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The chemistry of polycyclic and spirocyclic compounds
Branan, Bruce Monroe, Ph.D.
The Ohio State University, 1994
UMI 300 N.ZeebRd. Ann Arbor, MI 48106 THE CHEMISTRY OF POLYCYCLIC AND SPIROCYCLIC COMPOUNDS
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the
Graduate School of The Ohio State University
by
Bruce Monroe Branan
*****
The Ohio State University 1994
Dissertation Committee: Approved by Professor Leo A. Paquette
Professor Viresh H. Rawal Adviser Professor Harold Shechter Department of Chemistry For the Glory of My Lord and Savior,
Jesus Christ.
Proverbs 9:10 A CKNO WLEDG EMENTS
This work would not exist without the assistance of numerous people, and it is a
pleasure to begin by expressing my sincere appreciation to Professor Paquette for his
guidance, support, and understanding throughout my stay in Columbus, and for the hard
work that he always demanded, as well as provided. I thank Professor Rawal and
Professor Shechter for serving on my Dissertation Committee, and Dr. Kurt Loening for
assistance in naming the many compounds included in this document. Special thank-you
is also given to Donna Rothe for her patience and endless smiles while going out of her way to help, and to Dr. Kevin Daniels for his generous assistance the numerous times I required aid with the computer. I am indebted to the many members of the Paquette
Research Group both past and present, for their valuable chemical insights and assistance. I am grateful to Peter and Betsy Martindale and family, and Living Water
Church for providing me with family and friends away from the laboratory. To my
Mother and Father, and to my brother and sisters, a thank-you does not seem large enough, for their love and support is always there to depend on. Any goal I achieve must be shared by them. Furthermore, I am particularly grateful to Professor J.C. Barborak and Professor R.L. Miller at UNCG for their friendship and guidance during my undergraduate and graduate years. Finally, I thank my wife Laura, for the never ending love and support that she gives her husband. VITA
May 28, 1967 ...... Bom, Winston-Salem, NC
May 14, 1989 ...... Bachelor of Science University of NC at Greensboro Greensboro, North Carolina
September, 1989-June, 1990...... Graduate Teaching Associate The Ohio State University
June, 1990-December, 1992 ...... Graduate Research Associate The Ohio State University
January, 1993-December 1993 ...... Graduate Fellow The Ohio State University
PUBLICATIONS
Paquette, L.A.; Branan, B.M.; Rogers, R.D. Tetrahedron 1992, 48, 297-306.
Branan, B.M.; Paquette, L.A.; Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1 99 2,114, 774-776.
Paquette, L.A.; Dullweber, U.; Branan, B.M. Heterocycles 1994,37, 187-191.
Paquette, L.A.; Branan, B.M.; Friedrich, D.; Edmondson, S.D.; Rogers, R.D. J. Am. Chem. Soc. 1994,116, 506-513.
FIELD OF STUDY
MAJOR HELD: Chemistry
Studies in Organic Chemistry
iv TABLE OF CONTENTS
DEDICATION...... ii
ACKNOWLEDGMENTS...... lii
VITA...... iv
LIST OF TABLES...... viii
LIST OF FIGURES...... x
LIST OF SCHEMES...... xiii
CHAPTER PAGE
I. STUDIES TOWARD THE SYNTHESIS OF PENTACYCLO- [7.2.1.04’11.06'9.!)6’ , 0 ]DODECA-1,4-DIENE: A BIS-ANNELATED SEMIBULL VALENE A. Introduction ...... 1 B. Results...... 7 C. Discussion ...... 13
II. GENERATION AND CHEMICAL TRAPPING OF A BIS(ETHANO) DERIVATIVE OF TRICYCLO[3.3.0.03 7 ]OCT-l(5)-ENE: THE CONSUMMATE MEMBER OF A SERIES OF PYRAMIDALIZED ALKENES A. Introduction...... 15 B. Results and Discussion ...... 16
III. PROGRESS TOWARDS THE SYNTHESIS OF TRICYCLO[4.4.1 04*11 ] UNDECA-1,3,5,7,9-PENTAENE VIA BROMINATION- DEHYDROBROMINATION METHODOLOGY A. Introduction ...... 22 B. Results...... 24 C. Discussion ...... 31
IV. ANALYSIS OF THE CONFORMATIONAL NATURE, RESOLVABILITY, AND THERMAL RACEMIZATION OF HETERO-2,3-DISPIRO CYCLOHEX ANONES A. Introduction ...... 34 B. Results...... 36 1. Synthetic Considerations ...... 36 2. Solid-State Structural Studies ...... 38 3. Solution Conformational Studies ...... 39 4. Assessment of the Relative Stabilities by Molecular Mechanics Calculations ...... 45 5. Acid-Catalyzed Syn/Anti Equilibration Studies...... 47 6 . Resolution of 72, 81, and 8 6 . Racemization under Acidic Conditions ...... 48 C. Discussion ...... 50 1. The 2-Heteroatom ketone Effect ...... 50 2. The Gauche Effect of Vicinal Polar Bonds on Six-Membered Rings ...... 52 3. Counterbalancing of Electronic and Steric Interactions in Hetero 2,3-Dispiro Cyclohexanones ...... 53 4. Heteroatom Control of Racemization at Two Vicinal Quaternary Carbons ...... 54
V. HETEROATOMIC EFFECTS ON THE ACID-CATALYZED REARRANGEMENTS OF DISPIRO[4.0.4.4]TETRADECA- 11,13-DIENES A. Introduction ...... 56 B. Results...... 57 1. Preparation of the Spirocyclic Dienes ...... 57 2. Acid Catalyzed Rearrangements ...... 62 3. Selected Reactions of the [4.4.4]- Propelladienes ...... 67 C. Discussion ...... 69
VI. INVESTIGATION OF HETEROATOM INFLUENCES ON THE DIELS-ALDER FACIAL SELECTIVITY OF DISPIRO[4.0.4.4]- TETR ADECA-11,13-DIENES A. Introduction ...... 72 B. Preparation of Starting Materials ...... 75 C. Results...... 76 1. Cycloadditions ...... 76 a. Diene 105 ...... 76 b. Diene 102 ...... 79 c. Diene 117 ...... 81 d. Diene 155 ...... 82 e. Diene 111 ...... 83 f. Diene 114 ...... 85 D. Discussion ...... 90
EXPERIMENTAL...... 95
vi APPENDICES
A. 'HNMR Spectra ...... 174 B. X-Ray Data...... 285
LIST OF REFERENCES...... 310 LIST OF TABLES
TABLE PAGE
3 .1. Bond Distance (A) and Angles (deg) for 6 6 ...... 286
3.2. Final Fractional Coordinates for 6 6 ...... 286
3.3. Final Fractional Coordinates for 6 6 ...... 287
3.4. Thermal Parameters for 6 6 ...... 287
4.1. Relevant Crystallographic Details ...... 41
4.2. MM2-Derived Strain Energies, Heats of Formation, and Total Energies for the Two Chair Conformations on the Hetero 2,3-Dispiro Cyclohexanones ...... 46
4.3. Acid-Promoted Equilibration of the Syn and Anti Isomers ...... 48 4.4. Bond Distance (A) and Angles (deg) for 80 ...... 288 4.5. Final Fractional Coordinates for 80 ...... 289
4.6. Final Fractional Coordinates for 80 ...... 289
4.7. Thermal Parameters for 80 ...... 290 4.8. Bond Distance (A) and Angles (deg) for 81 ...... 290 4.9. Final Fractional Coordinates for 81 ...... 291
4.10. Final Fractional Coordinates for 81 ...... 292
4.11. Thermal Parameters for 81 ...... 293
4 .12. Bond Distance (A) and Angles (deg) for 83 ...... 293 4.13. Final Fractional Coordinates for 83 ...... 294
4.14. Final Fractional Coordinates for 83 ...... 295 4.15. Bond Distance (A) and Angles (deg) for 84 ...... 295 4.16. Final Fractional Coordinates for 84 ...... 296
4.17. Final Fractional Coordinates for 84 ...... 297 4.18. Bond Distance (A) and Angles (deg) for 85 ...... 297 4.19. Final Fractional Coordinates for 85 ...... 298
4.20. Final Fractional Coordinates for 85 ...... 299
4.2 1. Bond Distance (A) and Angles (deg) for 8 6 ...... 299
4.22. Final Fractional Coordinates for 8 6 ...... 300
4.23. Final Fractional Coordinates for 8 6 ...... 301
5.1. Bond Distance (A) and Angles (deg) for 98 ...... 302
5.2. Final Fractional Coordinates for 98 ...... 303
5.3. Final Fractional Coordinates for 98 ...... 303
6 .1. Results of Competition Experiments ...... 89
6 .2 . Bond Distance (A) and Angles (deg) for 160...... 304
6.3. Least-Squares Planes for 160...... 305
6.4. Final Fractional Coordinates for 160...... 306
6.5. Final Fractional Coordinates for 160...... 307
6 .6 . Bond Distance (A) and Angles (deg) for 173 ...... 307
6.7. Final Fractional Coordinates for 173 ...... 308
6 .8 . Final Fractional Coordinates for 173 ...... 309
ix LIST OF FIGURES
FIGURE PAGE
1.1. 1,4-Cycloheptadiene from the rearrangement of cis- and rronj-divinylcyclopropanes ...... 2
1.2. cis-Divinylcyclopropanes and their AG$act for Cope rearrangement ...... 3
1.3. Representation of homotropilidine (3) at 180 °C ...... 3
1.4. Reaction coordinate for semibullvalenes possessing negative transition states ...... 4
1.5. Novel semibullvalenes predicted to have negative transition state energies ...... 5
1.6 . Products of bromination of diketone 10 ...... 7
1.7. Product of Na I NH3 reduction of 10 ...... 13
1.8 . Results of NOE analysis of dimesylates 25 and 26 ...... 14
2.1. Examples of highly pyramidalized alkenes ...... 15
3.1. Bicyclic[3.2.0]heptatrienes and derivatives ...... 22
3.2. Examples of [lOJannulenes...... 23
3.3. Computer-generated perspective drawing of tribromo ketone 6 6 as determined by x-ray crystallography ...... 30
3.4. lH NMR spectrum of methoxy tetraene 6 8 ...... 32
3.5. Dienone 69, bicyclo[3.2.0]hept-l(5)-ene (70), and bicyclo- [3.2.0]hept-l(7)-ene (71) ...... 33
4.1. Acid-induced equilibrium of cyclohexanones 72 and 73 ...... 34
x 4.2. Chairlike conformations of syn- and anti-2,3-dispiro cyclohexanones...... 39
4.3. Computer-generated perspective drawing of the hetero 2.3- dispiro cyclohexanones as determined by x-ray crystallography ...... 40
4.4. Conformational preferences for 81 and 83 ...... 42
4.5. Conformational behavior of spirocyclic ether 91 ...... 51
4.6. Heteroatom participation in acid-induced ring opening ...... 54
5.1. Computer-generated perspective drawing of bromo ketone 98 ...... 59
5.2. Conformational preferences of bromo ketone 98 ...... 59
5.3. Diene 127, and structure confirmation of 128 ...... 64
5.4. ,3C NMR resonances of selected carbons of 144...... 68
5.5. MTAD cycloadducts of the propelladienes ...... 68
5.6. NOE enhancements for 146 and 147...*...... 69
6 .1. Cieplak Model explanation for nucleophilic attack on cyclohexanones ...... 73
6.2. Systems examined for facial selectivity ...... 73
6.3. 1,2-Dihetero dispiro cyclohexadienes ...... 75
6.4. NOE results for cycloadduct 156...... 79
6.5. Computer-generated perspective drawing of 160 as determined by x-ray crystallography ...... 80
6 .6 . NOE results for cycloadducts 161 and 163...... 81
6.7. NOE results for cycloadducts 167 ...... 84
6 .8 . NOE results for cycloadduct 169...... 85
6.9. NOE results for cycloadduct 170 ...... 8 6
6.10. NOE results for cycloadduct 171 ...... 87
xi 6 .11. NOE results for cycloadducts 172 and 173 ...... 87
6 .12. Computer-generated perspective drawing of 173 as determined by x-ray crystallography ...... 88
6.13. Order of reactivity for dienes with MTAD ...... 90
6.14. The two faces attacked of diene 175 ...... 91
6.15. Dienes 139 and 176 and their MTAD cycloadducts ...... 92
6.16. Schematic representation of the transition states for cycloadditions with dienes 102 and 108 ...... 93
xii LIST OF SCHEMES
SCHEME PAGE
1.1. Synthetic routes toward semibullvalene 9 ...... 6
1.2. Cyclopropanation attempts with 12 and 15 ...... 8
1.3. Deoxygenation of dione 10 via the Shapiro reaction ...... 9
1.4. Alternative preparation of dienes 17 and 18 ...... 10
1.5. Inversion of alcohols with sulfur nucleophiles ...... 12
2.1. Dicarbonyl coupling reaction of diketone 10 ...... 17
2.2. Synthesis of anhydride 36 ...... 17
2.3. Synthesis of dibromide 37 and diiodide 39 ...... 18
2.4. Synthesis and deuterium labeling of hydrocarbons 41 and 42 ...... 19
2.5. Diels-Alder trapping of alkene 33 ...... 20
3.1. Synthesis of ketone 52 ...... 25
3.2. Bromination/dehydrobromination of TMS-enol ether 57 ...... 26
3.3. Synthesis of bromo ketone 61 ...... 27
3.4. Synthesis and dehydrobromination of bromo ketone 62 ...... 28
3.5. Formation of dibromo ketone 65 and tribromo ketone 6 6 ...... 29
3.6. Synthesis of trienone 67 by dehydrobromination of dibromo ketone 65 ...... 31
3.7. Synthesis of methoxy tetraene 6 8 ...... 32
4.1. Proposed mechanistic pathway for racemization ...... 35
4.2. Synthesis of cyclohexanones 80 and 81 ...... 36
xiii 4.3. Synthesis of cyclohexanones 85 and 8 6 ...... 37
4.4. Resolution of cyclohexanones 72, 81, and 8 6 ...... 49
5.1. Synthetic methodology to access 2,3-dihetero dispiro cyclohexanones ...... 56
5.2. Synthesis of propelladienes 95 from dispiro dienes 94 ...... 57
5.3. Synthesis of diene 102 ...... 58
5.4. Synthesis of dienes 105 and 108 ...... 61
5.5. Synthesis of dienes 111 and 114 ...... 61
5.6. Synthesis of dienes 117 and 120 ...... 62
5.7. Synthesis of 125 and 126 from 102 ...... 63
5.8. Synthesis of 127 and 128 from 105 ...... 65
5.9. Synthesis of 138 and 139 from 114 ...... 6 6
5.10. Synthesis and chemical derivitization of disulfide 142 ...... 67
6 .1. Reactions of maleic anhydride with C 5~substituted cyclopentadienes ...... 74
6.2. Synthesis of diene 155 ...... 75
6.3. Cycloadditions of diene 105 ...... 78
6.4. Cycloadditions of diene 102 ...... 80
6.5. Cycloadditions of diene 117 ...... 82
6 .6 . Cycloadditions of diene 155 ...... 83
6.7. Cycloadditions of diene 111 ...... 84
6 .8 . Cycloadditions of diene 114 ...... 8 6
6.9. Cycloadditions of diene 108 with MTAD ...... 89
xiv Chapter I
STUDIES TOWARD THE SYNTHESIS OF PENTACYCLO- [7.2.1.04.H.06-9.06,10]Do d ECA-1,4-DIENE: A BIS- ANNULATED SEMIBULLVALENE
A. INTRODUCTION
Since 1940 when Cope and Hardy discovered that ethyl-(l-methypropenyl)- allyicyanoacetate rearranged completely at 150-160 °C to ethyl-(l,2-dimethyl-4- pentenylidenej-cyanoacetate1, there has been widespread use of 1,5-diene rearrangements in natural and unnatural product synthesis .2 The rapid isomerization of cis- diviny Icyclopropane3® to 1,4-cycloheptadiene has received considerable attention due to the significantly milder conditions necessary for its Cope rearrangement -3 Comparison of this behavior with that of the much less reactive trans isomer3b attests to the assistance the Cope rearrangement derives from the relief of ring strain as well as from the kinetic advantage of having the 1,2-vinyl groups syn to one another. In their report of the synthesis of cis- divinylcyclopropane, Brown and Golding calculated a free energy of activation of 20.6 kcal/mol for the rearrangement of l.3c The trans isomer rearranges only at more elevated temperatures, presumably either by initial isomerization to 1 , or by a diradical species 4
(Figure 1.1).
Before Doering’s synthesis of homotropilidene (2) in 1963,5 there were no reported examples of fully degenerate Cope rearrangements. Homotropilidene contains a c/s-divinylcyclopropane unit in its framework (Figure 1.2). Yet instead of its Cope rearrangement leading to a more thermodynamically favored product, its degenerate isomerization simply yields the starting material, capable of further rearrangement. The *H
1 Figure 1.1: 1,4-Cycloheptadiene from the rearrangement of cis- and trans- divinylcyclopropanes.
NMR spectrum of 2 at 20 °C is extremely broad and inconclusive, yet at -50 °C the signals are sharp and well defined. At 180 °C, the spectrum is again sharp, yet different from that obtained at -50 °C. The occurence of a degenerate rearrangement, which is occurring rapidly on the NMR time scale, explains these results. At -50 °C the sigmatropic process is slowed sufficiently for the NMR method to detect the cis tautomeric form, where the cyclopropane, olefmic, and allylic methylene protons are all distinguishable. At higher temperatures, the rearrangement is faster than the NMR time scale, yet not completely averaged, thereby explaining the broad spectrum at 20 °C. It is only at temperatures at or above 180 °C that one observes a completely averaged spectrum, having signals in a relative ratio of 2:4:2:2, corresponding to 3 (Figure 1.3).
The elegant synthesis of bullvalene 6 (4) confirmed Doering’s prediction that great benefit would be obtained by incorporation of a third double bond in homotropilidene, locking the divinylcyclopropane in the kinetically advantaged syn conformation .7 The rapid Cope rearrangement within 4 enables all of its protons to become equivalent on the
NMR time scale, apparent by its single proton absorption at S 4.2 at 100 °C. The energy of activation for the rearrangement for 4 is low indeed--AG* = 12.8 kcal/mol .7 This is a decrease of ca. 1 kcal/mol from that calculated for homotropilidene .8 3
1 2 4 ca. 20 kcal/mol (5-20 °C)3c 13 7 kcal/mol (-35°C )Sb 12.8 kcal/mol (100 °C)7 CH
CN NC 5 6 7 5.5 kcal/mol (143 °C)8 3.1 kcal/mol (T =-158 °C)14 4.5 kcal/mol (25 °C)15
Figure 1.2: cis- Divinylcyclopropanes and their AG*act for Cope rearrangement.
He
Ha
3
Figure 1.3: Representation of homotropilidene (3) at 180 °C.
Other conformationally locked cis divinylcyclopropanes were soon to follow bullvalene. These include barbaralane ,9 barbaralone,9®, and semibull valene . 10 Of these, the most attention has been accorded to semibullvalene (5). A dehydro analogue of homotropilidene, the energetics of the Cope rearrangement of 5 benefit from the loss of mobility of its vinyl units to a greater extent than does bullvalene. The free energy of 4 activation for rearrangement of 5 was found to be 5.5 kcal/mol, cu. 8 kcal/mol lower than that of 2 .8
EWG EWG EWG EWG
EWG EDQ EWG EWG EDG EWG
EWG EWG
0X 3 EWGEWG
Figure 1.4: Reaction coordinate for semibullvalenes possessing negative transition states.
Predictions by Hoffmann and Stohrer 11 as well as by Dewar and co-workers 12 suggest that appropriate substitution about the framework of 5 would cause the free-energy of activation to be lowered, and perhaps even inverted (Figure 1.4). This would allow “the ultimate of transition state stabilization--a negative activation energy ” 11 to be achieved. The practical result of this would be that even at low temperatures the rearrangement could not be stopped.
Experimentally, this proposal has found some support. The x-ray crystal structure of 1-cyanosemibullvalene was seen to exist solely with the cyano group on the cyclopropane . 13 This confirms that electron-withdrawing groups at Cl strengthen the C2-
C 8 bond of the cyclopropane ring. Furthermore, l,5-dimethyl-2.6- dicyanosemibullvalene 14 (6 ) and 1,5-dimethylsemibullvalenc1-'' (7) have free energies of activation for rearrangement of 3.1 kcal/mol (T = -158 °C) and 4.5 kcal/mol (T = 298 K),
respectively. Compound 6 has the lowest activation energy for Cope rearrangement of any
compound thus synthesized . 14
Further theoretical treatment of the problem has uncovered novel possibilities for
lowering aG*. According to Dannenburg and co-workers, calculations predict that the
pinched barbaralane 8 should possess a negative activation energy of -9.1 kcal/mol . 16
Similar calculations by Williams and Kurtz on bis-ethanoannulated semibullvalene 9 predict it to be even more stabilized (AHact = -9.4 kcal/mol)17(Figure 1.5). The carbon skeleton of
9 is familiar, as it is common to many polycyclic compounds in the literature , 18 being quickly assembled via the Domino Diels-Alder reaction between dihydrofulvalene and dimethyl acetylenedicarboxylate.18a'b This fact and the possibility of confirming whether predictions about this semibullvalene are true make 9 an interesting target for synthesis.
8 9
Figure 1.5: Novel semibullvalenes predicted to have negative transition state energies.
The known diketone 10 , 19 obtainable in four steps from the diester product of the
Domino-Diels-Alder reaction between 9,10-dihydrofulvalene and dimethyl acetylenedicarboxylate, served as starting material for the present synthetic plan. This compound possesses all twelve carbons already correctly assembled and requires only functionality modification to access 9. Originally the synthesis was to proceed along one of two linear paths (Scheme 1.1).
Route A was to advance via a diketo cyclopropane; subsequent introduction of the double bonds would yield 9 in a minimum of steps. A somewhat longer synthesis would involve
introduction of the cyclopropane later in the route via reductive coupling of a dibromodiene,2^ the product of either allylic bromination of a diene or by dehydration of a dibromo diketone (Route B).
Scheme 1.1: Synthetic routes toward semibullvalene 9.
Route A Route B 7 B. RESULTS
Diketone 10 was readily available by hydrogenation of the previously characterized doubly unsaturated precursor (95 % ).20 Heating 10 with two equivalents of copper(II) bromide in an ethyl acetate-chloroform solvent system 21 resulted in conversion to a mixture of monobromide 11 and dibromides 12 and 13. Chromatographic separation on silica gel provided pure samples in isolated yields of 42, 7, and 10%, respectively. Suitable distinction between the latter two isomers was achieved by l3C NMR analysis, the Cs- symmetric 12 giving rise to seven distinct signals and the C 2-symmetric 13 to only six.
Tribromo derivative 14 was produced at reasonable levels when the proportion of
CuBr2 was increased to 3 equivalents under otherwise identical conditions. To arrive at exhaustively brominated diketone 15, it proved most expedient to heat 1 0 with excess bromine in acetic acid (Figure 1. 6 ).
11 12 13
14 15
Figure 1.6: Products of bromination of diketone 10.
Establishment of the cyclopropane ring (Route A) was attempted by treatment of 11 with base. Reaction of the monobromide with DBU in acetonitrile2,b yielded none of the desired product. Instead the formation of very polar and insoluble solids was observed. 8 This behavior was also seen when KHMDS and KOBu( were used as base. Starting material was recovered when KH or NaOMe was used.
The use of dibromide 12 and tetrabromide 15 to access the mono- or di cyclopropane, respectively, was also investigated. Stirring of 12 with Nal in acetone 22 resulted in loss of the starting material and formation once again of highly polar products.
A similar result was obtained with 15. Furthermore, only decomposition of 15 resulted when it was reacted with zinc and EDTA 23 in aqueous ethanol (Scheme 1.2).
Scheme 1.2: Cyclopropanation attempts with 12 and 15.
O o
12 12
O ---- 3If------► o - M - , °
15
The other proposed pathway (Route B) converged at a dibromo diene either by allylic bromination of a diene or by elimination of a dibromo diketone. The volatile dienes 17 and 18 were obtained as products of the reaction of bis-tosylhydrazone 16 with nBuLi in TMEDA .24 Extraction of the dienes into pentane, chromatography on silica gel, and evaporation of the solvent at atmospheric pressure produced the dienes 17 and 18 in a
95:5 ratio, respectively (Scheme 1.3). The major product was assigned as 17 on the basis of the six signals in its 13C NMR spectrum. Compound 18 on the other hand would have seven. Attempts at allylic bromination of the mixture with NBS and AIBN ,25 both 9
thermally and photochemically, gave complex product mixtures with none of the desired product recognized.
Scheme 1.3: Deoxygenation of dione 10 via the Shapiro reaction.
TsNHNH2 TsHNN NNHTs TsOH. MeOH 10 16
1. BuLi, 16 TMEDA 2. H20 17 ( 95 : 5 ) 18
This failure and the inability to induce cyclopropane formation led to the examination of 12 and 13 as possible precursors to the dibromo diene. Wary of reductive
methods for transformation of the ketones to olefins, we did not make recourse to the
Shapiro reaction used above. Alternatively, a mild elimination process designed to retain the bromine substituents was pursued. A model study with the simple diketone 10 was examined first (Scheme 1.4).
Reduction of 10 with lithium aluminum hydride afforded the symmetrical diol 19 in good yield ( 8 6 %), as evidenced by its simple 4-line ,3C NMR spectrum and its characteristic broad IR absorption band (3600-3200). Double dehydration at this point would have yielded the dienes; yet when the bis-xanthate was pyrolyzed ,26 no dienes were obtained. To decrease the dihedral angle between the hydroxy substituents and their vicinal protons, inversion of alcohol stereochemistry by means of the Mitsunobu procedure 27 was 10
investigated. After numerous attempts with various methods, only decompositon of the diol was ever seen.
Scheme 1.4: Alternative preparation of dienes 17 and 18.
1. LiAIH4 0 = < li >=0 ------<5 >-y-* OH — .. ►- MsO../-<5 y V y.,OMs 2. H20 \___ ( c h 2 c i 2 \ __ / 10 19 20
1. NaNi 20 ------► CIHjN—C I >-NH,CI KHaOaN—C I >-N(CH3)3l DMF, 120 °C ~ x / 2. H2, Pd-C, \ ___ / NaHCOj \___ f EtOH / CHCI3 21 2. Mel 22
1 . IRA-400 resin, 22 ► H2 O 2. 100°C
Nucleophilic inversion was not abandoned however. Compound 19 was converted in 8 8 % yield to dimesylate 2 0 by reaction with methanesulfonic anhydride and pyridine ,28 the diagnostic singlet at 6 3.02 integrating for 6 protons and the symmetrical 5-line 13C
NMR spectrum confirming that both hydroxyls had reacted. Attempts at displacement of these leaving groups with KO 229 were fruitless, yet 2 0 did react with azide ion 30 to furnish bis-ammonium hydrochloride salt 21 (70%) after hydrogenation of the diazide in ethanol- chloroform solvent system .31 *H NMR analysis of 21 in DMSO revealed that the ammonium protons appear as a broad absorption centered at ca. 5 8 . Eschweiler-Clark methylation 32 of 2 1 followed by stirring in methyl iodide produced the quaternary ammonium iodide 22, displaying a broad singlet at 3.03 ppm for its 18 methyl protons. 11
The l3C NMR spectrum of 22 is almost identical with that of 21, except for an absorption
at 85.73 ppm belonging to the six equivalent methyl carbons on the nitrogen.
An aqueous solution of the bis-quaternary ammonium salt was eluted through a column of Amberlite IRA-400, an ion-exchange resin which had previously been made
basic, and was converted to the bis-ammonium hydroxide salt. This intermediate underwent Hoffmann elimination 33 when heated to afford the dienes 17 and 18 in a 2:1 ratio.
This success prompted application of this route to the dibromo diketones 12 and 13. Hydride reduction and mesylation went well, affording dibromo dimesylates 25 and
26 in 95% and 62% combined yields, respectively. We were disappointed, however, when all attempts to invert their oxygen-bonded centers with azide ion (sodium azide and
BU4NN 3)34 were unsuccessful. An attempt to eliminate 25 with DBU in benzene35, as well as with KOBut, only resulted in decomposition.
Another possibility lay in successful inversion of the carbinol centers with sulfur nucleophiles. When 19 was treated with diphenyldisulfide and tributylphosphine36, the monothioether 27, identified by its aromatic proton absorptions and OH infrared stretch, was the sole product obtained even after extended reaction times. Treatment of 27 with N- thiophenylsuccinimide and tributylphosphine 37 was more successful and gave in 63% yield the doubly inverted product 28 (Scheme 1.5). Again the results were not as rewarding with 25 and 26 under these conditions, with starting material being the only compounds recovered. Grieco, et al, has reported success at inverting alcohols with selenium.38c Therefore the seleno version of this reagent, N-phenylselenosuccinimide, was prepared .38 Heating it with tributylphosphine and 25 gave after three days largely recovered starting material, in addition to a small amount of a new compound. The 1H NMR spectrum of this product displayed absorptions Scheme 1.5: Inversion of alcohols with sulfur nucleophiles.
PhSSPh /AA. H O "< I /■" OH ------► HO"‘\ I > — SPh V S ^ Bu ,P
H O ..M -S . ^ W""' .
27 “o 28 & C ^801 ho '-< J L > -'O H N.R. w —B u,P & 23 o
,Br N -SePh HO*"< I > -'O H S.M. & ^\ / w O- o SePti B u 3P 24 THF
in the areas expected and in a ratio of 10:2:4:8, exactly as required for the desired product.
However, mass spectral and ,3C NMR analysis did not support this assignment. In actuality, the selenated tetrahydrofuran had formed instead.
The ability of dissolving metal reduction to produce different alcohol stereochemistry than hydride reduction is known .39 In an effort to access the diexo diol, diketone 10 was stirred with sodium in ammonia. A diol was obtained, and initial analysis indicating that it was a symmetrical diol different from 19. Ultimately, the product was shown to be pinacol 29, resulting from coupling of a biradical intermediate (Figure 1.7 ).40 13
^ E s b T OH OH 2 9
Figure 1.7: Product of Na / NH 3 reduction of 10.
C. DISCUSSION
While semibullvalene 9 has yet to be synthesized, many new and interesting polycyclic intermediates have been prepared, and much has been learned about this system and how it relates to 9. For example, failure to form the cyclopropane early in the project suggested that the strained [ 2 . 1.0 ] system might not be easily accommodated (ie, too high in energy) in such a conformationally locked system. This supports a prediction that neither of the classical structures represented in Figure 1.4 would be thermodynamically favored, causing 9 to instead exist as a homoaromatic hydrocarbon or as a biradical . 17
The framework in some ways seems to work against acquiring 9. An example is the allylic bromination of 17 and 18. There are three (for 18) and four (for 17) additional allylic sites for bromination which can compete with the positions desired. The Mitsunobu reaction also failed. This perhaps may have been due to steric crowding on the underside of the skeleton. Cook, et al, 41 have also found similar resistance to elimination (and inversion of alcohol stereocenters) on an almost identical system.
Dibromo diols 23 and 24, as well as their mesylates, failed to undergo inversion with azide, sulfur, and selenium nucleophiles. Perhaps this is due to shielding by the bromines of the backside of the carbon-oxygen bond, successfully preventing Sn2 reaction.
Hydride reduction of the dibromo diketones does work, however, possibly offering future hope for small nucleophiles. Since inversion was so difficult and since the bromine atoms 14
are so large, one might assume that reduction had proceeded from below the molecule to
yield the diexo dibromo diols. This possibility was quickly disproven, as n.O.e. results
convincingly show that both 25 and 26 have their oxygens oriented endo (Figure 1.8).
Compound 25 clearly shows respectable enhancements between the hydroxy a-H and the
Cl 1 protons (2.5%). With 26 the same is true, with enhancements of 1.5% and 2.5% being observed.
Figure 1.8: Results of NOE analysis of dimesylates 25 and 26. Chapter II
GENERATION AND CHEMICAL TRAPPING OF A BIS(ETHANO) DERIVATIVE OF TRICYCLO[3.3.0.03*7]OCT- 1(5)-ENE: THE CONSUMMATE MEMBER OF A SERIES OF PYRAMIDALIZED ALKENES42
A. INTRODUCTION
Tricyclo[3.3.0.0 3*7]oct-l(5)-ene (30) is the consummate member of a homologous series43 of pyramidalized olefins 44 which have been studied. The hydrogenation energy of
30 is calculated to be greater than that of the unbridged alkene, bicyclo[3.3.0]oct-l(5)-ene, by fully 70.6 kca 1/mol ,45*46 and to exceed even those of cubene 3145‘47 and homocub-
4(5)-ene 3246*48 by 11.9 and 5.1 kcal/mol, respectively(Figure 2.1).
30 31 32 33 n = 0
Figure 2.1: Examples of highly pyramidalized alkenes.
The very high olefin strain energy 45- 49 (70.6 kcal/mol) computed for 30 is due largely to the weakness of the highly pyramidalized “n” bond in this olefin, which is calculated to have a dissociation energy of only 13.3 kcal/mol 50 This bond dissociation energy (BDE) is 52.9 kcal/mol less than the calculated ‘V ’ BDE of bicyclo[3.3.01oct-l(5)-ene, 9.7 kcal/mol less than the “n” BDE of cubene 31, and 4.6 kcal/mol less than that of homocub-
4(5)-ene 32.50*52 The calculated energy difference between the singlet 46 and the lowest
15 16
triplet state **1 of 30 is only 14.8 kcal/mol. This energy separation is 11.3 kcal/mol smaller
than that computed for 3 153*1 and just 4.5 kcal/mol larger than that calculated 533-*5 for 1,4- dehydrocubane.53ac
Alkene 33 may be regarded as a bis(ethano) derivative of 30. Not surprisingly,
therefore, calculations using the AMI semiempirical method 54 predict very similar
geometries for the double bonds in 30 and 33 and heats of hydrogenation that differ by
only 1 kcal/mol .55 The ease of preparing the skeleton of 33 by a domino Diels-Alder
reaction ,56 followed by catalytic hydrogenation and hydrolysis of the diester cycloadduct to
access diacid 34,56b make 33 a potentially more easily accessible synthetic target than 30.
Moreover, in addition to being a potentially readily preparable derivative of 30, 33 can be
regarded as a dehydro derivative of jyn-sesquinorbomene,57a in which the additional C-C
bond in 33 enforces pyramidalization in the opposite sense to that found in the latter
hydrocarbon.44’57*5^
B. RESULTS AND DISCUSSION
Access to 33 by via carbonyl coupling 58 was first investigated (Scheme 2.1).
When 10 was stirred with TiCl 3(DM E)i.5 and Zn/Cu in refluxing DME58d in the presence of the Diels-Alder trapping agent 35 59 for 6 h, only 35 was recovered,
In anticipation that an alkyllithium might add across the newly formed double bond ,44*47*48 the heating time was shortened to 2 h and and rm-butyllithium was added to the cooled reaction mixture for 30 min. The product formed was not a hydrocarbon, but rather diol 29, identical in all respects to the product of Na/NH 3 reduction of dione 10 .60
The best yield (72%) resulted after a heating time of 3.5 h. Lack of any evidence that the alkene had formed suggests that the McMurry reaction stops at the diol stage without eliminating to form the double bond. 17
Scheme 2.1: Dicarbonyl coupling reaction of diketone 10.
TiCIjfDME), 5. Zn/Cu. ______Decomposition DME. reflux,
10 1.TiCI3(DME)LSi Zn/Cu, 35 DME, reflux 2. t-BuLi, -78 °C
| OH OH CfCHafe 29 42 not detected
Compound 36 was synthesized to see whether 33 could be obtained by CO 2/CO extrusion .61 Simple heating of the diacid 34 in thionyl chloride afforded the anhydride in good yield ( 6 6 %) (Scheme 2.2). The promise this route might hold was suggested by the mass spectrum of 36, in which no parent peak was detected, being replaced by a fragment of mass 186 (M+ - CO2).
Scheme 2.2: Synthesis of anhydride 36.
SOC1 reflux 18 As an alternative, dihalides 37 and 39 were made. The disilver dicarboxylate of diacid 34 was heated in CCI 4 with either bromine or iodine to yield dibromide 3756b and diiodide 39,62 respectively, as mixtures with bromochloride 38 and chloroiodide 40
(Scheme 2.3). The mixtures were easily separated by preparative gas chromatography, and their identities were assigned by ,3C NMR analysis as well as by mass spectrometry.
Dihalides 37 and 39 had a simple l3C NMR of 4 absorptions, whereas 38 and 40 each displayed seven.
Scheme 2.3: Synthesis of dibromide 37 and diiodide 39.
1. A gN 03, KOH, H.O
c o 2h CO2H 65 °C Br Br 34 37 38 1. AgNQ3, KOH. H ,0
CO^H 65 °C 34 39 40
Treatment of either dibromide 37 or diiodide 39 with excess /m-butyllithium afforded two volatile products, the reduced hydrocarbon 4156b and the rer/-butyl adduct 42 in ratios that ranged from 1:20 from the reaction of 39 in 1:1 ether/pentane at 0 °C to 1:2.4 from the reaction of 39 in THF at -78 °C (Scheme 2.4). The reduction product 41 was identified by comparison of its ’H NMR spectrum with that reported in the literature
[(CDCI3, 220 MHz) 5 1.48 (s, 10 H), 2.15 (s, 6 H)],56b and this structural assignment was confirmed by the appearance of only four peaks in the 13C NMR spectrum 63 [(CDCI3,
75 MHz) ppm 52.93 (CH), 48.19 (CH), 46.35 (CH), 25.75 (CH2)]. The 'H NMR 19
spectrum of 42 [(CDCI3, 300 MHz) 8 2.15 {s. 4 H), 2.03 (d, J = 2 Hz, 2 H), 196-1.91
(m, 2 H), 1.54-1.52 (m, 1 H), 1.50-1.41 (m, 6 H), 1.03 (s, 9 H)] was less useful than the
I3C NMR spectrum [(CDCI 3, 75 MHz) ppm 57.47 (C), 57.36 (CH2), 53.76 (CH2), 48.72
(CH), 48.16 (CH), 33.31 (C), 28.95 (CH3), 27.25 (CH2), 23.06 (CH2)J in establishing
the structure. Selective 'H NMR decoupling showed that the unique proton in 42 at 8
1.54-1.52 is attached to the tertiary carbon that appears at 48.72 ppm.
Scheme 2.4: Synthesis and deuterium labeling of hydrocarbons 41 and 42.
/ J E z b I Br 2 . H 20 I H | h Br H C(CH ^ 3 37 41 42
1:20 (ether/pentane, 0 °C) 1:2 (THF, -78 °C)
T B r 2. d 2o T D | D B r H C(CH ^ 3
37 41-di 42-d1
When the reaction of 37 with fm-butyllithium was repeated and D20 was used to quench the reaction mixture, mass spectral analysis 64 showed that only one deuterium was incorporated into both 41 (45% d\) and 42 (35% d\). In the 2H NMR spectrum of the 42-d\ thus formed, only one deuterium resonance (5 1.54) was observed, and the proton- decoupled 13C NMR spectrum of this material showed the peak at 48.72 ppm to be split into a triplet (7 = 22 Hz) by this deuterium. 20
These spectral data establish that in 42-r/j deuterium is incorporated in the fashion
expected from formation of 33. followed by addition of excess rerr-butyllithium across the
pyramidalized double bond6S and quenching of the resulting organolithium species by deuterium capture. Similarly, the observation that 41 incorporates just one deuterium suggests that this product may be formed by reduction of 33, either by transfer of an electron into its very low-lying LUMO ,46 followed by hydrogen atom abstraction, or simply by transfer of hydride. In either case, just one deuterium would be incorporated on workup, whereas two deuteriums would presumably be incorporated if 41 were formed by double lithium-bromine exchange of 37 ,66 instead of via the intermediacy of 33.
The formation of 33 was confirmed by trapping of the olefin in a Diels-Alder reaction with diphenylisobenzofuran (DPIBF, 45 ).67 Reaction of 39 with a 20% excess of n-butyllithium in THF at -78 °C in the presence of 1.2 equiv of DPIBF led, after workup and column chromatography on silica gel, to a quantitative yield of an adduct.
Recrystallization from hexane/CH 2Cl2 afforded an 80% yield of white needles, mp 222.5-
223.5 °C. Both the *H and ,3C NMR spectra of this material were wholly consistent with the formulation of its structure as 46, that expected from a Diels-Alder reaction between 45 and 33 (Scheme 2.5).
Scheme 2.5: Diels-Alder trapping of alkene 33.
1. n-BuLi, THF, -78 °C,
46 45 21 Our finding that, despite the very weak n bond expected in 33, this highly
pyramidalized alkene can be generated in solution and lives long enough to be intercepted chemically suggests that it may be possible to obtain 33 using matrix isolation conditions
and also to trap it as a (Ph 3P)2Pt complex. The success of these two additional experiments, which are planned, would allow an assessment of how the additional pyramidalization in 33 causes its IR and UV spectra and the ,3C NMR spectra of its
(PlvjP^Pt complex to differ from those measured for higher homologues of 30.43-68-69 Chapter III
PROGRESS TOWARDS THE SYNTHESIS OF TRICYCLO[4.4.1.04.*»]. UNDECA-1,3,5,7,9-PENTAENE VIA BROMINATION- DEHYDROBROMINATION METHODOLOGY
A. INTRODUCTION
Breslow, Washburn, and Bergman reported in 1969 on the synthesis of bicyclol3.2.0]hepta-l,3,6-triene (47), an unstable compound that dimerized rapidly upon formation (Figure 3. 1).70 Deuterium capture by the anion (49) gave 47-dj, structural assignment to which was supported by the symmetric dideutero dimers that resulted .71
3
Fe(CO)3
47 48 49 50
Figure 3.1: Bicyclic[3.2.0]heptatrienes and derivatives.
Quenching 49 with acids of various strength allowed an approximate pKa of 29 to be determined. This value is 11 units higher than that of cyclopentadiene. Because of the antiaromatic character of cyclobutadiene, the destabilization of the anion by the cyclobutadiene-containing resonance forms of 49 was postulated to be the cause of this high pKa value.
22 23 The isomeric bicyclo[3.2.0]hepta-1,4,6-triene (48), on the other hand, was more s ta b le . 72 Synthesized by Bergman and co-workers by pyrolysis of 1,2- diethynylcyclopropane, 48 was isolated as an oil which was stable in solution for days at 0
°C, but was reactive toward oxygen and polymerized in neat form. As with 47, the same results were obtained upon deprotonation—protonation at C5 and dimerization .73
Metal complexation of triene 48 was achieved using Fe 3(C O )i2.74 Heating this compound with 1.1 equiv of the organometallic in hexane afforded the complex 50 that contained a cyclobutadiene ligand. The double bonds within bicyclic triene had rearranged, yet association with the metal resulted in increased stability, decreasing the molecule’s tendency to polymerize.
A possible method for the study of these unstable trienes would be to incorporate them into a larger carbon skeleton. Tricyclo^^.l.O 4’1 ^undeca-l^SJ^-pentaene (51) contains the bicyclo[3.2.0]penta-l,3,6-triene unit, yet the 4 and 6 positions have been joined by a 1,3-butadiene tether (Figure 3.2). The known ketone 52,75 which is available in just three steps from cyclohexenone and has the carbon framework suitably assembled with functionality present, would be an excellent starting material to attempt the synthesis of 51.
51 53 54
Figure 3.2: Examples of [10]annulenes. 24
Pentaene 51 is an example of a [ I0]annulene ,76 compounds that are potentially aromatic, but for which planarity causes severe strain or steric interactions. Such
derivatives exhibit many of the physical and chemical properties of aromatic systems.
Examples include Vogel’s l,6-methano[10]annulene (53 ),77 as well as 7b-methyl-7b//-
cyclopent[cJ]indene (54 ).78 Their NMR spectra reflect the presence of a diamagnetic
ring current, observed in the downfield shifts of the peripheral protons (6 7.4-8.2) and a
marked upfield absorption of the metheno and methyl protons above the ring at 8 -0 .5 and
-1.67 for 53 and 54, respectively. Furthermore, the delocalization of electrons is
manifested, even when complete planarity is not possible, by the equivalence of the bond lengths among the conjugated carbon atoms.
A synthesis of pentaene 51 was attempted in order to examine the nature of the
bicyclo[3.2.0]pentatriene unit within the molecule, in addition to determine the extent of
conjugation about the annulene. Endowed with a single sp 3 hybridized carbon atom, the
target molecule might also enable information to be obtained concerning its anion, cation,
or radical. This report summarizes the progress made toward synthesizing 51 exercising
successive bromination-dehydrobromination reactions to introduce unsaturation.
B. RESULTS
Ketone 52 was prepared in a manner similar to that reported earlier .79 80
Photolysis of cyclohexenone and methoxyallene 81 in ether for 24 h yielded bicyclic ketone
55 in 76% yield as approximately a 1:1 mixture of endo and exo methoxy groups.
Addition of vinylmagnesium bromide in THF at -60 °C to this mixture afforded a 2:1 mixture of endo and exo methoxy alcohols (56), respectively, in 54% isolated yield. The typical doublet of doublets splitting pattern in the *H NMR was seen for the vinyl proton at 5 5.98 (56a) and 6 5.89 (56b). Treatment of the mixture under anionic oxy-Cope reaction conditions 82 gave the desired ketone 52 as the only product (65%) (Scheme 3.1).
Scheme 3.1: Synthesis of ketone 52.
MgBr,
THF, -60 °C OM e ether,-78 OM e 76% 55 54% 56a: endo ratio = 1:1 56b:exo ratio = 2 :1 endorexo
1. KH, 18-crown-6,
THF, 65 °C OMe 2. H20
56a,b 65% 52
Before work-up of the reaction mixture, the enolate of 52 could be captured as its silyl enol ether 57a. Attempts to transform this derivative into the a,P-unsaturated ketone using Pd(OAc) 283 or DDQ 84 resulted in decomposition. The enones 59 and 60 were prepared instead by LiF-Li 2C0 3 dehydrobromination 85 of an a-bromo ketone, the product of bromination of 57a with N-bromosuccinimide (39 % ).86 A key feature of a-bromo ketones such as 58 is that the proton geminal to the halogen usually appears as a doublet of doublets in the NMR spectrum (5 4.59 for 58). This facet along with the presence of an additional tertiary carbon atom 63 downfield (57.43 ppm) in the ,3C NMR spectrum was very helpful for identification (Scheme 3.2). 26
Scheme 3.2 Bromination and Dehydrobromination of TMS-enol ether 57.
HQ KH, K+ 0 18-crown- 6, R^SiCI
OMe THF, 65 X
56 57
(a) R 3 = ButMe2
(b) R3= Me 3
LiF, NBS, Br 57 LijCOy m propylene oxide. powdered glass, // THF, OX HMPA, 85-90 °C 58 59 60 T = 3 h: ratio = 1:2(40%) T = 5 h: ratio = <3:9720%)
The dienones 59 and 60 were separated chromatographically as closely eluting compounds on silica gel. The *H NMR spectrum of 59 contained typical enone coupling, as well as a singlet absorption for the cyclobutene alkene proton at 6 5.81. Isomer 60 possessed similar spectra, yet the three olefinic protons were mutually coupled, indicating that the double bond of the cyclobutene had moved into conjugation. Additional evidence was the quaternary olefinic carbon resonance seen far down field (152.39 ppm) in the 13C
NMR spectrum, representing the terminal carbon of dienone conjugation. This product is perhaps the more thermodynamically stable of the two isomers, for after heating the bromo ketone with LiF and Li 2C0 3 in HMPA and powdered glass for 3 h, a 40% yield of a 1:2 mixture of 59 and 60, respectively, was obtained. After 5 h of heating, only 60 persisted
(2 0 % yield). 27 Iterative use of this reaction was attempted. To induce formation of the thermodynamic enolate of 58, the bromo ketone was stirred with HMDS and TMSI for 12
h ,87 then treated as usual with N-bromosuccinimide in THF with propylene oxide. Instead
of the expected dibromo ketone, the product isolated in 38% yield was isomeric with
starting material. The *H NMR spectrum did not show the usual doublet of doublets (ca 6
4.5) implicating an a-bromo ketone, nor was any quaternary absorption in the ,3C NMR
spectrum observed to indicate formation of the isomeric a ’-bromo ketone. COSY, CH- correlation and selective DEPT 45 experiments identified the product as bromo ketone 61
(Scheme 3.3). Apparently compound 58 was dehalogenated by the TMSI and underwent subsequent allylic bromination to afford 61. Small NOE enhancements associated with the proton geminal to the bromine indicate that the bromine is on the p-face of the molecule.
Scheme 3.3: Synthesis of bromo ketone 61.
1. HMDS, TMSI 2. NBS, propylene oxide, 58 H THF, 0°C 38%
Synthesis of the isomeric a ’-bromo ketone 62 was achieved by bromination of the
TMS-enol ether(s) derived from the parent ketone 52 (Scheme 3.4). Interestingly there was no preference for one a-position over the other when 52 was deprotonated. A mixture
(ca. 1:1) of 58 and 62 was obtained regardless of whether thermodynamic conditions
(Et3N, TMSC1, DMF or /-Pr 2NMgBr/Et20 )88-89 or kinetic conditions (LDA, THF, -78
°C) were used. This behavior contrasts with the results of the oxy-Cope process discussed above, where the sole product of silylation and bromination was 58. Spectral support for 28
the new bromo ketone included the quaternary carbon absorption at 69.73 ppm in the I:,C NMR spectrum. On this basis, the bromine must reside at the desired tertiary position.
Scheme 3.4: Synthesis and dehydrobromination of bromo ketone 62.
1. LDA, -78 'C Br< 2. TMSCI, Et3N
3. NBS, propylene oxide, 52 58 62 THF, 0 LiF, LijCOj. powdered glass, HMPA, 85-90 °C 62 32% 63 64 not detected Dehydrobromination of 62 produced in 32% yield the dienone 63, which contained a double bond exocyclic to the seven-membered ring. Two trisubstituted olefinic carbons were evident by NMR analysis. Isomer 64, which possesses only one trisubstituted olefin and which appears to be extremely strained by models, was not detected. Examination of the progress to this point was not encouraging. The yields were not high and the bromo ketones and enones synthesized tended to decompose quickly. If 51 were to be constructed using this methodology, increased levels of unsaturation had to be introduced more rapidly. Attention again turned to the synthesis of dibromo ketone 65. A pathway involving enolization/bromination of 58 was not followed as preferential deprotonation was predicted 29 to occur at the already brominated carbon. This undesirable outcome could be avoided, however, by using bromo ketone 62 where only one enolate is possible. The bromination of the TMS-enol ether of 62 proceeded smoothly to afford 65 in 67% yield (Scheme 3.5). This compound displays the typical doublet of doublets in the 'H NMR at 6 4.40 as observed for 58, and also had a quaternary carbon at 66.33 ppm as seen with the isomeric 62. The double elimination of this dibromide would incorporate three of the double bonds required in the target 51. In order to direct all resources toward this compound, bromo ketone 58 was recycled to the parent ketone 52 by stirring with Nal and TMSC1 in acetonitrile .90 Additional 62 was then acquired by the subsequent enolization/bromination sequence. Scheme 3.5: Formation of dibromo ketone 65 and tribromo ketone 66. o 1. LDA, -78 °C 2. TMSC1, Et,N 3. NBS. propylene oxide, 62 THF, 0 °C 66 67% 44% Unwanted formation of the tribromide 6 6 complicated matters, for it was the sole product of bromination of the TMS-enol ether of 62 on numerous occasions, even when only one equiv of NBS was used. It was found that the conditions for TMS-enol ether isolation were crucial for determining those products that had formed. When the THF was evaporated and the TMS-enol ether extracted into pentane from the precipitated lithium chloride, solvent evaporation and bromination gave almost exclusively the tribromide 6 6 (44%). If the TMS-enol ether solution was instead poured into saturated aqueous NaHCC >3 solution and extracted into ether, evaporation of the solvent and NBS bromination afforded 30 the desired dibromide 65, free of any tribromide. The structure of 6 6 was difficult to ascertain from NMR and mass spectral analysis, with all of the data suggesting a species having a molecular formula of C| i H ] jB^O, impossible by mass spectral rules .91 X-ray crystallographic analysis solved the mystery, showing unambiguously that three bromines were present (Figure 3.3). Cl c» cu CIO c* CJ Cl Figure 3.3: Computer-generated perspective drawing of tribromo ketone 6 6 as determined by x-ray crystallography. Dehydrohalogenation of 65 with LiBr and LiC 0 3 in dimethylacetamide 92 at 150 °C gave the trienone 67 in poor (17%) yield. Greater yields were found to result using LiBr instead of LiF and dimethylacetamide, which was less toxic than HMPA and less prone towards decomposition than DMF. As expected, six trigonal carbon resonances were seen in the 13C NMR spectrum (two quaternary, four C-H) in addition to the carbonyl and four alkyl carbons. Contrary to the results with dehydrobromination of 58, NMR analysis determined that no conjugated coupling existed between the enones and the cyclobutene 31 olefin, confirming that the cyclobutene double bond had not moved into conjugation. Enone 63, the product of dehydrobromination of 62. was a side product (10% ) resulting from reductive loss of one bromine atom (Scheme 3.6). Scheme 3.6: Synthesis of trienone 67 by dehydrobromination of dibromo ketone 65. o o o LiBr, U 2CO3, Dimethylacetamide, 150 °C 65 67 63 17% 12% Trienone 67 proved to be very unstable, decomposing over a period of days at 0 °C. In an attempt to induce isomerization to the tropone, 67 was stirred with RhCl 3 3 H2O in ethanol,93 yet decomposition of the trienone occurred. Further progress toward 51 was pursued. A cooled (-78 °C) solution of 67 and HMPA (2 equiv) in THF was treated with KHMDS (1.3 equiv) for 15 min followed by quenching of the enolate with methyl triflate (2.5 equiv)94. Evaporation of the solvent and chromatography on Florisil furnished methoxytetraene 68 in 40% purified yield. Five well-separated absortions belonging to the olefinic protons dominated the ]H NMR spectrum (Figure 3.4). The cyclobutene protons appeared at 8 3.25, farther upfield than usual due perhaps to a combination of strain and its allylic nature. The methoxy methyl absorption (8 3.2) and the two methylene protons (8 2.4 and 1.75) complete the spectrum. C. DISCUSSION Of the compounds synthesized, tetraene 68 has been by far the closest to the target compound 51, possessing four of the Five necessary sites of unsaturation. This polyolefin 32 Scheme 3.7: Synthesis of methoxy tetraene 6 8 . O 1. KHMDS, HMPA. THF. -78 °C 2. CH^OTf 67 68 * 4* * *• 4 t i m * m 1 1 H t ft I « * *» i «• t 99 9H i m Figure 3.4: 1H NMR spectrum of methoxy tetraene 68. was quite sensitive as expected, polymerizing rapidly upon exposure to air or when neat, yet was found to be stable for days frozen in benzene. The strain in this tricyclic system is evident by the low yields and rapid decomposition of products observed throughout the study. Use of a double dehydrobromination reaction to obtain 67 was low yielding, yet preferable over a stepwise 33 procedure which would have involved a-bromo enones. species predicted to be extremely sensitive. Although not pursued, N-bromosuccinimide bromination of 52 would most likely have produced the ally! bromo ketone 61. Dehydrobromination of this intermediate possibly would have produced the dienone 69 (Figure 3.5), which can be envisaged as a way to access the other necessary olefin using similar chemistry. As appealing as this route may seem, calculations on the less strained systems 70 and 71 suggest that the bridgehead alkene would not be as stable located between the C 1 and C7, preferring instead to reside between Cl and C5 by 3.8 kcal/mol .95 Perhaps any conjugative stabilization derived from 51 would allow observation of this structure, which has so far been obtained only as its Diels-Alder cycloadduct with diphenylisobenzofuran .96 o 69 70 71 Figure 3.5: Dienone 69, bicyclo[3.2.0]hept-l(5)-ene (70) and bicyclo[3.2.0]hept- l(7)-ene (71). Chapter IV ANALYSIS OF THE CONFORMATIONAL NATURE, RESOLVABILITY, AND THERMAL RACEMIZATION OF HETERO 2,3- DISPIRO CYCLOHEXANONES A. INTRODUCTION Recent development of the oxonium ion-initiated pinacol rearrangement 97 as a tool for the directed synthesis of polyspirocyclic tetrahydrofurans 98 has resulted in the discovery of a concise synthetic entry to the hetero 2,3-dispiro cyclohexanones 72 and 73. When heated in chloroform solution containing a catalytic quantity of p-toluenesulfonic 72 73 Figure 4.1: Acid induced equilibrium of cyclohexanones 72 and 73. acid, 72 and 73 undergo mutual equilibration, ultimately favoring 73 at equilibrium (Keq = syn/anti = 0.56).99 This reversible chemical transformation constitutes an epimerization that operates within a framework constructed of two vicinal quaternary carbon centers. One possible way to rationalize this isomerization on mechanistic grounds is to invoke a push-pull fragmentation involving electron flow from the p-oxido atom to the protonated carbonyl as in 74. The tethered oxonium ion-enol pair 75 results (Scheme 4.1). Rotation of either terminus of the chain relative to the other prior to intramolecular recyclization provides the enabling means for losing stereochemical "memory". 34 35 Scheme 4.1: Proposed mechanistic pathway for racemization. & o 74 75 76 Several facets of this pathway invite systematic investigation. For example, since both 72 and 73 are chiral while 75 is not, optically enriched samples of either ketone should experience racemization under the conditions of equilibration. The issue of heteroatom dependence also surfaces. Are both oxygens necessary? What observable kinetic consequences would accompany systematic replacement by sulfur? Another concern is whether the electron flow depicted in 74 and 76 is more favorable when the C- O and (see below) C-S bond is projected axially or equatorially. We now report an extended study of several congeners of 72 and 73 that defines their conformational properties in the solid (by crystallographic analysis), liquid (by NMR methods), and gaseous state (by molecular mechanics calculations). Several of these dispiro cyclohexanones have been resolved and subsequently isomerized to determine if racemization operates concurrently. Finally, consideration is given to a pair of electronic interactions that necessarily operate in these molecules. The first is the interaction that occurs between the carbonyl group and the immediately neighboring hetero atom. Also relevant are the lone-pair interactions between the electronegative substituents themselves, a dihedral angle dependence to which has previously been recognized . 100 These effects may 36 operate cooperatively or be inimical to each other. When the latter condition prevails, it becomes possible to gain an appreciation of which interaction is overriding. B. RESULTS 1. Synthetic Considerations. The preparation of monospirocyclic ketone 77 has been described previously.98b The conversion of this intermediate to 80 and 81 demanded that 2,3-dihydrothiophene be capable of C-5 metalation as in 78 and that carbinol 79 be amenable to conversion to its thionium ion as a prelude to Wagner- Meerwein 1,2-shift (Scheme 4.2). The method developed by Sosnovsky for the synthesis of 2,3-dihydrothiophene was adopted . 101 Our expectation that the deprotonation of this unstable heterocycle to give 78 would be uncomplicated was founded on the ease with Scheme 4.2: Synthesis of cyclohexanones 80 and 81. Dowex-50X 80 81 which acyclic vinyl sulfides undergo a-proton abstraction with alkyllithium reagents . 102 Indeed, the conversion to 78 with fer/-butyllithium in THF at -78 °C proceeded as readily as with 2,3-dihydrofuran . 103 Conversion to the vinyl cerate was implemented so as to curb non-productive enolization . 104 37 Thionium ions are known to play a useful role in electrophilic aromatic substitution reactions and are considered to be less stabilized and more electrophilic than oxonium ions . 105 106 Notwithstanding, when 79 was stirred with Dowex-50X resin in CH 2CI2 at rt for 24 h, isomerization to a 1:4.4 mixture of 80 and 81 occurred. The less polar anti isomer was readily separated from its syn counterpart by silica gel chromatography. As will be discussed, the stereochemical assignments to these ketones follow from definitive spectroscopic and crystallographic evidence. Scheme 4.3: Synthesis of cyclohexanones 85 and 86. 1. 78. THF -78 “C u 2. Dowex-30X THF, -78 *C CHjCIj , rt 2. Dowex-50X CH jClj.rt 82 S3 CeCI2 82 + THF. -78 °C 2. Dowex-50X CH 2CI2 , rt 85 86 In approaching a synthesis of the regioreversed isomers 83 and 84, we focused again upon sequential introduction of the hetero spirocyclic rings, with initial acquisition of 82. This ketone is readily obtained by exposure of commercially available cyclobutanone to 78 and subsequent acid-catalyzed rearrangement as before (Scheme 4.3). The second- 38 stage ring expansion proceeded with high efficiency (96% combined yield) to deliver a more equitable distribution of the syn and anti stereoisomers (1:1.24). When 82 was reacted instead with the dihydrothiophene cerium reagent 107 and the resulting carbinol exposed to Dowex-50X resin, 85 and 86 were produced without complication ( 6 8 %, ratio 1:1.2 ). 2. Solid-State Structural Studies. The X-ray derived three-dimensional features of 72 have been reported earlier.98b This analysis established that its cyclohexanone core adopts a well-defined chairlike arrangement. However, in contrast to expectations based upon the minimization of electrostatic interactions between the carbonyl group and the flanking polar C-O bond , 108’109 the a-electronegative substituent was disposed equatorially. Adoption of this arrangement demands, of course, that the p C-O linkage be projected axially as in A (X=Y=0) (Figure 4.2 ) .110 Diastereomer 73 could not be induced to crystallize. All six ketones prepared in the course of this investigation proved to be highly crystalline solids well suited to X-ray crystallographic analysis. Several intriguing structural features have been made evident as a result. As seen in Figure 4.3, the syn isomers 80, 83, and 85 do not share with 72 a common preference for conformation A. Rather, all three ketones feature an axial a-hetero substituent as in B, irrespective of whether X represents oxygen or sulfur. One consequence of this behavior is the mandatory equatorial disposition of Y. The relevant X-C-C-Y dihedral angles adopted across the syn series (see Table 4.1) are informative in connection with the gauche effect 100 as discussed subsequently. Inspection of the crystallographic data indicates further that when X is axially oriented, the bond linking the carbonyl group to C(4) is somewhat lengthened relative to that seen in the lone equatorial example 72 (Table 4.1). In line with precedent, the interconnective carbon-carbon bonds in the X-C-C-Y units become longer as the progressive change from oxygen to sulfur is made. 39 A B C D Figure 4.2: Chairlike conformations of syn- and anti-2,3-dispiro cyclohexanones. It is noteworthy that the structural results involving anti isomers 81, 84, and 86 constitute a cohesive conformational profile in which a well-defined cyclohexanone chair uniformly has both electronegative atoms oriented axially as in C. Although crystal packing forces must be considered, the uniformity of solid-state conformation suggests that steric and electronic factors combine to render C more thermodynamically stable than D. Both C-S bond lengths in 8 6 are considerably shorter than they are in 85 and the other sulfur-containing congeners (Table 4.1). This may be a reflection of the significant disorder encountered in 81 and 8 6 . 3. Solution Conformational Studies.111 Although the NMR spectra of the ketone pair 80/81 in both CDCI 3 and C&D6 at 300 MHz exhibit considerable overlap, each revealed vicinal coupling patterns indicative for adoption of a unique chair-like cyclohexanone conformation, i.e., clearly distinguished axial (diaxial 37 = 12-14 Hz) and equatorial (all -V = 2-5 Hz) protons. Chair-like conformations are further supported by diagnostic W-couplings between the equatorial cyclohexanone a- and y-protons in both compounds (12-Heq/14-Heq, 4./h.H = 1.5-2 Hz). Additionally, the deshielding experienced 40 80 81 83 8 4 85 8 6 Figure 4.3: Computer-generated perspective drawings of the hetero 2,3-dispiro cyclohexanones as determined by x-ray crystallography. 4] Table 4.1: Relevant Crystallographic Details.a X-C-C-Y ______hond lengths. A dihedral angle, dcg C(4)-C(5) C(4)-C(9) X-C(4) Y-C(9) /n series: 72 57.3 1.536(3) 1.526(3) 1.423(3) 1.453(3) 80 -60.4 1.525(9) 1.557(3) 1.858(3) 1.426(2) 83 -58.0 1.539(5) 1.545(5) 1.444(4) 1.848(3) 85 -56.9 1.535(4) 1.554(3) 1.859(3) 1.848(3) nti series: 81b - 176.4 1.54(2) 1.55(1) 1.84(1) 1.45(1) 84 -178.1 1.536(7) 1.545(6) 1.457(5) 1.844(4) 86b -176.1 1.540(7) 1.541(7) 1.804(4) 1.811(4) a See representation A in Figure 4.2 for atomic numbering. b Significant disorder observed. by the axial six-membered ring protons relative to their geminal equatorial partners provided key information about the disposition of the hetero atoms. In both compounds, significant deshielding of the axial protons a to the carbonyl is observed (for 80: 12-Hax/6 2.98, 12-Heq/5 2.24; for 81: 12-Hax/6 2.86, 12-Heq/5 2.28). This phenomenon is construed to be a clear indication of their 1,3-diaxial relationship to the sulfur atom. A similar deshielding operates on the axial p-proton in 81 ( 13-Hax/5 1.90, 13-Heq/5 1.34) as a consequence of its 1,3-diaxial relationship to the ether oxygen (see E, Figure 4.4). The corresponding effect is absent in 80 (13-Hax/S 1.42, 13-Heq/5 1.84). 42 12 HH EF Figure 4.4: Conformational preferences for 81 and 83. In line with these assignments, both compounds show a very large chemical shift anisotropy of the geminal pair of protons in the y-position of the tetrahydrothiophene ring (for 80: 10-HeXo^ 2.46, 10-Hendo/5 1.64; 81: 10-HCXO/S 2.82, 10-Hendo/S 1.26). This effect results from placement of the respective exo proton on the equatorially-oriented C-10 methylene group directly in the deshielding core of the carbonyl group. Although the remaining protons of 80 and 81 could be located by DQF-COS Y and HETCOR methods, signal overlap precluded detailed investigation of NOE interactions involving most of the stereochemically relevant protons. Nevertheless, two diagnostic enhancements were observed for 81 that confirm the two heterocyclic rings to be fixed anti as depicted in E: H-10endo{H-4endo) = 1.5% and H-4cndo{H-10endo} = 1%. Ketone 80 lacked the corresponding enhancements. The fairly crowded *H NMR spectra of 85 and 8 6 could be fully assigned from 400 MHz DQF-COSY and HMQC spectra in C 14-Hax/6 1.88, 14-Heq/6 1.65) and large shift anisotropy of those tetrahydrothiophene y- protons proximal to the carbonyl (for 85: 10-Hexo/5 2.66, 10-Hendc/6 1.97; for 8 6 : 10- 43 Hcxo/8 3.08, 10-Hcmio/6 1.43) serve to define axial orientation of the sulfur atom a to the carbonyl. In line with these assignments, deshieding by a 1,3-diaxial relationship to sulfur is also observed for the axial cyclohexanone p-proton in 86 (13-Hax/6 1.90, 13-Heq/8 1.44). This effect is absent in 85 (13-Hax/8 1.21, 13-Heq/8 1.28), where the respective heteroatom is oriented equatorially, as is further confirmed by a diagnostic W-coupling (14-Hax/5 2.26, 4-Hendo^8 t -29; 4^h,H = 1 Hz) that requires axial attachment of the C-4 methylene group. Supporting NOE studies were not feasible for 85 and 86, since all of the more relevant protons are located in highly crowded regions of their *H NMR spectra. The 300 MHz lH NMR spectrum of 83 in C 6D6 solution was sufficiently well resolved to permit detailed conformational analysis following its complete assignment based on DQF-COSY, RCT-COSY, and HETCOR methods. Again, characteristic vicinal coupling patterns and well-defined W-coupling (11-Heq/13-Heq, 4^h,h = 2 Hz) served to define a unique chair-like cyclohexanone conformation. As before, a further W-coupling (4^H,H - 1-5 Hz) involving 11-Hax (8 2.46) and 10-Hendo (8 113) is considered diagnostic for axial attachment of the associated methylene group and thus for equatorial orientation of the sulfur atom. In further confirmation of the F geometry, axial protons 13-Hax (8 2.90) and 11- Hax (8 2.46) are strongly deshielded relative to 13-Heq (5 2.03) and 1 1-Hcq (8 1.66) as a result of the close proximity of the first pair to oxygen. The chemical shift of 4-Hcxo (8 2.56) relative to 4-Hend0 (8 1.84) requires it to be experiencing strong carbonyl anisotropy. Finally, the observation of the transannular NOE interactions H-4exo{H-10encioK H- 4endo{H-10endol, H-10endo{H-4Cndo} and H-8e„do{H-4endo) (all at approximately 2%) are in complete agreement with the chemical shift and scalar coupling arguments given above. 44 In all of the above examples where strong preference for conformations B and C is obvious, the structures adopted in solution appear essentially identical to those present in the solid state. In contrast, the dioxygen compounds 72 and 73 clearly do not adopt unique chair- like conformations in solution. For both compounds, the observed vicinal coupling patterns reflect the time-averaging of the axial and equatorial positions in the cyclohexanone core (for 72: 12-H, 5 2.69, J = 9.5, 6.5 Hz; 12-H, 8 2.06, J = 6.5, 6.5 Hz; 13-H, 8 1.71, J = 6.5, 6.5, 6.5, 5 Hz; 13 -H, 8 1.14, J = 10, 9.5, 5.5, 4.5 Hz; 14-H, 8 2.05, J = 10, 5 Hz; 14 -H, 8 1.32, J = 6.5, 4.5 Hz; for 73: 12-H, 8 2.47, J = 8 , 5.5 Hz; 12’-H, 8 2.12, J ~ 8 , 5.5 Hz; 14-H, 8 1.70, J = 8 , 4 Hz). Furthermore, several broad resonances in the lH NMR spectrum of 72 at 25 °C (400 MHz/CeDg) that sharpen upon warming to 60 °C provide direct evidence for a dynamical exchange process. Evaluation of the coupling information available for 72 permits attribution of greater axial character to H-12, H-13’, and H-14. The downfield shifts of H-12 (vs H-12'), H-14 ( v j H-14') and the contrasting upfield position of H-13’ ( v j H-13) combine to indicate a preference of 72 in solution for conformation B with an axially oriented a-heteroatom. The alternative option A is preferred in the solid state. A considerably lower activation barrier for conformational exchange must be operative for 73 where all 1H-resonances are already fully time-averaged (sharp) at 25 °C (400 MHz/C6D6). Furthermore, the virtually identical vicinal splitting patterns observed for the geminal 12-H/12-H pair indicate the two interconverting conformers of 73 to be roughly equivalent energetically. As a noteworthy, more subtle manifestation of dynamic exchange between two chair-like conformers, W-coupling is observed for both 12-H (4^H,H = 1 Hz; to 14-H) and 12-H (Vh.h = 1 Hz; to 14'-H, 8 1.52). In this context, it is interesting to recall that 73 is the only compound in the entire series that could not be induced to crystallize. 45 4. Assessment of the Relative Stabilities by Molecular Mechanics Calculations. MM2 calculations ' 12 were also performed on each of the eight structures. Geometries preminimized on MODEL version KS 2.99 1 l3a were individually subjected to a multiconformer run that encompassed all three rings. Over 55 conformations were generated and minimized in each instance in order to ensure proper identification of the global minimum energy conformer. The MMX program (version 90.000) was then utilized to optimize the lowest energy chair conformations of the two possible chair arrangements. The calculated energies have been compiled in Table 4.2. " 3b The effect of the a-hetero atom in the syn series is seen to exert a strong preference for adoption by the cyclohexanone ring of chair conformation B. The extent to which B is favored over A ranges from 2 to 4 kcal/mol and appears to be only modestly dependent on the specific nature of X (O or S). We therefore conclude that the chair conformation with X axial and Y equatorial is energetically optimal and that the adoption by 72 of conformation A in the solid state is a likely consequence of energetic overriding by an unaccounted electronic effect since crystal packing forces are unlikely to contribute a discrepancy as large as 2.6 kcal/mol. In this regard, it is relevant that the calculated difference in kcal/mol between 72A and 72B in the gas phase is on the more modest end of the scale. The data gathered for the anti isomers shown in Table 4.2 reveal a dominance of conformer C over D to a level that exceeds 5.5 kcal/mol in the case of the disulfur system 8 6 . Thus, the energetic rewards of positioning both X and Y as axial substituents can be substantial and certainly adequate to make C the only observable structure for 81, 84, and 8 6 on the NMR time scale and in adopted crystalline forms. As a lead-in to the equilibration experiments, it is appropriate to point out the calculated energetic relationships between each syn/anti isomer pair. In the absence of solvation effects, we see that the anticipated arrangement of hetero atoms provides for a 46 Table 4.2: MM2-Derived Strain Energies, Heats of Formation, and Total Energies for the Two Chair Conformations on the Hetero 2,3-Dispiro Cyclohexanones. Compound Conformer AEstrain- kcal/mol AETotal< kcal/mol Syn series: 72 A 14.7 31.6 B 12.5 29.4 80 A 17.3 28.8 B 13.4 24.8 83 A 15.0 26.5 B 12.8 24.3 85 A 15.7 22.7 B 12.6 19.7 Anti series: 73 C 11.7 2 8 .6 D 15.4 32.3 81 C 12.4 23.9 D 17.3 28.8 84 C 11.8 23.3 D 15.3 26.8 86 C 11.3 18.3 D 16.9 2 4 .0 47 greater level of intrinsic stabilization. For 72B/73C, the difference in AEtola| amounts to only 0.8 kcal/mol, while for 85B/86C, this disparity climbs to 1.4 kcal/mol. 5. Acid-Catalyzed Syn/Anti Equilbration Studies. The standard conditions adopted for the equilibration experiments involved refluxing a chloroform solution of the isomerically pure ketone in the presence of a catalytic quantity of p- toluenesulfonic acid for extended periods of time. The resulting two components in the isomeric mixture were separated chromatographically and accurately weighed to assess their distribution. Exposure of 72 to the standard conditions for 31 h has previously been shown to produce a 1:1.8 mixture of 72 and 73. When beginning with 73 (21 h reaction time), a comparable syn/anti ratio (1:1.9) was realized (Table 4.3). Accordingly, the anti isomer is clearly favored thermodynamically, with aG °334 residing within the limits of 0.39-0.43 kcal/mol. Analogous processing of 80 and 81 revealed their equilibration to proceed more slowly, such that heating for 96 h did not result in arrival at the true equilibrium position. However, recovery of the ketones remained high. As a consequence, it is possible to surmise that the anti isomer is again the thermodynamic sink and by a factor somewhat larger than that governing the dioxygen example (0.55-0.78 kcal/mol, Table 4.3). When a sulfur atom is resident |J to the ketone carbonyl as in 83-86, the rates of isomerization are further depressed. Thermal degradation of the substrates was seen to be kinetically competitive and recovery levels in the 40-60% range became the norm. Despite the fact that complete equilibration could not be realized because of these complications, it is still apparent that mutual isomerization does operate. The predominance of 85 in the product mixtures resulting from the heating of either 85 or 8 6 in an acidic environment must be viewed with caution. It is possible and even 48 Table 4.3: Acid-Promoted Equilibration of the Syn and Anti Isomers. Starting Ketone reaction time, h syn/anti ratio total % recovery AG°334. kcal/mol 7 2 31 1: 1.8 ----- 0.39 73 21 1:1.9 83 0.43 8 0 96 1:2.3 96 0.55 81 97 1:3.25 83 0.78 8 3 456 2 .22:1 49 a 8 4 456 1:8.63 43 a 85 183 1.86:1 52 a 8 6 183 1.2:1 60 a a Incomplete equilibration with concurrent decomposition of the substrates. likely that 86 degrades more rapidly under these experimental conditions than does 85. Such behavior would obviously skew the final results improperly. 6. Resolution of 72, 81, and 86. Racemization under Acidic Conditions. All three ketones were resolved through application of Johnson's sulfoximine method 114 (Scheme 4.4). Addition of the optically pure carbanion derived from the (S)-(+)-enantiomer to 72 afforded four diastereomers after chromatographic separation in isolated yields of 37%, 24%, and 10% (the last is a mixture of the opposite facial isomers). Since knowledge of the absolute configurations was unimportant, definitive stereochemical assignments to the adducts and to the ketones recovered from the thermal degradation of 87 and 88 were not pursued. Heating the pure major sulfoximine adduct, [a£° +44.8°, in toluene furnished optically pure dextrorotatory 72, [a]^ +54.1°. 49 Similar processing of the second most prevalent diastereomer arbitrarily labeled as 8 8 afforded 72 having the opposite configuration, (a]D -52.8°.20 Scheme 4.4: Resolution of cyclohexanones 72, 81, and 86. Ph NCHiII <+>-ch ,~ -IIs— Ph HO,„ o 72 n-BuLi THF. -78 °C 87 88 toluene. reflux o 'O [ « $ +54.1° [aft -52.8 CrhN = S = 0 NCHiII (+J-CH,— Ph ______O toluene 81 r -BuLi THF. -78 °C [ a f t +83.8° C H jN asg^ NCH, II <+>-CHi —S—II Ph ______O toluene R-BuLi THF. -78 °C 90 [a ft -120.1° 50 In related experiments, 81 was transformed via 89, [a]p +38.2°, into its dextrorotatory enantiomer, [a]p° +83.8°. Lastly, the disulfur series was represented by the acquisition of (-)- 8 6 , [ a ] ^ - 121 .8 °. When the antipodal samples of 72 were heated in CHCI 3 containing catalytic amounts of p-toluenesulfonic acid for 19 h, complete racemization was observed in both cases. Neither the syn nor the anti isomer recovered from these reactions exhibited any vestige of residual rotatory power. That (+)-81 was equally subject to ready racemization was apparent after its exposure to p-toluenesulfonic acid in hot chloroform for 24 h. Ensuing chromatographic separation and purification by crystallization returned an anti stereoisomer that exhibited an [<*]d of 0! When the dithia analogue (->-86 was comparably treated for a similar period of time, the rotation of recovered 8 6 had dropped to -33.0°. As expected, the syn isomer 85 produced under these conditions was substantially less optically active, [a]D +3.6°.20 Clearly, the disufur compounds racemize more slowly. C. DISCUSSION 1. The 2-Heteroatom Ketone Effect. The issue of conformational preferences for 2 -substituted cyclohexanones has provoked considerable interest and attention. As early as 1955,1 15 it was recognized that an increase in the steric size of a 2- alkyl substituent was met with an enhancement in the level of the axial conformer. The 2- alkyl ketone effect, as this phenomenon is now known,116'] 17 is attributable to the allylic 1,3 strain that develops between the carbonyl oxygen and R group . 108 While the consequences of R = methyl are rather negligible, progression to ethyl and isopropyl has been shown via equilibration experiments to destabilize the equatorial conformer by 0.7 kcal/mol and 1.7 kcal/mol, respectively . 118 51 A change in (he nature of R to a polar substituent superimposes the added factor of dipole-dipole interaction. First studied with 2-halocyclohexanones,10K the consequences of enhanced electrostatic repulsion is also to destabilize the more polar equatorial conformer, as long as the solvent polarity is not especially elevated. For heptane solutions of 2- bromo-, 2 -chloro-, and 2 -fluorocyclohexanone, the axial conformer dominates to the extent of 85%, 76%, and 48%, respectively . 119 Under comparable conditions, the axial conformers of 2 -methoxy- and 2 -methylthiocyclohexanone are favored to the extent of 6 3 % l08 b an(j 7 0 % respectively .120 This preference is dictated by the minimization of steric and dipole-dipole interactions, as well as hyperconjugative effects of the type oc-x n* c=o and no -» 7t*c=Ol21 in conformance with the generalized anomeric effect . 122 Similar considerations have been invoked to explain conformational interactions in 2- hetero-substituted methylenecyclohexanes. 123,124 When spiro heterocyclic rings are involved, consideration must also be accorded to the counterbalancing of diaxial nonbonded steric compression (Figure 4.5). Thus, 91 Figure 4.5: Conformational behavior of spirocyclic ether 91. quantitation of the conformational behavior of 91 in CS 2 solution at 35 °C has shown the O-axial isomer to predominate (- 6 8 % ).125 This preference, which corresponds to aG°308 of 0.46 kcal/mol, has been logically rationalized in terms of the relief in syn-axial compression that materializes between HA/HD and HB/HC when the oxygen atom is projected axially. No deformation of the cyclohexane chair was detected following X-ray crystallographic analysis of derivatives of 91. Since the A values for ethyl and methoxy 52 are 2.1 and 0.6 kcal/mol, respectively, the preference for the O-axial isomer is seen to be less than additive. This arises presumably because of bending within the five-membered ring of either O or CH 2 away from and Hg, with the larger CH 2 deriving the larger benefit. A doubling of the number of resident spirocyclic rings as in the present series of compounds introduces added nonbonded steric ramifications that must be similarly addressed. Relevantly, our X-ray diffraction results confirm that no deformation of the cyclohexanone chair materializes. 2. The Gauche Effect of Vicinal Polar Bonds on Six-Membered R ings. Originally discovered in connection with studies aimed at establishing the conformational preference of substituted ethanes , 126 the pronounced tendency of highly electronegative substituents to adopt a gauche relationship has been subjected to detailed quantum-mechanical analysis . 127 Zefirov and his co-workers have been predominantly responsible for extending this field into the realm of tr a n s - 1 , 2 -disubstituted cyclohexanes . 128 For the usual repulsive dipole-dipole reasons, this class of compounds should prefer to position both X and Y axially. However, this spatial arrangement lacks all vestiges of the gauche effect, which can only materialize when the diequatorial conformer is reached. Through adaptation of the Hill equation for subtracting out steric effects , 129 the Russian workers have shown that while strongly electronegative oxygen substituents exert added electrostatic attraction (the gauche effect), atoms of the second period such as sulfur actually experience heightened repulsion. The consequences of placing two trans-related ether oxygens on a cyclohexane ring are to favor the gauche relationship present uniquely in the diequatorial conformer. The tendency for the equivalent structure substituted with two sulfur atoms is to project the hetero atoms as distal as possible. The O/S interaction is also slightly repulsive in nature . 1083 53 3. Counterbalancing of Electronic and Steric Interactions in Hetero 2,3-Dispiro Cyclohexanones. Since the subclass most relevant to the preceding discussion involves the anti isomers 81, 84, and 8 6 , their uniform preference for adoption of conformation C (Figure 4.2) is analyzed first. A minimum of three salient factors needs to be considered in evaluating the strong bias disfavoring the diequatorial arrangement D. The first involves the minimization of nonbonded steric interactions. From the dynamic conformational behavior of the simple spirocycle 91, it has been determined that the magnitude of the multiply-directed 1,3-diaxial interaction to the ring methylene group is 0.46 kcal/mol. On this basis, the intuitive expectation is that D would be sterically destabilized relative to C by roughly 0.7 kcal/mol because of the additive contributions of three approximately equivalent interactions. This value is considerably smaller than the steric energies derived by MM2 methods (Table 4.2) and may therefore be an under estimate because other non-bonded interactions stemming from the proximal five- membered rings have not been factored in. The second effect that adds to the preferred stabilization of C is the minimization of the carbonyl-a-hetero atom dipole-dipole interaction. We estimate the magnitude of the favorable energetic interaction arising from adoption of this geometry to be 0.3 kcal/mol. That is, the full extent of the axial preference seen in 2-methoxycyclohexanone is taken as operational in 84. Since the experimental data for 2-methylthiocyclohexanone is comparable, the energy values for 81 and 8 6 should be entirely similar. The gauche effect contributes too little to override the steric and dipole contributions. 130 The trends evident in the syn series suggest that the energetic differences between conformers A and B are more closely balanced. Ketones 72 and 83 are particularly noteworthy in this regard. While the adoption of conformation B might well decrease the energy content because of the onset of the 2 -heteroatom effect, the facility with which 72 adopts conformation A is most readily rationalized by invoking an additional effect 54 involving the p-hetero atom. Does the equatorial orientation of Y in B introduce an interaction that is especially unfavorable when X and Y are strongly negative oxygen atoms? Since 80 and 83 do not share with 72 any detectable tendency to exist as conformer A, it may well be that atoms mismatched in their electronegativity do not give rise to an equivalently significant effect. 4. Heteroatom Control of Racemization at Two Vicinal Quaternary Carbons. Turning finally to the acid-catalyzed stereoinversions experienced by these ketones, we wish to draw attention to the rate retardations that accompany the introduction of sulfur at X, Y or X/Y in tandem. Protonation of the carbonyl oxygen is recognized to be met with the buildup of positive charge at carbon without significant change in the the sp2- hybridization at that center. The two issues of interest focus on Y and center about: Q H Figure 4.6: Heteroatom participation in acid-induced ring opening. (a) a possible orientational dependence to the relative ease of responding electronically at the electron-deficient center (as indicated by the electron flow in G and H); and (b) a detectable inherent difference in the ability of oxygen and sulfur to proceed to open-chain oxonium- and thionium-ion intermediates, respectively (see Scheme 4.1). The experimental data that has been gathered (Table 4.3) suggest that the kinetic requirement for suitable stereoelectronic alignment can be met in both the syn and anti isomers without significant buildup of steric strain. 55 Heteroatom effects are quite a different matter. C=S+ p-d overlap is well known to be much less favorable than C=O+,10S as evidenced by the ease of acid hydrolysis of acetals relative to mono- and dithioacetals. As a consequence, ketones 72 and 73, those substrates substituted by two tetrahydrofuran rings, lose stereochemical "memory" most rapidly. Replacement of the a-oxygen by sulfur has demonstrable rate-retarding ramifications. Formation of a thionium ion is yet more difficult to accomplish in 83-86. I C hapter V HETEROATOMIC EFFECTS ON THE ACID-CATALYZED REARRANGEMENTS OF DISPIRO[4.0.4.4] TETRADECA-11,13-DIENES A. INTRODUCTION Oxonium ion-activated pinacol rearrangements 131 have established themselves as synthetically useful reactions , 132 particularly when utilized in a reiterative mode . 133 Negri has reported, inter alia, that twofold addition of 5-lithio-2,3-dihydrofuran and -thio- phene 134 to cyclobutanone constitutes a highly efficient synthetic entry to cis- (92) and /rans-hetero 2,3-dispirocyclohexanones (93)133a (Scheme 5.1). Heterocyclic compounds of this general type have been scrutinized as to preferred conformation.,33d Once resolved, Scheme 5.1: Synthetic methodology to access 2,3-diheterodispiro cyclohexanones. 92 93 these ketones undergo acid-catalyzed epimerization and racemization, thereby establishing their ease of fragmentation to tethered onium ion-enol pairs and the ready recombination of these achiral intermediates . 13341 As part of a program designed to develop our base of knowledge surrounding polyspirocyclic heteroatomic systems, the cyclohexadienes corresponding to 92 and 93 have now been prepared. First to be surveyed was the response of cyclic conjugated 56 57 olefins of type 94 to acid-catalyzed rearrangement . 1-15 In the course of this study, the discovery has been made that conversion to a previously unknown type of [4.4.4]- propelladiene, viz., 95, can be achieved from either isomer of 94 (Scheme 5.2). An aromatization pathway also operates and this paper details the mechanistic basis of these Scheme 5.2: Synthesis of propefladienes 95 from dispiro dienes 94. 94 95 carbocationic processes as well as the role played by oxygen and sulfur atoms in channeling the possible competitive reaction alternatives. B. RESULTS 1. Preparation of the Spirocyclic Dienes. Although the major focus of this study was a detailed examination of the manner in which dihetero substituted systems respond to acid-catalyzed rearrangement, an important reference point involved the presence of a lone oxygen atom in the spirocyclic network. Ketone 96, previously described by Krieger, et al .,136 has provided the means for the direct acquisition of 102 starting from cyclopentanone (Scheme 5.3), Condensation of 96 with the cerate derived from 5-lithio-2,3-dihydrofuran133d was necessary in order to curtail in a significant way the tendency of this ketone to undergo enolization . 137 The resulting carbinol proved quite amenable to ring expansion simply upon being stirred with Dowex-50 ion exchange resin in CH 2CI2 at rt. This process led to the isolation of 97 in 91% yield. When the monobromination of 97 with pyridinium hydrotribromide in THF at 0 °C was found to give a 4.75:1 distribution of a-bromo stereoisomers, curiosity as to the preferred direction of electrophilic capture prompted the chromatographic separation of 98 58 Scheme 5.3: Synthesis of diene 102. ' O . i - O - O A s TTsOH.sOH.QH, C. THF. -78 X '' 2. Br(CH3)4Br,BrfCH 2. Dowcx-50, CH,CN CH2CI2, rt 3. H ,6 + 96 Br.„ + 97 98 99 LiBr. Li2COj C H £ O N M e2, I70°C (<-Bu )2A1H CHj|Ct2 101 100 NOs ,OaN - d - SCI • E t3N. CICHjCH jCI.A 102 from 99 and submission of the minor diastereomer to X-ray crystallographic analysis. Two important issues emerge from the ORTEP diagram of 99 depicted in Figure 5.1. The more obvious is the cis relative stereochemistry of the bromine and oxygen substituents. This observed product distribution reveals that the more reactive enol conformation of 97 must be A (Figure 5.2), with axial attack by the positive bromine source occurring on the face of the six-membered ring opposite that occupied by the equatorially disposed ether 59 oxygen. Once B is produced, conformational chair-to-chair interconversion can occur to deliver C. Since 2-bromo- and 2-methoxycyclohexanones both prefer to exist as the axial conformers and to appreciable levels (85%138 and 63%,139 respectively), conformation B may well be favored for the trans isomer. The geometry adopted by cis-99 in the crystalline state projects both the bromine and oxygen atoms equatorially (see Fig. 5.1). This particular bias would appear to be sterically driven . 13315 Figure 5.1: Computer-generated perspective drawing of bromo ketone 98. B C Figure 5.2: Conformational preferences of bromo ketone 98. 60 In the ensuing dehydrobrominations, both stereoisomers gave evidence of reacting equally well. These substrates delivered 100 in good yield upon being heated with lithium bromide and lithium carbonate in dimethylacetamide (DMA) at 170 °C for the purpose of introducing the conjugated double bond. Reduction of 100 with diisobutylaluminum hydride in CH 2CI2 proceeded to give an inseparable 2.3:1 mixture of ally lie alcohols 101. Subsequent treatment of this mixture with 2,4-dinitrobenzenesulfenyl chloride and triethylamine in refluxing 1,2-dichloroethane 140 provided 102 in 57% yield. In view of the established sensitivity of this sigmatropic rearrangement-elimination sequence to steric effects, 141 it is highly probable that 1 0 2 is produced with rather different efficiencies from its two stereoisomeric precursors. The structural assignment to 102 rests securely on its 300 MHz *H NMR spectrum which consists, inter alia, of two vinyl proton multiplets each of area 2 at 6 5.80-5.72 and S 5.70-5.61, a pair of protons a to the ether oxygen which are well separated (8 3.77-3.70 and 3.67-3.60) as a consequence of their appreciable chemical nonequivalence, and two protons from the adjoining cyclopentane ring (8 2.47-2.37 and 2.03-1.92) which are strongly differentiated by virtue of their divergent spatial relationships relative to the magnetic anisotropies generated by the oxygen center and diene n network. A comparable sequence has proven effective in gaining access to the dioxa dienes 105 and 108 (Scheme 5.4). The only significant change was recourse to the Luche procedure 142 for effecting the 1,2-reduction of 104 and 107. This process does not bring the diastereofacial aspects of allylic alcohol production under control but greatly facilitates workup. Notably, 104 and 107 respond quite differently toward the NaBH 4 -C eC l3 complex. In the syn dioxa example, the two carbinols are produced in a 6 .8 :1 ratio. When the oxygen atoms are disposed trans, a closer correspondence is seen between the two isomers (1.4:1). No effort was expended to ascertain the relative stereochemistry either of these alcohols or of their a-bromo ketone precursors. 61 Scheme 5.4: Synthesis of dienes 105 and 108. u 72 104 105 73 107 108 u Py*HBr3, THF. h UBr, Li2C 03. DMA. renux. ‘ NaBH4, CeCI^HjO. d 2,4-(NOj),C6H3SC1. Et3N, CICH2CH2CI. renux. The route followed in Schemes 5.3 and 5.4 is not viable for the production of sulfide congeners of 105 and 108 because of the reactivity of divalent sulfur toward electrophilic brominating agents such as Py*HBr 3. For this reason, arrival at the oxathia dienes 111 and 114 required that ketones 85 and 84 be converted into enones 110 and 113 by the action of N-bromosuccinimide on the respective trimethylsilyl enol ethers 86 under conditions where propylene oxide served as a buffer. These conditions gave the a- Scheme 5.5: Synthesis of dienes 111 and 114. 83 no in 84 113 114 u LDA, THF; M e3SiCl. Et3N. h NBS. propylene oxide. THF. ' LiBr. LiiC 03, DMA. renux. ‘/NaBH4. CeCI3»7HjO. CH,OH. ' 2.4-(N0‘ >,C6H3SCI. Et,N. CICH,CH,CI. rcfiux. * 62 bromo derivatives of 83 and 84 in 9 4 % and 9 9 % yield, respectively (Scheme 5 .5 ) . In keeping with this successful series of reactions, the syn and anti dithia ketones 85 and 8 6 were satisfactorily transformed into dienes 117 and 120 by comparable means (Scheme 5 .6 ) . These products proved to be crystalline solids with good shelf stability. In fact, none of the dienes exhibited sensitivity to oxidation or some alternative destructive process when stored under standard laboratory conditions for prolonged periods of time. Scheme 5.6: Synthesis of dienes 117 and 120. 85 116 117 86 119 120 ° LDA, THF; Me3SiCI, Et3N. * NBS, propylene oxide. THF. r LiBr, Li2C 0 3, DMA, reflux. d NaBH*. CeCl3*7H20, CH3OH. ' 2,4-{Nd^)2C6HjSCl, Et3N, C lC H jC H p. reflux. 2. Acid-Catalyzed Rearrangements. A systematic investigation of the fate of the structurally and stereochemically varied cyclohexadienes described above under acidic conditions was next undertaken. After preliminaty experiments demonstrated that certain rearrangement products did not stain well on thin layer chromatography, the decision was made to follow the progress of these reactions directly in the probe of an NMR spectrometer. Although a variety of options can be envisioned for the selection of a catalyst, recourse was made throughout to the use of p-toluenesulfonic acid in CDCI 3 solution. Following exposure of 102 to approximately 8 mol percent of /?-TsOH at 25 °C, no remaining diene could be detected by ’H NMR after 5 min. Chromatography of the sample on silica gel led to the isolation of propellane 126 and alcohol 125 in a 2:1 ratio. In a formal sense, these isomerizations are consistent with initial bond heterolysis within the protonated dispiro ether 121 to generate pentadienyl cation 122 (Scheme 5.7). Arrival at this intermediate sets the stage for two possible 1,2-Wagner-Meerwein shifts labelled as a and b, both of which lead to dismantling of the second spirocyclic center. Adherence to path a gives rise to 123, irreversible proton loss from which results in the establishment of benzenoid aromaticity. Pathway b defines an alkyl migration that eventuates in the generation of a new quaternary carbon center as in 124. Intramolecular nucleophilic attack by the hydroxyl oxygen completes the conversion to 126. Scheme 5.7: Synthesis of 125 and 126 from 102. 64 The reproducibility with which 102 experiences such rearrangement has made it abundantly clear that the b process is kinetically favored. Although inspection of molecular models of 1 2 2 has not provided us with a convincing rationale for this contrasteric migratory preference, it was considered important to ascertain how a second hetero atom might impact on the course of events. H H H 127 128 129 Figure 5.3: Diene 127, and structure confirmation of 128. Comparable treatment of 105 furnished a 1.1:1 mixture of 127 and 128 in good yield. The trans dioxa diene 108 responded in an identical manner, both systems requiring approximately 2 h to be completely consumed. The Cs symmetry of 127 was apparent from its 9-line 13C NMR spectrum and the appearance of four distinctive olefinic proton signals at 300 MHz. The structural features assigned to 128 were confirmed on the basis of NOE experiments in which the two pairs of benzylic protons were separately irradiated (Figure 5.3). In both experiments, an integral enhancement was observed for the signal arising from the neighboring aromatic proton. On this basis, the isomer 129 can be dismissed from further explicit consideration. The mechanistic profile likely followed by the dioxa isomers is diagrammed in Scheme 5.8. In these examples, we have obtained no evidence indicating that the ether oxygen atom in 131 enters into 1,2-migration. Furthermore, the near-identical amounts of 127 and 128 suggest that the need to involve oxonium ions 132 and 133 brings the mechanistic options a and b closer into balance. 65 Scheme 5.8: Synthesis of 127 and 128 from 105. OH 132 133 | - H + j-H* 128 127 The oxathia dienes 111 and 114 offer attractive chemical elements designed to probe still more deeply into these mechanistic issues. The presence of both an oxygen and a sulfur atom provides the opportunity to determine which C-X bond heterolysis will initiate the reaction cascade. Beyond that, the intervention of less electronically favorable 134 thionium ions should offer further indication if the competitive a/b migratory profile can experience increased selectivity. Isomerization of 111 or 114 under the influence of p-TsOH in CDCI 3 solution ultimately gave rise to a lone isomeric product identified as 138. These strikingly chemospecific conversions imply that the C-S bond is less prone to cleavage than its C-O counterpart and that cation 135 is first generated (Scheme 5.9). Impressively, intemediate 135 advances to product uniquely by pathway a, at least under conditions where a sulfonic acid catalyst is involved. In a serendipitous experiment performed almost simultaneously, a CDCI 3 solution of 114 was allowed to evaporate slowly over the course of two weeks at room tempera ture. Redissolution of the sample and a second recording of the NMR spectrum revealed 66 that isomerization to a mixture of 138 and 139 (ratio 4 : 1) had occurred during this period. The catalyst was presumably the Brpnsted acid slowly liberated upon degradation of the isotopically labeled solvent. TCNE likewise promotes (in a shorter time frame) the conversion of 114 predominantly to 139, although a different mechanism is likely operative under these circumstances . 135 It must be emphasized that one cannot be fully committed to the 135 -»137 -> 139 pathway outlined in Scheme 5.9. The reverse timing of the C-X bond ruptures could be operative and not be recognized. However, some might want to invoke Occam's razor in order to simplify matters in favor of 135. Scheme 5.9: Synthesis of 138 and 139 from 114. + OH 134 135 OH 136 137 OH 138 139 The syn dithia analog of 117 was transformed uniquely during 48 h into disulfide 142 following addition of 10 mol percent p-toluenesulfonic acid to CDCI 3 solutions. The formation of this end product correlates well with initial ionization to pentadienyl cation 141 followed by intramolecular nucleophilic attack by mercapto sulfur at the sulfide center 67 with direct aromatization of the benzene ring (Scheme 5.10). Thus, we see for the first time that the spirocyclic cations invoked as the initially-formed intermediates can indeed be intercepted prior to Wagner-Meerwein shift when the heteroatom residing at the terminus of the propyl chain is made sufficiently nucleophilic. The structural constitution of 142, deduced initially on the basis of its simplified *H and 13C (six-line) NMR spectra, was confirmed by chemical conversion to 143 via lithium aluminum hydride reduction and direct S-methylation. The bisthio ether exhibits Scheme 5.10: Synthesis and chemical derivitization of disulfide 142. 140 141 LiAIHt; s c h 3 CH.I ccc s c h 3 142 143 the same symmetry characteristics as 142, thereby requiring that the disulfide linkage present in 142 reside in the mirror plane responsible for the meso nature of these compounds. Selected Reactions of the [4.4.4]Propelladienes. With several heteroatomic propelladienes of type 95 in hand, some attention was accorded to the regio- and stereochemical aspects of epoxidation and cycloaddition reactions. Thus, treatment of 127 with buffered m-chloroperbenzoic acid was found to proceed slowly at room temperature with the formation of 144. There is, of course, no issue of facial selectivity 68 a. 61.7 ppm />. 3.VM ppm r. 96. 1 ppm J. 61.9 ppm 144 Figure 5.4: ,3C NMR resonances of selected carbons of 144. in this instance. However, the fact that the double bond most distal from the oxygen atoms was the seat of reaction was determined by a 5 Hz tuned semi-selective INEPT experiment capable of detecting V and 4J interactions. Saturation of the y-pyranyl proton that appears at 6 1.62 (dddd, J = 13, 3.5, 3.5 2 Hz) produced enhancements at the four carbons labeled as a-d (Figure 5.4). Since one of these four carbon centers belongs to the epoxide subunit, the proximal relationship shown is required. The observed regio-selectivity is attributed to inductive effects. y - r 145 146 Hj, H j 147 148 Figure 5.5: MTAD cycloadducts of the propelladienes. Although 127 was unreactive toward N-phenylmaleimide even under forcing conditions (175,000 psi, CH 2CI2), cycloaddition occurred slowly in the presence of N- methyltriazolinedione (MTAD) at room temperature (CH 2CI2 solution). After 5 days, the extent of conversion to 145 was 73% (Figure 5.5). The processing of 126 under 69 analogous conditions was accompanied by the interesting observation that dienophile capture occurs only from that direction syn to the cyclohexane ring. The identity of 146 was established by ’H-’H COSY, COSY, and INEPT experiments, which permitted all relevant protons and carbons to be identified. Once accomplished, NOE data such as that indicated below (Figure 5.6) confirmed the relative spatial proximity of the tetrahydropyranyl ring to the unsaturated bridge. The condensation of 139 with MTAD afforded to two adducts 147 and 148 in 86% yield and a ratio of 20:1. As before, the proximity of the sulfur-containing six- membered ring to the ethylene 7C-bond was corroborated by NOE results (Figure 5.6). NOE's for 146: NOE's for 147: Hb (8 6.49-6.45) Hb (8 6.56-6.51) H„: 4.5% H, (82.57) : 1.4% "*► H»: 1.1% Hc (8 6.37-6.32) Hc (8 6.45-6.38) Hr (82.57): 0.2% Hd: 4.5% H*(6 3.88-3.81) H/: 1.8% no effect on H& or Hc Figure 5.6: NOE enhancements for 146 and 147. It is noteworthy that MTAD adds anti to oxygen when the monooxa propelladiene 126 is involved, but preferentially syn to oxygen in the oxathia example. Competition experiments, undertaken to gauge of relative reactivity of the three dienes toward MTAD, revealed 139 to be most reactive and 127 the least. The experimentally derived ratios for 139:126:127 were 2.1:1.4:1. The higher reactivity of 139 suggests that inductive effects do not alone contribute to the ability of these dienes to engage in (4+2) cycloaddition. C. DISCUSSION The present survey of the acid-catalyzed isomerization of dispiro[4.0.4.4]tetra- deca-11,13-dienes containing one or two hetero atoms has provided insight into those 70 control elements that dictate regioselectivity. If 102 is viewed as a suitable point of reference, we see that this system is inherently capable of producing only the cyclohexadienyl carbocation 122. Once generated, this intermediate partitions itself along two Wagner-Meerwein reaction channels, with that involving the greater buildup of steric congestion being favored by a factor of two. Subsequent to the mechanistically related conversions of 105 and 108 to 131, the pair of 1,2-shift options now operate with essentially equal efficiency. In this specific example, migration of the methylene group may perhaps be facilitated because of the involvement of nonbonded electron pairs from the tetrahydrofuranyl oxygen atom. One might inquire whether the evolution of oxonium ions 132 and 133 so levels the energetics of the competing Wagner-Meerwein steps that they are no longer kinetically imbalanced. This working assumption is lent credence by the regioselectivity exhibited by 135. Formed by heterolytic scission of the C-O bond in the oxathia dispiro diene, 135 is expected to be less favorably inclined than either 122 or 131 to advance to thionium ion(s) 136 and/or 137 because of their lower stability and higher reactivity.134>l 43 This diminution in driving force is anticipated to result in a substantive enhancement in the selectivity of the ensuing Wagner-Meerwein shift. Indeed, the resident sulfur atom in 135 causes the pathway leading to the sterically less crowded intermediate 136 to operate as the exclusive exit step. Our ability to isolate 139 under modified reaction conditions suggests that the partitioning between 136 and 137 may be subject to modulation. In support of the preceding mechanistic detail, it is noted that 141 is sufficiently reluctant to enter into the Wagner-Meerwein manifold (with requisite development of thionium ion character) and that it is entirely prone to intramolecular nucleophilic attack at sulfur by the pendant sulfhydryl group. Thus, we have shown that heteratomic effects manifest themselves in clear-cut fashion during acid-catalyzed rearrangement of the title dienes. A new class of [4.4.4]- 71 propelladienes cun be accessed in this manner. Rationalization of the stereoselectivity with which these propelladienes enter into Diels-Alder reaction with N-methyltriazolinedione is deferred to Chapter 6 which will also detail the cycloaddition stereochemistry exhibited by 102, 105, 108, 111, 114, and 117. Chapter VI INVESTIGATION OF HETEROATOM INFLUENCES ON THE DIELS-ALDER FACIAL SELECTIVITY OF DISPIRO- [4.0.4.4]TETRADECA-11,13-DIENES A. INTRODUCTION The popularity of the Diels-Alder reaction in synthesis resides largely on the ability of this cycloaddition to form two new bonds and up to four new contiguous stereocenters in one laboratory operation.144 Factors such as substituent effects on the reaction rate and control of endo/exo ratios have been the focus of much investigation. The problem of successfully predicting (and controlling) n-facial selectivity is still a matter of active investigation and debate.145 Thirteen years have passed since Cieplak first reported that the axial preference for nucleophilic and electrophilic addition to cyclohexanones was explainable in terms of the hyperconjugative stabilization of the a* orbital of the forming bond by vicinal C-H bonds at C2 and Cft of the six-membered ring.146 This hyperconjugative o-assistance (or Cieplak model as it is known) directs addition preferentially anti to the cr-bond that is the better donor (Figure 6.1). Predictions concerning facial selectivity can be made, according to the model, by using the Baker-Nathan ordering of o-donor ability, which is (in increasing order) CFco < <*CN < <*CCl < °C C < <*CH < CTCS-147 Use has been made of this model to explain the observed facial selectivity in other systems, including such varied reactions as the 1,4-reduction of enones148a and the dihydroxylation of alkenes.148b Notably, the S-substituted adamantanones 149 were 72 73 found to undergo addition syn to the C 5 substituent by nucleophiles and electrophiles . 149 Axial Attack (Preferred) Equatorial Attack Figure 6.1: Cieplak-Model explanation for nucleophilic attack on cyclohexanones. As these adamantanones are for all practical purposes free of steric bias about the ketone, these results were most readily explainable by invoking the Cieplak model, whereas other well known models by Felkin and by Ahn incorrectly predicted the opposite stereochemistry for some of the cases.145d The products of both thermal and photochemical cycloaddition reactions of the thiocarbonyl derivative of 149 were found to follow Cieplak’s model as well.150 o x 149 150 151 Figure 6.2: Systems examined for facial selectivity. The facial selectivity in the Diels-Alder reactions of substituted pentamethylcyclopentadienes 150 has also been reported,151 and addition was seen to proceed syn when X = oxygen and nitrogen and anti when X = sulfur, exactly as one would predict according to o-donating efficiency. Thus a C-C bond stabilizes the incipient o* orbital to a greater extent than does a C-O or C-N bond, resulting in the syn transition state predominating. Likewise C-S bonds, being better donors than C-C bonds, give the 74 opposite selectivity (Scheme 6.1). Scheme 6.1: Reactions of maleic anhydride with Cs-substituted cyclopentadienes. o Syn O O Anti O The results of cycloaddition to the c«-cyclohexa-3,5-diene-l,2-diol system 151 have been explained not by a hyperconjugative stereoelectronic model, but rather by steric control.152 Bulky derivatives of 151 were observed to undergo Diels-Alder reactions with N-phenylmaleimide (NPM) from the anti face, opposite to that predicted by the Cieplak model. Others have found similar results with systems containing steric and electronic features absent in 149 and ISO.153 Hexadienes of type 94, which are similar to 151 in that the two heteroatoms are vicinal to one another, offer the opportutity for reexamination of functionalized cyclohexadiene cycloadditions free of the steric biases that exist in derivatives of 151. Furthermore, the synthetic control over the substituents X and Y (0,S,CH2) that is possible allows the capability to probe the a-donating effects of both C-O and C-S bonds for comparison with the results found with 150. Finally, with a diheterohexadiene available possessing both oxygen and sulfur on opposite faces of the diene, the interesting question arises concerning competition between the heteroatoms for controlling facial selectivity. 75 94 Figure 6.3: 1,2-Dihetero dispiro cyclohexadienes. B. PREPARATION OF STARTING MATERIALS The dispiro dienes studied were those previously synthesized (Chapter 5). In addition, the mono-sulfur diene 155 was desired and its synthesis (Scheme 6.2) was similar to that of the disulfur analogs 117 and 120. Scheme 6.2: Synthesis of diene 155. 1. LDA o , s v^CeCU 2. TMSC1, ■VJ EtjN THF, -78 °C 3. NBS, 2. Dowex-50X, propylene oxide. 96 CHp: THF. 0 °C (17%)* 152 4. LiBr. LijCOj, 153 CHjCON(CHj )2 170 °C NaBH*, ArSCl, CeCl (7H2Q, EtjM. MeOH ClCHjCHjCl (87%) A (57%) Ar - 2,4-(N02)2Pti 154 155 The dispiro cyclohexanone 152 was prepared by cerium-mediated addition of dihydrothiophene anion to the known cyclopentanone 96.136 The allylic alcohol product was subsequently stirred with Dowex-50X acidic resin in CH 2CI2 for 2 days, and purification by chromatography on silica gel, then alumina, afforded the saturated ketone in 17% yield as a colorless solid. The absense of any olefinic absorptions in the lH NMR 76 spectrum and the presence of two quaternary carbons at 74.5 and 53.4 ppm among the thirteen resonances in the l3C NMR spectrum supported the assigned structure. The a,p-unsaturation, introduced as before via the a-brom ination- dehydrobromination sequence in 95% overall yield, was recognizable in enone 153 by diagnostic absorptions in the IR (1675 c m 1), 'H NMR (5 6.67 (ddd), 5.97 (ddd)), and 13C NMR (196.6, 146.5, 127.9 ppm) spectra. This compound was reduced using sodium borohydride and cerium trichloride heptahydrate to furnish a 3:2 mixture of co-eluting epimeric alcohols 154 in high yield (87%). The OH stretch (3600-3200 cm '1), although indicative of alcohol functionality, gave no indication of the epimeric mixture. Integration in the 1H NMR spectrum of the absorptions belonging to the hydrogens alpha to the ether oxygen (6 4.18-4.17 (m, 0.4 H), 3.98 (br d (0.6 H» made possible the quantitation of the mixture, and this was confirmed by the doubling of signals in the 13C NMR spectrum. Access to 155 was achieved as were the other dienes via the reaction of this mixture of alcohols with 2,4-dinitrobenzenesulfenyl chloride. Chromatography on silica gel afforded 155 as a colorless oil in 57% yield. Although the diene appeared free of impurities (t.l.c. analysis), decomposition was evident by *H and ,3C NMR spectroscopy. The diene functionality was evidenced by the presence of four coupled hydrogen absorptions in the olefinic region of the •H NMR spectrum. More telling, however, were the four olefinic carbon signals in the ,3C NMR (140.7, 137.1, 121.5, 119.9 ppm), similar to the dienes prepared previously. C. RESULTS 1. C ycloadditlons (a) Diene 105. The initial studies to be performed involved diene 105. Reactions with N- phenylmaleimide (NPM), maleic anhydride, p-benzoquinone, and naphthoquinone each 77 proceeded well to afford a single product in each case (Scheme 6.3). The assigned syn stereochemistry was determined usually by measurements of NOE enhancements between the hydrogens at the newly formed ring fusion (protons a to the amide in 156, Scheme 6.3) and the alkoxy protons of the spiro rings, and enhancements (or lack thereof) observed upon similar examination of the olefinic hydrogens. The symmetrical nature of 105 and of the dienophiles was evidenced by the simple *H NMR spectrum and the reduced number of peaks in the ,3C NMR spectrum of the cycloadducts. For 156 the alkene was determined to be on the opposite side of the bicyclic framework than the ether oxygens due to no observable NOE’s at the alkoxy hydrogens upon saturation of the olefinic protons, and by the 3.5% NOE observed for the exo protons on the y-carbon of the tetrahydrofuranyl rings (Figure 6.4). That the spiro rings are bent outward from one another is a diagnostic feature which causes the exo y-protons situated above the olefin to absorb slightly upfield (8 1.6-1.5 for 156) than their geminal neighbors, and was evident in the majority of the dispirocyclic dienes studied. The endo addition of the dienophile was established by a 1.7% NOE between the alkene and protons of the aromatic ring, a factor also repeatedly observed. The facial selectivity assignment of cycloadduct 157 was achieved in a similar way. No NOE enhancements were measured between the alkoxy protons and those adjacent to the anhydride. However, as with 156, a significant (2.7%) NOE was seen at the two exo y^spirocyclic protons (5 1.58-1.48) upon saturation of the olefinic hydrogens (8 6.23 (dd)). The spatial orientation within 158 is such that the alkoxy protons could be utilized for the identification of stereochemistry. Saturation of the hydrogens on the ring jucture adjacent to the ketones resulted in a 2.2% NOE at the alkoxy hydrogens. Likewise, double irradiation of the olefinic protons resulted in the usual 3.1% NOE at the exo y-protons of the THF rings. 78 Scheme 6.3: Cycloadditions of diene 105. O O tj-O___ QD„. A o Ph 72 h (83%) O 105 156 O d3 105 __ Q_ OJVA 20 h (46%) 105 CH2CI2, 175,000 psi 72 h (67%) 105 ------o------CHjClj, 175.000 psi 5 d (69%) O n V NMb 105 ______Q______THF. -78 °C-»0‘>C 5 h (82%) When naphthoquinone was used as dienophile, cycloadduct 159 was the sole product. As with most of the previous cases, no NOE was measured between the hydrogens alpha to the ketones and those hydrogens adjacent to the ethers. The two hydrogens on the exo y-tetrahydrofuranyl carbons (6 1.58-1.50) did, however, display enhancement (3.3%) upon irradiation of the olefinic hydrogens (6 6.10 (dd)). 79 Ph 1.7% Figure 6.4: NOE results for cycloadduct 156. N-Methyltriazoline-3,5-dione (MTAD) is one of the most reactive dienophiles known,154 and reaction between it and diene 105 produced a solid in 82% yield that displayed no usable NOE enhancements for determination of the facial selectivity. Single crystal x-ray crystallography of 160 determined that addition had occurred anti to the heteroatoms (Figure 6.5). (b) Diene 102. Cycloadditions involving diene 102 were examined to see what effect the number of heteroatoms had on influencing facial selectivity. NPM was used as a representative alkene dienophile and MTAD was examined because of the crossover observed with diene 105. Scheme 6.4 summarizes the results of cycloadditions involving diene 102. Reaction with NPM afforded a mixture of 161 and 162 (13:1 ratio, respectively) in 85% combined yield. The connectivity of the various hydrogens and carbons was established by ,H-1H and !H-I3C COSY experiments on the major product. Facial selectivity was then a matter of NOE determination. For 161, positive enhancement was measured between the a-carbonyl proton beneath the ether oxygen and the alkoxy protons (1.4%), as well as between the two olefinic hydrogens and those exo protons located on the y 80 tetrahydrofurany] and 8-cyclopentyl carbons (1.5-2.2%), respectively (Figure 6.6). Figure 6.5: Computer-generated perspective drawing of 160 as determined by x-ray crystallography. Scheme 6.4: Cycloadditions of diene 102. e g CHjjCI j (iPOjNEt, Ph Ph 150.000 psi. 1*2 (6%) 102 72 h T NCHj N'Tf 102 __ a CH jCI, -78 “C-*0°C 45 min 81 0.8 % 1.4% 2 .2% Ph O 163 Figure 6.6: NOE results for cycloadducts 161 and 163. For compound 163, only anti addition was again found to have resulted. By simple inspection of the *H NMR spectrum, it was evident that only one exo proton on a spiro ring carbon in the proximity of the alkene was present, ruling out the syn facial isomer. In addition, saturation of the olefinic proton (5 6.31-6.46, m) caused a 1.4% enhancement to be measured at this hydrogen (Figure 6.6). The outward folding of the THF ring was also seen by the differing absorptions of the hydrogens on the carbon adjacent to the ether oxygen (5 3.89-3.82 and 8 3.79-3.71), the more deshielded of the two being exo, as suggested by NOE enhancements of the alkene hydrogens upon irradiation. Similar enhancements were absent upon saturation of the geminal neighbor. When both alkoxy protons were irradiated, enhancements of 0.8% and 0.7% were measured at the olefinic hydrogens. (c) Diene 117. According to the Cieplak model, the C-S bond is a better o-donor than the C-O bond. Therefore, the reactions of 117 were of interest to determine if selectivity opposite to that obtained for 105 would be observed. Much to our disappointment, no reactivity was seen using such classical dienophiles as NPM and maleic anhydride. No trace of cycloadditon was evident even 82 Scheme 6.5: Cycloadditions of diene 117. .0 NPh NR 175.000 psi. 117 30 d o 117 %------NR CH2CI> 175.000 psi. o N-^ « NCH* 117 O CHp2. -78 °C—Mt 3 h 164 (87%) after 117 and NPM were submitted to high pressure conditions (175,000 psi) over a 30- day period. This decrease in reactivity was not without precedent, as it was also observed with the sulfur analog of 150.151 MTAD did react with 117, however, and a single cycloadduct was produced in high yield (Scheme 6.5). The facial selectivity was found to be anti due to the positive enhancements measured at the protons alpha to the sulfur (0.6%) when the olefinic protons were irradiated. The absence of any upfield y- tetrahydrothiophenyl protons in the NMR spectrum was also indicative of anti attack by the dienophile. (d) Diene 155. The instability of this diene has previously been discussed. In order to maximize cycloaddition yields, all reactions were performed on 155 immediately following its preparation. High pressure techniques gave better, although still poorer results than with the disulfur analog, as seen by its successful addition with both NPM and MTAD (Scheme 83 6.6). The high pressure-induced reaction between 155 and NPM proceeded at 175,000 psi for 16 days. After chromatographic purification, the starling material was found by *H and ,3C NMR analysis to have changed (polymerized?), as evidenced by the presence of a plethora of l3C absorptions. Two crystalline cycloadducts (165/166) were also obtained in 14% and 12% yields. NOE experiments were inconclusive, and because of the nearly equal selectivity observed the relative stereochemistry was not determined. Scheme 6.6: Cycloadditions of diene 155. 165,166 (iPr)jNEl, CH2C12, (ca. 1:1) Ph 175,000 psi. O 155 I6d New, 155 o CHjCIj, -78°C—*0°C 15 mm 167 (87%) 168 (4%) Quite different results were observed with MTAD, which underwent preferential anti addition (11:1) to produce 167 and 168 in 45% and 4% yields, respectively. Mutual NOE enhancements on the major isomer were measured between the a-sulfido protons (5 2.84, dd, 2H) and the olefinic hydrogens (S 6.52-6.42, m). The absorption at 8 1.38-1.31 with an integral area of 1, respresenting the exo hydrogen on the 8-cyclopentyl carbon over the alkene, was also enhanced upon irradiation of the olefinic hydrogens (Figure 6.7). (e) Diene 111. Of great interest to us were the reactions of dienes 111 and 114, for these dienes contained both oxygen and sulfur heteroatoms, which have been found to induce opposite 84 facial selection in other systems.15* Isomer 111, which possesses a syn arrangement of the oxygen and the sulfur, reacted with both NPM and MTAD to afford a single cycloadduct in each case (Scheme 6.7). H»g l~ T \ 0.8 % pmallf s ' c h 3 167 167 Figure 6.7: NOE results for cycloadduct 167. Cycloadduct 169 was obtained as the only product in 56% yield (based on unrecovered diene), and syn selectivity was immediately apparent by the presence of two exo protons on the y-carbons of the spirocyclic rings (6 1.65-1.56) in the 'H NMR spectrum. Measurable enhancements were observed at these hydrogens upon irradiation of Scheme 6.7: Cycloadditions of diene 111. (iPrJjNEt. CH2C12 Ph 150,000 psi, in O 5 d h UCHj in o CHjCIj -78 t —irt. 170(100%) 1 h 85 either of the olefinic hydrogens. Additional evidence came from NOE enhancements between the amide proton located beneath the thio ether (6 3.69, dd) and the alkoxy protons (S 3.98-3.88, m). The observed anisotropy of the a-carbonyl protons at the ring fusion (6 3.84 (dd) and 5 3.69 (dd)) is also noteworthy as it is caused by the proximity of the different syn- situated heteroatoms (Figure 6.8). O Ph Figure 6.8: NOE results for cycloadduct 169. The cycloaddition product 170, resulting from reaction of 111 with MTAD, lacked much of the spectral data discussed above. No upfield absorptions were observed in the 1H NMR spectrum due to exo hydrogens on y-carbons of the spiro rings, and no protons alpha to an amide exist. By virtue of the NOE evidence depicted in Figure 6.9 the heteroatoms were found to be on the side of the alkene. (f) Diene 114. The final diene examined was the anti isomer 114, and this diene underwent reaction with the two dienophiles in good yields (Scheme 6.8). Facial selectivity for the maleimide adduct 171 was once again based upon NOE results (Figure 6.10). No measurable enhancements were seen at the a-alkoxy or sulfido hydrogens when the olefinic hydrogens were saturated, although a 1.6% NOE was seen for a lone upfield exo proton (6 1.86-1.71) belonging to a y-carbon on one of the spirocyclic rings, thus Figure 6.9: NOE results for cycloadduct 170. confirming that the heteroatoms were oriented on opposite faces. Significant anisotropy of the protons alpha to an amide (5 3.59 (dd) and 5 3.25 (dd)) was also observed. Saturation of the downfield member of this duo caused a 1.4% NOE at the exo alkoxy proton (6 4.01- 3.94 (m)). That the two alkoxy protons have such different chemical shifts attests again to the non planar nature of these spirocyclic rings. Scheme 6.8: Cycloadditions of diene 114. (iPrfeNEt, CH2C12, 175.000 psi.psi.175.000 114 18 h O 171 (70%) O 114 O CH^Clj, H -78 °C -irt 1 h 172 (35%) 173 (50%) 87 H I {*» 1.6% Ph Figure 6.10: NOE results for cycloadduct 171. The mixture of cycloadducts 172 and 173 resulting from the reaction of 114 with MTAD was surprising, for this was the first example seen in this study of a mixture being produced with this electron-rich dieneophile. Decisions about relative stereochemistries using NOE results was not without risk, for only one useful, although small (0.8%), enhancement between the exo alkoxy proton and olefinic proton of 172 was noted (Figure 6.11). No useful enhancements were detected for 173 upon irradiation of the a-sulfido, a-alkoxy, or olefinic hydrogens. Compound 173 was sufficiently crystalline, however, to allow the determination of its structure via x-ray crystallography (Figure 6.12), thus establishing by elimination the relative stereochemistry of the minor product 172. 1.3% C 172 173 Figure 6.11: NOE results for cycloadducts 172 and 173. 88 Figure 6.12: Computer-generated perspective drawing of 173 as determined by x-ray crystallography. 2. Competition Experiments. To gain additional insight into what factors enhance (or detract from) the reactivity of MTAD with the dispiro dienes of interest, competition experiments were initiated with various mixtures of two dienes and MTAD. The product ratios, presented in Table 6.1, have been determined from 1H NMR integration of the cycloaddition reaction mixtures, and are in most cases the result of duplicate runs. The procedure followed involved treatment of an equimolar mixture of two dienes with slightly less than 0.5 mol of MTAD. With the dispiro dienes, the reactions were complete within 30 min (the propelladienes of Ch. 5 required longer periods). Careful integration of the *H NMR spectrum of the mixture containing two dienes and two (and in some cases three) cycloadducts allowed the addition product ratio to be determined (Table 6.1). From these results an ordering of reactivity relative to diene 105 (assigned a reactivity of 1) was possible (Figure 6.13). 89 Trans dioxa diene 108 was examined as well. In the competitive reaction between MTAD and dienes 105 and 108, cycloadduct 174 was formed in 97% yield (based on unrecovered starting material) (Scheme 6.9). Unreacted diene 105 was recovered quantitatively. As this diene is symmetrical, no determination of facial selectivity was necessary. Scheme 6.9: Cycloaddition of diene 108 with MTAD. ,° /TT\o c h :c i2. y ^ CH3 -78 ‘C-»i, O 4 h 108 174 (97%) Table 6.1: Results of Competition Experiments. Experiment Dienes Products (major, minor) Ratio 1 105, 117 164, 160 2.4 : 1 2 105, 102 163, 160 100:0 3 105, 114 173/172, 160 8.4 : 1 4 105, 111 169, 160 8.3 : 1 5 105, 108 174, 160 100: 1 6 114, 102 163, 173/172 2 : 1 7 117, 111 169, 164 4 : 1 8 102, 108 174, 163 1.5 : 1 9 111. 114 169, 173/172 1.3 : 1 10 111. 102 163, 169 1.6 : 1 90 O o s 105 117 114 (1) (2.4) (7.6) 111 102 174 (9.6) (15.4) (22 .8 ) Figure 6.13: Order of reactivity for dienes with MTAD. D. DISCUSSION. Scheme 6.3 is representative of the trend seen throughout the project, that being the addition of alkene dienophiles to the less hindered face of the diene. This was seen repeatedly with NPM. A good example is diene 111, where the oxygen and sulfur atoms are syn to one another. Only the single product 170, that of syn addition , was obtained / This result was surprising, because based on considerations involving the o-donor ability of C-S bonds,147 we predicted that the other isomer, or at least a mixture of the two facial adducts, would have formed. Disappointingly, the lack of reactivity displayed by diene 117 did not allow the classical test of the Cieplak model to be examined, that being a reversal in facial selectivity for the sulfur analog relative to that obtained for dioxa diene 105. Examination of the available results of these dispiro dienes with N-phenylmaleimide, however, does seem to indicate that steric factors are the major influence upon facial selection, with the dienophile attacking syn to oxygen, which is the face of least steric hindrance. Alkene dienophiles are specified above because MTAD was found to add in a sense opposite to NPM with almost all cases studied. We attributed this behavior initially to a 91 repulsive interaction between the lone pairs of the heteroatoms with the highly electron-rich N=N bond. Coxon and coworkers have seen this same behavior with diene 175 and N- phenytriazolinedione (Figure 6.14).155 Alkene dienophiles such as NPM and maleic anhydride were observed to react from the less sterically congested face of the diene syn to the ether, whereas DMAD and triazolinedione gave different selectivity, adding from the more sterically congested face of the cyclobutane. Other investigators discovered that this same hydrocarbon system, without the ether oxygen, undergoes reaction with all dienophiles (including PTAD) from the same face.156 Upon study of the products obtained with MTAD, this explanation was satisfactory for the dioxygen diene 105, mono oxygen diene 102, di and mono sulfur dienes 117 and 155, and the syn 0,S diene 111. Except for 155, each produced a single cycloadduct, with cycloaddition occurring from approach of the dienophile anti to the heteroatoms. 175 Figure 6.14: The two faces attacked of diene 175. When the oxygen and sulfur were involved on opposite faces of the diene in 114, this simple model was not followed. Predictions were that the MTAD would have a greater electrostatic interaction with oxygen than with sulfur. Energetically this is due to the n-lone pairs of the aza group being closer in energy to the 2p lone pair of oxygen than for sulfur, thus causing syn addition to the sulfur to be favored.157 The mixture actually produced was puzzling, because x-ray crystallography firmly established that the major product 92 (1.5:1) was due to cycloaddition to the oxygen bearing face (Figure 6. i 2). This result might have been discounted as anomalous were it not for two related observations. The First is that propelladiene 139 (Chapter 5) underwent reaction with MTAD to produce a 20:1 mixture of cycloadducts, the major product (147) again being that of syn addition to oxygen (Figure 6.15). Secondly it was found that propelladiene 176 (and its related sulfone) undergoes addition solely from the side syn to the sulfur functionality to furnish 777/' 58 The almost complete crossover on such a similar system is remarkable. Due to the seemingly simple explanation for cycloadditions of NPM with our system, and the inconsistencies of the MTAD reactions, we initiated further study in the form of competition experiments between MTAD and mixtures of two of the dienes. From these we hoped to determine what factors affect the cycloaddition reactions of this dienophile. 0 5 c & CH. O 139 147 176 177 Figure 6.15: Dienes 139 and 176 and their MTAD cycloadducts. Figure 6.13 lists the results obtained from this investigation. Most apparent is the higher reactivity of 117 over that of 105, especially considering the complete inertness that was observed between 117 with alkene dienophiles. Furthermore, just by the orientation of a spirocyclic THF ring (compare 105 and 108) the difference in reactivity is greater than a factor of 20. The last two dienes of Figure 6.13 deserve special comment. The increased reactivity of 108 over 102 (ca. 1.5) is surprising. Predictions based on a repulsion based 93 argument, as discussed above, would support 102 as being the more reactive of the two (Figure 6,16). In a proposed transition state with diene 102, the MTAD can undergo addition anti to the heteroatom as depicted in 178 to afford the observed cycloadduct 163, thereby minimizing heteroatomic interactions. MTAD cycloaddition with diene 108 does not have this possibility available, for attack occurs syn to an oxygen on whichever face reacts. Answers to these puzzling results, forthcoming in the form of calculations and modeling of transition states, are currently unavailable. Ginsburg has attributed the maverick behavior of MTAD with diene propellanes to be a result of secondary orbital effects.159 The results obtained in this study seem to not follow that explanation, nor do they follow completely the repulsive model of Coxon155 or even an explanation governed by sterics.152*153a 178 179 Figure 6.16: Schematic repesentation of the transition states for cycloadditions with dienes 102 and 108. Caution must be exercised in an interpretation of these MTAD results, for recent evidence indicates that triazolinediones react not by a concerted Diels-Alder mechanism, but via the intermediacy of an aziridinium imide intermediate.160 The original goal to see whether an orbital interaction model would be followed in predicting facial selectivity was not found to be supported. We have found, as have others, 152*153a that the results obtained with 5-substituted cyclopenadienes will not 94 extrapolate to our cyclohexadiene system, where steric factors seem to dominate for classical alkene dieneophiles. 95 EXPERIMENTAL General Methods Melting points were measured using a Thomas Hoover (Uni-Melt) capillary melting point apparatus and are uncorrected. Optical rotations were measured using a Perkin-Elmer Model 241 polarimeter and concentrations are given in g/ml. Infrared (IR) spectra were recorded with a Perkin-Elmer 1320 spectrometer and are expressed in reciprocal centimeters (cm'1). Proton nuclear magnetic resonance spectra (*H NMR) were measured at the indicated field strengths and the splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint., quintuplet; m, multiplet. Carbon-13 NMR (,3C NMR) were recorded the indicated field strengths. The chemical shifts are given in parts per million (8 or ppm) downfield from tetramethylsilane and the coupling constants are expressed in hertz (Hz). Combustion analyses were performed by the Scandinavian Microanalytical Laboratory, Herlev, Denmark. Exact mass measurements were determined at The Ohio State University Chemical Instrument Center with a Kratos MS-30 mass spectrometer. Gas chromatograph/mass spectrum (GC/MS) analyses were performed using a Hewlett Packard 5970 series mass selective detector GC/MS fitted with a 12 m x 0.20 mm methyl silicone gum column with a flow rate of 0.2 ml/min calibrated at 100 °C and split ratio 30:1 on injection. Capillary gas chromatography (GC) analyses were performed using a Carlo Erba Strumentazione Fractovap 4130 GC fitted with a 30 m x 0.25 mm Durabond 5 column with a flow rate of 2 ml/min. Preparative GC separations were carried out using a Perkin-Elmer Model 960 GC fitted with a thermal conductivity detector and a 1.1 m x 6 mm column of 5% SE 30 on Chromosorb W. 96 All solvents used were reagent grade and were pre-dried via standard methods. Unless otherwise indicated, all reactions involving nonaqueous solution were performed under an inert atmosphere. Tetracyclo[7.2.1.04’II.06’1°]dodecane-5,12-dione (10). A solution of the known diene dione19a (3.78 g, 20.3 mmol) o in ethyl acetate (300 ml) was hydrogenated over 5% Pd-C (55 mg) at 50 psi in a Parr apparatus. Filtration through Celite to remove the catalyst and solvent evaporation gave 3.67 g (95%) of 10 as a colorless solid, mp 129-131 °C; IR (KBr, cm '1) 2940, 2860, 1715, 1460, 1440, 1320, 1295, 1275, 1250, 1200, 1170, 1130, 1100, 1010, 950, 920, 865, 620; ‘H NMR (300 MHz, CDCI3) 6 3.56-3.45 (m, 2 H), 3.00-2.96 (m, 4 H), 1.99-1.79 (m, 8 H); 13C NMR (20 MHz, CDCI3) ppm 223.91, 55.54, 44.01, 30.78; MS m/z (M+) calcd. 190.0994, obsd. 190.0982. Anal. Calcd. forCi 2H i40 2: C, 75.75; H, 7.42. Found: C, 75.56; H, 7.43. l,6-Dibromotetracyclo[7.2.1.04>11.06*10]dodecane*5,12-dione (13). A nitrogen-blanketed refluxing solution of 10 (504 mg, 2.65 mmol) in 1:1 ethyl acetate-chloroform (10 ml) was treated portionwise (ca 200 mg) with CuBr 2 (1.19 g, 2 equiv.) with care to add the subsequent amount only after the initial green color had disappeared. Solid CuBr was observed to precipitate and the solution turned yellow. The cooled mixture was filtered through Celite and the pad was washed well with ethyl acetate. The evaporated filtrate gave a residue that was separated into its components by chromatography on silica gel (elution with 20% ethyl acetate in petroleum ether). The first product to elute was 13 (Rf = 0.88, 93 mg, 10%); colorless crystals, mp 117-118 °C (from ether); IR (CCI 4, cm'*) 2970, 2940, 2880, 2860, 1750, 1465, 1445, 1315, 1250, 1160, 1115; *H NMR (300 97 MHz, CDCI3 ) 6 3.76-3.68 (m, 2 H). 3.59-3.46 (m, 2 H). 2.60-2.51 (m, 4 H), 1.65-1.52 (m, 2 H); t3C NMR (75 MHz, CDCI3 ) ppm 212.50, 65.68, 51.83, 49.79, 39.41, 27.21; MS m/z (M+) calcd. 345.9204, obsd. 345.9206. Anal. Calcd. for C | 2H |2Br2 0 2 : C, 41.63; H, 3.50, Found: C, 41.84; H, 3.49. l^-Dibrom otetracyclolT^.l.O4’11. 06**°]dodecane-5,12-dione (12), The second compound to elute was 12 (Rf = 0.73, 62 mg, 7%); colorless solid, mp 127-128 °C (from ether); IR (CCI 4 , cm*1) 2970, 2920, 1730, 1465, 1450, 1285, 1200, 1155, 1100, 925; lH NMR (300 MHz, CDCI3) 6 3.87 (d, J = 10.1 Hz, 1 H), 3.64 (q, J = 10.3 Hz, 1 H), 3.42- 3.35 (m, 2 H), 2.50-2.40 (m, 2.H), 2.36-2.25 (m, 2 H), 2.08-1.97 (m, 2 H), 1.94-1.85 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 213.47, 64.80, 64.00, 51.90, 40.58, 38.83, 30.06; MS m/z (M+) calcd. 345.9203, obsd. 345.9201. Anal. Calcd. for Ci 2H]2Br2 0 2 : C, 41.63; H, 3.50. Found; C, 41.85; H, 3.62. l-Bromotetracyclo[7.2.1.04'1,06’10]dodecane-5,12-dione (11). The most polar constituent was 11 (Rf = 0.35), a colorless O solid (301 mg, 42%) having mp 87-88 °C (from ether); IR (CCI 4. cm-1) 2960, 2940, 2870, 1735, 1460, 1440, 1320, 1250, 1165, 1120, 775; 'H NMR (300 MHz, CDCI3) 8 3.69-3.53 (m, 2 H), 3.45-3.38 (m, 1 H), 3.14- 3.05 (m, 1 H), 3.02-2.95 (m, 1 H), 2.53-2.44 (m, 1 H), 2.24-2.07 (m, 2 H), 2.04-1.84 (m, 4 H), 1.65-1.52 (m, 1 H); l3C NMR (75 MHz, CDCI3) ppm 221.91, 214.66, 66.58, 55.54, 54.21, 53.95, 51.93, 42.30, 40.16, 30.98, 29.75, 28.94; MS m/z (M+) calcd. 268.0098, obsd. 268.0133. Anal. Calcd. for Ci 2H i3Br0 2 : C, 53.73; H, 4.89. Found; C, 53.32; H, 4.90. 98 l,4,6-Tribromotetracyclo[7.2.1.0 4 * 110 6 ’10]dodecane-5,12-dione (14). A refluxing solution of 10 (890 mg, 4.7 mmol) in 1:1 ethyl acetate-chloroform (2 0 mi) was treated under nitrogen with CuBr 2 (3.14 g, 14.1 mmol, 3 equiv.) as described above. Purification by MPLC removed all bromination products except the 1,6-dibromide (13) which co-eluted with 14. Repeated recrystallization of this material from ethyl ether afforded pure 14 (274 mg, 14%) as colorless crystals, mp 124-126 °C; IR (CCI 4 , cm*1) 2980, 2940, 1755, 1445, 1310, 1160, 1105; 'H NMR (300 MHz, CDCI3) 6 3.96 (d, J = 10.3 Hz, 1 H), 3.82 (t, J = 10.8 Hz, 1 H), 3.54-3.45 (m, 1 H), 2.62-2.36 (m, 4 H), 2.33-2.15 (m, 2 H), 2.03-1.92 (m, 1 H), 1.71-1.55 (m, 1 H); ,3C NMR (75 MHz, CDCI3) ppm 212.50, 208.97, 63.77, 63.47, 61.52, 58.93, 51.76, 50.82, 41.50, 39.97, 38.56, 28.59; MS m /z (M+) calcd. 432.8310, obsd. 432.8312. Anal. Calcd. for C 12H 11 Br30 2 : C, 33.98; H, 2.62. Found: C, 33.99; H, 2.73. 1,4,6,9-Tetrabrom otetracy clo[7.2.1.0 4 *110 6 ’10]dodecane-5,12-dione (15). A solution of 10 (108 mg, 0.57 mmol) in glacial acetic acid (2 0 ml) was heated to reflux under nitrogen and treated with bromine (0.35 ml, 1.09 g, 6.9 mmol) over 5 min. Heating was continued for 2 h. The cooled reaction mixture was diluted with water (1 0 ml) and CH 2CI2 (10 ml), and the aqueous layer was extracted with CH 2CI2 (3 x 10 ml). The combined organic phases were washed with water (3 x 10 ml), saturated NaHC0 3 solution (3 x 10 ml) and brine (10 ml) prior to drying and solvent evaporation. The residue was purified by chromatography (silica gel, elution with 20% ethyl acetate in petroleum ether) to give 229 mg (80%) of 15 as a colorless solid, mp 182-191 °C (dec.) (from ether); IR (CHC13, cm-1) 2940, 2920, 2855, 1750, 1450, 1300, 1200, 1155, 1110, 1075, 990, 870, 860-690 (br); *H NMR 99 (300 MHz, CDCI3 ) 5 4.01 (s. 2 H). 2.61-2.49 (m, 4 H), 2.26-2.13 (m, 4 H); 13C NMR (75 MHz, CDC1-0 ppm 208.41, 62.77, 58.78, 39.65; MS m/z (M+) calcd. 501.7415, obsd. 501.7352. Anal. Calcd. for Ci 2HioBr 40 2 : C, 28.70; H, 2.01. Found: C, 28.52; H, 2.06. p>Toluenesulfonic acid[(2aa,3aa,5aa,6aa,6ba,6ca)>decahydrodicyclopenta> [cd,£/i]pentalene-3,6-diylidene]dihydrazide (16). To a nitrogen-blanketed solution of diketone TosHNN NNHTos (10)(0.846 g, 4.45 mmol) in methanol (130 ml) was added p-toluenesulfonylhydrazine (1.66 g, 8.91 mmol) and /Moluenesulfonic acid (0.05 g), and this mixture was stirred and heated to reflux for 9 h. A white precipitate was observed afer 2 h. Filtration of the cooled mixture followed by washing with cold methanol afforded 1.70 g (72%) of 16 for which no further purification was necessary, mp 250 °C (dec.); IR (KBr, cm-1) 3295, 2975, 2935, 2875, 1595, 1395, 1335, 1325, 1165, 1095, 1030, 1015, 935, 885, 815, 685, 665; >H NMR (300 MHz, DMSO-d6) 6 9.86 (s, 2 H), 7.68 (d, 4 H, J - 8.1 Hz), 7.36 (d, 4 H, J = 8.1 Hz), 3.30-3.22 (m, 2 H), 3.08-2.94 (m, 4 H), 2.36 (s, 6 H), 2.16-2.07 (m, 2 H), 1.79- 1.62 (m, 4 H), 1.07-0.94 (m, 2 H); 13C NMR (75 MHz, DMSO-ds) ppm 172.76, 142.95, 136.34, 129.30, 127.22, 51.99, 49.95, 47.14, 35.19, 28.45, 20.95; MS m/z (M+) calcd. 526.1709, obsd. 187.1259 (C 12H 15N2); calcd. for C 12H 15N2 187.1235. Anal. Calcd. for C 26H30N4O4 S2 : C, 59.29; H, 5.74. Found: C, 59.11; H, 5.74. 100 (2aa,6aa,6ba,6ca)-l,2,2a,4,5,6a,6b,6c-Octahydrodicyclopenta[cd, To a solution of bistosylhydrazone 16 (1.06 g, 1.90 mmol) in TMEDA (20 ml) at 0 °C was added n- BuLi (1.3 M in hexanes, 95 ml, 0.124 mol). The cooling bath was removed and the yellow solution was stirred at room temperature for 7 h. After being cooled to 0 °C, the mixture was carefully diluted with water (10 ml), stirred overnight, poured into water, and extracted with pentane (2 x 30 ml). After drying and solvent evaporation (atmospheric pressure), the resultant yellow oil was chromatographed (silica gel, pentane elution). The diene containing fractions were evaporated at atmospheric pressure to yield 83 mg (28%) of diene as a 95 : 5 mixture of 17 and 18, respectively. Further purification was achieved by preparative gas chromatography (90 °C, 20 ml/min, 1.5 m, 5% SE-30 on Chromosorb W). For 17: *H NMR (300 MHz, CDCI 3) 5 4.88 (br s. 2 H), 3.29 (br s, 2 H), 3.21-3.18 (m, 2 H), 2.18-1.98 (m, 6 H), 1.64-1.56 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 149.76, 125.46, 56.62, 49.31, 31.63, 24.66; MS m/z (M+) calcd. 158.1096, obsd. 158.1098. Partial NMR data for minor product 18: *H NMR (300 MHz, CDCI 3) 8 4.93 (s, 2 H), 3.62 (d, 1 H), 3.47 (m, 2 H), 2.95 (dd, 1 H). (2aa,3p,3aa,5aa,6p,6aa,6ba,6ca)-Dodecahydrodicyclopenta[c Lithium aluminum hydride (1.04 g, 27.4 mmol) was added to a solution of diketone 10 (2.3290 g, 12.26 mmol) in dry THF (100 ml) at 0 °C. Sequential addition of water (1.4 ml), 30% NaOH solution (1.1 ml), and water (3 ml) was made after 1 h. After being stirred for 101 10 min, the mixture was poured into water (500 ml) and extracted with CH 2CI2 (5 x 200 ml). Drying and solvent evaporation afforded 2.04 g ( 8 6 %) of diol 19, mp 212-214 °C; IR (KBr, cm*1) 3600-3200, 3055, 1585, 1485, 1435, 1310, 1185, 1115, 1070, 995, 750, 720, 695; ‘H NMR (300 MHz, DMSO-d6) 5 4.42 (d, J = 4.64 Hz, 2 H), 4.21-4.14 H), 2.66-2.48 (m, 6 H), 1.95-1.83 (m, 4 H), 1.42-1.30 (m, 4 H); I3C NMR (75 MHz, DMSO-d6) ppm 74.91, 50.59, 49.96, 26.91; MS m/z (M+) calcd. 194.1306, obsd. 194.1272. Anal. Calcd. for Ci 2H i8 0 2: C, 74.18; H, 9.34. Found: C, 74.19; H, 9.43. (2aa,3p,3aa,5aa,6(M>aa,6ba,6ca)-Dodecahydrodicyclopenta[c pentalene-3,6-diol dimethanesulfonate (20). Pyridine (0.60 ml, 7.4 mmol) was added slowly over 2 min. to a stirred solution of diol 19 (20 mg, 0.1 mmol) and methanesulfonic anhydride (78.9 mg, 0.452 mmol) in CH 2CI2 (3 ml). After 30 min. no diol remained, and after 1 h. the reaction mixture was diluted with ether (10 ml) and washed with 5% HC1 aq. (5 ml) and brine (5 ml). Drying and solvent evaporation produced a yellow semisolid which was chromatographed (silica gel, elution with 50% ethyl-acetate in hexanes) to afford 31.8 mg ( 8 8 %) of 20, mp 155 °C (dec.); *H NMR (300 MHz, CDCI3) 5 5.16 (t, 2 H), 3.02 (s, 6 H), 2.97-2.87 (m, 6 H), 2.03-1.98 (m, 4 H), 1.77-1.69 (m, 4 H); ,3C NMR (75 MHz, CDCI 3) ppm 84.63, 50.39, 48.84, 38.06, 28.46; MS m/z (M+) calcd. 350.0858, obsd. 158.1107 (M+ - 2(0S0 2CH3)). Anal. Calcd. for Ci 4H220 6S2: C, 47.99; H, 6.33; C, 47.76; H, 6.39. 102 (2aa,3a,3aa,5aa,6a,6aa,6ba,6ca)-Dodecahydrodicyclopenta[c Dimesylate 20 (0.337 g, 0.963 mmol) and sodium CIH3 N NH3 CI azide (0.250 g, 3.85 mmol, 4 equiv.) were dissolved in DMF (10 ml) and stirred at 120 °C for 1.5 h. After being cooled, the contents were poured into ice-water (30 ml) and extracted with CH 2CI2 (3 x 10 ml). After drying and solvent evaporation, a yellow oil was obtained which was dissolved in ethanol (25 ml) containing chloroform (1 ml) and 5% Pd-C (0 .1 g), and hydrogenated (50 psi) for 1.5 h. Filtration through Celite to remove the catalyst and solvent evaporation yielded 0.165 g (70%) of 21 as a white solid, mp 210 °C (from ethanol/acetonitrile); IR (KBr, cm*1) 3470, 3400, 2960, 2070, 1610, 1525, 1400, 1180, 1035; 'H NMR (300 MHz, DMSO-d6) 8 9.00-7.00 (br s, 6 H), 3.15-3.07 (m, 2 H), 2.95-2.92 (t, J = 5.1 Hz, 2 H), 2.50-2.48 (m, 4 H), 1.76-1.71 (m, 8 H); l3C NMR (50 MHz, DMSO-d6) ppm 61.48, 53.86, 52.05, 31.12; MS m/z (M+) calcd. 264.1160, obsd. 176.1437 (M+ - NH 4 CI2). Anal. Calcd. for Q 2H22CI2N2 1.25 H20: C, 50.09; H, 8.58. Found: C, 50.18; H, 8.47. [(2aa,3a,3aa,5aa,6a,6aa,6ba,6ca)-Dodecahydrodicyclopenta[cd,?A]- pentalene-3,6-ylene]bis[trimethylammonium]diiodide (22). A mixture of bis-hydrochloride salt 21 (2.15 l(H3C)3N N(CH3)3I g, 8.14 mmol), sodium bicarbonate (1.50 g, 17.9 mmol), formic acid (12.3 ml, 0.326 mol), and 37% formaldehyde (9.15 ml, 0.122 mol) was stirred at reflux for 36 h. After cooling, 10 N HC1 (20 ml) was added and the mixture was concentrated to ca. 5 ml. A 25% KOH solution (1 0 0 ml) and water (2 0 0 ml) were added and the product was extracted into CH2CI2 (4 x 100 ml). Drying and solvent evaporation yielded the diamine, which was not 103 isolated but treated with excess methyl iodide (25 ml). Precipitation occurred instantly, yet the mixture was heated to 60 °C in a sealed tube for 3 h. to insure alkylation at both centers. Filtration yielded a solid which was dissolved into hot methanol (insoluble material filtered off)- Cooling yielded 2.08 g (48%) of the bis-iodide salt 22, mp 220 °C (dec.) (from methanol/ether); IR (KBr, cm 1) 3020, 2950, 2860, 1470, 955, 880, 860; *H NMR (300 MHz, DMSO-d6) 6 3.66 (t, J = 4.1 Hz, 2 H), 3.20-3.12 (m, 2 H); 3.03 (br s, 22 H), 1.90-1.81 (m, 4 H), 1.74-1.70 (m, 4 H); ^C NMR (75 MHz, DMSO-d6) ppm 85.73, 54.96, 50.36, 48.15, 33.23; MS m/z (M+) calcd. 532.0809, obsd. 405.17 (FAB, M+ - 1). Anal. Calcd. for C 18 H 34I2N 2 H 20: C, 39.29; H, 6.59. Found: C, 39.68; H, 6.59. (2aa,6aa,6ba,6ca)-l,2,2a,4,5,6a,6b,6c>Octahydrodicyclopenta[c The bis-ammonium iodide salt 22 (2.08 g, 3.91 mmol) was dissolved in water (2 0 ml) and passed through an Amberlite IRA 400 anion exchange resin that had previously been made basic with 1 M KOH solution. The resulting bis-ammonium hydroxide salt (in water) was wanned to 100 °C at reduced pressure until the water had distilled to dryness. The collected water distillate and reaction vessel were extracted with pentane, and the extracts were dried and evaporated at atmospheric pressure to afford the desired dienes 17 and 18 in 2 :1 ratio (GC analysis) as a yellow oil. 104 (2aa,3P'3aa,5aa,6p,6aa,6ba,6ca)-2a,6a-Dibromododecahydro- dicyclopenta[c To a nitrogen-blanketed solution of dibromo diketone 12 (51 mg, 0.15 mmol) in THF (5 ml) at 0 °C was added lithium aluminum hydride (12 mg, 0.32 mmol). After 30 min. the reaction mixture was quenched by sequential addition of water (0.012 ml), 30% NaOH solution (0.012 ml), and water (0.036 ml). After filtration (CH 2CI2 rinse), evaporation of the solvent afforded 49.4 mg (96%) of 23, mp 153-155 °C (from methanol/hexanes); SH NMR (300 MHz, acetone-r/6) 5 4.77 (dd, J = 9.1 Hz, 5.3 Hz, 2 H), 4.62 (d, J = 5.3 Hz, 1 H), 3.31-3.29 (m, 1 H), 2.81-2.65 (m, 6 H), 2.40-2.20 (m, 2 H), 2.05-1.90 (m, 2 H), 1.60-1.45 (m, 2 H); ^C NMR (75 MHz, aceton c-d6) ppm 85.42, 80.96, 74.10, 49.87, 49.37, 40.43, 27.48; MS m/z (M+- HBr) calcd. 270.0256, obsd. 270.0307. Anal. Calcd. for Ci 2H]6Br2 0 2 : C, 41.15; H, 4.61. Found: C, 41.14; H, 4.71. (±)-(2aa,3p,3&<*,5aa,6p,6aa,6ba,6ca)-2a,5a-Dibromododecahydro- dicy clopenta[cd,g/t]-pentalene-3,6-diol (24). To a nitrogen-blanketed solution of 13 (0.508 g, 1.47 OH mmol) in THF (30 ml) at 0 °C was added lithium aluminum * ' hydride (0.17 g, 4.4 mmol). After 90 min., the reaction mixture was quenched by sequential addition of water (0.17 ml), 30% NaOH solution (0.17 ml), and water (0.5 ml). Filtration and solvent evaporation yielded an oil which was chromatographed (silica gel, elution with 30% ethyl acetate in hexanes) to afford 0.371 g (72%) of 24, mp 152-154 °C (from ethyl acetate/hexanes); IR (KBr, cm-1) 3620,-3100, 2960, 2900, 1730, 1450, 1380, 1125, 1100, 990, 880, 860; >H NMR (300 MHz, DMSO- d6) 8 5.48 (d, J = 5.4 Hz, 2 H), 4.55 (q, J = 5.4 Hz, 9.5 Hz, 2 H), 3.26 (q, J = 6 .6 Hz, 3.1 Hz, 2 H), 2.89-2.79 (m, 2 H), 2.29-2.08 (m, 4 H), 1.99-1.73 (m, 4 H); NMR 105 (75 MHz, DMSO-df,) ppm 84.80, 82.85, 60.56, 46.51, 39.82. 25.36; MS m/z Anal. Calcd. for C | 2H |6 Br2 0 2: C, 40.94; H, 4.58. Found; C, 40.92; H, 4.58. (2aa,3p,3aa,5aa,6p,6aa,6ba,6ca)-2a,6a-Dibromododecahydro- dicyclopenta[cd,£A]-pentalene-3,6-dioI dimethanesulfonate (25). To a nitrogen-blanketed solution of 23 (214 mg, 0.61 MsO1 mmol) and methanesulfonic anhydride (468 mg, 2.69 mmol) in CH 2C12 (2 0 ml) at room temperature was slowly added pyridine (3.5 ml, 43 mmol) by syringe over a period of two min. After 30 min. the reaction mixture was diluted with ether (20 ml) and washed with 5% HC1 (2 x 10 ml). Drying and solvent evaporation yielded a brown oil that was chromatographed (silica gel, elution with 50% ethyl acetate in hexanes) to afford 306 mg (99%) of 25, mp 163.5-164 °C (from ethyl acetate/hexanes); IR (KBr, cm 1) 2965, 2940, 2880, 1740, 1465, 1435, 1265, 1205, 1180, 1060; >H NMR (300 MHz, CDCI 3 ) S 5.41 (d, J = 9.2 Hz, 2 H), 3.67 (d, J = 11.4 Hz, 1 H), 3.26 (q, J = 11.4 Hz, 9.9 Hz, 1 H), 3.17 (s, 6 H), 3.14-3.02 (m, 2 H), 2.74-2.63 (m, 2 H), 2.60-2.48 (m, 2 H), 2.03-1.92 (m, 2 H), 1.91-1.80 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 92.11, 72.28, 71.70, 49.49, 47.69, 40.45, 38.32, 27.72; MS m/z (M+) calcd. 158.1096 (M+ - 2 Br, -2 OSO 2CH3), obsd. (FAB) 158.11. Anal. Calcd. for C i^ o B ^ C ^ : C, 33.09; H, 3.97. Found; C, 33.03; H, 4.09. 106 (±)-(2aa,3|i,3aa,5au,6(i,6aa,6b«,6ca)-2a,5a-Dibromododecahydro- dicyclopenta[cd,g/t]-pentalene-3,6-diol dimethanesulfonate (26). To a nitrogen-blanketed solution of 24 (309 mg, MsO"-< >"'OMs 0.882 mmol) and methanesulfonic anhydride (675 mg, 3.88 * .... ' mmol) in CH 2CI2 (30 ml) at room temperature was slowly added pyridine (5.0 ml, 62 mmol) by syringe over a period of 2 min. After 30 min. the reaction mixture was diluted with ether (30 ml) and washed with 5% HCI (2 x 10 ml). Drying and solvent evaporation yielded a brown oil that was chromatographed (silica gel, elution with 50% ethyl acetate in hexanes) to afford 386 mg (87%) of 26, mp 181-182 °C (dec.) (from ethyl acetate/hexanes); IR (CDCI 3, cm '1) 2990, 2270, 1375, 1185, 1090, 1010, 975, 955, 880, 860; »H NMR (300 MHz, CDCI 3) 6 5.37 (d, J = 9.4 Hz, 2 H), 3.46-3.42 (m, 2 H), 3.36-3.29 (m, 2 H), 3.19 (s, 6 H), 2.44-2.34 (m, 2 H), 2.29-2.17 (m, 6 H); NMR (75 MHz, CDCI3) ppm 91.69, 75.26, 60.81, 46.48, 40.77, 38.42, 26.91; MS m/z (M+) calcd. 505.9068, obsd. 505.93 (FAB). Anal. Calcd. for C| 4 H2oBr 206S2: C, 33.09; H, 3.97. Found: C, 33.20; H, 4.00. (2aa,3a,3aa,5aa,6a,6aa,6ba,6ca)-Dodecahydro-3,6-bis(phenylthio)- dicyclopenta[cd,g7t Jpentalene (28). To a nitrogen-blanketed solution of 19 (78.5 mg, 0.41 PhS' SPh mmol) in dry DME (10 ml) was added tributyphosphine (0.5 ml, 2 mmol) followed by rapid addition of diphenyldisulfide (442 mg, 2.02 mmol) and this mixture was stirred at reflux for 3.5 h. After cooling, the solvent was evaporated and the residue was chromatographed (silica gel, elution with 2 0 % ethyl acetate in hexanes) to afford 101 mg (87%) of the mono-inverted alcohol 27 as an oil; IR (NaCl, cm_l) 3650-3110 (br s), 3080, 3060, 2950, 2860, 1700, 1580, 1470, 1435, 107 1215, 1175, 1105, 1080, 1020, 1000, 910. 860, 820, 745, 690; 'H NMR (80 MHz, CDCI3 ) 6 7.6-7.4 (m, 2 H), 7.4-7.15 (m, 3 H), 4.6-4.3 (br m, 1 H), 3.0-2.4 (m, 6 H), 1.9-1.4 (m, 10 H). A solution of 27 (78.4 mg, 0.286 mmol) in benzene (2 ml) was added via cannula to a nitrogen-blanketed solution of N-thiophenylsuccinimide (77 mg, 0.37 mol), tributylphosphine (0.1 ml, 0.37 mol) and benzene (5 ml) which had previously been stirring for 5 min. After 19 h of stirring at room temperature, the solvent was evaporated and the mixture was chromatographed (silica gel, elution with 2 0 % ethyl acetate in hexanes). First to elute was a mixture of the desired compound and diphenyldisulfide, followed by starting material (25 mg, 32.5%). The mixture was rechromatographed (silica gel, elution with hexanes, then 5% ethyl acetate in hexanes) to afford 45.9 mg (63%) of 28 as an oil; IR (NaCl, cm 1) 3080, 3060, 2950, 2880, 1580, 1480, 1435, 1220, 1090, 1065, 1020, 910, 735, 690; *H NMR (300 MHz, CDCI 3) 6 7.44-7.40 (m, 4 H), 7.32-7.20 (m, 6 H), 3.13-3.04 (m, 4 H), 2.64-2.58 (m, 4 H), 1.77-1.68 (m, 4 H), 1.65-1.54 (m, 4 H); 13C NMR (75 MHz, CDCI3) ppm 135.73, 132.20, 128.76, 126.82, 58.62, 55.21, 55.13, 32.86; MS m/z (M+) calcd. 378.1475, obsd. 378.1480. Anal. Calcd. for C 24H26S2: C, 76.18; H, 6.93. Found: C, 75.86; H, 7.06. Decahydro-3,4,7-metheno-7/if-cyclopenta[a]pentalene-7,8-dfol (29). Sodium metal (1 0 0 mg, 4.35 mmol) was added to a flask T oh containing liquid ammonia (15 ml), stirred for 15 min, and treated OH with diketone 10 (99.7 mg, 0.53 mmol) in ether (2 ml) followed by r- butanol (0.3 ml). The bath was removed and the reaction mixture was stirred at reflux for 2.5 h, after which the flask was again cooled to -78 °C and methanol (2 ml) was added. After overnight warming, the residue was diluted with water and extracted with ether. 108 Drying and solvent evaporation yielded 28.5 mg (28%) of 29, mp 141-142.5 °C (from hexanes); IR (KBr, cm"1) 3700-3040, 2950, 2880, 1730, 1470, 1215, 1190, 1125, 1090, 1065, 840, 800, 730; >H NMR (300 MHz, acetone-d6) 6 3.55 (br s, 2 H), 2.14-2.10 (m, 6 H), 1.76-1.69 (m, 4 H), 1.40-1.32 (m, 4 H); l3C NMR (75 MHz, acetone-d^) ppm 78.89, 55.59, 41.74, 21.05; MS m/z (M+) calcd. 192.1150, obsd. 192.1165. Anal. Calcd. for Ci 2H |60 2: C, 74.97; H, 8.39. Found: C, 74.78; H, 8.83. Decahydro-3,4,7-metheno-7/f-cyclopenta[n]pentalene-7,8-diol (29). A mixture of TiCl 3(D M E)i,5 complex (3.0 g, 13 mmol) and Zn/Cu (2.1 g, 32 mmol) in DME (80 ml) was stirred at reflux for 2 h. Diketone 10 (244 mg, 1.28 mmol) in DME (10 ml) was then added by syringe and heating was continued for an additional 3.5 h. The mixture was cooled to -78 °C and treated with ferr-butyllithium (1.7 M in pentane, 7.5 ml) stirred for 30 min, at which point saturated NH 4CI solution (5 ml) was added. Following overnight stirring, the reaction mixture was diluted with pentane and filtered through a pad of Florisil, using pentane and ethyl acetate to rinse. Concentration of the filtrate afforded 178 mg (72%) of 29, mp 141-142.5 °C (from pet. ether); IR (KBr, cm 1) 3700-3040, 2950, 2880, 1730, 1470, 1215, 1190, 1125, 1090, 1065, 840, 800, 730; 3.55 (br s, 2 H), 2.14-2.10 (m, 6 H), 1.76-1.69 (m, 4 H), 1.40-1.32 (m, 4 H); NMR (75 MHz, acetone d6) ppm 78.89, 55.59, 41.74, 21.05; MS m/z (M+) calcd. 192.1150, obsd. 192.1165. Anal. Calcd. for C i 2Hi602: C, 74.97; H, 8.39. Found: C, 74.78; H, 8.83. 109 Decahydro-3,4,7-metheno-7//-cyclopenta[a]pentalene-7,8-dicarboxylic anhydride (36). Diacid 34 (3.00 g, 12.1 mmol) was stirred with thionyi chloride (30 ml, 49 mmol) at 70 °C for 40 min. Solvent evaporation followed by recrystallization of the residue (2 0 % ethyl acetate in hexanes) afforded 1.85 g ( 6 6 %) of the anhydride, mp 181-183 °C; IR (CCI 4 , cm-1) 2970, 2880, 1850, 1780, 1290, 1280, 1270, 1060, 915; 'H NMR (300 MHz, CDC13) 6 2.80 (d, J = 2.0 Hz, 4 H), 2.64, (s, 2 H), 1.77-1.66 (m, 8 H); l3C NMR (75 MHz, CDCI3) ppm 170.88, 63.78, 57.04, 52.14, 22.81; MS m/z (M+) calcd. 186.1045, obsd. 186.1071. Anal. Calcd. for C] 4H i4 0 3: C, 73.03; H, 6.13. Found; C, 72.61; H, 6.34. 7,8-Dibromodecahydro*3,4,7-metheno-l/7>cyclopenta[a]pentalene (37). Bromine (0.55 g, 0.18 mmol) was added to a stirred mixture |bt^ °f disilver dicarboxylate 69 (0.400 g, 0.866 mmol) in dry CCI 4 (20 Br ml) at 65 °C and stirred for 2 h. Saturated Na 2S0 3 solution (2 mi) was added to the cooled mixture and stirred until the red bromine color had been replaced with a bright yellow precipitate. The liquid was decanted, the salts were washed with CH 2CI2, and the organic layers were combined and washed with saturated NaHC 0 3 solution and brine. Solvent drying and evaporation yielded a solid which was purified by preparative gas chromatography to afford first the bromochloride 38, followed by 84 mg (31%) of dibromide 37, mp 159-162 °C; IR (CC14, cm 1) 2960, 2670, 1460, 1285, 970; •H NMR (300 MHz, CDCI3) 6 2.50-2.47 (m, 2 H), 2.41-2.38 (m, 4 H), 1.94-1.87 (m, 4 H), 1.63-1.55 (m, 4 H); l3C NMR (75 MHz, CDCI3 ) ppm 76.00, 60.18, 44.79, 22.47; MS m/z (M+- Br) calcd. 237.0279, obsd. 237.0275. Anal. Calcd. for Ct 2H i4 Br2: C, 45.32; H, 4.44. Found: C, 45.93; H, 4.55. The bromochloride 38 eluted before the dibromide, usually in yields of 20-40%; 1 10 mp 106-107 °C: IR (CC14, cm 1) 2980, 2920, 2890, 1790, 1470, 1295, 1220, 1040, 1030, 1000, 985, 940; 'H NMR (300 MHz, CDCI 3 ) 8 2.50 (br s, 2 H), 2.45 (br s, 2 H), 2.35 (br s, 2 H), 1.92-1.83 (m, 4 H), 1.60-1.52 (m, 4 H); >3C NMR (75 MHz, C 6D6) ppm 77.54, 75.75, 60.46, 59.04, 44.42, 22.88, 21.29; MS m/z (M+) calcd. 271.9968, obsd. 271.9964. Decahydro-7,8-diiodO‘3,4.7-metheno>l//-cyclopeiita[a]pentalene (39). Iodine (4.12 g, 16.2 mmol) was added to a stirred mixture of disilver dicarboxylate 69 (0.50 g, 1.1 mmol) in dry CCI 4 (20 ml) at 65 I °C and stirred for 14 h. Saturated NaSC >3 solution (3 ml) was added to the cooled mixture and stirred until the burgundy color was replaced by a yellow precipitate. The mixture was filtered through Celite using generous amounts of CH 2CI2 to transfer and rinse the pad. Washing of the filtrate with saturated NaHCC >3 solution and brine, drying, and evaporation afforded a yellow solid that was dissolved in ethyl acetate and purified by preparative gas chromatography. First to elute was the chloroiodide, followed by 40 mg (22%) of the diiodide 39, mp 125 °C (dec.); IR (CCI 4 , cm-1) 2960, 2900, 2865, 1750, 1460, 1120, 955, 945, 930; lH NMR (300 MHz, CDCI 3) 8 2.34 (br s, 4 H), 2.29 (s, 2 H), 1.88-1.76 (m, 4 H), 1.72-1.62 (m, 4 H); 13C NMR (75 MHz, CDCI3 ) ppm 67.19, 62.33, 45.73, 24.92; MS m /z (M+) calcd. 411.9183, obsd. 411.9176. Ana/. Calcd. for Cj 2H 14I2: C, 34.98; H, 3.42. Found: C, 35.08; H, 3.55. The choroiodide 40 (9 mg, 6.5%) eluted prior to the diiodide and was identified by its mass and NMR spectra; mp 150-152 °C; IR (CC14, cm-1): 2960, 2870, 1845, 1775, 1460, 1290, 1260, 955, 910; lH NMR (300 MHz, CDCI 3) 8 2.48 (br m, 4 H), 2.25 (br s, 2 H), 1.92-1.47 (m, 8 H); *3C NMR (75 MHz, CDCI 3) ppm 62.64, 58.22, 57.06, 45.22, 25.24, 22.84, 20.85; MS m/z (M+) calcd. 319.9828, obsd. 319.9815. 111 7-ler/-Buty Ideca hydro-3,4,7-met heno- l//-cydopenta[a)pentalene (43). To a stirred solution of dibromide 37 (173 mg, 548 mmol) in |^ ether (10 ml) at 0 °C was added /err-butyllithium (1.7 M in pentane, C(CH3)3 3.25 ml) by syringe, causing a red color to develop immediately. After 6.5 h of stirring stirring at this temperature, saturated NH 4CI solution (1 ml) was added and the mixture was poured into water and extracted with CH 2CI2 (3 x 10 ml). GC- MS analysis revealed a 1:2.4 ratio of C 12 to Cje hydrocarbons. Due to the volatility of the C 12 product, drying and evaporation of solvent yielded an oil consisting almost entirely of the C 16 compound. Purification of the oil by preparative gas chromatography afforded 25 mg (21%) of the t-butyl hydrocarbon 42, mp 82-86 °C; IR (NaCl, cm '1) 2950, 2870, 1730, 1465, 1365, 1295; «H NMR (300 MHz, CDCI3) 8 2.18-2.12 (br m, 4 H), 2.07- 2.01 (br m, 2 H), 2.01-1.87 (m, 2 H), 1.53 (br s, 1 H), 1.51-1.36 (m, 6 H), 1.03 (s, 9H); 13C NMR (75 MHz, CDCI 3) ppm 57.47, 57.36, 53.76, 48.72, 48.16, 33.31, 28.95, 27.25, 23.06; MS m/z (M+) calcd. 216.1878, obsd. 216.1903. Anal. Calcd. for Ci 6H24 : C, 88.82; H, 11.18. Found: C, 88.47; H, 11.09. For compound 41: *H NMR (300 MHz, CDCI 3) 8 2.15-2.09 (m, 6 H), 1.52- 1.44 (m, 10 H); I3C NMR (75 MHz, CDCI3 ) ppm 52.93, 48.19, 46.35, 25.56; MS m/z (M+) calcd. 160.1252, obsd. 160.1213. 8-/er/-Butyldecahydro-3,4,7-metheno>7f/-cyclopenta[a]pentaIene-7-d (41); Decahydro-3,4,7-metheno-7//-cyclopenta[a]pentalene-7-d (42). To a stirred solution of 37 (116 mg, .37 mmol) in ether (10 ml) at 0 °C was added C(CH3)3 D fe/7-butyllithium (1.7 M in pentane, 2.15 ml). D 2O (0.1 ml, 5.5 mmol) was added after 1 min and the mixture was filtered and concentrated (no heat) to ca. 1 ml, then separated by preparative gas chromatography. 112 Mass spectral analysis of 41 revealed 45% d\ incorporation, whereas the 1H NMR spectrum of 42 indicated 35% d\ content to be present. (la/?,3a/?,7bS)-la,2,3,3a,5,6,7,7b-Octahydro-4f/-cyclobut[c was added via cannula to a mixture of potassium hydride (1.10 g, 27.5 mmol) and 18-crown-6 (7.26 g, 27.5 mmol) in THF (100 ml), and the mixture was heated to reflux for 6 h. The cooled mixture was quenched by careful addition of saturated aqueous ammonium chloride solution and extracted with ether. The combined organic phases were dried and concentrated, then chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to afford 1.17 g (65%) of 52; IR (neat, cm 1) 2950, 1694, 1610; ]H NMR (300 MHz, CDC13) 8 5.68 (d, J = 2.0 Hz, 1 H), 3.18- 3.12 (m, 2 H), 2.52-2.42 (m, 3 H), 2.40-2.31 (m, 1 H), 2.22-2.15 (m, 1 H), 2.00-1.89 (m, 2 H), 1.79-1.65 (m, 2 H), 1.60-1.53 (m, 1 H), 1.40-1.30 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 215.52, 147.99, 129.75, 52.19, 47.26, 44.91, 42.70, 30.01, 28.38, 26.07, 23.46; MS m/z (M+) calcd 162.1045, obsd 162.1049. Anal Calcd for Ci 1H 14O: C, 81.44; H, 8.70. Found: C, 81.17; H, 8.82. From debromination of 58. A mixture of 58 (1.031 g, 4.28 mmol), sodium iodide (1.923 g, 12.8 mmol), and trimethylsilylchloride (1.61 ml, 8 .6 mmol) in acetonitrile (30 ml) was stirred at room temperature for 2 h, poured into 10% aqueous sodium thiosulfate solution, and extracted with ether (3 x 20 ml). The extracts were washed consecutively with water and brine, then dried. Rotary evaporation yielded an oil that was chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to afford 0.54 g (77%) of 52. 113 (la/f,3a/f,5/?,7bS)-5-Bromo-la,2,3,3a,5,6,7,7b-octahydro-4//-cyclobutlc*/)azulen-4- one (58). O To a mixture of potassium hydride (0.532 g, 13.7 mmol) and 18-crown-6 (3.70 g, 14.0 mmol) in THF (30 ml) was added the mixture of alcohols 56a,b(0.533 g, 2.75 mmol) in THF (20 ml). The reaction mixture was stirred and heated to reflux for 4 h, then was cooled to -78 °C and quenched by the addtion via cannula of premixed trimethylsilyl chloride (1.75 ml, 13.7 mmol) and triethylamine (0.48 ml, 3.5 mmol). After being warmed to room temperature, the mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ether. The organic layers were dried and evaporated to yield an oil that was immediately dissolved in dry THF (10 ml) and propylene oxide (0.20 ml, 2.9 mmol) at 0 °C. N-Bromosuccinimide (511 mg, 2.89 mmol) was added to the solution, the cooling bath was removed, and the mixture was stirred at room temperature for 5 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with CH 2CI2 (3x5 ml), and the extracts were dried and concentrated to leave an oil that was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to afford 351 mg (53%) of 58; IR (neat, cm 1) 3040, 2940, 2860, 1690, 1400, 1425, 1250, 830, 790; lH NMR (300 MHz, CDCI 3) 6 5.71 (t J = 1 Hz, 1 H), 4.59 (dd, J = 7.4 Hz, 1.6 Hz, 1 H), 3.50 (dd, J = 7.3 Hz, 3.1 Hz, 1 H), 3.17-3.13 (m, 1 H), 2.81-2.72 (m, 1 H), 2.57- 2.45 (m, 1 H), 2.40-2.31 (m, 1 H), 2.20-1.87 (m, 4 H), 1.60-1.53 (m, 1 H), 1.45-1.32 (m, 1 H); >3C NMR (75 MHz, CDCI3) ppm 206.64, 147.61, 130.21, 57.43, 49.08, 46.64, 45.11, 31.68, 29.50, 27.06, 26.07; MS m /z (CnHi 380 BrO) calcd 242.0130, obsd 242.0134. 114 (la/?,3a/?,7bS)-la,2,3,3a,7,7b-Hexahydro>4f/>cyclobut(c4 mmol), powdered glass (200 mg), and HMPA (5 ml) was heated to 90 °C for 3 h. The cooled reaction mixture was poured into brine (15 ml) and extracted with ether (3 x 10 ml). The organic phases were washed with saturated aqueous copper sulfate solution, dried, concentrated, and chromatographed on silica gel (elution with 10% ethyl acetate in hexanes). Dienone 59 (10 mg, 12%) was the first compound to elute; *H NMR (300 MHz, CDCI3 ) 8 6.05 (dd,7 = 10.1 Hz, 3.3 Hz, 1 H), 5.81 (s, 1 H), 5.70 £td, J = 9.8 Hz, 3.3 Hz, 1 H\ 3.87-3.80 (m, 1 H), 3.63 (dd, J = 7.6 Hz, 3.5 Hz, 1 H), 3.27-3.24 (m, 1 H), 2.89-2.82 (m, 1 H), 2.78-2.69 (m, 1 H), 2.10-2.01 (m, 1 H), 1.98-1.88 (m, 1 H), 1.72- 1.66 (m, 1 H), 1.63-1.50 (m, 1 H); 13C NMR (75 MHz, CDCI3 ) ppm 209.86, 145.04, 131.30, 125.12, 124.93, 51.16, 46.84, 45.52, 44.43, 28.41, 25.63; MS m/z (M+) calcd 160.0888, obsd 160.0852. (la/f ,3aR,7bS)-1,1 a,2,3,3a,7b-Hexahydro-4//-cyclobut[ftf]azulen-4-one (60). O The second compound to elute was the conjugated dienone 60; IR (CDCI3, cm-1) 2970, 2950, 2870, 2260, 1725, 1660, 1635, 1465, 1450, 1310, 920; lH NMR (300 MHz, CDCI3) 8 6.42 (ddd, J = 12.4 Hz, 6.5 Hz, 0.6 Hz, 1 H), 5.93 (d, J = 12.4 Hz, 1 H), 5.77-5.72 (m, 1 H), 3.55-3.53 (br m, 1 H), 3.15-3.06 (m, 1 H), 2.87-2.77 (m, 1 H), 2.71-2.62 (m, 1 H), 2.33-2.17 (m, 2 H), 2.00-1.92 (m, 1 H), 1.84-1.70 (m, 2 H); 13C NMR (75 MHz, CDCI 3) ppm 203.36, 152.39, 137.30, 129.42, 118.42, 57.15,46.40, 36.74, 33.24, 30.42, 27.81; MS m/z (M+) calcd 160.0888, obsd 160.0935. 115 (IR,laS,3a/?,7bR)-l-Bromo>l, la,2,3,3a,5,6,7b-octahydro>4ff-cyclobut[c hexamethyldisilazane (0.48 ml, 2.27 mmol) in CH 2CI2 (10 ml) was »Br added via syringe trimethylsilyl iodide (0.28 ml, 2.1 mmol). After being stirred at room temperature for 48 h, the red solution was poured into saturated aqueous sodium bicarbonate solution and extracted with ether (2x5 ml) and dichloromethane (3x5 ml). The combined extracts were dried and concentrated, and the residual oil was dissolved immediately in dry THF (10 ml) and propylene oxide (0.15 ml, 2.1 mmol) at 0 °C. N-Bromosuccinimide (368 mg, 2.1 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to furnish 173 mg (38%) of 61; IR (neat, cm*1) 3030 (w), 2950, 2860, 1700 (s), 1440, 1340, 1305, 1190, 1160, 1120; ‘H NMR (300 MHz, C 6D6) 8 5.18 (d, J = 2.8 Hz, 1 H),4.11 (d,7= 1.3 Hz, 1 H), 3.56-3.50 (m, 1 H), 2.75-2.68 (m, I H), 2.56-2.45 (m, 1 H), 2.36-2.28 (m, 1 H), 1.94-1.81 (m, 3 H), 1.79-1.65 (m, 2 H), 1.30-1.14 (m, 2 H); NMR (75 MHz, C 6D6) ppm 209.86, 142.09, 126.38, 57.91, 50.38, 49.13, 45.48, 39.80, 31.10, 28.09, 27.83; MS m/z (M+) calcd 240.0150, obsd 240.0145. Anal. Calcd for C | 1H 13B1O: C, 54.79; H, 5.43. Found: C, 54.64; H, 5.55. (la/?,3aS,7b/?)-3a-Bromo-la,2,3,3a,5,6,7,7b-octahydro*4f/-cyclobut[cd]azulen-4-one (62). »r A solution of n-butyllithium in hexanes (1.0 ml, 1.3 mmol) was added via syringe to a solution of dry diisopropylamine (0.2 ml, 1.4 mmol) in dry THF (3 ml) at -78 °C and stirred for 10 min. Ketone 52 (196 mg, 1.21 mmol) in anhydrous THF (1 ml) was added via cannula, and stirring was 1 16 maintained for 20 min prior to treatment with premixed trimethylsily] chloride ( 0 .3 5 ml, 2.7 mmol) and triethylamine (0.55 ml, 4.0 mmol). After 30 min at room temperature, the solvent was evaporated. The residual lithium chloride slurry was repeatedly triturated with aliquots of pentane that were subsequently combined and concentrated. The resultant oil was dissolved immediately into dry THF (5 ml) and propylene oxide (0.09 ml, 1.3 mmol) at 0 °C. After addition of N-bromosuccinimide (225 mg, 1.27 mmol), the mixture was stirred for 15 min, poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined extracts were dried and concentrated, and the residual oil was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to afford 93 mg (32%) of 58 followed closely by 102 mg (35%) of 62; IR (neat, cm 1) 3040, 2950, 1715 (s), 1435, 1255, 845; NMR (300 MHz, CDCI3) S 5.73 (d, J = 1.2 Hz, 1 H), 3.51 (d, J = 2.3 Hz, 1 H), 3.38-3.31 (m, 1 H), 2.85 (br t, J = 12.0 Hz, 1 H), 2.62-2.56 (m, 1 H), 2.48-2.28 (m, 3 H), 2.18-2.00 (m, 2 H), 1.99- 1.84 (m, 1 H), 1.68-1.52 (m, 2 H); ‘3C NMR (75 MHz, CDCI 3) ppm 206.75, 149.72, 131.22, 69.73, 57.85, 45.21, 40.55, 36.52, 29.33, 25.42, 24.56; MS m /z (M+) calcd 240.0150, obsd 240.0123. Anal. Calcd for Cj 1H 13B1O: C, 54.79; H, 5.43. Found: C, 54.36; H, 5.41. (la/f,7b/?)-la,2,5,6,7,7b-Hexahydro-4//-cyclobut[c and powdered glass (100 mg) in HMPA (4 ml) was stirred and heated to 90 °C for 5 h. The cooled reaction mixture was poured into brine (15 ml) and water (10 ml to transfer) and extracted with ether. The extracts were washed with saturated aqueous copper sulfate solution, dried, and concentrated. The resulting oil was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to afford 14 117 mg (32%) of 63; IR (neat, c m 1) 3040, 2940, 1683 (s), 1610; >H NMR (300 MHz, CDCI3) 6 6.22-6.21 (m, 1 H), 5.64 (s, 1 H), 3.70 (d, J = 2.7 Hz, 1 H), 3.37-3.32 (m, I H), 2.68-2.54 (m, 3 H), 2.49-2.34 (m, 2 H), 2.26-2.15 (m, 1 H), 2.06-1.96 (m, 1 H), 1.67-1.52 (m, 1 H); I3C NMR (75 MHz, CDCb) ppm 201.45, 159.85, 147.25, 136.22, 128.03, 54.87,43.92, 42.18, 34.35, 31.20, 25.58; MS m/z (M+) calcd 160.0933, obsd 160.0916. (1 a/?,3aS £R ,7bR )-3a»5-Dibromo- la,2,3,3a,5,6,7,7b-octahydro-4//-cycIobut[c II SRr V, A solution of 62 (608 mg, 2.52 mmol) in anhydrous THF (3 ml) was added to a solution of lithium diisopropylamide (2.65 mmol)[prepared by the addition of a solution of n-butyllithium in hexanes (1.89 ml, 2.65 mmol) to a solution of dry diisopropylamine (0.37 ml, 2.65 mmol)] in dry THF (12 ml) at -78 °C. After being stirred for 30 min, the reaction mixture was quenched by the addition of premixed trimethylsilyl chloride (0.34 ml, 2.7 mmol) and triethylamine (0.095 ml, 0.68 mmol). The mixture was wanned to room temperature over 2 h, poured into saturated aqueous sodium bicarbonate solution, and extracted with ether. Drying and evaporation of the solvent afforded an oil that was dissolved immediately in anhydrous THF (15 ml) and propylene oxide (0.2 ml, 3 mmol) at -78 °C. N-Bromosuccinimide (470 mg, 2.65 mmol) was added and stirring was maintained for 2 h. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to yield 54.3 mg (67%) of 65; IR (neat, cm*1) 3040, 2940, 2865, 1700 (s), 1430, 1245, 1155, 1100, 1030, 905, 840; *H NMR (300 MHz, C6D6) 5 5.20 (d, J = 2.0 Hz, 1 H), 4.40 (dd, J = 7.5 Hz, 1.2 Hz, 1 H), 3.92-3.91 (m, 1 H), 3.05-2.98 (m, 1 H), 2.46-2.12 (m, 2 H), 2.10-1.91 (m, 1 H), 1.90-1.49 (m, 2 H), 1.46-1.35 (m, 1 H), 1.31-1.09 (m, 2 H); 13C NMR (75 MHz, C 6D6) ppm 200.20, 149.00, I 18 131.19, 66.33, 56.84, 54.81, 45.24, 38.57, 31.01, 26.27, 24.17; MS m /z (M+) calcd 317.9255, obsd 317.9278. (la/?,3aS,7b/?)-3a,5,5’-Tribromo-la,2,3,3a,5,6,7,7b-octahydro-4//-cyclobut[cd]- azulen-4-one ( 6 6 ). O _ A solution of n-butyllithium in hexanes (4.7 ml, 6.1 mmol) was added via syringe to a solution of dry diisopropylamine (0.90 ml, 6.4 mmol) in anhydrous THF (35 ml) at -78 °C and stirred for 15 min. Bromo ketone 62 (1.40 g, 5.82 mmol) in dry THF (5 ml) was added via cannula, and stirring was maintained for 30 min before the addition via cannula of premixed trimethylsilyl chloride (0.83 ml, 6.5 mmol) and triethylamine (0.22 ml, 1.6 mmol). After 30 min of stirring at room temperature, the solvent was evaporated and the residual lithium chloride slurry was repeatedly triturated with pentane. The combined pentane extracts were concentrated, and the resulting oil was dissolved immediately in dry THF (30 ml) and propylene oxide (0.45 ml, 6.5 mmol) at 0 °C. N-Bromosuccinimide (1.16 g, 6.5 mmol) was added and the mixture was stirred for 30 min. Solvent evaporation followed by chromatography of the residue on silica gel (elution with 5% ethyl acetate in hexanes) funished 1.02 g (44%) of tribromoketone 6 6 ; *H NMR (300 MHz, CDCI 3 ) 5 5.78 (d, J = 2.1 Hz, 1 H), 3.86 (s, 1 H), 3.38-3.34 (m, 1 H), 3.05-2.96 (m, 1 H), 2.72-2.52 (m, 1 H), 2.50-2.26 (m, 4 H), 1.98-1.88 (m, 1 H), 1.60 (dd, J =13.2 Hz, 6.3 Hz, 1 H); 13C NMR (75 MHz, CDCI3) ppm 193.17, 147.22, 131.83, 71.29, 64.08, 56.48, 46.13, 45.41, 39.64, 29.43, 23.44; MS m/z (M+ - Br) calcd 316.9177, obsd 316.9183. 1 19 (1alft7bR)-la,2,7,7b-Tetrahydro-4//-cyclobut[cd]azulen*4-one (67). A stirred mixture of 65 (232 mg. 0.723 mmol), lithium bromide (157 mg, 1.81 mmol) [dried at 140 °C and 1 Torr overnight prior to use], and lithium carbonate (161 mg, 2.17 mmol) in N,N- dimethylacetamide (10 ml) was heated to 150 °C until the bromo ketone was no longer detectable by t.l.c. analysis. The cooled mixture was poured into water (100ml) and extracted with ether. The combined extracts were washed consecutively with water and brine, dried, and concentrated. Chromatography of the residual oil on silica gel (elution with 10% ethyl acetate in hexanes) afforded 12 mg ( 10%) of 63 followed by 2 0 mg (17%) of 67; IR (CH 2C12, cm*1) 3065, 2995, 2920, 1635 (s), 1610, 1565, 1435, 1325, 1265, 895, 830; >H NMR (300 MHz, C 6D6) 6 6.19-6.08 (m, 2 H), 5.97-5.95 (m, 1 H), 5.20-5.16 (m, 1 H), 3.56-3.51 (m, 1 H), 2.87-2.77 (m, 1 H), 2.39-2.25 (m, 2 H), 2.02-1.94 (m, 1 H), 1.90-1.79 (m, 1 H); 13C NMR (75 MHz, C 6 D6) ppm 189.26, 152.36, 145.66, 137.66, 134.21, 130.64, 115.77, 52.20, 39.17, 37.99, 30.50; MS m/z (M+) calcd 158.0732, obsd 158.0734. (laR ,7bR)-la,7b-Dihydro-4-methoxy-2//-cyclobut[cd]azulene ( 6 8 ). MeO To a solution of trienone 67 (17.8 mg, 0.113 mmol) and dry HMPA (0.04 ml, 0.23 mmol) in THF (1 ml) at -78 °C was added dropwise a solution of potassium hexamethyldisilazide in toluene (0.3 ml, 0.15 mmol). The reaction mixture was stirred for 15 min, treated with methyl triflate (0.04 ml, 0.28 mmol), and stirred for an additional 15 min before being warmed to room temperature. Evaporation of the solvent afforded an oily residue that was chromatographed on Florisil (elution with 5% ether and 2% triethylamine in hexanes) to afford 8 mg (40%) of 6 8 as a yellow oil; ’H NMR (300 MHz, QsD 6) 6 6.19 (d, J = 11.4 Hz, 1 H), 5.87 (dd, J = 11.2 Hz, 9.0 Hz, 1 H), 5.58 (s, 1 H), 5.38 (t, J = 2.6 Hz, 1 H), 4.98 120 (d,7 = 8.8 Hz, 1 H), 3.31-3.22 (m, 2 H),3.20 (ddm, 7 = 18.9 Hz, 3.5 Hz, 1 H); 13C NMR {125 MHz, Q,D6) ppm 153.60, 140.74, 126.50, 125.80, 122.98, 119.71, 96.85, 54.63, 50.86,41.71; MS m/z (M+) calcd 172.0888, obsd 172.0885. (±)-(5/?*,6S*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradecan-ll-one (80); (±)-(57?*,6/?*)-l- Oxa-7-thiadispiro[4.0.4.4]tetradecan-l 1 -one (81). A solution of 2,3-dihydrothiophene (4.31 g, 50 mmol) in cold (-78 °C), dry THF (200 mL) was treated with rm-butyllithium (32.4 mL of 1.7 M in pentane) and stirred at this temperature for 1 h prior to the addition of 77 (6.75 g, 48.2 mmol) dissolved in THF (10 mL). After an additional 3 h of stirring at -78 °C, the reaction mixture was quenched with saturated NaHCC >3 solution, poured onto a larger volume of NaHC 0 3 solution, and extracted with ether. The combined extracts were washed with brine and dried prior to solvent evaporation. The residual oil was stirred with Dowex-50X resin (4.0 g) in CH 2CI2 (2000 mL) for 24 h, filtered, and concentrated. Chromatography on silica gel (elution with 20% ether in hexane) gave first 81 (5.06 g, 46%) and subsequently 80 (1.16 g, 11%). For 80: colorless crystals, mp 59-62 °C (from hexanes); IR (KBr, cm 1) 2950, 2875, 1705, 1445, 1430, 1310, 1235, 1080, 1070, 1045, 940, 890; >H NMR (300 MHz, CDCI3) 6 3.98-3.91 (m, 1 H), 3.88-3.80 (m, 1 H), 3.04-2.90 (m, 1 H), 2.89-2.80 (m, 2 H), 2.48-2.41 (m, 1 H), 2.27-2.24 (m, 1 H), 2.19-2.09 (m, 1 H), 2.01-1.59 (series of m, 9 H), 1.50-1.36 (m, 1 H); ,3C NMR (75 MHz, CDCI3) ppm 207.6, 87.5, 75.9, 68.3, 36.8, 36.3, 33.8, 32.5, 30.8, 30.5, 26.9, 19.3; MS m/z (M+) calcd. 210.1078, obsd. 210.1036. 121 For 81: colorless crystals, mp 60-62 °C (from hexanes); IR (KBr, cm 1) 1695; !H NMR (300 MHz, CDCI3 ) 5 3.90-3.83 (m, 1 H), 3.80-3.73 (m, 1 H), 2.95-2.77 (m, 3 H), 2.63 (ddd, J = 13.0, 5.9, 3.3 Hz, 1 H), 2.28-2.22 (m, 1 H), 2.18-2.06 (m, 2 H), 2.05-1.75 (m, 7 H), 1.74-1.65 (m, I H), 1.49 (ddd, J= 10.8, 12.9, 6 .6 Hz, 1 H), ’^C NMR (75 MHz, CDCI3) ppm 207.9, 90.7, 71.4, 69.0, 37.0, 36.0, 34.4, 34.3, 31.3, 30.9, 25.9, 20.3; MS m/z (M+-H) calcd. 209.1000, obsd. 209.0967. Anal. Calcd for Ci 2Hig02S: C, 63.68; H, 8.02. Found: C, 63.59; H, 7.95. l-Thiaspiro[4.5]decan-6-one (82). O A 1.73 g (20.1 mmol) sample of 2,3-dihydrothiophene dissolved in dry THF (80 mL) was metalated as described above with tert- butyllithium (12.4 mL of 1.7 M). Cyclobutanone (1.28 g, 18.3 mmol) was introduced via cannula, followed 3 h later by the same workup. The resulting unpurified carbinol was stirred with Dowex-50X resin (3.0 g) in CH 2C12 (1000 mL) for 2 days; subsequent purification by silica gel chromatography (elution with 10% ethyl acetate in hexanes) gave 2.55 g (89%) of 82 as a colorless oil; IR (neat, cm*1) 1745; *H NMR (300 MHz, CDCI3) 6 3.00-2.94 (m, 2 H), 2.53-2.42 (m, 1 H), 2.41-2.31 (m, 1 H), 2.25-2.04 (m, 5 H), 2.02-1.92 (m, 1 H), 1.91-1.75 (m, 2 H); NMR (75 MHz, CDCI 3) ppm 216.0, 63.5, 38.3, 36.8, 35.3, 33.2, 30.6, 19.8; MS m/z (M+) calcd. 156.0609, obsd. 156.0610. A nal Calcd for C 8 H i2OS: C, 61.50; H, 7.74. Found: C, 61.58; H, 7.73. 122 (±)-(5/?*,6/?*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradecan-14-one (83); (±)-(5/?*,6S*)-l- Oxa-7-thiadispiro[4.0.4.4]tetradecan-14-one (84). Cerium trichloride heptahydrate (5.77 g, 15.5 mmol) was heated at 140 °C and 1 Torr overnight. After cooling, anhydrous THF (100 mL) was introduced and the slurry was stirred at rt for 3 h, cooled to -78 °C, and treated dropwise with /err-butyllithium until a pink color persisted. A solution of 5-lithio-2,3-dihydrofuran in dry THF (25 mL) (prepared from 987 mg (14.1 mmol) of 2,3-dihydrofuran and 9.11 mL of 1.7 M /erf-butyllithium] was next introduced and the reaction mixture was stirred at -78 °C for 2 h before the addition of 82 (2.003 g, 12.8 mmol) via cannula. After an additional 3 h in the cold, the mixture was allowed to warm to rt and worked up in the predescribed manner. The unpurified carbinol was dissolved in CH 2CI2 (1000 mL) and stirred with Dowex-50X resin (3.0 g) for 48 h. The products, isolated as before, were separated by chromatography on silica gel (elution with 10% ether in hexanes). The first to elute was 83 (1.536 g, 53%) to be followed by 84 (1.239 g, 43%). For 83: colorless crystals (from hexanes), mp 50-52 °C; IR (KBr, cm '1) 1710; *H NMR (300 MHz, C6D6) 6 3.77 (dd, J = 14.7, 7.6 Hz, 1 H), 3.48 (dt, J = 5.1, 7.7 Hz, 1 H), 2.95-2.84 (m, 1 H), 2.61-2.35 (m, 4 H), 2.06-2.00 (m, 1 H), 1.89-1.80 (m, 1 H). 1.75-1.46 (m, 6 H), 1.45-1.22 (m, 2 H), 1.18-1.08 (m, 1 H); 13C NMR (75 MHz, C 6D6) ppm 208.9, 94.3, 69.2, 68.9, 37.4, 36.9, 34.7, 32.4, 31.0, 26.9, 26.6, 23.6; MS m /z (M+) calcd. 226.1028, obsd. 226.1027. For 84: colorless crystals, mp 63-65 °C (from hexanes); IR (KBr, cm*1) 1705; ’H NMR (300 MHz, C6D6) 6 3.72-3.65 (m, 1 H), 3.58-3.51 (m, 1 H), 2.60-2.42 (m, 4 H), 2.17-2.05 (m, 2 H), 1.92-1.78 (m, 2 H), 1.77-1.45 (m, 8 H); ,3C NMR (75 MHz, C 6D6) 123 ppm 207.3, 93.5, 69.4, 67.8, 38.31, 38.26, 37.6, 33.5, 30.9, 29.1, 26.6, 23.0; MS m/z (M+) calcd. 226.1028, obsd. 226.1028. Anal. Calcd for C 12H 18 O2S: C, 63.68; H, 8.02. Found: C, 63.83; H, 8.12. (±)-(5/f *,6J?*)-1,7-Dithiadispiro[4.0.4.4]tetradecan-11-one (85); (±)-(5/?*,6S*)-l,7- Dithiadispiro[4.0.4.4]tetradecan-11-one (86). Cerium trichloride heptahydrate (7.357 g, 19.8 mmol) was heated at 140 °C and 1 Torr overnight. After cooling, dry THF (125 mL) was added and the slurry was stirred at rt for 3 h prior to cooling to -78 °C and dropwise titration with rm-butyllithium until a faint pink color persisted. At this point, a solution of 5-lithio-2,3-dihydrothiophene [from 1.547 g (17.9 mmol) of 2,3- dihydrothiophene and 11.62 mL of 1.7 M ferr-butyllithium in dry THF (35 mL)] was introduced via cannula. The slurry was stirred for 2 h in the cold before 82 (2.55 g, 16.3 mmol) was added. This mixture was stirred at -78 °C for 3 h, then warmed to rt and worked up as predescribed. The resulting oily carbinol was dissolved in CH 2CI2 (1000 mL), stirred with Dowex-50X (5.0 g) for 6 days, filtered, and evaporated. The residue was subjected to silica gel chromatography (elution with 5% ether in hexanes) to furnish initially 86 (1.476 g, 37%) and subsequently 85 (1.223 g, 31%). For 85: colorless crystals, mp 92.5-95 °C (from hexanes); IR (KBr, cn r1) 1695; 'H NMR (300 MHz, CDCI3) 6 3.04 (td,7 = 13.9, 7.1 Hz, 1 H), 2.96-2.71 (m, 4 H), 2.58 (dd, J = 11.6, 5.5 Hz, 1 H), 2.28-2.16 (m, 3 H), 2.14-1.99 (m, 4 H), 1.92-1.78 (m, 2 H), 1.76-1.56 (m, 3 H); 13C NMR (75 MHz, CDCI3) ppm 207.4, 75.2, 70.8, 41.2, 37.0, 35.5, 34.4, 32.4, 32.1, 32.0, 31.2, 22.2; MS m/z (M+) calcd. 242.0799, obsd. 242.0802. Ana/. Calcd for Ci 2H 18 OS2: C, 59.46; H, 7.48. Found: C, 59.44; H, 7.47. 124 For 8 6 : colorless crystals, mp 107-1 10 °C (from hexanes); IR (KBr, cm'1) 1690; 'H NMR (300 MHz, CDCI3 ) 6 2.97-2.75 (m, 6 H), 2.26-1.78 (m, 11 H). 1.68-1.57 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 206.2, 74.5, 6 8 .8 , 40.4, 39.8, 36.9, 35.1, 34.7, 32.7, 31.1, 30.1, 22.0; MS m/z (M+) calcd. 242.0799, obsd. 242.0809. (S)-S-[[(5J?,6lf,l 1S)-1 1-Hydroxy-1,7-dioxadispiro[4.0.4.4]tetradec-l l-yl]methyl]-jV- methyl-S-phenylstilfoximine (87). Ph J A solution of (+)-(S)-iV5-Dimethyl-(5)-phenylsulfoximine (885 mg, 5.23 mmol) in dry THF (35 mL) was cooled to -78 °C and HO After 30 min, a cold (-78 °C) solution of (±)-72 (1.00 g, 4.76 mmol) in the same solvent (5 mL) was introduced via cannula. The reaction mixture was stirred under nitrogen for 1 h before being poured into saturated NH 4CI solution. The products were extracted into ether and the combined organic phases were dried and evaporated. The residual viscous gum was chromatographed on silica gel (elution with 60% ether in hexanes) to separate the two most prevalent diastereo-meric adducts. The least polar isomer, referred to as 87 (642 mg, 36%) was isolated in a pure state. The more polar product 8 8 was resubjected to MPLC (silica gel, elution with 50% ether in hexanes) for further purification (196 mg, 11%). A third fraction composed of 8 8 and a third diastereomer (263 mg, 15%) was also obtained. For 87: colorless crystals, mp 167-169 °C (from hexanes); IR (KBr, cm '1) 3500- 3100, 1440, 1300, 1210, 1145, 1070, 1040, 880, 850, 740; >H NMR (250 MHz, C 6 D6, 350 K) 6 7.78-7.72 (m, 2 H), 7.23 (br s, 1 H), 7.04-6.96 (m, 3 H), 4.53-4.47 (br m, 1 H), 4.13-4.10 (br m, 1 H), 3.93-3.78 (m, 2 H), 3.62-3.48 (m, 2 H), 3.20-3.00 (br s, 1 H), 2.54 125 (s, 3 H), 2.54-2.45 C6D6)ppm 140.1, 132.4, 129.4, 129.1,92.5,89.0,79.7,71.1,68.9,59.0, 36.6, 36.4,33.7, 30.9, 28.9, 27.4, 25.5, 19.8; MS m/z (M+) calcd. 379.1817, obsd. 379.1814; [a^°+44.8° Anal. Calcd for C 20H29 NO4S: C, 63.30; H, 7.70. Found: C, 63.35; H, 7.77. Thermal Activation of 87. The adduct 87 (642 mg, 1.69 mmol) was heated at reflux in toluene (25 mL) for 48 h, cooled, and introduced directly on a silica gel column. After removal of the toluene by hexane elution, recourse to ethyl acetate-hexane ( 1: 1) eluted fractions containing pure (+)-72, which was recrystallized from hexane; [ajp +54.1° (c 9.93, CHCI 3). The second adduct 8 8 (196 mg, 0.52 mmol) was likewise heated in toluene (10 mL) for 20 h to give (-)-72 quantitatively, [cc ]^0 -52.8° (c 6.16, CHCI 3). (S)-S-[[5S»6tf,ll/?)-ll-Hydroxy-l-oxa-7-thiadispiro[4.0.4.4]tetradec-ll-yl]methyl]- jV-niethyI-5-phenylsulfoximine (89). Ph f Condensation of the (S)-(+)-sulfoximine (635 mg, 3.75 mmol) with 81 (772 mg, 3.41 mmol) in the predescribed manner HO followed by silica gel chromatography (gradient elution 10-50% ethyl acetate in hexanes) returned 97 mg (13%) of unreacted 81 and permitted the isolation of three adducts: A (432 mg, 37%), B (283 mg, 24%), and C (121 mg, 10%). For the major diastereomer (89): colorless solid, mp 159-161 °C (from ethyl acetate); IR (KBr, cm '1) 3400-3030, 1445, 1340, 1240, 1150, 1080, 1030, 995, 880; *H NMR (300 MHz, CDCI3) 6 7.88-7.85 (m, 2 H), 7.63-7.52 (m, 3 H), 7.26 (br s, 1 H), 3.75 126 (I, J - 6 .6 Hz, 2 H), 3.0-1.3 (series of m, 21 H); l3C NMR (62.5 MHz, C 6D6 ) ppm 140.9, 132.6, 129.5, 129.1, 89.7, 79.6, 77.1, 67.8, 62.0, 36.5, 36.0, 35.1, 34.2, 34.0, 33.5, 28.7, 26.8, 19.8; MS m/z (M,+) calcd. 395.1589, obsd. 395.1600; [a£°+38.2° (c 9.88, CH 2CI2). Anal. Calcd for C 2qH29 N0 3 S2: C, 60.73; H, 7.39. Found: C, 60.58; H, 7.40. Thermal Activation of 89. A solution of this adduct (384 mg, 0.97 mmol) in toluene (20 mL) was refluxed for 40 h, evaporated, and directly chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to furnish (+)-81 (213 mg, 97%), [a ]^0 +83.3° (c 6.25, CH2C12). (S)-S-l[5lf,6S, I l/f)-l 1-Hydroxy-1,7-dithiadispiro[4.0.4.4]tetradec-l 1 -yl]methyl]-jV- me thy 1-5-phenylsulfoxi mine (90). Ph Analoguous condensation of 8 6 (1.340 g, 5.53 mmol) with the O OH (S)-(+)-sulfoximine (1.029 g, 6.08 mmol) and comparable workup afforded four diastereomeric adducts; A (114 mg, 5%), B (397 mg, 17%), C, (746 mg, 33%), and D (753 mg, 33%). For diastereomer C (90): colorless solid, mp 167.5-170 °C (from ether-hexanes); IR (KBr, cm-1) 3600-3000, 1455, 1440, 1425, 1345, 1300, 1230, 1145, 1070, 980, 760, 735, 690, 630; «H NMR (300 MHz, CDC13) 8 7.87-7.84 (m, 2 H), 7.64-7.53 (m, 3 H), 3.90 (br 8 , J = 13.5 Hz, 1 H), 3.57 (br 8 , J = 13.2 Hz, 1 H), 2.83-2.79 (m, 2 H), 2.77-2.65 (m, 2 H), 2.60-2.54 (m, 1 H), 2.54 (s, 3 H), 2.49-2.31 (m, 1 H), 2.15- 1.63 (series of m, 12 H), 1.47 (dm, J = 13.3 Hz, 1 H); 13C NMR (75 MHz, CDCI3) ppm 138.7, 133.2, 129.6, 128.7, 78.4, 67.8, 61.7, 41.61, 41.55, 39.6, 35.1, 33.9, 33.7, 33.6, 28.5, 26.3, 17.7 (1C not observed due to conformational exchange broadening); MS m/z (M+-PhSONMe) calcd. 257.1034, obsd. 257.0993; [a ]*0 +39.1° (c 7.68, CH 2C12). 127 Anal. Calcd for C 20H29 NO2S3: C, 58.36; H, 7.10. Found: C, 58.57; H, 7.32. Thermal Activation of 90. A solution of this adduct (237 mg, 0.575 mmol) in toluene (10 mL) was refluxed for 72 h, evaporated, and chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to give (-)- 8 6 , mp 107-110 °C, [a]^° -121.8° (c 3.33, CH 2C12). (±)-l -Oxadispiro[4.0.4.4]tetradecan-14-one (97). o II °" ^ \ Cerium trichloride heptahydrate (11.64 g, 31.2 mmol) was heated I at 140 °C and 1 Torr overnight. After the solid had cooled, anhydrous —/ THF (90 mL) was introduced and the slurry was stirred at rt for 3 h, cooled to -78 °C, and treated dropwise with /er/-butyllithium until a pink color persisted. A solution of 5-lithio-2,3-dihydrofuran in dry THF (25 mL) [prepared from 2.190 g (31.2 mmol) of 2,3-dihydrofuran 103 and 20.22 mL of 1.7 M tert- butyllithium] was next introduced, and the reaction mixture was stirred at -78 °C for 3 h before the introduction via cannula of 96136 (3.598 g, 26.0 mmol) dissolved in dry THF (2 mL). After an additional 4 h in the cold, the mixture was allowed to warm to rt, poured into saturated NaHCC >3 solution, and extracted into ether (2x) and CH 2CI2 (2x). The combined extracts were washed with brine and dried prior to solvent evaporation. The unpurified carbinol was stirred with Dowex-50X resin (2.0 g) in CH 2CI2 (200 mL) for 20 h, filtered, and concentrated. Chromatography of the oil on silica gel (elution with 15% ethyl acetate in hexanes) furnished 4.913 g (90.6%) of 6 ; IR (neat, c m 1) 2960, 2880, 1715, 1445, 1300, 1090, 1050; JH NMR (300 MHz, CDCI 3) 83.92-3.85 (m, 1 H), 3.77-3.69 (m, 1 H), 2.72-2.63 (m, 1 H), 2.38-2.20 (m, 2 H), 1.89-1.69 (m, 7 H), 1.68-1.23 128 (m, 8 H); 13C NMR (75 MHz, CDCI3) ppm 212.4, 93.6, 68.5, 53.5, 37.8, 35.4, 33.9, 33.3, 28.2, 26.2, 25.9, 25.7, 22.7; MS m/z (M+) calcd 208.1463, obsd 208.1469. Anal. Calcd for C 13H20O2: C, 74.96; H, 9.68. Found: C, 75.06; H, 9.73. (5X*,13J?*)-13-Bromo-l-oxadispiro[4.0.4.4]tetradecan-14-one (98); (5/f*,135*)-13- Bromo-l-oxadispiro[4.0.4.4]tetradecan-14-one (99). o o A solution of 97 (500 mg, 2.40 mmol) in THF (5 mL) was transferred by cannula to a stirred mixture of pyridinium hydrobromide perbromide (806 mg, 2.52 mmol) in THF (5 mL) at 0 °C. Additional brominating agent (100 mg) was added after 30 min, and again after 1 h. After an additional 2 h of stirring, the reaction mixture was diluted with ether, washed with 10% Na 2S2 0 3 solution and brine, then dried. Evaporation of the solvent and chromatography of the residue on silica gel (elution with 2 0 % ethyl acetate in hexanes) gave first the anti isomer 98 (524 mg, 76%) and subsequently the syn isomer 99 (111 mg, 16%). For 98: IR (neat, cm '1) 2955, 2875, 1735, 1450, 1290, 1050; »H NMR (300 MHz, CDCI3) 6 5.36 (dd, J = 12.5 Hz, 6.5 Hz, 1 H), 3.89-3.81 (m, 1 H), 3.68-3.60 (m, 1 H), 2.70-2.61 (m, 1 H), 2.51-2.43 (m, 1 H), 2.22-1.96 (m, 2 H), 1.88-1.74 (m, 3 H), 1.67- 1.41 (m, 6 H), 1.40-1.29 (m, 2 H), 1.26-1.18 (m, 1 H); 13C NMR (75 MHz, CDCI 3) ppm 203.0, 94.8, 68.9, 54.3, 53.6, 36.0, 35.5, 32.1, 26.2, 26.1, 25.9, 25.8; MS m/z (M+) calcd 286.0569, obsd 286.0568. For 99: mp 85-86 °C (from hexanes); IR (CH 2CI2, cm-1) 2960, 2880, 1740, 1450, 1260, 1200, 1115, 1095, 1055, 990, 910; ‘H NMR (300 MHz, CDCI 3) 5 4.82 (dd, J = 12.8 Hz, 6 .8 Hz, 1 H), 3.99-3.84 (m, 2 H), 2.49-2.40 (m, 1 H), 2.21-2.00 (m, 2 H), 1.97- 129 1.78 (m, 3 H). 1.77-1.55 (m, 7 H), 1.49-1.33 (m, 2 H), 1.24-1.14 MHz, CDC13) ppm 2 0 2 . 1, 93.7, 6 8 .6 , 53.5, 53.4, 36.1, 34.6, 34.2, 32.2, 32.1, 26.4, 25.7, 25.1; MS m/z (M+) calcd 286.0569, obsd 286.0580. Anal. Calcd for C 13H 19 B1O 2 : C, 54.37; H, 6.67. Found: C, 54.47; H, 6.71. (±)-1 -Oxadispiro[4.0.4.4]tetradec- 12-en-l 4-one (100). o Lithium bromide (5.643 g, 65.0 mmol) was heated to 140 °C and 1 Torr for 3 h. After the solid had cooled, N,N-dimethylacetamide (200 mL) was introduced followed by Li 2CC>3 (4.072 g, 55.1 mmol). The mixture was heated to 100 °C, a solution of 98 and 99 (4.78 g, 16.6 mmol) in N,N-dimethylacetamide (10 mL) was added, and the temperature was raised to 170 °C. After 75 min at this temperature, none of the starting material remained. The cooled mixture was diluted with ether and filtered through a pad of Celite. Concentration of the filtrate followed by Kugelrohr distillation of the acetamide left a dark residue which was triturated with ether. Filtration and evaporation of the solvent followed by chromato graphy of the oil on silica gel (elution with 10% ether in hexanes) afforded 2.85 g (83%) of 100; IR (neat, c m 1) 3035, 2955, 2875, 1680, 1450, 1425, 1380, 1090, 795; ‘H NMR (300 MHz, CDCI3) 6 6 .6 8 (dt, J = 10.0 Hz, 4.0 Hz, 1 H), 5.86 (dt, J = 10 Hz, 1.7 Hz, 1 H), 4.00-3.85 (br m, 1 H), 3.85-3.78 (m, 1 H), 2.40-2.21 (m, 2 H), 2.04-1.58 (m, 5 H), 1.52 (br d, J = 7.4 Hz, 5 H), 1.32-1.25 (m, 2 H); 13C NMR (62.5 MHz, 330K, CDCI3) ppm 200.0, 147.4, 127.9, 90.3, 69.4, 51.2, 39.6, 33.8, 33.7, 29.2, 25.7, 25.4, 25.2; MS m/z (M+) calcd 206.1307, obsd 206.1304. Anal. Calcd for C 13H 18 O 2: C, 75.69; H, 8.79. Found; C, 75.98; H, 8.82. 130 l-Oxadispiro[4.0.4.4]tetradec-12-en-14-ol (101). OH A stirred mixture of 100 (2.85 g, 13.8 mmol) and cerium trichloride heptahydrate (5.66 g, 15.2 mmol) in methanol (50 mL) was treated with sodium borohydride (575 mg, 15.2 mmol). When TLC analysis indicated that starting material remained after 10 min , small additional quantities of hydride reagent were added until UV-active compounds were no longer detected. The reaction mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated and the residual oil was chromatographed on silica gel (elution with 40% ethyl acetate in hexanes) to afford 2.631 g (91%) of a 2.3 : 1 mixture of allylic alcohols 101; IR (neat, cm '1) 3635-3095, 3030, 2955, 2875, 1655, 1450, 1425, 1300, 1230, 1100, 1050, 975, 910, 825, 740; >H NMR (300 MHz, C 6D6) 5 5.79 (dq, J = 10.0 Hz, 4.4 Hz, 2.4 Hz, 1 H), 5.69 (dm, J = 10 Hz, 0.43 H), 5.62-5.55 (m, 1 H), 5.45-5.38 (m, 0.43 H), 4.34 (br s, 0.43 H), 3.95-3.88 (m, 0.43 H), 3.83 (br d, J = 8.4 Hz, 1 H), 3.73-3.60 (m, 2.62 H), 2.29 (d, J = 8.4 Hz, 1 H), 2.19-2.05 (m, 2 H), 2.02-1.85 (m, 1.2 H), 1.82-1.65 (m, 6 H), 1.63-1.32 (m, 11 H), 1.28-1.23 (m, 2.4 H), 1.09-1.01 (m, 0.6 H); ,3C NMR (75 MHz, C6D6) ppm 131.3, 129.8, 128.4, 127.1, 89.1, 87.9, 73.8, 72.6, 70.4, 70.1, 51.1, 49.9, 38.5, 36.9, 34.6, 34.4, 34.1, 32.5, 30.8, 28.4, 28.1, 27.3, 25.5, 24.7, 24.4 (one signal not resolved); MS m/z (M+- H 2O) calcd 190.1358, obsd 190.1383. Anal. Calcd for C | 3H2o02: C, 74.96; H, 9.68. Found: C, 74.58; H, 9.72. (±)-l-Oxadisplro[4.0.4.4]tetradeca-l 1,13-diene (102). To a stirred solution of allylic alcohols 101 (363 mg, 1.74 mmol) and triethylamine (1.0 mL, 7.0 mmol) in 1,2-dichloroethane (15 mL) was added 2,4-dinitrobenzenesulfenyl chloride (1.23 g, 5.23 mmol). The mixture was stirred at reflux for 8 h, cooled, poured into ether, and filtered through Celite. Evaporation of the solvent afforded a dark oil that was chromatographed on silica 131 gel (elution with 5% ethyl acetate and 1 7c triethylamine in hexanes) to afford 187 mg (57%) of 102 as a colorless oil; IR (neat, c m 1) 3040, 2960, 2880, 1725, 1450, 1070, 735; ’H NMR (300 MHz, C6 D6) 5 5.80-5.72 (m, 2 H), 5.70-5.61 (m, 2 H), 3.77-3.70 (m, I H), 3.67-3.60 (m, 1 H), 2.47-2.37 (m, 1 H), 2.03-1.92 (m, 1 H), 1.78-1.44 (m, 10 H); ,3C NMR (75 MHz,C 6D6)ppm 140.3, 136.6, 122.5, 121.0, 86.2, 67.9,51.3, 34.3, 33.5,33.2, 26.3, 25.21, 25.1; MS m/z (M+) calcd 190.1358, obsd 190.1359. Anal. Calcd forCisHisO: C, 82.06; H, 9.53. Found: C, 81.76; H, 9.62. (±M5£*,6#?*)-l,7-Dtoxadispiro[4.0.4.4]tetradec-12-en-l 1-one (104). O To a stirred solution of pyridinium hydrobromide perbromide (3.838 g, 12.00 mmol) in THF (35 mL) at 0 °C was added via cannula a solution of 72 (2.41 g, 11.5 mmol) in THF (10 mL). After being stirred for 30 min, the reaction mixture was diluted with ether and washed consecutively with 10% Na2S2C>3 solution, water, and brine. The organic layer was dried and evaporated, and the residue was chromatographed on silica gel (elution with 30% ethyl acetate in hexanes) to furnish 2.19 g ( 6 6 %) of the major diastereomer followed by 0.59 g (17.8%) of the minor diastereomer. For the major diastereomer; mp 63-64 °C; IR (CDCI 3, cm*1) 2980, 1730, 1440, 1075; ’H NMR (300 MHz, CDCl3 )8 5.21 (dd, J= 11.3 Hz, 6.7 Hz, 1 H), 3.93-3.85 (m, 3 H), 3.81-3.75 (m, 1 H), 2.61-2.44 (m, 2 H), 2.34-2.24 (m, 1 H), 1.98-1.85 (m, 3 H), 1.83- 1.63 (m, 4 H), 1.61-1.57 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 201.3, 94.5, 87.6, 69.4, 69.0, 52.7, 33.1, 32.2, 31.2, 26.2, 26.1, 25.9; MS m/z (M+) calcd 288.0362, obsd 288.0347. A solution of the above bromo ketones (2.758 g, 9.537 mmol) in N,N- dimethylacetamide (10 mL) was added to a mixture of lithium bromide (2.930 g, 23.84 mmol) [heated overnight at 140 °C and 1 Torr before use] and lithium carbonate (2.114 g. 132 28.61 mmol) in the same solvent (40 mL). The mixture was heated to 170 °C for 3 h, cooled, poured into ether, and filtered through Celite. Rotary evaporation of the ether and Kugelrohr distillation of the acetamide left a solid that was triturated with ether. Filtration of the extracts and evaporation afforded an oil that was chromatographed on silica gel (elution with 1:1 ethyl acetate-hexanes) to furnish 1.331 g (67%) of 104 as a colorless oil; IR (neat, c m 1) 2990, 1690, 1450, 1380, 1200, 1100, 1050; 'H NMR (300 MHz, 373K, toluene-dg) 8 6.26 (dt, J - 10.1 Hz, 4.3 Hz, 1 H), 5.85 (dt, J = 10.1 Hz, 2.1 Hz, 1 H), 3.84-3.71 (m, 2 H), 3.69-3.65 (m, 2 H), 2.63 (br d, J = 7.9 Hz, 1 H), 2.16-2.09 (br m, 1 H), 2.05-1.44 (m, 7 H), 1.33-1.22 (m, 1 H); 13C NMR (75 MHz, 373K, toluene- d%) ppm 145.2, 128.5, 91.1, 87.4, 69.5, 6 8 .8 , 38.2, 33.1, 26.4, 26.1 (two signals not observed); MS m/z (M+) calcd 208.1099, obsd 208.1101. A nal Calcd for C\2H i60 3: C, 69.21; H, 7.74. Found: C, 69.24; H, 7.89. (5/?*,6/?*)-l,7-Dioxadisplro[4.0.4.4]tetradeca-ll,13-diene (105). Use of Dibal-H. i y cooled to 0 °C and treated with a solution of diisobutylaluminum hydride in hexanes (11.3 mL, 11.3 mmol). The reaction mixture was stirred for 1 h, methanol (3 mL) was added, and stirring was maintained for 8 h. The mixture was poured into 50 mL each of 10% HC1 and brine, and extracted with ether. The combined organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 1:1 ethyl acetate-hexanes) to afford a quantitative yield of one allylic alcohol; IR (neat, cm ') 3700-3120, 3040, 2990, 2880, 1465, 1430, 1070, 930, 840, 740, 710; 'H NMR (250 MHz, 350K, C 6 D6) 8 5.72-5.65 (m, I H), 5.52-5.44 (m, 1 H), 3.98-3.79 (m, 3 H), 3.70-3.56 (m, 2 H), 2.65 (br s, 1 H), 2.47 (dd, J = 17.3 Hz, 2.2 Hz, 1 H), 1.81-1.68 (m, 5 H), 1.61-1.43 (m, 3 H), 1.40-1.29 (m, 1 H); ' 3C NMR (62.5 133 MHz, 350K, C6 D6) ppm 130.7, 127.0, 87.9, 87.5, 72.6, 70.1, 68.3, 36.2, 33.0, 29.6, 27.0, 25.5; MS m/z (M+) calcd 210.1256, obsd 210.1228. Anal. Calcd forC^HisO.r C, 68.55; H, 8.63. Found: C, 68.22; H, 8.72. B. Use of NaBH 4 -C eC l3, To a mixture of 104 {500 mg, 2.4 mmol) and CeCl3* 7 H2 0 (895 mg, 2.4 mmol) in methanol (6 mL) was added sodium borohydride (91 mg, 2.4 mmol). Two additional amounts of NaBH 4 (ca 20 mg each) were added until none of the enone could be detected by TLC analysis. The reaction mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 60% ethyl acetate in hexanes) to afford 307 mg (61%) of the alcohol described above, followed by 45 mg (9%) of its epimer; IR (neat, c m 1) 3700-3120, 3040, 2995, 2985, 1465, 1430, 1070, 930, 840, 735, 710; >H NMR (300 MHz, CDCI 3) 8 5.67-5.54 (m, 2 H), 4.56 (br s, 1 H), 4.10- 4.01 (m, 1 H), 3.98-3.91 (m, 1 H), 3.86-3.75 (m, 2 H), 2.21-1.74 (m, 9 H), 1.59-1.48 (m, 2 H); »3C NMR (75 MHz, CDCI3) ppm 130.1, 126.1, 89.3, 87.2, 72.8, 70.3, 68.3, 38.1, 32.1, 29.0, 27.2, 25.9; MS m/z (M+) calcd. 210.1256, obsd. 210.1251. To a stirred solution of the above alcohol (1.279 g, 6.08 mmol) and triethylamine (2.5 mL, 18 mmol) in 1,2-dichloroethane (30 mL) was added 2,4-dinitrobenzenesulfenyl chloride (2.854 g, 12.2 mmol). The mixture was stirred and heated to reflux for 12 h, then poured into saturated NaHC 0 3 solution, and extracted with CH 2C 12- The combined organic phases were dried and evaporated. Chromatography of the residual brown oil on silica gel (elution with 1:1 ethyl acetate-hexanes) followed by rechroma-tography of the diene-containing fractions on neutral alumina (elution with 10% ethyl acetate in hexanes) afforded 663 mg (57%) of 105 as a colorless solid, mp 52-54 °C (sublimation); IR (KBr, c m 1) 3050, 2950, 2870, 1450, 1405, 1310, 1200, 1100, 1075, 1050, 935, 865, 725, 660; 'H NMR (300 MHz, CDCI3) 5 5.92-5.83 (m, 4 H), 4.00-3.94 (m, 2 H), 3.90-3.82 (m, 2 H), 2.16-2.06 (m. 2 H), 1.98-1.89 (m, 4 H), 1.83-1.76 (quint, J = 5.6 Hz, 2 H); 13C NMR 134 (75 MHz. CDCI3 ) ppm 135.6, 123.1, 85.3, 68.7, 33.5, 26.2; MS m/z (M+) calcd 192.1150, obsd 192.1147. Anal. Calcd for C | 2H |60 2: C, 74.97; H, 8.39. Found: C, 74.88; H, 8.54. (±)^5R*,6S* )-1,7-Dioxadispiro[4.0.4.4]tetradec-12-en-l 1 -one (107). To a solution of pyridinium hydrobromide perbromide (2.71 g, 8.85 mmol) in THF (35 mL) at 0 °C was added dropwise a solution of 73 (1.77 g, 8.36 mmol) in THF (10 mL). The reaction mixture was allowed to warm to rt and, after 15 min, TLC analysis indicated the reaction to be complete. The mixture was diluted with ether and washed consecutively with 10% Na 2S2C>3 solution, water, and brine, then dried. Filtration and rotary evaporation gave a pale yellow oil that was purified by MPLC (silica gel, elution with 10% ether in petroleum ether) to afford 1.84 g (76%) of the major diastereomer accompanied by 0.60 g (24%) of the minor diastereomer. For the major diastereomer: IR (neat, c n r 1) 2980, 1740, 1450, 1290, 1060, 920; lH NMR (300 MHz, CDCI3) 6 5.14 (dd, J = 11.6 Hz, 6.7 Hz, 1 H), 3.87-3.79 (m, 2 H), 3.74-3.42 (m, 2 H), 2.65 (quintet, J = 6 .6 Hz, 1 H), 2.35-2.21 (m, 2 H), 2.19-2.05 (m, 1 H), 1.99-1.58 (m, 8 H); 13C NMR (75 MHz, CDCI3) ppm 200.5, 92.2, 88.7, 69.1, 68.2, 53.5, 34.1, 33.4, 32.8, 26.2, 25.9, 25.9; MS m/z (M+) calcd 288.0361, obsd 288.0354. For the minor diastereomer: IR (CHCI 3, cm*1) 2960, 2885, 1735, 1055; ,3C NMR (75 MHz, CDCI3) ppm 200.4, 94.5, 87.8, 69.0, 69.0, 52.5, 35.8, 32.0, 31.6, 31.3, 26.5, 26.0; MS m/z (M+) calcd 288.0361, obsd 288.0322. To a solution of the above a-bromo ketones (1.74 g, 6.02 mmol) in N,N- dimethylacetamide (35 mL) was added lithium carbonate (1.44 g, 19.0 mmol) and lithium bromide (1.41 g, 16.25 mmol). The reaction mixture was heated to 170 °C for 1.5 h, cooled, and freed of solvent by Kugelrohr distillation (0.1 Torr, 30-40 °C). The residue 135 was taken up in ether and filtered through a short pad of Celite. The filtrate was concentrated and chromatographed on silica gel (elution with 40% ether in petroleum ether) to afford 1.09 g (87%) of 107 as a colorless oil; IR (neat, c n r') 2990, 1690, 1380, 1220, 1090, 1060; >H NMR (300 MHz, CDCI3) 6 6.82 (ddd, J = 10.1 Hz, 5.7 Hz, 2.5 Hz, 1 H), 5.99 (ddd, J= 10.1 Hz, 3.0 Hz, 0.7 Hz, 1 H), 4.15-4.09 (m, 1 H), 3.96-3.77 (m, 3 H), 2.65 (dt, J = 18.9 Hz, 2.7 Hz, 1 H), 2.50-2.35 (m, 2 H), 2.23-2.12 (m, 1 H), 2.12-1.75 (m, 5 H), 1.65-1.57 (m, 1 H); 13CNMR (75 MHz,CDCl3) ppm 200.8, 146.7, 128.1,91.8, 86.1, 69.9, 69.2, 39.7, 32.3, 29.4, 26.3, 25.6; MS m /z (M+) calcd 208.1099, obsd 208.1105. Ana/. Calcd for CJ 2H 16O 3: C, 69.21; H, 7.74. Found: C, 68.97; H, 7.88. (±M5#F*,6J?,,,)-1,7-Dioxadispiro[4.0.4.4]tetradeca 15.6 mmol) in methanol (50 mL) was added sodium borohydride (617 mg, 16.3 mmol). After being stirred for 10 min, the reaction mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 1:1 ethyl acetate-hexanes) to afford 2.33 g (71.4%) of a 1.4:1 mixture of alcohols; IR (neat, cm*1) 3675-3095, 3035, 2965, 2875, 2685, 1740, 1720, 1435, 1240, 1055; >H NMR (300 MHz, CDCI3) 8 5.70-5.69 (m, 0.62 H), 5.60-5.55 (m, 0.88 H), 4.11-4.09 (m, 0.41 H), 3.97-3.62 (m, 4.16 H), 2.66 (d, J = 4.2 Hz, 0.32 H), 2.55 (d, J- 4.5 Hz, 0.46 H), 2.28-2.11 (m, 3.0 H), 2.10-1.77 (m, 6.3 H), 1.65-1.49 (m, 1.42 H); 13C NMR (75 MHz, CDCI 3) ppm 129.5, 128.5, 127.7, 126.4, 8 8 .6 , 8 6 .6 , 86.2, 84.6, 73.2, 73.1, 69.7, 69.3, 68.1, 67.7, 38.5, 37.8, 32.3, 31.9, 30.4, 27.9, 26.8, 26.6, 26.5, 26.2; MS m /z (M+) calcd 210.1256, obsd 210.1253. Anal. Calcd for Ci 2H i8 0 3: C, 68.55; H, 8.63. Found: C, 68.38; H, 8.74. 136 To a stirred solution of the above alcohols (2.118 g, 10.1 mmol) and triethylamine (4.2 mL, 30.2 mmol) in 1,2-dichioroethane (50 mL) was added 2,4-dinitrobenzenesul- fenyl chloride (4.725 g, 20.1 mmol). This mixture was heated to reflux for 15 h, cooled, poured into saturated NaHCC >3 solution, and extracted with CH 2CI2 . The organic phases were dried and evaporated, and the brown oil was twice chromatographed on silica gel (elution with 10% ethyl acetate in hexanes) to yield 1.34 g (69%) of 108; IR (neat, cm-1) 3039, 2974, 2866, 1400, 1075, 1031, 993, 945, 707; >H NMR (300 MHz, CDCI 3) 8 5.79- 5.74 (m, 2 H), 5.69-5.65 (m, 2 H), 3.91-3.77 (m, 4 H), 2.79-2.70 (m, 2 H), 2.01-1.76 (m, 4 H), 1.65-1.56 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 137.8, 121.7, 88.4, 68.7, 31.7, 26.4; MS m/z (M+) calcd 192.1150, obsd 192.1189. Anal. Calcd for Ci 2H i6C>2: C, 74.97; H, 8.39. Found: C, 74.98; H, 8.40. (±)-(5/?*,6S*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradec-12-en-14-one (110). O A solution of n-butyllithium in hexanes (8.27 mL, 13.2 mmol) was added via syringe to a solution of dry diisopropylamine (1.94 mL, 13.9 mmol) in anhydrous THF (40 mL) at -78 °C. This solution stirred for 15 min before being treated with a solution of 83 (2.852 g, 12.6 mmol) in dry THF (10 mL). The reaction mixture was quenched after 30 min by the addition of premixed trimethylsilyl chloride (1.78 mL, 14.0 mmol) and triethylamine (0.49 mL, 3.5 mmol). After being allowed to warm to rt during 1 h, the mixture was poured into saturated NaHC0 3 solution and extracted with ether. The extracts were dried and evaporated, and the residual oil was dissolved immediately in THF (40 mL) containing propylene oxide (0.98 mL, 14.0 mmol) at 0 °C. N-Bromosuccinimide (2.492 g, 14.0 mmol) was added and stirring was maintained for 1 h. Solvent evaporation followed by chromatography of the residue on silica gel (elution with 20% ethyl acetate in hexanes) afforded 3.611 g (94%) of a mixture of epimeric a-bromo ketones. 137 A solution of the bromo ketones (3.611 g, 11.8 mmol) in N,N-dimethylacetamide (5 mL) was added to a stirred mixture of dry lithium bromide (3.87 g, 31.5 mmol)[heated to 140 °C at 1 Torr overnight immediately prior to use] and lithium carbonate (2.622 g, 35.5 mmol) in the same solvent (75 mL). The reaction mixture was heated to 170 °C for 5 h, cooled, poured into ether, and filtered through Celite. Evaporation of the ether and Kugelrohr distillation of the dimethylacetamide left a semisolid residue that was triturated with ether. Filtration of the extracts through Celite followed by concentration of the filtrate furnished an oil that was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to afford 2.10 g (79%) of 110; IR (neat, c m 1) 3040, 2960, 2880, 1680, 1440, 1380, 1045; 'H NMR (300 MHz, C 6D6 ) 6 6.19-6.13 (m, 1 H), 5.95 (dd, / = 10.0 Hz, 2.1 Hz, 1 H), 3.84-3.73 (br m, 1 H), 3.64-3.46 (br m, 1 H), 3.03-2.91 (br m, 1 H), 2.62-2.56 (br m, 1 H), 2.55-2.39 (br m, 1 H), 2.34-2.22 (br m, 1 H), 2.11 (dd, J = 19.0 Hz, 5.3 Hz, 1 H), 2.03-1.66 (br m, 2 H), 1.65-1.26 (br m, 4 H), 1.24-0.84 (br m, 1 H); 13C NMR (75 MHz, CDC13) ppm 195.2, 148.5, 127.3, 90.4, 68.9, 65.4, 40.4, 37.0, 33.2, 30.4, 27.0, 26.0; MS m/z (M+) calcd 224.0871, obsd 224.0872. A nal Calcd for C 12H i60 2S: C, 64.25; H, 7.19. Found: C, 64.10; H, 7.25. (±)-(5/?*,6S*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradeca-11,13-diene (111). A stirred mixture of 110 (1.127 g, 5.02 mmol) and cerium trichloride heptahydrate (2.059 g, 5.53 mmol) in methanol (20 mL) was treated with sodium borohydride (212 mg, 5.60 mmol). An additional amount of hydride reagent was added after 5 min when TLC analysis indicated a UV- active component to remain. After being stirred for 10 min, the reaction mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 1:1 ethyl 138 acetate-hexanes) lo furnish 1.077 g (95%) of a 7.6 : 1 mixture of epimeric allylic alcohols with Rf = 0.4 and 0.25, respectively. For the major epimer: IR (KBr, c m 1) 3680-3095, 3035, 2945, 2865, 1655, 1445, 1055; 1H NMR (300 MHz, CDCI3) 8 5.66-5.57 (m, I H), 5.56-5.53 (br d, J = 10.2 Hz, 1 H), 4.05-3.90 (m, 3 H), 2.89-2.83 (m, 1 H), 2.75-2.65 (m, 1 H), 2.56 (br d, 7 * 18.1 Hz. I H), 2.28-1.79 (m, 9 H), 1.42-1.32 (m, 1 H); >3C NMR (75 MHz, CDCI 3) ppm 129.6, 128.2, 88.5, 73.0, 70.6, 65.4, 39.5, 37.2, 33.0, 31.6, 29.6, 27.5; MS m/z (M+) calcd 226.1028, obsd 226.1027. To a stirred solution of the above allylic alcohols (239 mg, 1.05 mmol) and triethylamine (0.59 mL, 4.2 mmol) in 1,2-dichloroethane (10 mL) was added 2,4- dinitrobenzenesulfenyl chloride (742 mg, 3.16 mmol). This mixture was heated to reflux for 5 h, stirred at rt overnight, then heated for an additional 4 h. The cooled reaction mixture was poured into ether and filtered through Celite. Evaporation of the solvent yielded a dark oil that was chromatographed on silica gel (elution with 10% ethyl acetate and 1% triethylamine in hexane) to furnish 110 mg (50%) of 111 as a white solid, mp 61- 63 °C (sublimation); IR (neat, c m 1) 3040, 2960, 2870, 1440, 1340, 1050, 865, 730, 680; >H NMR (300 MHz, C 6D6) 6 6.10 (br d, J = 9.3 Hz, 1 H), 5.77-5.67 (m, 2 H), 5.62-5.57 (ddd, J = 9.3 Hz, 4.8 Hz, 1.4 Hz, 1 H), 3.76-3.70 (m, 2 H), 2.68-2.58 (m, 2 H), 2.19-2.06 (m, 1 H), 1.80-1.51 (m, 7 H); ^C NMR (75 MHz, C 6D6) ppm 140.0, 135.7, 123.2, 120.3, 85.3, 68.2, 66.1, 38.8, 34.1, 32.6, 31.2, 26.4; MS m/z (M+) calcd 208.0922, obsd 208.0923. Anal . Calcd for C 12H 16OS: C, 69.19; H, 7.74. Found: C, 69.15; H, 7.75. 139 (±)-(5/?*,6/f*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradec-12-en-14-one (113). O A solution of n-butyllithium in hexanes (7.04 mL, 11.3 mmol) was added via syringe to a solution of dry diisopropylamine (1.65 mL, 11.8 mmol) in anhydrous THF (40 mL) at -78 °C. This solution stirred for 15 min before being treated with a solution of 84 (2.426 g, 10.72 mmol) in dry THF (10 mL). After being stirred for 30 min, the reaction mixture was quenched by the addition of premixed trimethylsilyl chloride (1.52 mL, 12.0 mmol) and triethylamine (0.42 mL, 3.0 mmol). The mixture was brought to rt over 1 hr, poured into saturated NaHCC >3 solution, and extracted with ether. The extracts were dried and evaporated, and the residual oil was dissolved immediately in THF (40 mL) containing propylene oxide (0.84 mL, 12.0 mmol) at 0 °C. N-Bromosuccinimide (2.136 g, 12.0 mmol) was added and stirring was maintained for 1 h. Solvent evaporation and chromatography of the residue on silica gel (elution with 2 0 % ethyl acetate in hexanes) afforded 3.232 (99%) of the a- bromo ketones as a mixture of epimers. These bromo ketones (3.232 g, 10.6 mmol) were added as a solution in N,N- dimethylacetamide (5 mL) to a stirred mixture of dry lithium bromide (3.253 g, 37.4 mmol) [heated to 140 °C at 1 Torr overnight immediately prior to use] and Li 2CC>3 (2.348 g, 31.8 mmol) in the same solvent (70 mL). The reaction mixture was heated to 170 °C for 5 h, cooled, poured into ether, and filtered through Celite. Evaporation of the ether followed by Kugelrohr distillation of the acetamide yielded a reside that was triturated with ether. Filtration through Celite and concentration furnished an oil that was chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to afford 1.687 g (71%) of 113 as a white crystalline solid, mp 58-59 °C (from hexanes); IR (CDCI3, cm' >) 3040, 2960, 2880, 2245, 1685, 1625, 1440, 1420, 1380, 1265, 1180, 1090, 1050, 990; 1H NMR (300 MHz, CDCI3) 6 6.74 (dt, J = 10.1 Hz, 4.0 Hz, 1 H), 5.92 (dt, J = 10.1 Hz, 1.9 Hz, 1 H), 4.03 (br s, 1 H), 3.95 (dd, J = 14.2 Hz, 7.7 Hz, 1 H), 2.79 (dd, J = 7.6 Hz, 140 4.8 Hz, 2 H), 2.68 (br d, J = 1.9 Hz, 2 H), 2.21-2.13 (m, 1 H), 2.03-1.81 (m, 6 H), 1.74- 1.67 v4/ta/. Calcd for C | 2H]6 0 2 S: C, 64.25; H, 7.19. Found: C, 64.75; H, 7.20. (±)-(5/?*,6/?*)-l-Oxa-7-thiadispiro[4.0.4.4]tetradeca-l 1,13-diene (114). } A stirred mixture of 113 (1.034 g, 4.61 mmol) and cerium ] **'// trichloride heptahydrate (1.889 g, 5.07 mmol) in methanol (20 mL) was treated with sodium borohydride (182 mg, 4.80 mmol). When TLC analysis after 2 0 min indicated that starting material remained, additional hydride reagent was added in small quantities until UV-active material could no longer be detected. The reaction mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromato-graphed on silica gel (elution with 40% ethyl acetate in hexanes) to afford 1.000 g (96%) of allylic alcohols; IR (neat, cm*1) 3600-3100. To a stirred solution of the above alcohols (248 mg, 1.10 mmol) and triethylamine (0.61 mL, 4.4 mmol) in 1,2-dichloroethane (10 mL) was added 2,4-dinitrobenzene- sulfenyl chloride (771 mg, 3.29 mmol). This mixture was stirred and heated at reflux for 5 h, cooled, poured into ether, and filtered through Celite. Evaporation of the solvent yielded a dark oil that was chromatographed on silica gel (elution with 10% ethyl acetate and 1 % triethylamine in hexanes). The nonpolar compounds which preceeded the diene off the column were stirred and heated with triethylamine in dichloroethane as before for 30 h. Evaporation of the solvent and chromatography of the oil furnished 146 mg (64% combined yield) of 114 as a colorless oil; IR (neat, cm-1) 3045, 2960, 2870, 1440, 1080, 1045, 805; *H NMR (300 MHz, C 6 D6) 5 5.96 (br d, J = 9.3 Hz, 1 H), 5.71-5.70 (m, 2 H), 5.58 (ddd, J = 9.4 Hz, 3.7 Hz, 2.6 Hz, 1 H), 3.78-3.65 (m, 2 H), 2.71-2.54 (m, 2 H), 2.27- 141 2.11 (m. 2 H). 1.94-1.86 (m, 3 H), 1.84-1.58 (m, 3 H); l*C NMR (75 MHz, C 6 D6) ppm 139.3, 135.5, 123.3, 119.6, 85.8, 69.0, 64.7, 36.7, 36.2, 33.5, 30.8, 26.3; MS m/z Anal. Calcd forCi 2H i60S: C, 69.19; H, 7.74. Found: C, 68.78; H, 7.81. (±)^5i?*,6S*)-l,7-Dithiadispiro[4.0.4.4]tetradec-12-en-l 1-one (116). A solution of /i-butyllithium in hexanes (2.37 mL, 3.79 mmol) was added via syringe to a solution of dry diisopropylamine (0.56 mL, 4.0 mmol) in anhydrous THF (7.5 mL) at -78 °C. This solution was stirred for 20 min before being treated with 85 (874 mg, 3.61 mmol) in dry THF (7.5 mL). Stirring was maintained for 30 min before the reaction mixture was quenched by the addition of premixed trimethylsilyl chloride (0.51 mL, 4.0 mmol) and triethylamine (0.14 mL, 1.0 mmol). The cooling bath was removed and after 10 min the reaction mixture was poured into saturated NaHC 0 3 solution and extracted with ether. The extracts were dried and evaporated and the residual oil was dissolved immediately in THF (15 mL) containing propylene oxide (0.28 mL, 4.0 mmol) at 0 °C. N-Bromosuccinimide (712 mg, 4.00 mmol) was added and stirring was maintained for 1 h. Solvent evaporation and chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) afforded first 873 mg (75%) of one bromo ketone, followed subsequently by 212 mg (18%) of its epimer. A solution of the above bromo ketones (1.085 g, 3.38 mmol) in N,N-dimethyl- acetamide (10 mL) was added to a stirred mixture of dry lithium bromide (1.038 g, 8.45 mmol) [heated to 140 °C at 1 Torr for 3 h immediately prior to use] and lithium carbonate (749 mg, 10.1 mmol) in the same solvent (30 mL). The reaction mixture was heated to 170 °C for 2.5 h, cooled, poured into ether, and filtered through Celite. Evaporation of the ether and Kugelrohr distillation of the acetamide furnished a solid residue that was 142 triturated with ether. Filtration and evaporation of the filtrate produced an oil that was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to afford first unreacted a-bromo ketone (261 mg, 24%) followed closely by 116 (552 mg, 6 8 %), mp 86-87 °C (from hexanes); IR (KBr, c m 1) 2935, 2860, 1660 (s), 1435, 1415, 1380, 1305, 1250, 1220, 975, 815, 680; 'H NMR (300 MHz, CDC13) 8 6.69-6.63 (m, 1 H), 5.96 (dd,7 = 10.2 Hz, 2.8 Hz, 1 H), 3.00-2.69 (m, 5 H), 2.61 (dd, 7= 19.6 Hz, 5.5 Hz, 1 H), 2.57- 2.38 (br m, 1 H), 2.30-2.10 (m, 4 H), 2.06-1.90 (m, 1 H), 1.87-1.80 (m, 1 H), 1.68-1.43 (br m, 1 H); l3CNMR (75 MHz, CDCI 3) ppm 195.1, 146.3, 127.8,71.3, 67.8,43.1,37.4, 33.9, 33.0, 32.6, 32.2, 31.7; MS m/z (M+) calcd 240.0643, obsd 240.0645. j4na/. Calcd for C 12H 16OS2: C, 59.96; H, 6.71. Found: C, 59.81; H, 6.82. (5/?,6S)-l,7-Dithiadtspiro[4.0.4.4]tetradeca-ll,13-diene (117). \. / A stirred mixture of 116 (679 mg, 2.82 mmol) and cerium trichloride heptahydrate (1.252 g, 3.36 mmol) in methanol (25 mL) was a treated with sodium borohydride (455 mg, 12.0 mmol). Additional hydride reagent was added in small amounts until the presence of 116 was no longer detectable by TLC analysis. The reaction mixture was poured into 10% HC1 and extracted with ether. The organic phases were dried and evaporated and the residual oil was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to furnish 665 mg (97%) of separately eluting alcohols (15 : 1, respectively). For the major epimer: colorless crystals, mp 79.5-81.5 °C (from ether); *H NMR (300 MHz, CDCI3) 8 5.65-5.49 (m, 2 H), 4.09-4.04 (m, 1 H), 3.00-2.89 (m, 1 H), 2.88- 2.66 (m, 5 H), 2.46-1.88 (m, 8 H), 1.63-1.51 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 131.7, 127.7, 73.3, 72.6, 65.7,42.1, 37.5, 36.8, 34.2, 33.2, 32.8, 31.0. To a stirred solution of the above allylic alcohols (190 mg, 0.783 mmol) and triethylamine (0.44 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) was added 2,4- 143 dinitrobenzenesulfenyl chloride (551 mg, 2.35 mmol). The reaction mixture was heated to reflux for 8 h, cooled, poured into ether, and filtered through Celite. Evaporation of the solvent yielded a dark oil that was chromatographed on silica gel (elution with 5% ethyl acetate and 1% triethylamine in hexanes) to afford 103 mg (58%) of 117 as colorless crystals, mp 69.5-71.5 °C (from hexanes); IR (KBr, c m 1) 3040, 2940, 2860, 1435, 1260, 1000, 740; >H NMR (300 MHz, CDCI3) 6 6 .11 (dd, J = 7.6 Hz, 2.9 Hz, 2 H), 5.76 (dd, J = 7.6 Hz, 3.0 Hz, 2 H), 2.94-2.82 (m, 4 H), 2.27-2.20 (m, 2 H), 2.19-1.93 (m, 6 H); 13C NMR (75 MHz, CDCI3) ppm 139.1, 120.8, 66.3, 38.1, 32.8, 31.2; MS m/z (M+) calcd 224.0693, obsd 224.0690. Anal. Calcd for C 12H i6S2: C, 64.24; H, 7.19. Found: C, 64.32; H, 7.21. (±)-(5/?*,6/?*)-l,7-Dithiadispiro[4.0.4.4]tetradec-12-en-l 1-one (119). O A solution of n-butyllithium in hexanes (1.54 mL, 2.47 mmol) was added via syringe to a solution of dry diisopropylamine (0.36 mL, 2.6 mmol) in anhydrous THF (5 mL) at -78 °C. This solution stirred for 20 min before being treated with 8 6 (570 mg, 2.35 mmol) in dry THF (5 mL). After being stirred for 30 min, the reaction mixture was quenched by the addition of premixed trimethylsilyl chloride (0.32 mL, 2.5 mmol) and triethylamine (0.09 mL, 0.7 mmol). The cooling bath was removed and after 10 min the mixture was poured into saturated NaHCC>3 solution and extracted with ether. The extracts were dried and evaporated, and the residual oil was dissolved immediately in THF (10 mL) and propylene oxide (0.18 mL, 2.5 mmol) at 0 °C. N-Bromosuccinimide (445 mg, 2.50 mmol) was added, and stirring was maintained for 1 h. Solvent evaporation followed by chromatography of the residue on silica gel (elution with 10% ether in petroleum ether) afforded 690 mg (91%) of a closely eluting mixture of a-bromo ketones. 144 A solution of the above bromo ketones (3.660 g, 11.40 mmol) in N,N- dimethylacetamide (20 mL) was added to a stirred mixture of dry lithium bromide (3.50 g, 28.5 mmol) [heated to 140 °C at 1 Torr for 3 h immediately prior to usej and lithium carbonate (2.53 g, 34.2 mmol) in the same solvent (130 mL). The reaction mixture was heated to 170 °C for 2.5 h, cooled, poured into ether, and filtered through Celite. Evaporation of the ether and Kugelrohr distillation of the acetamide furnished an oil that was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to afford 2.628 g (96%) of the 119 as colorless crystals, mp 60-63 °C (from ether); IR (KBr, cm*1) 2970, 2940, 2870, 1720, 1675, 1435, 1415, 1380, 1265, 1235, 1130, 1000, 840,775, 685; >H NMR (300 MHz, C6D6) 8 6.23 (ddd, J = 10.1 Hz, 5.7 Hz, 2.2 Hz, 1 H), 6.06 (dd, J = 10.2 Hz, 2.8 Hz, 1 H), 2.94-2.87 (m, 1 H), 2.76-2.65 (m, 1 H), 2.60-2.44 (m, 4 H), 2.29 (dd, J = 18.9 Hz, 5.7 Hz, 1 H), 2.24-2.15 (m, 1 H), 1.89-1.54 (m, 6 H); *3C NMR (75 MHz, C6D6) ppm 194.1, 145.6, 128.7, 71.9, 6 6 . 1, 43.6, 39.0, 34.7, 34.2, 33.4, 32.9, 30.6; MS m/z (M+) calcd 240.0643, obsd 240.0642. Ann/. Calcd for C i 2H i6OS2: C, 59.96; H, 6.71. Found: C, 59.62; H, 6 .6 8 . (±)-(5/?*,6/?*)-l,7-Dlthladispiro[4.0.4.4]tetradeca-ll,13-diene (120). A stirred mixture of 119 (2.628 g, 10.9 mmol) and cerium trichloride heptahydrate (4.486 g, 12.0 mmol) in methanol (35 mL) was treated with sodium borohydride (455 mg, 12.0 mmol). Stirring was maintained for 10 min before the mixture was poured into 5% HC1 and extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to furnish 2.595 g (98%) of co-eluting epimeric alcohols; IR (neat, cm '1) 3600-3100, 3030, 2930, 2860, 1435, 1265, 1225, 1065; *H NMR (300 MHz, CDCI 3 ) 8 5.80-5.52 (m, 2 H), 4.19- 4.11 (m, 1 H), 3.04-2.81 (m,4H), 2.76 (brd, J= 10.2 Hz, 1 H), 2.71-2.52 (m, 1 H), 2.50- 145 2.39 (m, 1 H), 2.37-1.76 (m, 8 H); l3C NMR (75 MHz. CDCI3 ) ppm 128.9, 127.9. 127.8, 127.3, 73.9, 73.2, 72.9, 66.0, 41.5, 40.8, 40.2, 40.0, 36.4, 35.1, 34.9, 34.1, 33.7, 33.3, 32.5, 31.1 (remaining absorptions not observed); MS m /z (M+) calcd 242.0799, obsd 242.0803. To a stirred solution of these allylic alcohols (142 mg, 0.587 mmol) and triethylamine (0.25 mL, 1.8 mmol) in 1,2-dichloroethane (5 mL) was added 2,4- dinitrobenzenesulfeny! chloride (275 mg, 1.17 mmol). This mixture was heated to reflux for 4 h, stirred at rt overnight, then poured into saturated NaHCC >3 solution and extracted with CH 2CI2 . The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 10% ethyl ether in hexanes) to furnish 49 mg (37%) of 120 as colorless crystals, mp 96.5-97.5 °C (from hexanes); IR (KBr, cm-1) 3030, 2950, 2925, 2850, 1435, 1255, 1150, 750; 'H NMR (300 MHz, CDCI 3) 8 6.01 (dd, J = 7.4 Hz, 3.0 Hz, 2 H), 5.84 (dd, J = 7.4 Hz, 3.0 Hz, 2 H), 3.02-2.95 (m, 2 H), 2.87 (dd, J = 15.9 Hz, 5.2 Hz, 1 H), 2.86 (dd, J = 15.9 Hz, 5.4 Hz, 1 H), 2.42-2.35 (m, 2 H), 2.32- 2.20 (m, 2 H), 2.18-2.04 (m, 2 H), 2.00-1.90 (m, 2 H); NMR (75 MHz, CDCI 3) ppm 137.5, 120.2, 64.6, 37.9, 33.5, 30.1; MS m/z (M+) calcd 224.0693, obsd 224.0689. Anal. Calcd for C 12H 16S2 : C, 64.24; H, 7.19. Found: C, 64.35; H, 7.30. (±)-(4a/?*,8aS*)-3,4-Dihydro-4a,8a-butano-2//-l-benzopy ran (126). Acid-Catalyzed Rearrangement of 102. To an NMR tube was added a mixture of 102 (52 mg, 0.27 mmol) and p-toluenesulfonic acid (3.9 mg, 2.1xl0 *5 mol) in CDCI 3 (1 mL). After 5 min, none of the starting material was detected by NMR analysis. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 1 0% ethyl acetate and 1% triethylamine in hexanes). The first compound to elute was 126 (21 mg, 40%); IR (neat. 146 cm -1) 3035, 2940, 2865, 1445, 1165, 1140, 1120, 1080, 1010, 690; 'H NMR (300 MHz, CDCI3) 8 5.92 (ddd, J = 9.7 Hz, 5.0 Hz, 1.1 Hz, 1 H), 5.81 (dd, J = 9.6 Hz, 5.0 Hz, 1 H), 5.62 (dd, 7 = 9.7 Hz, 3.0 Hz, 2 H), 3.85-3.66 (m, 2 H), 2.02-1.93 (m, 1 H), 1.81-1.61 (m, 3 H), 1.60-1.19 (m, 7 H), 1.14-1.08 (m, 4 H); ,3C NMR (75 MHz, CDCI 3 ) ppm 140.0, 135.2, 123.8, 121.8, 78.1, 63.7, 38.0, 33.6, 31.4, 31.1, 22.8, 20.7, 19.7; MS m /z (M+) calcd 190.1358, obsd 190.1355. Anal. Calcd forC| 3H i8 0: C, 82.06; H, 9.53. Found; C, 81.95; H, 9.61. 5,6,7,8-Tetrahydro-1 -naphthalenepropanol (125). The second compound to elute was 125 (13 mg, 20%); IR (neat, cm*1) 3670-3090, 3010, 2930, 2860, 1580, 1450, 1050; JH NMR (300 MHz, CDCI3) 5 7.38-6.95 (m, 3 H), 3.73 (t, J = 6.4 Hz, 2 H), 2.81 (t, J = OH 6.0 Hz, 2 H), 2.74 (t, J = 6.2 Hz, 2 H), 2.68 (t, J = 7.8 Hz, 2 H), 1.91- 1.75 (m, 6 H), 1.60 (s, 1 H); NMR (75 MHz, CDCI3) ppm 139.9, 137.4, 135.0, 127.2, 12616, 125.2,62.7, 32.9, 30.1,28.9, 26.1,23.4, 22.8; MS m/z (M+) calcd 190.1358, obsd 190.1365. A nal Calcd for C i 3H i8 0; C, 82.06; H, 9.53. Found; C, 81.95; H, 9.48. 3,4,6,7-Tetrahydro-4a,8a-[lr3]butadieno-2//^H-pyrano[2r3-^]-pyran (127). Acid-Catalyzed Rearrangement of 105. Into an NMR tube was placed 105 (77 mg, 0.40 mmol) and p-toluenesulfonic acid (4.8 mg, 2.6 x lO 5 mol) in CDCI 3 (1 mL). After 2 h, NMR analysis showed none of the starting material to remain. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 20% ethyl acetate in hexanes). The first compound to elute was 127, a colorless solid, mp 68-70 °C (25 mg, 33%); IR (CDCI3, 147 cm-' ) 3035, 2960, 2870, 2250, 1435, 1210, 1085. 1070, 1030, 905, 720; 'H NMR (300 MHz, CDCI3) 6 6.72 (ddd, J = 9.6 Hz, 5.2 Hz, 1.4 Hz, 1 H), 5.97 (dd, J = 9.5 Hz, 5.2 Hz, 1 H), 5.76 (br d, J = 9.5 Hz, 1 H), 5.63 (br d, J ~ 9.6 Hz, 1 H), 3.95-3.87 (m, 2 H), 3.65- 3.58 (m, 2 H), 1.88-1.80 (m, 2 H), 1.70-1.45 (m, 4 H), 1.43-1.34 (m, 2 H); '^C NMR (75 MHz, CDCI3) ppm 140.4, 128 9, 127.9, 121.9, 98.4, 62.2, 38.0, 30.9, 21.1; MS m/z (M+) calcd 192.1150, obsd 192.1152. Anal. Calcd forC] 2H |602: C, 74.97; H, 8.38. Found: C, 74.54; H, 8.50. 8-Chromanpropanol (128). The second compound to elute was 128 (22 mg, 29%); IR (neat, cm 1) 3690-3100, 3020, 2950, 2870, 1590, 1470, 1455, 1215, 1190, 1050, 765, 740; ‘H NMR (300 MHz, CDCI3) 6 6.95 (d, J = 7.3 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 6.78 (t, J = 7.4 Hz, 1 H), 4.21 (t, J = 5.2 Hz, 2 H), 3.60 (t, J = 6.2 Hz, 2 H), 2.80 (t, J = 6.5 Hz, 2 H), 2.68 (t, J = 7.2 Hz, 2 H), 2.04-1.95 (m, 3 H), 1.89-1.80 (m, 2 H); NMR (75 MHz, CDCI 3) ppm 152.8, 129.3, 127.9, 127.8, 121.9, 119.9, 6 6 .6 , 61.9, 33.0, 25.6, 25.1, 22.5; MS m/z (M+) calcd 192.1150, obsd 192.1150. Anal. Calcd for C i 2H i60 2: C, 74.97; H, 8.39. Found: C, 75.02; H, 8.48. Comparable treatment of a 1 : 1 mixture of 105 and 108 (316 mg, 1.64 mmol) with p-toluenesufonic acid (30 mg, 0.16 mmol) in dry CH 2C12 (5 mL) for 24 h afforded 52 mg (17%) of 127 and 133 mg (42%) of 128. 148 Thioch roman-8-propanol (138). Acid-Catalyzed Rearrangement of 114. To an NMR tube was added a mixture of 114 (48 mg, 0.23 mmol) and / 7-toluenesulfonic acid (2.7 mg, 1.4x1 O ' 5 mol) in CDCI 3 (1 mL). After several hours, the solvent was evaporated and the residue was chromatographed on silica gel (elution with 40% ethyl acetate and 1% triethylamine in hexanes) to give 25 mg (53%) of 138 as a colorless solid, mp 64-65 °C (from 10% ethyl acetate in hexanes); IR (neat, cm 1) 3700-3120, 2950, 2880, 1455, 1060; >H NMR (300 MHz, CDCI 3) 6 7.00- 6.97 (m, 2 H), 6.91-6.86 (m, 1 H), 3.70 (t, J = 6.3 Hz, 2 H), 2.99 (t, J = 6.0 Hz, 2 H), 2.80-2.76 (m, 2 H), 2.70-2.64 (m, 2 H), 2.18-2.10 (m, 2 H), 1.87-1.77 (m, 2 H), 1.38 (s, 1 H); *3C NMR (75 MHz, CDCI 3 ) ppm 140.5, 133.2, 132.2, 125.9, 125.3, 125.0, 62.5, 33.1, 29.3, 27.2, 25.1, 23.5; MS m/z (M+) calcd 208.0922, obsd 208.0928. Anal. Calcd for Ci 2H i6OS: C, 69.19; H, 7.74. Found; C, 68.95; H, 7.76. Comparable treatment of 111 (34 mg) with p-toluenesulfonic acid (1.7 mg) in CDCI3 (1 mL) for 2.5 days and silica gel chromatography furnished 14 mg (40%) of 138. (±M4aR*,8a5*)-3,4,6,7-Tetrahydro-4a,8a-[l,3]butadieno-2f/,5//-tliiopyrano[2,3- £]pyran (139). A solution of 114 (96 mg, 0.46 mmol) in CDCI 3 (5 mL) was kept at rt for 2 weeks on the benchtop. Periodic TLC analysis revealed the original disappearance of 114 and appearance of 138 and 139. The solvent was evaporated and the residue was chromatographed on silica gel (gradient elution with 20% ethyl acetate in hexanes, then 1:1 ethyl acetate-hexanes). The first compound to elute was 139 (11 mg, 11%) followed by the aromatic alcohol 138 (41 mg, 42%). 149 For 139: colorless oil; IR (neat, cm 1) 3040, 2960, 2860, 1720, 1685, 1460, 1445, 1290, 1250, 1210, 1150, 1080, 850, 725, 685; 'H NMR (300 MHz, CDClj) 6 6.04-5.92 (m, 3 H), 5.75-5.72 (m, 1 H), 3.88-3.81 (m, 1 H), 3.75-3.67 (m, 1 H), 2.77-2.61 (m, 1 H), 2.55-2.47 (m, 1 H); 13C NMR (62.5 MHz, CDCI3) ppm 138.8, 134.9, 124.3, 123.8, 75.1, 62.6, 47.2, 32.0, 31.1, 25.7, 23.0, 21.7; MS m/z (M+) calcd 208.0922, obsd 208.0924. Anal . Calcd forC 12H]6OS: C, 69.19; H, 7.74. Found; C, 69.07; H, 7.80. Disulfide (142). s Acid-Catalyzed Rearrangement of 117. Into an NMR s occ tube was added a mixture of 117 (54 mg, 0.24 mmol) and p- toluenesulfonic acid (4.6 mg, 2.5xl0 ' 5 mol) in CDCI 3 (1 mL). After 48 h, no remaining 117 was evident by NMR analysis. The reaction mixture was flash chromatographed on neutral alumina (dichloromethane elution). Evaporation left 142 as a colorless oil; IR (neat, c m 1) 3020, 2940, 2870, 1490, 1450, 1290, 1250, 750; >H NMR (300 MHz, CDCI3) 6 7.19-7.11 (m, 4 H), 2.85-2.60 (m, 8 H), 2.05-1.89 (m, 4 H); 13C NMR (75 MHz, CDCI3) ppm 139.2, 129.3, 126.2, 38.4, 31.2, 30.3; MS m/z (M+) calcd 224.0693, 224.0700. o-Bis[3-(methylthio)propyl]benzene (143). A solution of 142 (49 mg, 0.22 mmol) in dry THF (5 mL) at 0 °C was treated with lithium aluminun hydride (14 mg, 0.37 mmol). After 10 min, methyl iodide (0.20 mL, 0.67 mmol) was introduced via syringe and stirring was maintained for 30 min. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 150 5% ethyl acetate in hexanes) to furnish 32 mg (519c) of 143 as a colorless oil; IR (neat, c m '1) 2914, 2851, 1487, 1436, 1287, 1256, 749; >H NMR (300 MHz, CDCI3)S 7.19-7.12 (m, 4 H), 2.80-2.71 (m, 4 H), 2.59-2.53 (m, 4 H), 2.12 (s, 6 H), 1.94-1.84 (m, 4 H); l3C NMR (75 MHz, CDC13) ppm 139.4, 129.3, 126.1, 34.0, 31.5, 30.4, 15.5; MS m/z (M+) calcd 254.1163, obsd 254.1160. Anal. Calcd for Q 4H22S2: C, 66.09; H, 8.71. Found: C, 66.23; H, 8.78. ll,12-Epoxy-3,4,6,7-tetrahydro-8a,4a-[l]buteno-2//,5//-pyrano[2,3-6]pyran (144). A solution of 127 (35 mg, 0.18 mmol) in CH 2CI2 (2 mL) was stirred vigorously with an aqueous solution of NaHC03 (46 mg, 0.55 mmol) in water (2 mL). This two-phase mixture was treated over 5 min with MCPBA (32 mg, 0.18 mmol) in approximately 10 mg lots. Additional MCPBA was added (50 mg, in 10 mg lots every 12 h) when TLC analysis revealed that starting material remained. Stirring was maintained for 4 5 after which time the organic phase was separated and the aqueous phase was extracted with CH 2CI2. The combined organic layers were washed successively with 10% NaOH solution and water, dried, and evaporated. The residual oil was chromatographed on silica gel (elution with 30% ethyl acetate in hexanes) to afford 20 mg (53%) of 144 as a colorless solid, mp 96-104 °C; IR (CDCI3, cm 1) 2975, 2955, 2880, 1450, 1225, 1175, 1080, 1035, 975, 840; >H NMR (300 MHz, acetone-dft) 8 6.19 (dd, J = 10.0 Hz, 3.9 Hz, 1 H), 5.62 (dd, J = 1.6 Hz, 10.0 Hz, 1 H), 3.86-3.73 (m, 2 H), 3.50-3.41 (m, 2 H), 3.14 (dt, J = 3.9 Hz, 1.6 Hz, 1 H), 3.01 (d,7 = 4.0 Hz, 1 H), 2.26 (dt, J = 13.3 Hz, 4.2 Hz, 1 H), 2.02-1.92 (m, 1 H), 1.86-1.70 (m, 1 H), 1.62 (dddd, J = 13 Hz, 3.5 Hz, 3.5 Hz, 2 Hz, 1 H), 1.48-1.27 (m, 4 H); 13C NMR (75 MHz, acetone-dfc) ppm 136.9, 129.6, 96.1, 64.8, 61.9, 61.7, 45.2, 33.9, 32.1, 28.2, 23.2, 21.0; MS m/z (M+) calcd. 208.1099, obsd. 208.1104. 151 Anal. Calcd. for C^HiftO.i: C, 69.21: H, 7.74. Found: C, 68.76; H, 7.69. Diels-Alder Addition of N-Methyltriazolinedione to the [4.4.4]Propelladienes. A. (5S,8R)-3,4-Dihydro-jV-methyl-8a,4a-(epoxypropano)-5,8-etheno-2//-pyrano[2,3- rf]pyridazine-6,7(5//,8//)-dicarboxiniide (145). A solution of freshly sublimed N-methyltriazolinedione (12 mg, 0.11 mmol) in CH 2CI2 (2 mL) at -78 °C was added via cannula to a solution of 127 (20 mg, 0.10 mmol) in CH 2CI2 (3 mL) at o the same temperature. The red solution was warmed to rt where stirring was maintained for 5 d. Chromatography on silica gel (elution with 1:1 ethyl acetate in hexanes) yielded unreacted 127 (3 mg, 15%) followed by 145 (23 mg, 73%) as a colorless solid, mp 202-203 °C (from 30% ethyl acetate in hexanes); IR (KBr, cm*1) 3080, 2970, 2900, 1780, 1720, 1455, 1395, 1275, 1210, 1090, 1065, 785; *H NMR (300 MHz, CDCI3) 6 6.44-6.35 (m, 2 H), 4.54 (dd, J = 5.3 Hz, 2.0 Hz, 1 H), 4.29 (dd, J = 5.2 Hz, 2.0 Hz, 1 H), 4.05-3.84 (m, 3 H), 3.76-3.67 (m, 1 H), 2.99 (s, 3 H), 2.20-2.10 (m, I H), 1.92-1.62 (m, 5 H), 1.59-1.51 (m, 1 H), 1.47-1.37 (m, 1 H); ,3C NMR (75 MHz, CDCI3) ppm 157.9, 157.5, 129.5, 129.3, 96.4, 63.6, 61.5, 60.1, 60.0, 37.5, 31.7, 30.1, 25.4, 21.1, 19.1; MS m/z (M+) calcd. 305.1376, obsd. 305.1362. Ana/. Calcd. for C 15H 19 N 3O4: C, 59.01; H, 6.27. Found: C, 59.03; H, 6.59. B. (4aR*t5S*,8/f*,8a#f*)-3,4-Dihydro-jV-methyI*4a,8a-butano-5,8-etheno-2//- pyrano[2,3-dicarboximide (146). A solution of freshly sublimed N-methyltriazolinedione (46 mg, 0.40 mmol) in CH 2CI2 (2 mL) at -78 °C was added via cannula to a solution of 126 (70 mg, 0.37 mmol) in CH 2CI2 (3 O mL) at the same temperature. The red solution was warmed to 152 rt where stirring was maintained for 5 d. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 30% ethyl acetate in hexanes) to furnish 14 mg (21%) of recovered 126, followed by 78 mg (70%) of 146, a colorless solid, mp 131- 133 °C (from 20% ethyl acetate in hexanes); IR (KBr, cm *■) 2975, 2935, 2885, 1770, 1750, 1455, 1390, 1195, 785; >H NMR (300 MHz, CDCI 3) 6 6.49-6.38 (m, 2 H), 4.39 (dd, J = 5.4 Hz, 1.7 Hz, 1 H), 4.23 (dd, J = 5.5 Hz, 1.6 Hz, 1 H), 3.77-3.69 (m, 1 H), 3.65- 3.57 (m, 1 H), 2.98 (s, 3 H), 2.18-2.01 (m, 2 H), 1.68-1.56 (m, 8 H), 1.49-1.33 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 157.9, 157.8, 129.9, 129.7, 75.1, 61.8, 61.2, 60.4, 38.3, 32.6, 32.1, 30.8, 25.4, 20.8, 18.3, 17.0; MS m/z (M+) calcd. 303.1583, obsd. 303.1578. Anal. Calcd. for Cj 6H21N 3O 3: C, 63.35; H, 6.98. Found: C, 63.26; H, 7.07. C. (4ait*,55*,8X*,8aJt*)>3,4-Dihydro-Ar-methyl>8a,4a-(epithiopropano)-5,8>etheno- 2/f-pyrano[2,3- 'N~~[ (33 mg, 0.29 mmol) in CH 2CI2 (3 mL) at -78 °C was added via N\ N Y ^CH-* cannula to a solution of 139 (55 mg, 0.27 mmol) in CH 2CI2 (3 ° mL) at the same temperature. The red solution was warmed to rt where stirring was maintained for 5 d. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 1:1 ethyl acetate-hexanes) to give 3.5 mg (4%) of 148 followed by 70 mg (82%) of 147 as a colorless solid, mp 196-197 °C (from 75% ethyl acetate in hexanes); IR (KBr, cm-1) 2950, 2890, 1775, 1460, 1395, 1195; *H NMR (300 MHz, CDCI3) 5 6.56-6.51 (m, 1 H), 6.37-6.32 (m, 1 H), 4.54-4.50 (m, 2 H), 3.88-3.81 (m, 2 H), 2.94 (s, 3 H), 2.57 (t, J = 7.0 Hz, 2 H), 2.37 (td, J = 13.5 Hz, 3.9 Hz, 1 H), 2.21-1.98 (m, 2 H), 1.96-1.86 (m, 1 H), 1.78-1.62 (m, 2 H), 1.46-1.37 (m, 2 H); 13c NMR (75 MHz, CDCI3 ) ppm 157.1, 157.0, 130.9, 127.2, 73.2, 61.1, 59.8, 59.6, 47.3, 31.2, 28.8, 25.3, 24.8, 20.1, 17.5; MS m/z (M+) calcd. 321.1147, obsd. 321.1142. 153 Anal. Calcd. for C 15H 19 N3O 3S: C, 56.06: H, 5.96. Found: C, 56.00; H, 5.92. The minor adduct 148 exhibited the following characteristic signals: 1H NMR (300 MHz, CDCI3) 5 6.48-6.43 (m, 1 H), 6.43-6.4 Competition Experiments. A. Between 126 and 127. A solution of freshly sublimed N-methyltriazolinedione (22 mg, 0.19 mmol) in CH 2CI2 (5 mL) at -78 °C was added via cannula to a solution containing 126 (41 mg, 0.21 mmol) and 127 (41 mg, 0.21 mmol) in CH 2CI2 (5 mL) at the same temperature. The red solution was warmed to rt where stirring was maintained for 4 d. The solvent was evaporated and the residue was chromatographed on silica get (gradient elution with 30-40% ethyl acetate in hexanes) to give 20 mg (49%) of 126, 25 mg (61%) of 127, 13 mg (22%) of 146, and 9 mg (16%) of 145. B. Between 127 and 139. A solution of freshly sublimed N-methyltriazolinedione (10 mg, 9.1 x 1 0 '5 mol) in CH 2CI2 (2 mL) at -78 °C was added via cannula to a solution containing 139 (23 mg, 0.11 mmol) and 127 (21 mg, 0.11 mmol) in CH 2CI2 (3 mL) at the same temperature. The red solution was warmed to rt and stirred for 4 d. *H NMR analysis revealed a 2.15 : 1 ratio of 147 to 145 to have been produced. C. Between 126 and 139. A solution of freshly sublimed N-methyltriazolinedione (14 mg, 0 .1 2 mmol) in CH 2CI2 (2 mL) at -78 °C was added via cannula to a solution containing 139 (30 mg, 0.14 mmol) and 126 (27 mg, 0.14 mmol) in CH 2CI2 (3 mL) at the same temperature. The red solution was warmed to rt and stirred for 4 d. The solvent was evaporated and the residue was chromatographed on silica get (gradient elution with 154 10-70% ethyl acetate and 1% triethylamine in hexanes) to provide (in order) 126 (18 mg. 6 6 %). 139 (13 mg. 42%). 146 (7 mg, 20%), and 147 (15 mg, 39%). (±)-l-Thiadispiro[4.0.4.4]tetradecan-14-one (152). O Cerium trichloride heptahydrate (14.93 g, 40.06 mmol) was heated at 140 °C and 1 Torr overnight. After the reaction mixture had cooled, anhydrous THF (150 ml) was introduced and the slurry was stirred at room temperature for 3 h, cooled to -78 °C, and treated dropwise with tert- butyllithium until a pink color persisted. A solution of 5-lithio-2,3-dihydrothiophene in dry THF (50 ml) [prepared from 2.424 g (28.1 mmol) of 2,3-dihydrothiophene and 18.21 ml of 1.7M fe/7-butyllithium at -78 °C] was next introduced, and the reaction mixture was stirred at -78 °C for 2 h before the addition via cannula of ketone 96 (3.536 g, 25.58 mmol) in dry THF (2 ml). After an additional 1 h in the cold, the mixture was allowed to warm to room temperature, poured into saturated aqueous sodium bicarbonate solution, and extracted with ether. The combined extracts were dried prior to solvent evaporation. The unpurified carbinol was stirred with Dowex-50X resin (3.35 g) in CH 2CI2 (1 L) heated to reflux for 48 h, filtered, and concentrated. Chromatography of the oil on silica gel (elution with 5% ethyl acetate in hexanes) and on neutral alumina (elution with 10% ethyl acetate in hexanes) furnished 0.985 g (17%) of 152, mp 57-59 °C (from hexanes); IR (KBr, c m 1) 2960, 2945, 2870, 1695, 1440, 1305, 1265, 1250, 1235, 1125; >H NMR (300 MHz, CDCI3) 6 3.10-2.98 (m, 1 H), 2.84-2.71 (m, 2 H), 2.54 (ddd, J = 12.4 Hz, 5.7 Hz, 2.0 Hz, 1 H), 2.22-2.14 (m, 1 H), 2.13-2.04 (m, 1 H), 1.91-1.40 (m, 12 H), 1.38-1.27 (m, 2 H); *3C NMR (75 MHz, CDCI 3 ) ppm 209.38, 74.54, 53.35, 38.30, 37.18, 37.06, 33.77, 33.35, 31.42, 30.66, 27.23, 25.32, 21.81; MS m/z (M+) calcd. 224.1235, obsd. 224.1233. Anal. Calcd. for C 13H20OS: C, 69.59; H, 8.98. Found: C, 69.48; H, 8.93. 155 (±)-l-Thiadispiro[4.0.4.4]tetradec-12-en-14-one (153). O A solution of n-butyllithium in hexanes (3.44 ml, 4.47 mmol) was added via syringe to a solution of dry diisopropylamine (0.66 ml, 4.7 mmol) in anhydrous THF (40 ml) at -78 °C. This solution was stirred for 15 min before being treated with ketone 152 (0.955 g, 4.26 mmol) in dry THF (10 ml). The reaction mixture was quenched after 30 min by the addition of premixed trimethylsilyl chloride (0.60 ml, 4.7 mmol) and triethylamine (0.16 ml, 1.2 mmol). After being warmed to room temperature over 15 min, the mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ether. The extracts were dried and evaporated, and the residual oil was dissolved immediately in THF (30 ml) and propylene oxide (0.33 ml, 4.7 mmol) at 0 °C. N-Bromosuccinimide (0.837 g, 4.70 mmol) was added and stirring was maintained for 45 min. Solvent evaporation followed by chromatography of the residue on silica gel (elution with 10% ethyl acetate in hexanes) afforded a quantitative yield of a-bromo ketones. A solution of the bromo ketones (1.291 g, 4.26 mmol) in N,N-dimethylacetamide (5 ml) was added to a stirred mixture of dry lithium bromide (1.33 g, 10.8 mmol) [heated to 140 °C and 1 Torr overnight immediately prior to use] and lithium carbonate (0.961 g, 13.0 mmol) in the same solvent (20 ml). The reaction mixture was heated to 170 °C for 2 h, cooled, poured into ether, and filtered through a pad of Celite. Evaporation of the ether and Kugelrohr distillation of the dimethyl acetamide produced a semisolid residue that was triturated with ether. Filtration of the extracts through a pad of Celite followed by concentration of the filtrate furnished an oil that was chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to afford 0.903 g (95%) of enone 153, mp 41-43 °C (from hexanes); IR (KBr, cm'*) 3035, 2945, 2870, 1675, 1420, 1385, 1260, 1235; lH NMR (300 MHz, CDC13) 6 6.67 (ddd, J = 10.1 Hz, 5.4 Hz, 2.5 Hz, 1 H), 5.97 (dd, J = 10.2 Hz, 2.1 Hz, 1 H), 2.83 (dd, J = 7.3 Hz, 5.7 Hz, 2 H), 2.46 (br d, J = 19.2 Hz, 2 156 H), 2.22 (dd, J = 19.3 Hz. 5.5 Hz. 1 H), 2.16-2.04 (m, 8 H); 1 ^C NMR (75 MHz. CDCl?) ppm 196.55, 146.52, 127.90, 71.00, 50.99, 40.72, 36.08, 35.45, 33.31, 32.02, 31.31, 26.59, 26.08; MS m/z (M+) calcd. 222.1078, obsd. 222.1071. Anal. Calcd. for Ci 3H |8 OS: C, 70.23; H, 8.16. Found: C, 70.19; H, 8.09. l-Thiadispiro[4.0.4.4]tetradec-12*en-14-ol (154). OH To a mixture of enone 153 (0.776 g, 3.49 mmol) and cerium trichloride heptahydrate (1.56 g, 4.19 mmol) in methanol (15 ml) was added sodium borohydride (0.145 g, 3.84 mmol). Additional small lots of hydride reagent were added until the enone was no lonjer detected (t.l.c. analysis). The reaction mixture was poured into 10% aqueous HC1 solution and was extracted with ether. The organic phases were dried and evaporated, and the residual oil was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to furnish 0.680 g (87%) of a 3:2 mixture of epimeric alcohols 154; IR (neat, cm '1) 3600-3200 (br s), 3040, 2960, 2870, 1430, 1265, 1230; »H NMR (300 MHz, CDCI 3) 6 5.77-5.55 (m, 2 H), 4.18-4.17 (m, 0.4 H), 3.98 (br d, J = 11 Hz, 0.6 H), 2.95-2.69 (m, 2.6 H), 2.54 (d, J = 1.7 Hz, 0.4 H), 2.21-1.88 (m, 6 H), 1.85-1.71 (m, 1 H), 1.69-1.37 (m, 6 H), 1.32- 1.20 (m, 1 H); NMR (75 MHz, CDCI3 ) ppm 128.91, 128.05, 129.93, 127.59, 73.99, 72.97, 72.88, 72.38, 51.12, 50.59, 38.49, 37.14, 36.71, 36.60, 35.96, 35.77, 34.53, 34.35, 33.97, 33.91, 33.65, 32.73, 25.17, 25.15, 24.69, 24.45; MS m /z (M+) calcd. 224.1235, obsd. 224.1225. Anal . Calcd. for C 13H20OS: C, 69.59; H, 8.98. Found: C, 69.31; H, 8.99. 157 (±)-l-Thiadispiro[4.0.4.4]tetradeca*l 1,13-diene (155). S' , To a stirred solution of alcohols 154 (0.363 g, 1.74 mmol) and triethylamine {1.0 ml, 7.2 mmol) in 1,2-dichloroethane (15 ml) was added 2,4-dinitrobenzenesulfenyl chloride (1.227 g, 5.23 mmol). The mixture was stirred and heated to reflux for 8 h, cooled, then poured into ether and filtered through a pad of Celite. The filtrate was evaporated and the residual oil was chromatographed on silica gel (elution with 5% ethyl acetate and 1% triethylamine in hexanes) to furnish 0.187 g (57%) of 155; IR (neat, cm >) 3035, 2955, 2830, 1450, 1440, 840, 795, 755; »H NMR (300 MHz, CDCI3) 6 5.92 (d, J = 9.2 Hz, 1 H), 5.89-5.76 (m, 2 H), 5.73-5.68 (m, 1 H), 2.92-2.85 (m, 1 H), 2.81-2.59 (m, 2 H), 2.25-2.15 (m, 1 H), 2.14-1.90 (m, 2 H), 1.88- 1.27 (m, 8 H); >3C NMR (75 MHz, CDCI3 ) ppm 140.65, 137.08, 121.52, 119.91, 64.96, 50.33, 36.58, 35.67, 35.16, 32.23, 30.03, 25.63, 24.51; MS m/z (M+) calcd. 206.1129, obsd. 206.1128. (l*#t,2S,3,J?,4’S,5’l?,6’S)-4,4” ,5,5,’-Tetrahydro-(V-phenyldispiro[furan- 2(3/f ),2*-bicyclo[2.2.2joct[7]ene*3’,2” (3” £f )-furan]-5*,6*-dicarboximide (156). A stirred solution of dioxa diene 105 (53 mg, 0.28 mmol), N-phenylmaleimide (95 mg, 0.55 mmol), and benzene (2 ml) was heated to reflux for 72 h. The solution was cooled and concentrated and the residual oil was purified by MPLC (silica gel, elution with 1:1 “ ethyl acetate-hexanes) to afford 83 mg (83%) of the syn cycloadduct 156 as the only product, mp 222-224 °C (from hexanes); IR (KBr, cm*1) 2975, 1710 (s), 1500, 1385, 1180, 1055; «H NMR (300 MHz, CDCI 3) 5 7.43-7.30 (m, 3 H), 7.18-7.14 (m, 2 H), 6.21 (dd, J - 4.4 Hz, 3.4 Hz, 2 H), 3.99-3.87 (m, 4 H), 3.62 (d, J = 1.3 Hz, 2 H), 3.14-3.12 (m, 2 H), 2.08-1.80 (m, 6 H), 1.60-1.50 (m, 2 H); l3C NMR (75 MHz, 158 CDCh) ppm 178.74, 132.03, 131.90, 128.94, 128.39, 126.47, 84.94, 67.85, 44.72, 39.55, 36.14, 25.55; MS m/z (M+) calcd. 365.1627, obsd. 365.1623. Anal. Calcd. for C 22H23NO4 : C, 72.31; H, 6.34. Found: C, 72.19; H, 6.24. (l’R,2S,3’IM ’S,5’R,6’S)-4,4” ,5,5” -Tetrahydrodispiro[furan-2(3ff),2’- bicyclo[2.2.2]oct[7]ene-3%2” (3t’//)-furan]-5’,6’-dicarboxylic anhydride (157). A stirred solution of 105 (73 mg, 0.38 mmol), maleic anhydride (41 mg, 0.42 mmol), and benzene (5 ml) was heated to reflux for 20 h. T.l.c. analysis indicated that diene rearrangement had competed with cycloaddition. The solvent was cooled and concentrated, and the residue was chromatographed on silica gel (elution with 40% ethyl acetate in hexanes) to furnish in order of elution propelladiene 127 (9 mg, 12%), benzopyran 128 (4 mg, 5%), diene 105 (7 mg, 9%), and cycloadduct 157 (51 mg, 46%), mp 253-256 °C (from ethyl acetate); IR (KBr, cm*1) 2970, 2895, 2885, 1870, 1840, 1785 (s), 1230, 1090, 1060, 1040, 925, 770; >H NMR (300 MHz, CDCI 3) 6 6.23 (dd, J = 4.5 Hz, 3.3 Hz, 2 H), 3.94-3.83 (m, 4 H), 3.72-3.70 (t, J = 1.7 Hz, 2 H), 3.08-3.04 (m, 2 H), 2.06-1.79 (m, 6 H), 1.58-1.48 (m, 2 H); 13C NMR (75 MHz, CDCI3) ppm 173.65, 132.46, 84.39, 67.95, 44.44, 40.42, 35.93, 25.55; MS m/z (M+) calcd. 290.1154, obsd. 290.10 (FAB). Ana/. Calcd. for Ci 6H 18 0 5: C, 66.20; H, 6.25. Found: C, 66.13; H, 6.29. 159 (l’/r,2/M ’S,4'a/f,8’aS,10’S )-l\4,4\4’\4 ,a,5,5’\8 ’a-Octahydrodispiro- [furan-2(3//),9,-[l,4]ethanonaphthalene-10,,2” (3” //)-furanJ-5\8,-dione (1 5 8 ). j I \ o A solution of 105 (51 mg, 0.26 mmol), benzoquinone (28 mg, O 0.26 mmol), and CH 2CI2 (3 ml) was submitted to high pressure \ (175,000 psi) for 3 d. The solvent was evaporated and the residue was Jh— * purified by MPLC (silica gel, elution with 3:1 ethyl acetate in hexanes) O to yield 53 mg (67%) of 158, mp 160-162 °C (from ether); IR (KBr, cm-') (hydroquinone) 3700-3100 (br s), 2980, 2900, 1750, 1665, 1345, 1305, 1255, 1140, 1060; 'H NMR (300 MHz, CDCI3) 5 6.64 (s, 2 H), 6.15 (dd, J = 4.6 Hz, 3.3 Hz, 2 H), 3.98-3.87 (m, 4 H), 3.64 (t, J = 1 Hz, 2 H), 3.18-3.14 (m, 2 H), 2.10-1.93 (m, 2 H), 1.93-1.79 (m, 4 H), 1.58-1.46 (m, 2 H); '^C NMR (75 MHz, CDCI 3) ppm 199.87, 141.79, 133.08, 84.84, 67.60, 46.86, 44.00, 35.84, 25.52; MS m /z (M+) calcd. 300.1362, obsd. 300.1362. Anal. Calcd. for Ci 8 H i20 4: C, 71.98; H, 6.71. Found: C, 71.98; H, 6.78. (l\R,2J?,4’S,4’atf,9’aS,12,S )-r,4,4’,4’\4 ’a,5,5” ,9’a-Octahydrodispiro- [furan-2(3i/),ll’-[l,4]ethanoanthracene-12\2” (3”//)-furan]-9’,10’-dione (1 5 9 ). A solution of 105 (56 mg, 0.29 mmol), naphthoquinone (47 mg, 0.30 mmol), and CH 2CI2 (2 ml) was submitted to high pressure (175,000 psi) for 5 d. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 40% ethyl acetate in hexanes) to afford 70 mg (69%) of 159, mp 219- 220 °C (from ethyl acetate); IR (KBr, cm-') 2980, 2880, 1675 (s), 1275, 1065, 720; 'H NMR (300 MHz, CDCI3) 6 8.02-7.96 (m, 2 H), 7.68-7.62 (m, 2 H), 6.10 (dd, J = 4.6 160 Hz. 3.3 Hz, 2 H). 4.00-3.85 (m, 4 H), 3.84 (t, J = 1.1 Hz, 2 H), 3.32-3.28 (m, 2 H), 2.11-1.75 (m, 6 H), 1.58-1.50 (m, 2 H); l3C NMR (75 MHz, CDCI 3 ) ppm 198.26, 135.70, 133.83, 133.47, 126.61, 85.02, 67.64, 47.09, 45.01, 35.90, 25.60; MS m /z (M+) calcd. 350.1518, obsd. 350.1524. Anal. Calcd. for C 22H22O4 : C, 75.41; H, 6.33. Found: C, 75.37; H, 6.37. ( l’tf,2l?,4’S,6,S)-4,4’\5 ,5 ” -Tetrahydro-;V-niethyldispiro[furan-2(3jy),5’- [2,3]diazabicyclo[2.2.2]oct[7]ene-6’,2” (3” /f )-furan]-2*,3’-dicarboximlde (160). A solution of freshly sublimed N-methyltriazoline-3,5-dione O- ^ ✓7 (3.5 mg, 0.31 mmol) in CH 2CI2 (2 ml) was added via cannula to a \ stirred solution of 105 (60 mg, 0.31 mmol) in CH 2CI2 (3 ml) cooled Me to -78 °C. The reaction mixture was allowed to warm to room O temperature over 45 min, at which time the red color was no longer present. Additional triazolinedione (10 mg) was added as a solid when t.l.c. analysis indicated that a trace of diene remained. The reaction mixture was stirred for 4 h, then concentrated and purified by MPLC (silica gel, elution with 1:1 ethyl acetate-hexanes) to furnish 78 mg (82%) of 160, mp 178-181 °C (from ethyl acetate); IR (KBr, cm"1) 2985, 2885, 1775, 1760 (s), 1455, 1395, 1220, 1075, 1020, 780, 750; ‘H NMR (300 MHz, CDCI3) 8 6.44-6.40 (m, 2 H), 4.45-4.43 (m, 2 H), 3.92-3.71 (m, 4 H), 2.95 (s, 3 H), 2.16-1.97 (m, 6 H), 195-1.83 (m, 2 H); 13C NMR (75 MHz, CDCI 3 ) ppm 157.29, 129.73, 85.31, 68.65, 58.22, 33.13, 25.35, 25.35; MS m/z (M+) calcd. 305.1376, obsd. 305.1365. Anal. Calcd. for Q 5 H19 N3O4 : C, 59.01; H, 6.27. Found: C, 59.04; H, 6.41. 161 (1 ’S,3’S,4’/f ,5’S,6’R )-4” ,5” -Dihydro-Ar-phenyldispiro[cyclopentane- l,2’-bicyclo[2.2.2]oct[7]ene-3’,2” (3” fO-furan]-5’,6*-dicarboximtde (161). A solution of 102 (64 mg, 0.34 mmol), N-phenylmaleimide (60 mg, 0.34 mmol), and diisopropylethylamine (4.4 mg, 0.034 mmol) in CH 2CI2 (2 ml) was submitted to high pressure (150,000 Ph psi) for 3 d. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes). The first compound to elute was 161 (97 mg, 79%), mp 199.5-200.5 °C (from 1:1 ethyl acetate-hexanes); IR (KBr, cm-') 2950, 2870, 1770, 1705 (s), 1495, 1380, 1170, 1050, 730; >H NMR (300 MHz, CDCI3) 6 7.39-7.28 (m, 3 H), 7.11 (d, / = 8.2 Hz, 2 H), 6.33-6.28 (m, 1 H), 6.12-6.07 (m, 1 H), 3.90-3.83 (m, 1 H), 3.80-3.72 (m, 1 H), 3.50 (dd, J = 8.2 Hz, 3.1 Hz, 1 H), 3.20 (dd, J = 8.2 Hz, 2.9 Hz, 1 H), 3.07-3.04 (m, 1 H), 2.86-2.84 (m, 1 H), 1.97-1.79 (m, 3 H), 1.76-1.36 (m, 10 H), 1.26-1.17 (m, 2 H); 13c NMR (75 MHz, CDCI3) ppm 179.24, 178.64, 134.70, 132.10, 130.18, 128.91, 128.31, 126.45, 87.59, 67.31, 52.92, 44.78, 43.87, 41.06, 39.76, 38.63, 34.66, 33.27, 25.05, 24.73, 24.33; MS m/z (M+) calcd. 363.1834, obsd. 363.1841. Anal. Calcd. for C 23H25NO3: C, 76.01; H, 6.93. Found: C, 75.91; H, 6.89. 162 ( ,5’/?,6’S)-4”,5,’-Dihydro-Af-phenyldispirofcyclopentane- l,2*-bicyclo[2.2.2]oct[7]ene-3’,2” (3’ ,A/)-furanJ-5,,6,-dicarboxiir»ide (162). The second compound to elute was 162 (7 mg, 6 %), mp 229- 230 °C (from 1:1 ethyl acetate-hexanes); IR (KBr, cnr') 2955, 2875, 1710 (s), 1500, 1380, 1175, 1050, 735; 'H NMR (300 MHz, Ph CDC13) 8 7.46-7.34 (m, 3 H), 7.16 (br d, J = 7.2 Hz, 2 H), 6.42- 6.38 (m, 1 H), 6.30-6.25 (m, 1 H), 3.87-3.79 (m, 2 H), 3.19 (dd, J = 8.2 Hz, 3.2 Hz, 1 H), 3.12 (br d, J = 5.9 Hz, I H), 3.06 (dd, J = 8.2 Hz, 2.8 Hz, 1 H), 2.98-2.95 (m, 1 H), 2.12-1.42 (m, 10 H), 1.38-1.25 (m, 2 H); I3C NMR (75 MHz, CDCI3) ppm 178.30, 177.83, 132.76, 131.93, 131.22, 129.11, 128.62, 126.49, 88.65, 67.49, 54.11, 44.41, 43.19, 40.95, 40.83, 35.74, 32.86, 26.13, 24.16, 23.66; MS m/z (M+) calcd. 363.1834, obsd. 363.1839. ( l ’#t,4,S,6,l^)-4,^5” -Dihydro-A^-methyldispiro[cyclopentane-l,5,- [2,3]diazabicyclo[2.2.2]oct[7]ene-6\2"(3”//)-furan]-2’,3’-dicarboximide (1 6 3 ). A solution of freshly sublimed N-methyltriazoline-3,5-dione (34 mg, 0.30 mmol) in CH 2CI2 (5 ml) was added via cannula to a stirred solution of 102 (56 mg, 0.29 mmol) and triethylamine (420 N V Me pi, 0.030 mmol) in CH 2CI2 (5 ml) at -78 °C. The reaction mixture O was stirred at room temperature for 45 min, then concentrated. Chromatography of the residue on silica gel (elution with 1; 1 ethyl acetate in hexanes) furnished 40 mg (45 %) of 163, mp 153-155 °C (from 20% ethyl acetate in hexanes); IR (KBr, cm-') 2980, 2890, 1775, 1710 (s), 1460, 1215, 1065, 1020; >H NMR (300 MHz, CDCI3) 8 6.51-6.46 (m, 1 H), 6.38-6.33 (m, 1 H), 4.43 (dd, J = 5.5 Hz, 1.5 Hz, 1 H), 163 4.36 (dd, J = 5.6 Hz, 1.5 Hz, 1 H), 3.89-3.82 (m, 1 H), 3.79-3.71 (m, 1 H), 2.97 (s, 3 H), 2.18-2.11 (m, 1 H), 2.10-1.86 (m, 3 H), 1.85-1.71 1.27-1.19 (m, 1 H); l3C NMR (75 MHz, CDCI 3) ppm 157.82, 157.57, 130.65, 129.50, 85.69, 68.48, 58.42, 58.10, 53.69, 34.78, 33.54, 32.24, 25.38, 25.36, 24.19, 23.69; MS m/z (M+) calcd. 303.1583, obsd. 303.1581. Anal. Calcd. for C 16H21N 3O 3: C, 63.35; H, 6.98. Found: C, 63.43; H, 7.12. ( l’A,2A,4’5,6,S)-4,4*’,5,5” >Tetrahydro-Ar-methyIdispiro[thiophene- 2(3//),5’-[2,3]diazabicyclo[2.2.2]oct[7]ene-6’,2” (3” //)-thiophene]-2’,3’- dicarboximide (164). A solution of freshly sublimed N-methyltriazoline-3.5-dione S . " (31 mg, 0.28 mmol) in CH 2CI2 (2 ml) was added via cannula to a / stirred solution of 117 (57 mg, 0.25 mmol) in CH 2CI2 (3 ml) at -78 [[ Me °C. The solution was warmed to room temperature, stirred for 3 h, O and concentrated. Chromatography of the residue on silica gel (elution with 1:1 ethyl acetate in hexanes) afforded 74 mg (87%) of 164, mp 156-157 °C (from 30% etyl acetate in hexanes); IR (KBr, cm-1) 2950, 1775 (s), 1710 (s), 1445, 1390, 1260, 1205, 1020, 915, 765; »H NMR (300 MHz, CDCI3 ) 6 6.55 (dd, J = 3.9 Hz, 3.3 Hz, 2 H), 4.65-4.63 (m, 2 H), 2.94 (s, 3 H), 2.94-2.79 (m, 4 H), 2.25-2.08 (m, 8 H); 13C NMR (75 MHz, CDCI3) ppm 157.20, 131.01, 6 6 .6 8 , 59.10, 37.18, 32.17, 29.66, 25.35; MS m/z (M+) calcd.337.0919, obsd. 337.0917. Anal. Calcd. for C 15H 19 N3O 2S2: C, 53.39; H, 5.67. Found: C, 53.40; H, 5.76. 164 (1 'R,3'S,4'S,5'R ,6’S)-4” ,5’’-Dihydro-Ar-phenyldispiro[cyclopentane- l,2’-bicyclo[2.2.2]oct[7]ene-3’,2” (3” //)-thiophene]-5\6’-dicarboximide; (1 ’S ,3 ’S ,4 ’/?,5 ’R ,6 ’/f )-4” t5” -Dihydro-jV-phenyldispiro[cyclopentane- l,2’-bicyclo[2.2.2]oct[7]ene-3\2” (3” //)-thiophene]-5\6’-dicarboximide (165 / 166). A solution of 155 (37 mg, 0.18 mmol), N-phenylmaleimide (34 mg, 0.20 mmol), and diisopropylethylamine (2.9 mg, 0.022 mmol) in CH 2CI2 (2 ml) was submitted to high pressure (175,000 Ph psi) for 16 d. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 2 0 % ethyl acetate and 1% triethylamine in hexanes) to furnish decomposed starting material (23 mg, 62%) followed by 10 mg (14%) of one cycloadduct (A) followed by 8 mg (12%) of its facial isomer (B) (relative stereochemistry was not determined). For A: mp 203-204 °C (from 30% ethyl acetate in hexanes); IR (KBr, c m 1) 3160, 2970, 2940, 2890, 2260, 1800, 1710, 1470, 1385, 1100, 915, 790; »H NMR (300 MHz, CDCI3) 8 7.47-7.33 (m, 3 H), 7.18-7.14 (m, 2 H), 6.38-6.24 (m, 2 H), 3.87 (dd, J = 8.3 Hz, 3.2 Hz, 1 H), 3.21 (dd, J = 8.3 Hz, 3.2 Hz, 1 H), 3.18-3.15 (m, 1 H), 2.95-2.89 (m, 3 H), 2.14-1.97 (m, 3 H), 1.89-1.51 (m, 9 H); 13C NMR (75 MHz, CDCI 3) ppm 178.89, 178.53, 133.50, 132.04, 131.92, 129.07, 128.52, 126.51, 68.35, 52.45, 46.51, 43.99, 41.63, 41.35, 40.83, 39.28, 37.03, 31.42, 28.83, 23.64, 23.48; MS m/z (M+) calcd.379.1606, obsd. 379.1603. For B: mp 226-227 °C (from 1:1 ethyl acetate-hexanes); IR (KBr, cm '1) 2955, 2870, 1715 (s), 1385, 1180; »H NMR (300 MHz, CDCI 3) 8 7.47-7.33 (m, 3 H), 7.17-7.13 (m, 2 H), 6.44-6.35 (m, 2 H), 3.36-3.32 (m, 1 H), 3.24 (dd, J = 8.2 Hz, 3.1 Hz, 1 H), 3.19 (dd, J = 8.2 Hz, 2.8 Hz, 1 H), 2.98-2.95 (m, 1 H), 2.89-2.81 (m, 2 H), 2.23-2.03 (m, 2 H), 2.00-1.91 (m, 3 H), 1.84-1.58 (m, 6 H), 1.49-1.43 (m, 1 H); 13C NMR (75 MHz, 165 CDCI3) ppm 178.31, 177.73, 133.52, 133.42, 131.91, 129.12, 128.61, 126.45, 67.42, 54.02, 47.06, 42.36, 42.04, 41.16, 41.03, 38.81, 33.78, 31.76, 30.19, 23.23, 23.07; MS m/z (M+) calcd.379.1606, obsd. 379.1602. Anal. Calcd. for C 23H25NO2S: C, 72.79; H, 6.64. Found: C, 72.47; H, 6.57. (1 ’/?,4’S,6’/?)-4’\5*,-Dihydro-jV-methyldispiro[cyclopentane-l,5’- [2,3]diazabicyclo[2.2.2]oct[7]ene-6*2” (3” /f )>thiophene]-2’,3*- dicarboximide (167). A solution of N-methyltriazoline-3,5-dione (34 mg, 0.30 mmol) in CH 2CI2 (3 ml) was added via cannula to a stirred solution ' \ of 155 (57 mg, 0.27 mmol) in CH 2 CI2 (4 ml) at -78 °C. The "Me cooling bath was removed and the solution stirred at room O temperature for 15 min. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 30% ethyl acetate and 1% triethylamine in hexanes). The first compound to elute was 167 (40 mg, 45%), mp 166-167 °C (from 30% ethyl acetate in hexanes); IR (KBr, cm"1) 2960, 2870, 1770 (s), 1720 (s), 1455, 1400, 1210, 1035, 1020, 1010, 770; >H NMR (300 MHz, CDCI3) 8 6.52-6.42 (m, 2 H), 4.62 (dd, J = 5.3 Hz, 1.5 Hz, 1 H), 4.38 (dd, J = 5.4 Hz, 1.7 Hz, 1 H), 2.97 (s, 3 H), 2.84 (dd, J = 7.4 Hz, 5.6 Hz, 2 H), 2.30-2.23 (m, 1 H), 2.14-2.02 (m, 2 H), 2.00-1.58 (m, 8 H), 1.38-1.31 (m, 1 H); ^C NMR (75 MHz, CDCI 3) ppm 157.67, 157.63, 131.21, 130.51, 64.58. 59.83, 57.69, 53.71, 39.57, 37.98, 33.38, 32.55, 29.51, 25.37, 23.11, 22.99; MS m/z (M+) calcd.319.1355, obsd. 319.1360. Anal. Calcd. for C 16H21N3O2S: C, 60.16; H, 6.63. Found: C, 60.43; H, 6.74. 166 (1 ’5,4’/f ,6’R )>4” ,5” -Dihydro-A-methyldispiro[cyclopentane-1,5’* [2,3]diazabicyclo[2.2.2]oct[7]ene-6’2” (3” */)-thiophene]-2%3’- dicarboximide (168). The second compound to elute was 168 (4 mg, 4%), mp 188-190 °C; >H NMR (300 MHz, CDCI 3 ) 8 6.54-6.43 (m, 2 H), 4.52 (dd, J = 5.4 Hz, 1.7 Hz, 1 H), 4.27 (dd, J = 5.4 Hz, 1.7 Hz, 1 N)jT"N'Me H), 3.00 (s, 3 H), 2.79-2.58 (m, 2 H), 2.47-2.25 (m, 2 H), 2.11- ° 1.92 (m, 2 H), 1.91-1.78 (m, 1 H), 1.78-1.64 (m, 3 H), 1.63-1.50 (m, 4 H); MS m/z (M+) calcd.319.1355, obsd. 319.1352. (l,R,2S,3,J?,4’S,5*S,6,S)-4,4,’,5,5” -Tetrahydro-./V-phenyldIsplro[furan- 2(3tf),2’-bicyclo[2.2.2]oct[7]ene-3’,2” (3” /y)-thiophene]-5\6’- dicarboximide (169). A solution of 111 (51 mg, 0.24 mmol), N-phenylmaleimide (47 mg, 0.27 mmol), and diisopropylethylamine (3.2 mg, 0.025 mmol) in CH 2CI2 (2 ml) was submitted to high pressure (150,000 Ph psi) for 5 d. The solvent was evaporated and the residue was chromatographed on silica gel (gradient elution with 2 0 % ethyl acetate in hexanes, then 30% ethyl acetate in hexanes) to afford 13 mg (25%) of 111 followed by 39 mg (56% based on unrecovered diene) of 169, mp 221-222 °C (from 1:1 ethyl acetate- hexanes); IR (KBr, cm*1) 2960, 2860, 1780, 1705 (s), 1500, 1385, 1175, 1065, 730; >H NMR (300 MHz, CDCI3) 8 7.45-7.32 (m, 3 H), 7.19-7.15 (m, 2 H), 6.37-6.31 (m, 1 H), 6.24-6.19 (m, 1 H), 3.98-3.88 (m, 2 H), 3.84 (dd, J = 8.2 Hz, 3.0 Hz, 1 H), 3.69 (dd, J = 8.3 Hz, 3.5 Hz, 1 H), 3.20-3.13 (m, 2 H), 2.87-2.79 (m, 2 H), 2.17-2.05 (m, 2 H), 2.04-1.92 (m, 4 H), 1.65-1.56 (m, 2 H); I3C NMR (75 MHz, CDCI 3 ) ppm 178.84, 178.77, 134.05, 132.08, 130.64, 128.99, 128.42, 126.50, 86.01, 69.96, 68.19, 46.40. 167 45.20, 41.76, 41.23, 40.23, 34.63, 30.02. 29.64, 25.91; MS m/z Anal. Calcd. for C 22H23NO3S: C, 69.27; H, 6.08. Found: C, 69.08; H, 5.99. (r#t,2tf,4’S,6’S)-4,4’\5,5” *Tetrahydro-;V-inethyldispiro[furan-2(3tfh5*- [2,3]diazabicyclo[2.2.2]oct[7]ene-6’,2’*(3” i/)thiophene]-2%3*- dicarboximide (170). A solution of freshly sublimed N-methyltriazoline-3,5-dione S . ' ^1 (28 mg, 0.24 mmol) in CH 2CI2 (3 ml) was added via cannula to a - " ' s . n ^ v 'O * stirred solution of 111 (48 mg, 0.23 mmol) in CH 2CI2 (4 ml) at -78 Y The cooling bath was removed and the reaction mixture was O stirred at room temperature for 30 min before being treated with additional dienophile (9 mg). Stirring was maintained for an additional 30 min, after which the solvent was evaporated. Chromatography on the residue on silica gel (elution with 1:1 ethyl acetate-hexanes) furnished 170 in quantitative yield, mp 140.5-142 °C (from 30% ethyl acetate in hexanes); IR (KBr, cm’1) 2955, 2880, 1775 (s), 1715 (s), 1445, 1395, 1205, 1075, 775; >H NMR (300 MHz, CDCI3) 6 6.56-6.51 (m, 1 H), 6.39-6.34 (m, 1 H), 4.57 (dd, J = 5.6 Hz, 1.5 Hz, 1 H), 4.42 (dd, J - 5.6 Hz, 1.6 Hz, 1 H), 3.82 (br t, J = 6 .6 Hz, 2 H), 2.93 (s, 3 H), 2.84-2.75 (m, 2 H), 2.19-2.06 (m, 5 H), 2.05-1.90 (m, 3 H); 13C NMR (75 MHz, CDCI3) ppm 157.52, 156.94, 130.65, 129.55, 85.99, 68.75, 66.81, 59.07, 58.98, 38.10, 31.84, 31.05, 29.92, 25.60, 25.29; MS m /z A n a l. Calcd. for C 15H 19 N 3O 3S: C, 56.06; H, 5.96. Found: C, 56.14; H, 5.97. 168 (1 *R ,2S,3’S,4’S,5’.S,6’S)-4,4,\5 ,5 ” -Tetrahydro-Ar-phenyldispiro[furan- 2(3//),2’-bicyclo[ 2.2.2]oct[7]ene-3’,2” (31 ’// )-thiophene]-5’,6’- dicarboximide (171). A solution of 114 (50 mg, 0.24 mmol), N-phenylmaleimide (45 mg, 0.26 mmol) and diisopropylethylamine (3.5 mg, 0.026 mmol) in CH 2CI2 (1.5 ml) was submitted to high pressure (175,000 NL Ph psi) for 18 h. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 2 0 % ethyl acetate in hexanes) to furnish 63 mg (70%) of 171, mp 189-190 °C (from 1:1 ethyl acetate in hexanes); IR (KBr, cm 1) 2955, 2870, 1710 (s), 1500, 1380, 1180, 1055; *H NMR (300 MHz, CDCI3) 5 7.45-7.32 (m, 3 H), 7.17-7.13 (m, 2 H), 6.47-6.42 (m, 1 H), 6.25-6.19 (m, 1 H), 4.01-3.94 (m, 1 H), 3.90-3.82 (m,l H), 3.59 (dd, J = 8.2 Hz, 3.4 Hz, 1 H), 3.37-3.34 (m, 1 H), 3.25 (dd, J = 8.2 Hz, 3.0 Hz, 1 H), 3.18-3.14 (m, 1 H), 2.93-2.76 (m, 2 H), 2.39-2.28 (m, 1 H), 2.20-1.88 (m, 6 H), 1.86-1.71 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 178.75, 177.61, 135.12, 131.93, 131.22, 128.97, 128.44, 126.40, 89.03, 68.64, 68.09, 46.75, 43.86, 41.32, 39.95, 39.15, 36.93, 33.21, 30.21, 25.24; MS m/z (M+) calcd.381.1399, obsd. 381.1393. Anal. Calcd. for C 22H23NO3S: C, 69.27; H, 6.08. Found: C, 69.28; H, 6.08. 169 (1 ’S,2S,4’/?,6*S)-4,4*\5,5” -Tetrahydro-Ar-methyldispiro[fiiran-2(3// ),5’- [2,3]diazabicyclo[2.2.2]oct[7]ene-6’,2” (3” // )thiophene]-2*,3’> dicarboximide (172). A solution of freshly sublimed N-methyltriazoline-3,5-dione (38 mg, 0.34 mmol) in CH 2CI2 (4 ml) was added via cannula to a stirred solution of 114 (64 mg, 0.31 mmol) in CHCI 2 (3 ml) at *78 Me °C. After being warmed slowly to room temperature over 60 min, O the reaction mixture was concentrated and the residue was chromatographed on silica gel (elution with 75% ether in hexanes). The first compound to elute was 172 (35 mg, 35%), mp 159.5-162 °C; IR (KBr, cm 1) 3000, 2960, 2880, 1775 (s), 1715 (s), 1450, 1395, 1205, 1055, 1025, 780, 750; >H NMR (300 MHz, CDCI 3) 5 6.49-6.36 (m, 2 H), 4.64 (dd, J = 5.5 Hz, 1.8 Hz, 1 H), 4.47 (dd, J = 5.4 Hz, 1.8 Hz, 1 H), 3.93-3.78 (m, 2 H), 2.98 (s, 3 H), 2.96-2.86 (m, 2 H), 2.57 (dt, J = 13.5 Hz, 7.9 Hz, 1 H), 2.25-2.17 (m, 1 H), 2.10-1.92 (m, 5 H), 1.68-1.54 (m, 1 H); 13C NMR (75 MHz, CDCI3) ppm 157.41, 157.20, 130.11, 129.96, 86.17, 69.63, 68.14, 62.59, 57.98, 38.44, 36.87, 32.92, 30.10, 25.59, 25.43; MS m /z (M+) calcd.321.1147, obsd. 321.1151. (l,J?,2S,4*S,6*S)-4,4’\5 ,5 ” -Tetrahydro-iV-niethyIdisplro[furan-2(3lf),5’- l2,3]diazabicyclol2.2.2]oct[7]ene-6\2” (3,,//)thiophene]-2\3’- dicarboximide (173). The second compound to elute was 173 (50 mg, 50%), mp 206-207 °C (from 1:1 ethyl acetate-hexanes); IR (KBr, cm*1) 2950, 2870, 1770 (s), 1715 (s), 1455, 1400, 1210, 1055, 775; >H NMR ^ N'M e (300 MHz, CDCI3) 6 6.59-6.54 (m, 1 H), 6.42-6.35 (m, 1 H), 4.69 ° (dd, J = 5.6 Hz, 1.5 Hz, 1 H), 4.53 (dd, J = 5.9 Hz, 1.5 Hz, 1 H), 170 4.04-3.87 (m, 2 H), 2.98 (s, 3 H), 2.92-2.78 (m. 2 H), 2.39-2.29 (m, I H), 2.26-2.16 (m, 1 H), 2.15-1.91 (m, 5 H), 1.69-1.60 (m, 1 H); 13C NMR (75 MHz, CDCI 3 ) ppm 156.66, 156.10, 133.21, 129.16, 87.22, 69.14, 66.19, 58.86, 58.37, 37.83, 36.19, 33.93, 29.71, 25.32, 25.17; MS m/z (M+) calcd.321.1147, obsd. 321.1142. Anal. Calcd. for C 15H 19 N3O3S: C, 56.06; H, 5.96. Found: C, 56.08; H, 6.02. (l’l?,2S,4’S,6’S)-4,4” ,5,5” -Tetrahydro-;V-inethyldispiro[furan-2(3JT),5*- [2,3]diazabicyclo[2.2.2]oct[7]ene-6,,2” (3” 7/)-furan]-2’,3’-dicarboximide (1 7 4 ). Competition Experiments. A. Between 105 and 108. A solution of freshly sublimed N-methyltriazoline-3,5-dione (27 mg, 0.24 mmol) in CH 2CI2 (5 ml) was added via cannula to a stirred solution of 105 (58 mg, 0.30 mmol) and 108 (58 mg, 0.30 mmol) in CH 2CI2 (5 ml) at -78 °C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated and the residue was chromatographed on silica gel (elution with 1:1 ethyl acetate-hexanes) to afford (in order of elution) 22 mg (38%) of 108, 58 mg (100%) of 105, and 55 mg (97% based on unrecovered diene) of 174, mp 165-166.5 °C (from 30% ethyl acetate in hexanes); IR (KBr, cm 1) 2960, 2875, 1770 (m), 1710 (s), 1450, 1400, 1210, 1065, 1025; »H NMR (300 MHz, CDCI3 ) 6 6.46-6.35 (m, 2 H), 4.53 (dd, J = 5.1 Hz, 2.3 Hz, 1 H), 4.45 (dd, J = 4.9 Hz, 2.3 Hz, 1 H), 4.09-3.97 (m, 1 H), 3.94-3.85 (m, 2 H), 3.76 (dd, J = 7.9 Hz, 6.7 Hz, 1 H), 2.96 (s, 3 H), 2.28-2.18 (m, 1 H), 2.14-2.03 (m, 2 H), 2.01-1.79 (m, 4 H), 1.52-1.44 (m, 1 H); NMR (75 MHz, CDCI3) ppm 157.12, 156.73, 131.27, 128.62, 86.83, 86.38, 69.68, 69.22, 58.40, 57.41, 32.16, 30.51, 25.48, 25.40, 25.27; MS m/z (M+) calcd.305.1376, obsd. 305.1371. 171 Anal. Calcd. for C 15H 19 N 3O 4: C, 59.01; H. 6.27. Found: C, 58.93; H, 6.32. B. Between 105 and 117 (General Procedure). A solution of freshly sublimed N-methyltriazoline-3,5-dione (9.5 mg, 0.084 mmol) in CH 2CI2 (3 ml) was added via cannula to a solution of 105 (22 mg, 0.12 mmol) and 117 (24 mg, 0 .1 1 mmol) in CH 2CI2 (2.5 ml) at -78 °C. The cooling bath was removed and the mixture was stirred at room temperature until the red color had disappeared. The solvent was evaporated and lH NMR analysis of the reaction mixture revealed a ratio of 2.4:1 between 164 and 160, respectively. The residue was chromatographed on silica gel (gradient elution with 20-30% ethyl acetate in hexanes, 70% ethyl acetate in hexanes) to afford 11 mg (47%) of 117, 12.5 mg (56%) of 105, 12 mg (44%) of 164, and 4 mg (15%) of 160. C. Between 105 and 102. The procedure was followed as before using 105 (41 mg, 0.21 mmol), 102 (41 mg, 0.21 mmol), and N-methyltriazoline-3,5-dione (19 mg, 0.17 mmol). Once the color had disappeared, 'H NMR analysis of the reaction mixture revealed that only 102 had reacted. The mixture was chromatographed on silica gel to afford 102 (14 mg, 34%), 105 (40 mg, 99%), and 163 (40 mg, 77%). D. Between 105 and 114. The procedure was followed as before using 105 (38 mg, 0.20 mmol), 114 (41 mg, 0.20 mmol), and N-methyltriazoline-3,5-dione (19 mg, 0.16 mmol). After the color was no longer visible NMR analysis of the reaction mixture indicated an 8.4:1 mixture of 172/173 and 160, respectively. 172 E. Between 105 and 111. The above procedure was followed with 105 (32 mg, 0.17 mmol), 111 (35 mg, 0.17 mmol), and N-methyltriazolinedione (15 mg, 0.14 mmol). After the color was no longer visible, ’H NMR analysis of the reaction mixture revealed an 8.3:1 ratio of 170 to 160. F. Between 102 and 114. The above procedure was followed with 102 (31 mg, 0.16 mmol), 114 (34 mg, 0.16 mmol), and N-methyltriazoline-3,5-dione (15 mg, 0.13 mmol). After the color was no longer visible, lH NMR analysis of the reaction mixture displayed a 2:1 ratio of 163 to 172/173. Chromatographic separation of the components yielded 18 mg (46%) 163 and 10 mg (25%) of the mixture of 172 and 173. G. Between 102 and 108. The above procedure was followed with 102 (39 mg, 0.21 mmol), 108 (41 mg, 0.21 mmol), and N-methyltriazoline-3,5-dione (19 mg, 0.17 mmol). After the red color was no longer visible, *H NMR analysis of the reaction mixture indicated a 1.5:1 ratio of 174 to 163. Chromatographic separation of the components furnished 11 mg (22%) of 163 followed by 18 mg (36%) of 174. H. Between 102 and 111. The above procedure was followed with 102 (34 mg, 0.18 mmol), 111 (37 mg, 0.18 mmol), and N-methyltriazolinedione (17 mg, 0.15 mmol). After the red color was no longer visible, *H NMR analysis of the reaction mixture revealed a 1.6:1 ratio of 163 to 173 170. Chromatographic separation of the components afforded 29 mg (65%) o f 163 followed by 19 mg (40%) of 170. 1. Between 111 and 114. The above procedure was followed with 111 (43 mg, 0.21 mmol), 114 (43 mg, 0.21 mmol), and N-methyltriazoline-3,5-dione (19 mg, 0.17 mmol). After the red color was no longer visible, *H NMR analysis of the reaction mixture displayed a 1.3:1 ratio of 170 to the mixture of 172 and 173. J. Between 111 and 117. The above procedure was followed with 111 (33 mg, 0.16 mmol), 117 (36 mg, 0.16 mmol), and N-methyltriazoline-3,5-dione (17 mg, 0.15 mmol). After the red color was no longer visible, *H NMR analysis of the reaction mixture indicated a 4:1 ratio of 170 to 164. Chromatographic separation of the components afforded 42 mg (88%) of 170 followed by 9 mg (18%) of 164. APPENDIX A lH NMR SPECTRA 174 175 176 O 9 9 00 8 50 9 00 7 50 7.00 6 50 6.00 5.50 5.00 4 50 4.00 3 .SO 3.00 ? 50 2 00 1 50 177 50 50 8 00 7 SO 7.00 6 50 6.00 5.50 5.00 4 50 4.00 3.50 3.00 3.50 3.00 I 50 1 00 B B 9 00 178 1 7 9 S l O 6 DO fl OS 6* C - 466* t*OOS 6 00 1 0000 — L. A— 2 «dd d /« W 0 52 DOOl 00? C 5/ 10/7* / 5 ICO O ec OOr € OOC €€1 ooc n t ooor ooo t 960 0 00005 000 ►r? ocOiS ooc t e o (0 0005 000 9 WC iW 99 o or oo IHIATOC 3 D U n - e - 6 i 0 0 0/D 0 0 BSt S C 4 0 0 c 1/ Ocf 5 t o 15 5 » « l?C M l i COC > 1 l ? 0005 01 t e c w 0? 0? AS 01? 0 100 j «#/7 u > 3i»P NTM SI wc BT »D DO *c ?p di"* 0* O cw 00 1# I* »s M SN 31 30 IS 35 h a f 180 50 7 50 7.00 6.50 6.00 5 50 5.00 4.50 4 00 3.50 3 00 ?.50 ? 00 9 9 00 B 50 e 00 U s«ic II5 tqshnn =^P^^ nnhtos 182 I* 183 9 00 6.00 1 507 00 6 .5 0 6.00 5 .5 0 5 .0 0 4.00 50 I 502 184 ~*1— ' T ' — ' 'T* — ■T “ ■ N IM ■ M SM IM 4.M 186 co DGS204C.00I DATE 1 -1 1-M TIME 12; SI KI.IS 300.139 HO" .701 PM 967 303 59 10600 50000 000 DP tOL P0 LB 200 I 000 75 027 250 187 0 00 7 .00 6 50 6.00 5 50 5 .0 0 4 .50 4 .0 03 50 3 .0 0 2 00 1 .0 0 & £ * <& > 190 f 38* I 13 » ! P « *ihpc •• Ii* siSSasssal ims*s a l£a SPh "T" 5.00 4.30 l.H ).« ) H Ml !.« I 50 < H » I 9 0 0 n 192 193 H .8 [ 'Drt)i«| 194 Br 5 SO 6 .5 0 6.00 8 00 7.50 1 00 196 m "m X O 199 < 200 ■ - * o 201 4 203 J .3 204 Ml 206 207 208 O 209 .8 i-8 .8 .8 .8 .8 .8 .8 .8 .8 Ls !• i. 2 1 0 212 214 r> 216 L 217 219 r S D “ - co n Ph HO, niattMtt. K \zz -* .Jt 51 .» -* .* m .** .« .1 K .X m .X m 223 224 225 < 226 y I » I M 1,1) ?.w I M >.M l.H 9.M IJI t.M l. M IVY .M YV 22S (in Toluene d8) Jtl V jl t i vy y v w T » 7 # •• !1 1.1 JUI «•v J.S ).* H »!, tj IO vO o (in Benzene d6) i ...... r 1 ■■ "1 "1 M r.M I.N I.N 9.M «w H ).M l.W vww I S I H ,'jo IM M r r 230 Major AIJ M y v ,w w ? N I N I.M Minor 233 234 236 237 o o 5 ~ \ _ ) 238 239 O 240 •• 06 2 4 2 6I MS S M M'S l K 06'I z>“ D“ 244 Q£> _ o -* .8 .* _8 : ** p.* -* m .8 w .8 *> .8 tfi s -*■I .8 •» .8 .8 ,8 .8 248 l C /3 250 .2 252 5 M 05? Ml 05 1 K M i i a r L OH J) ______ i .. [J. l V. « .* V,1.9* I.M 1 t 99 w I.M I. M 0 V 253 254 ET\ K l l l i v l C /3 o c o Jk l.H 2 . 3* 2 .** 1.90 I M .90 0 0 IJ VI O' SCHj o c c SCH3 257 259 o £ - 260 €* -* 5 f r0/"z. t U Nm 262 263 -4 264 265 266 267 I > “ - 3 s 269 270 > - ■ v_ unimi L 271 ce 273 274 275 276 i . . Tr K l M K • • ------1 ------rmrrn 1 _ . , r 1 , | j I I ------I --- 9 1 . T ------I IK L 278 s i 279 -* Q. 280 281 282 284 -* • ■t I— ___ «* . J m * — H 5: •« * • o & y - \ ------~ * n 2: \ 1 I. rE 0 *% ■ * * APPENDIX B X-RAY DATA 285 286 Table 3.1: Bond Distances (A) and Angles (deg) for 66 . Atoms Distance Atoms Distance BrO)-C(l) 1.96(1) Br(2)-C( 1) 1.97(1) Br(3)-C(3) 1.99(1) O ~C(2) 117(1) C(1 )-C(2) 1.53(1) C(l)-C(10) 1.53(1) C(2)-C(3) 1.53(1) C(3)-C(4) 1.55(1) C(3)-C(l 1) 1.51(1) C(4)-C(5) 1.51(1) C(5)-C{6) 1.51(2) C(6)-C(7) 1.49(2) C(6)-C( 11) 1.57(2) C(7)-C(8) 1.30(2) C(8)-C(9) 1.50(2) C(8)-C(l 1) 1.49(1) C(9)-C(10) 1.51(2) Atoms Angle Atoms Angle Br( 1 )-C( 1 )-Br(2) 105.5(5) Br(l)-C(l)-C(2) 108.0(8) Br(2)-C( 1 )-C(2) 109.6(6) Br(l)-C(l)-C(10) 106.6(7) Br(2)-C(l)-C(10) 111.2(8) C(2)-C(l)-C(10) 115.4(9) 0-C(2)-C( I) 120(1) 0-C(2)-C(3) 120(1) C(I )-C(2)-C(3) 120(1) Br(3)-C(3)-C(2) 103.5(7) Br(3)-C(3)-C(4) 106.5(7) C(2)-C(3)-C(4) 109.5(8) Br(3)-C(3)-C( 11) 108.5(7) C(2)-C(3)-C(l 1) 121.6(9) C(4)-C(3)-C(ll) 106.5(9) C(3)-C(4)-C(5) 104.9(9) C(4)-C(5)-C(6) 103.9(9) C(5)-C(6)-C(7) 118(1) C(5)-C(6)-C(l 1) 108.3(9) C(7)-C(6)-C(l 1) 85.6(9) C(6)-C(7)-C(8) 94(1) C(7)-C(8)-C(9) 138(1) C(7)-C(8)-C(l 1) 96(1) C(9)-C(8)-C(l 1) 126(1) C(8)-C(9)-C(10) 119(1) C(l)-C(10)-C(9) 115.8(9) C(3)-C(l 1 )-C(6) 104.8(9) C(3)-C( 11 )-C(8) 112.8(9) C(6)-C( 11)-C(8) 84.0(9) Table 3.2: Final Fractional Coordinates for 66. Atom x/a y/b z/c B(eqv)a Br( 1) 0.3860(2) 0.0820(1) 0.40439(7) 4.89 Br(2) 0.1074(2) 0.2405(1) 0.27248(8) 4.32 Br(3) 0.1629(2) 0.0777(1) 0.06820(7) 3.67 O 0.501(1) 0.0180(7) 0.2418(5) 4.08 C(l) 0.388(2) 0.179(1) 0.3035(6) 2.67 C(2) 0.432(1) 0.107(1) 0.2277(6) 2.27 287 r'i N 13 l f s c C v u o U 3 • r^*t»nxr^oe^£ — -N(NMNN(S(NM u u u u u u u u u CONOCO ooP in in d C — m t/"i £ X dccdcdodd >fit rr r>i INrn <*> d — IN IN tn •w c St 3^ o o IN 8 S W — r*- r** o o 3 O p in rn 00 t n , ^ i n ^ » r i n o X 00 ■S o — IN 3 3 $ Tf ,_, —O' ^ oo ^ —O' np ' h C C S «t r*- •c o — r- oc ON nr IN ro rn no d IN r- 00 S Tf v© P on d d in oo — I IN r- IN n*. IN N * IN N * IN IN * * * CB x A D X oo oo X ^ 2 * D X XI IN w D S D w*- * Table 3.3: Final Fractional Coordinates for 66. •s r-«OTrr'Ttr--TficxiioiN * N — IN — N I — S — 2 —* S N I £ — S £ N I £ ^ 2 - £ S S doddddddddd doddddddddd fnr- C(2) 0.020(5) 0.039(8) 0.025(5) -0.002(5) -0.002(4) -0.007(5) 288 Table 3.4 (continued): C(3) 0.019(5) 0.037(7) 0.024(5) 0.001(5) 0.009(4) -0.005(5) C(4) 0.038(7) 0.040(7) 0.033(6) 0.002(6) 0.008(5) 0.003(5) C(5) 0.045(8) 0.050(8) 0.041(7) -0.003(7) 0.014(6) 0.020(6) C(6) 0.048(8) 0.037(8) 0.042(7) -0.005(6) 0.004(6) 0.009(6) C(7) 0..047{8) 0.034(8) 0.08(1) -0.0.014(6) 0.022(7) -0.009(7) C(8) 0.051(8) 0.028(7) 0.048(7) -0.015(6) 0.012(6) -0.013(6) C(9) 0.048(8) 0.06(1) 0.068(9) -0.022(7) 0.018(7) -0.019(8) C(10) 0.037(7) 0.044(8) 0.050(7) -0.011(6) -0.001(6) -0.015(6) C(ll) 0.030(6) 0.027(7) 0.044(7) -0.004(5) 0.004(5) -0.002(5) Anisotropic thermal parameters are defined by: exp[-2p2(h2a*2Ul 1 + k2b*2U22 + l2c*2U33 + 2hka*b*UI2 + 2klbVlJ23 + 2hla*c*U13)] Hydrogen atoms were given a fixed isotropic thermal parameter of B s 5.5A2. T able 4.4: Bond Distances (A) and Angles (deg) for 80. Atoms Distance Atoms Distance S-C(l) 1.799(3) S-C(4) 1.858(2) 0(1)-C(5) 1.213(3) 0(2)-C(9> 1.436(3) CK2)-C(12) 1.430(3) C(l)-C(2) 1.510(5) C(2)-C(3) 1.520(4) C(3)-C(4) 1.529(3) C(4)-C(5) 1.525(4) C(4)-C(9) 1.557(3) C(5)-C(6) 1.507(4) C(6)-C(7) 1.536(4) C(7)-C(8) 1.519(4) C(8)-C(9) 1.527(4) C(9)-C(10) 1.537(3) C(10)-C(ll) 1.520(4) C(11)-C(12) 1.509(5) Atoms Angle Atoms Angle C(l)-S-C(4) 94.4(1) C(9)-0(2)-C(12) 110.1(2) S-C(1)-C(2) 106.3(2) C(l)-C(2)-C(3) 106.1(2) C(2)-C(3)-C(4) 109.3(2) S-C(4)-C(3) 105.3(2) S-C(4)-C(5) 105.4(2) C(3)-C(4)-C(5) 112.9(2) S-C(4)-C(9) 110.8(2) C(3)-C(4)-C(9) 114.0(2) C(5)-C(4)-C(9) 108.1(2) 0(1)-C(5)-C(4) 121.2(3) 0(1 )-C(5)-C(6) 122.6(3) C(4)-C(5)-C(6) 116.2(2) C(5)-C(6)-C(7) 112.1(2) C(6)-C(7)-C(8) 112.1(2) C(7)-C(8)-C(9) 112.9(2) 0(2)-C(9)-C(4) 108.7(2) 0(2)-C(9)-C(8) 108.6(2) C(4)-C(9)-C(8) 110.2(2) O(2)-C(9)-C(10) 105.4(2) C(4)-C(9)-C(I0) 112.0(2) C(8)-C(9)-C(10) 111.8(2) C(9)-C(10)-C(l 1) 102.5(2) C(10)-C(l 1)-C(12) 101.4(2) 0(2)-C(12)-C(l 1) 105.9(2) 289 Table 4.5: Final Fractional Coordinates for 80. Alom x/a y/b ?Jc B(eqv)a S -0.3114(1) -0.1108(1) -0.10986(7) 3.05 CKD -0.1886(3) -0.2086(3) -0.4521(2) 3.63 0(2) -0.2878(3) 0.2651(3) -0.1422(2) 2.95 C(l) -0.5587(5) -0.2570(5) -0.1653(3) 3.89 C(2) -0.5888(5) -0.2987(4) -0.3209(4) 3.54 C(3) -0.4646(4) -0.1141(4) -0.3507(3) 2.80 C(4) -0.2713(3) -0.0241(3) -0.2647(2) 2.07 C(5) -0.1392(4) -0.0943(4) -0.3374(3) 2.56 C(6) 0.0530(4) -0.0157(5) -0.2579(3) 3.45 C(7) 0.1466(4) 0.2015(4) -0.2006(3) 3.06 Atom x/a y/b z/c B(eqv)a C(8) 0.0155(4) 0.2733(4) -0.1295(3) 2.46 C(9) -0.1712(3) 0.1966(3) -0.2208(2) 2.04 C(10) -0.1472(4) 0.2729(4) -0.3465(3) 2.64 C(11) -0.1709(5) 0.4515(4) -0.2918(4) 3.59 C(12) -0.3215(5) 0.3897(5) -0.2019(4) 3.63 aB(eqv) = (8p2/3)[a2u j i(a*)2 + b^U22(b*)^ + c2(J33(c*)2 + ab(cosg)U 12a*b* ♦ ac(cosb)U j 3a*c* + .at ifc_ bc(cosa)U 23b’,c*] T able 4.6: Final Fractional Coordinates for 80. Atom x/a y/b z/c H(1)IC(1)| -0.600 -0.371 -0.141 H(2)[C(1)] -0.626 -0.191 -0.124 H( 1 )[C(2)] -0.716 -0.340 -0.354 H(2)[C(2)] -0.553 -0.394 -0.364 H(1)[C(3)] -0.452 -0.139 -0.446 H(2){C(3>] -0.519 -0.030 -0.327 H( 1 )[C(6)] 0.129 -0.052 -0.318 H(2)[C(6)] 0.042 -0.067 -0.183 H(1 )[C(7)] 0.186 0.254 -0.275 H(2)[C(7)] 0.253 0.241 -0.135 H(1)[C(8)] -0.009 0.235 -0.048 K» sO O n o 9 5 c B9 2 JT b\ fD a. o — c — jj ; uj uj p o pp p ui *s i/i lu O lu W O » i/i *s ui jj Ul M 9 A ^ LA» - XXXXXXI p w p Q ^wbklOKtC p -J - pty S p p p y> ua u O w y> k> — k> k> — 0 0 0k> 0 0 0 5 M — K» —. M — fj — M —. K» — M nononno # o vl * (O -Ui « -ww ui ui oo •n o ’ •n O H H 9" n E. y S3 3 » 2 !T a * •• o O A to m C U22 U33 U12 U13 U23 g c 2 s s — O •—. •—. y ^ y“ s l —« NjUlU(ODOOO — — N) KJ — — y“ S y"*\ ■w N_y 'W' V (J| w y-S y—v y*“s y*“s y-S y—v y ^ k, k, S £ £ 00 n y“ v — o u> u> 3 . . 00 — K)wtO- — OOWKJ — — OOWKJ — K)wtO- — O UJ w — — — — — — — hs)KJ —s O u> i288£S2§3§§8S32® c — — —— T3 m •sj LH •sj S?£ W W W W W W W v '—' W' w ^ w Ij) V' ■’— V' — s — * — * —* — » — v y—\ y—s /—s. ^ y » » — — >. 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I I t A ^ 00 K> K> nn> w SO — N> so so \C M — — W — 06 — W — — N) — U* — w w >~ w w K> — o — K> y*v y—y y^Sy*v y—y s s £ y“y y“y — y*. £ y *S y—s, C(l)-C<2) 1.49(2) C(2)-C(3) 1.49(2) C(3)-C(4) 1.54(1) C(4)-C(5) 1.54(2) O' (N s 9®>vS?Qt®"55'C'OAi»n 'w O O' O' p O; 9 00 xt O n » •'i P', oo 00 «mri^nm- 81. >* ddoddddddddddo — ^ ^ r- O' oo — Table 4.9 (continued): Atom x/a y/b z/c B(eqv)a C(12) 0.173(2) 0.323(2) 0.609(1) 3.7(5) b C(lt)’ 0.129(2) 0.173(2) 0.619(1) 3.4(5) b C(I2)’ 0.136(2) 0.329(2) 0.606(1) 4.5(6) b aB(eqv) = (8p2/3)[a2u i J(a*)^ + b ^ l)2 2(b*)^ + c^U33(c*)2 + ab(cosg)U 12a*b* + ac(cosb)U| 3a*c* + bc(cosa)U 23b*c*] ^Isotropic refinement. Table 4.10: Final Fractional Coordinates for 81. Atom x/a y/b z/c H(1)[C(1)] -0.090 0.128 0.361 H(2)[C(1)] -0.072 0.164 0.270 H(1)[C(2)] -0.118 0.346 0.363 H(2)[C(2)] -0.037 0.373 0.301 H(I)(C(3)] 0.023 0.439 0.423 H(2)[C(3)] -0.016 0.314 0.467 H(1)[C(6)] 0.257 0.224 0.292 H(2)[C(6)] 0.300 0.366 0.301 H(1)[C(7)] 0.327 0.337 0.439 H(2)[C(7)] 0.372 0.217 0.393 H(1)[C(8>] 0.243 0.087 0.423 H(2)[C(8)1 0.286 0.143 0.504 H(1)[C(10)] 0.127 0.048 0.535 H(2)[C(10)] 0.037 0.133 0.520 H(1)[C(I1)] 0.038 0.256 0.628 H(2){C(11)] 0.117 0.164 0.663 H( 1 )[C( 12)] 0.233 0.298 0.629 H(2)[C(12)] 0.152 0.401 0.637 H(1)[C(11)’] 0.085 0.145 0.660 H(2)[C(11)’] 0.190 0.139 0.631 H( 1 )[C( 12)’ ] 0.174 0.373 0.647 H(1)[C(12)’] 0.073 0.362 0.609 293 Table 4.11: Thermal Parameters for 81. Atom U ll U22 U33 U12 Ul 3 U23 S 0.058(2) 0.044( 1) 0.045(2) -0.004(2) -0.010(2) -0.008(2) 0(1) 0.089(7) 0.048(5) 0.061(6) -0.022(6) -0.021(5) 0.022(5) 0(2) 0.075(6) 0.046(5) 0.030(5) -0.013(5) 0.004(4) -0.009(4) CO) 0.07(1) 0.073(9) 0.059(9) 0.000(8) -0.024(8) -0.007(8) C(2) 0.045(9) 0.08(1) 0.07(1) 0.018(8) -0.007(9) -0.012(8) C(3) 0.048(8) 0.064(9) 0.061(9) 0.014(8) -0.006(7) -0.014(7) C(4) 0.040(7) 0.035(7) 0.019(6) -0.001(7) 0.005(6) 0.003(6) C(5) 0.055(9) 0.046(8) 0.025(6) -0.013(7) -0.001(7) 0.000(7) C(6) 0.07(1) 0.074(9) 0.053(9) -0.025(8) 0.018(9) -0.004(8) C(7> 0.032(8) 0.073(9) 0.067(9) 0.004(9) 0.010(8) 0.013(8) C(8) 0.050(7) 0.048(8) 0.049(7) 0.011(8) -0.016(8) -0.013(6) C(9) 0.049(9) 0.033(7) 0.038(8) -0.010(7) -0.002(7) -0.001(6) C(10) 0.09(1) 0.058(8) 0.044(7) -0.002(9) -0.009(7) 0.005(7) C(ll) 3.8(5) CO 2) 3.7(5) C(ll)* 3.4(5) C( 12)* 4.5(6) Anisotropic thermal parameters are defined by: exp[-2p2( h V 2Ul | + k2b*2U22 + l2c*2U33 + 2hkaVui2 + 2klbV lJ23 + 2 h la V u i3 )] Hydrogen atoms were given a fixed isotropic thermal parameter of B = 5.5A2. Table 4.12: Bond Distances (A) and Angles (deg) for 83. Atoms Distance Atoms Distance S-C(9) 1.848(3) S-C(12) 1.818(5) 0(1)-C(5) 1.211(4) 0(2)-C (l) 1.433(5) CX2)-C(4) 1.444(4) C(l)-C(2) 1.505(6) C(2)-C(3) 1.504(6) C(3)-C(4) 1.525(5) C(4)-C(5) 1.539(5) C(4)-C(9) 1.545(5) C(5)-C{6) 1.493(5) C(6)-C(7) 1.532(6) C(7)-C(8) 1.525(5) C(8)-C(9) 1.534(5) C(9)-C(10) 1.540(5) C(10)-C(ll) 1.512(5) C( 11 )-C( 12) 1.516(6) () 039() .404 033() 3.04 4.27 0.3430(3) 0.0459(3) 0.6400(4) 0.7037(4) -0.3691(4) -0.5315(5) 0(2) 0(1) -.002 021() .791 3.58 0.3779(1) 0.2711(2) -0.0040(2) S Table 2 ST 09 ynnnnnnnnnnnn " V y—s y—s .«—S y— s y —s y—S. y—s y—s y—N y—s. y—y oowwononoonon KJ — ©W W V^W W W W -^V o s S 1 S i. ^3 i. 2 '"7* jT 'T* V V 'T' "T* 3 ^5rrG5nnnnnn« t/l £ I 83. for Coordinates Fractional Final 4.13: S’ o C H i 0 3 9 3 2 2 2 9 - 0 £t to .— 0 4 0 0 9SS-J5555556S n o* -a y - ^ y™s y—s - y ^ y—s y—s » y—s • fj 3 # to vOO^'OvOUt^tO ft *> » r-s w 2 s o' 3 to 0 a fiT 3 to 3 C 3 OC V * ^ I I I I I I ( I I I o. * OOopOOOOOOOO > To — o — wiyiyi^Iuw — k>k> O to O 4s s to 2 00 u> 8 to P p p OJ s O' + 2^- oSNw*Q«»'e a k > — y—s TL k L 04jo jo 00 La 2 jo to Table 4.14: Final Fractional Coordinates for 83. Atom x/a y/b z/c H Table 4.15: Bond Distances (A) and Angles (deg) for 84. Atoms Distance Atoms Distance S-C(9) 1.844(4) S-C(12) 1.802(8) OO)-C(l) 1.412(6) 0(1)-C(4) 1.457(5) 0(2)-C(5) 1.213(6) C(l)-C(2) 1.437(8) C(2)-C(3) 1.505(7) C(3)-C(4) 1.522(6) C(4)-C(5) 1.536(7) C(4)-C(9) 1.545(6) C(5)-C(6) 1.481(7) C(6)-C(7) 1.530(8) C(7)-C(8) 1.513(7) C(8)-C(9) 1.536(6) C(9)-C(I0) 1.544(6) C(10)-C(ll) 1.467(8) C( 11 )-C( 12) 1.44(1) () 026() 035() 063() 4.88 3.00 -0.6233(6) -0.7555(4) -0.3957(2) -0.4510(1) -0.2669(6) 0.1128(5) 0(2) 0(1) S S> 84. for Coordinates Fractional Final 4.16: Table y—Vnononnnnnono y—S y“ S y —S y—S y—s y-s. y—S y—s y—s QQVVSQQQSgnon V) 09s > — — — vjD00-JOU i + 0 O O © O ipb^'COb Lj La ^ La i-fcWOOs) * -J T n -J 00 Ul -J u» O ro ^ — to y—s y—* y—s y—s T -4 O 00 00 W ' w ’W > S $ k>p _S“^ — 5 — SSS 3 gcbj-““S — y—s oujiO'jiobc-vjOi y^i y—s <*s y—s -*—s y—s y—s -—s. — y—s L/i y—s fT to lnift'U£kUi£tt/ivi£h'^^Ui'U T -J yj ro Ui AUKIWUiA K»si Lb u> bouW ^U -J ro ic vC •JC--JUI- < 6 9 2 297 Table 4.17: Final Fractional Coordinates for 84. Atom x/a y/h z/c H( I )[C( 1)1 0.228 -0.500 -0.548 H(2)[C(1)] 0.374 -0.458 -0.616 H(1)[C(2)] 0.148 -0.430 -0.389 H(2)[C(2)] 0.346 -0.401 -0.399 H(1)[C(3>] 0.207 -0.333 -0.595 H(2)[C(3)1 0.027 -0.344 -0.514 H(1 )[C(6)] -0.238 -0.482 -0.910 H(2)[C{6)] -0.429 -0.450 -0.894 H(I)[C(7)] -0.360 -0.371 -1.072 H(2)[C(7)1 -0.350 -0.431 -1.176 H(1)|C(8)] -0.085 -0.370 -1.190 H(2)fC(8)] -0.020 -0.431 -1.094 H( I )[C( 10)J 0.272 -0.375 -1.021 H(2)[C(10)J 0.320 -0.349 -0.828 H( 1 )[C( 11)] 0.210 -0.286 -1.139 H(2)[C(11)] 0.380 -0.271 -0.981 H(1)[C(12)] 0.193 -0.226 -0.835 H(2)[C(12)] 0.090 -0.209 -1.028 Table 4.18: Bond Distances (A) and Angles (deg) for 85. Atoms Distance Atoms Distance S Table 4.18 (continued): Atoms Angle Atoms Angle C(1 )-S(l)-C(4) 94.6( 1) C(9)-S(2)-C( 12) 94.7(1) S(l)-C(l)-C(2> 105.5(2) C(l)-C(2)-C(3) 106.5(2) C(2)-C(3)-C(4) 109.0(2) S(l)-C(4)-C(3) 105.3(2) S(l)-C(4)-C(5) 104.5(2) C(3)-C(4)-C(5) 111.1(2) S( 1 )-C(4)-C(9) 109.7(2) C(3)-C(4)-C(9) 115.3(2) C(5)-C(4)-C(9) 110.2(2) 0-C(5)-C(4) 121.6(3) 0-C(5)-C(6) 121.7(3) C(4)-C(5)-C(6) 116.7(2) C(5)-C(6)-C(7) 112.4(3) C(6)-C(7)-C(8) 111.5(3) C(7)-C(8)-C(9) 113.1(2) S(2)-C(9)-C(4) 109.1(2) S(2)-C(9)-C(8) 108.9(2) C(4)-C(9)-C(8) 109.9(2) S(2)-C(9)-C(10) 104.7(2) C(4)-C(9)-C(10) 112.2(2) C(8)-C(9)-C(10) 111.9(2) C(9)-C( 10)-C( 11) 107.6(2) C(10)-C(l 1 )-C( 12) 106.7(3) S(2)-C(12)-C(11) 106.9(2) Table 4.19: Final Fractional Coordinates for 85. Atom x/a y/b z/c B(eqv)a S(l) -0.4304(1) -0.5708(1) -0.86361(6) 2.65 S(2) -0.0400(1) -0.1910(1) -0.86164(7) 3.37 O -0.1371(4) -0.6726(3) -0.6212(2) 3.96 C (l) -0.3572(6) -0.7167(4) -0.9548(3) 3.78 C(2) -0.1691(6) -0.7581(4) -0.8821(3) 3.87 C(3) -0.0128(5) -0.5777(4) -0.8029(2) 3.12 C(4) -0.1525(4) -0.4846(3) -0.7571(2) 2.13 C(5) -0.2004(5) -0.5545(4) -0.6551(2) 2.58 C(6) -0.3326(5) -0.4718(5) -0.6005(3) 3.62 C(7) -0.2438(6) -0.2624(5) -0.5815(3) 3.80 C(8) -0.2091(5) -0.1959(4) -0.6852(2) 3.08 C(9) -0.0557(4) -0.2708(4) -0.7322(2) 2.24 C(10) 0.1883(5) -0.1909(4) -0.6556(3) 2.99 C (ll) 0.3020(6) -0.0058(5) -0.6813(3) 4.02 C(12) 0.2471(6) -0.0341(5) -0.8049(3) 4.41 aB(eqv) * (8p2/3)[a2Ui i(a*)2 + b2U22(b*)2 + c2U 33(c*)2 + ab(cosg)U 12a*b* + ac(cosb)Ui 3a*c* + bc(cosa)U 23b*c*] ^Isotropic refinement. 299 Table 4.20: Final Fractional Coordinates for 85. Atom x/a y/b d c H(I)(C(1)] -0.482 -0.826 -0.991 H(2)[C{1>] -0.307 -0.654 -1.007 H(1)[C{2)] -0.093 -0.806 -0.925 H(2)[C(2)] -0.228 -0.845 -0.841 H(l)fC(3)l 0.067 -0.500 -0.843 H(2)[C(3)] 0.090 -0.600 -0.744 H( 1 )[C(6)] -0.483 -0.517 -0.647 H(2)[C(6)j -0.329 -0.507 -0.532 H( 1 )[C(7)] -0.105 -0.216 -0.525 H(2)[C(7)] -0.348 -0.219 -0.559 H(1)[C{8)] -0.143 -0.065 -0.668 H(2)[C(8)] -0.350 -0.233 -0.740 H( 1 )[C( 10)] 0.191 -0.178 -0.581 H(2)[C(10)1 0.264 -0.270 -0.671 H(l )[C(11)] 0.241 0.079 -0.656 H(2)[C(11)] 0.459 0.040 -0.647 H(1)IC(12)] 0.343 -0.087 -0.828 H(2)|C(12)] 0.265 0.079 -0.829 Table 4.21: Bond Distances (A) and Angles (deg) for 86. Atoms Distance Atoms Distance S(l)-C (l) 1.848(6) S( 1 )-C(4) 1.804(4) S(2)-C(9) 1.811(4) S(2)-C(I2) 1.814(6) 0-C(5) 1.214(7) S (l)’-C(2) 1.832(9) S (t)’-C(4) 1.667(9) S(2)’-C(9) 1.568(9) S(2)’-C(U ) 1.799(8) 0 ’-C(8)’ 1.22(3) C(l)-C(2) 1.498(7) C(l)-C(3)' 1.43(3) C(2)-C(3) 1.549(9) C(3)-C(4) 1.550(6) C(3)’-C(4) 1.76(3) C(4)-C(5) 1.540(7) C(4)-C(5)’ 1.71(2) C(4)-C(9) 1.541(7) C(5)-C(6) 1.521(7) C(5)’-C(6) 1.84(2) C(6)-C(7) 1.508(9) C(7)-C(8) 1.503(8) C(7)-C(8)’ 1.69(2) C(8)-C(9) 1.589(7) C(8)*-C(9) 1.56(3) C(9)-C( 10) 1.576(7) C(9)-C{10)’ 1.80(2) COO)-C(ll) 1.488(9) C(10)’-C(12) 1.51(3) C(11)-C(12) 1.482(8) 300 Table 4.21 (continued): Atoms Angle Atoms Angle C(l)-S(l)-C<4> 93.6(2) C(9)-S(2)-C(12) 93.0(2) C(2)-S(l)’-C{4) 91.5(4) C(9)-S(2)‘-C( 11) 95.7(4) S(l)-C(1)-C(2) 107.0(4) C(2)-C( 1 )-C(3)’ 94(1) S( 1 )’-C(2)-C(l) 112.4(4) C(I)-C(2)-C(3) 104.0(4) C(2)-C(3)-C(4) 108.1(4) C(l)-C(3)'-C(4) 113(2) S(l)-C(4)-C(3) 106.9(3) S(l)’-C(4)-C(3)’ 104(1) S(l)-C(4)-C(5) 106.2(3) C(3)-C(4)-C(5) 108.4(4) S(l)’-C(4)-C(5)’ 110.2(9) C(3)’-C(4)-C(5)’ 89(1) S(l)-C(4)-C(9) 114.6(3) S( 1 )’-C(4)-C(9) 140.7(4) C(3)-C(4)-C(9) 112.0(4) C(3)'-C(4)-C(9) 105(1) C(5)-C(4)-C(9) 108.4(4) C(5)’-C(4)-C(9) 96.9(9) 0-C(5)-C(4) 122.3(5) 0-C(5)-C(6) 123.0(5) C(4)-C(5)-C(6) 114.6(4) C(4)-C(5)'-C(6) 93(1) C(5)-C(6)-C(7) 108,5(4) C(5)’-C(6)-C(7) 97.1(9) C(6)-C(7)-C{8) 109.6(5) C(6)-C(7)-C(8)’ 98(1) C(7)-C(8)-C(9) 110.6(4) 0 ’-C(8)’-C(7) 124(2) 0 ’-C(8)’-C(9) 131(2) C(7)-C(8)’-C(9) 103(1) S(2)-C(9)-C(4) 113.5(3) S(2)’-C(9)-C(4) 134.3(5) S(2)-C(9)-C(8) 108.5(4) C(4)-C(9)-C{8) 108.0(4) S(2)’-C(9)-C(8)f 121(1) C(4)-C(9)-C(8)’ 97(1) S(2)-C(9)-C(10) 106.6(3) C(4)-C(9)-C(10) 112.8(4) C(8)-C(9)-C(10) 107.2(4) S(2)’-C(9)-C(10)’ 107.1(9) C(4)-C(9)-C(10)* 93(1) C(8)’-C(9)-C(10)’ 93(1) C(9)-C(10)-C(l1) 109.5(5) C(9)-C( 10)’-C( 12) 105(1) S(2)’-C(l 1)-C(12) 114.4(5) C(10)-C(l 1)-C(12) 106.6(6) S(2)-C(12)-C(l 1) 107.0(4) C(10)’-C(12)-C(ll) 99(1) Table 4.22: Final Fractional Coordinates for 86. Atom x/a y/b z/c B(eqv)a S(l) 0.54315(9) -0.0689(2) 0.61452(7) 2.94 S(2) 0.8225(1) 0.1496(2) 0.62772(7) 3.41 O 0.6312(3) 0.3901(6) 0.6676(2) 4.00 S(l)' 0.6451(5) 0.206(1) 0.6921(3) 5.0(1) b S<2)’ 0.7193(5) -0.147(1) 0.5597(3) 5.5(1) b O’ 0.803(1) 0.329(3) 0.6056(9) 7.2(5) b C(l) 0.5601(4) -0.1454(8) 0.6912(2) 4.46 C(2) 0.6237(3) -0.0022(8) 0.7320(2) 3.95 C(3) 0.6989(3) 0.0342(8) 0.7042(2) 2.64 C(3)’ 0.613(2) -0.158(3) 0.653(1) 4.9(5) b C(4) 0.6494(3) 0.0675(6) 0.6366(2) 2.63 t V"S w f l'O M Viw N V S Vi y M O V, V S(N rs (N (N (N . V) uo if oc r- 00 » ^ . on O' CO £1:^ P -C -iJ.i'a + 3,'r-vCO©r'i # -D fN H uuuuuuuuuuu « j£ .E"1 H(2)[C(8>] H(l)[C(10)] 0.698 0.696 0.05! -0.257 0.512 0.567 302 Table 4.23 (continued): H(2)[C( 10)) 0.731 -0.256 0.636 H( 1 )[C(10)’l 0.758 -0.037 0.666 H(2)[C(10)’] 0.850 0.060 0.705 H(1 )[C(t 1)] 0.838 -0.198 0.566 H(2)(C(11)] 0.857 -0.345 0.618 H(1)*[C(I1)] 0.865 -0.247 0.577 H(2)’[C(I1)] 0.833 -0.332 0.626 H(1 )[C(12)] 0.899 -0.107 0.685 H(2)(C(12)) 0.949 -0.053 0.641 H (inC(12)J 0.916 -0.129 0.683 H(2)’(C(I2)) 0.038 -0.028 0.632 Table 5.1: Bond Distances (A) and Angles (deg) for 98. Atoms Distance Atoms Distance Br-C(6) 1.936(4) O d)-C(l) 1.420(5) 0(1)-C(4) 1.423(4) CX2)-C(5) 1.207(5) C(l)-C(2> 1.495(7) C(2)-C(3) 1.524(6) C(3)-C(4) 1.536(5) C(4)-C(5) 1.537(5) C(4)-C(9) 1.545(5) C(5)-C(6) 1.509(5) C(6)-C(7) 1.517(6) C(7)-C(8) 1.513(6) C(8)-C(9) 1.539(5) C(9)-C(10) 1.557(5) C(9)-C(13) 1.547(5) C(10)-C(ll) 1.537(8) C(10)-C(11V 1.40(1) C(11)-C(I2) 1.458(8) C(11)’-C(12) 1.60(1) C(12)-C(13) 1.512(6) Atoms Angle Atoms Angle C(1)-CK1)-C(4) 110.3(3) CX1)-C(1)-C(2) 108.1(4) C(l)-C(2)-C(3) 103.1(3) C(2)-C(3)-C(4) 102.1(3) 0 ( 1 )-C(4)-C(3) 104.9(3) 0(1)-C(4)-C(5) 109.5(3) C(3)-C(4)-C(5) 108.8(3) CK1 )-C(4)-C(9) 108.0(3) C(3)-C(4)-C(9) 115.8(3) C(5)-C(4)-C(9) 109.6(3) 0(2)-C(5)-C(4) 121.6(4) 0(2)-C(5)-C(6) 123.5(4) C(4)-C(5)-C(6) 114.9(3) Br-C(6)-C(5) 112.1(3) Br-C(6)-C(7) 111.3(2) C(5)-C(6)-C(7) 111.0(3) C(6)-C(7)-C(8) 110.8(3) C(7)-C(8)-C(9) 113.2(3) C(4)-C(9)-C(8) 108.6(3) C(4)-C(9)-C(10) 112.0(3) C(8)-C(9)-C(10) 110.3(3) C(4)-C(9)-C(13) 112.1(3) C(8)-C(9)-C(13) 110.3(3) C(10)-C(9)-C(13) 103.5(3) 303 Table 5.1 (continued): C(9)-C(10)-C(11) 104.7(4) C(9)-C(10)-C(l 1)’ 108.1(6) C(10)-C(M)-C(12) 106.1(5) C(IO)-C(tl)'-C(l2) 105.2(7) C( 11 )-C( 12 )-C( 13) 102.4(4) C(l l)’-C(12)-C(13) 106.0(5) C(9)-C(I3)-C(12) 106.7(3) Table 5.2: Final Fractional Coordinates for 98. Atom x/a y/b z/c B(eqv)a Br -0.25364(7) -0.19500(6) -0.56160(3) 4.93 0(1) -0.0236(3) -0.2701(2) -0.8757(2) 3.04 0(2) -0.1673(4) -0.3296(3) -0.7297(2) 3.92 C (l) -0.1492(6) -0.2947(4) -0.9527(3) 4.29 C(2) -0.2861(6) -0.2060(4) -0.9470(3) 3.79 C(3) -0.2034(4) -0.0996(4) -0.8871(2) 2.64 C(4) -0.0683(4) -0.1686(3) -0.8215(2) 2.25 C(5) -0.1389(4) -0.2197(4) -0.7372(3) 2.49 C(6) -0.1718(5) -0.1222(4) -0.6673(2) 2.80 C(7) -0.0217(5) -0.0432(4) -0.6351(3) 3.16 C(8) 0.0445(5) 0.0097(3) -0.7184(3) 2.76 C(9) 0.0866(4) -0.0916(3) -0.7861(2) 2.22 C(10) 0.2284(5) -0.1751(4) -0.7367(3) 2.99 C(I1) 0.3597(8) -0.1665(6) -0.7998(4) 3.31 C (ll)’ 0.376(1) -0.116(1) -0.7457(9) 3.79 C(12) 0.3406(5) -0.0438(4) -0.8442(3) 3.92 C(13) 0.1577(5) -0.0309(4) -0.8678(3) 3.12 aB(eqv) = (8p^/3)[a^U j j(a*)^ + b2U22(b*)^ + c^U 33(c*)^ + ab(cosg)U| 2a*b* + ac(cosb)U| 3a*c* + bc(cosa)U 23b*c*J Table 5.3: Final Fractional Coordinates for 98. Atom x/a y/b z/c H(1)(C(1)1 -0.109 -0.281 -1.009 H(2)[C(1)] -0.185 -0.379 -0.951 H{l)tC(2)] -0.336 -0.177 -1.007 H(2)(C(2)] -0.366 -0.245 -0.917 H( I )[C(3)] -0.159 -0.040 -0.925 304 Table 5.3 (continued): H(2)[C(3)J -0.276 -0.059 -0.853 H{ 1 )[C(6)J -0.253 -0.068 -0.699 H( 1 )|C(7)J -0.047 0.023 -0.596 H(2)(C(7)) 0.059 -0.096 -0.601 H(I)[C(8)1 -0.037 0.062 -0.752 H(2)(C(8)) 0.139 0.058 -0.697 H( 1 )[C( 10)] 0.269 -0.144 -0.676 H(2)[C(I0>] 0.192 -0.259 -0.732 H(1)[C(10)’] 0.217 -0.257 -0.762 H(2)[C(10)'J 0.225 -0.178 -0.671 H( 1 )[C( 11)] 0.342 -0.229 -0.847 H(2)[C(11)] 0.465 -0.176 -0.764 H(1)(C(M)’] 0.420 -0.065 -0.694 H(2){C(11)’] 0.451 -0.181 -0.753 H(1)[C(12)] 0.385 0.019 -0.801 H(2)[C(12)] 0.390 -0.039 -0.899 H(1)[C(12)’] 0.382 -0.084 -0.894 H(2)[C(12)’] 0.389 0.037 -0.834 H(1)(C(13)] 0.126 0.054 -0.875 H(2)[C(13)] 0.120 -0.074 -0.925 Table 6.2: Bond Distances (A) and Angles (deg) for 160. Atoms Distance Atoms Distance 0(1)-C(1) 1.204(6) 0(2)-C(2) 1.195(7) 0(3)-C(7) 1.428(6) O(3)-C(10) 1.423(7) 0(4)-C( 11) 1.429(6) CK4)-C(14) 1.340(7) N( 1 )-C( 1) 1.375(6) N(l)-C(2) 1.389(7) N(l)-C(15) 1.452(6) N(2)-N(3) 1.419(6) N(2)-C(2) 1.383(7) N(2)-C(3) 1.471(7) N(3)-C(l) 1.390(6) N(3)-C(6) 1.482(6) C(3)-C(4) 1.495(7) C(3)-C(l 1) 1.551(7) C(4)-C(5) 1.320(8) C(5)-C(6) 1.494(7) C(6)-C(7) 1.549(7) C(7)-C(8) 1.528(7) C(7)-C( 11) 1.577(7) C(8)-C(9) 1.446(9) C(9)-C(10) 1.45(1) C(11)-C(12) 1.540(7) C(I2)-C(13) 1.459(8) C(13)-C( 14) 1.451(9) Atoms Angle Atoms Angle C(7)-O(3)-C(10) 110.5(4 ) C(1 l)-0(4)-C(l4) 110.2(4) C(l)-N(l)-C(2) 112.3(4 ) C(l)-N(l)-C(15) 123.4(5) 305 Table 6.2 (continued): C(2)-N(l )-C(15) 124.2(5) N(3)-N(2)-C(2) 109.0(4) N(3)-N(2)-C(3) 111.5(4) C(2)-N(2)-C(3) 121.4(4) N(2)-N(3)-C(l) 107.8(4) N(2)-N(3)-C(6) 1 1 1.6(4) C(1 )-N(3)-C(6) 121.1(4) 0 ( 1 )-C( 1 )-N( 1) 127.3(5) 0(1 )-C(1 )-N(3) 127.5(5) N( 1 )-C( 1 )-N(3) 105.1(4) G(2)-C(2)-N(l) 128.0(5) Of2)-C(2)-N(2) 127.7(5) N(1 )-C(2)-N(2) 104.2(5) N(2)-C(3)-C(4) 108.3(4) N(2)-C(3)-C(l 1) 104.3(4) C(4)-C(3)-C(l 1) 111.9(5) C(3)-C(4)-C(5) 113.2(5) C(4)-C(5)-C(6) 113.5(5) N(3)-C(6)-C(5) 108.5(4) N(3)-C(6)-C(7) 106.2(4) C(5)-C(6)-C(7) 109.2(4) 0(3)-C(7)-C(6) 106.1(4) 0(3)-C(7)-C(8) 104.9(4) C(6)-C(7)-C(8) 111.0(4) 0{3)-C(7)-C(l 1) 110.1(4) C(6)-C(7)-C( 11) 107.4(4) C(8)-C(7)-C(l 1) 116.9(4) C(7)-C(8)-C(9) 104.1(5) C(8)-C(9)-C(10) 107.1(6) O(3)-C(10)-C(9) 106.1(5) 0(4)-C(11)-C(3) 107.0(4) 0(4)-C(!!)-C(7) 110.4(4) C(3)-C(I I )-C(7) 107.2(4) 0(4)-C(l I )-C( 12) 104.8(4) C(3)-C(l 1)-C(12) 110.4(5) C(7)-C{11)-C(12) 116.7(4) C(11)-C(I2)-C(13) 104.7(5) C(12)-C(I3)-C(14) 104.7(6) 0(4)-C(14)-C(13) 111.6(5) Table 6.3: Least-Squares Planes for 160. Equation of Plane 1: <0.4626)X + (0.6917)Y + (-0.5546)Z = (2.3869) Atom ______Deviation (The first 5 atoms define plane I). N1 0.06991 C l -0.05362 N3 0.01720 N2 0.02323 C2 -0,05673 01 -0.14503 0 2 -0.15773 C15 0.25001 306 Table 6.3 (continued): Equation of Plane 2: (-0.7192)X + (0.1340)Y + (-0.6818)Z = (-6.4556) Atom_____ Deviation (The first 4 atoms define plane 2). C3 0.00187 C4 -0.00357 C5 0.00356 C6 -0.00189 The angle between plane 1 and plane 2 is 82.06. Table 6.4: Final Fractional Coordinates for 160. Atom x/a y/b z/c B(eqv)» 0(1) -0.0394(5) 0.7507(3) 0.5575(2) 3.74 0(2) -0.2542(6) 1.0090(3) 0.7480(3) 4.11 0(3) 0.3202(4) 0.7354(3) 0.8790(3) 3.48 0(4) 0.2222(4) 0.8979(3) 0.9740(2) 3.48 N(l) -0.1688(5) 0.8928(3) 0.6269(3) 2.73 N(2) -0.0134(5) 0.9246(3) 0.7518(3) 2.50 N(3) 0.0542(5) 0.8436(3) 0.6934(3) 2.32 C(l) -0.0514(6) 0.8190(4) 0.6187(3) 2.66 C(2) -0.1598(6) 0.9493(4) 0.7144(4) 2.78 C(3) 0.0108(6) 0.9052(4) 0.8577(4) 2.76 C(4) -0.0546(6) 0.7991(4) 0.8821(4) 3.00 C(5) 0.0051(6) 0.7228(4) 0.8277(4) 2.74 C(6) 0.1253(5) 0.7601(4) 0.7554(3) 2.44 C(7) 0.2621(5) 0.8130(4) 0.8120(3) 2.42 C(8) 0.3995(6) 0.8364(5) 0.7429(4) 3.57 C(9) 0.5023(9) 0.7466(6) 0.7548(7) 5.60 C(10) 0.4754(7) 0.7049(5) 0.8527(5) 4.08 C{11) 0.1915(6) 0.9091(4) 0.8709(3) 2.67 C(12) 0.2546(8) 1.0190(4) 0.8442(4) 3.45 C( 13) 0.356(1) 1.0476(5) 0.9265(5) 5.87 C(I4) 0.307(1) 0.9797(6) 1.0068(5) 6.69 C(I5) -0.2920(7) 0.9061(6) 0.5539(5) 4.32 aB(eqv) s (8p2/3)[a2U | |(a*)2 + b2U22(b*)2 + c2U 33(c*)2 + ab(cosg)U] 2a*h* + ac{cosb)U 13a*c* + bc(cosa)U 23b*c*] 307 Table 6.5: Final Fractional Coordinates for 160. Atom x/a y/b ?Jc H(1 )|C(3)] -0.041 0.954 0.900 H(1)[C(4)] -0.130 0.787 0.932 H(I)IC(5)| -0.026 0.651 0.834 H(I)[C(6)] 0.160 0.702 0.717 H(I)[C(8)] 0.451 0.899 0.763 H(2)[C(8)] 0.366 0.844 0.676 H( 1 )|C(9)j 0.609 0.767 0.747 H(2)[C(9)] 0.477 0.695 0.707 H( 1 >[C( 10)] 0.549 0.734 0.898 H(2)[C(10)] 0.485 0.630 0.853 H(1)[C(12)] 0.171 1.068 0.842 H(2)[C(12)J 0.308 1.018 0.783 H(1)|C(13)] 0.351 1.120 0.942 H(2)[C(13)J 0.461 1.030 0.909 H( 1 )[C( 14)] 0.245 1.021 1.049 H(2)tC(t4>] 0.396 0.953 1.040 H(1)[C(15)] -0.338 0.970 0.575 H(2)[C(15)J -0.371 0.853 0.549 H(3){C(15)| -0.244 0.916 0.491 Table 6.6: Bond Distances (A) and Angles (deg) for 173. Atoms Distance Atoms Distance S-C(l) 1.787(9) S-C(4) 1.833(7) 0(I)-C<9) 1.441(9) 0(1)-C(12) 1-42(1) CK2)-C( 13) 1.227(9) 0(3)-C(14) 1.208(9) N( 1 )-N(2) 1.427(8) N(!)-C{5) 1.471(8) N< 1 )-C( 13) 1.369(9) N(2)-C(8) 1.490(9) N(2)-C(14) 1.386(9) N(3)-C(13) 1.365(9) N(3)-C(14) 1.36(1) N(3)-C(15) 1.44(1) C( 1 )-C(2) 1.50(1) C(2)-C(3) 1.45(1) C(3)-C(4) 1.53(1) C(4)-C(5) 1.53(1) C(4)-C(9) 1.59(1) C(5)-C(6) 1.50(1) C(6)-C{7) 1.33(1) C(7)-C(8) 1.48(1) C(8)-C(9) 1.55(1) C(9)-C(10) 1.55(1) C(10)-C(ll) 1.39(1) C(11 )-C(12) 1.46(1) 308 Table 6.6 (continued): Atoms Angle Atoms Angle C(l)-S-C(4) 95.1(4) C(9)-O0)-C(12) 109.3(7) N(2)-N(l)-C(5) 111.4(6) N(2)-N(I)-C(13) 107.3(6) C(5)-N(l )-C( 13) 120.2(7) N(l)-N(2)-C(8) 110.9(5) N(l)-N(2)-C(14) 106.9(6) C(8)-N(2)-C( 14) 119.7(7) C(13)-N(3)-C( 14) 110.3(7) C(13)-N(3)-C(15) 125.1(7) C(14)-N(3)-C(15) 123.8(8) S-C(l )-C(2) 105.6(7) C( 1 )-C(2)-C(3) 109.6(9) C(2)-C(3)-C(4) 110.5(8) S-C(4)-C(3) 105.0(5) S-C(4)-C(5) 105.6(5) C(3)-C(4)-C(5) 111.1(7) S-C(4)-C(9) 114.1(5) C{3)-C(4)-C(9) 113.1(7) C(5)-C(4)-C(9) 107.7(6) N(1 )-C(5)-C(4) 108.8(6) N(l)-C(5)-C(6) 107.5(6) C(4)-C(5)-C(6) 109.3(7) C(5)-C(6)-C(7) 112.9(8) C(6)-C(7)-C(8) 113.3(8) N(2)-C(8)-C(7) 108.3(7) N(2)-C(8)-C(9) 107.0(7) C(7)-C(8)-C(9) 109.6(7) 0(1)-C(9)-C(4) 110.5(7) 0(1 )-C(9)-C(8) 107.9(6) C(4)-C(9)-C(8) 106.6(6) O(l)-C(9)-C(l0) 107.0(7) C(4)-C(9)-C( 10) 115.5(6) C(8)-C(9)-C(10) 109.2(7) C(9)-C(IO)-C(lt) 101.6(9) C(10)-C(U)-C(12) 113(1) 0(1)-C(12)-C(11) 105.2(8) 0(2)-C(13)-N(l) 126.2(8) CK2)-C(13)-N(3) 126.4(8) N(1 )-C(13)-N(3) 107.4(7) 0(3)-C(14)-N(2) 126.0(8) 0(3)-C(l4)-N<3) 127.0(8) N(2)-C(14)-N(3) 106.9(7) Table 6.7: Final Fractional Coordinates for 173. Atom x/a y/b z/c B(eqv)a S -0.1423(4) -0.7066(3) -0.27089(9) 3.76 0(1) -0.1532(9) -0.6085(7) -0.4232(2) 3.35 0(2) -0.6168(8) -1.1425(9) -0.3746(2) 4.25 0(3) -0.2172(9) -1.1165(8) -0.5019(2) 4.25 N(l) -0.4006(8) -0.9466(8) -0.3929(2) 2.09 N(2) -0.2741(8) -0.9383(8) -0.4326(2) 2.05 N(3) -0.4526(9) -1.1551(8) -0.4490(3) 2.38 C(l) -0.290(1) -0.540(1) -0.2554(3) 4.37 C(2) -0.447(2) -0.555(2) -0.2950(4) 6.04 C(3) -0.386(1) -0.605(1) -0.3458(3) 3.14 C(4) -0.238(1) -0.737(1) -0.3386(3) 2.30 C(5) -0.316(1) -0.915(1) -0.3398(3) 2.52 C(6) -0.168(1) -1.040(1) -0.3307(3) 3.09 309 Table 6.7 (continued): C(7) -0.049( 1) -1.033(1) -0.3674(4) 3.1 1 C(8 ) -0.092( 1) -0.904{ 1) -0.4086(3) 2.54 C(9) -0.096( 1) -0.727(1) -0.3827(3) 2.57 C(IO) 0.096(1) -0.677( 1) -0.3626(4) 3.37 C(I1) 0.106(2) -0.514(2) -0.3814(6) 9.53 C(12) -0.025(2) -0.478( 1) -0.4248(4) 5.62 C(13) -0.501(1) -1.089(1) -0.4022(3) 2.43 C(14) -0.303(1) -1.077(1) -0.4650(3) 2.50 C(15) -0.528(1) -1.304(1) -0.4735(3) 3.87 * aB(eqv) = (8p2/3)(a2U[ i(a*)2 + + c 2tJ33(c*)2 + ab(cosg)Ui 2a*b* + ac(cosb)U] 3a* c + bc(cosa)U 23b*c*] Table 6.8: Final Fractional Coordinates for 173. Atom x/a y/b z/c H(1)[C(1)] -0.235 -0.434 -0.260 H(2){C(I)] -0.342 -0.549 -0.220 H(1)[C(2)] -0.514 -0.454 -0.298 H(2)IC(2)] -0.520 -0.644 -0.284 H(1)[C(3)] -0.481 -0.643 -0.369 H(2)[C(3)] -0.334 -0.507 -0.360 H(1)(C(5)] -0.398 -0.926 -0.313 H(1)IC(6)] -0.160 -1.115 -0.302 H(1)(C(7)] 0.053 -1.103 -0.367 H(I)[C(8 )] -0.004 -0.912 -0.434 H( 1 )fC( 10)1 0.182 -0.741 -0.379 H(2)(C(10)1 0 . 1 1 1 -0.691 -0.325 H(1)[C(11)] 0.076 -0.443 -0.353 H(2)(C(11)] 0.224 -0.489 -0.391 H(I)[C(12)] 0.035 -0.484 -0.457 H(2)[C(12)] -0.081 -0.371 -0.423 H(1 )fC(!5)] -0.654 -1.296 -0.472 H(2)[C(15>] -0.488 -1.405 -0.457 H(3)[C(15)] -0.498 -1.306 -0.509 310 LIST OF REFERENCES 1. Cope, A.C.; Hardy, E.M. J. Am. Chem. Soc. 1940, 62, 441. 2. Rhoads, S.J.; Raulins, N.R. Org. React. 1975, 22, 1; Paquette, L.A. Angew. Chem., Internal. Ed. Eng. 1990, 29, 609. 3. (a) Vogel, E. Angew. Chem. 1960; 72, 4; (b) Vogel, E.; Ott, K.-H.; Gajek, K. Justus Liebigs Ann. Chem. 1961, 644, 172; (c) Brown, J.M.; Golding, B.T.; Stofko, J.J., Jr. J. Chem. Soc., Chem. Commun. 1973, 319; (d) Schneider, M.P.; Rebell, J. J. Chem. Soc., Chem. Commun. 1975, 283; (e) For a review see Hudlickey, T.; Fan, R.; Reed, J.W.; Gadamasetti, K.G. Org. React. 1992,41, 1. 4. (a) Arai, M.; Crawford, R.J. Can. J. Chem. 1972, 250, 2158; (b) Dewar, M.J.S.; Wade, L.E. J. Am. Chem. Soc. 1977, 99, 4417; (c) Wehril, R.; Bellus, D.E.; Hansen, H.; Schmid, H. Chimia 1976 ,30, 416; Helv. Chim. Acta \911^60, 1325; (d) Padwa, A.; Blacklock, T.J. J. Am. Chem. Soc. 1980, 102, 102. 5. (a) Doering, W.v.E.; Roth, W.R. Tetrahedron 1963, 715; (b) Gunther, H.; Pawliczek, J.B.; Ulmen, J.; Grimme, W. Angew. Chem., Intemat. Ed. Eng. 1 9 7 2 , 11, 517. 6. Schroder, G. Angew. Chem., Intemat. Ed. Eng. 1963,2, 481. 7. Anet, F.A.L.; Schenck, G. Tetrahedron Lett. 1970, 4237. 8. Cheng, A.K.; Anet, F.A.L.; Mioduski, J.; Meinwald, J. J. Am. Chem. Soc. 1974, 96, 2887. 9. (a) Doering, W.v.E.; Ferrier, B.M.; Fossel, E.T.; Hartenstein, J.M.; Jones, M., Jr.; Klump, G.; Rubin, R.M.; Saunders, M. Tetrahedron 1967,23, 3943; (b) Tsuruta, H.; Kurabayashi, K.; Mukai, T. Tetrahedron Lett. 1967, 3775; (c) Biethan, U.; Klusacek, H.; Musso, H. Angew. Chem., Intemat. Ed. Eng. 1967, 6, 176. 10. Zimmerman, H.E.; Grunewald, L. J. Am. Chem. Soc. 1966, 88, 183. 11. Hoffmann, R.; Stohrer, W.D. J. Am. Chem. Soc. 1971, 93, 6941. 12. (a) Dewar, M.J.S.; Schoeller, D.W. J. Am. Chem. Soc. 1971, 93, 1481; (b) Dewar, M.J.S.; Lo, D.H. J. Am. Chem. Soc. 1971, 93, 7201; (c) Bingham, R.C.; Dewar, M.J.S.; Lo, D.M. J. Am. Chem. Soc. 1975, 97, 1294. 13. Christoph, G.; Beno, M. J. Am. Chem. Soc. 1978, 100, 3156. 31 1 14. Quasi, H.; Christ, J. Angew. Chem., Internal. Ed. Eng. 1984,23, 631; Quasi, H.; Gorlach, Y.; Christ, J.; Peters, E.-M.; Peters, K.; Schnering, H.G.; Jackman, L.M.; Ibar, G.; Freyer, A.J. Tetrahedron Lett. 1983, 5595. 15. Moskau, D.; Aydin, R.; Leger, W.; Gunther, H.; Quast, H.; Martin, H.-D.; Hassenriick, K.; Miller, L.S.; Grohmann, K. Chem. Ber. 1989, 122, 925. 16. Miller, L.S.; Grohmann, K.; Dannenberg, J.J. J. Am. Chem. Soc. 1983, 105, 6862. 17. Williams, R.V.; Kurtz, H.A. J. Org. Chem. 1988, 53, 3626. 18. (a) Wyvratt, M.J.; Paquette, L.A. J. Am. Chem. Soc. 1974, 96, 4671;McNeil, D.; Vogt, B.R.; Sudol, S.; Theodoropoulos, S.; Hedaya, E. J. Am. Chem. Soc. 1974, 96, 4673; (c) Paquette, L.A. Top. Curr. Chem. 1979, 79, 41; (d) Paquette, L.A.; Ibid, 1984, 119, 1; (e) Paquette, L.A.; Doherty, A.M. Polyquinane Chemistry ; Springer- Verlag: Berlin, 1987. 19. (a) Paquette, L.A.; Nakamura, K.; Engle, P. Chem. Ber. 1987, J19, 3782; (b) Paquette, L.A.; Nakamura, K.; Fischer, J.W. Tetrahedron Lett.. 1985, 4051; (c) Mehta, G.; Nair, M.S. J. Am. Chem. Soc. 1985, 107, 7519. 20. Paquette, L.A.; Bran an, B.M.; Rogers, R.D. Tetrahedron, 1992,45, 297. 21. (a) King, L.C.; Ostrum, G.K. J. Org.Chem. 1964, 29, 3459; (b) Gleiter, R.; Jahne, G.; Mtiller, G.; Nixdorf, M.; Imgartinger, H. Helv. Chim. Acta. 19 86, 69, 71. 22. Vogel, E.; Nitsche, R.; Krieg, H.-U. Angew. Chem., Internat. Ed. Eng. 1981, 20, 811. 23. (a) Appelquist, D.E.; Fanta, G.F.; Henrikson, B.W. J. Am. Chem. Soc. 1958, 23, 1715; (b) Kochi, J.K.; Singleton, D.M. J. Org. Chem. 1968, 33, 1027. 24. (a) Shapiro, R.H.; Heath, M.J. J. Am. Chem. Soc. 1967, 89, 5734; (b) Kaufman, G.; Cook, F.; Shechter, H.; Bayless, J.; Friedman, L. J. Am. Chem. Soc. 1967, 89, 5736; Shapiro, R.H. Org. React. 1976, 23, 405. 25. (a) Weber, J.; Csoregh, I.; Stensland, B.; Czugler, M. J. Am. Chem. Soc. 1984, 106, 3297; (b) Dauben, W.G.; Kohler, B.; Roesle, A. J. Org. Chem. 1985, 50, 2007; (c) Seeger, D.E.; Lahti, P.M.; Rossi, A.R.; Berson, J.A. J. Am. Chem. Soc. 1986, 108, 1251. 26. (a) Nace, H.R. Org. React. 1962, 12, 57; (b) Paquette, L.A.; Trova, M.P. Tetrahedron Lett. 1987, 2795. 27. (a) Bose, A.K.; Lai, B.; Hoffmann, W.A., III; Manas, M.S. Tetrahedron Lett. 1973, 1619; (b) Georgies, M.; Mackay, D.; Fraser-Reid, B. Can. J. Chem. 1984, 62, 1539; (c) Hughes, D.L. Org. React. 1991, 42, 335. 28. (a) Paquette, L.A.; Friedrich, D.; Rogers, R.D. J. Org. Chem. 1991, 56, 3841; (b) Methanesulfonic anhydride was prepared according to Owen, L.N.; Whitelaw, S.P. J. Chem. Soc. 1953, 3723. 312 29. Corey, E.J.; Nicolaou, K.C.; Shibasaki, M.; Machida, Y.; Shiner, C.S. Tetrahedron Lett. 1975, 3183. 30. (a) Scriven, E.F.V.; Turnbull, K. Chem. Rev. 1988, 88, 297; (b) Rebek, J., Jr.; Shaber, S.H.; Shue, Y.-K.; Gehret, J.-C.; Zimmerman, S. J. Org. Chem. 1984, 4 9, 5164. 31. Secrist, J.A.; Logue, M.W. J. Org. Chem. 1972, 37, 335. 32. Clark, H.T.; Gillespie, H.B.; Wisshaus, S.Z. J. Am. Chem. Soc. 1933, 55, 4571. 33. (a) Paquette, L.A.; Slomp, G. J. Am. Chem. Soc. 1963, 85, 765; (b) Paquette, L.A.; Wise, L.D.; J. Am. Chem. Soc. 1965, 87, 1561; (c) Paquette, L.A.; Barrett, J.H.; Kuhla, D.E. J. Am. Chem. Soc. 1969, 91, 3616. 34. Brandstrom, A.; Lamm, B.; Palmertz, 1. Acta. Chem. Scand. 1974, 28B, 699. 35. Deslongchamps, P.; Saucy, P. Tetrahedron 1981, 37, 4385. 36. Cleary, D.G. Synth. Comm. 1989, 19, 737. 37. (a) Walker, K.A.M. Tetrahedron Lett. 1977, 51, 4475; (b) N-Thiophenylsuccinimide was prepared according to Abe, Y.; Nakabayashi, T.; Tsurugi, J. Bull. Chem. Soc. Jpn. 1973, 46, 1898. 38. (a) Sharpless, K.B.; Tetsuo, H. J. Org. Chem. 1979, 44, 4208; (b) Nicolaou, K.C.; Claremon, D.A.; Barnette, W.E.; Seitz, S.P. J. Am. Chem. Soc. 1979, 101, 3704; (c) Grieco, P.A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485. 39. Pradhan, S.K. Tetrahedron 1986 ,4 2 , 6351. 40. Montellano, B.R.O.d.; Loving, B.A.; Shields, T.C.; Gardner, P.D. J. Am. Chem. Soc. 1967, 89, 3365; (b) Schreibmann, A.A.P. Tetrahedron Lett. 1970, 4271. 41. Gupta, A.K.; Sambasivarao, K.; Opansky, B.; Cook, J.M. J. Am. Chem. Soc. 1990, 55, 4480. 42. Branan, B.M.; Paquette, L.A.; Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1992, 114, 774. 43. (a) Synthesis of the homologue with n = 1, Renzoni, G.E.; Yin, T.-K.; Borden, W.T. J. Am. Chem. Soc. 1986, 108, 7121; (b) For n = 2, Yin, T.-K.; Miyake, F.; Renzoni, G.E.; Borden, W.T.; Radziszewski, J.G.; Michl, J. J. Am. Chem. Soc. 1986, 108, 3544; Radziszewski, J.G.; Michl, J.; Yin, T.-K.; Renzoni, G.E.; Borden, W.T. J. Am. Chem. Soc. 1987, 109, 820; (c) Se derivative of homologue with n - 3, Hrovat, D.A.; Miyake, F.; Trammell, G.; Gilbert, K.E.; Mitchell, J.; Clardy, J.; Borden, W.T. J. Am. Chem. Soc. 1987, 109, 5524. 44. Review: Borden, W.T. Chem. Rev. 1989, 89, 1095. 45. Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1988, 110, 4710. 313 46. Computed at the (TC)SCF/6-31G*//(TC)SCF/3-21G level, using SCF for alkanes and two configuration SCF (TCSCF) for alkenes. 47. Synthesis: Eaton, P.E.; Maggini, M. J. Am. Chem. Soc. 1988, 110, 7230. 48. Synthesis: Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1988, 110, 7229; Schafer, J.; Szeimies, G. Tetrahedron Lett. 1988, 5253. 49. Maier, W.F.; Schleyer, P. von R. J. Am. Chem. Soc. 1981, 103, 1891. 50. C a lc u la te d ,46,51 using the definition proposed by Benson (Benson, S.W. J. Chem. Educ. 1965, 42, 502), as the negative of the radical disproportionation energy, 2 alkene- H* -* alkene + alkane. 51. Energies of doublet and triplet states were calculated at the ROHF/6-31 G*/AJHF/3- 2 1G level. 52. The more strained of the two isomers of prismene, in which the double bond is contained in two of the four-membered rings, is calculated to have a hydrogenation energy that is 6.3 kcal/mol higher than that of 30, but a it BDE and a singlet-triplet splitting that differ insignificantly from those computed for 30. The less strained prismene isomer is calculated to have a n BDE that is 10.4 kcal/mol higher and a singlet-triplet splitting that is 11.5 kcal/mol larger than the more strained isomer. These highly pyramidalized alkenes are as yet unknown, but Szeimies and co-workers have succeeded in generating two quadricyclene isomers,44 which may be regarded as homologues of the two prismenes: Hamisch, J.; Baumgartel, O.; Szeimies, G.; Van Meerssche, M.; Germain, G.; Declerq, J.-P. J. Am. Chem. Soc. 1979, 101, 3370; Baumgartel, O.; Szeimies, G. Chem, Ber. 1983, 116, 2180; Baumgartel, O.; Hamisch, J.; Szeimies, G.; Van Meerssche, M.; Germain, G.; Declerq, J.-P. Chem. Ber. 1983, 116, 2205; Kenndoff, J.; Polbom, K.; Szeimies, G. J. Am. Chem. Soc. 1990, 112, 6117. Tricyclo[3.1.0.02,6]hex-l(6)-ene, which has also been generated and trapped by Szeimies and co-workers,44 js computed4? to have a hydrogenation energy that is about 6 kcal/mol less than that of 30. 53. (a) Hassenriick, K.; Radziszewski, J.G.; Balaji, V.; Murthy, G.S.; McKinley, A.J.; David, D.E.; Lynch, V.M.; Martin, H.-D.; Michl, J. J. Am. Chem. Soc. 1 9 9 0 , 112, 872; (b) Hrovat, D.A.; Borden, W.T. J. Am. Chem. Soc. 1990, 112, 875; (c) Eaton, P.E.; Tsanaktsidis, J. J. Am. Chem. Soc. 1990, 112, 876. 54. Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P. J. Am. Chem. Soc. 1985, 107, 3903. 55. AMI gives heats of hydrogenation of 121.2 kcal/mol for 30 and 120.2 kcal/mol for 33. 56. (a) Wyvratt, J.J.; Paquette, L.A. J. Am. Chem. Soc. 1974, 96, 4671; (b) McNeil, D.; Vogt, B.R ; Sudol, S.; Theodoropoulos, S.; Hedaya, E. J. Am. Chem. Soc. 1974, 96, 4673; (c) Paquette, L.A.; Wyvratt, M.J.; Berk, H.C.; Moerck, R.E. J. Am. Chem. Soc. 1978, 100, 876; (d) Paquette, L.A.; Weber, J.J.; Kobayashi, T.; Miyahara, Y. J. Am. Chem. Soc. 1988, 110, 8591; (e) Taylor, R.T.; Pelter, M.W.; Paquette, L.A. Org. Synth. 1989, 68, 198. 314 57. (a) Paquette, L.A.; Carr, R.V.C.; Bohm, M.C.; Gleiter, R. 7. Am. Chem. Soc. 1980, 102, 1186, 7218; (b) Watson, W.H.; Galloy, J.; Bartlett, P.D.; Roof, A.A.M. J. Am. Chem. Soc. 1981, 105, 5980; (d) Houk, K.N.; Rondan, N.G.; Brown, F.K. lsr. J. Chem. 1983, 23, 3. 58. (a) McMurry, J.E.; Fleming, M.P. J. Org. Chem. 1976, 41, 897; (b) McMurry, J.E.; Krepski, L.R. J. Org. Chem. 1976, 41, 3929; (c) McMurry, J.E.; Fleming, M.P.; Kees, K.L.; Krepski, L.R. J. Org. Chem. 1978, 43, 3255; (d) McMurry, J.E.; Lectka, T.; Rico, J.G. J. Org. Chem. 1989, 54, 3748. 59. (a) Hart, H.; Bashir-Hashemi, A.; Luo, J.; Meador, M.A. Tetrahedron 1986, 42, 1641; (b) Eaton, P.E.; Maggini, M. J. Am. Chem. Soc. 1 988, 110, 7230. 60. This document, Chapter 1. 61. (a) Aclam, W.; Baeza, J.; Lie, J.-C. J. Am. Chem. Soc. 1972, 94, 2000; (b) Hara, S.; Taguchi, H.; Vamamoto, H.; Nozaki, H. Tetrahedron Lett. 1975, 1545; (c) Marshall, J.A.; Faubl, H. J. Am. Chem. Soc. 1970, 92, 948. 62. Diiodide 39 can also be prepared in 50% yield by a modified Hunsdiecker reaction, using HgO under photochemical conditions; Cristol, S.J.; Firth, W.C., Jr. J. Org. Chem. 1961, 26, 280; Meyers, A.I.; Fleming, M.P. J. Org. Chem. 1979, 44, 3405. 63. The number of protons attached to each carbon was deduced from experiments using the DEPT pulse sequence: Doddiell, D.M.; Pegg, D.T.; Bendall, M.R. J. Magn. Reson. 1982, 48, 323. 64. Biemann, K. Mass Spectrometry: Organic Chemical Applications; McGraw Hill: New York, 1962, pp. 223-227. 65. Addition of alkyllithium reagents is frequently observed to compete successfully with dimerization of highly pyramidalized alkenes. 44,47,48 66. This working hypothesis assumes that the resulting dilithio compound would survive until quenching, rather than capturing one proton prior to the addition of D 2O. Additional studies of the mechanism of formation of 41 are in progress. 67. Borden, W.T.; private communication. 68. The IR spectrum of the matrix-isolated n = 1 olefin, formed by potassium vapor dehalogenation of the diiodide precursor, 43a shows a weak band at 1496 cm*1: Radziszewski, J.G.; Michl, J.; Yin, T.-K.; Renzoni, G.E.; Borden, W.T., unpublished results. 69. Kumar, A.; Lichtenhan, J.D.; Critchlow, S.C.; Eichinger, B.E.; Borden, W.T. J. Am. Chem. Soc. 1 9 9 0 ,112, 5633. 70. Breslow, R.; Washburn, W,; Bergman, R.G. J. Am. Chem. Soc. 1969, 91, 196. 71. Breslow, R.; Washburn, W. J. Am. Chem. Soc. 1970, 92, 427. 315 72. D’Amore, M.B.; Bergman, R.G. J. Am. Chem. Soc. 1969, 97. 5694. 73. Bergman, R.G. Acc. Chem. Res. 1973, 6, 25. 74. King, R.B.; Harmon, C.A. J. Am. Chem. Soc. 1976, 98, 2409. 75. Paquette, L.A.; Reagan, J.; Schreiber, S.L.; Teleha, C.A. J. Am. Chem. Soc. 1989, 111, 2331. 76. Reviews: Masamune, S.; Darby, N. Acc. Chem. Res. 1972, 5, 272; Burkoth, T.L.; Van Tamelen, E.E. in “Nonbenzenoid Aromatics”, Snyder, J.P., Ed.; Academic Press, New York, 1969-1971; Vol l,pp63-116. 77. Vogel, E.; Klug, W.; Brever, A. Org. Synth. 1974, 54, 11. 78. McCague, R.; Moody, C.J.; Rees, C.W. J. Chem. Soc., Perkin Trans. 1 1984, 165. 79. Schreiber, S.L.; Santini, C. Tetrahedron Lett. 1981, 4651; Schreiber, S.L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038. 80. Reagan, J.D. Ph.D. Dissertation, Yale University, 1987. 81. Hoff, S.; Brandsma, L.; Arens, J.F. Reel. Trav. Chim. 1968, 87, 916. 82. Paquette, L.A.; DeRussy, D.T.; Cottrell, C.E. J. Am. Chem. Soc. 1 9 8 8 , 110, 890; MacDonald, T.L.; Natalie, K.J., Jr.; Prasad, G.; Sawyer, J.S. J. Org. Chem. 1986, 51, 1124; Evans, D.A.; Golob, A.M. J. Am. Chem. Soc. 1975, 97, 4765. 83. Sugimura, T.; Paquette, L.A. J. Am. Chem. Soc. 1987, 109, 3017; Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. 84. Fleming, I.; Paterson, I. Synthesis 1979, 736. 85. King, P.F.; Paquette, L.A. Synthesis 1977, 279. 86. Reuss, R.H.; Hassner, A. J. Org. Chem. 1974, 39, 1785. 87. Miller, R.D.; McKean, D.R. Synthesis 1979, 730. 88. House, H.O.; Gall, M.; Olmstead, H.D. J. Org. Chem. 1 9 7 1 ,3 6 , 2361; House, H.O.; Czuba, L.J.; Gall, M.; Olmstead, H.D. J. Org, Chem. 1969, 34, 2324. 89. Kraft, M.E.; Holton, R.A. Tetrahedron Lett. 1983, 24, 1345. 90. Olah, G.A.; Arvanaghi, M.; Vankar, Y.D. J. Org. Chem. 1980, 45, 3531. 91. McLafferty, F.W. Interpretation o f Mass Spectra-, University Science: California, 1980, p. 23. 316 92. Joly, R.; Warnant, J.; Nomine’. G.; Berlin, D. Bull. Chim. Soc. Fr. 1958, 366; Stottier, P.L.; Hill, K.A. J. Org. Chem. 1973, 38, 2576; Collington, E.W.; Jones, G. J. Chem. Soc. (C) 1969, 2656. 93. Grieco, P.A.; Nishizawa, M.; Marinovic, N.; Ehmann, W.J. J. Am. Chem. Soc. 1976, 98, 7102. 94. Guevel, R.; Paquette, L.A. J. Am. Chem. Soc. 1994, 116, 1776. 95. Maier, W.F.; Schleyer, P.von.R. J. Am. Chem. Soc. 1981, 103, 1891. 96. Hoffmann, H.M.R.; Wulferding, A. Synlett 1993, 415. 97. Paquette, L. A.; Lawhom, D. E.; Teleha, C. A. Heterocycles 1990, 30, 765. 98. (a) Negri, J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113, 5073. (b) Paquette, L. A.; Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992, 57, 3947. 99. Paquette, L. A.; Andrews, J. F. P.; Vanucci, C.; Lawhom, D. E.; Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992, 57, 3956. 100. Reviews: (a) Wolfe, S. Acc. Chem. Res. 197 2 , 5, 102. (b) Zefirov, N. S. Tetrahedron 1977, 33, 3193. 101. Sosnovsky, G. Tetrahedron 1962,18, 15,903. 102. (a) Oshima, K.; Shimozi, K.; Takahashi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1973, 95, 2694. (b) Cookson, R. C.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1976, 990. (c) Vlattas, I.; Della Vecchia, L.; Lee, A. O. J. Am. Chem. Soc. 1976, 98, 2008. (d) Harirchian, B.; Magnus, P. J. Chem. Soc., Chem. Commun. 1977, 522. (e) Schmidt, R. R.; Schmid, B. Tetrahedron Lett. 1977, 3583. 103. Boeckman, R. K.; Bruza, K. J. Tetrahedron Lett. 1977, 4187. 104. (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Paquette, L. A.; He, W.; Rogers, R. D. J. Org. Chem. 1989, 54, 2291 and relevant references cited therein. 105. (a) Trost, B. M.; Mikhail, G. K. J. Am. Chem. Soc. 1 9 8 7 , 109, 4124. (b) Trost, B. M.; Sato, T. J. Am. Chem. Soc. 1985, 107, 719. (c) Trost, M. B.; Murayama, E. Tetrahedron Lett. 1982, 23, 1047. 106. Paquette, L. A.; Dullweber, U.; Branan, B. M. Heterocycles 1994, 37, 187. 107. The cerates are depicted as dichloro derivatives in order to reflect the approximate stoichiometry associated with their preparation. For a discussion of the probable structure of organocerium reagents, see Denmark, S. E.; Edwards, J. P.; Nicaise, O. J. Org. Chem. 1993,58, 569. 108. (a) Eliel, E. L.; Allinger, N. L.; Angyal, S. Y.; Morrison, C. A. Conformational Analysis-, Interscience: New York, 1965; pp 460-469. (b) Lambert, J. B, In The 317 Conformational Analysis of Cvclohexenes, Cyclohexadienes, and Related Hydroaromatic Compounds; Rabideau, P., Ed.; VCH; Weinheim, 1989; Chapter 2. 109. Denmark, S. E.; Dappen, M. S.; Sear, N. L.; Jacobs, R. T. J. Am. Chem. Soc. 1990, 772, 3466 and relevant references cited therein. 110. This projection is drawn enantiomerically to those illustrated two-dimensionally in the schemes in order to facilitate viewing of the molecules. The crystallographic studies were performed on the racemic compounds; the ORTEP diagrams also depict the enantiomeric structural formulas. The numbering scheme is arbitrary but consistent throughout the entire series of dispiro ketones. 111. The numbering schemes used in this section follow the systematic nomenclature (see Experimental Section) and are indicated in the representative structures E and F, respectively. 112. (a) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127. (b) Burkert, U.; A1 linger, N. L. Molecular Mechanics, American Chemical Society, Washington, D.C., 1982, Monograph 177. 113. (a) We thank Professor K. Steliou for making this program available to us. (b) The MMX minimized energies in Table II were obtained utilizing a Coulombic interaction potential instead of bond dipole-bond dipole interactions. MMX energies using dipole-dipole interactions were also performed (available on request from the authors) and the resultant energies reflect the same trends. The difference between these calculations has been documented [Gajewski, J. J.; Gilbert, K. E.; McKelvey, J. Advances in Molecular Modeling, Liotta, E., Ed.; Jai Press Inc., Greenwich, Connecticut: 1990, Vol. 2, p 69]. 114. Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104,4021. 115. Robins, P. A.; Walker, J. J. Chem. Soc. 1955, 1789. 116. Malhotra, S. K.; Johnson, F. J. Am. Chem. Soc. 1965, 87, 5493. 117. Johnson, F. Chem. Rev. 1968, 68, 375. 118. Rickbom, B. J. Am. Chem. Soc. 1962, 8 4 ,2414. 119. Bingham, R. C. J. Am. Chem. Soc. 1976, 98, 535. 120. Wladislaw, B.; Viertler, H.; Olivato, P. R.; Calegao, I. C. C.; Pardini, V. L.; Rittner, R. J. Chem. Soc. Perkin I I 1980, 453. 121. (a) Eisenstein, O.; Anh, N. T.; Jean, Y.; Devaquet, A.; Cantacuzene, J.; Salem, L. Tetrahedron 1974, 30, 1717. (b) Consult footnote 20 in reference 109. 122. (a) Szarek, W. A.; Horton, D., Eds. Anomeric Effect: Origin and Consequences', ACS Symposium Series No. 87; American Chemical Society: Washington, D.C., 1979. (b) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen; Springer-Verlag: Berlin, 1983. (c) Deslongchamps, P. Stereoelectronic Effects in 318 Organic Chemistry, Pergamon: New York, 1983. (d) Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019. 123. (a) Ou^drango, A.; Phan Viet, M. T.; Saunders, J. K.; Lessard, J. Can. J. Chem. 1987, 65, 1761. (b) Lessard, J.; Saunders, J. K.; Phan Viet, M. T. Tetrahedron Lett. 1982, 23, 2059. (c) Phan Viet, M. T.; Lessard, J.; Saunders, J. K. Tetrahedron Lett. 1979, 317. (d) Lessard, J.; Phan Viet, M. T.; Martino, R.; Saunders, J. K. Can. J. Chem. 1977, 55, 1015. 124. Zefirov, N. S.; Baranenkov, I. V. Tetrahedron 1983, 39, 1769. 125. (a) Picard, P.; Moulines, J. Tetrahedron 1978, 34, 671. (b) Picard, P.; Moulines, J. Tetrahedron Lett. 1970, 5133. 126. Eliel, E. L. Acc. Chem. Res. 1970, 3, 1. 127. (a) Whangbo, M-H.; Wolfe, S. Can. J. Chem. 1976, 54, 949. (b) Van-Catledge, F. A. J. Am. Chem. Soc. 1974, 96, 5693. (c) Wolfe, S.; Tel, L. M.; Haines, W. J.; Robb, M. A.; Csizmadia, I. G. J. Am. Chem. Soc. 1973, 95, 4863. (d) Wolfe, S.; Tel, L. M.; Csizmadia, I. G. Can. J. Chem. 1973, 57, 2423. (e) Philips, L.; Wray, V. J. Chem. Soc., Chem. Commun. 1973, 90. (f) Wolfe, S.; Rauk, A.; Tel, L. M.; Csizmadia, I. G. J. Chem. Soc. B 1971, 136. 128. (a) Zefirov, N. S.; Gurvich, L. G.; Shashkov, A. S.; Krimer, M. Z.; Vorob'eva, E. A. Tetrahedron 1976, 32, 1211. (b) Zefirov, N. S.; Samoshin, V. V.; Subbotin, O. A.; Baranenkov, V. I.; Wolfe, S. Tetrahedron 1978, 34, 2953. (c) Zefirov, N. S.; Samoshin, V. V.; Palyulin, V. A. Zh. Org. Khim. 1983, 19, 1888. 129. Hill, T. L. J. Chem. Phys. 1948, 16, 399. 130. Burkert, U. Tetrahedron 1979, 35, 1945. 131. Paquette, L. A.; Lawhom, D. E.; Teleha, C. A. Heterocycles 1990, 30, 765. 132. (a) Paquette, L. A.; Lord, M. D.; Negri, J. T. Tetrahedron Lett. 1993, 34, 5693. (b) Paquette, L. A.; Dullweber, U.; Cowgill, L. D. Tetrahedron Lett. 1993, 34, 8019. 133. (a) Negri, J. T.; Rogers, R. D.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113, 5073. (b) Paquette, L. A.; Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992, 57, 3947. (c) Paquette, L. A.; Andrews, J. F. P.; Vanucci, C.; Lawhom, D. E.; Negri, J. T.; Rogers, R. D. J. Org. Chem. 1992, 57, 3956. (d) Paquette, L. A.; Branan, B. M.; Friedrich, D.; Edmondson, S. D.; Rogers, R. D. J. Am. Chem. Soc. 1994,116, 506. 134. Paquette, L. A.; Dullweber, U.; Branan, B. M. Heterocycles 1994, 37, 187. 135. The subject dienes are also prone to isomerization in the presence of TCNE: Paquette, L. A.; Branan, B. M. submitted for publication. 136. Krieger, H.; Routsalainen, H.; Montin, J. Chem. Ber. 1966, 99, 3715. 319 137. (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Paquette, L. A.; He, W.; Rogers, R. D. J. Org. Chem. 1989, 54, 2291 and relevant references cited therein. 138. Bingham, R. C. J. Am. Chem. Soc. 1976, 98, 535. 139. Lambert, J. B. In The Conformational Analysis of Cyclohexenes, Cyclohexa-dienes, and Related Hydroaromatic Compounds', Rabideau, P., Ed.; VCH: Weinheim, Germany, 1989; Chapter 2. 140. (a) Reich, H. J.; Wollowitz, S. J. Am. Chem. Soc. 1982, 104, 7051. (b) Wang, T.- Z.; Paquette, L. A. J. Org. Chem. 1986, 51, 5232. 141. (a) Wang, T.-Z.; Paquette, L. A. Tetrahedron Lett. 1988, 29, 41. (b) Paquette, L. A.; Wang, T.-Z.; Luo, J.; Cottrell, C. E.; Clough, A. E.; Anderson, L. B. J. Am. Chem. Soc. 1990,112, 239. 142. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454. 143. (a) Trost, B. M.; Mikhail, G. K. J. Am. Chem. Soc. 1987, 109, 4124. (b) Trost, M. B.; Sato, T. J. Am. Chem. Soc. 1985, 107, 719. (c) Trost, B. M.; Murayama, E. Tetrahedron Lett. 1982, 23, 1047. 144. (a) Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460 ,98; (b) KJoetzel, M.C. Org. Reactions 1948, IV, 2; (c) Holmes, H.L. ibid, 1948, IV, 60; (d) Sauer, J.; Sustmann, R. Angew. Chem. Int. Ed. Eng. 1980, 19, 779; (e) Oppolzer, W. Angew. Chem. Int. Ed. Eng. 1984, 23, 876. 145. (a) Gleiter, R.; Paquette, L.A. Acc. Chem. Res. 1983, 16, 328; (b) Coxon, J.M.; Maclagan, R.G.A.R.; McDonald, D.Q.; Steel, P.J. J. Org. Chem. 1991, 56, 2542; (c) Wu, Y.-D.; Tucker, J.A.; Houk, K.N. J. Am. Chem. Soc. 1991,113, 5018; (d) Li, H.; le Noble, W.J. Reel. Trav. Chim. Pays-Bas 1992, 111, 199. 146. Cieplak, A.S. J. Am. Chem. Soc. 1981, 103,4540. 147. (a) Baker, J.W. Hyperconjugation\ Oxford University Press: London, 1952; (b) Taft, R.W.; Lewis, I.C. Tetrahedron 1959, 5, 210; (c) Epiotis, N.D.; Cherry, W.R.; Shaik, S.; Yates, R.L.; Bemardi, F. Top. Curr. Chem. 1977, 70, 1. 148. (a) Sonoda, S.; Houchigai, H.; Asaoka, M.; Takai, H. Tetrahedron Lett. 1992, 3145; (b) Jones, G.R.; Vogel, P. J. Chem. Soc., Chem. Commun. 1993, 769. 149. (a) le Noble, W.J.; Chiou, D.-M.; Okaya, Y. Tetrahedron Lett. 1978, 1961; (b) le Noble, W.J.; Chiou, D.-M.; Okaya, Y. J. Am. Chem. Soc. 1979,101, 3244; (c) Cheung, C.K.; Tseng, L.T.; Lin, M.H.; Srivastava, S.; le Noble, W.J. J. Am. Chem. Soc. 1986, 108, 1598; 1987, 109, 7239; (d) Srivastava, S.; le Noble, W.J. J. Am. Chem. Soc. 1987, 109, 5874. 150. Chung, W.-S.; Turro, N.J.; Srivastava, S.; Li, H.; le Noble, W.J. J. Am. Chem. Soc. 1988, 110, 7882. 320 151. Macaulay, J.B.; Fallis, A.G. J. Am. Chem. Soc. 1990, 112, 1136. 152. Gillard, J.R.; Burnell, D.J. Can. J. Chem. 1992, 70, 1296. 153. (a) Fisher, M.J.; Hehre, W.J.; Kahn, S.D.; Overman, L.E. J. Am. Chem. Soc. 1988, 110,4625; (b) Paddon-Row, M.N.; Wu, Y.-D.; Houk, K.N. J. Am. Chem. Soc. 1992,114, 10638; (c) Das, G.; Thornton, E.R. J. Am. Chem. Soc. 1993,115, 1302. 154. (a) Cook son, R.C.; Gilani, S.S.H.; Stevens, I.D.R. Tetrahedron Lett. 1962, 615; Cookson, R.C.; Gupte, S.S.; Stevens, I.D.R.; Watts, C.T. Org. Synth. 1971, 51, 121. 155. Coxon, J.M.; Fong, S.T.; McDonald, D.Q.; Steel, P.J. Tetrahedron Lett. 1993, 163. 156. Fessner, W.-D.; Grand, C.; Prinzbach, H. Tetrahedron Lett. 1991, 5935. 157. Bohm, M.; Gleiter, R. Tetrahedron 1980, 36, 3209. 158. Gleiter, R.; Ginsburg, D. Pure & Appl. Chem. 1979,51, 1301. 159. Ginsburg, D. Tetrahedron 1983, 39, 2095. 160. (a) Jensen, F.; Foote, C.S. J. Am. Chem. Soc. 1987, 109, 6376; (b) Clennan, E.L.; Early wine, A.D. J. Am. Chem. Soc. 1987, 109, 7104. 0 4 to y—s >—s y—s y—s. y—s y—\ y—s y—s y * s 04to to S_y o> o» o>04 OJ C 'S—'9'9umi9iUi9tU)Ui9i'J9'