65 6 3 -13 75 70 4 4 14 80 89 4 8 -7 67 58 5 3 -12 120 111 5 5 -14 56 59 6 8 -5 111 112 5 3 -11 78 71 4 5 -12 92 110 5 8 -4 47 44 7 3 -10 117 111 5 5 -8 49 50 6 8 -3 47 44 7 3 -9 86 96 4 5 -7 82 88 4 8 -2 76 75 4 3 -8 85 77 4 5 -6 46 40 5 8 -1 64 69 5 3 -7 122 98 4 5 -5 162 157 4 8 8 49 48 7 3 -6 152 151 3 5 -2 162 145 4 9 -5 48 38 7 3 -5 136 160 3 5 -1 167 171 4 9 -1 65 68 6 3 -4 134 152 3 5 1 96 94 4 10 -3 81 75 5 3 -3 462 468 3 5 2 112 110 5 10 2 94 103 5 3 -2 168 177 3 5 3 96 87 4 10 4 70 77 6 3 -1 245 249 3 5 4 332 332 3 10 5 64 61 7 3 0 239 224 3 5 5 88 92 3 3 1 239 240 3 5 6 66 64 4 ------h 2 3 2 81 75 3 5 8 65 51 4 3 3 203 208 3 5 9 63 62 5 0 -18 62 86 6 3 4 337 332 3 5 10 55 59 6 0 -17 74 76 5 3 5 211 216 3 5 11 140 133 6 0 -16 112 116 5 3 6 182 177 3 5 12 56 46 6 0 -15 49 37 6 3 7 51 60 4 5 13 121 112 5 0 -12 93 94 4 3 8 123 117 4 6 -14 73 53 5 0 -10 88 93 4 3 9 137 131 4 6 -9 62 64 5 0 -9 170 158 3 12 64 59 4 6 -8 146 151 5 0 -8 253 259 3 13 94 94 4 6 -7 111 131 4 0 -7 341 344 3 16 79 75 4 6 —6 51 31 5 0 -6 446 446 3 -15 52 65 6 6 -5 113 122 6 0 -5 76 47 3 -12 151 145 5 6 -4 131 129 5 0 -4 223 210 2 -11 88 98 4 6 -3 126 132 5 0 -3 413 417 3 -10 80 86 4 6 -2 63 61 4 0 -2 51 57 2 -9 73 82 4 6 -1 158 159 4 0 -1 990 998 5 —8 114 111 5 6 0 75 61 4 0 0 238 237 2 -7 320 302 3 6 2 87 77 4 0 1 642 659 4 —6 153 125 4 6 3 159 147 4 0 4 240 244 3 -5 210 232 3 6 4 70 60 4 0 5 37 30 4 -4 113 130 4 6 9 70 80 5 0 7 692 700 4 -3 561 540 4 6 10 73 80 5 0 8 458 456 3 -1 392 395 3 6 11 78 63 5 0 9 106 133 5 0 344 352 3 6 14 68 70 5 0 10 43 45 5 1 91 82 4 6 17 55 52 7 0 13 117 96 6 Table B.20. (continued). 416 k 1 Fo Fc sigF k 1 FO Fc sigF k 1 Fo Fc si 0 15 90 105 4 2 6 149 137 3 4 15 48 27 7 0 16 67 89 6 2 7 159 166 4 4 16 83 67 5 0 20 66 66 6 2 8 72 74 3 5 -14 89 78 4 -17 119 111 5 2 9 182 169 4 5 -13 107 116 5 -16 128 127 4 2 11 156 165 4 5 -12 80 75 4 -15 144 158 5 2 12 51 49 5 5 -10 63 59 5 -13 116 129 6 2 14 52 62 6 5 -9 73 77 4 -12 110 108 5 2 15 72 79 5 5 -8 67 73 4 -11 141 142 4 3 -14 106 94 5 5 -7 124 114 5 -10 163 163 4 3 -13 85 83 4 5 — 6 80 92 3 -9 143 135 4 3 -12 51 57 6 5 -5 70 50 4 -8 323 306 3 3 -11 189 182 4 5 -4 248 252 3 -7 338 325 3 3 -10 79 74 4 5 -3 280 283 3 —6 311 312 3 3 -9 91 99 4 5 -2 64 45 4 -5 505 504 3 3 -8 102 108 5 5 -1 252 240 3 -4 48 49 3 3 -7 64 61 3 5 0 318 311 3 -3 269 273 2 3 —6 121 116 4 5 1 215 213 4 -2 894 899 5 3 -5 300 302 3 5 2 192 189 4 -1 342 344 2 3 -4 378 379 3 5 3 248 245 4 0 183 177 2 3 -3 358 364 3 5 4 91 93 4 2 283 275 2 3 -2 453 449 3 5 6 83 92 4 3 599 604 4 3 -1 73 74 3 5 8 136 135 5 4 379 378 3 3 1 70 64 3 5 9 137 153 6 5 101 111 4 3 2 209 201 3 5 10 133 131 6 6 291 294 3 3 3 41 65 4 5 12 83 94 4 7 549 531 4 3 4 167 189 3 5 13 103 94 4 9 117 125 5 3 5 42 38 4 5 14 75 75 5 12 49 54 5 3 6 56 56 3 6 -17 58 49 7 13 84 80 4 3 7 137 151 4 6 -13 88 100 4 15 70 64 5 3 8 118 128 4 6 -12 55 55 6 19 57 33 6 3 13 90 77 4 6 -10 150 151 5 2 -16 63 67 5 3 14 54 40 6 6 —6 166 161 5 2 -14 156 153 5 3 17 69 49 5 6 -5 138 142 5 2 -12 356 366 4 4 -18 60 29 6 6 -4 55 45 5 2 -11 89 85 4 4 -14 76 66 4 6 -3 71 68 4 2 -10 137 139 4 4 -13 69 69 5 6 -1 51 55 5 2 -9 53 47 4 4 -8 96 91 4 6 0 42 43 6 2 -8 201 195 3 4 -7 88 85 4 6 1 128 155 5 2 -7 269 273 3 4 —6 87 88 4 6 2 197 201 4 2 —6 426 419 3 4 -5 112 102 4 6 3 103 108 4 2 -5 417 390 3 4 -3 87 69 3 6 4 118 141 4 2 -3 744 733 4 4 -2 91 83 3 6 8 53 60 6 2 -2 557 543 3 4 -1 79 91 4 6 9 112 117 5 2 -1 159 131 3 4 1 146 140 4 6 11 209 200 5 2 0 224 232 2 4 2 286 290 3 6 13 56 57 7 2 1 68 80 3 4 3 237 250 3 7 —6 190 181 5 2 2 181 168 3 4 5 123 128 4 7 -5 123 142 6 2 3 319 324 3 4 9 102 101 4 7 -3 44 86 7 2 4 53 51 3 4 11 46 31 6 7 -2 213 215 5 2 5 86 75 3 4 14 79 69 4 7 -1 109 109 5 Table B.20. (continued). 417 k 1 Fo Fc sigF k 1 Fo Fc sigF k 1 Fo Fc si 7 0 108 114 4 1 8 50 33 4 3 7 176 178 4 7 1 121 135 4 1 10 109 113 4 3 8 126 121 5 7 2 74 72 4 1 12 66 52 4 3 9 61 46 4 7 5 88 75 4 1 15 91 124 4 3 12 75 79 4 7 6 51 36 6 1 17 56 46 6 3 15 62 56 6 7 7 99 109 4 2 —18 94 102 4 4 -13 92 102 4 7 8 69 62 5 2 -16 58 65 6 4 -11 58 58 5 7 10 79 57 5 2 -14 65 63 5 4 -10 116 133 5 G -16 60 59 8 2 -13 58 76 5 4 -9 109 93 5 0 -10 64 42 6 2 -12 67 64 4 4 -8 44 33 5 8 -6 77 74 5 2 -10 181 183 4 4 —6 162 176 4 8 -4 59 56 6 2 -9 133 105 4 4 -4 298 296 3 8 -3 83 84 4 2 -8 87 87 4 4 -2 191 181 3 8 -2 58 64 6 2 -7 305 298 3 4 -1 234 230 3 8 -1 91 84 5 2 -6 168 153 3 4 0 306 311 3 8 0 76 66 5 2 -5 303 294 3 4 1 85 85 4 8 1 48 48 7 2 -4 279 266 3 4 2 347 331 3 8 2 75 82 5 2 -3 40 35 4 4 3 44 56 5 8 3 57 59 6 2 -2 498 497 3 4 S 48 46 5 9 -7 70 73 6 2 -1 559 572 3 4 6 61 38 4 9 -3 46 17 8 2 0 419 421 3 4 7 69 79 4 9 -2 48 50 8 2 1 248 251 3 4 9 63 65 5 9 2 75 75 5 2 2 81 87 3 4 10 69 71 4 9 4 65 61 6 2 3 135 145 3 4 11 154 159 5 11 -3 52 35 9 2 4 242 239 3 4 12 61 59 6 11 2 56 41 8 2 5 76 71 3 4 13 89 88 4 2 7 122 127 4 4 20 51 24 8 h ■= 3 2 8 228 227 3 5 -8 95 91 4 2 11 97 110 4 5 —6 145 142 5 1 -16 114 111 5 2 13 53 60 6 5 2 61 73 4 1 -15 50 37 6 2 14 77 67 4 5 3 165 158 4 1 -14 47 40 6 3 -15 50 56 7 5 4 56 61 5 1 -13 64 57 4 3 -14 200 215 5 5 5 117 114 5 1 -12 90 103 4 3 -12 61 54 5 5 6 88 86 4 1 -9 302 306 3 3 -11 93 90 4 5 7 47 56 6 1 — 8 34 36 6 3 -9 115 119 5 5 8 90 94 4 1 -7 114 110 4 3 —8 49 44 4 5 9 70 56 4 1 —6 263 265 3 3 -7 44 49 5 5 10 148 136 6 1 -5 473 453 3 3 -6 167 155 3 5 11 65 87 6 1 -4 407 406 3 3 -5 535 514 4 5 12 77 81 5 1 -2 154 143 3 3 -4 67 74 3 5 18 51 29 8 1 -1 222 216 2 3 -3 237 228 3 6 -12 115 107 5 1 0 487 499 3 3 -2 184 187 3 6 -11 88 77 4 1 1 34 28 4 3 -1 255 244 3 6 -10 97 89 4 1 2 205 214 3 3 0 253 249 3 6 -9 81 79 4 1 3 115 98 3 3 1 61 46 3 6 -7 136 133 5 1 4 180 199 3 3 2 242 222 3 6 -6 52 61 6 1 5 68 72 3 3 3 63 53 3 6 -5 93 85 4 1 6 235 225 3 3 4 105 104 4 6 -4 86 74 4 1 7 81 62 4 3 5 100 94 5 6 -2 141 144 5 Table B.20. (continued). 418 k 1 FO Fc SigF k 1 Fo Fc sigF k 1 Fo Fc sigF 6 -1 50 49 6 0 -2 125 118 3 2 -3 169 164 3 6 1 59 49 5 0 -1 140 148 3 2 -2 149 171 3 6 2 54 61 5 0 0 214 220 3 2 -1 130 141 3 6 5 131 132 6 0 1 281 282 3 2 1 157 171 3 6 8 60 63 5 0 2 70 62 3 2 2 174 186 3 6 10 87 107 4 0 3 600 596 4 2 3 70 51 3 7 -18 58 31 8 0 4 394 394 3 2 4 261 254 3 7 -17 51 17 8 0 5 63 67 3 2 5 142 140 4 7 -14 59 42 7 0 7 300 291 3 2 7 108 113 4 7 -10 65 65 5 0 9 95 85 4 2 8 43 25 6 7 -8 99 107 4 0 10 49 54 5 2 9 111 110 4 7 -7 83 82 4 0 12 60 58 5 3 -12 91 95 5 7 -4 68 61 5 0 13 71 94 5 3 -11 64 73 4 7 -3 78 89 4 0 17 68 82 6 3 -10 55 56 5 7 -2 113 116 5 1 -17 107 106 5 3 -9 86 102 4 7 -1 47 40 7 1 -12 133 122 5 3 —8 127 113 4 7 1 154 164 6 1 -11 90 87 4 3 -7 90 88 4 7 4 65 73 5 1 -10 206 198 4 3 -6 99 85 5 7 5 76 83 5 1 -9 416 412 3 3 -5 284 286 3 8 -9 81 74 5 1 -8 46 50 5 3 -4 53 37 4 8 -7 52 58 7 1 -7 182 171 3 3 -3 214 216 3 8 -4 112 137 5 1 —6 139 136 3 3 -2 534 527 4 8 -2 48 52 7 1 -5 101 93 4 3 -1 207 183 3 8 1 73 89 5 1 -4 432 442 3 3 0 487 461 4 8 2 64 59 6 1 -3 108 111 4 3 1 180 177 3 9 -1 76 77 5 1 -2 160 149 3 3 2 54 41 4 9 0 80 91 5 1 -1 70 85 3 3 4 71 69 3 10 1 76 71 6 1 0 147 156 3 3 5 91 92 4 10 4 67 54 6 1 1 51 44 3 3 6 198 198 4 10 8 58 53 8 1 2 73 64 4 3 7 127 118 5 11 -2 70 59 7 1 4 258 235 3 3 8 92 90 4 1 5 63 72 3 3 9 75 73 4 ----- h 4 1 6 36 31 6 3 12 65 64 5 1 7 292 286 3 4 -19 51 57 8 0 -22 53 54 8 1 8 112 95 5 4 -15 76 86 5 0 -18 109 97 5 1 9 100 110 4 4 -13 77 88 4 0 -17 106 120 5 1 10 102 101 4 4 -12 87 82 4 0 -16 179 184 5 1 11 86 87 4 4 -9 117 127 6 0 -15 94 101 4 1 12 81 75 4 4 -8 58 53 5 0 -14 166 170 5 1 13 44 37 7 4 -7 239 242 4 0 -13 72 61 4 1 15 51 43 6 4 —6 96 95 4 0 -12 79 77 4 1 18 48 36 8 4 -5 236 239 4 0 -11 111 113 5 2 -16 79 67 4 4 -4 81 90 3 0 -9 253 251 3 2 -12 97 82 4 4 -3 197 198 4 0 -8 290 286 3 2 -9 128 125 4 4 -2 70 69 3 0 -7 118 131 4 2 -8 97 106 4 4 -1 145 132 4 0 -6 431 413 3 2 -7 73 96 3 4 0 114 109 5 0 -5 104 109 4 2 —6 295 282 3 4 1 107 96 5 0 -4 259 281 3 2 -5 376 371 3 4 2 65 65 4 0 -3 55 63 3 2 -4 146 150 3 4 5 103 98 4 Table B.20. (continued). 419 k 1 Fo FC sigF k 1 Fo Fc sigF k 1 Fo Fc sigF -1 7 120 109 6 8 -8 48 45 8 2 4 162 164 4 4 11 93 111 4 8 -4 60 51 6 2 5 248 241 4 5 -15 56 56 7 8 -3 66 98 6 2 6 132 142 5 5 -14 62 75 6 8 -1 132 144 6 2 7 254 259 4 5 -10 131 144 6 8 1 59 67 6 2 11 138 121 6 5 6 243 241 4 8 3 62 62 6 2 13 70 66 5 5 -4 48 52 5 8 5 77 60 5 2 14 50 56 7 5 -3 42 75 6 8 6 54 41 7 3 -20 55 40 7 5 -2 76 71 4 8 8 70 75 6 3 -15 52 58 6 5 -1 82 87 4 9 7 51 33 8 3 -14 86 76 4 5 1 73 67 4 3 -13 70 74 5 5 2 45 48 6 h = 5 ...... 3 -12 46 38 6 c 3 64 63 4 3 -9 146 144 4 5 4 111 118 4 1 -20 64 66 7 3 -8 57 62 4 5 5 59 62 5 1 -17 128 140 5 3 -7 104 111 5 5 6 109 103 4 1 -15 152 156 5 3 -6 235 229 4 5 9 119 121 4 1 -14 61 65 5 3 -5 144 148 4 5 12 54 68 7 1 -13 54 62 5 3 -4 419 410 4 5 14 71 58 5 1 -12 76 82 4 3 -3 189 188 4 5 15 53 40 7 1 -10 118 131 5 3 -2 346 329 3 6 -15 77 69 5 1 -9 182 163 4 3 0 41 46 5 6 -14 62 48 6 1 -7 110 103 5 3 1 145 145 4 6 -11 90 91 4 1 —6 99 107 5 3 2 85 70 4 6 -10 123 110 6 1 -5 138 135 4 3 3 39 40 6 6 —8 129 126 6 1 -3 361 352 3 3 6 187 181 4 6 -7 191 220 5 1 -2 61 64 3 3 8 99 96 5 6 -5 42 61 7 1 -1 259 276 3 3 9 88 102 4 6 -3 142 149 5 1 1 210 208 3 3 10 150 159 5 6 -2 43 60 7 1 2 145 157 4 3 11 57 81 6 6 1 43 24 7 1 3 157 146 4 3 12 84 101 5 6 7 84 89 4 1 4 73 71 3 4 -16 49 37 7 6 8 50 51 7 1 6 249 261 4 4 -13 99 102 4 6 9 88 79 4 1 7 115 115 5 4 -11 53 60 6 6 10 84 95 5 1 8 81 69 4 4 -9 76 82 4 6 11 54 46 7 1 9 96 77 4 4 -8 61 58 5 -10 78 82 5 2 -18 54 67 7 4 -7 303 310 4 -9 76 49 5 2 -17 56 48 7 4 -6 96 87 4 -8 56 51 6 2 -10 130 128 5 4 -5 174 203 4 -6 70 60 5 2 -9 67 94 4 4 -4 103 109 4 -5 160 159 5 2 —8 296 297 3 4 -3 73 71 4 -4 188 192 5 2 -7 164 147 4 4 -2 101 114 4 -3 63 66 6 2 -6 110 107 5 4 -1 85 80 4 -2 132 128 6 2 -5 300 280 3 4 0 67 68 4 -1 58 83 6 2 -4 116 101 4 4 2 45 35 6 1 122 111 4 2 -2 320 319 3 4 4 59 49 5 3 95 107 5 2 -1 281 274 3 4 6 99 100 5 4 92 96 4 2 0 361 362 3 4 10 102 101 4 6 103 106 4 2 1 110 96 4 4 11 53 60 7 10 67 61 6 2 2 60 64 4 5 -14 50 50 7 12 61 46 7 2 3 50 49 4 5 -11 122 127 4 Table B.20. (continued). 420 k 1 Fo Fc sigF k 1 Fo Fc sigF k 1 Fo Fc si 5 -10 61 61 5 0 -4 239 242 3 2 12 95 103 4 5 -8 S3 61 6 0 -3 563 550 4 3 -18 56 62 7 5 -7 85 86 4 0 -2 188 193 3 3 -16 54 51 7 5 -6 69 62 5 0 -1 241 233 3 3 -12 97 96 5 5 -5 143 158 5 0 0 182 186 3 3 -10 96 109 5 5 -4 83 88 4 0 1 254 240 3 3 -9 66 76 4 5 -1 70 83 4 0 2 115 112 5 3 -3 89 82 4 5 5 95 80 4 0 4 193 195 4 3 -2 76 70 3 5 8 74 81 5 0 5 47 40 5 3 0 49 49 5 5 9 128 114 5 0 6 113 114 5 3 1 75 62 3 6 -10 136 131 6 0 7 125 132 5 3 2 68 73 4 6 -7 76 59 4 0 9 124 113 6 3 4 100 86 4 6 -5 171 179 5 0 16 60 45 7 3 5 176 171 5 6 -4 79 84 4 1 -14 51 69 6 3 6 52 56 6 6 -3 143 147 5 1 -13 102 104 5 3 9 126 100 6 6 -2 77 79 4 1 -11 161 175 5 3 11 82 87 4 6 0 94 86 4 1 -7 171 155 4 4 -13 65 64 5 6 1 51 40 6 1 —6 147 159 4 4 -10 90 101 4 6 2 111 117 4 1 -5 49 44 4 4 -8 87 96 4 6 5 102 36 5 1 -4 169 180 4 4 —6 91 101 4 6 6 119 136 5 1 -3 109 92 4 4 -5 45 55 6 6 9 64 57 6 1 -2 229 236 3 4 -4 144 144 5 7 -8 66 63 5 1 1 49 36 4 4 -3 54 49 5 7 —6 103 92 5 1 2 70 82 3 4 -2 152 165 5 7 177 176 5 1 3 73 80 3 4 -1 48 46 6 7 143 155 6 1 S 82 93 4 4 0 119 118 5 7 102 111 4 1 6 119 117 5 4 1 94 88 4 7 3 62 59 6 1 9 71 87 5 4 3 44 37 6 7 4 91 87 4 1 11 105 95 5 4 4 69 66 4 7 7 64 56 6 1 13 44 19 7 4 5 139 130 6 8 —2 72 76 5 2 -17 62 60 6 4 7 107 102 5 9 64 67 7 2 -16 83 84 5 5 -14 76 76 5 9 65 63 6 2 -15 83 86 4 5 -12 57 48 6 9 52 51 8 2 -12 47 39 6 5 -9 143 143 6 9 5 60 34 7 2 -11 66 54 4 5 —8 142 155 6 10 -3 61 59 7 2 -10 62 54 4 5 -6 280 306 4 2 -9 117 113 5 5 -4 89 105 4 h “ 6 2 -8 63 52 4 5 -3 103 118 5 2 -7 103 95 4 5 -2 75 71 4 0 -20 75 49 6 2 -6 94 92 4 5 -1 45 56 7 0 -16 144 123 6 2 -5 105 87 5 5 3 116 104 6 0 -15 61 65 6 2 -4 62 70 4 5 5 89 84 4 0 -13 43 10 6 2 -2 189 173 3 5 6 95 93 4 0 -12 49 46 6 2 -1 247 248 3 6 -11 61 89 6 0 -11 63 87 5 2 0 103 106 5 6 -9 131 122 6 0 -10 286 286 4 2 1 348 346 3 6 -8 110 79 5 0 -9 101 100 4 2 3 69 61 4 6 -7 110 108 5 0 -8 239 228 4 2 5 52 60 5 6 —6 70 71 5 0 -7 255 261 3 2 7 86 88 4 6 -5 71 68 5 0 -5 483 468 4 2 10 110 134 5 6 -4 194 193 5 Table B.20. (continued). 421 k 1 Fo Fc sigF k 1 Fo Fc sigF k 1 FO FC si 6 -3 131 114 6 2 4 170 166 4 5 -8 104 91 5 6 -2 65 58 5 2 5 94 94 4 5 -6 262 264 4 6 -1 118 118 5 2 6 122 133 6 5 -5 55 21 6 6 2 62 51 5 2 7 68 72 5 5 -4 190 218 5 6 4 102 90 4 2 8 45 49 7 5 -3 55 50 6 6 5 78 83 5 2 11 65 65 6 5 -2 61 80 5 7 -3 63 70 6 2 13 63 52 6 5 0 56 68 6 7 0 85 98 4 2 15 52 2 7 5 1 92 109 4 7 2 133 129 6 3 -13 82 72 4 5 2 47 57 7 7 3 65 48 6 3 -11 218 214 5 5 4 48 47 7 7 5 77 85 5 3 -10 45 56 7 5 5 53 44 6 8 -10 57 39 7 3 -9 46 31 7 5 12 59 52 7 8 -1 56 29 7 3 -7 156 157 5 6 -17 63 34 7 8 4 53 57 8 3 -6 116 104 6 6 -8 67 66 5 9 -II 69 64 6 3 -5 116 127 6 6 -7 64 61 6 3 -4 67 61 4 6 -6 120 112 5 h = 7 ...... 3 -3 147 139 5 6 -2 110 104 5 3 -2 187 191 4 6 -1 50 41 7 -16 137 122 6 3 -1 113 106 5 6 0 47 56 8 -14 90 100 4 3 0 43 15 6 6 2 53 36 6 -13 100 105 4 3 1 120 129 5 6 4 54 43 7 -12 46 22 6 3 2 115 122 6 6 8 70 56 6 -II 88 90 4 3 3 44 52 7 7 3 74 76 5 -10 58 66 5 3 4 189 193 5 7 8 67 70 6 -9 126 136 5 3 5 112 103 5 9 -4 56 46 8 -8 106 108 4 3 6 136 124 6 -5 61 72 4 3 7 78 79 4 ■ ■■ h 8 -4 92 105 4 3 8 114 131 5 -2 228 222 4 3 10 54 66 7 0 -20 69 64 6 -I 99 97 4 4 -10 182 187 5 0 -18 49 28 8 0 309 309 4 4 -9 155 173 6 0 -15 85 64 4 I 251 257 4 4 -8 82 70 4 0 -14 149 142 6 2 70 68 4 4 -7 324 335 4 0 -10 266 257 4 4 98 98 4 4 -6 238 244 4 0 -9 152 162 5 5 88 82 4 4 -4 50 32 6 0 -8 49 56 6 6 131 133 5 4 -3 96 110 5 0 -7 49 71 6 7 59 60 5 4 -2 53 51 6 0 -6 160 135 4 II 45 32 7 4 0 89 71 4 0 -5 155 169 5 2 -15 50 38 7 4 1 111 108 4 0 -4 193 186 4 2 -11 123 114 6 4 2 110 93 5 0 -3 59 64 5 2 -9 53 44 5 4 3 164 179 5 0 -2 260 271 4 2 -7 l i s 119 5 4 4 51 48 6 0 -1 93 95 5 2 -5 81 67 4 4 5 139 149 6 0 0 277 273 4 2 -4 58 51 4 4 8 103 91 4 0 1 76 75 4 2 -3 126 137 5 4 9 60 68 6 0 2 45 56 6 2 -2 134 140 5 4 10 54 58 7 0 3 148 137 5 2 -1 64 64 4 4 13 50 43 8 0 5 239 232 4 2 0 57 45 5 5 -15 49 43 8 0 6 91 111 5 2 I 58 52 4 5 -11 53 51 7 0 7 149 140 6 2 2 86 100 4 5 -9 137 119 6 0 8 100 104 4 Table B.20. (continued). 4 2 2 sigF k 1 Fo Fc sigi k 1 Fo Fc sigF k 1 Fo 117 5 2 4 131 113 6 -13 46 48 7 4 -7 114 5 3 -14 54 69 7 -11 T8 70 4 4 -6 123 130 4 3 -12 117 122 5 -6 103 102 4 4 -4 92 99 5 3 -10 97 90 4 -3 114 106 5 4 -3 59 49 5 3 -9 60 63 6 -2 109 97 4 4 -2 107 118 5 3 -7 76 77 5 -1 106 114 4 4 0 67 52 7 3 -6 93 88 5 0 122 117 5 4 1 50 56 7 3 -5 133 117 6 1 62 75 5 4 5 48 51 6 3 -4 132 139 6 5 170 163 5 4 10 67 57 5 3 -3 73 72 5 6 55 51 6 5 -9 81 75 4 3 -2 83 79 4 7 79 77 4 5 -8 97 93 3 0 71 77 5 8 79 68 5 5 -7 199 202 5 5 3 1 94 102 4 9 61 54 6 5 -3 209 218 6 3 3 50 57 7 13 64 44 6 5 -2 134 133 4 3 5 78 59 5 15 55 11 7 5 0 100 91 5 3 10 57 61 7 2 -16 53 51 7 5 1 72 72 6 4 -9 54 39 7 2 -14 76 85 5 5 2 52 42 4 4 -8 165 155 6 2 -13 67 68 5 6 -5 95 116 6 4 -7 71 75 5 2 -12 60 59 6 6 -4 63 62 5 4 -5 47 54 7 2 -11 44 33 7 6 1 72 84 6 4 -4 96 101 5 2 -9 145 143 6 6 2 69 74 5 4 -3 197 222 5 2 —8 135 142 6 6 3 85 80 4 -2 76 78 5 2 -7 126 127 6 7 -10 64 59 6 4 -1 94 110 5 2 —6 66 62 5 7 -8 69 76 6 4 0 133 134 7 2 -5 108 109 4 7 —6 93 86 5 5 -14 55 22 7 2 -4 49 47 6 9 0 62 58 8 5 -6 49 30 7 2 -3 60 77 5 5 -5 85 85 4 2 -2 48 54 6 h = 5 -4 76 57 5 2 -1 56 53 5 5 0 111 107 5 2 1 126 122 5 1 -14 83 77 5 5 2 82 88 5 2 2 63 72 5 1 -10 212 214 5 6 -14 53 46 9 2 4 175 179 5 1 -9 128 127 6 4 6 -11 73 75 6 2 5 66 63 5 1 — 8 130 136 6 -10 73 48 6 2 7 95 104 5 1 -7 137 153 6 4 6 -9 62 86 7 3 -9 158 158 5 1 -6 92 96 149 146 5 6 -8 58 46 7 3 — 0 51 47 6 1 -4 4 6 -7 66 63 6 3 -7 143 147 6 1 -3 75 68 6 -5 54 40 7 3 —6 44 48 7 1 4 53 51 6 6 0 71 69 6 3 -3 52 65 6 1 5 136 152 6 6 1 65 72 6 3 0 99 107 4 1 6 73 57 5 7 -12 61 44 7 3 1 90 91 4 1 7 126 136 5 7 -7 72 61 6 3 3 75 77 4 2 -14 56 49 7 8 -8 71 54 6 3 4 49 34 6 2 -13 80 78 5 3 8 69 62 5 2 -11 73 81 5 h = 10 4 -15 85 82 5 2 -10 81 75 4 4 -13 65 72 6 2 -9 59 68 6 -16 51 46 8 4 -12 72 73 5 2 -6 100 93 5 0 0 -12 47 63 8 4 -11 120 120 5 2 -5 139 128 5 0 -11 85 95 5 4 -10 75 75 5 2 -1 47 46 7 0 -10 171 182 5 4 -9 61 56 6 2 1 164 166 5 Table B.20. (continued). 42 3 1 Fo Fc sii k 1 Fo Fc sig Fo Fc SigF -8 209 221 5 1 -7 109 113 5 -7 150 172 6 1 -5 65 68 6 —6 74 80 5 1 -4 66 64 5 -5 47 45 7 1 -3 46 36 7 -4 118 139 5 2 -17 56 49 8 -3 95 102 4 2 -14 64 71 7 0 129 133 6 2 -12 61 72 7 1 47 45 7 2 -3 97 91 5 3 81 74 4 2 -2 59 58 6 4 99 100 4 3 -9 51 63 8 6 147 140 5 3 -3 66 49 6 7 74 85 5 4 -15 64 35 7 -16 51 51 8 4 -13 62 52 7 -12 63 74 6 5 -2 59 54 7 -6 83 70 4 5 -1 57 42 7 -5 53 34 6 6 -12 64 55 8 -1 83 94 4 6 -8 53 46 9 0 73 77 5 6 -5 65 62 7 1 94 91 5 3 108 103 4 h = 12 4 53 49 7 5 73 69 5 0 -14 77 74 6 -14 51 54 8 0 -9 56 47 7 -7 84 88 4 0 -5 57 61 7 -6 95 100 5 1 -15 58 49 8 -5 113 116 5 1 -11 56 64 8 -4 106 106 4 1 -9 57 64 7 -2 67 64 5 1 -2 48 28 8 -12 75 67 5 1 -1 81 79 5 -10 67 63 6 2 -9 78 71 5 -8 54 51 7 2 -4 66 62 6 -7 56 50 7 2 -2 57 63 7 -5 109 112 4 2 7 51 21 8 -3 104 104 5 3 1 57 52 7 -2 87 87 4 4 -4 50 32 8 5 54 51 7 7 54 46 7 h = 14 -5 87 89 4 -4 49 30 7 0 -8 77 72 7 3 52 17 7 0 -6 53 60 9 -11 76 73 6 0 -2 60 41 8 -1 64 54 6 3 52 46 8 4 50 55 8 -11 79 72 6 -9 65 69 7 h = 11 1 -13 54 42 Table B.20. (continued). 424 01 C12 C13 C il C16 C15 CIO e u C2 C9 C4 C3 C5 C17 02 C18 C7 C6 Figure B.5. Computer-generated perspective drawing of the final X-ray model of 103. 425 Compd C18 H26O2 Color/shape colorless/parallelepiped For. wt. 274.41 Space group Pbca (#61) Temp., "C 20 Cell Constants^ a.A 16.760(4) b. 15.319(2) C.A 12.059(5) Cell vol. A3 3096.1 Formula units/unit cell 8 Dcalc' 9 cm 3 1.18 WcalC' ^ ^ 0.80 Diffractometer/scan Enraf Nonius CAD-4/d)-20 Radiation, graphite monochromator MoKa (%. = 0.71073) Max crystal dimensions, mm 0.30 X 0.35 X 0.45 Scan width 0.80 + 0.35 tan0 Standard reflections 600; 060; 006 Decay of standards ± 1.1% Reflections measured 3094 2 0 range, deg 2<20<5O Range of h, k, I +19, -18, +14 Reflections observed [Fq > Sc CFq)]*^ 718 Computer programs*- SHELXl Stnjcture solution SHELXS2 No. of parameters varied 187 Weights (o (Fo)2 + 0.0004 Fo2)-1 GOF 0.94 R = Z||FoHFc||/Z|Fo| 0.056 Rw 0.059 Largest feature final diff. map 1 .Oe‘ A'3 Table B.21. Crystal data and summary of intensity data collection and structure refinement for 103. ^Least-squares refinement of (sim/x)^ values for 25 reflections 0 > 12° ^Corrections: Lorentz-polarization. ^Neutral scattering factors and anomalous dispersion corrections from ref. 1. 426 Atom x/a y/b z/c B(eqv). 0(1) 0.7048(4) 0.4353(4) -0.2603(5) 2.74 0(2) 0.6665(3) 0.4933(4) 0.1140(4) 2.04 0(1) 0.6901(5) 0.4277(6) -0.1601(7) 1.98 0(2) 0.6250(5) 0.3759(5) -0.1159(7) 1.73 0(3) 0.6278(5) 0.3787(5) -0.0046(7) 1.61 0(4) 0.6970(4) 0.4293(6) 0.0390(7) 1.72 0(5) 0.7642(5) 0.3742(6) 0.0902(7) 2.27 0(6) 0.7573(5) 0.2883(5) 0.1536(7) 2.63 0(7) 0.8445(5) 0.2541(6) 0.1511(9) 4.02 0(8) 0.8868(5) 0.3035(6) 0.0569(9) 4.11 0(9) 0.8181(5) 0.3490(6) -0.0039(7) 2.86 0(10) 0.8250(4) 0.4327(6) -0.0731(7) 2.40 0(11) 0.8769(5) 0.5073(7) -0.0312(7) 3.40 0(12) 0.8361(6) 0.5868(6) -0.0778(9) 4.27 0(13) 0.7479(5) 0.5680(5) -0.0766(8) 2.94 0(14) 0.7389(5) 0.4679(5) -0.0694(7) 1.80 0(15) 0.5687(4) 0.3266(6) -0.1905(7) 2.51 0(16) 0.5113(5) 0.3846(6) -0.2547(8) 3.49 0(17) 0.5696(5) 0.3382(6) 0.0746(9) 2.88 0(18) 0.4929(5) 0.3907(6) 0.0881(9) 3.71 a B(eqv) = (8^/3) [a^U^(a')^ + b*U 2 2 Table B.22. Final fractional coordinates for 103. 427 Atom x/a y/b z/c H(l) 0(2) ] 0.717 0.506 0.163 H(l) C(5) ] 0.780 0.414 0.146 H(l) 0(6)] 0.740 0.297 0.228 H(2) 0(6)] 0.722 0.250 0.117 H(l) 0(7)] 0.845 0.193 0.136 H(2) 0(7)] 0.871 0.265 0.220 H(l) 0(8)] 0.923 0.345 0.086 H{2) 0(8) ] 0.914 0.264 0.009 H(l) 0(9) ] 0.804 0.308 -0.060 H(l) 0(10) ] 0.849 0.416 -0.141 H(l) 0(11) ] 0.930 0.502 -0.058 H(2) 0(11) ] 0.877 0.509 0.048 H(l) 0(12) ] 0.848 0.636 -0.033 H(2) 0(12) ] 0.854 0.597 -0.151 H(l) 0(13) ] 0.724 0.588 -0.143 H(2) 0(13) ] 0.723 0.595 -0.015 H(l) 0(15) ] 0.600 0.296 -0.243 H(2) 0(15) ] 0.539 0.286 -0.147 H(l) 0(16) ] 0.485 0.348 -0.307 H(2) 0(16) ] 0.544 0.425 -0.293 H(3) 0(16) ] 0.473 0.415 -0.212 H(l) 0(17) ] 0.555 0.283 0.045 H(2) 0(17) ] 0.594 0.330 0.145 H(l) 0(18) ] 0.462 0.361 0.143 H(2) t(18) ] 0.463 0.395 0.021 H(3) 0(18) ] 0.506 0.448 0.114 « —. ^ — ------ Table B.22 (continued). Final fractional coordinates for 103. 4 2 8 5* t r (D n o o n o n n o n n o o o o n n n OD to tPk ^ vD i n •sj in 4» inN) fO4k N) nnnnnnnnnnno i-iMh-»-*aoaNin4ku»foM»-- 8 I I I 1 ) I t I I I i I i I I I I I I I I I I I 11111111(111 o OD n o o o o o o o o n o o o n n n I I I I I I I I I I 1 I 3 0 in 3 00 ONi n 4k 4kw w oooonnooooon Q. Mh-*»-»h-*V0'»40Nin4k4xJNJH' Q. 0 0 4 k t o t—' »*X ««X» «—X » _ ' ««-X »xx '.-x I I I I I I I I I I t I I I I I I I I « \ I I \ \ I I ) I I I \ nnnnnnnnnn o o o o o o n o 1 H* »-• I-* 4k ' VO VO M i n M 4k M »“• I04kv-*0’*—’*-'*^4k 4 k w • o i n 4k I inininininininin4kw 4k fsj W4kMf0l0inw4kt04k in w 0) H-h-»OOOOh-»OOOOOMMMh-»K)Mrv> > 3 4k-0'Oh-'ONUlVDOJOorOONfNJ4krovOU»h-'H-'4k 3 {U n # *## ## «# «*4 ** * #* *$NÛ m 3 OtOOOOO*^N)4kV04kH'(Oh-*vO>«ja>4k«OONO 4 ^ Q. r o sJ'O'sJO\00 00CD'sj'O~4"s*ON"»U'O00(X)'sj~0€D (O § (Q 8 oooonononooooooonoo lOMI-*H'h-»l-*V0C0inaN0N4kU>C4fOrv>U>MH* " a (D ooooononooo (Q \ \ I I I I I I I > I 1 ) I t t MMMVD«sJin*^lON>MK> I I I I I I I I I I I I i I I I noonnoonnoooooooooo o )-*H*>~*M»-*>-*>-*vovD'^inin4k4k4kcororo>-' I I I I I I I I I t I 3 o «0 4k to O ^ W««wr «MI> «M» «W (/) w nnnnnnnnnnn I I I I I I I I I I I I i I I I ( I MMMMOOvOMMH*H-*4k t ) 1 I I I I I I i I i I I I I I I ON W 4k o —' «XX 4& »0 in 4k onononnnooooonnnnon »-*H*M»-'h-»H-»H*H»C»OOVOONI-^inU>»-»l-»OJH'f s «"-X X—* X—» X—> X—» X-». X "^ X—» X—S X~s X—> » X—». X*^ X—s X—» 00 W lo O 4k to O " »—X '—X ^ X H'OMH-'OOOfOOOOrOOMOfOfOOfO > ininininininoNininin4k CJ4k4kO0NC0h-*l/lNJ0NH-004kin'»J(7NV0004k D N>h-*4kU»4kOOOl-'OfO 01 • •••**••••••••••••• iO 3 4k»0VDU>'»JOvÛ>JOüJ»0MN)K.)inœ4k004k o X""» X"S X—» X-» X—% X«*N X“S X"» X-X X"» X-V x-s X*V X ^ X-^ x ^ X—» x ^ 00*«J00'»J'O*»J'sJ0D00CD-J'*sJ’*-J*>0ONVOC0000D Atom Ull U22 U33 U12 U13 U23 0(1) 0.048(4) 0.066(5) 0.026(4) -0.021(4) 0.003(3) 0.011(4) 0(2) 0.030(4) 0.044(4) 0.030(3) 0.006(3) 0.001(3) -0.005(3) C(l) 0.025(6) 0.044(7) 0.032(6) 0.006(5) -0.002(5) 0.005(6) C(2) 0.027(5) 0.023(5) 0.038(6) -0.003(5) -0.003(6) -0.003(5) C(3) 0.027(5) 0.024(6) 0.031(5) 0.006(5) -0.005(5) 0.000(5) C(4) 0.024(5) 0.032(5) 0.030(6) -0.002(5) 0.004(4) -0.006(5) C(5) 0.042(6) 0.046(6) 0.027(6) 0.012(5) -0.005(5) -0.009(6) C(6) 0.055(7) 0.033(6) 0.046(6) 0.004(5) -0.020(5) -0.001(5) C(7) 0.076(8) 0.049(8) 0.08(1) 0.013(7) -0.040(6) -0.004(7) C(8) 0.065(8) 0.061(8) 0.082(9) 0.023(7) -0.014(8) -0.010(8) C(9) 0.048(6) 0.056(8) 0.041(7) 0.021(6) -0.005(5) -0.012(5) C(10) 0.027(5) 0.058(6) 0.037(6) -0.001(5) 0.005(5) -0.016(6) C(ll) 0.027(6) 0.091(9) 0.054(7) -0.017(6) 0.006(6) -0.005(7) C(12) 0.063(7) 0.061(8) 0.09(1) -0.029(6) -0.006(7) -0.011(7) C(13) 0.064(7) 0.042(6) 0.043(6) -0.016(6) 0.002(5) 0.001(6) C(14) 0.031(5) 0.037(6) 0.023(5) -0.006(4) 0.009(5) -0.002(5) C(15) 0.038(6) 0.046(6) 0.042(7) -0.012(5) -0.010(5) -0.003(5) C(16) 0.038(6) 0.084(8) 0.054(7) -0.015(6) -0.006(5) -0.008(7) C(17) 0.039(6) 0.054(7) 0.052(7) -0.007(5) 0.007(5) 0.011(6) C(18) 0.056(8) 0.064(8) 0.068(9) -0.002(6) 0.028(6) 0.006(7) Anisotropic thermal parameters are defined by exp[-2pi(pi) {hha*a*Ull + kkb*b*U22 + Hc*c*U33 + 2hka*b*U12 + 2klb*c*U23 + 2hla*c*U13)]. Hydrogen atoms were given a fixed isotropic thermal parameter of B = 5.5 angstroms squared. Table B.24. Thermal parameters for 103. 4 3 0 C T T i Figure B.6. Computer-generated perspective drawing of the final X-ray model of 199. 431 Compound LAP193 (II-TM-212B) Color / Shape colorless / paralellepiped Empirical formula So«32°4 Formula weight 336.46 Temperature 173(2) K Crystal system Monoclinic Space group P2^/c Unit cell dimensions a = 12.8181(10) À a = 90° (4526 reflections b = 12.5504(10) A f = 94.177(1)° in full 6 range) c = 12.0498(9) A Y = 90° Volume 1933.3(3) A^ Z 4 Density (calculated) 1.156 Mg/m^ — 1 Absorption coefficient 0.079 mm Diffractometer / scan Siemens SMART / CCD area detector Radiation / wavelength MoKa (graphite monochrom.) / 0.71073 A F(OOO) 736 Crystal size 0.5 X 0.2 X 0.1 mm 6 range for data collection 1.59 to 23.48° Index ranges -14 ^ 14, -13 Table B.25. Crystal data and structure refinement for 199. 432 Atom x/a y/b z/c 0(eq) - 0(1) 732(2) 1020(2) 1904(2) 64(1) 0(2) 2673(2) 168(2) 1107(2) 59(1) 0(3) 2292(2) -2260(2) 985(2) 62(1) 0(4) 942(2) -2660(2) 2620(2) 58(1) 0(1) 921(3) 59(3) 1888(3) 53(1) 0(2) 1859(3) -405(3) 1494(3) 53(1) 0(3) 1725(3) -1489(3) 1407(3) 53(1) 0(4) 712(3) -1847(3) 1819(3) 54(1) 0(5) -86(3) -2200(3) 870(3) 57(1) 0(6) -1141(3) -1857(3) 1247(3) 57(1) 0(7) -938(3) -764(3) 1794(2) 53(1) 0(8) -1590(3) -502(3) 2798(3) 54(1) 0(9) -951(3) -1060(3) 3759(2) 59(1) 0(10) 169(3) -768(3) 3565(3) 57(1) 0(11) 222(3) -810(3) 2286(3) 54(1) 0(12) 3054(3) 1061(3) 1798(3) 62(1) 0(13) 3399(4) 691(4) 2969(4) 92(2) 0(14) 3936(3) 1526(3) 1197(4) 71(1) 0(15) 3263(3) -2023(3) 465(3) 58(1) 0(16) 3268(4) -2763(3) -524(3) 68(1) 0(17) 4152(4) -2196(3) 1316(3) 74(1) 0(18) -2750(3) -781(3) 2657(3) 57(1) 0(19) -3280(3) -618(3) 3729(3) 72(1) 0(20) -3289(3) -120(3) 1720(3) 69(1) U(eq) is defined as onethird of the trace of the orthoqonalized u . . tensor. Table B.26. Atomic coordinates ( x 10^) and equivalent Isotropic displacement parameters ( x 10^) for 199. 4 3 3 0(1)-C(1) 1.231(4) 0(2)-C(2) 1.375(4) 0(2)-C(12) 1.460(4) 0(3)-C(3) 1.333(4) 0(3)-C(lS) 1.465(4) 0(4)-C{4) 1.421(4) C(l)-C(2) 1.446(5) C (l)-C (ll) 1.512(5) C(2)-C(3) 1.374(5) C(3)-C(4) 1.493(5) C(4)-C(S) 1.542(5) C(4)-C(ll) 1.567(5) C(S)-C(6) 1.520(5) C(6)-C{7) 1.536(5) C(7)-C(8) 1.554(5) C(7)-C(ll) 1.560(5) C(8)-C(18) 1.526(5) C(8)-C(9) 1.537(5) C(9)-C(10) 1.515(5) C(10)-C(ll) 1.549(5) C(12)-C(14) 1.504(5) C(12)-C(13) 1.521(6) C(1S)-C(17) 1.493(6) C(15)-C(16) 1.511(5) C(18)-C(19) 1.517(5) C(18)-C(2Q) 1.525(5) C(2)-0(2)-C(12) 116.0(2) C(3)-0(3)-C(15) 121.3(3) 0(1)-C(1)-C(2) 124.6(3) 0(1)-C(1)-C(11) 125.5(3) C(2)-C(1)-C{H) 109.9(3) C(3)-C(2)-0(2) 125.8(3) C(3)-C(2)-C(l) 108.7(3) 0(2)-C(2)-C(l) 124.8(3) 0(3)-C(3)-C(2) 132.8(3) 0(3)-C(3)-C(4) 114.8(3) C(2)-C(3)-C(4) 112.3(3) 0(4)-C(4)-C(3) 107.4(3) 0(4)-C(4)-C(S) 113.0(3) C(3)-C(4)-C(S) 112.7(3) 0(4)-C{4)-C(ll) 114.9(2) C(3)-C(4)-C(ll) 104.5(3) C(S)-C(4)-C{H) 104.0(3) C(6)-C(S)-C(4) 104.7(3) C(S)-C(6)-C(7) 104.7(3) C(6)-C(7)-C(8) 116.0(3) C(6)-C(7)-C(ll) 104.9(3) C(8)-C(7)-C(ll) 105.3(3) C(18)-C(8)-C(9) 116.2(3) C(18)-C(8)-C(7) 116.1(3) C(9)-C(8)-C(7) 101.7(3) C(10)-C(9)-C(8) 103.4(3) C(9)-C(10)-C(ll) 104.8(3) C(l)-C(ll)-C(10) 111.1(3) C(l)-C(ll)-C(7) 115.1(3) C(10)-C(ll)-C(7) 105.5(3) C(l)-C(ll)-C(4) 102.9(3) C(10)-C(ll)-C(4) 115.7(3) C(7)-C(ll)-C(4) 106.9(3) 0(2)-C(12)-C(14) 104.8(3) 0(2)-C(12)-C(13) 111.0(3) C(14)-C(12)-C(13) 112.8(4) 0(3)-C(15)-C(17) 107.8(3) 0(3)-C(lS)-C(16) 105.4(3) C(X7)-C(15)-C(16) 114.0(3) C(19)-C(18)-C(20) 110.5(3) C(19)-C(18)-C(8) 111.6(3) C(20)-C(18)-C(8) 110.1(3) Table B.27. Bond lengths (Â) and angles (deg) for 199. 434 Atom Ull 022 033 023 013 012 0(1) 72(2) 50(2) 69(2) -2(1) 12(1) 4(1) 0(2) 67(2) 55(2) 57(2) -4(1) 18(1) -8(1) 0(3) 69(2) 55(2) 65(2) -1(1) 22(1) 0(1) 0(4) 64(2) 56(2) 53(2) 6(1) 10(1) -1(1) C(l) 63(2) 50(2) 47(2) 1(1) 8(2) 2(2) C(2) 62(2) 56(2) 43(2) -1(1) 10(2) -3(2) C(3) 63(2) 52(2) 45(2) 0(1) 11(2) 5(2) C(4) 62(2) 53(2) 48(2) 5(1) 8(2) 2(2) C(S) 63(2) 57(2) 50(2) -3(1) 8(2) -2(2) C(6) 64(2) 64(2) 44(2) -3(1) 7(2) -6(2) C(7) 65(2) 53(2) 42(2) -2(1) 8(2) 6(2) C(8) 66(3) 46(2) 50(2) 1(1) 11(2) 3(2) C(9) 76(3) 64(2) 37(2) 0(1) 9(2) 1(2) C(10) 66(2) 61(2) 43(2) -5(1) 8(2) 1(2) C (ll) 63(2) 56(2) 42(2) -2(1) 8(2) 1(2) C(12) 68(2) 55(2) 64(2) -11(2) 10(2) -7(2) C(13) 104(4) 102(4) 70(3) 1(2) -5(2) -26(3) C(14) 66(3) 63(3) 86(3) -6(2) 15(2) -7(2) C(15) 67(3) 56(2) 54(2) 2(2) 14(2) 1(2) C(16) 83(3) 67(3) 58(2) -8(2) 24(2) 6(2) C(17) 75(3) 83(3) 65(3) 3(2) 15(2) 0(2) C(18) 62(2) 49(2) 60(2) -2(2) 10(2) 2(2) C(19) 73(3) 82(3) 64(2) -1(2) 25(2) -1(2) C(20) 63(3) 78(3) 65(2) 1(2) 5(2) 5(2) The anisotropic displacement factor exponent takes the form: 2 *2 - 2 t [ (ha ) U 11 + 2hka*b*U^2 I- Table B.28. Anisotropic displacement parameters (Â2 x 1Q3) for 199. 43 5 Atom X y z 0(eq) H(4) 439(14) -3089(19) 2615(26) 69 H(SA) 57(3) -1847(3) 163(3) 68 H(SB) -63(3) -2932(3) 765(3) 68 H(6A) -1397(3) -2372(3) 1788(3) 69 H(6B) -1666(3) -1800(3) 605(3) 69 H(7) -1025(3) -187(3) 1222(2) 64 H(8) -1535(3) 283(3) 2933(3) 64 H(9A) -1146(3) -794(3) 4488(2) 70 H(9B) -1054(3) -1841(3) 3727(2) 70 H(IOA) 663(3) -1284(3) 3937(3) 68 H(IOB) 339(3) -45(3) 3853(3) 68 H(12) 2486(3) 1603(3) 1833(3) 75 H(13A) 3661(25) 1302(6) 3414(9) 111 H(13B) 3956(18) 160(20) 2936(4) 111 H(X3C) 2802(7) 374(25) 3313(11) 111 H(14A> 4213(14) 2156(12) 1599(12) 85 H(14B) 3678(6) 1730(19) 442(8) 85 H(14C) 4493(9) 995(8) 1161(19) 85 H(15) 3259(3) -1265(3) 207(3) 70 H(16A) 3913(9) -2657(15) -900(13) 82 H(16B) 2663(11) -2608(14) -1044(11) 82 H(16C) 3231(21) -3503(3) -271(4) 82 H(17A) 4815(4) -2138(22) 964(6) 88 H(17B) 4096(12) -2908(9) 1642(17) 88 HC17C) 4129(13) -1658(14) 1903(12) 88 H(18) -2815(3) -1550(3) 2446(3) 68 H(19A) -3197(18) 126(6) 3969(12) 87 H(19B) -2960(14) -1088(15) 4307(7) 87 H(19C) -4026(5) -785(20) 3605(6) 87 H(20A) -2973(14) -277(16) 1022(5) 83 H(20B) -3205(18) 639(3) 1895(11) 83 H(20C) -4035(5) -298(16) 1643(15) 83 Table B.29. Hydrogen coordinates ( x 104) and isotropic displacement parameters (A2 x 103) for 199. 436 2 Figure B.7. Preliminary ORTEP diagram derived from a crystallographic study of 70. 437 LIST OF REFERENCES 1 International Tables for X-ray Crystallography, Kynoch Press, Birmingham, England, Vo! IV, 1974, 72, 99, 149. 438 BIBLIOGRAPHY CHAPTER 1 1 (a) Cohen, S.; Lâcher, J.; Park, J. J. Am. Chem. Soc. 1959, 81, 3480. (b) Paine, A.J. Tetrahedron Lett. 1984, 25, 135. Squaric acid can be purchased on a kilogram scale from Aldrich Chemical Company. 2 (a) Schmidt, A.H.; Ried, W. Synthesis 1978, 1. (b) Knorr, H.; Ried, W. Synthesis 1976, 649. (c) Schmidt, A.H.; Ried, W. Synthesis 1978, 869. 3 Park, J.D.; Cohen, S.; Lâcher, J.R. J. Am. Chem. Soc. 1962, 84, 2919. 4 Cohen, S.; Cohen, S.G. J. Am. Chem. Soc. 1966, 88, 1533. 5 Campbell, E.F.; Park, A.K.; Kinney, W.A.; Fengl, R.W.; Liebeskind, L.S. J. Org. Chem. 1995, 60, 1470. 6 Kinney, W.A.; Leen N.E.; Garrison, D.T.; Podlesny, E.J.; Simmonds, J.T.; Bramlett, D.; Notvest, R.R.; Kowal, D.M.; Tasse, R.P. J. Med. Chem. 1992, 35, 4720. 7 Tomas, S.; Rotger, M.C.; Gonzalez, J.F.; Deya, P.M.; Ballester, P.; Costa, A. Tetrahedron Lett.. 1995, 36, 2523. 8 Franck, B. Angew. Chem., Int. Ed. Eng. 1984, 23, 493. 9 (a) Xu, S.L.; Xia, H.; Moore, H.W. J. Org. Chem. 1991, 56, 6094. (b) Yamamoto, Y.; Ohno, M.; Eguchi, S. J. Org. Chem. 1994, 59, 4707. (c) Moore, H.W.; Decker, O.H.W. Chem. Rev. 1986, 86, 821. (d) Liebeskind, L.S.; Birchler, A.G.; Liu, F. J. Org. Chem. 1994, 59, 7737. (e) Liebeskind, L.S. Tetrahedron 1989, 45, 3053. (f) Paquette, L.A.; Sturino, C.; Doussot, P. Submitted for publication, (g) Santora, V.J.; Moore, H.W. J. Am. Chem. Soc. 1995, 117, 8486. (h) Winters, M.P.; Stranberg, M.; Moore, H.W. J. Org. Chem. 1994, 59, 7572. 10 (a) Reed, M.W.; Pollart, D.J.; Perri, S.T.; Poland, L.D.; Moore, H.W. J. Org. Chem. 1988, 53, 2477. (b) Liebeskind, L.S.; Wang, J. Tetrahedron Lett. 1990, 31, 4293. (c) Liebeskind, L.S.; Fengl, R.W. J. Org. Chem. 1990, 55, 439 5359. (d) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Crg. Chem. 1988, 53, 2482. (e) Sidduri, A.; Budries, N.; Laine, R.M.; Knochel, P. Tetrahedron Lett. 1992, 33, 7515. (f) Mehta, P.G. Synthetic Comm. 1994, 24, 2497. (a) Paquette, L.A.; Doherty, A.M. Polyquinane Chemistry, Springer- Veriag: Berlin Heidelberg, 1987. (b) Ibid. 195-197. (c) Ibid. 169-173. (d) Ibid. 206-208. (e) Ibid. 85-88. 12 Compound 8 was prepared in 10 steps from dimethyl squarate (40% overall). 13 Reaction of diisopropyl squarate with an excess of two equivalents of the anion of dihydrofuran or cyclopentenyllithium was carried out by Joanna Negri, a post-doctoral student under the supervision of Dr. Leo Paquette. Her products and yields are shown in Scheme 5. Structural verification was accomplished by X-ray crystallography. 14 Transition state pathways were predicted on the basis of stereochemical markers at the bond-forming centers. See Chapter 2 for details. Following the initial bond reorganization, protonation and transannular aldol chemistry ensue, leading to the observed products. 15 Berson, J.A.; Den/an, P.B.; Jenkins, J.A. J. Am. Chem. Soc. 1972, 94, 7598. 16 Huisgen, R.; Dahmen, A.; Huber, H. J. Am. Chem. Soc. 1967, 89, 7130. 17 (a) Shen, G.Y.; Tapia, R.; Okamura, W.H. J. Am. Chem. Soc. 1987, 109, 7499. (b) Skattebol, L. Tetrahedron "\969, 25, 4933. (c) Jensen, F. J. Am. Chem. Soc. 1995, 117, 7487. 18 Anke, T.; Heim, J.; Knoch, F.; Mocek, U.; Steffan, B.; Steglich, W.; Angew. Chem. Int. Ed. Engl. 1985, 24, 709. CHAPTER 2 1 (a) Paquette, L.A.; Lawhom, D.E.; Teleha, C.A. Heterocycles 1990, 30, 765. (b) Paquette, L.A.; Lanter, J.C.; Wang, H-L. J. Org. Chem. 1996, 61, 1119. (c) Paquette, L.A.; Wang, H-L. Tetrahedron Lett. 1995, 36, 6005. (d) Negri, J.T.; Rogers, R.D.; Paquette, L.A. J. Am. Chem. Soc. 1991, 113, 5073. (e) Paquette, L.A.; Negri, J.T.; Rogers, R.D. J. Org. Chem. 1992, 57, 3947. (f) Paquette, L.A.; Branan, B.M.; Friedrich, D.; Edmondson, S.D.; Rogers, R.D. J. Am. Chem. Soc. 1994, 116, 506. (g) Paquette, LA.; Branan, B.M. Heterocycles ^99S, 60, 1852. (h) Paquette, L.A.; Branan, B.M.; Rogers, R.D.; Bond, A.H.; Lange, H.; Gleiter, R. J. Am. Chem. Soc. 1995, 117, 5992. 4 4 0 (i) Paquette, LA.; Lord, M.D.; Negri, J.T. Tetrahedron Lett. 1993, 34, 5693. (j) Lord, M.D.; Negri, J.T.; Paquette, L.A. J. Org. Chem. 1995, 60, 191. (k) Paquette, L.A.; Doussot, P. Research Chem. Intermed, submitted for publication. (I) Paquette, L.A.; Sturino, C.; Doussot, P. submitted for publication. 2 Boeckman, R.K., Jr.; Bruza, K.J. Tetrahedron Lett. 1977, 4187. 3 See, for example: (a) Paquette, L.A.; Opiinger, J.A. Tetrahedron 1989, 45, 107. (b) Paquette, LA.; Dullweber, U.; Cowgill, L.D. Tetrahedron Lett. 1993, 34, 8019 and relevant references cited therein. 4 (a) Barton, D.H.R.; Bashiardes, G.; Fourrey, J. Tetrahedron Lett. 1983, 24, 1605. (b) Barton, D.H.R.; Bashiardes, G.; Fourrey, J. Tetrahedron '{QSS, 44, 147. 5 (a) Hambrecht, J.; Straub, H. Tetrahedron Lett. 1976, 1079. (b) Hambrecht, J.; Straub, H.; Müller, E. Chem. Ber. 1974, 107, 3962. 6 Brands, M.; Wey, H.; Bruckmann, J.; Kruger, C; Butenschon, H. Chem. Eur. J. 1996, 2, 182 and relevant references cited therein. 7 For reviews of the oxy-Cope reaction: (a) Paquette, L.A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609. (b) Lutz, R.P. Chem. Rev. 1984, 84, 206. 8 Liebeskind, L.S.; Wirtz, K.R. J. Org. Chem. 1990, 55, 5350. 9 (a) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Org. Chem. 1988, 53, 2482. (b) Dehmlow, E.V.; Schell, H.G. Chem. Ber. 1980, 113, 1. (c) Kraus, J.L. Tetrahedron Lett. 1985, 26, 1867. 10 Berson, J.A.; Dervan, P.B.; Jenkins, J.A. J. Am. Chem. Soc. 1972, 94, 7598. 11 Anionic acceleration of oxy-Cope rearrangements was originally described by Evans. Evans, D.A.; Golob, A.M.; J. Am. Chem. Soc. 1975, 97, 4765. 12 Hammond, G.S.; DeBoer, C.D. J. Am. Chem. Soc. 1964, 86, 899. 13 Berson, J.A.; Dervan, P.B. J. Am. Chem. Soc. 1972, 94, 8949. 14 Bamier, J.P.; Ollivier, J.; Salaun, J. Tetrahedron Lett. 1989, 30, 2525. 15 Yamamoto, Y.; Ohno, M.; Eguchi, S. J. Am. Chem. Soc. 1995, 117, 9653 and relevant references cited therein. 441 (a) Nakamura, K,; Houk, K.N. J. Org. Chem. 1995, 60, 686. (b) Rudolf, K.; Spellmeyer, D.; Houk, K.N. J. Org. Chem. 1987, 52, 3708. (c) Rondan, N.; Houk, K.N. J. Am. Chem. Soc. 1985, 107, 2099. Piers, E.; Ellis, K.A.; Tetrahedron Lett. 1993, 34, 1875. The reversal of torquoselectivity with Lewis acids has been reported: (a) Niwayama, S. J. Org. Chem. 1996, 61, 640. (b) Niwayama, S.; Houk, K.N. Tetrahedron Lett. 1993, 34, 1251. See also Chapter 1, ref 9a, c-e, g, h. 18 (a) Die Erhaltung der Orbitalsymmetrie; Verlag Chemie, Weinheim 1970; (b) The Conservation of Orbital Symmetry, Verlag Chemie, Weinheim/Academic Press, New York 1970; (c) Angew. Chem. 1969, 81, 797; (d) Angew. Chem., Int. Ed. Engl. 1969, 8, 781. 19 (a) Huisgen, R.; Boche, G.; Dahmen, A.; HechtI, W. Tetrahedron Lett. 1968, 5215, (b) Huisgen, R.; Dahmen, A.; Huber, H. Tetrahedron Lett. 1969, 1461. (c) See also Chapter 1, Ref. 16. 20 (a) Marvell, E.N.; Seubert, J.; Vogt, G.; Zimmer, G.; Moy, G.; Siegmann, J.R. Tetrahedron "[978, 34, 1323, (b) Review: Marvell, E.N. Thermal Electrocyclic Reactions, Academic Press, New York, 1980, Chapter 8. 21 Thomas, B.E. IV; Evanseck, J.D.; Houk, K.N. J. Am. Chem. Soc. 1993, 115, 4165. 22 (a) Pohnert, G.; Boland, W. Tetrahedron 1994, 5 0 ,10235. (b) Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555, and relevant references cited therein. 23 Still, W.C.; Steliou, K. private communication. Through use of the Grid Search function within MODEL, a multiconformer run was performed within each molecule incorporating the appropriately stereodisposed bond construction. In each case, over 300 conformers were generated and minimized to ensure arrival at the global minimum energy conformer. The MMX software program was then used to optimize the lowest energy conformer in each instance. 24 (a) Bax, A. J. Magn. Reson. 1984, 57, 314. (b) Bax, A.; Nin, C.H. J. Am. Chem. Soc. 1984, 106, 1150. (c) Mûler, N.; Bauer, A. J. Magn. Reson. 1989, 82, 400. CHAPTER 3 1 See Chapter 1, ref 10d. 442 2 Drying procedure for CeCIs 7 H2O can be found In The Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A. Ed., John Wiley & Sons, New York, 1995, Vol. II, 1031. (b) Review of lanthanide reagents in organic synthesis: Molander, G.A. Tetrahedron, 1986, 42, 6573. 3 Vinyllithium was generated from vinylstannane by treatment with n- butyllithium or directly from vinyl bromide: Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 4839. ^ (a) Dreiding, A.S.; Pratt, R.J. J. Am. Chem. Soc. 1954, 76, 1902. The isomerically pure bromides are currently available from Aldrich Chemical Company. 5 (a) Hayashi, T.; Konishi, M.; Ocamoto, Y.; Kabeta, K.; Kumuda, M. J. Org. Chem. 1986, 51, 3772. (b) Miller, S.A.; Gadwood, B.C. J. Org. Chem. 1988, 53, 2214. For the exchange with f-butyllithium in this case, temperature must be strictly maintained at -78°C to avoid formation of 1-propynyllithium. 6 See Chapter 2, ref 11a. 7 (a) Paquette, L.A.; Temansky, R.J.; Balogh, D.W. J. Am. Chem. Soc. 1982, 104, 4502. (b) Paquette, LA.; Temansky, R.J.; Balogh, D.W.; Taylor, W.J. J. Am. Chem. Soc. 1983, 105, 5441. (c) Paquette, L.A.; Balogh, D.W.; Temansky, R.J.; Begley, W.J.; Banwell, M.G. J. Org. Chem. 1983, 48, 3282. 8 The reaction using conditions A was carried out by Pete Wilson, a post doctoral student working in the Paquette group. 9 Strictly speaking, 75 is drawn in an enantiomeric relationship to the formal cyclization product of 78b for the purpose of showing its structural relationship to 74 more clearly. 10 (a) Boeckman, R.K., Jr.; Blum, P.M.; Ganem, B.-T.; Halvey, N. Org. Synth. 1978, 58, 152. (b) Grobel, B.-T.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 83. (c) Zweifel, G.; Lewis, W. J. Org. Chem. 1978, 43, 2739. (d) The Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A., Ed. John Wiley & Sons, New York, 1995, Vol. 7, 5322. 11 Kraus, J.L. Tetrahedron Lett. 1985, 26, 1867. See also Chapter 1, ref lOd. 12 Mitchell, G.H.; Sondheimer, F. J. Am. Chem. Soc. 1969, 91, 7520. 13 (a) Moore, H.W.; Yerxa, B.R. Chemtracts: Org. Chem. 1992, 5, 273. See also Chapter 1, ref 9c. 443 (a) Cook, F.L; Caruso, T.C.; Byrne, M.P.; Bowers, C.W.; Speck, D.H.; Liotta, C.L Tetrahedron Lett. 1974, 4029. (b) Gokel, G.W. Crown Ethers and Cryptands, The Royal Society of Chemistry, Cambridge, 1991. (c) Gokel, G.W.; Durst, H.D. Synthesis 168. 15 (a) Birchler, A.G.; Liu, F.; Liebeskind, L.A. J. Org. Chem. 1994, 59, 7737. (b) Edwards, J.P.; Krysan, D.J.; Liebeskind, L.A. J. Org. Chem. 1993, 58, 3942. (c) Danheiser, R.L. Org. Synth. 1990, 68, 32. (d) Zhao, D-C.; Tidwell, T.T. J. Am. Chem. Soc. 1992, 114, 10980. 16 The experimental and spectroscopic data for this reaction can be found in Joanna Negri's notebook, ll-JN-194. 17 (a) Liebeskind, L.S.; Fengl, R.W.; Wirtz, K.R.; Shawe, T.T. J. Org. Chem. 1988, 53, 2482. (b) Liebeskind, L.S.; Wang, J. Tetrahedron Lett. 1990, 31 4293. 18 Liebeskind, L.S. Tetrahedron 1989, 45, 3053. 19 (a) Schmidt, A.H.; Kircher, G.; Maus, S.; Bach, H. J. Org. Chem. 1996, 61, 2085. (b) Maahs, G.; Hegenberg, P. Angew. Chem., Int. Ed. Engl. 1966, 5, 888. (c) DeSelms, R.C.; Fox, C.J.; Riordan, R.C. Tetrahedron Lett. 1970, 781. (d) Green, B.R.; Neuse, E.W. Synfhes/s 1974, 45. (e) Neuse, E.W.; Green, B. J. Org. Chem. 1974, 39, 1585. CHAPTER 4 1 Review on cyclobutene ring opening reactions: (a) Durst, T.; Breau, L. in Comprehensive Organic Synthesis] Trost, B.M.; Fleming, I., Eds.; Pergamon Press, Oxford, 1991, Vol. 5, Chapter 6.1. (b) Marvell, E.N. Thermal Electrocyclic Reactions, Academic Press, New York, 1980, 124. (c) See also Chapter 1, ref. 9; Chapter 2, ref. 16,17. 2 See Chapter 2, refs 19 to 22. 3 Yamomoto, Y.; Ohno, M.; Eguchi, S. Tetrahedron 1994, 50, 7783. 4 While electrocyclic ring opening of cyclobutenes has been thououghly studied, the anionic version has limited literature precedent. See: (a) Organic Reactions, John Wiley & Sons, New York, 1993, Chapter 2, 143. (b) Kametani, T.; Tsubuki, M.; Nemoto, H.; Suzuki, K.J. Am. Chem. Soc. 1981, 103, 1256. (c) Thies, R.W.; Shih, H-H.J. J. Org. 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(b) Carey, F.A. Sundberg, R.J. Advanced Organic Chemistry, Part A, Plenum Press, New York, 1990, 215. 3 Ryu, I.; Hayama, Y.; Harai, A.; Sonoda, N.; Orita, A.; Ohe, K.; Murai, S. J. Am. Chem. Soc. 1990, 112, 7061. 4 Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem. Commun. 1984, 29. 5 Paquette, L.A.; Doyon, J. J. Am. Chem. Soc. 1995, 117, 6799. 6 Enolate 137 is drawn in an enantiomeric relationship to 67 for purposes of comparison to 136. 7 Paquette, LA.; Kuo, L.H.; Hamme, A.T. II; Kreuzholz, R.; Doyon, J. Submitted for publication. 445 CHAPTER 6 1 (a) The Chemistry of Ketenes, Alienee and Related Compounds, Patai, S., Ed., John Wiley, New York, 1980. (b) The Chemistry of the Alienee, Landor, S.R., Ed., Academic Press, London, 1982. (c) Schuster, H.F.; Coppola, G.M. Alienee In Organic Synthesis-, John Wiley, New York, 1984. 2 (a) Balme, G.; Doutheau, A.; Gore J; Malacria, M. Synthesis 1979, 508. (b) Kobayashi, S., Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392. (c) Creary, X. J. 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Sac., Chem. Commun 1987, 1578. (c) Schwartz, C.E.; Curran, D.P.; J. Am. Chem. Soc. 1990, 112, 9272. (d) Mehta, G.; Rao, K.S.; Reffy, M.S. Tetrahedron Lett. 1988, 29, 5025. (e) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11. 3 Work toward the synthesis of the requisite vinyl bromide (racemic) was done by Pete Wilson, Paquette research group, unpublished results. 4 Corey, E.J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. 5 Trost, B.M.; Fray, M.J. Tetrahedron Lett. 1988, 27, 2163. 5 (a) Dess, D.B.; Martin, J.C. J. Org. Chem. 1983, 48, 4155. (b) Ireland, R.E.; Liu, L.J. Org. Chem. 1993, 58, 2899. 7 This method has been used for the bromide, (a) Joly, R.; Wamant, J.; Nomine', G.; Bertin, D. Bull. Chlm. Soc. Fr. 1958, 366. (b) Hanna, R. Tetrahedron Lett. 1968, 2105. (c) Branan, B.M.; Paquette, L.A. J. Am. Chem Soc. 1994, 116, 7658. 8 Seebach, D. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624. 8 For a potential enantioselective addition of the cuprate see: (a) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275, . (b) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 35, 895. (c) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4273. (d) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 895. (e) Kanai, M.; Koga, K.; Tomioka, K. Tetrahedron Lett. 1992, 33, 7193. 13 (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025. (b) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I Tetrahedron Lett. 1986, 27, 4029. 447 (a) McMurry, J.E.; Scott, W J. Tetrahedron Lett. 1983, 24, 979. For a more reactive triflating reagent see: Comins, D.L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299. 12 For reviews, see: (a) Stang, P.J. Acc. Chem. Res. 1978, 11, 107. (b) Stang, P.J.; Hanack, M.; Subramanian, LR. Synthesis, 1982, 85. 13 Gilbertson, S.R.; Challener, C.A.; Bos, M.E.; Wulff, W.D. Tetrahedron Lett. 1988, 29, 4795. 14 For methods of removal of tin by-products see: (a) Leibner, J.E.; Jacobus, J. J. Org. Chem. 1979, 44, 449. (b) Curran, D.; Chang, V. H-T. J. Org. Chem. 1989, 54, 3152. 13 Paquette, LA.; Dahnke, K.; Doyon, J.; He, W.; Wyant, K.; Friedrich, D. J. Org. Chem. 1991, 56, 6199. 16 Barton, D.H.R.; Lâcher, B.; Zard, S.Z. Tetrahedron, 1987, 43, 4321. 17 (a) Tanaka, K.; Kishigami, S.; Toda, F. J. Org. Chem. 1991, 56, 4333. (b) Petrier, 0.; Luche, J.-L. J. Org. Chem. 1985, 50, 910. 18 Dorsch, M.; Jager, V.; Sponlein, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 798. 18 (a) Crandall, J.; Apparu, M. in Organic Reactions, Dauben, W.G., Ed., John Wiley & Sons, New York, 1983, Vol. 29, Chapter 3. Morgan, K.M.; Gajewski, J.J. J. Org. Chem. 1996, 61, 820. 20 Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. 21 This reagent is useful for oxidation of double bonds in the presence of ketones. For a more reactive perimidic acid reagent (Cl3CC(NH)00H), see Arias, L.A.; Adkins, S.; Nagel, C.J.; Bach, R.D. J. Org. Chem. 1983, 48, 888. This reagent is also capable of epoxidizing enones. 22 See Chapter 5, ref 4. 23 For reactions of epoxysilanes and allylsilanes see Silicon In Organic Synthesis, Colvin, E.W., Buttenworths, Boston, 1989, Chapters 8, 9. CHAPTER 8 1 Kofron, W.G.; Baclawski, L.M. J. Org. Chem. 1976, 41, 1879. 2 See Chapter 1, ref 10d. 448 3 See Chapter 2, ref 4. 4 See Chapter 3, ref 2. 5 See Chapter 3, ref 4. 6 See Chapter 3, ref 3. 7 (a) Schmidt, C. Can. J. Chem. 1976, 54, 2310. (b) Huffman, J.W.; Arapakos, P.G. J. Org Chem. 1965, 30, 1604. APPENDIX B 1 Intemational Tables for X-ray Crystallography, Kynoch Press, Birmingham, England, Vol IV, 1974, 72, 99, 149. 449