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Studies directed toward the synthesis ofStrychnos alkaloids: Stereoselective synthesis of dehydrotubifoline
Michoud, Christophe, Ph.D.
The Ohio State University, 1993
UMI 300 N. Zeeb Rd. Ann Arbor, MI 48106
STUDIES DIRECTED TOWARD THE SYNTHESIS OF STRYCHNOS ALKALOIDS:
STEREOSELECTIVE SYNTHESIS OF DEHYDROTUBIFOLINE.
DISSERTATION
Presented in Partial Fulfillment of the Requirements for
the Degree Doctor of Philosophy in the Graduate
School of the Ohio State University
By
Christophe Michoud
The Ohio State University
1993
Dissertation Gommitee: Approved by
Dr. Viresh H. Rawal
Dr. David J. Hart
Dr. Leo A. Paquette Adviser Department of Chemistry To My Parents ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to Dr. Viresh Rawal for his support and
guidance during the course of this work. His communicative enthusiasm for chemistry, and his
encouragement have been of great help. I wish also to thank Dr. Jean Huet from ESCIL, who helped to organize niy coming to the States.
To the members of the Rawal group, I express my gratitude. Stimulating discussions have often contributed to the advancement of our research projects.
I would like to acknowledge 0. Cottrell and C. Engelman for recording ^ H and ^ ^ 0 NMR spectra, and providing useful information about NMR experiments.
Finally, a lot of thanks should go to my friends in Columbus, who contributed to making my stay in the States more enjoyable. VITA
April 29, 1965 ...... Born, Voiron, France
1984 ...... Baccalauréat C, Lycee Edouart Herriot, Voiron, France
1984-1986 ...... Math Sup.- Math Spe., Lycee Champollion, Grenoble, France
1986-1988 ...... ESCIL, Lyon, France
1988-1990 ...... Teaching Assistant, The Ohio State University, Columbus
1991-199 2 ...... Rohm and Haas Industrial Fellow, The Ohio State University
1992-199 3 ...... Research Associate, The Ohio State University, Columbus
PUBLICATIONS
Rawal, V. H; Michoud, C. “A General Solution to the Synthesis of 2-Azabicyclo [3.3.1] nonane Unit of Strychnos Alkaloids”, Tetrahedron Lett. 1991,32, 1695.
Rawal, V. H.; Singh, S., Dufour, C.; Michoud, C. “Cyclization of Alkoxymethyi Radicals”, J. Org. Chem. 1991. 56, 5245.
Rawal, V. H.; Michoud, C.; Monestel, R. “General Strategy for the Stereocontrolled Synthesis of S/rychnos Alkaloids: A Concise Synthesis of (±)-Dehydrotubifoline”, J. Am. Chem. Sac. 19 93, 115, 3030.
Rawal, V. H.; Singh, S.; Dufour, C.; Michoud, C. "Cyclization of Alkoxymethyi Radicals: Scope and Limitations”, Manuscript in preparation, 19 93.
Rawal, V. H.; Michoud, C. “An Unusual Heck Cyclization", Manuscript in preparation, 1 9 9 3 .
iv FIELD OF STUDY
Major Field : Chemistry Studies in Organic Chemistry TABLE OF CONTENTS
DEDICATION...... ii
ACKNOWLEDGEMENT...... ill
VITA...... iv
LIST OF TABLES...... viii
LIST OF FIGURES...... ix
LIST OF SCHEMES...... xii
CHAPTER PAGE
I. The Heck Reaction: Recent Application in Synthesis
1-...... Introduction ...... 01
2- Intramolecular Coupling Reactions ...... 03
2.1- Unactivated Olefins ...... 04
2.2- Activated Olefins ...... 07
3- Carbocyclizations ...... 11
3.1- 5-Membered Ring ...... 11
3.2- 6-Membered Ring ...... 15
3.3- Polycyclization ...... 19
4- Heterocyclizations ...... 20
4.1- Oxygen Heterocycles ...... 21
4.2- Nitrogen Heterocycles ...... 23
5- Conclusion ...... 28
vi II. Background and Synthetic Studies
Background ...... 29
Synthetic Studies ...... 31
III Retrosynthetic Analysis and Model Studies
Synthetic Strategy...... 48
Model Studies ...... 51
IV. Total Synthesis of Dehydrotubifoline ...... 68
EXPERIMENTAL...... 94
LIST OF REFERENCES...... 132
APPENDICES
^NMR and ^^C NMR Spectra of Selected Compounds ...... 142
VII LIST OF TABLES
TABLE PAGE
1. N-Alkylationof 261 with 2,3-Dlbromopropene ...... 64
2. Alkylation of Ortho-Nitrophenyl Acetonitrile ...... 72
3. Preparation of 3 07, Reaction Conditions ...... 80
4. Hydrolysis of Bis-carbamate 31 8 ...... 86
5. ^^0 NMR of Dehydrotubifoline ...... 92
VIII LIST OF FIGURES
FIGURE P A G E
1. Examples of Strychnos Alkaloids...... 29
2. Model Compounds for tfie Heck Cyclization ...... 53
3. 6-Exo versus 7-Endo Cyclization ...... 56
4. nOe Experiments on Bicycles 2 40 and 2 41 ...... 58
5. Aspidosperma and Strychnos Skeletons ...... 83
6. Spectroscopic Data of Tetracycle 318 ...... 84
7. Spectroscopic Data of Pentacycie 3 2 7 ...... 88
8. ■' h NMR Spectrumof2 27 ...... 143
9. "'^C NMR Spectrum of 2 2 7 ...... 144
10. ^HNMR Spectrum of 2 2 9 ...... 145
11. ■'^c NMR Spectrum of 229 ...... 146
12. ^HNMR Spectrum of 21 8 ...... 147
13. ^ ^C NMR Spectrum of 21 8 ...... 148
14. ^ H NMR Spectrum of 2 3 0 ...... 149
15. ^^C NMR Spectrum of 2 3 0 ...... 150
16. ■’h NMR Spectmmof 2 1 9...... 151
17. ■'^c NMR Spectrum of 21 9 ...... 152
18. H NMR Spectrum of 2 2 0 ...... 153
ix 19. ^ NMR Spectnjm Of 2 2 0 ...... 154
20. NMR Spectrum of 2 4 0 ...... 155
21. ■’3cNMRSpectrumof240 ...... 156
22. ^HNMRSpeclrumof241 ...... 157
23. ■^^CNMRSpecttumof 241 ...... 158
24. ^ H NMR Spectrum of 2 4 4 ...... 159
25. ^ NMR Spectmm of 2 4 4 ...... 160
26. ■■ H NMR Spectrum of 2 4 6 ...... 161
27. ^ NMR Spectrum of 2 4 6 ...... 162
28. 1H NMR Spectrum of 2 4 5 ...... 163
29. ^ NMR Spectrum of 2 4 5 ...... 164
30. ^ H NMR Spectrum of 2 4 7 ...... 165
31. ■'^c NMR Spectrum of 2 4 7 ...... 166
32. "* H NMR Spectrum of 2 4 9 ...... 167
33. ^ NMR Spectrum of 2 4 9 ...... 168
34. ■'h NMR Spectrum of 2 5 0 ...... 169
35. ^ NMR Spectrum of 2 5 0 ...... 170
36. ■’h NMR Spectrum of 2 6 0 ...... 171
37. ■'^C NMR Spectrum of 2 6 0 ...... 172
38. ■' h NMR Spectrum of 2 6 1 ...... 173
39. ■ ' NMR Spectrum of 2 6 1 ...... 174
40. ^ H NMR Spectrum of 2 6 2 ...... 175
41. ^ NMR Spectrum of 2 6 2 ...... 176
42. ^ H NMR Spectrum of 2 5 8 ...... 177
43. ^ NMR Spectrum of 2 5 8 ...... 178
44. NMR Spectrum of .2 6 3 ...... 179
X 45. ■'^c NMR Spectrum of 2 6 3 ...... 180
46. ■'h NMR Spectrum of 2 7 9 ...... 181
47. ■‘^ c NMR Spectrum of 2 7 9 ...... 182
48. ■’h NMR Spectrum of 2 8 0...... 183
49. ^ NMR Spectrum of 2 8 0 ...... 184
50. NMR Spectrum of 2 8 2...... 185
51. ■'^c NMR Spectrum of 2 8 2...... 186
52. ■'HNMRSpectrumof299 ...... 187
53. NMRSpectrumof29 9 ...... 188
54. ^ H NMR Spectrum of 3 0 0...... 189
55. ^ % NMR Spectrum of 3 0 0...... 190
56. ■'h NMR Spectrum of 3 0 7 ...... 191
57. ^ NMR Spectrum of 3 0 7...... 192
58. NMR Spectrum of .31 8 ...... 193
59. ■'^c NMR Spectrum of 31 8 ...... 194
60. NMR Spectrum of .3 2 4 ...... 195
61. ^ NMR Spectrum of 3 2 4 ...... 196
62. ■* H NMR Spectrum of 3 2 5...... 197
63. ■'^C NMR Spectrum of 3 2 5 ...... 198
64. ■'H NMR Spectrum of 3 2 7 ...... 199
65. "I H NMR COSY Spectrum of 3 2 7...... 200
66. NMRSpectrumof32 7 ...... 201
67. ^ H NMR Spectrum of 3 4 4 ...... 202
68. ^ NMR Spectrum of 3 4 4 ...... 203
69. ^HNMRSpectrumof123 ...... 204
70. ■'^CNMRSpectrumof 1 23 ...... 205
XI LIST OF SCHEMES
SCHEME PAGE
1. Mechanism of the Heck Reaction ...... 2
2. Intermediates in the Heck Reaction of Linear Alkenes ...... 4
3. Michael Arylation ...... 8
4. Palladium Mediated C-Glycoside Formation ...... 10
5. An Asymmetric Heck Cyclization ...... 15
6. Gore's Cylclopentanation Reaction ...... 15
7. Exo versus Endo Cyclization ...... 18
8. Overman’s Tazettine Synthesis - Boat versus Chair...... 22
9. Overman’s Asymmetric Heck Cyclization ...... 27
10. Biosynthesis of Strychnos Alkaloids ...... 30
11. Woodward’s Synthesis of Strychnine ...... 34
12. Magnus’ Synthesis of Strychnine ...... 35
13. Biochemical Conversion StemmadenineStrychnos ...... 38
14. Harley-Mason’s Syntheses of Tubifoline and Condyfoline ...... 37
15. Ban’s Approach to Stemmadenine ...... 38
16. Takano’s Synthesis of Dehydrotubifoline...... 39
17. Kim’s Approach to Strychnine ...... 40
18. Vollhardt’s Approach to Strychnine ...... 41
19. Overman’s Synthesis of Dehydrotubifoline ...... 42
xii 20. Kraus' Approach to Strychnine ...... 43
21. Bosch’s Second Synthesis of Tubifoiidine ...... 44
22. Kuehne’s Synthesis of Tubotaiwine ...... 45
23. Vercauteren’s Synthesis of 19-Hydroxytubotaiwine ...... 46
24. Retrosynthetic Analysis of Strychnine ...... 49
25. Regiochemistry of the Coupling Process: Endo vs Exo ...... 52
26. Preparation of Vinyl Bromide 21 8 ...... 54
27. Reduction of Pd(OAc )2 by PPhg ...... 55
28. Heck Cyclization of Vinyl Bromide 2 1 8 ...... 55
29. Syntheses of Vinyl Iodides 219 and 2 2 0 ...... 56
30. Preparation of Vinyl Iodides 234 and 2 37 ...... 57
31. Heck Cyclization of Vinyl Iodides 2 1 9 and 2 2 0 ...... 58
32. Preparation of 2 4 5, First Route ...... 59
33. Preparation of 2 4 5, Second Route ...... 60
34. Regiochemistry of the ^-Elimination Step ...... 60
35. Palladium Assisted Synthesis of 2-Methyl-lndole ...... 62
36. Model Studies-Construction of the Indole Nucleus ...... 63
37. Synthesis of Aniline Derivative 2 5 8 ...... 64
38. Double Cyclization ...... 66
39. Retrosynthesis of Dehydrotubifoline ...... 69
40. Cyclopropyl-iminium Ion Rearrangement ...... 70
41. Stevens’ Formal Synthesis of Aspidospermine ...... 71
42. Synthesis of Cyciopropyl-lmine 281 ...... 72
43. TMSI Promoted Cycloprpyl-lminium Ion Rearrangement ...... 75
44. Attempted Intermolecular Cycloadditions ...... 77
45. Preparation of Carbamate 2 9 9 ...... 78
xiii 46. Preparation of Dienamides from a,p-unsaturated Aldehydes ...... 79
47. Preparation of Dienamide 3 0 7 ...... 80
48. Diels-Alder Cycloaddition of Dienamide 3 0 7 ...... 83
49. TMSI Promoted Hydrolysis of Carbamates-Mechanism ...... 85
50. Our First Approach to Dehydrotubifoline and Akuammicine ...... 87
51. Heck Cyclization of Indoline Carbamate 3 2 5 ...... 88
52. Inversion of Alkene Geometry via an Exo-mode Cyclization ...... 89
53. Formation of 3 2 7-Mechanism ...... 89
54. Heck Cyclopropanation ...... 90
55. Final Steps in the Synthesis of Dehydrotubifoline ...... 92
XIV Chapter I
The Heck Reaction: Recent Applications In Synthesis
i. Introduction
The palladium mediated coupling reaction of an aryl or vinyl halide with an alkene — the
Heck reaction— was first reported by Heck^ in 1968. Although some interesting extensions of
this reaction were reported by Heck^'^ and others^ in the subsequent years, it was not until the
last decade that a considerable amount of investigation has extended the scope of this
transformation.®’^ Not surprisingly, the Heck reaction is now used extensively in organic
synthesis.^ The objective of the present chapter is to review the recent applications of the Heck
reaction in organic synthesis. This survey of the literature will discuss intermolecular and intramolecular Heck coupling reactions, including carlDocyclizations and heterocyclizations.
The basic mechanism of the Heck reaction involves four steps® (Schem e 1 ):
(1) Palladium Insertion: An oxidative addition of Pd(0) into the sp® carlx)n-halide (or
triflate) bond forms a vinyl (or aryl) palladium (II) species. This complex can also be
generated from a vinyl (or aryl) mercury acetate upon treatment with a Pd(ll) salt
(fransmetallation).^
{2}Complexation: The Pd(ll) intermediate reacts with the alkene to afford a jt-complex.
(3) Addition: The rc-complex collapses by 1,2-syn-addition to create a new carbon-
cartxjn fcwnd and a a-pal!adium-cait)on tx)nd.
(4) p-Elimination: The palladium cr-adduct decomposes with elimination of palladium
hydride and product formation. The elimination of HX from HPdX ensures the
regeneration of the active Pd(0) catalyst.
1 Scheme 1: Mechanism of the Heck Reaction
R— X
Pd(0) R— Pd-L HX
R— Pd-L HPdX
(3)
This general mechanism provides a useful framework for the discussion of various
aspects of the reaction. The Pd(0) catalyst is usually generated in situ by reduction of a stable palladium II complex, most often Pd(0Ac)2- The reduction is induced by the alkene in solution or by a phosphine ligand.® The regeneration of the active catalyst from HPdX is promoted by a base. Commonly used bases include tertiary amines, acetates, cartx)nates or bicabonates.^ A polar solvent is often mandatory to keep the catalyst in solution. Dimethylformamide (Df\^F) and acetonitrile are both used extensively, although dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and hexamethylphosphoramide (HfvlPA) are used occasionally.^ In cases where non coordinating solvents like toluene are employed, more ligand has to be added to solubilize the catalyst. The Heck olefination reaction can be applied to various organic halides, triflates, diazonium salts, carlDoxylic acid chlorides, sulfonyl chlorides and sulfinate salts.^ This chapter will be limited to the Heck reactions of organic bromides, iodides, and triflates, as most synthetically useful applications have been obtained with these derivatives. Alkyl halides (or triflates) with 3 p-hydrogen generally undergo p-elimination of palladium hydride under the condiiions of the
Heck reaction.^ Consequently, this review will be limited to the addition of sp^ hybridized
carbons.
2. Intermolecular Coupling Reactions
The Heck reaction is limited to alkenyl halides (or triflates). But, it is a general process with
regard to the alkene partner, which can be a simple olefin, or an olefin substituted by electron withdrawing, or donating groups. The reaction is sensitive to steric hindrance. Mono-subsituted alkenes are the most reactive olefins, and increasing substitution lowers the reactivity. With substituted alkenes, caibon-cartTon bond formation usually takes place at the less hindered side of the double bond. Electronic factors, however, can override steric effects (see enol ethers).
Selected examples of intermolecular Heck reactions are presented below to illustrate the scope of the coupling process.
To begin with, I would like to illustrate the mildness of the method. The Heck reaction represents an exceptionally mild, and often selective, method for the construction of carbon- carbon bonds between sp^ centers. It has been employed with success in the derivatization of complex natural products. ^ An example by Witty and co-workers dramatically illustrates the selectivity obtainable by the Heck reaction. These authors explored the structure-activity relationship of avermectin derivatives.^^ The sensitivity of the avermectin molecule prevented the use of acidic or basic reagents. Selective substitution on the terminal alkene was achieved without any protection of the sensitive functionalities, using a neutral palladium reagent. The polyene macrocyclic lactone containing a sensitive spiroketal moiety did not suffer any decomposition during the arylation reaction (Equation 1 ). RO.
HO Pd(OAc)2, EI3N HO
MeCN, reflux, 24h OM0 54%
OH OH
(E q n .1 )”
This section, deaiing with intermolecular Heck reactions of alkenes with various halides
and triflates, has been divided into two parts: reaction of unactivated olefins and reactions of activated olefins.
2.1 Unactlvated Olefins
2.1.1 Terminal Alkenes
Numerous examples show that monosubstituted alkenes undergo Heck coupling reactions at the terminal carbon exclusively, to produce the thermodynamically more stable (E) olefin. During vinylation reaction, the geometry of the vinylic halide or triflate is generally retained.'^ As shown in Scheme 2, the coupling product arises from syn elimination of palladium hydride. Two possible intermediates A and B are available, intermediate B is higher in energy due to the steric repulsion between the eclipsed substituents. The E isomer arises from the collapse of intermediate A.
Scheme 2: Intermediates In the Heck Reaction of Linear Alkenes
syn H iu . ^ r B Z I Pd elimination C•Ar H H. R R "ArPdBr"
syn addition I =d Ar syn Ar,„..2$r A 1 Pd elimination H ./ Two inhibitors of the thromboxane synthase enzyme (5 and 8) were prepared by
vinyiation of 3-bromo-pyridine (Equation 2 and 3).^® Derivatives of 2,3-dihydro-7-iodoindole
have been coupled to 2-methyl-3-buten-2-ol to afford an intermediate in the total synthesis of
annodine an indole alkaloid isolated from a West African medicinal plant. Quinolinones^ ®
and other derivatized heterocycles^ ^ have also been prepared by coupling with 2-methyl-3-
buten-2-ol. Some 3-indolyi halides^® and triflates^® have been reported to undergo Heck
reaction with a variety of terminal alkenes in fair to good yields. Vinylation of haloazulenes and
halotropolones with styrenes and 2-vinylpyridines represents a convenient method for the
introduction of conjugated carbon side chains to these compounds.^ ^ Mercuriated derivatives
of quinolones have been reported to participate in the Heck transformation. A full equivalent of
Pd(0Ac)2 is required in these reactions, because a palladium (II) complex is produced by
transmetallation."’ ®
P d (0 A c )2 1 P (o -to l),
5 (Eqn.2)1®
GOgMô P d (O A c)2 CO2M0 Cr“ P(o-tol)3
(Eqn.3)^®
Unlike mercuriated compounds, vinyl silanes do not appear to participate in transmetallation reactions. Vinyl silanes have, however, been used as alkene partners in the
Heck reaction.^®"^^ In 1985, Hallberg and co-workers reported that the treatment of aryl iodides with vinyltrimethylsilane under ordinary Heck arylation conditions resulted in the formation of 6 Styrene derivatives (Equation They found that the desilyiation could be suppressed
by adding one equivalent of a silver(l) salt (Equation 4 b), in which case the product 1 5 resulted
from arylation at the less substituted carbon, in 1990, Tanaka^^ found that, even in the absence
of a silver salt, the reaction proceeded without desilyiation, provided that the starting vinylsilane
had electronegative substituents attached to the silicon (Equation 4c).
P d (O A c )2, PPhg Arl + P d (O A c )2, PPha + '^SiMea (Eqn.4b)20 Ar, + 16 (Eqn.4c)22 The synthesis of non-proteinogenic a-amino acids, which are potential enzyme inhibitors, has recently attracted much attention. Crisp and co-workers reported the synthesis of various glycine derivatives, through the Heck coupling reactions of vinyl glycine and alkenyl halides or triflates.^^® They observed no racemization during the coupling process (Equation 4d). Itaya has demonstrated the utility of the Heck reaction with optically active vinyl glycine derivatives in his synthesis of the fluorescent nucleoside, wybutosine, a component of the yeast phenylalanine tRNA.^^^ ,COOH Pd(OAc)2. P (o -to l)3 + COOH aOT, NHCBz 9 10 NHCBz (Eqn.4d)23a The Heck reaction of terminal dienes has been described.^^'^® However, low yields are obtained when the diene is not activated by a carbonyl or a phenyl group. Recently, Jeffery developed a procedure to couple unactivated terminal dienes to aryl iodides.^® Good yields of (E,E) conjugated aromatic dienes were obtained upon treatment of benzyl iodide and linear terminal dienes with palladium acetate, triphenylphosphine and silver cartxjnate, in DMF. This procedure has not been yet extended to the vinyiation reaction. 2.1.2 Internal Alkenes Symmetrical alkenes undergo the Heck coupling reaction with no regiochemical consequences.^^ On the other hand, unsymmetrical alkenes do usually produce mixtures of regioisomers.^®’^® The major product arises from coupling at the less hindered olefinic carbon.®® 2.2 Activated Olefins 2.2.1 Electron-Poor Alkenes Electron deficient alkenes have been used extensively in Heck coupling reactions. Arylation and vinyiation of a,p-unsaturated esters,® ^acids,^® amides,'*^nitriles,®® ketones,®® and aldehydes,®® occur regiospecifically at the jî-cartx)n. A series of substituted pyrazole mevalonolactones was synthesized by palladium catalyzed vinyiation with ethyl acrylate (Equation 5).®^ Transmetallation of mercurated pyrrole 5 with PdCl 2, followed by coupling with methyl acrylate, conveniently afforded the tetrasubstituted pyrrole 6, in 84% yield (Equation 6).®® Halogenochromones sen/ed as common precursors for the synthesis of chromones functionalized with unsaturated esters.®® The (E) isomer is often exclusively obtained. F 67% COgEt PdClzfPPib) DMF. EtjN (Eqn.5)®^ \ H g C I •sS^COaMe J ~ \ 84% EtOgCX N k PdClg, LiCI EtOgC C02tBu MeCN, reflux COatBu (Eqn.6)®® As the above cases illustrate, the coupling of a.p-unsaturated esters to aikenes affords exclusively the E isomer. This observation reflects the preference for intermediate A (see Scheme 2), where the substituents are in a staggered arrangement. The same result is not aiways true for a,p-unsaturated nitriles, which can give rise to a mixture of isomers.^^ This observation indicates that nitriies are not as stericaliy demanding as esters. In contrast to acyclic cases, cyclic esters cannot adopt the conformation required for syn p-elimination of palladium hydride. According to Stokker,^^ lactone 1 7 (Scheme 3) underwent a Michael arylation upon treatment with Pd(0) and triethylamine. in this transformation, triethyiamine was the source of hydride. A proposed mechanism for this unusual reaction is depicted in Schem e 3. Scheme 3: Michael arylation “ ci '» Pdl^ Ph R Ri R"-( \-"Pd-L Et2N+=\^ ° Acrylamide derivatives show only moderate activity in standard Heck reactions.^ ^ Strong chelation of the amide group to the cataiyst generaliy prevents a good turn over. Two solutions to this problem have been developed. Zhuangyu and co-workers investigated a polymer-bound Pd(0) catalyst that efficiently promotes the arylation of acrylamide (Equation 7).^^ Heck arylation of acrylamides and a-amidoacrylates has also been achieved using an excess of lithium chloride (Equation 8).^® The chloride anion is believed to chelate the catalyst. This chelation is likely to preclude a strong coordination of the amide nitrogen. The reaction is regioselective, affording the (2) isomer only. Aromatic amino acids have been prepared by Heck arylation of a-amidoacrylates followed by catalytic hydrogenation.^® CONH, .CONH, Polymer-Pd(O) %» 8 2 -9 9 % DMF, HjO. NaOAc 100°C (E q n .7 )4 2 COgMe NHAC NHAc K2CO 3, Pd/C, DMF LiCI, 100°C , 77% 2 0 Ts (E q n .8 )2 9 in a similar way, a-methoxyacrylates react stereospecificaly with vinyl triflates and aryl iodides to give (2) enol ethers of pyruvate derivatives (Equation 9).®® C«H OM0 MeQ. P d (0 A c )2 , nBugNCI TfO NaHCO* DMF, 80°C 72% 22 (E q n .9 )2 8 2.2.2 Electron rich aikenes The Heck arylations and vinylations of acyclic enol ethers often yield a mixture of regioisomers.®’ 36,44-46 arylation of n-butyl vinyl ether with iodobenzene, for instance, affords a 2/3 mixture of p- and a - arylated enol ethers. Consequently, the Heck reaction of acyclic enol ethers has not been used in synthesis. The reason for this lack of selectivity is not well understood.®’^^"'^® On the other hand, cyclic enol ethers undergo regiospecific palladium promoted arylation and vinylation. Derivatives of 3,4-dihydropyran and 2,3-dihydrofuran troth undergo coupling at the a-carbon, site of lower electron density.^^'®® Hayashi and Ozawa 10 recently reported that high enantioseiectivity (>90% ee) could be achieved in the arylation of 2,3- dihydropyran with aryl triflates when a chiral phosphorus ligand (BINAP) was employed.®^ The Heck reaction of cyclic enol ethers has been used extensively in carbohydrate chemistry for the synthesis of C-glycosides.^' 52-57 chemistry was recently reviewed by Daves, and will not be discussed at length.®^ The Pd alkenyl or aryl complex is delivered from the less hindered side of the carbohydrate unit. The resulting o-alkyl complex decomposes via several competing modes®^ (Scheme 4). Whenever possible, traditional syn p-elimination of HPdX is preferred (2 5). In a case where an axial acetate was present on the cartoon a to the palladated center, elimination of palladium acetate has been observed (2 6). An unusually stable palladium a complex (27 a) was isolated from the reaction mixture of 2 7 and 2 4 with Pd(OAc) 2 - In this example, an intramolecular chelation through a six-membered ring was responsible for the stability of 27a. (3-elimination did not occur, because chelate formation prevented proper alignement of the syn p-hydrogen and the carbon-palladium bond. The complex 27a was isolated, and treated with hydrogen to afford the reduction product 2 8.^® Scheme 4: Palladium Mediated C-Glycoslde Formation Me AcO' AcO' AcOHg' MeN. NMe 23 24 25 Me Me Me + r j Ph' r"^ AcOHg'^ If Me -PdfOAc); A cO Q 26 OAc OAc JO. ^ O A C - ^ — NMe 27 27= 28 MeN—/ NMe O 11 The intermolecular coupling reactions of acyclic enamides, like enol ethers, give rise to mixtures of regioisomers.®’®® No application in synthesis has been reported. A number of cyclizations of enamides have been developed, and examples are discussed in part four. 3. Carbocycllzations In connection with the synthesis of natural products, there is increasing interest in the development of intramolecular variants of the Heck reaction that offer a general route to caitKDcycles. These transformations are similar to the radical cyclizations, and usually proceed predictably and in high yield. A variety of 5- and 6-membered carbocycles have been prepared very efficiently. In the recent years, the Heck methodology has also been extended to polycyclization processes. 3.1 5-membered Carfaocvcles 2-halo-1,6-dienes and 1-halo-1,5-dienes undergo smooth conversion to 5-membered ring upon treatment with a Pd(0) catalyst (Equation 10a and 10 b). Like in radical chemistry, 5- exo cyclization is usually preferred over 6-endo cyclization. But, unlike radical processes, the cyclization step is not followed by a reduction, but by an elimination reaction that regenerates the alkene. Equation 10a and 10b illustrate the two possible 5-exo Heck cyclizations. The first reaction leads to a cisoid diene, and the second one affords the transoid isomer. (E q n .lO a) (E q n .lO b ) Grigg and co-workers®®'®^ investigated the chemistry of substituted 2-bromo-1,6- heptadienes (Equation 11). Although the cyclizations proceeded in good yields, the reactions were not specific, a minor amount of 6-membered rings (endo cyclization) being obtained.®® 12 Pd(O A c)2. P P h s K2CQ 3, M eCN Br 74% 2 9: E= COMe (E q n .11)59 A more sophisticated version of this chemistry has been reported by Gaudin,®^ as part of his ongoing work on the construction of functionalized 5-membered carbocycles. A series of aiiylic alcohols possessing a suitable vinyl (or aryl) bromide appendage were submitted to the Heck cyclization conditions (equations 1 2 to 1 4). In the first example (Equation 1 2) the initial 5- exo cyclization yields a o-palladium complex (32 a), which collapses to afford the aldehyde 3 3 through an enolic tautomerization. In the case of a secondary allylic alcohol (3 4), a ketone is produced (Equation 1 3). The substituted bromobenzene 3 6 does not follow a similar reaction pathway (Equation 1 4). Eiimination of palladium hydride cannot occur so as to generate an enol. In this case, a mixture of diastereomeric alcohols (3 7 and 3 8 ) is produced. Gaudin has also combined, in one operation, a Pd(0) catalyzed alkylation of a vinyl epoxide (3 9) and a Heck cyclization, to afford the bicycle 4 1 in 60% overall yield (Equation 1 5). The intermediate in this transformation is believed to be the allylic alcohoi 39 a. Pd(OAc)2 , PPhj 60% OH OH ■OHO 32a 32b 33 (Eqn.12)® 2 Pd(0Ac)2, PPhg ■o ------83% EtgN, M eC N HO' BrLgPd 34a 35 (Eqn.13)®2 13 Pd(OAc)2. PPha ■ ' > 'Br ^ EtgN, MeCN 3 6 nCgHi, (E q n .l4)® 2 NaH, Pd(OAc)j PPha, THF, 60% HO HO' 40:E=CO2Me 39a 41 (Eqn.15)® 2 Recently, vinyl®^’®^ and aryl®^ triflates of elaborated systems have also been submitted to the intramolecular Heck reaction. Paquette®^ investigated the regioselectivity of the p- hydride elimination step in systems related to diquinanes (Equation 1 Band 1 7). In his studies, non activated olefins (4 2) were converted to the less conjugated cyclization product (4 3), whereas activated olefins (4 4) afforded a mixture of conjugated (4 5) and non-conjugated (4 6) dienes. The major product was reported to be the conjugated isomer. Formation of 45 was not the result of Pd-mediated equilibration, as longer reaction times did not alter the ratio of products (kinetic control). Moreover, pure samples of isomers 4 5 and 4 6 were found to be stable to the reaction conditions. OTBDMS Pd(P Ph3)„, LiCI LigCOg, THF, reflux OTBDMS 91% e 4 3 (Eqn.16)' 63 14 COjEt pd(pp(i3)^ UCI + LIgCOg, THF, reflux 4 4 i 4 5 (Eqn. 17)63 Within the past few years, there has been increasing interest in the development of enantioselective transformations. Several examples of asymmetric Heck reactions®'^"^®’^^ ^ have been reported. Asymmetric palladium promoted synthesis of cyclopentanoids have been achieved by Shibasaki.®'^’ 63 The c/s-hydrindan derivative 4 8 was obtained from vinyl iodide 4 7, in 78% yield and 82% ee using a catalytic amount of PdCl 2(R-BINAP) (Equation 1 8).63 Differentiation of the two enantiotopic endocyclic double bonds resulted from chelation with the chiral phosphorus ligand, R-BINAP. OTBDMS OTBDMS PddgfA-BINAP) 8 2 % e e AggCO^ CaCOg NMP, 60°C, 78% 4 7 4 8 (Eqn. 18)66 In a related study, the author developed a catalytic asymmetric preparation of a key intermediate (5 0) in the synthesis of capnellenol sesquiterpenes. 6^ Treatment of the vinyl iodide 4 9 with [Pd(allyl)Cl 2]2 (10mol%), (f?,R)-Chiraphos (10mol%), and nBu^NOAc in toluene provided the bicyclic allylic acetate 5 0 in fair yield, but low ee (20% ee). As shown in Scheme 5, complexation of the endocyclic alkene to the vinyl palladium moiety necessitated the dissociation of at least one chiral phosphorus ligand. This dissociation, obviously, decreased the possibility of asymmetric induction. In an effort to overcome this problem, Shibasaki and al. carried out the reaction in the presence of a silver (I) salt, which, by abstracting I", was expected to liberate a coordination site. The starting iodide, unfortunately, suffered extensive decomposition in the presence of silver cartxinate. Very good leaving groups, like triflate, do not usually require the 15 assistance of sliver (I) salts. Indeed, the cyclization of vinyl trifalte 5 1 proceeded efficiently in the absence of silver salt, with an enantiomeric excess of 80%. Scheme 5: An Asymmetric Heck Cyclization Pd-L* Pd-L* Pd(0), nBu^NOAc 61% P A o jff L*-CHIRAPHOS, 2 0 % ee toluene, 60°iC -L* M e 5 0 TfO' TIO' L* Pd*r Pd(OAc)a. S-BINAP 8 9 % P A c nBu^NOAc, DMSO 8 0 % e e Gore has developed an interesting approach to cyclopentane derivatives.^^ A cascade of reactions, leading to 5-membered carbocycles, was triggered by Heck additions of vinyl (or aryl) iodides (or bromides) to aikenes. This transformation is believed to involve a reductive cyclization with a maionate anion. An example of these new Pd(0) promoted cyclopentanellation reactions is depicted in Scheme 6 .^^ Scheme 6: Gore’s Cylclopentanatloii Reaction R, PdXLa R-X, Pd(0) NaH, DMSO, 85% h o EcCOgMo R-X: _ 0 _l MeO-0 - l Br yield: 57% 8 0 % 7 8 % 3.2. giM embered Catbocycles Some of the annulation procedures developed for 5-membered cartxtcycles have been extended to cyclohexyi homologues, albeit less successfully. The cyclizations of 2-bromo- 16 1,7-octadienes, reported by Griggs, gave rise to a mixture of the expected exo-cyclization product 5 3, along with the Isomerized diene 5 4 (Equation i 59,61 -p^e cyclization of allylic alcohoi 5 5 (Equation 2 0), described by Gaudin in 1991, yielded the aldehyde 5 6, through a mechanism similar to the one depicted in Equation 1 2.®^ Shibasaki has demonstrated that the transformation of cyclohexadiene 5 7 to decalin 58 (Equation 21a) proceeded with high enatiomeric excess, when the chiral ligand R-BINAP was employed.®®’ ®^- P d (O A c )2, PPhg K 2CO 3, M e C N 86% (Eqn.19)® ^ E . E Pd(O A c)2, P P h 3 EtgN, M e C N 6 2 % OHO 5 5 : E -C O a M e (Eqn.20)® 2 OTBDMS OTBDMS / Pd(OAc)a fTBINAP 9 1 % e e TfO . KgCOg, toluene 60°C;, 5 4 % CO H 57 5 8 (Eqn.21a)'^® Ishibashi and Ikeda have taken advantage of the Heck cartx)cyclization in their studies directed toward the total synthesis of podophyllum\\gnans7^ The radical cyclization (nBugSnH, AIBN) of aryl bromide 5 9 afforded a mixture of 5-exo and 6-endo adducts. On the other hand, the palladium promoted cyclization cleanly yielded the desired substituted cyclohexene 6 0 (Equation 21 b). 17 Pd(OAc)2. PPha E%N. MeCN. 28% MeO*^ '^OMe MeO*^ ^OMe OMe 60 (Eqn.21b)^® Recent studies by Negishi^^ have demonstrated that some 6-membered cartx)cycies, which are products of apparent endo cyclizations,®^’ could be arising through a more complex mechanism. The palladium catalyzed cyclization of vinyl iodide 61, for example, afforded cyclohexene 62 exclusively. It is significant to note that the cyclization proceeded with complete inversion of the exocyclic olefin geometry (Equation 2 2 )7 ^ This reaction is not a traditional endo-cyclization. •OH PdClgfPPhg); EtgN, EtjNH DMF, SO^C 69% 62 (E qn.22K ® The mechanism of this transformation has been investigated by Negishi.^® The first step involves the expected exo-cyclization, to give the neopentyl type o-alkyl palladium complex 6 1 a (Scheme 7). As it is connected to a quaternary carbon, this complex cannot undergo p- elimination. It reacts intramolecularly with the alkene to yield the cyclopropane derivative 61b. After proper alignement of the o-alkyl palladium bond with the internal cyclopropane carbon- cartxjn bond, ring cleavage occurs to produce a new o-alkyl palladium complex (61c). During this step, the geometry of the exocyclic double bond is inverted. The complex 61c, which can undergo a fast p-elimination, collapses to provide the isolated diene 6 2. Cyclopropanations of alkylpalladium species have been reported.^®'®^ 18 Scheme 7: Exo versus Endo Cyclization CHgOH PdlLg — PdlLg 6 1 a CHgOH CHgOH PdlLa PdlL. 6 1 c An other intriguing type of palladium promoted annulation reaction has been reported by De Meijere and co-workers.®^"®'* Their process combines intermolecular and intramolecular Heck arylations (Equation 2 3). Although the mechanism of this reaction has not been thoroughly investigated, the participation of Pd(IV) intermediates has been speculated.®® Pd(OAc)2, I^CO^ nBu^Br, NMP J P h 62% 6 3 6 4 (3 eq ) 6 5 (E qn.23)® 4 A new palladium catalyzed carbocyclization, developed by Trost, is based on the carbopalladation of 1,6 and 1,7-enynes.®®"®^ The discovery that enynes could be reductively isomerized to cyclic dienes®®"®^(Equation 2 4) led to the investigation of alkylative cycloadditions, outlined in Equation 2 5 86-89 y^e potential of this transformation in the synthesis of complex structures has been demonstrated. Efficient strategies directed toward the vitamin D system®^'®® (Equation 2 6), as well a s other functionalized 6-membered caitocycles®® (Equation 2 7), have been published. 19 ,R HPdX P d (E q n .2 4 ) t-i R'PdX (E qn.25) 66 P d 2(d b a )3 • HCCIg ^OTBDMS 6 8 PPhs.E^N, toluene 76% TBDMSO TBDMSO’ 6:OTBDMS 67 TBDMSO’ 69 P h Br Pd(O A c)2. P P ha EI3N, toluene, 67% (E q n .27)89 Since the original communication of Overman®^ on the Heck-type polyene cartx)cyclizations, Pd(0) promoted multiannulations have been investigated by several different groups.9"^''’90 y^e power of this chemistry for assembling complex polycycles is illustrated in equations 2 8 through 30. A remarkable transformation^® was observed upon heating the 20 cycloheptene derivative 7 7 with a catalytic amount of Pd(0) in acetic acid (Equation 3 0). Tetracycle 7 8 was obtained via an initial Pd-ene cyclization of a ic-allyl palladium species, followed by two intramolecular Heck reactions. This synthesis of polyfused ring systems by intramolecular tandem palladium-ene/Heck reactions proceeded with high stereospecificity. The palladium-ene step afforded the thermodynamically more stable trans junction between rings A and B (77a), and the Heck cyclization occured with retention of configuration at the metalated cartxjns. Ag2CQ3, MôCN rt, 9 0 % 7 2 7 3 1.3 (Eqn.28)93a C O M e C O M e O M e P d (O A c )2, PPha EtO pC KgCO^, MeCN O M e 7 5 % EtOgC-^X 7 5 COgEt y 0 (Eqn. 29)94 Ptij{dba)3, P(o-furyl)3 E Pd AcOH, 110°C, 50% 77a 78 (E q n .30)95 4. Heterocycllzations The field of natural product synthesis provides a challenging arena to explore new preparations of heterocyles. Not surprisingly, the Heck cyclization methodology has been expanded to nitrogen containing heterocycles (alkaloids chemistry) and, to a lesser extent, to 21 oxygen containing heterocycles. 4.1 Oxygen Heterocvcles Some recent examples of Heck cyclizations leading to oxygenated heterocycles are presented below. To investigate the scope of their polycyclization procedure (see Equation 2 9), De Meijere^^ et al. submitted oxo-analogues of 75 to the Pd(0) catalyzed cyclization reaction. They isolated the expected tricycles in comparable yields. Phenolic ethers have been successfully cyclized to dihydropyrans by action of Pd(OAc) 2, PPhg, and triethylamine in acetonitrile.^®^ Bromo-propenyl allyl ethers (7 9),^®^ o-iodo benzyl allyl ethers (8 1),®^ and propargyl allyl ethers (8 3),®^ have also been converted to the corresponding oxocycles in good yield (Equations 31 to 3 3). Pd(OAc)a P(o-tol )3 ^ 7 EtgN,EtaN, lOO'C, 100°C, 47% q OHC—/HC- ^ 79 80 (Eqn.31)^0^ ‘OH Pd(0Ac)2, PPha EtgN, M e C N , 80=0 or 81 74% 82 OHoCHO (E q n .32)62 Ph Pda(dba) 3*HGCl 3 PPha, EtaN, toi. I Y 83 62% ' 84 (Eqn.33)66 The Heck cyclization has also been used for the synthesis of macrolides. Macrocyclic lactone 34, a model compound for the synthesis of carbonolide, was prepared by the intramolecular coupling reaction of a terminal iodide with a vinyl ketone, under high dilution conditions (Equation 3 4).^ 6® The instability of the catalyst during slow addition of the substrate required the use of a stoichiometric amount of PdCl 2(MeCN)2. Macrocyclic dienone 8 6, having the all trans geometry, was produced in 55% yield. 22 MeCN, 25°C 11 h. 55% Me' 86 (Eqn.34)^03 The construction of stericaliy demanding quaternary centers was recently achieved using Heck cyclizations. The central step in Overman’s syntheses of (±)-Tazettine and (±)- 6a- Epipretazettine was based on a palladium catalyzed construction of the benzopyran subunit (Equation 3 5).^ ^4 cyclization was performed in the presence of a stoichiometric amount of Ag(l) salt to prevent olefin isomerization. A high degree of stereoselection (>20/1) was observed in the formation of the quaternary center. This outcome can be rationalized by considering the two transition states, A and B (Scheme 8 ). The major product is believed to arise through the lower energy boat transition state, in which non-bonding interactions are minimized. P d(O A c)2, P P h j AgaCOa. THF 56-C, 70% w«o.CNH' 8 7 (E q n .3 s/H M Scfieme 8: Overman’s Tazetttne Synthesis - Boat versus Chair NHCOpMe N H C O ,M e VERSUS P d lL , \ _ 6 BOAT CHAIR fa v o red d isfa v o red 23 4.2 Nitrogen Heterocycles The synthesis of a variety of plant metabolites and analogues thereof necessitates the constaiction of nitrogen containing heterocycles. Numerous azacycles can arise through a Heck cyclization of linear amines, amides, carbamates and tosylates. o-Halo allylic phenyl amines,^ amides,^and carbam ates^ afforded indoles,indolines,^®® and quinolines^ in good yields. Similarly, a catalytic amount of Pd(0) in the presence of a base catalyzed the cyclization of halo-propenyl homoallylic sulfonamides to substituted piperidines.^^ Hegedus' original procedure^ has been improved using Jeffery’s palladium catalyst system (Equation 3 6 and 3 7).^®® The rate of the reaction at ambient temperature w as greatly increased when a phase transfer catalyst, usually nBu^NCI, was employed along with a base in the solid state, a carbonate or an acetate anion. It should be noted also that alkyl palladium complexes, generated by Heck caitopalladation of an olefin, have been trapped intramolecularly by nitrogen nucleophiles to afford pyrrolidines,^^ ^’®®pyrrolizidines,^®^ and quinolizidines.^ Pd(O A c)2, NafeCOg nBu^NCI, DMF, rt aI \ 9 7 % 8 9 (Eqn.36)^0® Pd(O A c)2, NaOgCH nBu^NCI, EtgN, DMF a 65% 9 1 (Eqn.37)106 An unusual combination of an intermolecular Heck olefination and an ortho-palladation of 1,2-diiodobenzene yielded the heterocycle 9 6 (Equation 3 8 ). The formation of indole-2- carboxylic ester 96 indicated the intermediacy of an ortho-palladated complex (9 5), originating from a second oxidative addition of Pd(0). 24 .COoBn Pd(0Ac)z(1eq) C C X s o c — NHBOC nBu^NCI, NaHCOs N DMF. 30% X a: r 'L BOC S 3 9 4 9 5 9 6 (Eqn. 38)^09 Intramolecular cyclizations of N-allyl substituted 2-bromo-l ,4-benzoquinones have been reported to give indoloquinones by Heck reactions. Rappoport described the synthesis of mitomycin analogues from 2,3-dibromo-1,4-benzoquinones (Equation 3 9).^^® In this example, the caitxipalladation evidently occurs through an endocyclization. MeO. MeO. M eCN , 97% O 97 98 (E q n .39^10 Several biologically important antimitotic agents possess the phenanthridone skeleton.A palladium promoted annulation has been used as the key step in two syntheses of these alkaloids (Equation 4 ^ The construction of the 6-lactam and the introduction of the conjugated alkene was achieved simultaneously. Analogues of the antineoplastic dimeric vinca alkaloids have also been prepared using palladium chemistry.^^ ^ Sunberg has shown that the Heck cyclization efficiently constructs 10 2, the 5,6-homologues of the iboga structure (Equation 4 1). OH kOR Pd(O A c)2, D IPH O S 'OR TlOAc, DMF, 68 % NH OR O 9 9: R=MOM 100 W =qn.40y"1 25 Pd(OAc)2, KaCOij OMe OMe nBu^NCI, DMF 89% OMe OMe Me lOliE-COgMe 102 (E q n .4 1 ^ ^ 3 Cyclization of ortho halo benzyl amides affords isoindolenones®®’®^’^®®’^^^'^^^ and isoquinolones^06,111,112,116 (Equation 4 2 to 4 4). Stereospecific construction of isoindolenone 106 is efficiently achieved with chiral induction (Equation 4 2).^^ ^ The chiral auxiliary is easily removed by reductive cleavage of the N-N a bond, to afford one enantiomer of the corresponding isoindolenone. In cases where the o-alkyl palladium species resulting from intramolecular cyclizations are not able to undergo p-elimination, trapping of the palladium complex by cartjon monoxide, or carbon-carbon double bonds, are observed. For instance, aryl iodide 103 reacts with a catalytic amount of Pd(0) to afford, after Heck cyclization, the intermediate 103a, which does not possess a p hydrogen. Under an atmosphere of carbon monoxide, complex 103a undergoes insertion of CO, followed by methanolysis, to produce ester 1 04 in 85% yield (Equation 4 3). The conversion of 1 07 to 1 08 doubly illustrates the same concept. Intramolecular carbopalladation of alkyne 107 affords an alkenyl palladium complex, which is trapped by a molecule of norbornene to yield a-alkyl complex 107a. In a subsequent step, 107a reacts intramolecularly with the exo cyclic olefin to produce cyclopropane 1 0 8 as a single isomer (Equation 4 4). Pd{OAo) 2. PPha OM e N—N KjCOa, MeCN AgNOa, OMe 8 117 1 0 5 ( ) 1 0 6 ( 8 ,8 ) (Eqn. 42) 26 IL,Pd P d C y P P h J z CO ,M eO H M eOH, CO, Tl(OAc). 85% 1 0 3 1 0 3 a (E q n .43)” ^ Me P d(0 A c)2, PPha, EtgN, MeCN, 40% 1 0 7 a 1 0 8 (Eqn.44)116 Analogous reactions of acetamide derivatives have been reported to give oxindoles.116’1^6 The lack of regioselectivity in the ^-elimination step, or double bond isomerization, have sometimes limited the value of these processes. Both TI(I)11^’H 6 and silver(l)116'1^6 salts have been used with success to improve the selectivity (equations 4 5 and 4 6). When treated with a catalytic amount of palladium diacetate, in the presence of triphenylphosphine and potassium carbonate, eneamide 10 9 was unselectively converted to a mixture of lactams (Equation 4 5). If 1.2 equivalents of thallium acetate were added to the reaction mixture, only one isomer (11 0) w as produced. Similarly, silver nitrate greatly increased the selectivity in the conversion of a,p-unsaturated amide 11 3 to pyrrolidinone 114 (Equation 4 6). PhCH Pd(OAc)2, PPhj KjCOj, MeCN 109 110 111 112 No additive: 1 1.95 4.86 TI(OAc)(1.2eq): 100 (Eqn.45) 144 27 NMe P d(0 Ac>2. PPhg BgN . M eCN 113 114 115 No additive: 1 A g N O a (1-Oeq) 26 (Eqn.45)118 Silver (I) was also found to alter the stereochemical outcome of an enatioselective Heck cyclization.11^ In 1992, Overman reported that, in the presence of R-BINAP, aryl iodide 1 1 6 underwent an asymmetric Heck cyclization (Scheme 9).H® Surprisingly, depending upon the presence of silver (I), either enantiomer could be generated with good selectivity, using a single enantiomer of the chiral diphosphine ligand (Scheme 9). In the examples studied, the enantioselection observed with the amine base was always opposite to the one observed with the silver salt. Scheme 9: Overman’s Asymmetric Heck Cyclization Me Pd(OAc)2 f^BINAP, NMP 140h, 77% M e 1 1 7 : (R)-66 % e e NMP= 1,2,2,6,6 pentamethyipiperidine Me 1 1 6 Pd(0Ac)2 A-BINAP, Ag^PO^ MeCGNMeg, 80°C 2 6 h , 81% 118: (S)-71%ee 28 In his studies directed toward getsemium alkaloids, Overman has also investigated the Heck cyclization of 2-brcmoanilide 11 9.^ He established that an intramolecular chelation of the palladium aryl intermadiate could control the stereochemistry of the coupling process (Equation 4 7). When the reaction was carried out in a “ligandless” medium, which was believed to favor the intramolecularly chelated intermediate 119a, spiroindolenone 1 2 0 was obtained selectively. Pdz(dba)3 N—SEM SEM SEM Br AgjPO^ MeOjC THF. 77% MgOjC MeOjC 1 1 9 a Br*^ 120 (Eqn.47)1203 5. Conclusion The palladium catalyzed vinylation and arylation of olefins provides a versatile and efficient method for the construction of a wide variety of complex structures. The Heck methodology is now often used in combination with other organometaliic reactions. Many extensions involve sequential coupling and trapping reactions, which allow the formation of two or more cartxDn-carbon bonds in one pot. Conditions have also been developed so that the Heck reaction can be carried out at ambient temperature. Consequently, we can predict an increase in the use of palladium catalyzed transformations in organic synthesis. Chapter II Background and Synthetic Studies B a c k g ro u n d The indole alkaloids comprise one of the largest groups of natural products. So far, over 800 kinds of indole alkaloids have been isolated, and most of their structures elucidated.^ The Strychnos type, which forms a large subset of them, includes those containing the pentacyclic 3,5-ethano-3H-pyrrolo [2,3-d] carbazole substructure, also called the curan skeleton (Figure 1 ). Strychnos alkaloids are isolated from the plant species Apocynaceae and Loganiaceae, which grow in the rain forests of Southeast Asia and India^ O O'' OM e 1 2 1 ; strychnine 1 2 2 akuammlclne 123; dehydrotublfoline hn & -N > 125: C-toxiferine I 124: Wieland-Gumlich aldehyde Figure 1: Examples of S try c h n os A lkaloids 29 30 Biogenetically, the Strychnos alkaloids derive from geissoschizine (128), the condensation product of tryptamine (126) and secologanin (127) (Scheme 1 0)J^^ Geissoschizine is recognized as an early intermediate in the syntheses of most of the indole alkaloids. Although several mechanism have been postulated to convert tetracyclic amine 1 2 Sto strychnan 130, the details of this rearrangement is stili unknown. ^ Scheme 1 0 illustrates one possible pathway. An oxidative cyclization of 1 28 furnishes the spiro polycycle 129, which rearranges by means of two successive a-bond migrations, as described in scheme 1 0. The conversion of 1 2 8 to 1 3 0 has not been accomplished in vitro. Scheme 10: Biosynthesis of S trychnos A lk alo id s .CHO CHO lOGIu A MeOgC 1 2 6 1 2 7 OH 1 2 8 1 2 9 M e O a C C H O ttV i MdOjC' ;h o 1 3 0 Strychnine (121), the most famous member of the Strychnos family, was first isolated in a pure form from the beans of Strychnos ignatti in 1818 by Pelletier and Caventou.^^'^ This isolation provided the first convincing evidence that complex nitrogenous bases can be elaborated in the vegetable kingdom. The structure of strychnine remained unknown for more than one hundred years, until the publication of the colossal work of Sir Robinson, who wrote 250 papers on the subject.^ At the same time, Leuchs and collaborators published more than 100 papers reporting their structural investigations of strychnine.^ These studies, completed before the time of NMR spectroscopy, surely represent the apogee of organic chemistry as a tool 31 to elucidate chemical structures. In 1954, Woodward reported his landmark total synthesis of “the tangled skein of atoms" which constitutes strychnine. This small assembly of atoms contains seven rings, and six contiguous chiral centers, it is remarkable-and a testimony to the complexity of its structure-that in the forty years since that feat, only one other (relay) synthesis of strychnine has been reported,^despite numerous efforts.^ The Strychnos alkaloids exhibit powerful biological activities. Akuammicine (1 2 2) sflows antitumor activity In vitro (Figure 1 C-toxiferine I (1 2 5), a dimeric alkaloid arising from the condensation of two molecules of Wieland-Gumlich aldehyde methachloride, induces muscular relaxation. Toxiferine-I has been found to be important in the treatment of tetanus, and in surgery requiring light anesthesia.^In recent years, there has been a resurgence of interest in the biological properties of strychnine.^Strychnine, which is well absorbed by mouth, is a powerful ONS stimulant, exerting its effect primarily as a potent antagonist of the hyperpolarizing effect of glycine on spinal neurons.^Small doses of strychnine sulfate (2 mg) were prescribed, at one time, as respiratory stimulant.^ Higher doses produce tonic convulsions leading to death. Strychnine shows also anticholinesterase action in vitro, but this property is not believed to be the basis of its action in vivo.^^®^ In modern medicine. Strychnine has become obsolete, because of its toxicity. The fatal dose for human is approximately 60 to 90 mg, although death has been reported with doses as small as 15 mg.^^®*^ Nowadays, some of strychnine’s actions are duplicated by less potent drugs such as morphine, thebaine, codeine, or brucine. Synthetic Studies The early works on the chemistry of Strychnos alkaloids has been reviewed by Smith.^^^® More recent reviews have summarized later accomplishments in the field.^^^^'^ This section reviews several representative strategies for the synthesis of strychnine, and this general class of alkaloids. 32 To illustrate the nature of the problems that synthetic chemists are facing with the Strychnos family, I would like to start by analyzing the architecture of strychnine. Although a relatively small assembly of atoms (25 atoms), strychnine possesses an intricate architecture (Figure 1 ). It contains seven intertwined rings, among which are several different heterocycles . At the center of the molecule, in ring C, are five contiguous chiral centers. In addition, ring C is connected to ring E through a [3,3,1] bridged-bicycle arrangement, arguably the most challenging structural feature of the Strychnos alkaloids. Another distinguishing structural feature is the C.|g-C 2o double bond exocyclic to ring E, which has an E geometry. The geometry of this alkene has been proven to be difficult to control in synthesis. Indeed, Woodward as well as Magnus introduced this component by low yielding and non-stereoselective processes (vide infra). Since Robinson^has converted 1 2 4 into strychnine by treatment with CH 2(C0 2 H)2 , NaOAc and AC2O (equation 4 8 ), the constaiction of rings F and G does not represent a synthetic challenge. Most of the synthetic efforts have therefore been directed toward the elaboration of the ABODE ring system, which is present in all the members of the Strychnos family. In this survey of the literature, emphasis will be given on the elaboration of this pentacyclic unit. -N> CH2(CCfeH)2 - NaOAc, Ac<^ H "A " CHgOH u " HO' 124: Wieland-Gumlich aldehyde 1 2 1 : strychnine (E q n .48) 1- Woodward's Synthesis of Strychnine The first and for a long time only total synthesis of strychnine was reported by Woodward and collaborators.^^® After confirmation of Robinson’s structure by two separate X-ray crystallographic investigations, Woodward decided to undertake a total synthesis of the molecule which was considered, at that time, as "the most complex substance known ". Woodward's 33 achievement remains today a major victory of organic synthesis. His starting material, 2-veratrylindole (1 31) (available in one step from phenylhydrazine and acetoveratrone), was converted to the spirocyclic muconic ester 132 in 9 steps (Scheme 11 ). A Mannich procedure was used to elatx>rate the tryptamine derivative of 1 3 1 , which was converted to a Schiff base by condensation with ethyl glyoxalate. A novel iminium ion induced cyclization, constructing the pyrrolidine ring, was promoted by the action of tosyl chloride. Finally, ozonolysis of the dimethoxy benzene provided the muconic ester 132 in a selective transformation, albeit in modest yield (29%). The dimethoxy phenyl substituent in 131 served two purposes. First, it blocked the a position of the indole nucleus toward electrophilic substitution. Elaboration of the spiro-fused pyrrolidine unit required disubsitution on the p site. Secondly, the veratryl group was selectively ozonolyzed to give the unsaturated diester 1 3 2, a good precursor for ring G of strychnine. Upon acidic treatment (HCI, MeOH), 1 3 2 was converted to a six-membered lactam, which isomerized to the aromatic tautomer 133. The formation of an alternative five-membered lactam would have necessitated the cyclization of the trans ester in 132. Vigorous hydrolysis of the sulfonamide (HI, red P), followed by acétylation (AcgO, Py) led to a diester which possessed a doubly activated methylene, suitable for Dieckman condensation (MeONa, MeOH). The conversion of 1 3 2 to the pentacyclic keto-ester 1 3 4 was thus accomplished efficiently in only four steps. Generation of the benzyl thioether (TsCI in pyridine, then PhSNa in methanol), followed by reduction (RaNi, then H 2/Pd/C) and hydrolysis (aqueous KOH in methanol) yielded the trans acid 1 3 5 . With the preparation of 1 35, the authors had reached their first relay point. Indeed, trans acid 135 was prepared on large scales from strychnine, by chemical degradation. When this acid was treated with acetic anhydride in pyridine, it was converted to an enol acetate which, after hydrolysis to the ketone and oxidation by selenium dioxide, provided the hexacycle 136 (second relay point). This sequence of transformations installed the bridged cycle E in a very elegant way. 34 The synthesis was carried on by addition of sodium acetylide, hydrogenation over Lindlar catalyst, reduction with LiAIH^, and acid promoted isomerization (HBr, AcOH) of the tertiary alcohol 1 3 7 . Unfortunately, the geometry of the exo-cyclic olefin in 1 3 8 could not be controlled. When the hydrochloride salt of carbinol 1 37 was heated to 120 °C, in a sealed tube, with 30% HBr, a complex mixture of tertiary amines was obtained. Careful purification by chromatography on neutral alumina, followed by recrystallization from methanol afforded isostrychnine (1 3 8 ) in 12% yield. The side products were not fully characterized. Finally, isostrychnine was converted to strychnine by treatment with ethanolic KOH. Woodward’s exceptional synthesis required 29 steps with two relay points, and proceeded in about 10'® % yield. Each ring of strychnine (beside the indole nucleus) was constructed successively, using transformations that illustrate the best in the art of organic synthesis. Scheme 11: Woodward's Synthesis of Strychnine NTs NCOMe COjMe a-g h-k COgMe Ac 1 3 2 1 3 3 NCOMe NCOMe OH q-r m-p 'COOH CCjMe 1 3 6 1 3 5 1 3 4 S4 Strychnine •OH HO 1 3 7 1 3 8 a) HOHO, MejNH, AcOH, (lioxane; then Mel; b) NaCN, DMF; c) UAIH4 THF; d) ethyl glyoxylate, PhH; e) TsCI, Py; f) NaBHa, EtOH g) AcjO, Py: h) O j. AcOH; I) HCI, MeOH; j) HI, P; k) HCI. MeOH; then A%0; I) MeONa. MeOH; m) TsCI. Py; n) PhSNa. MeOH 0) RaNi. BOH; then Hz. PdÆ; p) KOH. MeOH; q) AczO. Py; then H a. HzO; r) SeOz. BOH; s) NaCCH. THF; t)Hz. Pd/BaSO<, quinoline; u) LiAIH^. Et^O; v) HBr. AcOH; w) KOH. BOH. 35 In 1992, Magnus^ reported the second total synthesis of strychnine (Scheme 1 2). His starting point, amine 139, is obtained by condensation of tryptamine with 5-chIoro-4-keto- methyl pentanoate. In the first step, 13 9 is treated with a,a,a-trich!oroethyl chloroformate to give a ring-expended compound, carbamate 140. A ten-step standard procedure converts carbamate 1 40 to tetracyclic lactam 141, which yields strychnan 14 2, upon treatment with Hq(0 Ac)2 in acetic acid. This biomimetic cyclization is surprisingly selective. Oxidation of the tertiary amine ini 41 could possibly give rise to three iminium cations. Fortunately, the desired cation appears to be the least strained of the three; It is endocyclic to both the six and the nine membered ring. Formation of the iminium cation leading to strychnan 142 is thus favored. In addition, this cyclization is stereospecific with regard to the C-D ring junction (thermodynamic product). Scheme 12: Magnus’ Synthesis of Strychnine COgCH^CCI] H Î H 1 4 0 "M a O jC 141 . COgMe u I H 142 " COgMe OSiPrj OSiPr Strychnine H C H jO S iR a a) TrocClyCHjClj; b ) NaOfvte/NeOH: c)CICO,Me. NaOH, PTC, OUCU; d ) Zn, THF, AcOH: e) PhSCHjCOjH, BOPCI, E I 3 N . CHjOt: I) MCPBA, CH2Cl2 :g) NaH, THF;h ) TFAA, DBMP; I) H g O ,% P :|) BtCr^CHjOH, DBU, toluene; kfBHj.THF; IjNagCOg, MeOH; m) HgtOAcfe, AcOH;n)Zn, H2SO 4, MeOH; o) NaOMe, M eOH;p) TsCI, ElNiPr;, CHjClj; q) LIBH4, THF, HNCCHjCHpHja; r) HCIO/ s) (ElO),POCHjCN, KHMDS, THF; I ) DIBAL, O H ,O k then NaBH ,, MeOH; u) HCI, MeOH; v) TBDMSOTt, DBU, CHjClj; w ) SOj.Py, DMSO, E I 3 N ; x ) HF, Py; y) Na, anirhracenlde, DME;z ) C I-yC O jH jj, NaOAc, AcgO, 36 Six subsequent chemical manipulations provide the cyclic ketone 143, set up for the step intended to introduce the key exocyclic olefin. When ketone 143 is treated with (EtO)2POCH2 CN and base, the wittig adduct 1 4 4 is obtained in good yield (72%), but low selectivity (3:2 mixture of E,Zisomers). This step can be considered as the main drawback in Magnus' otherwise elegant strategy. Separation of the stereoisomers, followed by reduction of the nitrile (DIBAL-H, NaBH^), and deprotection (HgO'*'), yields diol 145, which can be converted to strychnine in 6 steps via the Wieland Gumlich aldehyde (1 46). This synthesis involves 29 steps and proceeds in about 10'^ % overall yield. Magnus' approach to strychnine does not address the critical issue of the selective introduction of the exocyclic double bond. 3- Svnthetic Approaches Based o n the Biomimetic Cyclization of a Stemmadenine Intermediate In scheme 1 0, is described the biochemical pathway by which the alkaloids of the S/rychnos family are synthesized in the plant kingdom. As mentioned earlier, in vitro experiments have, so far, failed to imitate this pathway. Yet, Magnus and others^ are describing their approaches as biomimetic syntheses. They are referring to an alternative biochemical pathway, which allows the conversion of stemmadenine alkaloids to Strychnos (Scheme 1 3). The stemmadenine (151) group of alkaloids are distinguished from the Strychnos group by the absence of the C 7-C3 bond^^S. Biochemical transformation of medium-sized ring 148 to akuammicine (1 2 2), or condylocarpine (147), occurs by enzymatic oxidation, via iminium compounds 1 5 0, or 1 4 9. Scheme 13: Biochemical Conversion Stemmadenlne-Strychnos COjMe CQaMe 147: condylocarpine ^ R COzMo 1 4 8 : R=H 151:R=CH20H COzMe H COzMe ISO 122: akuammicine 37 Magnus’ synthesis of strychnine evidently includes a biomimetic step, the transannular cyclization of amine 141 to pentacycle 142 (vide supra). This transannular ring formation was used earlier by other groups.^ Hariey-Masson, first, investigated this chemistry and developed a general strategy toward the pentacyclic Strychnos alkaloids (Scheme 1 4)."* His total syntheses of dehydrotubifoline and condifoline are summarized here. Lithium aluminum hydride reduction of lactam 15 2, obtained from the condensation of tryptamine and a-ketoglutaric acid, afforded the rearranged base 153. A ring expansion induced by 2,2’-dichlorobutyric anhydride yielded the versatile nine membered ring 154. Selective hydrolysis of the ester (cold NaOH), followed by oxidation (Mn 0 2 ), afforded the corresponding ketone, which was treated with sodium t-amyloxide in benzene to give, after Wolff-Kichner reduction, lactam 1 5 5 as a single isomer (thermodynamic control). A mixture of tubifoline (156) and condyfoline (157) was then generated by aerial oxidation over platinum oxide. Scheme 14: Harley-Mason’s Syntheses of Tubifoline and Condyfoline UAIH. (RCO)P R-C2H5CHCI OR 152 154 1-cold NaOH. HgO a-MnOg 3- tamylONa, PhH 4- N2H4, KOH 1-LIAIK 2-0 , PtO. 157: Condyfoline 156: Tubifoline 155 38 Both Ban^ and Takano^ have developed their own methodology to elaborate the nine membered ring. Ban took advantage of a novel photoisomerization of 1-acylindoles. When a solution of amide 1 5 8 in methanol was irradiated for a day, lactam 159, a possible precursor in the synthesis of stemmadenine, was obtained in good yield. The mechanism of this unusual transformation is depicted in scheme 1 5. Keto-indolenine 158a, the first intermediate, arises through the anticipated 1,3 caribonyl shift, in a second step, intramolecular addition of the primary amine to the ketone affords mixed-hemiketal 158 b, which collapses by retro-aldol condensation to give product 15 9. The regeneration of the indole nucleus drives this isomerization reaction toward product formation. Scheme 15: Ban’s Approach to Stemmadenine NHg NH. MeOH 158 158a 1 5 8 b 159 Takano's biomimetic approach^ to dehydrotubifoline (123) illustrates two key transformations: a reductive ring cleavage that constructs the nine-membered heterocycle 165, and a thioclaisen rearrangement that selectively introduces the 19-20(£) exocyclic double bond (Scheme 16). The synthesis begins with thiolactam 160 which reacts with methyl-y- bromocrotonate to give iminium salt 161. Sodium methoxide promotes transformation to the thioaminoketene, and subsequent [3,3] sigmatropic shift, affords the (£) o,p-unsaturated ester 162 in good yield. Bischler-Napieralski cyclization yields a quaternary iminium salt which is reduced to amine 163 with NaBH^. Ammonium salt 164 is obtained by intramolecular displacement of an allylic tosylate. The key ring cleavage (1 6 4—>1 65) is then achieved using sodium metal in liquid ammonia. Oxidation of 1 6 5 with mCPBA yieids an N-oxide which, when 39 submitted to the Polonovsky-Potier reaction, furnishes dehydrotubifoline in a selective manner. The formation of the alternative isomer 1 6 6 is not observed. Scheme 16: Takano’sSynthesIs of Dehydrotubifoline M 0 O2C Br 1-NaOMe H 2 - [3,3 1 6 0 1 61 r COjMe COaMe 1-POCI3 2-NaBK, Na. NH, 1-DBAL-H 2-TsCI COgMe 1-mCPBA 2-TFAA 123: dohydrotublfollne 166: dohydrocondyfollns Kim’s synthetic approach^ involves a series of inter- and intramolecular conjugate additions (Scheme 1 7). The stereoselective construction of the tricyclic ester 172 started from N-phenacyl amide (167). Robinson annulation directly afforded the cyclohexenone 16 8 which, after amide hydrolysis and cartxjethoxyacetylation under Schotten-Baumann condition provided enone 169. The intramolecular Michael adduct was generated upon treatment with NaH in refluxing THF, and converted to the lactam 170 by saponification and decarboxylation. Reduction of the amide, alkylation with propargyi bromide, carbométhoxylation and deprotection gave the keto ester 171, ready to undergo another intramolecular Michael addition. When conjugated alkyne 171 was treated with Triton B in DME at -20°C, tricycle 1 72 was isolated. 40 None of the desired exo-cyclic olefin isomer was produced, because complete isomerization of the double tx^nd occurred after ring closure. Scheme 17: Kim’s Approach to Strychnine 1-EtjO*, NaHCOj: MVK, EtONa then HOAc. NHAc EtOH, 88% 2-CICOCHjCC^Et COgEt NHAc Ph 1 6 7 1 6 8 1 6 0 1- NaH. THF 2-PTSA, (CHjOHfc M eO gC . 3-NaOH, MeOH 4-UI, diglyme MeOjC H I-UAIH 4 Triton B Z-CaHaBr DME 3-LDA, CICOaMe \ A I Ph 4-PTSA, acetone ph 1 7 2 1 7 1 1 7 0 6- MoJIhardt's Approach to Strychnine A cobalt mediated [2+2+2] cycloaddition is the basis for Vollhardt’s strategy^ (Scheme 1 8 ). The reaction of the substituted tryptamine 1 73 with trimethylsilyl-methoxyacetylene in the presence of cyclopentadienylcobalt dicarbonyl efficiently generated the tetracyle 174. This tetracycle was cleanly converted to the propellane derivative 1 7 5 upon treatment with ferricinium ion (Cp 2pe'^PFg']. Upon investigating conditions for the décomplexation of propellane diene 17 5, Vollhardt and co-workers made a striking discovery. The standard oxidative demetalation [CUCI2 , EtgN, DME-H2O] of 175 provided, not only the expected “ligand-free diene" 1 76 (4% yield), but also the pentacycle 177 (82% yield), an advanced intermediate toward strychnine. CUCI 2 also promoted direct conversion of 17 4 toi 77, but in an unspecified yield. 41 Scheme 18: Vollhardt’s Approach to Strychnine NHBn NHBn .OMe .OMe MgjSI—1— —OMa CpzFsVFs- C p C o (C O ) 2 , A 'CoCp NBn 1 7 3 174 • CuClz'HgO 1 7 5 ■ no yield reported NBn .OMe .OMe NBn 1 7 7 1 7 6 20 7- Overman’s Total Synthesis of Dehydrotubifoline Overman and co-workers^accomplished a total synthesis of dehydrotubifoline^^^® (1 23), a potential Intermediate In the synthesis of other members of the Strychnos family. The strychnan skeleton was constructed by an “aza-Cope-Mannlch” rearrangement of the 2- azabicylo[3.2.1 ]octane 179 (Scheme 1 9). The required piperidine moiety was Introduced by amlnolysis of chloro-epoxlde 178, obtained from 2-cyclopentenone In nine steps. Although direct amlnolysis of 178 with ammonia was not clean, the sodium salt of trifluoroacetamlde efficiently displaced the allylic chloride and ring-opened the epoxide. In one step, to provide piperidine 179 In fair yield. The cIs stereochemical relationship, between the styrene substituent and the amine, resulted from trans opening of the epoxide. This stereochemistry was required In order to put the styrene double bond and the nitrogen atom In close proximity. The key rearrangement, whose mechanism Is depicted In scheme 1 9, was triggered by condensation with formaldehyde. Hydrolysis of amide 180, then, provided dehydrotubifoline In 70% yield. The synthesis of dehydrotubifoline was accomplished In 12 steps from 2-cyclopentenone v;lth a 6 % overall yield. 42 Scheme 19: Overman’s Synthesis of Dehydrotubifoline 1-CFjCONHNa HOHO, H HO' RNH 2-KOH ,NHR ,NHR ,a 178;R-COtBu 1 7 8 [3.3] KOH, EtOH H,0 HO' RHN, ■NHR 1 2 3 1 8 0 The original approach of Kraus^ relies upon an intramolecular Diels-Alder reaction of 3-alkenylindole 182. His analysis is illustrated in scheme 2 0. The tetracyclic silyl enol ether 181 underwent a Lewis acid promoted alkylation, followed by ozonolysis of the terminal alkene, to afford keto aldehyde 133, which served as a key intermediate for subsequent elaboration. The sequence that converted 183 to 184 features a Sakurai reaction. Keto iodide 184 was condensed with ammonia to afford a cyclic imine, which was reduced to a pyrrolidine unit with sodium cyanoborohydride. Conversion to the Strychnos skeleton (186) was then achieved by ozonolysis of the double t)ond, followed by intramolecular condensation of the aldehyde with the pyrrolidine nitrogen. Hexacycle 186 contains functional groups that may allow Kraus and co workers to complete a total synthesis of strychnine. Implementation of the last ring will require further manipulation of the enamine double bond. It is worth noting that structural constraints in molecule 186 prevent a good overlap between the amine lone pair and the carbon-carbon double bond (not a true enamine). The construction of ring F of strychnine may not be therefore easily achieved by taking advantage of enamine chemistry. 43 Scheme 20: Kraus’ Approach to Strychnine OTMS OTMS » 121 1 8 1 1 8 2 a-e 1 6 4 a) nBu^NBHaCN. HgSO*. HMPA: b) TBDMSCI, Imidazole; c) TMSI, HMDS; then Pd(OAc)2 ; d) TMSCH2 CH=CH 2. TICU; e) TMSI; f) NH3 , CHjClz; g) NaBt^CN; h) O3 , MeOH. CH jC t; then Me^S, NazC0 3 , MeOH During the last ten years, Bosch and al. have intensively explored new strategies for the synthesis of pentacyclic Strychnos alkaloids. A series of papers summarizes their accomplishment in this field.They have reported two total syntheses of tubifolidine (1 9 4 ).'l393 >b Their first strategy is based upon the introduction of the pyrrolidine moiety at the end of the synthesis. I have chosen, here, to present their second approach,^w hich differs significantly from the first one. The crucial step of this synthesis involves the closure of the piperidine ring by an intramolecular Michael addition (Scheme 2 1). Bosch's starting material, p- diketone 187 (available in one step from 1,3-cyclohexadiene and o-fluoro-nitrobenzene), is treated with allyl bromide, to afford an allyl vinyl ether which undergoes a claisen rearrangement, followed by ozonolysis of the double bond, to yield dicarbonyl compound 188. Double reductive amination of 1 8 8 (MeNHgCI, MeOH, then NaBHgCN) provides octahydro-indolone 1 8 9 as a single stereoisomer. Conversion to the chloroethyl carbamate, followed by selenium promoted oxidation, gives enone 1 90 in 50% yield. At this stage, the author decided to introduce the piperidine ring. Standard deprotection of the pyrrolidine nitrogen, and 44 condensation with vinyl methyl ketone efficiently generate diketone 191, the anticipated precursor for the Michael addition. The base catalyzed cyclization is promoted by (H)-a- methylbenzylamine and molecular sieves. The tricycle 192 is isolated as a 4:1 mixture of the natural isomer (shown in scheme 2 1), and its epimer at the newly constructed chiral center. In order to complete their synthesis, the author needed to selectively reduce the exo-cyclic carbonyl. At ambient temperature, only one ketone reacts with ethanedithiol to give 19 3, which is directly reduced to tubifolidine (19 4) upon treatment with tributyltin hydride. This elegant step involves simultaneous desulfurization of the thioketal, reduction of the aryl nitro compound, and indoline ring closure. Scheme 21: Bosch’s Second Synthesis of Uibifolldine CH. CHOo 0 , N O 1 8 7 188 1 8 9 j o - i ^COjCHCICHa 0,N O OoN O 0 , N O 1 9 0 0 , N O H H H 194: tubifolidine a) BrCHgCH^CHg, KgCOa, acetone; b) toluene, ISO-C; cjOg, GHjClg; d) MeNHgCI, NaBHgCN, MeOH; e) GICOgCHCIGHa, GHjGIGHjGI; f) TMSI, HMDS, GH2 Gl2 ;g) PhSeGI, (PhSe)g, THF; h) O3 , IPfjNH, GHgGIg; i) MeOH, reflux; j) MVK, EigN, MeOH; k) {/?)-a-methylbenzylamine, 3- MS, THF; I) (HSGHjjg, AcOH; m) nBUgSnH, AIBN, PhH. 45 9- S yntheses O f TubQtaiwineand19-hvdrQxvtubotaiwine Tubotaiwine (1 9 5), as well as condylocarpine (structure 147 in scheme 1 3), belongs to a second type of Strychnos alkaloids. In the strychnan type (strychnine), a two-caiton side chain is connected to C 20. whereas in the condylocarpine type, it is connected to 4. The two types are, however, closely related, because they embody the same pentacyclic framework. To complete this survey of the literature, I would like to discuss two syntheses of condylocarpine like structures: kuehne’s synthesis of Tubotaiwine, and Vercauteren’s synthesis of 19- hydroxytubotaiwine. Scheme 22: Kuehne’s Synthesis of TUbotaiwlne NCH jPh M eCH O PhCHgBr 1 9 6 COMe 1 9 7 C O ,M e y — NH NCHgPh NCHgPh 1-H j, Pd 2 -(tBu0C0)20 NaBHL ^ COÜ- 3-tBuOCI, EtjN AcOH ^ 4 -T F A 201 " COjMe 2 0 0 " CO,Me 1 9 9 C O p M e n P rC H O [4 + 2 ] 4 2 0 L 202 OO2M0 ^ 1 9 5 0 0 2 ^ 6 Indoloazepine 196 (Scheme 2 2), the starting point of Kuehne’s synthesis,^is condensed with acetaldehyde to afford amine 197 as one diastereoisomer. In the next step, the tetracyclic amine 1 99 is obtained through a novel intramolecular cycloaddition. Triene 19 8 , generated in situ from 197 (PhCH 2Br, EtgN), cyclizes spontaneously and stereospecifically at 46 room temperature to afford tetracycle 199. Then, reductive cleavage of the benzylic carbon- cait>on bond (sodium Isorohydride, acetic acid) cleanly provides nine-membered ring 2 0 0, which is elaborated by familiar methods to the unsaturated ester 2 01. Condensation with butyraldéhyde gives 2 0 2, which spontaneously and stereospecifically isomerizes to 195 by means of an inverse-elect non-demand Diels-Alder reaction. Scheme 23: Vercauteren’s Synthesis of 19-Hydroxytubotalwlne ^CHgPh > O C H 0 'o o [4+2] OgMs COgMe COjMe 2 0 3 2 0 4 2 0 5 1-separatlon 1-MeLI 2-H , Pd/C 3-NaOMe MeOH 2 0 8 2 0 7 2 0 6 Lawesson reagent f? OH OH RaNi 19-hydroxytubotalwlne CCoMe 2 0 9 210 Vercauteren and co-worl (21 0), with the aim of establishing the stereochemistry of the naturally occurring isomer. Their key step involved a "Kuehene type" intramolecular Diels-Alder cycloaddition of enamine 204, generated in situ from ester 2 03 (Scheme 2 3). Deprotection of the ketone function (HgO/BFg) and reduction (NaBH^) afforded two diastereoisomeric alcohols (2 06), which were separated by crystallization from ethanol. The structures of the two epimeric alcohols were determined by X-ray 47 crystallographic analysis. After deprotection of the pyrrolidine nitrogen (H 2, Pd/C), the pentacyclic lactam 2 07 was obtained by treatment with sodium methoxide in methanol. Conversion to the methyl ketone (MeLi), followed by selenium dioxide oxidation, led directly to the formation of the bridging ring (2 08). Excess Lawesson reagent afforded the bis-thiocaitonyl compound 2 09, which was desulfurized by Raney nickel to yield 19-hydroxytubotaiwine (21 0). 11. Conclusion Having analyzed the synthetic efforts described atx)ve, one can recognize the complex and challenging features present in the Strychnos alkaloids: a) a spiro-fused pyrrolidine moiety, b) a 2-aza-bicyclo[3.3.1]nonane subunit, c) an exocyclic double bond of defined geometry (E), and d) a cyclohexyl ring, almost fully substituted, bearing 3 to 6 contiguous chiral centers. The following chapters of this dissertation will expose our synthetic strategy toward the Strychnos alkaloids. Chapter III will report our retrosynthetic analysis of strychnine as well as preliminary studies. Chapter IV will describe our total synthesis of dehydrotubifoline, a pentacyclic Strychnos alkaloid, potential intermediate toward other strychnans. Chapter III: Retrosynthetic Analysis and Model Studies I Synthetic Strategy In 1989, we initiated a research program directed toward the synthesis of strychnine. Despite numerous efforts (chapter II), the total synthesis of strychnine had been completed only twice in almost fifty years.^ Such a compact molecule represents a target of choice for those who wish to develop new routes to complex carbo- and heterocycles. The strategy that we are investigating differs significantly from those explored previously or under study. Our route has been designed with two goals: to complete the target in very few steps, and to control the stereocenters. The route described in our retrosynthetic analysis nicely supports these two goals. This retrosynthetic analysis is depicted in Scheme 24 and shows, first, that the two bottom rings of strychnine do not represent a real problem. Ring F of strychnine should be obtained by an intramolecular Michael addition of the alcohol derivative 2 11. Indeed, it has already been established that the action of a base (KOH, EtOH) on isostrychnine (1 3 8 ) promotes the closure of the seven-membered cyclic ether, via intermediate 2 11 (Equation 49a).^^®^ This transformation generates stereospecifically the two asymmetric centers at C^g and y, as the other configurations would be impossibly strained. Thus, because g in 2 11 is an epimerizable center, thermodynamic control will drive the formation of the natural stereoisomer (1 2 1 ). KOH BOH OH OH 138 211 121 (Eqn.49a)’'26b 48 49 Scheme 24: Retrosynthetic Analysis of Strychnine 1 9 20 .18 1 6 \ < = > ■22 2 3 OH 121: strychnine 211 CHO OR 212 route A route B NR. 214 213 NR. 216 215 NR, 217 50 The second disconnection (C2 2 -C-| 7 ) illustrates that ring G could be constructed by an intramolecular aldol condensation between the aldehyde and the acetamide moiety. Robinson et al. have already realized that transformation. They have demonstrated that epimerization of the aldehyde is not an Issue, since only one epimer can afford the cyclic vinyl amide (Equation 4 9 b). 'N V ^ ____ _ CHoOR CHoOR Our efforts were thus directed toward the construction of the ABODE ring system (212), which Is common to all the members of the strychnos family. The first key disconnection Is the cleavage of the axially oriented C 20—C -|5 bond to give the vinylic precursors 213 (route B) or 216 (route A). Various nucleophilic organometallic species can be considered to construct this bond. We examined the use of the Heck reaction to accomplish this fx)nd formation, since this process has been employed with success in synthesis (see chapter I). The transformation can be described as a 6-exo-trig cyclization, a process which is allowed by Baldwin’s rules.^'^^^ This strategy addresses the delicate problem of the g—C 20 double bond geometry, because the Heck cyclization Is expected to take place with retention of the double bond configuration. Indeed, isomer Eand Zshould be obtainable, at will, by a Heck coupling process. One will need to prepare the corresponding vinyl halide Isomer. It Is an important issue, since a new type of strychnos alkaloids, possessing a ( 2) exocyclic olefin, was recently isolated from the leaves of Rhazyastricta}^^^ In addition, the intramolecular Heck reaction will allow us to control the stereochemistry at C., 5. Two routes to pentacycle 212 were envisioned (Scheme 2 4). Route A would involve the intramolecular Heck cyclization onto a simple bicyclic precursor (21 6). We felt that, in a subsequent step, an intramolecular Michael addition of the aniline nitrogen In 2 1 4 would allow us 51 to close the indoline ring. Route B involves the formation of the key C 20— bond from a tetracyclic precursor (21 3), In which the Indole nucleus is already incorporated. Conveniently, both 2 1 3 and 21 6 could be obtained from the same starting material, p-aryl pynroline 217, by Diels-Alder cycloadditions. II Model Studies Directed Toward the Construction of Rings C and E 1- Nature of the Problem In order to confirm the viability of our strategy, we carried out extensive model studies. The key step in our strategy involves the formation of the bridged bicyclic C-E ring system by an intramolecular Heck reaction, a process which has been used with much success in organic synthesis (chapter I). In the present case, the strategic carbon-carbon bond formation was expected to be facilitated by the axial orientation of (see the three dimensional structure in Schem e 2 4). To test this hypothesis, we prepared model compound 218, which embodies the characteristic trans arrangement between the nitrogen side chain and the aryl substituent. Ts^ 218 Although the formation of fused bicycles by Heck cyclization has been extensively studied (chapter I), the construction of bridged polycycles has not received much attention. Our first objective was thus to investigate the Heck cyclization capability of model compound 218. The Heck reaction of 2 1 8 can, in principal, proceed in two ways (Scheme 2 5). Coupling at the a carbon (endo process) should produce the desired bicycle, 2 2 4, while coupling at the p carbon (exo process) should afford the bicyclo[3.2.2]nonane isomer, 2 2 5. Inspection of molecular 52 models does not suggest any obvious preference for one path over the other. A further potential complication is also illustrated in Scheme 2 5. The palladium promoted cyclization involves the formation of an intramolecular chelate (223), a process which requires a conformational isomerization (diequatorial —> diaxial) prior to caiton-carbon bond formation. In systems where coordination of the olefinic partner is slow,^ reduction of the a-alkyl palladium complex is a competing side reaction. Therefore, the success of this approach depends on the relative rates of chelate formation (conformational interconversion) and of o-palladium complex reduction. Scheme 25: Reglochemistry of the Coupling Process: Endo vs Exo L e n d o I Br— Pd-L 2 2 4 " 2-aza-blcyclo[3.3.1]nonane B r—P d - L I H 2 2 3 2 2 5 2-aza-bicyclo[3.2.2]nonane We also examined the cyclization of several related vinyl halides (Figure 2). The stereoisomeric vinyl iodides 219 and 2 20 were prepared in order to investigate the stereochemical outcome of the reaction. We have also studied the effect of substitution on the endocyclic olefin (2 21 ), and the effect of an amino substituent in the ortho position of the phenyl ring (2 2 2), because this substitution pattern is required for strychnine synthesis. 53 'NHj 221 2 2 2 : R= (CH2>2S02ph Figure 2: Model Compounds for the Heck Cyclization 2- Results and Discussion The required vinyl bromide 218 was prepared as outlined in Scheme 2 6. Diels-Alder cycloaddition of p-nitrostyrene (2 2 6) with 1,3-butadiene (toluene, 140°C) afforded the trans-nWro cyclohexene 2 2 We considered several conditions for the reduction of the aliphatic nitro group,and found that this transformation could be effected under mild conditions using aluminum amalgam in THF/H 2 0 .^^^® Under these conditions, the carbon-carbon double bond was not reduced. The reaction was very reproducible and was not sensitive to the exact details of the preparation of the amalgam. In a typical experiment, AI(Hg) was prepared by successive treatment of aluminum foil with aqueous potassium hydroxide, 0.5% aqueous HgCl 2, water and THF, and was added fresh to a THF/H 2O solution of nitro cyclohexene 2 2 7. The reduction took place cleanly, and the polar primary amine 228 was obtained chromatographically homogeneous, simply after filtration and concentration. Primary amine 228 was converted directly to the sulfonamide 2 2 9, upon treatment with TsCI, triethylamine and a catalytic amount of the acylating catalyst DMAP. Attempted alkylation with 2,3-dibromopropene using standard conditions (NaH or KH, THF) met failure (low yields). On the other hand, the desired alkylation was efficiently achieved by phase transfer catalysis.^W hen a benzene solution of sulfonamide 2 29 was treated with 50% sodium hydroxide, 2,3-dibromopropene, and tetrabutylammonium bisulfate, vinyl bromide 21 8 was obtained in 92% yield. 54 Scheme 26: Preparation of Vinyl Bromide 218 NO; NHg toluene, 140°C C r t ) 85% 226 2 2 7 2 2 8 TsCI, E^N DMAP. Ct^Clj 64% (from 227) Br > nSUtNHS04 ( X ô 50% NaOH C r% 2 1 3 PhH. 92% 229 With 218 in hand, we were ready to test our first intramolecular Heck coupling reaction. The traditional Heck reaction calls for the use of a Pd(ll) species [Pd( 0 Ac)2, PdCl2 (RCN)2 or PdCl2(PPhg) 2], a triarylphosphine (or phosphite) and a tertiary amine base. The active Pd(0) catalyst is generated in situ; the detailed mechanism of the initial reduction of Pd(ll) to Pd(0) has not been established. Although a number of pathways are conceivable, one possibility for generating the Pd(0) is depicted in Equation 5 0.^ It involves a 1,2-addition of palladium diacetate onto the vinyl halide double bond, followed by ^-elimination of HPd(OAc). Other possibilities include oxidation of the base and/or the ligand.^ Recently, some evidence suggests that formation of zerovalent palladium from a mixture of Pd( 0 Ac)2 and tripheny lphosphine takes place with concomitant generation of triphenylphosphine oxide (Scheme 2 7).® 1,2 P-Eliminallon Pd(0Ac)2 AcOmÿ ^ B r [ PdH(OAc) j Pd(0) 1,2addHfon ac O Pd(OAc) Pd(0Ac) A AcOH (Eqn.50)^ 55 Scheme 27: Reduction of Pd(0Ac)2 by PPhg P h jP OAc PhjP A cO \ 2 PPh 3^ Pd(O A c)2 A ' J P d(0) fast slow A cO P P h , PPha ■O. PhoP+—OAc + AcO’ 0 =PPh 3 — A c fi o In the actual cyclization, treatment of vinyl bromide 218 with 15 mol% of palladium diacetate, 45 mol% of triphenylphosphine, and two equivalents of triethylamine, in acetonitrile at reflux for 3 h, afforded a single bicycle in 85% yield (Scheme 2 8 ). The structure of the cyclization product was determined to be the 2-aza-bicyclo[3.3.1]nonane 2 30 through extensive spectroscopic studies. In particular, NfyiR decoupling experiments (Figure 3) confirmed the structure: the methyne proton positioned a to the sulfonamide (H 4 ), which resonates at 4.10 ppm, was shown to be coupled to protons at 1.40 and 1.70 ppm, and not to an ethylenic proton. This observation ruled out structure 2 31. Other correlations also were consistent with our assignment (Figure 3). In addition, it should be noted that the Heck cyclization proceeded to afford bicycle 230, and none of the isomeric product where the double loond had moved into conjugation with the aromatic ring. Scheme 28: Heck Cyclization of Vinyl Bromide 218 Ts„ TSv Br Pd(0Ac)2, PPh: B 3 N . MeCN ( A i e 2 1 8 85% syn addition Ts^ Ts, syn elimination — HPdBr CrMi 230 2 3 1 PdBr 56 proton 6 (ppm ) coupled to: T s Hi+Hj 1 .4 0 + 1 .7 7 H gand H4 6,7 Ha 2 .9 6 Hy.H, and Hj v e rsu s H5 , H ,a n d Hg H4 4 .1 0 Hs 3.61 H ^and Hg 5 .8 8 H ^and Hg 2 3 1 2 3 0 He Hy 5 .9 8 H g a n d H3 F igure 3: 6-Exo versus 7-Endo Cyclization Having demonstrated that the Heck cyclization was proceeding with the desired regiochemistry, we next investigated the stereochemical outcome of this transformation. We prepared the the two stereoisomeric vinyl iodides 219 and 22 0 by phase transfer alkylation of sulfonamide 229 (Scheme 2 9). The necessary alkylating agents, tosylates 2 38 and 2 39 were generated under standard conditions from the corresponding alcohols and were used without purification. Scheme 29: Syntheses of Vinyl Iodides 219 and 220 O T s 2 2 9 O T s n B u ^ N H S O ,, 5 0 % N a O H 2 3 9 b e n z e n e Ts, 219 220 57 The known alcohols 234^^® and 237^^® were prepared by hydrostannylation of 2-butyn-1-ol as depicted in Scheme 3 0. Radical promoted anti-addition of tributyltinhydride to the cartx)n-carbon triple bond afforded the vinyltin compound 233, which was not isolated but converted to the vinyl iodide 2 3 4, by treatment with iodine in caiton tetrachloride. The addition of the tin is presumably directed by the hydroxyl group. Only one isomer was obtained provided that an excess of the starting alcohol was used. The cis-hydrostannylation of 2-butyn-1-ol could be achieved under mild conditions with a palladium zero catalyst, Pd(PPhg)^. Under these conditions the directing effect of the hydroxyl group was modest: a 5 to 1 mixture of regioisomers 235 and 236 was obtained. The isomers were easily separated by flash chromatography on silica gel. Cleavage of the tin caiton bond and formation of the desired vinyl iodide 2 3 7 occurred upon treatment of the major isomer with I 2 in cariDon tetrachloride. Scheme 30: Preparation of Vinyl Iodides 234 and 237 neuaSnH /-OH \ ^OH H. ^OH %C — 232 AIBN, A / SnBuaSnRii. (y^ f SnBij SnBuj jgg'SnBUj nBugSnH ~ v Pd(PPh 3)4 b e n zen e H^^SnBU3 CCI4 h ' ^ I 235 237 234 B uaSn' H 236 The Heck cyclizations of vinyl iodides 2 1 9 and 2 2 0 (Scheme 3 1 ) were significantly more rapid than that of vinyl bromide 218. The reactions were over in less than an hour and did proceed stereospecifically. That the reactions had occurred with retention of configuration was confirmed through nOe studies. This technique was ideally suited for this problem, since we 58 had obtained both stereoisomers of the bridged bicycle. Significant nOe’s (13% and 18%) were recorded between the bridge-head hydrogen Hg and the ethyienic quartet in isomer 2 41 (Figure 4). In isomer 240, on the other hand, a large nOe was detected between Hg and the allylic methyl. The observed nOes were in total agreement with the assigned stereochemistry, and established with certainty the stereochemical profile of our intramolecular Heck reaction. Scheme 31: Heck Cyclfzatlon of Vinyl Iodides 219 and 220 Pd(O A c)2 , EtgN PPhg, MeCN.A 2 1 9 90% 2 4 0 P d (0 A c )2 , EtaN PPha, MeCN.A 220 90% 241 H . H 7% M e 10% 2 4 0 Figure 4: NOE Experiments on Bicycles 240 and 241 We then examined the cyclization of a system with substituents on both the endocyclic oiefin and the side chain alkene, to better model the strychnos skeleton. The necessary precursor 24 5 was prepared by two alternative sequences. Our first pathway (Scheme 3 2) 59 involves a Dieis-Alder cycloaddition of cinnamoyl chloride with isoprene (toluene, 190°C). The DIels-Alder adduct was not isolated, but treated, in the same pot, with an aqueous solution of sodium azide and tetrabutylammonlum bisulfate, to yield two Isomeric acyl azides. After extraction with toluene, the crude azides were directly submitted to a Curtius rearrangement to afford isomeric carbamates 243 and 244 In 80% overall yield. This high yielding sequence of three steps In one pot provided a 3:1 mixture of 244 and 243, indicating the Diels-Alder cycloaddition had proceeded with only modest selectivity. Fortunately, one crystallization from ether/hexane afforded pure 2 4 4 as a white crystalline solid. The Curtius reanangement, a versatile method to convert carboxyllc acids to derivatives ot amines, preserves the stereochemical Integrity of the migrating carbon.^ The trans relationship of the phenyl group and the nitrogen substituent in 2 4 5 was thus secured. Base-promoted hydrolysis of carbamate 244 (NaOH, EtOH) afforded a primary amine which was converted to the sulfonamide 2 4 5 by action of TsCI, triethylamine and DMAP in dichloromethane. Scheme 32: Preparation of 245, First Route NHCOjMe NHCOjMe NKTs 2-NaNa, nBu^NHSO^ 2-TsCI 2 4 2 HgO 2 4 3 2 4 4 I 3-tol. reflux;«..w. MeOH I 1 I h COCI CON3 — C r% . Another option for the preparation of 245 is outlined in Scheme 3 3. Initially we carried out the thermal Diels-Alder reaction between p-nitrostyrene and isoprene, and obtained an unseparable mixture (3:1) of regioisomers. We found, however, that the selectivity can be enhanced significantly using the highly polar LICI 0 ^ -E t2 0 medium that Grieco^^® and 60 Others^ have investigated, indeed, the ratio of isomers was increased up to 25, when the Diels-Alder reaction was performed at 70°C, in an ether solution saturated with LiCIO^. Reduction of the nitro group with aluminum amalgam, followed by sulfonamide formation, provided 2 4 5 in excellent yield. Scheme 33: Preparation of 245, Second Route -NO, C r ' isopren^ v isoprene \ T o NO. N H Ts 1- AI(Hg) 2-T sC C r * \ 3 : 1 Alkylation of sulfonamide 2 4 5 with iodo tosylate 2 3 8 , under phase-transfer conditions, afforded vinyl iodide 2 4 7 , precursor to the Heck reaction. Cyclization of 2 4 7 (Scheme 3 4) should proceed via the a-alkyl palladium complex 248, which could collapse by ^-elimination to generate either endocyclic olefin 2 4 9 , or exocyclic olefin 2 50. Scheme 34: Reglochemlstry of the p-Elimlnatlon Step Ts^ Pd(0) 2 4 8 Pdl 61 Cyclization of compound 247, under the standard conditions [Pd( 0 Ac)2 . E^,N, PPhg in acetonitrile] gave cleanly the endocyclic olefin 24 9 (90% yield). On the other hand, cyclization under Jeffery's conditions^® [Pd( 0 Ac)2, K2CO3 , nBu^NCI, in DMF] afforded a 2:1 mixture of 24 9 and 250. It is possible that the first set of conditions are promoting isomerization to the more stable olefin (24 9). This experiment confirmed that the Heck cyclization was not prevented by the presence of substituents on the cyclohexene double t>ond, in spite of the development of non-t)onding interactions between the two methyl groups. This set of model studies demonstrated that the C-E ring system of the strychnos alkaloids could be conveniently assem bled by a Heck cyclization. The difficult problem of controlling the geometry of the exocyclic double bond was specifically addressed. We then turned our attention to the preparation of more advanced intermediates toward strychnine. Part III of this chapter will deal with our initial studies directed toward the elaboration of the indoline unit (ring B) of the sfrychnosalkaloids. III. Model Studies Directed Toward the Introduction of the indoline Nucleus Having investigated the scope of the Heck cyclization, we next directed our efforts on the preparation of systems in which an ortho-amino substituent on the phenyl ring will give us the opportunity to assemble the indoline unit. As depicted in Equation 51, we planned to close the indoline ring, after formation of the C-E bicyclic array, by a process involving an intramolecular amination of an alkene. Intramolecular elimination amination (E q n .5 l) 62 Since this proposed ring closure necessitated a nucleophilic addition of the aniline moiety onto the endocyclic olefin, activation of the olefin by an electrophile was required. Common electrophiles such as bromonium or iodonium cations were not suitable, because they were expected to react with the electron rich aromatic ring. On the other hand, more selective electrophiles. such as Pd(ll) salts, appeared to offer a good solution. Indeed, Wacker like processes have been used with success in the synthesis of heterocycles from alkenyl precursors.^ Hegedus^SI has reported several examples of palladium (II) assisted amination of olefins. In particular, he has shown that o-allylaniiines can be converted to 2-methyl-indoles by treatment with stoichiometric^ or catalytic^ amount of Pd(il). The course of this reaction is outlined in Scheme 3 5. The initial step involves the formation of chelate 2 5 2 by complexation of both the aniline nitrogen and the double bond. At this stage, the amine is coordinated to the pailadium, and it cannot attack the olefin. Addition of triethylamine induces the displacement of the weakly basic aniline nitrogen (2 53), which can then achieve the trans stereochemistry needed for amination of the olefin (2 5 4). Finally, elimination of HCI and HPdCI provides the metal- free intermediate 255, which quickly rearranges to the aromatic indole (2 56) by hydrogen shift, a process that may be catalyzed by the palladium. Scheme 35: Palladium Assisted Synthesis of 2-Methyl-lndole 01 PdCl2(MeCN), ^ Eyi -P d -G I NEta 231 252 *^2 253 ^2 \ ___ HM,3 Shift _ -HG! NEta ■N N -H PdG I N* H H Hg 256 255 254 63 Our first objective was to investigate the palladium assisted amination procedure for model compound 257 (Scheme 3 6), in which R is a two-carbon side chain, possible precursor of the pyrrolidine ring. Scheme 36: Model Studles-Construction of the Indole Nucleus Pd(ll) - Pd(0) a ‘NHg Pd(ll) 257: R^CHjjjSOgPh The tertiary amine 258, our projected precursor for 2 57, was prepared as described in Scheme 3 7. Commercially available ortho-nitro cinnamic acid was converted to its acyl chloride by action of thionyl chloride in benzene at reflux. The crude acyl chloride underwent a Diels-Alder reaction with 1,3-butadiene (toluene, 140°C, 18 h) to afford a cyclohexyl acyl chloride, which was directly converted to the corresponding acyl azide, by action of an aqueous solution of sodium azide and tetrabutylammonium bisulfate. This unstable azide was not purified, but was treated with concentrated HCI in toiuene at refiux to yield the cyclohexenyl amine 2 60, as its hydrochloride salt. This convenient one pot procedure provided, after basic wor1<-up, amine 2 60 in 64% yield from ortho-nitro cinnamic acid. Michael addition of vinyl phenyl sulfone provided a two-carbon side chain in quantitative yield (261). Alkylation of the hindered secondary amine 2 61 with 2,3-dibromopropene proved to be surprisingly difficult: some representative examples of reaction conditions are given in Table 1. Alkylation could be achieved in very good yield with an excess of alkylating agent in DMF at 9G°C. 64 Scheme 37: Synthesis of Aniline Derivative 258 1-SOCb, PhH NHg 2- 1,3-butadleno toluene, 140°C 3-NaN3,lhonA MeOH, redux NO; 4-HpMhenNaOH 93% NO; 64% 260 PhSO; PhSOs, NaBH* Cu(OAc), MoOKrt NH. 95% 2 5 8 2 6 2 Table 1: N-alkylatlon of 261 with 2,3-dibromopropene: base solvent additive temp. (°C) time (h) yield (%) IPigNEt MeCN Nal 82 8 35® K2CO 3 MeOH Nal 6 4 8 31® K2CO 3 benzene Nal 80 . 7 30® K2CO3 toluene Nal 110 20 52 " K2CO 3 DMF / 90 6 94? a) 2.5 equivalents o( 2,3 dibromopfopene. b) 3 equivalents ot 2,3 dibromopropene. c) 5.0 equivalents of 2,3 dibromopropene. The conversion of 26 2 to the desired aniline derivative 258 necessitated the selective reduction of the nitro group. Although AI(Hg)^^^®is an efficient reducing agent of aliphatic nitro derivatives (vide supra), nitro aromatics are usually converted to mixtures of anilines and hydroxyl- amines. Thus, we did not apply this procedure for the reduction of 2 6 2. The standard transfer hydrogenation, using ammonium formate as hydrogen source and 10% Pd on charcoal as catalyst,^failed to afford any reduction product (starting material was recovered). However, 65 selective reduction of the nitro group in 262 could be achieved using Cowan's procedure (NaBH^, Gu(0 Ac)2 in methanol) As expected, sodium borohydride alone was not able to reduce 26 2. The mode of action of this combination of reagents is not well understood. It appears that the nitro group is activated toward hydride delivery, by means of coordination with the copper. With an access to the vinyl bromide 258 secured, we concentrated our efforts on cyclization procedures. We had projected that a Heck cyclization would afford bicycle 2 5 7. When an acetonitrile solution of 258 was treated at reflux with 15 mol% of Pd( 0 Ac)2, triphenyiphosphine and triethylamine, the mixture turned homogeneous. Thin layer chromatography indicated the slow disappearance of the starting material, with concomitant formation of two products of very similar polarity. After 4 h at reflux, three additional portions of catalyst (20 moi.% each) were added over a period of 3 h to push the reaction forward. Eventually, all the starting material was converted to the slower moving spot, as indicated by TLC. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel to afford a single compound in 53% yield. Spectroscopic data were not in agreement with the expected structure 2 57. In particular,^ H NMR showed only two singlets in the ethyienic region, and the ^ ^0 DEPT revealed the presence of 5 triplets below 70 ppm. These data revealed that the reaction afforded directly the indolic tetracycle 263 (Scheme 3 8 ). Evidently, the cyclization proceeded in the normal way to give 2 57. Then, under the reaction conditions, aniline 2 57 underwent a palladium (II) mediated intramolecular amination onto the endocyclic double bond. The resulting tetracyclic intermediate rearranged, through what is formally a 1,3-hydrogen shift, to indole 2 63. It is important to note that the second cyclization was catalyzed by a palladium (II) species-and not a palladium (0) species. The extra catalyst that was added during the reaction was essential, since palladium (II) was converted to palladium (0) during the second cyclization. In that regard, a catalytic version of the palladium assisted amination of olefins has been developed by Hegedus and co-workers. In this modification, the palladium zero which is formed during 66 the reaction, is reoxidized to palladium (II) by various oxidants, such as benzoquinone or Cu(OAc)2. However, attempted double cyclization under these conditions [15 mol.% Pd( 0 Ac)2, 1 equivalent benzoquinone, PPhg, EtgN, acetonitrile] proved to be unsuccessful: a low yield of tetracycle 2 6 3 being obtained (10%). Scheme 38: Double Cyclization PhSO;,. PhSO. PhSO. Pd(0) Pd(ll) PdX Heck reaction Pd assisted ,NH NH, amination 2 5 8 2 5 7 PhSOg PhSO; PhSO. 1,3 H shift 263 Finally, It should be noted that, whereas 2 58 gives the double cyclization, the related compound 259 gives only the monocylization product, under comparable conditions. The difference in the reactivity of these substrates can be rationalized by taking into account the basic nitrogen in 2 58, which may favor the chelation of a palladium (II) species from the most hindered face (the top face) of bicycle 257. Such chelation is required, in order to achieve the trans arrangement between the aniline nitrogen and the electrophilic palladium species. NH. 259 67 IV. Conclusion In this chapter, approaches to the BCE ring system of the strychnos skeleton were described. In the first section, we demonstrated that the C-E ring sub-unit can be easily elaborated by an intramolecular Heck reaction, and that the critical E exocyclic olefin is generated with specificity. In the second section, we reported an interesting methodology for the construction of the indole nucleus, that involves a palladium catalyzed double cyclization. An application of this strategy to the synthesis of a member of the strychnos famiiy is presented in the following chapter, which describes a stereoselective total synthesis of the pentacyclic strychnan, dehydrotubifoline. Chapter IV: Total Synthesis of Dehydrotubifoline I. Introduction As the model studies described in chapter III augured well for the success of our approach, we next undertook the synthesis of the strychnan skeleton. This chapter reports the successful implementation of our overall strategy to the synthesis of dehydrotubifoline, a typical pentacyclic strychnos alkaloid. Our retrosynthetic analysis is depicted in Scheme 3 9. The Imine form of dehydrotubifoline is in equilibrium with its enamine tautomer. As expected, the tautomeric equilibrium lies far toward the side of the imine. By considering the enamine tautomer, we could envision the cleavage of the 5—C20 bond as key disconnection. Encouraged by our model studies, we anticipated that this strategic bond could be formed by an intramolecular Heck reaction. Two possible precursors were considered: the tetracyclic vinyl iodide 2 64 and the aniline derivative 26 5. We projected that 265 could be converted to dehydrotubifoline by the double cyclization methodology we had developed during the model studies. Elaboration of 2 6 4 and 2 6 5 should be accomplished by, respectively, intra- and intermolecular cycloaddition of 3-aryl-52-pyrroline derivatives. Our initial objective was, therefore, to develop an effective route to the 3-aryl-02-pyrroline unit. 68 69 Scheme 39: Retrosynthesis of Dehydrotubifoline 2 6 4 123: dehydrotubifolino BOC NR, Br N-R BOC [4+2] c c'NHz O aNR, 266 3-aryl-5j-pyrroline CC II. Preparation of the Pyrrollne Unit Since numerous alkaloids contain the pyrrolidine subunit, there is a need for methods that rapidly construct substituted pyrroles, pyrrolines or pyrrolidines. At the beginning of our studies, we considered assembling pyrroline 266 through a transition-metal mediated coupling reaction of S-bromo-Ô 2-pyrrolines with substituted benzenes (Scheme 3 9). However, we were not able to brominate the desired position of the pyrroline. In addition, we carried out different palladium mediated coupling reactions of 83 -pyrrolines with ortho-iodo-nitrobenzene, and found that a mixture of mono-and disubstituted pyrrolines was obtained. Since this chemistry proved to be problematic, and since our primary goal was not to develop new syntheses of substituted 70 pyrrolines, we searched for a literature procedure to prepare our starting material 2 6 6 . A unique transformation allows the conversion of cyclopropyl-imines into 52-pyrroline.^® 2'^®3 Although, the reaction was discovered by Cloke in 1928,^®^ most of the synthetic work in the area was initiated by R. V. Stevens.^ Upon careful investigation of the cyclopropyl-imine rearrangement, Stevens and co-workers established that this transformation is not purely thermal, but that it requires an acid catalyst with a nucleophilic gegenion. The course of this reaction is depicted in Scheme 4 0. Scheme 40: Cyclopropyl-lmlnlum Ion Rearrangement h eat 2 6 7 ^2 H X, 120°C activation ring closure ring opening Rs "2 - „ 2 6 8 2 6 9 The mechanism of this reaction is believed to involve the activation of the cyclopropyl-imine through protonation of the nitrogen. Then, the activated cyclopropane is ring- opened by nucleophilic attack of the gegenion to afford enamine 269. In the last step, 2 69 undergoes an intramolecular substitution reaction to yield the five-membered heterocycle 270. Ammonium chloride has been extensively employed to promote this rearrangement. It is a mild acid which does not induce decomposition of the resulting enamine. Stevens and collaborators successfully explored this new methodology in the synthesis of complex alkaloids. For example, the cyclopropyl-imine rearrangement served as a key step in their formal synthesis of aspidospermine (Scheme 41).^®^® Condensation of aldehyde 271 71 with the protected keto amine 2 7 2 led to aldimine 2 73. This imine rearranged in 82% yield to S2-pyrroline 2 74, upon treatment with a catalytic amount of ammonium chloride at 160°C. Successive deprotection of the ketone and intramolecular aldol type condensation afforded bicycle 275, which was converted to 276 in 5 steps. This compound had been previously converted to aspidospermine 2 77.^®^^ Scheme 41: Stevens’ Formal Synthesis of Aspidospermine NH4CI EtOaC'^^CHO3 ^ + COgEt 160°C OOgEt 2 7 1 1-HCI a-KgCOj 5 ste p s Ac 2 7 7 2 7 6 2 7 5 We wanted to follow a strategy similar to the one developed by Stevens to prepare pyrroline 282 (Equation 5 2). The nitro group served two purposes: it masked the aniline function, and it enhanced the acidity of the methylene protons in 2 78. Although starting material 2 7 8 w as commercially available (Aldrich), it was readily prepared on large scale from ortho- nitrotoluene. 154 0 Q“ 282 281 2 7 8 (Eqn.52) 72 The desired cyclopropyl moiety was assembled by double alkylation with dibromoethane (Scheme 4 2). On a small scale, deprotonation of 2 7 8 with tBuOK in DMSO, followed by addition of dibromoethane (10 equivalents) afforded the expected cyclopropyl nitrite 279 in good yields. Unfortunately, the yields declined appreciably upon scaling up this procedure (Table 2). After examining numerous conditions, we discovered that the double alkylation can be carried out on large scale and in good yield using a phase transfer catalyst. Scheme 42: Synthesis of Cyclopropyl-imine 281 50% NaOH, MeCN ON OC nBu4NBr, BfCHgCHgBr NO. rt,12h, 96% 2 7 8 2 7 9 1-DIBAL-H, toi., •78°C 2-HCI. HgO NCHgPh PhCHgNHg OHO NO. 2 8 1 2 8 0 Table 2: Alkylation of Ortho-Nltrophenylacetonltrlle^ b a s e solvent additive scale (mmol) yield (%) tBuOK DMF / 1 50 tBuOK DMSO / 1 76 tBuOK DMSO / 5 4 8 tBuOK DMSO / 10 3 0 50% NaOH CHgClg nBu^NBr (0.1 eq) 1 19 50% NaOH CH2CI2 nBu^NBr (1.2 eq) 1 60 50% NaOH MeCN nBu^NBr (1.2 eq) 1 9 7 50% NaOH MeCN nBu^NBr (1.2 eq) 50 9 6 a) with 10 equivalents of dibromoethane 73 A useful approach to aldehydes consists in the partial reduction ot nitriles to imines. The imines are then hydrolyzed to aldehydes. Diisobutylaluminum hydride (DIBAL-H) seems to be the reagent ot ctioice tor this purpose. ^ Indeed, reduction ot cyclopropyl nitrile 2 79 with DIBAL-H, at -78°C in toluene, afforded the expected aldehyde (2 8 0) after acidic work-up (Schem e 4 2). Condensation with benzyl amine led to the imine 281, substrate tor the cyclopropyl-imine rearrangement. The imine 281 was not isolated, but directly submitted to the rearrangement conditions. Stevens’ original procedure (neat imine, NH^CI, 120°G)^^^® tailed to give the desired 62-pyrroline 2 82, but afforded the aromatized derivative 283 in 77% yield (Equation 53a). On the other hand, when the reaction was carried out in acetonitrile, 2 8 2 was obtained in 90% from aldehyde 2 8 0 (Equation 5 3 b). N ' ^Ph PhCHgNHg NCH jPh NH 4CI o 77% o S - 120°C. 4h OC 280 281 283 (Eqn.53a) N " " P h CHO 1- PhCH2NHa 90% 2- NH^CI.MeCN ^ 120”C, 4h CC 280 282 (Eqn.53b) Since this rearrangement was performed in a seaied tube, our procedure was not very practical on large scales. Therefore, we investigated further the reaction, and first examined the use of a higher twiling solvents. Indeed, the reaction can be promoted with ammonium chloride in DMF at 120°C, but the yields are modest (60%) and the reaction is not as clean. The finding by Stevens that the cyclopropyl-imine rearrangement does not proceed without a proton source, emphasizes the importance of the initial step, the iminium ion formation. Stevens suggested that the rate determining step in the rearrangement is the protonation of the imine by ammonium chloride. Consequently, it is expected that a stronger more solubie acid would speed up the 74 reaction. A potential problem with using strong, or mildly strong, acids is the acid sensitivity of the enamine product. To confirm that supposition, we reacted imine 281 with catalytic benzoic acid (15 mol%) and sodium iodide (15 mol%) in acetonitrile at reflux for 12 h. The reaction proceeded cleanly, and after 12 h, the starting material had disappeared. Unfortunately, the yield of isolated product remained low (30%). Faced with this complication, we decided to examine new methods to effect this rearrangement. We realized that a good electrophile-nucleophile reagent pair should promote the reaction, lodotrimethylsilane (TMSI)^®®, which has been used as a substitute for Bronsted acids over the last decade, appeared quite promising. The silyl part of TMSI serves as a hard Lewis acid, and the iodide as a soft Lewis base. Therefore, it reacts very readily with compounds containing hard bases, to form a bond between the silicon and the base. The iodide acts as a strong nucleophile in a subsequent step. For example, N-trimethylsilylaziridine (284)^®^ has been reacted with lodotrimethylsilane to afford a ring opened product (285), arising from the collapse of the Lewis acid-Lewis base adduct (Equation 5 4). r “> SiMog TMSI .SIMe, SN, SIMeq ^SIMea SIMe, 2 8 4 2 8 5 (E q n .5 4 ) Strained carbocycles have also been opened by TMSI. Relevant to our studies was the opening of the a-keto cyclopropane 286^®® to afford the linear alkyl iodide 2 8 7, as outlined in Equation 5 5. We anticipated that the ring cleavage of our cyclopropyl imine would be achieved by TMSI in a similar way. r TMSI '^SIMeg 2 8 6 2 8 7 (Eqn.55) 75 The series of events depicted in Scheme 43, indeed occurred, upon treatment of 281 with a catalytic amount of TMSI in DMF at 60°C. TMSI could also be generated in situ from TMSCI and ammonium iodide. We believe that 2 6 8 , the adduct of DMF and TMSI (Equation 5 6) is the true catalyst in this reaction, since TMSI has been sfiown to react readily with amides.^ ^ SÎM03 2 8 8 (E q n .5 6 ) Scheme 43: TMSI Promoted Cyclopropyl-lmlnlum Ion Rearrangement N '^ P h js!î'‘'''Y ^ ^ = N C H 2 P h E* Nu polar solvent OC 2 8 1 2 8 2 conditions: TMSI (0.2 eq). DMF, 60°C, 3 h TMSCI (0.2 eq), Bu^NI (0.2 eq), DMF, 60°G. 3 h + TMSI -TMSI SIMe. NO. NO. III. Attempted Intermolecular Cycloadditions with Enamine 282 With the synthesis of pyrroline 282, a route to the D ring of the strychnan skeleton was developed. In addition, the enamine function was positioned so as to allow the introduction of the cyclohexyl moiety (ring C). In fact, a possible precursor to dehydrotubifoline, bicycle 2 65 (Scheme 3 9) could, in principal, arise from a Diels-Alder cycloaddition of enamine 2 82 with 76 butadiene. Although enamides have served successfully as dienophlles In many Inter and Intramolecular cycioaddltlons,^®® enamlnes has not been widely used. Reports of enamlnes reacting as dienophlles are limited to Diels-Alder cycloadditions with strongly electron deficient dlenes.^ In a published approach to hasubanan alkaloids, for example, the reaction of sulfoxide 289 with enamine 290 gave cycloadduct 291 In good yield (Equation 5 7).^®®^ Backvall and co-workers^ described the Diels-Alder reaction of 2-(phenylsulfonyl)-1,3- butadlene (2 9 2) with enamine 2 9 3 (Equation 5 8 ). The addition proceeded In 70% yield to afford a single product, 2 94. Formally cycloadditions, these reactions may actually Involve a conjugate addition of the enamine to the activated diene, followed by ring closure. If Is worth mentioning that 2-(phenyl sulfonyl)-1,3-dlenes are showing an unusual dual reactivity, since they react with both electron rich and electron poor dienophlles. MeCN 70°C SO Ph Me 2 9 0 2 9 1 (E q n .5 7 ) PhSO. PhSO, GHgClg XX),N X • w rt, 70% 2 9 2 2 9 3 2 9 4 Û ^ O (E q n .5 8 ) As a test reaction, we first Investigated the Diels-Alder cycloaddition of 3-aryl-62-pyrroline 28 2 with 1,3-butadlene. Under the reaction conditions, 140°C In toluene, we obsen/ed a slow decomposition of the starting material and none of the desired cycloadduct. After 5 h at 140°C, we recovered 50% of enamine 2 8 2. Next, we Investigated the cycloaddition of 2 8 2 with electron deficient dienes. The phenylsulfonyl substituted 1,3-butadlene 2 9 2 was prepared 77 according to the procedure published by BackvallThis diene was kept in a dichloromethane solution (0.02M) in order to avoid dimerization, and was rapidly added to alkene 28 2. The mixture was stirred at ambient temperature for 2 h, during which time the diene was consumed. However, the enamine 2 8 2 did not react and was recovered intact in 87% yield. Similarly, we did not meet with any success with 2-carbomethoxy-1,3-butadiene (2 96), generated in situ from the corresponding sulfone 2 95, which was prepared according to a literature procedure.^S chem e 4 4 summarizes our attempted intermolecular Diels-Alder cycloadditions. We believes that pyrroline 28 2 does not easily undergo cycloaddition reactions, since it is not a typical enamine: the electron density of the double bond is greatly diminished by the presence of the ortho-nitro substituent on the benzene ring (push-pull effect). Scheme 44: Attempted Intermolecular Cycloadditions / — N Ph ------^ COjMe C l / / - ( i R=H: butadiene SOj R=C02Me:296 ' I 295 R=S02Ph:292 R IV. Intramolecular Diels-Alder Cycloaddition Since pyrroline 2 8 2 did not undergo intermolecular Diels-Alder reactions, we decided to investigate intramolecular transformations to construct the cyclohexyl moiety of dehydrotubifoiine. In preparation for the intramolecular cycloaddition, we needed to introduce the diene appendage. We projected to unmask the aniline nitrogen by chemoselective reduction of the nitro group in 2 8 2. However, insurmountable problems were encountered. The NaBH^/Cu(OAc)2/MeOH procedure (vide supra) afforded a complex mixture of uncharacterized materials. We also examined transfer hydrogenation conditions, which have been shown to be effective for the reduction of various aliphatic and aromatic nitro compounds.^ Unfortunately, under these conditions (NH 4HCO3, Pd/C, MeOH), the desired 78 aniline derivative could not be isolated in any appreciable yield. We suspected that the electron rich enamine was compiicating the reduction, and we investigated the possibility of deactivating the enamine. A common procedure for the conversion of tertiary benzyl amines to carbamates, involved alkylchloroformates. For example, Hanessian and co-worl conversion of the benzyl amine 2 9 7 to the caitamate 2 98 (Equation 5 9) was achieved by upon treatment with ethylchloroformate in benzene at reflux.^ .CO2M0 ^^G02Mg CICOaEt, PhH reflux E tO ' 298 (Eqn.59) In a similar way, enamine 282 was conveniently converted to the corresponding methyl carbamate 2 99 in quantitative yield (Scheme 4 5). To our knowledge, this transformation represents the first example of an alkylchloroformate promoted dealkylation of an enamine. Chemoselective reduction of the nitro group in 299 was then efficiently achieved by catalytic hydrogenation over Pd/C (HCOONH 4 , MeOH, rt)^^®^ to yield aniline derivative 3 00, our precursor of amino-diene 3 0 7 . Scheme 45: Preparation of Carbamate 299 f — u ' "Ph /—N'^OMeX /—N'^OMe X kXX 282 299 300 j — NINE E 307: E=CO,Me 79 In connection with alkaloid synthesis, N-acyl-1-amino-1,3-dienes (302) have become popular substrates for Diels-Alder cycloadditions. There are principally two versatile and complementary methods for their preparation. The first method is based on the Curtius rearrangement of dienoic acid azides. The second method, which is depicted in Schem e 4 6, involves the condensation of a,p-unsaturated aldehydes with primary amines to afford vinylimines (301), which are trapped by an acylating agent.^ 59b,163 Scheme 46: Preparation of DIenamldes from a,p-unsaturated Aldehydes + HgN— Ra R3COCI toluene cr PhE^N H *Cr + In recent years, there has been an increased utilization of dienamides such as 302 in Diels-Alder cycloadditions. ^ For example, in an approach toward the galanthane ring system common to many amaryllidacea alkaloids, dienamide 3 0 3 (Equation 6 0) afforded a single adduct (304) upon cycloaddition in refiuxing chlorobenzene.^®'^ The key step in Oppolzer total synthesis of (-)-pumiliotoxin involved the intramolecular Diels-Alder reaction of dieneamide 3 05 (Equation 6 1).^®® The chiral center in 305 derived from (S)-norvalin, and controlled the stereochemistry of the three new asymmetric centers, through a t)oat-like transition state in which the non-t)onding interactions were minimized. PhCI, reflux 52% 303 O 304 O (Eqn.60)^®^ 80 toluene, 230°C [4+2] 3 0 5 O' 3 0 6 In the actual synthesis of 3 0 7, the diene moiety was introduced by condensation with crotonaldehyde, followed by trapping with methyl chloroformate (Scheme 4 7). Five equivalents of crotonaldehyde were added to the starting aniline, and the mixture was stirred at room temperature for 1 h. The mixture w as diluted with toluene and concentrated to remove the water. The crude imine was then reacted with methyl chloroformate, under different sets of conditions. Table 3 summarizes some of the most representative trials. Scheme 47: Preparation of Dienamide 307 o A. •OMe D CICOjMe CC solvent, base additive 3 0 0 3 0 6 3 0 7 •OMe Table 3: Preparation of 307, Reaction Conditions b a se solvent additive yield (%) dllsopropylethylamlne CH2CI2 DMAP 4.3 dllsopropylethylamine MeCN DMAP 40 diethylanlllne toluene / 57 proton sponge® toluene DMAP 70 proton sponge® MeCN DMAP 50 proton sponge® E tjO DMAP 60 a) N,N,N',N' tetramethyl-1,8-diamino-naphtalene 81 The following generalizations can be made about this conversion. Higher yields were obtained when the reaction was carried out in a non polar solvent, such as toluene, using a non-nucleophiiic base. Oppolzer’s procedure^ calls for the use of diethylanlllne, but we found the reaction to proceed more cleanly, and in higher yields, with N,N,N’,N'-tetramethyl-1,8-diamino- naphtalene (proton sponge). Under our conditions, the ammonium salt precipitated cleanly and rapidly. Any acid-catalyzed side reaction was thus avoided. Many different conditions were examined for the key intramolecular Diels-Alder reaction. Early attempts to promote cycloaddition of dienamide 3 07 under thermal conditions proved unsuccessful. Lewis acid catalysis, the traditional way to accelerate a Diels-Alder reaction was not expected to be useful, as the dienophile and the diene were electronically very similar. Indeed, diethylaluminum chloride in dichloromethane did not induce any chemical transformation. The nature of substrate 307, in which both the diene and the dienophile are electron rich, prompted us to also investigate the possibiiity of catalyzing the cyclization using cation radical salts. The scope and the utility of the cation radical Diels-Alder cycloadditions^ has been enhanced by the discovery of efficient and stable chemical initiators, the triarylaminium salts, such as 31 2.^ The capacity of these salts to promote the cycloaddition of electron rich diene-dienophile systems is beautifully demonstrated by Equation 6 2. The stereospecific cyclization of 31 3 occurred at -78°C in 83% yield. A potential complication in the reaction of these salts is the formation of cyclobutane derivatives. Bauld and co-workers investigated the cation radical Diels-Alder reaction of N-vinyl-N-methyl-acetamide (31 6) with cyclohexadiene, and observed the exclusive formation of cyclobutane derivative 317 (Equation 6 3).^ O M e .OM e ArN'+SbClg- 3 1 2 -7 8 ° C , 83% 313 Ar= pB rPh 314 (Eqn.62) 82 I cation radical 0 o A 315 316 317 (Eqn, 63) According to Bauid’s procedure, our triene 307 was exposed to a catalytic amount of (pBrPh)gN'+SbClg" in dichloromethane at 0°C. An intractable mixture of decomposition products was obtained, and none of the cycloadduct could be detected. It was not possible to promote the transformation below 0°C, since the aminium salt was found to be too insoluble in dichloromethane. During the course of this work, Livinghouse and co-workers^ described the use of rhodium complexes, such as (PPhg)gRhCI, to catalyze Diels-Alder reactions between electron rich dienes and electron ricfi dienophlles. However, even under Livlnghouse’s conditions [(PPhg)gPhCI, trifluoroethanol], bis-carbamate 3 0 7 failed to undergo the desired cycloaddition. At this point, we decided to reinvestigate the thermal Diels-Alder reaction under more forcing conditions. We were pleasantly surprised to find that not only did the cyclization take place at higher temperature (220°C, toluene, steel bomb, 4h), but that it produced the desired adduct, 318, in high yield, as a single diastereomer (Scheme 4 8 ). The cycloadditlon evidently takes place through the exo transition state in which non-bonding interactions are minimized (Scheme 4 8 ). The endo transition state is not stabilized by any secondary orbital overlap, and is disfavored by non-bonding interactions between the ethyienic protons of the diene moiety and the methylenes of the pyrroline ring. Tetracycle 3 1 8 should prove to be quite versatile, since it can serve as an intermediate in the synthesis of t>oth strychnos a s anôaspidosperma alkaloids (Figure 5). 83 Scheme 48: Diels-Alder Cycloaddition of Dlenamlde 307 COjMe 220°C, toluene, 4 h steel bomb, 95% I COgMe 3 0 7 3 1 8 MsOgC versus MeOgC EXO ENDO aspldosperma skeleton strychnos skeleton Figure 5: Aspldosperma and Strychnos Skeletons The spectroscopic data observed for adduct 318 were consistent with the assigned structure. The and and NMRs of tetracycle 318 were recorded respectively, in toluene-dg and DMSO-dg, at 100°C. This temperature was required in order to overcome the rotational barrier of the carbamate carbon-nitrogen bonds, and resulted in simplified spectra. 84 The data from the and ^ NMR’s are summarized in Figure 6 . The stereochemistry of the tetracycle, in particular the orientation of Hg, was confirmed by nOe’s experiments. NMR in toluene at 370K characteristic nOes proton S (ppm) 1+2 1 .6 0 3 2 .1 5 4 2 .3 7 5 3 .2 6 6 3 .5 1 7 3 .7 9 8 4 .4 0 9 5 .5 3 10 6.00 11 6 .7 1 12 6 .8 3 1 3 7 .0 0 1 4 7 .8 6 E= COOMe nOes > 5% NMR in DMSO-dg at 370K carbon 5 (ppm) 2 6 2 .7 6 3 5 9 .4 5 5 4 4 .0 5 6 2 5 .4 9 7 5 1 .3 0 8 1 4 0 .1 3 10 9 122.22 10 1 2 7 .7 9 11 11 1 2 2 .8 5 12 1 1 4 .2 3 1 6 1 3 1 3 5 .2 5 1 4 3 7 .0 0 15+16 126.23+126.99 2x 0=0 154.59+152.40 2x0 Me 51.30+51.52 F igure 6 : Spectroscopic Data of Tetracycie 318 85 IV. Elaboration of Ring E - Heck Cyclizatlon To complete our total synthesis of dehydrotubifoline (12 3), we projected to assemble ring E by intramolecular Heck reaction. The introduction of a suitable appendage to tetracycle 318 necessitated first the hydrolysis of the carbamate functions. Again, at this stage, we took advantage of the high reactivity of iodotrimethylsilane. The hydrolysis of simple alkyl carbamates usually requires very acidic or basic reagents. Reactions are typically slow and yields are modest at best. In the last decade, TMSI has been used successfully as a substitute for acids in the hydrolysis of esters, amides, and carbamates.^ Because of the presence of the lone pair on the nitrogen, the carbonyl groups in carbamates are more polarized than in esters. For this reason, carbamates react more readily with iodotrimethylsilane. The first step in the TMSI promoted hydrolysis of carbamates (Scheme 4 9) is a transestérification reaction that generates a trimethylsilyl carbamate (3 2 0). Upon methanolic work-up, the silyl carbamate yields a carbamic acid (321), which collapses with spontaneous loss of carbon dioxide to release the free amine as its hydroiodide salt (32 2). Scheme 49: TMSI-Promoted Hydrolysis of Carbamates-Mechanlsm p - S I M e g K P- + Meg Si r / OMe Me R/^ 'OSiMeg 3 1 9 r 3 2 0 MaOH .NH, COfe MegSi—OMe + N—^ O / ^OH Y 3 2 2 3 2 1 We did not expect any selectivity in the TMSI-induced hydrolysis of bis-carbamate 318. However, we discovered that the reactivity of TMSI could be tuned by varying the solvent and the 86 number of equivalents of the reagent (Table 4). The more reactive carbamate could be preferentially hydrolyzed, by running the reaction in dichloromethane at reflux for 1 h with 2.2 equivalents of TMSI. Under forcing conditions, however, the fully deprotected diamine 3 2 4 was isolated in 94% yield. Table 4: Hydrolysis of Bis-carbamate 318 1 -TM SI. s o lv e n t 2-MeOH, then NaOH N' I H Me02C 3^3 MdOoC 3 2 3 3 2 4 TMSI (equivalent) solvent (reflux) time (h) ratio (323/324 yield (%) 2.2 CHaCIa 1 10/1.0 9 5 2.2 CHaCL 4 3.5/1.0 81 3.0 CHaCIa 1 2.5/1.0 85 5.0 CHaCIa 3 1.0/1.0 9 0 10 CHCI3 4 1.0/99 9 4 We chose first to investigate the chemistry of indoline carbamate 3 2 3 . N-alkylation was accomplished efficiently upon treatment with tosylate 238 in acetone containing potassium carbonate. The Heck cyclization of vinyl iodide 3 25 was expected to give strychnan 3 2 6, a versatile pentacyclio intermediate (Scheme 5 0). Carbamate 326 would have been one step away from both dehydrotubifoline (mild hydrolysis) and Akuammicine. The conversion of 32 6 to Akuammicine would have required transposition of the carbomethoxy group from the nitrogen to the p-carbon. It has already been shown that, under photochemical conditions, enamides predominantly undergo a [1,3]-acyl shift to produce vinylogous amides.^ 59b,170 87 Scheme 50: Our First Approach to Dehydrotubifoline and Akuammicine NH K2CO3 acetone, rt, 75% 3 2 3 3 2 5 Pd(0 Ac)2, DMF nBu^NCI, KgCO^ ho, benzene MeOaC 326 ‘OM e 122: akuammicine H3O* 123: dehydrotubifoline Unfortunately, when compound 325 was submitted to the Heck reaction (Pd( 0 Ac)2 , K2CO3 , DMF, 60°C), an unexpected pentacycie was obtained. The proton NMR spectrum clearly indicated the presence of three ethylenic hydrogens, two as triplets, and one as a quartet (Figure 7). Only a quartet and a doublet would be expected from structure 3 2 6. The ^ NMR spectrum unequivocally revealed the presence of two ethylenic doublets. A careful analysis of the spectroscopic data H correlation and nOes) confirmed that the cyclization had occurred to afford product 327 (Scheme 51). This unexpected cyclization, giving rise to the azabicyclo[3.2.2]nonane subunit, was in sharp contrast to the results from the many model system s (chapter ill). 88 Scheme 51: Heck Cyclization of indoiine Carbamate 325 P d(O A c)2, DMF nBu^NCI, K2CO 3 79% M eOoC 3 2 5 H NMR and COSY recorded in DMSO-dg at 343K proton 5 (ppm) coupled to (ppm) 1 1 .6 4 3 .1 4 2 2.13 2.65+3.40 3 2.65 2.13+3.40 3 .4 0 2 .1 3 + 2 .6 5 4 3 .1 4 1 .6 4 + 3 .3 3 3 .3 3 3 .1 4 5 3 .6 5 5 .8 9 1 6 3.80 3.95+6.17 7 3 .9 5 3 .8 0 11 8 5 .8 9 3 .6 5 9 6 .1 7 3 .8 0 10 5.70 1.64+3.14 NOE 1 —>4: 7% 11 + 12 6 .9 8 + 7 .0 8 1 3 7 .2 8 1 4 7 .7 0 Figure 7: Spectroscopic Data of Pentacycie 327 A more careful analysis of the spectroscopic data indicated that the cyclization had not simply taken place at the other end of the endocyclic olefin. NOe's experiment confirmed that the cyclization had occurred with inversion of the double bond geometry. This observation ruled out a direct 7-endo type mechanism for the coupling reaction. Negishi and co-workers have also observed inversion of configuration during the Heck cyclization of vinyl iodide 328 (Scheme 5 2).^^ Their proposed mechanism involves the standard exo-type cyclization to afford the neopentyl type o-alkyl palladium complex 3 2 9. Unlike typical Heck reaction intermediates, this palladium complex has no p-hydrogen to allow a reductive elimination, and undergoes a closure to cyclopropyl carbinyl palladium species 33 0. The cleavage of the internal carbon- carbon bond of the cyclopropane which occurs in the next step necessitates proper alignment of 89 the carbon-palladium a bond. Thus, formation of intermediate 331 was accompanied by inversion of the exo-cyclic olefin geometry. Scheme 52: inversion of Alkene Geometry via an Exo-mode Cyclization pdcypptv,)2, EyjH BaN.DMF.SO'C.Sh 3 2 8 3 3 2 y'exo .OH cyclization OH, OH ■PdXL; PdXLj = •OH PdXLj PdXLg 3 2 9 3 3 0 3 3 1 By analogy with Negishi’s work, we propose the following mechanism for the conversion of vinyl iodide 3 2 5 to the pentacyclio carbamate 3 2 7 (Scheme 5 3). Scheme 53: Formation of 327-Mechanism Pd(OAc)2, DMF nBu«NCI, K5CO3 I H 79% MeOaC gjg M eO ^^O MeO' M eO' 3 3 4 3 3 5 Pé-L > = 0 ' M eO 90 The initial step involves the expected exo-mode carbopalladation to produce a a-alkyl palladium species stabilized by intramolecular chelation (333). The ^-elimination does not occur, presumably because chelate formation prevents proper alignment between the p-hydrogen and the carbon-palladium bond. In situ trapping of the reactive carbon-palladium bond by the exocyciic olefin affords cyclopropane 33 4. Cleavage of the cyclopropane “back bond” yields 335, a a-aikyi palladium complex which is not stabilized by any intramolecular chelation. This unstable complex undergoes a fast elimination of HPdl to provide the observed product (3 27). This proposed mechanism is consistent with other observations. There is literature precedents for the formation of cyclopropane by double Heck cyclization (Scheme 5 4).^ The palladium promoted cyclopropyicarbinyl-homoallyl rearrangement is also well documented.^ In addition, there is at least one example in the literature of a stable a-alkyl palladium species possessing a syn p hydrogen. Daves and collaborators described the isolation and the characterization of 3 4 2, aa-paliadium complex stabilized by intramolecular chelation.®^-®®’®^ Scheme 54: Heck Cyclopropanation Pd P d (0 ) EtOaC COaEt 335 a 3 3 0 COjMe ■CO2MG pd( 0) 340 Ac 341 91 OAc NMe 3 4 2 :L - P P h g We realized that the removal of the carbamate function should prevent the “abnormal” cyclization from occurring. As mentioned before (Table 4), the two cartwmethoxy group in 31 8 could be removed cleanly, using an excess of iodotrimethylsilane in chloroform, to give 3 24 in 94% yield. The vinylic iodide appendage was then introduced by chemoselective alkylation of diamine 3 24 (Scheme 5 5). The alkylation was performed at -5°C, since above 0°C dialkylation was a competing reaction. It is worth mentioning that in the absence of tetrabutyl ammonium chloride the reaction was unselective, even at low temperature. It is possible that the allylic bromide 343 was converted in situ to the corresponding chloride, which might be a more selective alkylating agent. When iodide 344 was treated with a catalytic amount of Pd( 0 Ac)2 in DMF, in the presence of triphenylphosphine and potassium carbonate (Scheme 5 5), the anticipated Heck 6-exo cyclization was observed. The a-alkyl palladium intermediate 3 4 5 was not stabilized by any intramolecular chelation. Therefore, it underwent a fast elimination of palladium hydride to afford enamine 34 6, which rapidly tautomerized to 12 3. After chromatographic purification on silica gel (elution with 5% diethyl amine in ether) the pentacyclio strychnos alkaloid dehydrotubifoline (1 2 3) was isolated as a clear beige solid. The ^ H NMR and ^ NMR (Table 5) spectra of our synthetic sample correlated well with those provided by Professor L.E. Overman from the University of California at Irvine. For comparison purposes, the reduced spectra of Overman's samples are presented in appendices, along with the spectra of our synthetic samples. 92 Scheme 55: Final Steps In the Synthesis of Dehydrotubifoline ■NH Br- 343 .KgCC^ nBu^NCI, DMF, -5°C. 68% 3 2 4 3 4 4 P-elimination 3 4 6 3 4 5 tautomenzation 123 ; dehydrotubifoline Table 5: ^ NMR of dehydrotubifoline, recorded In chloroform at rt carbon 5 (ppm) 17 12.85 6 25.39 15 30.25 14,16 35.10 35.95 20 5 53.68 17 20 55.53 7 65.40 3 66.67 12,18 119.55 119.87 10 10 121.23 1 9,11 125.27 127.73 19 142.03 8 144.10 13 154.43 2 189.02 93 V. C onclusion This chapter presented our stereoselective total synthesis of {+) dehydrotubifoline (123). This synthesis, which required the formation of 4 rings and 5 carbon-carloon bonds,was executed in 11 steps and proceeded in 26% overall yield. Our approach, which uses an intramolecular Heck reaction to assemble the bridged bicyclic subunit, addresses also the critical problem of introducing the exocyciic double bond of defined geometry. Besides the Heck cyclization, two other key steps are worth mentioning: the iodotrimethylsilane promoted cyclopropylimine-pyrroline rearrangement, and the intramolecular Diels-Alder cycloaddition, which provided the tetracyclic core common to the strychnos and aspidosperma alkaloids. This overall strategy is currently being expanded to the synthesis of more complex members of the sfryc/Jnos family. EXPERIMENTAL General Aspects: The melting points were taken with Thomas Hoover capillary melting point apparatus and are uncorrected. Proton nuclear magnetic resonance spectra (^H NMR) were obtained on Brucker AC-200, Bruker AM-250, Bruker AC-300, or Bruker AM-500 spectrometers and recorded in parts per million from an internal standard (tetramethylsilane). The NMR are reported a s follow: chemical shift [multiplicity (b=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant (Hertz), integration, and interpretation]. ^^C nuclear magnetic resonance spectra ^C NMR) were obtained on Brucker AC-200, Bruker AM- 250, Bruker AC-300 or Bruker AM-500, and are reported as follow: chemical shift (multiplicity). Infrared spectra (IR) were taken with Perkin-Elmer 283b or 1600 infrared spectrophotometer. Mass spectra were obtained on Kratos MS-30 or Kratos VG70-250s instruments at an ionization energy of 70eV. Combustion analysis were performed by M.H.W. laboratories, Phoenix, Arizona. Column chromatography was performed over EM Science Laboratories silica gel (230- 400 mesh). Medium pressure liquid chromatography (MPLC) was performed using Merck Lobar Fertigsâule prepacked silica gel columns (40-63 mm). Analytical thin layer chromatography was conducted on Merck glass plates precoated with 0.25mm mm of silica gel 60F254. TLC plates were revealed using solutions of phosphomolybdic acid, anisaldehyde or potassium permanganate. All reactions were carried out under an argon atmosphere with use of standard techniques to exclude moisture. Solvents and reagents were purchased from Aldrich (reagent 94 95 grade) and were dried and purified prior to use when considered necessary. Tetrahydrofuran (THF) was purified by distillation from potassium-benzophenone ketyl. Benzene and toluene were distilled from sodium hydride. Dimethylfonnamide was distilled from calcium hydride. 1,3-butadiene toluene, 140°C 2 2 6 2 2 7 (±)-fra/is-(6-Nltro-3-cyclcfiexen-1-yl)-benzene (227); A suspension of p-nitrostyrene (5.00 g, 33.5 mmol) in toluene was introduced in a preweighted sealed tube, and cooled to -78°C. A stream of 1,3-butadiene was bubbled into the mixture until 5 g of 1,3-butadiene had been added. The tube was sealed and heated to 140°C for 18 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude material was crystallized in methanol to afford the desired product (5.8 g, 85% yield) as a white powder: mp. 102°C; ‘'h NMR (250 MHz. 00013)6 2.38 (m, 2H, ^CHOidg). 2.74 (m, 2H, =CHCH 2). 3.39 (m, 1H, PhCH), 4.93 (m, 1H, CHNOg), 5.71 (m, 2H, CüG=Cü), 7.22 (m, 5H, A r H ) ; ^MR (63 MHz, 00013) 631.21 (t), 33.14 (t), 44.19 (d), 87.29 (d), 122.65 (d), 126.57 (d), 127.36 (d), 127. 55 (d), 128.80 (d), 140.13 (s); IR (CHgClg) 3054, 1550, 1494, 1455, 1436, 1373, 1269, 895 cm'"'; MS (El) m/e calc'd for 0., sNOg: 203.0946, found 203.0949; 156 (61), 141 (14), 128 (15), 115 (23), 91 (100), 77 (19) : Analysis calc'd for 0., 3NO2 : 0, 70.92; H, 6.45; found: 0, 71.11; H, 6.40. 96 NOg 1-AI(Hg),THF/HgO 2-T s C I.E t3N.DMAP 227 CHgClg 229 (± )-fra/i9 -4-Methyl-A/-( 6-p h e n y l* 3-cyclohexen' 1-yl)-benzenesufonamide (229); Aluminum amalgam was prepared by sequential treatment of aluminum foil (Reynolds) wit hi warm IN KOH (100 ml_/g of Al, 30 s), distilled water (2X100 mUg of Al), warm 0.5% aqueous HgCl 2 (100 ml_/g of Al, 45 s), distilled water (100 mUg of Al) and THF (100 mUg of Al). To a THF/H 2O (150:15 mL) solution of nitrocyclohexene 2 2 7 (2.00 g,10 mmol) was added, at room temperature, freshly prepared AI(Hg) (2.7 g). The mixture was stirred for 2 h at room temperature and then poured in 300 mL of THF. The resulting mixture was filtered through a cake of Celite, dried over anhydrous magnesium sulfate, and concentrated to afford the crude amine (1.60 g) as a yellow oil. To a dichloromethane solution (60 mL) of this caide amine was added triethylamine (2.0 mL,13 mmol), a catalytic amount of DMAP, and TsCI (2.30 g,12 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (15 mL). The organic phase was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography over silica gel (elution with 40% hexane in dichloromethane) yielded a yellow brown powder. One crystallization from ether/hexane afforded the desired sulfonamide (2.03 g, 64% yield) as a white powder: mp. 104°C; ^HNMR (250 MHz, CDCIg)g2.30 (m, 2H, =CHCid 2), 2.40 (s, 3H, CHgAr), 2.65 (m, 2H, =CHCid2), 2.80 (m, 1H, TsNH), 4.80 (m, 1H, CHN), 5.60 (m, 2H, CH=CH), 6.90 (d, J=11 Hz, 2H, ArH), 7.18 (m, 5H, ArH), 7.48 (d, J=8.2 Hz, 2H, ArH); ''^C NMR (63 MHz, CDCI 3) 8 21.27 (q). 97 32.53 (t), 32.89 (t). 44.84 (d), 53.29 (d), 124.44 (d), 125.99 (d), 126.63 (d), 126.85 (d). 127.41 (d), 128.52 (d), 129.32 (d), 137.17 (s). 141.64 (s). 142.75 (S); IR (KBr) 3240, 3020, 2910, 1650, 1590, 1485, 1435, 1320, 1155, 1080, 890 cm''*; MS (El) m/e calc'd for CigHg^NSOg: 327.1292, found 327.1269; 327 ( 12), 273 (39), 236 (100), 155 (61), 118 (60), 91 (90); Analysis calc'd for C.,gH 2 iN S 0 2 : C, 69.69; H, 6.46; found: C, 69.70; H, 6.56. H I H 2,3-dlbromopropenG (^^''''îl ------ 50% NaOH, PhH 229 nBu^NHSO^ 218 (±)-f/a/is-/V-(2-Bromo-2-propenyl)-4-metfiyl'A/-(6*phe nyl-S-cyclofiexen- l'yO -benzenesulfonam lde (218): To a mixture of sulfonamide 2 29 (239 mg,0.73 mmol) and 2,3-dibromopropene (175 mg, 0.87 mmol) in benzene (7.5 mL) were added nBu^HSO^ (292 mg, 0.87 mmol) and 50% aqueous NaOH (1 mL). The mixture w as stirred vigorously at room temperature for 40 min, then quenched with aqueous ammonium chloride. The organic phase was separated. The aqueous layer was extracted twice with ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (elution with 50% hexane in dichloromethane) to give the desired product (300 mg, 92% yield) as a pale yellow powder: mp. 111°C; ■'h NMR (250 MHz, CDCI3) 5 2.35 (m, 4H, CJÜ2CH=CHCH2), 2.41 (s, 3H, Ar CHg), 3.05 (m, 2H, PhCH), 3.79 (d, J=17.8 Hz, 1H, CHHCBr=), 3.81 (d, J=17.8 Hz, 1H, CHHCBr=), 4.28 (m, 1H, CHN), 5.37 (s, 1H, =CJdH), 5.47 (s, 1H, =CHH), 5.60 (m, CJd=CJd), 7.25 (m, 7H, ArH), 7.55 (d, J=7.3 Hz, 2H, ArH); NMR (63 MHz, CDCI3) Ô 21.34 (q), 31.52 (t), 36.64 (t), 44.55 (d), 52.63 (t), 58.67 (d), 119.55 (t), 125.22 (d), 125.88 (d), 126.36 (d), 127.47 (d), 127.85 (d), 128.22 98 (d). 128.81 (s). 129.32 (d), 137.83 (s), 142.46 (s). 143.04 (s); IR (CHgClg) 3020. 2900, 1595, 1485, 1330, 1150, 1085, 895 cm*'’: MS (El) m/e calc'd for C22H24NS02Br: 445.0712, found 445.0723; 447 (11), 445 (11), 393 (7), 391 (7). 356 (43), 354 (42), 312 (21), 155 (42), 91 (82). ______^OH nBugSnH Ig, COU SnBua 232 AIBN.A 233 234 (Z)-2-lodo-2-buten*1-ol (234): To a mixture of 2-butyn- 1-ol (1.40 g, 20.0 mmol) and nBugSnH (1.96 mL, 7.25 mmol) w as added AIBN (164 mg, 1.00 mmol) at room temperature in one portion. The mixture was stirred at 85°C for 2 h. The solution was cooled to room temperature and diluted with CCI 4 (50 mL). An excess of iodine (1.90 g, 7.50 mmol) was added at 0°C. The mixture was warmed up to room temperature, stirred for 1 h, and quenched with 5% aqueous sodium bisulfite. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (30% hexane in dichloromethane) to afford the desired alcohol (1.24 g, 86 % yield based on nBugSnH) a s a pale yellow oil: ’ h NMR (250 MHz, CDCI 3) 5 1.70 (d, J=7 Hz, 3H, zzCHCHg), 2.92 (bs, 1H, OH), 4.21 (s, 2H, CH2), 5.98 (q, J=7 Hz, 1H, =CH); ’ NMR (63 MHz, CDCI 3 ) 5 21.4 (q), 71.4 (t), 109.6 (s), 131.0 (d); IR (neat) 3300,1650 cm*'’. 99 -O T s "I 2 3 8 50% NaOH, PhH 229 nBu^NHSO^ 219 (±)-[1 a(Z),6p]-W -(2-lodo-2-butenyl)-4-methyI-/V-(6-phe nyl-S-cyclohexen- l-yO-benzensulfonamide (219); A solution of alcohol 234 (1.1 g, 5.5 mmol), EtgN (836 mL, 6.0 mmol) and DMAP (61 mg, 0.5 mmol) in dichloromethane (10 mL) was treated with TsCI (1.05 g, 5.5 mmol) at 0°C. The mixture was stirred at room temperature for 3 h and quenched with water. The organic phase was separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to afford the cmde tosylate as a yellow oil which was used without further purification, ''h NMR (250 MHz, 00013)8 1.70 (d, J=6.5Hz, 3H, 0 Ü3 0 H=), 2.44 (s, 2H. ArOHg), 4.72 (s, 2H, OHgOTs), 6.02 (q, J=6.5 Hz, 1H, 0H=), 7.33 (d, J=7.8 Hz, 2H, ArH), 7.50 (d, J=7.8 Hz, 2H, ArH). To a mixture of sulfonamide 229 (100 mg, 0.3 mmol) and tosylate 2 38 (144 mg, 0.40 mmol) in benzene (3 mL) were added nBu^HS0^(134 mg, 0.40 mmol) and 50% aqueous NaOH (0.4 mL). The mixture was stirred vigorously at room temperature for 3 h, then quenched with IN HOI (1 mL) and distilled water (5 mL). The organic phase was separated. The aqueous layer was extracted twice with ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography over silica gel (elution with 50% dichloromethane in hexane) afforded the desired product (110 mg, 72% yield) as a pale yellow solid (crystallized from ether): mp. 77°0; ^H NMR (250 MHz, ODOI3) 5 1.49 (d, J =6 Hz, 3H, OjjgOH=), 2.30 (m, 4H, OH2 CH=OHOH2). 2.38 (s, 3H, 0 H3Ar), 3.05 (m, 1H, PhOH), 3.80 (d, J=17.8 Hz, 1H, NOHHOBr=), 3.95 (d, J=17.8 Hz, 1H, NOHHCBr=), 10 0 4.30 (m, 1H, CHN), 5.41 (q, J =6 Hz. 1H, czCHCHg), 5.61 (m, 2H. CHC=CtD, 7.10 (m, 7H, ArH). 7.52 (d. J=7 Hz. 2H. ArH); NMR (75 MHz. GDCIg) 621.33 (q). 21.86 (q). 31.44 (t). 36.84 (1). 44.65 (d). 56.68 (t). 58.59 (d). 104.19 (s). 125.21 (d), 125.86 (d). 126.27 (d). 127.53 (d). 127.92 (d). 128.14 (d), 129.21 (d). 133.41 (d). 138.12 (s). 142.73 (s). 142.85 (S); IR (CHgClg) 3010. 2900. 1592. 1485. 1330. 1150. 1085, 748 cm'^; MS (El) m/e calc'd for CggHggNSOgl: 507.0730, found 507.0691; 507 (18). 416 (55). 236 (43). 169 (60). 155 (50), 91 (100). ^ O H nBUgSnH Ig. CCU 232 23( 237 BuoSn' 235 (E)-2'lodo-2-buten-1-ol (237): To a mixture of 2-butyn-1-ol (215 mg, 3.0 mmol) and nBu^SnH (0.9 mL. 3.3 mmol) in benzene (6 mL) was added a catalytic amount of Pd(PPfig)^ (69 mg, 0.06 mmoi) at 0°G. The reaction mixture was stirred at room temperature for 8 h. The soiution was washed with 10% aqueous KF. The organic phase was separated. The aqueous layer was extracted twice with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gei (elution with 50% hexane in dichloromethane) to give two separable regioisomers 235 and 2 3 6 in a 5:1 ratio. Regioisomer 2 3 6 was further treated with iodine (0.95 g. 3.75 mmol) in GGI 4 (50 mL) at 0°G. The mixture was warmed up to room temperature, stirred for 1 h, and quenched with 5% aqueous sodium bisulfite. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous 101 magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (30% hexane in dichloromethane) to afford the desired alcohol (2 37) (420 mg, 70% yield) as a pale yellow oil: ^ H NMR (300 MHz, CDCIg)61.62 (d, J=7 Hz, 3H, =CHCHg), 3.48 (bs, 1H, OH), 4.11 (bs, 2H, CHg), 6.21 (q, J=7 Hz, 1H, =CHMe); NMR (75 MHz, CDCIg)8 16.36 (q), 63.81 (t), 102.23 (s), 137.37 (d); IR (neat) 3300,1650 cm ''. Ü! ^ 50% NaOH, PhH 229 nBu^NHSO^ 220 (±)-[1 a(E),6p]-Af-(2-lodo-2-butenyl)-4-methyl-Af-(6*phenyl-3-cyclohexen- 1-yl)-benzensulfonam ide (220). To a solution of alcohol 2 3 7 (222 mg, 1.1 mmol), EtgN (167 mL, 1.2 mmol) and DMAP (13 mg, 0.1 mmol) in dichloromethane (2 mL) was added TsCI (210 mg, 1.1 mmol) in one portion at 0°C. The mixture was stirred at room temperature for 3 h and quenched with water. The organic phase was separated. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to afford the crude tosylate as a yellow oil which was used without further purification. To a mixture of sulfonamide 2 2 9 (248 mg, 0.758 mmol) and allylic tosylate 2 3 9 (217 mg, 0.834 mmol) in benzene (5 mL) were added nBu^HSO^ (175 mg, 0.5 mmol) and 50% aqueous NaOH (0.5 mL). The mixture was stirred vigorously at room temperature for 30 min, then quenched with aqueous ammonium chloride. The organic phase was separated. The aqueous layer was exctracted twice with ether. The organic layers were combined, dried over anhydrous 102 sodium sulfate and concentrated under reduced pressure. Purification by flashi ctiromatograpfiy over silica gel (elution with 50% dichloromethane in hexane) afforded the desired product (321 mg, 84% yield) as a white solid; mp. 83°C; NMR (300 MHz, CDCIg) 51.57 (d, J=7 Hz, 3H, CH3CH4 , 2.30 (m. 2H, CH2CH=CHCH2), 2.37 (s, 3H, CHgAr), 2.57 (m, 1H, CH2CH=CHCJdH), 2.78 (m, 1H, CH 2CH=CHCHH), 3.30 (m, 1H, PhCH), 3.60 (d, J=15.6 Hz, 1H, NCJdH), 3.85 (d, J=15.6 Hz, 1H, NCHhD, 4.18 (m, 1H, CHN), 5.68 (m, 2H, CH=CH), 6.30 (q, J=7 Hz, 3H, =CHCjd3). 7.12 (d, J =8 Hz, 2H, ArH), 7.28 (m, 5H, ArH), 7.51 (d, J =8 Hz, 2H, ArH); NMR (63 MHz, CDCIg) 5 16.85 (q). 21.39 (q), 32.09 (t), 36.75 (t), 45.29 (d), 51.92 (t), 60.35 (d), 96.94 (s), 125.49 (d), 126.08 (d), 126.49 (d), 127.76 (d), 128.26 (d), 128.53 (d), 129.05 (d), 138.61 (s), 141.90 (d), 142.63 (S ), 142.79 (s); IR (KBr) 3027, 2918, 1494, 1453, 1434, 1338, 1155, 1092 cm'^;MS (El) m/e calc'd for CgsHgsNSOgi: 507.0730, found 507.0726; 507 (5), 416 (76), 326 (37), 236 (74), 170 (46), 91 (100); Analysis calc'd for CggHggNSOgI: C, 54.44; H, 5.16; found: C, 54.50; H, 5.24. 218 230 (±)-exo-4-M ethylene-2-[(4-m ethylphenyi)sulfonyl]'8-phenyl-2- azablcyclo[3.3.1]non-6-ene (230): To a solution of vinyl bromide 218 (177 mg,0.397 mmol) in acetonitrile (8 mL) were added sequentially at room temperature triethylamine (120 pL, 0.794 mmol), triphenylphosphine (53.1 mg, 0.202 mmol) and palladium acetate (15.1 mg, 0.068 mmol). The mixture was stirred at room temperature for 10 min, then at reflux for 3 h. The reaction 103 was monitored by TLC (elution with 10% ethyl acetate in hexane). The solution was concentrated and the brown residue was purified by flash chromatography over silica gel (elution with 50% hexane in dichloromethane) to afford the product (126 mg, 85% yield) as a white powder: mp. 102°C; ■'h NMR (500 MHz, 0 0 0 1 ^)6 1 .4 0 (d, J=12.5 Hz, 1H, 0HH0H(0H=)(0=)), 1.77 (d, J=12.5 Hz, 1H, 0HJd0H(0H=)(0=)), 2.38 (s, 3H, CHgAr), 2.96 (t. J=2.8 Hz, 1H, =COHO=), 3.61 (bs, 1H, PhOH), 4.05 (d, J=14.1 Hz, 1H. OHHNTs), 4.18 (d, J=14.1 Hz, 1H, OHJÜNTs), 4.10 (bs, 1H, OHNTs), 4.82 (s, 1H, =CJdH), 4.84 (s, 1H, =OHU), 5.88 (dd, J= 9.8,3.7 Hz, 1H, OM=CH), 5.98 (dd. J=9.8, 6.2 Hz, 1H, OH=OÜ), 7.25 (m, 7H, AiH), 7.72 (d, J=8.1 Hz, 2H, ArH); ^ % NMR (63 MHz, ODOIg) 6 21.38 (q), 26.25 (t), 36.80 (d), 45.36 (t), 46.30 (d), 54.53 (d), 109.71 (t), 126.62 (d), 126.98 (d), 128.27 (d), 128.40 (d), 129.27 (d), 129.54 (d), 130.09 (d), 137.70 (s), 142.02 (S), 142.39 (s), 143.06 (s); IR (KBr) 3010, 2905, 1595, 1485, 1435, 1335, 1150, 930 cm '^M S (El) m /e calc'd for O22H23NSO2 : 365.1449, found 365.1486; 365 (16), 210 (100), 167 (23), 155 (17), 91 (49). PdfOAc), PPh,, MeCN, A 2 1 9 2 4 0 (±)-(1 a,4E,5a,8a)-4-Ethylldene-2-[(4 -met hy Ip he nyl)sulfonyl]-8-phenyl-2- a z a b lc y c lo [3 .3 .1 ]n o n -6 -e n e (240): To a solution of vinyl iodide 2 1 9(268 mg,0.520 mmol) in acetonitrile (10 mL) were added sequentially, at room temperature, triethylamine (158 pL, 1.04 mmol), triphenylphosphine (70 mg, 0.265 mmol), and palladium acetate (20 mg, 0.088 mmol). The mixture was stirred at room temperature for 10 min, then at reflux for 45 min. The reaction 104 was monitored by TLC (elution with 10% ethyl acetate in hexane). The solution was concentrated and the brown residue was purified by flash chromatography over silica gel (elution with 50% hexane in dichloromethane) to afford the product (176 mg, 90% yield) as a white powder: mp. 103°G: ■’h NMR (250 MHz, CDCI 3) 6 1.30 (d, J=12.5 Hz. 1H, CHHCH(CH=)(C=)). 1.63 (d, J=S.5 Hz, 3H, CHgCH=), 1.75 (d, J=12.5 Hz, IN, OHJdOH(GH=)(C=)), 2.39 (bs, 3H, GHgPh), 3.32 (bs, 1H, PhGH), 3.62 (s, 1H, =GGHG=), 4.05 (m, 3H, GHNGH 2). 5.38 (q, J=6.5 Hz, 1H, =GÜCH 3), 5.82 (m, 2H, GH=GH), 7.23 (m, 7H, ArH), 7.71 (d, J=8.0 Hz, 2H, ArH); ^^G NMR (63 MHz, GDGI 3) Ô 12.44 (q), 21.46 (q), 25.66 (t), 29.81 (d), 46.30 (d), 46.95 (t), 55.21 (d), 119.30 (d), 126.64 (d), 127.18 (d), 128.44 (d), 129.18 (d), 129.55 (d), 133.27 (s), 137.71 (s), 142.29 (s), 143.02 (s); IR (KBr) 3010, 2920, 1595, 1490, 1440, 1335, 1150 cm‘‘>;MS(EI) m/e calc'd for G 23H25NSO2: 379.1606, found 379.1624; 379 (12), 224 (100), 169 (18), 117(12), 91 (39); Analysis calc'd for G23H25NSO2 : G, 72.79; H, 6.64; found: G, 72.64; H, 6.64. cA'220 241 (± )'(1 a,4Z,5a,8a)-4>Ethyl!dene-2-[(4-m ethylphenyl)sulfonyl]-8-phenyl-2> a z a b ic y c lo [3 .3 .1 ]n o n -6 -e n e (241): To a solution of vinyl iodide 2 2 0(191 mg,0.378 mmol) in acetonitrile (8 mL) were added sequentially, at room temperature triethylamine (116 pL, 0.757 mmol), triphenylphosphine (51 mg, 0.193 mmol), and palladium acetate (14.5 mg, 0.0643 mmol). The mixture was stirred at room temperature for 10 min, then at reflux for 90 min. The reaction 105 was monitored by TLC (elution with 10% ethyl acetate in hexane). The solution was concentrated and the brown residue was purified by flash chromatography over silica gel (elution with 50% hexane in dichloromethane) to afford the product (132 mg, 90% yield) as a white powder: mp. 105°C; "'h NMR (300 MHz, CDCIg) 5 1.30 (d, J=12.5 Hz, 1H, CiJHCH(CH=)(C=)), 1.61 (d, J=6.8 Hz, 3H, CHgCH=), 1.73 (d, J=12.5 Hz, 1H, CH|dCH(CH=)(C=)), 2.39 (bs, CHgAr), 2.83 (t, 2.6H, PhCH), 3.60 (S, 1H, =CCHC=), 3.83 (d, 14.4H, CHHN), 4.13 (s, 1H, CHN), 4.52 (d, 14.4H, CHHN), 5.30 (q, 6.8 H, =CHCHg), 5.80 (m, 2H, CH=CH), 7.25 (m. 7H, ArH), 7.70 (d, J=8.2 Hz, 2H, ArH): ■'^c NMR (75 MHz, CDCIg) 813.06 (q), 21.44 (q), 26.29 (t), 38.00 (d), 40.02 (t), 46.69 (d), 55.12 (d), 119.02 (d), 126.63 (d), 126.95 (d), 128.39 (d), 128.42 (d), 128.63 (d), 129.54 (d), 130.71 (d), 133.17 (S ), 138.04 (s), 142.24 (s), 142.98 (s); IR (KBr) 3025, 2923, 1598, 1493, 1450, 1338, 1158 cm"'': MS (El) m/e calc'd for CgsHggNSOg: 379.1606, found 379.1603; 379 (3), 224 (49), 169 (15), 117(19), 91 (100); Analysis calc'd for CggHggNSOg: C, 72.79; H, 6.64; found: C, 72.19; H, 6.80. 1- isoprene, toluene, A Z-NaNg, HgO, nBu^NHSO,, 2 4 2 3 -toluene, reflux; then MeOH 2 4 4 I 2 4 3 (±)-fra/is-[(N-Carbom ethoxy-6-am ino)-3-cyclohexen-l-yl]-be nzene(2 4 4): A toluene solution (10 ml) of isoprene (3 mL, 30 mmol) and cinnamoyl chloride (2.5 g,15 mmol) was heated in a sealed tube to 190°C for one day. After cooling to room temperature, an aqueous solution (5 mL) of sodium azide (1.17 g,18 mmol) and nBu^NHSO^ (1 g, 3 mmol) was added. The reaction mixture was stirred vigorously at room temperature for 15 min. The phases were 106 separated and the aqueous layer was exctracted twice with toiuene. The combined organic layers were dried over magnesium sulfate, and then heated to reflux for 4 h. h/fethanol (10 mL) was added to quench the isocyanate. The reaction mixture was kept at reflux for three hours. After cooling, the solvent was evaporated and the crude product was purified by flash chromatography over silica gel (elution with 50% hexane in dichloromethane) to afford a 3 to 1 mixture of regioisomers 243 and 2 44 (80% yield). One crystallization in ether/hexane yielded a single isomer (24 4) as a white powder: mp. 91 °C; NMR (300 MHz, CDCIg) S 1.70 (s, 3H, CHgC=), 1.95 (m. 1H, CüHCMe=), 2.25 (m, 2H, CH 2CMe=CHCÜ2). 2.50 (bd, J=12.5 Hz, 1H, CHJJCMe=), 2.90 (q, J=8.4 Hz, 1H, PhCH), 3.55 (s, 3H, OCHg), 3.98 (bs. 1H, CHN), 4.50 (bs, 1H, NH), 5.37 (bs, 1H. =CH), 7.20 (m, 5H, ArH); ^ NMR (63 MHz, CDCIg) 8 22.96 (q), 31.92 (t), 37.64 (t), 45.34 (d), 50.61 (q), 51.80 (d), 118.97 (d), 126.56 (d), 127.57 (d), 128.48 (d), 133.64 (S ), 142.90 (s), 156.45 (s); IR (KBr) 3300, 3025, 2940, 1680, 1535, 1430, 1245, 1165cm-1; MS (El) m/e calc'd for C^gH^gNOg: 245.1415, found 245.1406; 245 (3), 177 (46), 170 ( 100), 155 (32), 91 (32); Analysis calc'd for C^ gH^ gNOg: C, 73.44; H, 7.81 ; found: C, 73.58; H, 7.60. H- ^COgMe 1-NaOH, EtOH, reflux 2-TsCI, EtgN, DMAP CH2CI2 (±)-frans-4-MetfiyNA/-(4-methyl-6-phenyl-3>cyclohexen-l>yl)-bezensulfonamlde (245): Method A: To a solution of carbamate 244 (272 mg,1.11 mmol) in 95% ethanol (8 mL) was added 50% aqueous NaOH (2 mL). The solution was stirred at reflux for 16h. The mixture was concentrated to half its volume, washed with aqueous ammonium chloride, and 107 extracted with ether. The combined ether layers were dried over magnesium sulfate and concentrated. The crude amine was then dissolved in dichloromethane (15 mL). Triethylamine (222 jiL,1.44 mmol), TsCI (330 mg,1.7 mmol), and a catalytic amount of DMAP were successively added at room temperature. The mixture was stirred at room temperature ovemight. The reaction was quenched with aqueous ammonium chloride. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography over silica gel (elution with 40% hexane in dichloromethane) yielded the expected sulfonamide 2 4 5 (301 mg, 80%) as a pale yellow powder: mp. 112°C: ^ H NMR (300 MHz, CDCIg) 81.66 (s, 3H, CHgC-), 2.25 (m. 4H, CH2C=CHCH2). 2.43 (s, 3H. CHgAr), 2.82 (m, 1H, PhCH), 3.35 (m. 1H, CHN), 4.40 (bd, J=5.1 Hz, 1H, NH), 5.31 (bs, 1H, =CH), 6.90 (m, 2H, ArH), 7.19 (m, 5H, ArH), 7.50 (d, J=8.0 Hz, 2H, ArH): NMR (63 MHz, CDCIg) 8 21.50 (q), 22.89 (q), 32.57 (t), 37.16 (t), 45.33 (d), 53.39 (d), 118.71 (d), 126.97 (d), 127.16 (d), 127.52 (d), 128.81 (d), 129.52 (d), 133.44 (s), 137.05 (s), 141.70 (s), 143.07 (s); IR (neat) 3260, 3020, 2905, 1700, 1595, 1490, 1435, 1320, 1150 cm'"'; MS (El) m/ecalc'dforC2oH23NS02: 341.1449, found 341.1438; 341 (3), 273 (18), 191 (35), 170 (100), 155 (64), 118 (36), 91 ( 86 ). Isoprene, UCIO 4 ether, 70°C, 24h p-nltrostyrene 246 (±)-fra/)s-(4-Methyl-6-phenyl-3-cycfohexen-1-yl)-benzene (246): A mixture of p- nitrostyrene (5.0 g, 33.5 mmol), isoprene (10 mL, 100.5 mmol), and anhydrous lithium perchlorate (16 g, 150 mmol) in ether (35 mL) was heated in a sealed tube to 70°C for two days. 108 The mixture was diluted with ether (200 mL), and washed with water (2x100 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to afford the desired compound (6.50 g, 90% yield) as a pale yellow solid: mp. 97°C; NMR (250 MHz, CDCI 3) 5 1.68 (s, 3H, =CCH3), 2.30 (m, 2H, =CHChl 2). 2.70 (m. 2H. =CHCÜ2). 3.42 (m, 1H. PhCH), 4.90 (m, 1H, CHNOg), 5.38 (s, 1H. =CH), 7.20 (m, 5H, ArH); NMR (63 MHz. CDCI 3) 5 22.7 (q). 31.20 (t). 37.91 (t), 44.51 (d), 87.38 (d). 116.81 (d), 127.34 (d), 127.51 (d), 128.81 (d), 134.07 (s), 140.20 (s); IR (KBr) 3020, 2840, 1580, 1380, 690 cm"'': MS (El) ^Ve^70 (80), 155 (76), 91 (100), 77 (22). NO. 1-AI(Hg), THF, HgO 2-TsCI, EtaN, DMAP CH2CI2 2 4 6 2 4 5 (±)-frans-4-Methyl-W -(4-methyl-6-pheny!-3-cyclohexen-1-yl)-bezensulfonamlde (2 4 5 ): M ethod B: To a solution of nitro compound 2 4 6 (1.1 g, 5 mmol) in THF (75 mL) and water (7.5 mL), was added freshly prepared aluminum amalgam (2.7 g) in one portion at room temperature. The heterogeneous mixture was stirred at room temperature for 24 h, and then poured into 300 mL of THF. The mixture was filtered through a cake of Celite and the filtrate was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude primary amine, which was not further purified. The amine was dissolved in dichioromethane (30 mL). Triethylamine (1.0 mL, 6.5 mmol), TsCI (1.2 g, 6.0 mmol) and DMAP (50 mg, 0.40 mmol) were successively added at room temperature. The solution was stirred at room temperature for 16 h. The reaction was quenched with aqueous ammonium chloride. The layers were separated. The aqueous layer was extracted with dichioromethane. The combined organic layers were dried 109 over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography over silica gel (elution with 10% ethyl acetate in hexane) yielded the desired sulfonamide 2 4 5 (1.2 g, 70% yield) as a pale yellow powder. T s O - r 2 3 8 50% NaOH, PhH 2 4 5 I nBu,NHSO^ 2 4 7 (±)-[1 a(E),6P]-Af-(2-lodo-2-butenyl)-4-m ethyl*N-(4-m ethyl*6 1.20 mmol) and tosylate 2 3 8 (540 mg, 1.50 mmol) in benzene (10 mL) were added nBu^HSO^ (441 mg, 1.30 mmol), and 50% aqueous NaOH (2 mL). The mixture was stirred vigorously at room temperature for 2 h, then quenched with IN MCI (1 mL) and distilled water (5 mL). The organic phase was separated. The aqueous layer was extracted twice with ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (elution with 10% ethyl acetate in hexane) to give the desired product (432 mg, 70% yield) as a pale yellow viscous oil: ^HNMR (300 MHz, CDCIg) 6 1.48 (d, J=6.0 Hz, 3H, C%CH=), 1.60 (s, 3H, CHgC^), 2.20 (m, 4H, CÜ2C=CH), 2.39 (s, 3H, CH^Ar), 3.05 (m, 1H, PhCH), 3.82 (d, J=17.0 Hz, 1H, CJdHN), 3.90 (d, J=17.0 Hz, 1H, CHJdN), 4.26 (m, 1H, CHN), 5.29 (bs, 1H, =CHCH 2), 5.42 (q, J=6.0 Hz, 1H, =ChlCH 3), 7.12 (m, 7H, ArH), 7.54 (d, J=8.0 Hz, 2H, ArH); ^^CNMR (63 fvlHz, CDCIg)8 21.46 (q), 21.96 (q), 22.60 (q), 31.07 (t), 41.67 (t), 44.86 (d), 56.67 (t), 58.70 (d), 104.29 (s), 119.46 (d), 125.34 (s), 126.37 (d), 127.67 (d), 128.00 (d), 128.29 (d), 129.34 (d), 133.29 (s), 133.38 (d). 110 138.22 (s). 143.00 (s): IR (neat) 3020, 2900, 1595, 1590, 1430, 1330, 1150, 1085 cm"''; MS (El) m/e calc'd for Cg^HggNSOgl: 521.0887, found 521.0902; 521 (34), 453 (26), 430 (59), 326 (41), 170 (45), 91 (100). P d (O A c )2, EtgN PPha, MeCN, à 247 I 249 (±)-(1 a,4E,5a,8a)-4-Ethyllde ne-6-methyl-2-[(4-methylphenyl)sulfonyl]-8- p h e n y l-2 -a z a b ic y c lo [3 .3 .1 ]n o n -6 -e n e (249): To a solution of vinyl iodide 2 4 7 (1 5 7 mg, 0.300 mmol) in acetonitrile (6 mL) were added sequentially, at room temperature, triethylamine (92 pi, 0.600 mmol), triphenylphosphine (39 mg, 0.150 mmol), and palladium acetate (12 mg, 0.050 mmol). The mixture was stirred at room temperature for 10 min, then at reflux for 45 min. The reaction was monitored by TLC (elution with 10% ethyl acetate in hexane). The solution was quenched with water (3 mL). The organic phase v/as separated. The aqueous layer was extracted twice with dichioromethane. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown residue was purified by flash chromatography over silica gel (elution with 50% hexane in dichioromethane) to afford the product (106 mg, 90% yield) as a white powder: mp. 113°C; NMR (250 MHz, CDCIg) 6 1.30 (m, 1H, CUHCH(C=)2), 1.65 (m, 1H, CHHCH(C=)2), 1.68 (d, J=6.7 Hz, 3H, CHgCH=), 1.75 (S, 3H, CHgC=), 2.41 (s, 3H, CHgAr), 3.15 (bS, =CCHC=), 3.53 (bs, PhCH), 4.00 (m, 3H, CHNCJJg), 5.47 (q, J=6.7 Hz. 1H, =CHCHg), 5.56 (bs, 1H, =CÜCH), 7.20 (m, 7H, ArH), 7.73 (d, 8.0H, ArH); ‘‘^C NMR (63 MHz, CDCIg) 5 12.56 (q), 21.50 (q), 22.27 (q), 26.31 (t), 34.73 (d), 111 46.28 (d), 47.10 (t), 54.53 (d), 119.85 (d), 123.36 (d), 126.55 (d), 127.17 (d), 128.41 (d). 129.58 (d), 133.06 (s). 137.08 (s), 138.08 (S ) . 143.01 (S ) , 143.03 (s); IR (KBr) 3020, 2920, 1592, 1485, 1438, 1325, 1150, 1090 cm""': MS (El) m/e calc'd for Cg^HgyNSOg: 393.1762, found 393.1753; 393 (24), 238 (60), 183 (23), 155 (23), 91 (100); Analysis calc'd for Cg^HgyNSOg: C, 73.25; H, 6.92; found; C. 73.28; H, 6.99. Pd(OAc)î, DMF nBu^NBr. K^CO^ 247 ■ 249 > 250 (±)-frans-(1a,4£,5a,8a)-4-Ethylldene-6-metfienyl-2>[(4-metfiylpfienyl)sulfonyl]- 8-phenyl>2-azabicyclo[3.3.1]no-6-ene (250): To a solution of vinyl iodide 247 (45 mg,0.086 mmol) in DMF (1 mL) were added sequentially, at room temperature, K 2CO3 (60 mg, 0.432 mmol), nBu^NCI (37 mg, 0.129 mmol), and palladium acetate (1.0 mg, 0.004 mmol). The mixture was stirred at 80°C for 3h. The reaction was monitored by TLC (elution with 10% ethyl acetate in hexane). The solution was quenched with water (3 mL), and diluted with ether. The organic phase was separated. The aqueous layer was extracted twice with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The brown residue was purified, first by flash chromatography over silica gel (elution with 50% hexane in dichioromethane), then by MPLC (same eluent) to afford two fractions. The first fraction contained the exocyclic alkene 2 50 (8.5 mg, 25% yield), and the second, the endocyclic isomer 249 (17 mg, 50% yield). Bicycle 2 5 0: mp. 109°C; ^ H NMR (300 MHz, CDCIg) 6 1.40 (dt, J=13.7, 2.6 Hz, 1H, CJdHCH(C=)2), 1.60 (d, J=6.9 Hz, 3H, CHgCH^), 112 1.70 (dt. J=13.7, 2.6 Hz, 1H, CHJdCH(C=)2), 2.39 (s. 3H, CHgAr), 2.52 (d, J=15 Hz, 1H. CHHC=), 2.96 (dd, J=15, 7 Hz, 1H, CHJiC=), 3.37 (bs, 1H, CH(C=) 2). 3.50 (bd, J=7 Hz, 1H, PhCH), 3.61 (d, J=13.4 Hz, 1H, NCtlH), 3.93 (bs, 1H, CHN), 4.08 (d, J=13.4 Hz, 1H, NCHJd), 4.90 (s, 1H, =CHH), 5.00 (s, 1H, =CHH), 5.54 (q, 6.9H, =CHCHg), 7.22 (m, 5H, ArH), 7.53 (d, J=7.2 Hz, 2H, ArH), 7.70 (d, J=8.3 Hz, 2H, ArH); ^^C NMR (63 MHz, CDCIg) 5 13.15 (q), 21.48 (q), 25.33 (t), 30.88 (t), 38.47 (d), 45.69 (d), 48.88 (t), 55.90 (d), 110.54 (t), 123.40 (d), 126.17 (d), 127.43 (d), 128.21 (d), 128.39 (d), 129.68 (d), 133.69 (s), 134.79 (s), 143.32 (s), 144.32 (s), 147.32 (s); IR (CHgClg) 3040, 2920, 1595, 1490, 1450, 1345, 1160, 1090 cm''": MS (El) /TVecalc'dfor Cg^HgyNSOg: 393.1762, found 393.1753; 393 (4), 302 (10), 262 (29), 238 (36), 146 (13), 106 (16), 91 (100). NH. 1-SOCIg, PhH, refux 2-1,3-butadlene, toi., 140°C S-NaNa, HgO, toL.oBu^NHSO^ 4-HCI, toi., reflux; then NaOH NO. 2 5 9 2 6 0 (± )-fra n 9 -2-(6-A m lno- 3-cyclohexen- 1>yl)-1-nltro-benzene (260): A mixture of ortho nitro cinnamic acid (800 mg, 4 mmol), thionyl chloride (8 mL) and benzene (8 mL) w as stirred at reflux for 35 min. The solution was then cooled to room temperature and concentrated to afford a quantitative yield of ortho nitro cinnamoyl chloride, a beige solid which was used in the next step without further purification. A suspension of ortho nitro cinnamoyl chloride (846 mg, 4 mmol) in toluene (4 mL) was cooled to -78°C (dry ice acetone bath), and a stream of butadiene was bubbled into the preweighted sealed tube ( 2.6 g,48 mmol of butadiene were added). The tube was sealed and heated to 140°C (oil bath) for 18 h. After cooling to room temperature, a solution of nBu^NHSO^ (330 mg,1 mmol) and sodium azide (667 mg, 10 mmol) in water (2 mL) was added. 113 The mixture was stirred vigorously at room temperature for 20 min. The phases were separated and the aqueous layer was extracted with toluene. The combined organic layers were dried over magnesium sulfate and filtered. Concentrated HOI (0.5 mL) was added to the toluene solution, which was then heated to reflux for 1h. The heterogeneous mixture was cooled to 0°C (ice water bath) and the ammonium salt (651 mg) was collected by suction filtration. The free amine was obtained upon basification with aqueous sodium hydroxide, followed by extraction with ether (558 mg, 64% yield): mp. 96°C: NMR (200 MHz, CDCIg) S 1.12 (bs, 2H, NHg), 1.95 (m, 1H, =CCH), 2.22 (m, 1H, =CCH), 2.50 (m, 2H, =CH), 3.27 (m, 2H, CHN and ArCH), 5.31 (m, 2H, CH=CH), 7.37 (t, J=8.1 Hz, 1H, ArH), 7.46 (d, J=8.1 Hz, 1H, ArH), 7.61 (t, J=8.1 Hz, 1H, ArH), 7.71 (d, J=8.1 Hz, 1H, ArH); 1 3 c NMR (63 MHz, CDCIg) 534.07 (t), 35.44 (t), 43.67 (d), 50.85 (d), 123.74 (d), 125.57 (d), 125.91 (d), 126.96 (d), 128.09 (d), 132.58 (d), 138.07 (s), 151.61 (S); IR (CHgClg) 3408, 3029, 2923, 1644, 1608, 1520, 1435, 1351 cm‘1; MS (El) m/e calc'd for C12H14N2O2: 218.1055, found 218.1131; 219 (11), 184(12), 172(15), 147(12), 115(13), 82 (100), 77 (15), 51 ( 8 ); Analysis calc'd for C^ 4 N2 O2 : C, 66.04; H, 6.47; found: C, 66.07; H, 6.31. S O gP h NH. S O gPh NO. MeOH, reflux, 2 h 2 6 0 (±)-fra/}s-2-[/V-(2-Phenylsulfonyl)ethyl-6>amlno-3-cyclohexe n-1 -y I]-1-nitro b e n z e n e (261 ): A mixture of amine 2 6 0 (863 mg, 3.959 mmol) and vinyl phenyl sulfone (673 mg, 3.959 mmol) in methanol ( 8 mL) was stirred at reflux for 2 h. The solution was cooled to room 114 temperature and concentrated. One recrystallization in ettier / hexane afforded the product (1.5 g, 98% yield) as a pure yellow solid: mp. 95°C (dec); NMR (300 MHz, CDCIg)S 1.80 (m, 1H, =CCH), 2.20 (m, 1H, =CCH), 2.42 (m, 2H, =CCH x2). 3.00 (m. 5H, NCU2C h 2S 0 2 Ph and CHN). 3.32 (m. 1H, ArCH), 5.70 (m, 2H, CH=CH), 7.50 (m, 9H, ArH); ^ ^C NMR (63 MHz, CDCIg) 5 31.58 (t), 32.84 (t), 40.01 (d), 40.14 (t), 55.95 (d), 56.12 (t), 124.03 (d), 124.86 (d), 126.05 (d), 127.17 (d). 127.82 (d), 128.37 (d), 129.24 (d), 132.70 (d), 133.70 (d), 137.75 (s). 139.25 (s), 151.06 (s); IR (CHgClg) 3395, 3028, 2928, 1666, 1607, 1524, 1306, 1148 cm'"'; MS (El) m/e calc'd for C2 0 H2 2 N2 SO 4 : 386.1300, found 386.1291; 386 (12), 369 (21). 341 (21), 315 (41), 250 (100), 137 (49), 77 (94); Analysis calc'd for C2 0 H2 2 N2 SO 4 : C, 62.16; H. 5.74; found: C, 62.30; H, 5.71. 2,3-dibromopropene DMF,K2C03,90‘>C, 6 h NO; NO; 2 6 1 2 6 2 (±)-frans-2-[N-(2-Phenylsulfonyl)ethyl-W -(2-bromo-2-propenyl)-6-amlno-3- cyclohexen-1-yl]*1>nltro-benzene (262): A mixture of secondary amine 261 (405 mg, 1.117 mmol), 2,3-dibromopropene (577 mL, 5.587 mmol) and KgCOg (772 mg, 5.587 mmol) in DMF (2 mL) w as stirred at 90°C for 6 h. The mixture was diiuted with dichioromethane and washed with water. The phases were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (elution with 17% ethyl acetate in hexane) to give the tertiary amine 2 6 2 (531 mg, 94% yieid) as a paie yellow solid: mp. 122®C (dec); ^HNMR (250 MHz, CDCIg) 52.15 (m, 3H, =CCH x3), 2.50 (m. 115 1H, =CCH), 2.72 (m. 2H, CH2SO 2 PN, 2.85 (m, 1H, CHN), 3.10 (m, 4H. CHN x4), 3.45 (m, 1H, ArH), 5.22 (two s, 2H, =GH2), 5.68 (m, 2H, CH=CH), 7.35 (m, 2H, ArH), 7.60 (m, 3H, ArH), 7.85 (d, J=8.0 Hz, 2H, ArH): ‘‘^ 0 NMR (63 MHz, CDGI 3 ) 8 25.52 (t), 36.28 (t), 38.50 (d). 44.25 (t), 55.08 (t), 59.10 (t). 59.97 (d), 118.33 (t), 123.76 (d), 125.13 (d), 126.10 (d), 126.77 (d), 127.81 (d), 129.29 (d), 129.88 (d), 131.65 (s), 132.18 (d), 133.73 (d). 137.76 (s). 139.02 (s), 150.64 (s); IR (GH2GI2) 3026, 2917, 1607, 1520, 1480, 1446, 1352, 1306, 1148 c m 'MS (El) m/e calc'd for ^ 23^ 25^ 2 0 4 8 8 ^ 504.0719, found 504.0736; 504 ( 8 ), 425 (10), 370 (100), 290 (15), 250 (13), 167(16), 141 (12), 77 (44). PhO gS N aB H ^, C u(0 A c)2 MeOH, rt, 45 min (±)-frans>2-[/V-(2-Phenylsulfonyl)ethyl-Af-(2*bromo-2 -propenyl)-6-am lno-3- cyclohexen>1-yl]-anlllne (258): Compound 2 6 2 was dissolved in methanol saturated with copper acetate (9 mL). Sodium borohydride (212 mg, 5.54 mmol) w as added in five portions at room temperature, over a period of 30 min. The reaction was monitored by TLC (eiution with 30% ethyl acetate in hexane). After disappearance of the starting material (atxjut 45 min), the black mixture was filtered through a cake of Celite. The filtrate was diluted with ether and washed with 2N aqueous sodium hydroxide. The organic phase was separated and dried over anhydrous sodium sulfate and concentrated to afford the desired product (261 mg, 99% yield) as a beige solid: mp. 109"C (dec.); ^H NMR (300 MHz, CDCIg) 82.18 (m, 4H. =CHCH 2), 2.70 (m, 5H, ArCH, CHgCHgSOgPh), 3.12 (d, J=15.4 Hz, 1H, =CCJdHN), 3.20 (m, 1H, CHN), 3.27 (d, J=15.4 Hz, 1H, 116 =CCHHN). 3.55 (bs, 2H, NHg), 5.26 (s, 1H, =CHH), 5.40 (s. 1H. =CHÜ), 5.70 (m. 2H, CH=CH), 6.62 (d, J=6.5 Hz, 1H, ArH), 6.70 (t, J=6.5 Hz, 1H, ArH), 6.95 (m, 2H, ArH), 7.58 (m, 3H, ArH), 7.81 (m, 2H, ArH): NMR (63 MHz, CDCIg) 6 27.13, 34.58, 38.32, 43.81, 55.47, 60.98, 61.13, 116.71, 118.07, 119.28, 125.64, 126.74, 126.94, 127.95, 128.22, 129.23, 129.29, 132.49, 133.67, 139.59, 143.83; IB (CHgClg) 3300, 3020, 2920, 1520, 1450, 1300, 1150, 1080, 730 cm'"'; MS (El) m /e370 (100), 290 (11), 170 (20), 106 (49), 77 (58). PhO gS Pd(O A c)2, PP hg EtgN, M eCN NH. 258 (±)-1 a,3,4,5a,6,7-Hexahydro-4*m ethylene-2-[2-(phenylsulfonyl)ethyl]-1,5- methano*2/f-azoclno[4,3-b]indole (263): A mixture of vinyl bromide 2 5 8 (69 mg, 0.145 mmol), triethylamine (40 pi, 0.290 mmol), triphenylphosphine (19 mg, 0.74 mmol) and Pd( 0 Ac)2 (5,5 mg, 0.025 mmol) in acetonitrile (3 mL) w as stirred at room temperature for 10 min, then at reflux for 4h. The mixture was cooled to room temperature and additional palladium acetate (32 mg, 0.145 mmol) was added. The mixture was refluxed for 2 h, cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) to afford tetracycle 2 63 (30 mg, 53% yield) as a pale yellow solid: mp. 190°C (dec.); ^ H NMR (250 MHz, CDCIg) 6 1.76 (bd, J=12.1 Hz, 1H, NCHCHH), 1.90 (bd, J=12.1 Hz, 1H, NCHCHÜ), 2.51 (m, 1H, CMHCHgSOgPh), 2.53 (d, J=17.2 Hz, 1H, =CCÜHN), 2.57 (d, J=12.7 Hz, 1H, N(C=)ChIH), 2.78 (d, J=12.7 Hz, 1H, 117 N(C=)CHH), 2.82 (bs, 1H, CHC=), 3.00 (d. J=17.2 Hz. 1H. =CCHJdN), 3.12 (m, 1H. CHHCHgSOgPh). 3.43 (m, 2H, CHgSOgPh). 4.03 (bs. 1H. =CCHN); ^^CNMR (63 MHz. 00013)8 30.07 (t), 33.24 (I). 35.27 (d), 50.07 (t). 50.53 (d). 52.14 (I). 54.86 (t). 106.38 (S ). 109.02 (t). 110.55 (d). 118.02 (d), 119.94 (d). 121.22 (d). 127.82 (s), 128.40 (d). 129.07 (d), 131.92 (s). 132.17 (d). 135.80 (S). 139.75 (S). 147.99 (s); IR (OHgOI ) 3360. 3040, 2920, 1660, 1445, 1300, 1140, 730 cm"'*; MS (El) m/e calc'd for OggHg^NgSOg: 392.1558. found 392.1564; 392 (23), 354 (18). 288 (35). 262 (21). 208 (63). 169 (81). 168 (100), 130 ( 68 ). 125 (47). 77 (82). ^ C N 1,2 -dibromoethane NO.NO, 50% NaOH in H 2O MeCN. nSu^NBr a2 7 8 1-(2>Ni!rophenyl)-cyclopranecarbonltrile (279). To a solution of 2-nitrophenyl- acetonitrile (2.65 g. 16 mmol), dibromoethane (13.6 mL. 160 mL) and nBu^^NBr (5.21 g. 16 mmol) in acetonitrile (40ml) was added 50% aqueous NaOH (8.0 mL). in one portion, at room temperature. The dark purple solution was stirred at room temperature for 12 h. The reaction mixture was then quenched with 2N HOI (64 mL). and the layers were separated. The aqueous layer was extracted twice with ether. The combined organic layers were washed with saturated aqueous NaHCÛQ and brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The brown residue was purified by flash chromatography over silica gel (elution with 30% hexane in dichioromethane) to afford the desired product (2.92 g. 96% yield) a s a pale yellow solid: mp. 78°C; ^ H NMR (200 MHz. CDCI 3) 5 1.26 (dd. J=7, 5 Hz. 2H, CjjHCHH). 1.74 (dd. J=7, 5 Hz, 2H, CHMCHhl). 7.55 (m. 3H. ArH), 7.98 (d. J=6.5 Hz. 1H. ArH); ^ NMR (63 118 MHz. CDCIg) 512.8 (s). 16.2 (t), 121.4 (s), 125.0 (d), 130.0 (d). 130.5 (s), 132.8 (d). 133.6 (d), 150.0 (s): IR (KBr) 3032, 2234, 1750, 1738, 1676, 1654, 1444, 1256, 1173 cm'"'; MS (El) m/e calc'd for C^oHgNgOg: 188.0586, found 188.0506; 160 (27), 140 ( 22), 116 (98), 102 (100), 89 (17), 77 (22), 63 (23), 51 (28); Analysis calc'd for C.JQH 3N2O2 : 0, 63.83; H, 4.28; found: 0, 63.72; H, 4.49. 1- DIBAL-H, toi., -78°C 2- MCI. H2O 2 7 9 2 8 0 1>(2-Nltrophenyl)-cyclopropanecarboxaldehyde (280). A 1.0 M hexane solution of DIBAL-H (1.46 mL, 1.46 mnx)l) w as added to a chilled solution (-78°C) of cyclopropanenitrile 2 7 9 (154 mg, 0.81 mmol) in toluene (4.5 mL). After 5 min at -78°C, water was added (1 mL), and the reaction mixture was allowed to warm up to room temperature. The mixture was poured into IN HOI (9 mL) and stirred at room temperature for 5 min. The phases were separated, and the aqueous layer was extracted six times with ether. The combined organic layers were washed with saturated aqueous bicarbonate and brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the expected aldehyde (160 mg, 97% yield) as a yellow oil which was not further purified (aldehyde 2 80 was unstable over silica gel): ^H NMR (200 MHz, CDCIg) S 1.34 (dd, J=7.7, 4.6 Hz, 2H, CJjHCHH), 1.69 (dd, J=7.7, 4.6 Hz, 2H, CHÜCHhl), 7.55 (m, 3H, ArH), 7.98 (dd, J= 7 .9 ,1.4 Hz, 1H, ArH), 9.10 (s, 1H, CHO); ^ ^C NMR (63 MHz, CDCIg) 6 15.64 (I), 35.32 (s), 124.69 (d), 129.02 (d), 132.61 (s), 133.22 (d), 133.36 (d), 151.01 (s), 198.08 (d); IR (neat) 3086, 2830, 1713, 1610, 1575, 1520, 1348, 1249, 903 cm'"'; 119 MS (El) ni/ecalc'd for C 10H9 NO3 : 191.0582, found 191.0556; 191 (1). 134 (90), 115 (64). 104 (100), 91 (45), 79 (63), 63 (44), 51 (47). y — N ' ^Ph 1- PhNHp, ether 2- method A or B o f 2 8 0 2 8 2 2,3-Dlhydro-3>(2 cyclopropylaldehyde 28 0 (580 mg, 3.0 mmol) and benzylamine (345 mL, 3.2 mmol) In ether (5 mL) was stirred at room temperature for 4 h. The solution was diluted with toluene (10 mL) and concentrated under reduced pressure to afford the crude imine (831 mg, 99% yield) as a brown oil, which was used as such in the next step . Method A: To a solution of the crude imine in acetonitrile (25 mL) was added solid ammonium chloride (53 mg, 1 mmol). The mixture was placed in a sealed tube and heated to 125°C for 4 h. The resulting dark red solution was cooled to room temperature and washed with water. The phases were separated and the aqueous layer was extracted with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography over silica gel (elution with 50% hexane in dichioromethane) afforded the product (750 mg, 91% yield) as a dark red solid. M ethod B: To a solution of the crude imine (1.70 g, 6.34 mmol) in DMF (22ml) was added, at room temperature, nBu^NI (867 mg, 2.35mmol), and TMSCI (406 mL, 3.14 mmol). The mixture was stirred at 60°C for 3 h, cooled to room temperature, and washed with 2 N NaOH (5 mL) and water (50 mL). The mixture was extracted with ether/hexane (1:1). The combined organic 12 0 layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude oil was purified by flash chromatoraphy over silica gel (elution with 50% hexane in dichioromethane) to yield the product (1.53 g, 90% yield) as a red solid: mp. 50°C (dec.): ‘‘h NMR (250 MHz. CDCIg) Ô 2.70 (t, J=9.5 Hz, 2H, CJdaCHgN), 3.17 (t, J=9.5 Hz, 2H, CHgCHgN), 4.06 (s, 2H, PhCHg), 6.57 (t, J=1.3 Hz, 1H, CHN), 7.03 (t, J=7.2 Hz, 1H. ArH), 7.18 (d, J=9.4 Hz, 1H, ArH), 7.30 (m, 6H, ArH), 7.46 (d, J=8.0 Hz, 1H, ArH); ^ NMR (63 MHz, CDCIg) 631.0 (t), 51.8 (t), 56.2 (t), 107.6 (s), 123.7 (d), 123.8 (d), 127.4 (d), 127.7 (d), 128.2 (d), 128.5 (d), 130.6 (s), 131.3 (d), 137.3 (s), 141.8 (d), 147.1 (s); IR (neat) 3020, 2980, 1588, 1515, 1357, 1158 cm"^ ; MS (El) nVecalc'd for C^ yH., gNgOg: 280.1212. found 280.1211; 280 (12), 145(11), 115 (12), 91 (100), 65 (20); Analysis calc'd for C.|yH.| 6^2^2- 72.84; H, 5.75; found: C, 72.84; H, 5.85. yC—N '^ P h CHO 1- PhNHg, ether D 2- NH4CI, 120°G . n e a t NO; or■‘NO, 2 8 0 2 8 3 3-(2-nitrophenyl)-l-phenylmethyl-1H-pyrrole (283): An heterogeneous mixture of the crude imine 281 (323 mg, 1.24 mmol) and ammonium chloride (14 mg, 0.264 mmol) was heated to 120°C under an Argon atmosphere for 12 h. The cmde mixture was directly purified by flash chromatography over silica gel (elution with 10% ethyl acetate in hexane) to afford the product (265 mg, 77%) as a yellow oil. ^ H NMR (250 MHz, CDCIg) 55.06 (s, 2H, CH2N). 6.30 (t, J=4 Hz, ArH pyrrole), 6.71 (t, J=4Hz, ArH pyrrole), 6.88 (t, J=4 Hz, ArH pyrrole), 7.40 (m, 9H, ArH); ^ % NMR (75 MHz, CDCIg)653.59 (t), 108.61 (d), 119.12 (s), 120.07 (d), 122.14(d), 123.23 (d). 121 126.11 (d), 127.10 (d). 127.86 (d). 128.81 (d). 129.68 (S). 130.69 (d), 131.37 (d). 137.34 (s), 149.04 (s): IR (neat) 3020, 2980, 1585, 1515, 1357 cm'"'; MS (El) m/ecalc'd for gNgOg: 278.1053, found 278.1089; 278 (14), 91 (100), 65 (34). ^ X /—-N Ph r — N OMe 2 8 2 2 9 9 1-Carbomethoxy-2,3-dlhydro-3-(2-nltrophenyl)-1-H-pyrrole (299). To an acetone solution (8 mL) of ttie pyrroline 2 8 2 (470 mg, 1.68 mmol) w as added at room tem perature methylchloroformate (1.3 mL, 16.8 mmol). The mixture was stirred at room temperature for 16 h, then diluted with dichioromethane, and washed with aqueous ammonium chloride. The phases were separated and the aqueous layer was extracted with dichioromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (elution with 20% ethyl acetate in hexane) to give 375 mg (90% yield) of the desired product as a yellow solid: mp. 80°C; ‘' h NMR (300 MHz, CDCIg)S 2.90 (t. J=9.0 Hz, 2H. CHgCHgN). 3.77 (s. 3H, OMe), 3.91 (m, 2H, CHgCtlgN). 6.78(bs, 1H, =CHN), 6.91 (bs, 1H, =CHN other amide rotamer), 7.35 (m, 2H, ArH), 7.48 (t, J=6.4 Hz, 1H, ArH), 7.70 (d, J=9.0Hz, 1H, ArH); NMR (75 MHz, CDCIg) 5 30.3 (t), 31.2 (t), 45.8 (t), 52.7 (q), 117.4 (s), 117.7 (s), 123.9 (d), 127.3 (d), 128.2 (d), 129.1 (d), 129.5 (s), 129.8 (d), 130.0 (d), 132.0 (d), 148.3 (s), 152.4 (s), 153.1 (s); IR (CHCIg) 3000, 2960, 1710, 1630, 1530, 1450, 1410, 1260, 1130, 980 cm"'' ; MS (El) m/e calc'd for C ^ 2^2°4: 248.0797, found 278.0789; 248 (22), 145 (100), 115 (76), 90 (39), 77 (30), 59 (56); Analysis 122 cak'd for 0 ^2^ 12^ 2 0 4 : C, 58.06; H. 4.87; found; 0, 58.24; H, 4.67. O O X A a j — N '^ O M e j— N ^^O M e 5 % pd/c.MeOH NO 2 H O O O N H , 299 300 1-Oarbomettioxy*2,3-dihydro-3-(2-aminophenyl)-1H-pyrrole (300): To a mixture of the starting nitro aromatic 2 9 9 (424 mg, 1.70 mmol) and 5% Pd/C (170 mg) in methanol (8.4 mL) was added ammonium formate (1.11 g, 17.0 mmol) at 20°G (water bath), over a period of 1 h. The reaction mixture was filtered through a cake of Celite and concentrated under reduced pressure. The crude residue was triturated with water and the insoluble product (349 mg, 95% yield, yellow solid) was isolated by suction filtration: mp. 106°C; NMR (250 MHz, CDCIg)6 3.01 (m, 2H, CH2CH2N), 3.65 (s. 3H, OMe). 3.88 (m, 2H, CH 2CH2N). 6.70 (m, 2H, ArH and =CHN), 7.00 (m, 3H, ArH); ■'^C NMR (75 MHz, CDCIg)631.4 (t), 32.6 (t), 44.4 (t), 44.6 (t), 52.5 (q), 116.2 (d), 118.5 (d), 118.7 (d), 119.4 (s). 119.6 (s), 120.6 (s), 120.8 (s), 125.7 (d), 126.2 (d), 127.2 (d), 143.8 (s); IR (CHgClg) 3430, 3350, 3050, 2980, 1700, 1615, 1495, 1460, 1405, 1265, 1120 cm'"'; MS (El) m/ecalc'd for C., 21^14^202: 218.1055, found 218.1053; 218 (31), 143 (13), 130 ( 100), 117 (9), 77(10), 59 (7); Analysis calc'd for C.I 2H.I4N2O2 : C, 66.04; H, 6.47; found: C, 65.93; H, 6.49. 123 O O Il II / — N '^ O M e j — N *^ O M e a 1 -crotonaldehyda » jg u 2 -CICO 2M 0 , toluene ^ proton sponge, 0°C—>rt | CO2M0 3 0 0 3 0 7 l-Carbomethoxy>2,3-dihydro-3-[A/'“(1,3-butadie n- 1-yl)-W’-carbom ethoxy- 2 - amlnophenyl]-1/V-pyrrole (307): To the aniline derivative 300 (750mg, 3.438 mmol) was added crotonaldehyde at room temperature (1.54 mL, 17.20 mmol). The mixture was stirred at room temperature for 1 h, and then diluted with toluene (100 mL). After concentration under reduced pressure, the crude imine was dissolved in toluene (17.0 mL). DMAP ( 84 mg, 0.688 mmol), N,N,N’,N’-tetramethyl- 1,8 -diaminonaphtalene (proton sponge) (960 mg, 4.470 mmol) and methylchloroformate (320 mL, 4.126 mmol) were sequentially added at 0*C (ice water bath). The mixture was allowed to warm up to room temperature, stirred for 8 h, and quenched with aqueous ammonium chloride. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) to afford the expected product (750 mg, 70% yield) as a yellow solid: mp. 118°C (dec.); NMR (300 MHz, CDCI3 ) 52.90 (t, J=7H z, 2H, CHgCHgN), 3.71 (m, 6H, 2x OMe), 3.82 (m, 2H, CH 2CH2N), 4.83 (m, 2H, CH=CÜ 2). 5.02 (dd, J=12.7, 7.5 Hz, 1H, CH=CH2), 6.32 (m, 1H, N(CÜ2Me)CH=CJd), 6.86 (two bs, 1H, ArC=CHN), 7.12 (d, J=7.1 Hz, 1H, N(C0 2 Me)CH=CH), 7.32 (m, 4H, ArH); ^^cn M R (63 MHz, C D C I g ) 6 30.67 (t), 31.66 (t), 45.35 (t), 52.80 (q), 53.66 (q), 113.36 (d), 113.92 (t), 117.91 (s), 127.32 (s), 127.58 (d), 128.10 (d), 128.71 (d), 129.18 (s), 130.12 (d), 131.86 (d), 133.59 (s), 134.19 (s), 134.69 (d); IR (KBr) 124 3040, 2950, 1700, 1600, 1485, 1445, 1380 cm''’; MS (El) m/e calc'd for C^gHgoNgO^: 328.1423, found 328.1429; 328 (11), 227 (14), 201 (76), 167 (32), 140 (100), 115 (29), 85 (22), 59 (42): Analysis calc'd for C.JQH 20N2O4 : C, 65.84; H, 6.14; found: C, 65.86; H, 6.15. N OMe OM e toluene 220°C I COgMe 307 318 (±)-(3aa,6ap)-3,7-Dlcarbom ethoxy-2,3,3a,4,6a,7-hexatiydro-1 H-pyrrolo [2,3-d]carbazole (318): A toluene solution (300 mL) of the starting bis-carbamate 307 (1.0 g, 3.1 mmol) was introduced in a 1 L steel bomb. The air was removed and the mixture placed under an argon atmosphere. The bomb was heated to 220°C for 4 h, then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography over silica gel (elution with 20% ethyl acetate in hexane) to afford the desired tetracycle 3 1 8 (940 mg, 94% yield) as a pale yellow solid: mp. 121°C; ^ H NMR (250 MHz, toluene-dg at 370K) 5 1.60 (m, 2H, CH 2CH2N), 2.15 (m, 1H, CüHCH=), 2.37 (dt. J=16.6, 5.3 Hz, 1H, CHHCH=), 3.26 (m, 1H, CHgCHHN), 3.51 (m, 1H, CH2CHHN), 3.52 (s, 3H, OMe), 3.55 (s, 3H, OMe), 3.79 (dd, J=5.3, 5.2 Hz, 1H, CHN), 4.40 (bs, 1H, NCHC=), 5.53 (m, 1H, NCHGH=CH), 6.00 (d, J=10.1 Hz, 1H, NCHCJÜ=CH), 6.75 (m, 2H, ArH), 7.00 (m, 1H, ArH), 7.86 (d, J=8.1 Hz, 1H, ArH); ^^0 NMR (63 MHz, DMSO-dg at 370K) 825.5 (t). 32.0 (t). 44.0 (t). 51.3 (s), 51.5 (q), 52.1 (q). 59.4 (d), 62.8 (d), 114.2 (d), 122.2 (d). 122.8 (d), 126.2 (d), 127.0 (d). 125 127.8 (d). 135.3 (s), 140.1 (s). 152.4 (s). 154.6 (s); IR (CHgClg) 2954, 1694, 1599, 1485, 1444, 1384, 1283, 1250, 1125, 867 cm'^: MS (El) m/e calc'd for gH 2oN 2 0 4 : 328.1423, found 328.1427; 328 (35), 226 (14), 201 (87), 167 (33), 140 (100), 112 (20), 88 (47), 59 (34); Analysis calc’d for C.J0H2 ON2O4 : C, 65.84; H, 6.14; found: C, 66.01 ; H, 6.24. TMSI, CH3CI reflux, 4h I H M0O2C 318 324 (±)*(3aa,6ap)-2,3,3a,4,6a,7-hexahydro-lH-pyrrolo[2,3-d]carbazole (324): To a solution of bis carbamate 3 1 8 (1.097 g, 3.342 mmol) in mettianol-free chloroform (20 mL) was added at room temperature in one portion TMSI (4.9 mL, 33.42 mmol). The mixture was stirred at reflux for 4 h, cooled to room temperature, and quenched with methanol (evolution of CO 2). The solution was concentrated under reduced pressure and the residue was partitioned between ether and 1N HCI. The organic phase was separated. The aqueous layer was basified with 50% aqueous NaOH (pH=12) and extracted with dichioromethane. The dichioromethane solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product (677 mg, 95%) as a yellow solid: mp. 119°C; ^ H NMR (300 MHz, DMSO-dg) Ô 1.85 (m, 1H, CHHCHgN), 2.25 (m, 3H, CH 2CH= and CHHCH 2N), 3.29 (m, 2H, CH2CH2N). 3.88 (bs, 1H, CHN), 3.98 (bs, 1H, CüNHAr), 5.62 (m, 2H, CM=Chi), 5.90 (bs, 1H, NH), 6.48 (d, J=6.0 Hz, 1H, ArH), 6.53 (t, J=6.0 Hz, 1H, ArH), 6.91 (t, J=6.0 Hz, 1H, ArH), 7.11 (d, J=6.0 Hz, 1H, ArH); 126 13,C NMR (63 MHz, DMSO-dg) S 22.86 (t), 37.32 (t). 41.68 (t), 51.27 (s). 56.76 (d), 58.87 (d), 109.09 (d). 117.39 (d), 122.16 (d), 122.43 (d), 128.35 (s), 128.39 (d), 128.97 (d), 150.95 (s); IR (CHgClg) 3340. 3020, 2870, 1600, 1480, 1460, 1020 cm"^;MS(EI) m/e calc'd for Ci^H^gNg: 212.1313, found 212.1314; 212 (100), 182 (52), 168 (78), 131 (89), 82 (79). N B S,PPha CHaCla 0°C 2 3 4 3 4 3 (Z)-l-Bromc-2-iodo-2-butene (343): To a mixture of frans 2-iodo- 2-buten-l-ol (2 34) (631 mg, 3.188 mmol) and triphenylphosphine (1.26 g, 4.781 mmol) in dichioromethane (30 mL) was added at 0°C N-bromosuccinimide (851 mg, 4.781 mmol). The mixture was stirred at 0°C for 10 min, then concentrated. The crude residue was purified by flash chromatography over silica gel (elution with hexane) to afford the desired allylic bromide 3 4 3 (682 mg, 82% yield) as a colorless oil. ^ H NMR (250 MHz, CDCIg)Ô 1.78 (d, J=6.5 Hz, 3H, =CHCjjg), 4.34(s, 2H, -CHgBr), 6.03 (q, J=6.5 Hz, 1H, =CJdMe); NMR (63 MHz, CDCIg) 6 22.22 (q), 43.33 (t), 103.36 (s), 135.96 (d). Br- 343 nBu,^NCI, KgCO^ DMF, -5°C H 324 344 (±)-[3aa(Z),6ap]-2,3 ,3a,4,6a,7-hexahydro-3-(2-iodo-2-buten-l -yl)-1 H- pyrrolo[2,3-d]carbazole (344): To a mixture of bis-amine 3 24 (675 mg, 3.182 mmol), K2CO3 (1.32 g, 9.546 mmol) and nBu^NCI (1.35 g, 4.773 mmol) in DMF ( 30 mL) was added 127 allylic bromide 3 4 3 (785 mg, 3.023 mmol) at - 8 °C (NaCI / ice water bath). The mixture was stirred at -5°C for 2 h 40 min, then diluted with ether, and washed with 0.2N aqueous NaOH (400 mL). The layers were separated. The ether layer was extracted with 1N HCI. The acidic water solution was separated, basified with 50% aqueous NaOH (pH=12), and extracted with ether. The ether layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (elution with 20% ethyl acetate in hexane) to give the product (815 mg, 68 % yield) as a pale yellow solid: mp. 148°C; ^H NMR (300 MHz, CDCIg) Ô 1.77 (d, J=6.4 Hz, 3H, CHgCH=), 1.90 (m, 1H, GJÜHCHgN), 2.11 (m. 2H, CU 2CH4 , 2.68 (m, 1H, CHHCHgN), 3.10 (m, 2H, NCH2C4 , 3.34 (d, J=14.4 Hz. 1H, CHgCHHN), 3.63 (d, J=14.4 Hz. 1H, CHgCHHN). 3.98 (bs, 1H, CHNHAr), 5.63 (m, 2H, Cü=CJd), 5.90 (q, J=6.4 Hz, 1H. =CüMe). 6.61 (d, J=7.4 Hz, 1H, ArH), 6.73 (t. J=7.4 Hz, 1H, ArH), 7.03 (t. J=7.4 Hz. 1H, ArH), 7.13 (d, J=7.4 Hz, 1H, ArH): NMR (63 MHz, CDCIg)5 21.71 (q), 24.41 (t). 37.96 (t), 50.37 (t), 53.19 (s). 62.17 (d), 62.93 (d), 65.57 (t), 109.59 (s), 109.94 (d). 119.03 (d). 123.44 (d). 125.64 (d), 127.84 (d), 130.52 (d), 134.02 (s). 150.04 (s); IR (CHgClg) 3364, 3022, 2912, 1649, 1605, 1483, 1346, 812 cm"''; MS (El) m/e calc'd for C^gHgiNgl: 392.0749, found 392.0726; 392 (46). 262 (100). 211 (300). 168 (67). 130 (37). 82 (26). 53 (49). ■COsMe T sO TMSI 2 3 8 K2CO3, acetone I H MeOjC 318 323 3 2 5 (±)-[3acc(Z),6ap]-7-Carbomethoxy-2,3,3a, 4,6a,7-hexahydro-3-(2-iodo-2- buten-1-yl)-1/y-py^rolo[2,3-d]carbazole (325); To a solution of bis carbamate 31 8(200 128 mg, 0.60 mmol) in dichioromethane (10 mL) was added at room temperature in one portion TMSI (200 pi, 1.32 mmol). The mixture was stirred at reflux for 1 h, cooled to room temperature and quenched with methanol (evolution of CO 2). The solution was concentrated under reduced pressure and the residue was partitioned between ether and IN HCI. The organic phase was separated. The aqueous layer was basified with 50% aqueous NaOH (pH=l2) and extracted with dichioromethane. The dichioromethane solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford monocarbamate 323 (160 mg), contaminated with about 10 % of diamine 3 2 4. The monocarbamate could not be further purified and was directly submitted to the alkylation reaction. To a mixture of the cmde monocarbamate 3 23 (90 mg, < 0.33mmol) and KgCOg (460 mg, 3.3 mmol) in acetone (3 mL) was added at room temperature the allylic tosylate 238(150 mg, 0.43 mmol). The mixture was stirred at room temperature for 2 h, then filtered and concentrated. The residue was partitioned between ether and 1N HCI. The organic phase was separated. The aqueous layer was basified with 50% aqueous NaOH (pH=12) and extracted with dichioromethane. The dichioromethane solution was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (elution with 10 % ethyl acetate in hexane) to afford the desired vinyl iodide 325 (117 mg, 79% yield from 318) as a yellow viscous oil: ^ H NMR (250 MHz, DMSO-dg at 40°C) 51.72 (d, J=7 Hz, 3H, =CHCHg), 2.05 (m, 3H, CÜ2CH2N and =CHCHH), 2.54 (m, 1H, =CHCHH), 3.08 (m, 1H, CHN), 3.28 (m, 3H, CHNx3), 3.65 (d, J=12 Hz, 1H, =CCÜHN), 3.79 (s, 3H, OMe), 4.50 (bs, 1H, Me 0 2 CCH), 5.67 (m, 2H, CH=CH), 6.00 (q, J=7 Hz, 1H, =CHCHg), 6.99 (t, J =8 Hz, 1H, ArH), 7.21 (m, 2H, ArH), 7.60 (m, 1H, ArH); NMR (63 MHz, DMSO-dg at40°C) 521.19 (q), 23.64 (t), 38.62 (t), 49.60 (t), 50.88 (s), 52.28 (q), 61.50 (d), 63.25 (d), 65.03 (t), 110.04 (s), 114.44 (d), 122.70 (d), 122.83 (d), 124.51 (d), 126.09 (d), 127.67 (d), 130.19 (d), 134.98 (s), 140.82 (s), 152.69 (s); IR (CHgClg) 3031, 2951, 129 1714, 1651. 1601, 1486, 1462, 1443, 1385, 751 cm '''; MS (El) m/ë calc'd for CgQHggNgOgl: 450.0804, found 450.0806; 450 (10), 323 (33), 262 (100), 202 (13), 167 (25), 128 (18), 82 (34), 53 (22). Pd(OAc)g^ KgCOg nBu^NCI, DMF I H MsOgG MôOpC 325 327 (±)-[3aa,6a,6ap, 1 3(Z)]-7-Carbom ethoxy-13-ethylide ne-1,2,3a,6,6a,7- hexahydro-3,6-ethano-3H-pyrrolo[2,3-d]carbazole (327). A catalytic amount of Pd(0 Ac)2 (3 mg, 0.013 mmol) was added at room temperature to a mixture of the vinyi iodide 3 2 5 (60 mg, 0.133 mmol), K2CO3 (92 mg, 0.666 mmol), and nBu,^NCI (40 mg, 0.266 mmol) in DMF (1.2 mL). The heterogeneous mixture was heated to 65°C and stirred for 2 h. The dark solution was filtered, diltuted with water and exctracted with ether. The organic layers were combined and extracted with 2N HCI. The aqueous layer was basified with 50% aqueous NaOH (pH=12), and exctracted with dichioromethane. The dichioromethane solution was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (elution with 5% diethyl amine in ether) to yield the carbamate 3 2 7 (36 mg, 84%) as a viscous yellow oil: ^H NMR (300 MHz, DMSO-dg at 343 K) S 1.64 (d, J= 6.8 Hz, 3H, CH3C4 . 2.12 (m, 2H, CH2CH2N), 2.65 (m. 1H, CH2CÜHN), 3.14 (d, J=15.4 Hz, 1H, =CCJdHN), 3.33 (d, J=15.4 Hz, 1H, =CCHHN), 3.40 (m, 1H, CHgCHHN), 3.65 (d, J=6.6 Hz, 1H, =CHCHN), 3.80 (m, 1H, =CCHC=), 3.81 (s, 3H, OMe), 3.95 (d, J=2 Hz, 1H, CHNCO), 5.70 (q, J= 6.8 Hz, 1H, =CHMe), 130 5.89 (dd. J=7, 6.6 Hz, IN, =CldCHN), 6.17 (t, J=7 Hz. 1H. JJC=CHCHN). 6.98 (t. J=7.0 Hz. 1H. ArH). 7.08 (d. J=7.0 Hz, 1H. ArH). 7.28 (d. J=7.0 Hz. 1H. ArH). 7.70 (m. 1H. ArH); NMR (75 MHz. DMSO-dg at 343 K) 5 12.57 (q). 39.39 (t). 46.25 (d). 48.52 (I). 49.96 (t), 52.03 (q), 56.13 (s). 66.27 (d). 73.58 (d). 113.60 (d). 122.22 (d). 122.25 (d). 123.57 (d). 126.92 (d). 127.09 (d). 132.70 (d). 133.46 (s). 133.79 (s). 142.99 (S). 152.94 (s); IR (neat) 3045, 2924, 1713, 1599, 1486, 1462. 1441. 1385. 1074 cm"'': MS (El) m/e C^\c'àiox C2q ^2 2 ^ 2 ^ 2 - 322.1681. found 322.1683: 322 (49). 251 ( 6). 201 (6). 134 (100). 105 (8 ), 91 (9), 84 (16). 66 (17). Pd(OAc)2.K2CXDi nBu^NCI. DMF 344 H 123 (±)-(19E)-1,2,19,20-Tetrahydro-17-norcuran (dehydrotublfoline) (123). A catalytic amount of Pd(OAc )2 (7.3 mg, 0.032 mmol) was added at room temperature to a mixture of ttie vinyl iodide 3 4 4 (255 mg. 0.650 mmol). K 2CO3 (449 mg, 3.25 mmol) and nBu^NCI (277 mg, 0.975 mmol) in DMF (6.5 mL). The mixture was stirred at 75°C for 1h. The dart< brown solution was cooled to room temperature, washed with 0.2N NaOH (70 mL) and extracted four times with ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel (elution with 3% diethyl amine in ether) to afford dehydrotubifoline, 1 2 3 , (137 mg, 79% yield) as a beige solid: mp. 75°C (dec); ‘'h NMR (300 MHz, CDCI 3) d 1.10 (d, J=14.2 Hz, 1H, GIJHCHN), 1.66 (d, J=6.6 Hz, 3H, =CHCJd3), 1.80 (d, J=14.2 Hz, 1H, CHJdCHN), 2.17 (m, 2H, CH 2CH2N), 2.70 (d, J=15.2 Hz, 1H, =CCHHN), 3.16 (d, J=15.2 Hz, 1H, =CCHhlN), 3.22 (bs, 1H, CHC=), 3.32 131 (m, 3H. CH2CÜ2N and CHHC=N), 3.77 (d. J=15.4 Hz, 1H, CHüC=N), 4.00 (s, 1H, CHN). 5.40 (t. J= 6.6 Hz, 1H, zzCHCHg), 7.21 (m, 3H, ArH), 7.53 (d, J=7.5 Hz, 1H, ArH); n m r (63 MHz, 00013)6 12.85 (q), 25.39 (t), 30.25 (d), 35.10 (t), 35.95 (t), 53.68 (t), 55.53 (t), 65.40 (s), 66.67 (d), 119.55 (d), 119.87 (d), 121.23 (d), 125.27 (d). 127.73 (d), 142.03 (s), 144.10 (s), 154.43 (s), 189.02 (s); IR (OH 2OI2) 3040, 2920, 1570, 1480, 1450, 1110 cm"'*; MS (El) m/e calc'd for ^18^20^2: 264.1626, found 264.1619; 264 (18), 245 (15), 158 (47). 121 (38), 93 (37), 83 (14), 71 (64), 57 (100); Analysis calc'd for C^gHgoNg: 0, 81.78; H, 7.63; found: 0, 81.66; H, 7.57. LIST OF REFERENCES 1. Heck, R. F. J. Am. Chem. Soc. 1 9 6 8 , 90, 5518-5548. 2. Heck, R. F. Palladium Reagents In Organic Synthesis; katritzky, A. R., Ed.; Academic Press, New York, 1985. 3. Heck, R. F. J. Am. Chem. Soc. 1 969,91, 6707 4. Heck, R. F. Org. Reactions 1 9 8 2 ,2 7 , 345. 5. Tsuji, J. Organic Synthesis with Pd Compounds; Springer-Verlag, New York, 19 80. 6 . Daves, G. D.; Hailberg, A. Chem. 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APPENDICES 142 227 KVBin.OOS DATE 14 1 83 SF 250.,133 SY 83.0 01 4104.,552 SI 32768 TO 32768 Stf 3496,.503 HZ/PT ,213 PH 8.,0 RD 0..0 AO 4,.686 RG 10 N5 24 TE 303 FM 4400 02 50000..000 DP 30L PO LB 0..0 GB 0..0 ex 34,.00 CY 0,.0 FI 10..OOOP F2 .500P HZ/CH 77.,2 4 8 PPM/CH .309 * SR 2867..84 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 0.0 PPM Figure 8 : ‘•h NMR spectrum of 227 (250 MHz, CDCI3 ) O) \/ BFV17A DATE 14-1-93 62.896 9 3 .0 2600.000 32763 32760 14705.862 HZ/PT .898 227 J!L I Hi FW 18400 02 4350.000 OP 20H CPO ^ g:g g FI 160.OOOP F2 -4.999P HZ/CH 305.229 PPH/CH 4.853 SR -4041.79 "I"' 140 100 80 70 50 PPM Figure 9: ^ NMR spectrum ot 227 (63 MHz, CDCI3 ) 229 MVBiil.005 o w e 14-1-93 IÇ 32768 I 3496.503 HZ/PT .213 PK U 4.666 ii I 303 FH • 4400 02 50000.000 DP 30L PO LB 68 1:1 10.OOOP 1 -.500P HZ/CH 77.240 PPH/CH .309 Sn 2856.32 9.5 7.5 7.0 6.5 5.5 5.0 4.0 3.5 3.0 2.5 2.0 PPM Figure 10: ^ H NMR spectrum of 229 (250 MHz, CDCIg) in CHI293 C l) ea AMO OCPr AK<2S0-2 CM9.004 Çfil IW î |f§. flôîSSo 1#: 5 229 ta 02 4490.0C0 M "4040.W 140120 110 100 90 60 70 60 80 30 20 10 PPK Figure 11; ^ ®C NMR spectrum of 229 (63 MHz, CDCI3 ) O) H. I J 218 BWœR KHBin.OOS DATE 14-1-93 SF 250.133 sr 63.0 01 4104.552 SI 32766 ID 32760 SM 3496.503 HZ/PT .213 PH 6.0 RO 0.0 AQ 4.666 RG 10 NS 29 TE 303 FH 4400 02 50000.000 DP 30L PO LB 0.0 GB 0.0 CX 34.00 CY 0.0 FI 10.OOOP F2 -.500P HZ/CH 77.248 PPH/CH .309 SR 2860.59 5.0 4.5 4.0 3.5 3.0 2.5 2 .0 0.0 PPM F igure 12: ‘*H NMR sp ectru m of 218 (250 MHz, CDCIg) CHII009 C13 68 AND OEPT AH-250-2 11 I Ï ' - - T' 1 p CK9.00-4 DATE 19-1-93 62,896 9 3 , 0 2600,000 32768 32768 1 14705,662 HZ/PT .898 Pk 1.5 RO 0.0 AO 1.114 RG BOO MS 348 TE 303 FW 18400 02 4350.000 OP cOH CPO LB 1.500 GB 0.0 CX 34.00 CY 16.00 FI 151.394P F2 -1.118P HZ/CH 282.129 PPH/CH 4.486 SR -4033.65 140 130 90 70 30 Figure 13: ^ NMR spectrum of 218 (63 MHz, CDCI3 ) CO CKOJO.OOl DATE 4-12-90 TlKE fi: 38 500.135 fi 7500.000 tÔ 32768 HZ/PT®°^'*.’36B 230 PK 8..0 BO 0..0 AO 2..720 HS 32 TE 297 FW 7600 02 0. 0 DP 63L 00 LB ,300 CX 35..00 CY 20.,00 FI 8..700P F2 .300P HZ/CH 128..605 PPH/CH .257 SR 5431..42 8.0 7.0 6.0 5.5 5.0 4 .5 3 .5 3 .0 2.5 2.0 1 .5 PPM 0.0 Figure 14: NMR spectrum of 230 (250 MHz, CDCI3 ) co CMlIOiO C13 ea AKO OCPT AM-2S0-2 ^ ? CHI.004 AU PROG: BBKC.AU DATE 18-7-90 TIKE 12:17 SF 62.696 SY 93.0 01 2600.000 SI 32768 TO 32768 230 SK 14705.662 HZ/PT .098 PH 1.5 RD 0.0 AQ 1.114 RG 400 NS 1800 TE 303 FW 18400 02 4450.000 DP 20H CPO IB 3.500 GB 0.0 CX 34.00 CY 16.00 FI 146.26SP F2 16.433P HZ/CH 235.511 PPH/CH 3.760 SR -4035.45 140 130 120 110 100 90 80 70 60 50 40 20 PPM Figure 15: ^ NMR spectrum of 230 (63 MHz, CDCIg) O l o 219 DATE 5-7-90 TIKE 17:34 250.133 4100.000 4000.000 HZ/PT .244 PW no AO 4.096i:5 J# i 303 FK 5000 02 50000.000 OP G3L PO LB S:§ 6.001P -.500P iHZ/CH 62.536 PPH/CH .250 SR 2860.01 7.5 7.0 5.5 5.5 5.0 4.5 3.5 3.0 2.5 2.0 PPM 0.0 Figure 16: ‘‘ h NMR spectrum of 219 (250 MHz, CDCI q) tn CHII003 Ci3 BD AND DEPT AC-300 DATE 6-7-90 TIKE 8:33 SF 75.469 SF02 300.130 SY 75.0 s* 3^*: TO 32766 HZ/Pp^^lIiSO PW 2.6 RO .300 AQ .685 RG 400 NS 063 TE 303 DE 36.3 OR 12 OW 27 FH 23200 02 4900.000 OP 15L CPO L9 1.500 08 0.0 NC 4 DC 1.000 HZ/CH 293.241 PPH/CH 3.666 IS 1 SR -1390.10 140 130 120 n o 100 90 80 70 60 50 40 30 20 PPM Figure 17: ^ n m R spectrum of 219 (75 MHz, CDCIg) cn fO r;P 220 % J:S !l ill 02 60009.009 ! ! ® S S / //// //. LI w -A liiil A- ^ M/\. s ! s »Io i l s i:o 7 ls j ! o' e!: '«!» sis' '»!«' Z:' *Io s lo jI o ' ' ' 'ilo' ' ' ' ' 'olo Figure 18: ^ H NMR spectrum ot 220 (300 MHz, CDCI3 ) Ü1 CO CMlVllO Ct3 88 AMO D € P J AM-2S0-2 t M 1 0 .0 0 4 TIKE 14: SFO ellsoo w o .n o 01 ssoo.ooo uuus HZ/PT .0 9 0 J"" 1R 02 4 4 9 0 .0 8 0 220 wo n o 120 no loo so so 70 «0 to « 30 w Figure 19: 1 NMR spectrum of 220 (63 MHz, CDCI3 ) 0 1 ORCatCL.OIO Çîii îf ir " B, lîî-Ml 240 i l ' ”” N <5 ê§ Ï1 Î5! 02 80000.000 K g Figure 20: NMR spectrum of 240 (300 MHz, CDClg) en cn CH-XI«009 CIS BB W<0 OEPT AM-250-2 I ;; CM.004 AUaeoepi.oFz PROC: TIKE 5XVWT cocn Tr 2 4 0 TO^^I5«25.000 32768 PW i . S RO 0 .,0 AO 1,,049 RG SEOO HS 2 0939 TE 3 0 ) r v 16600 02 44S0..000 OP 26H CPO Lfi 1 .500 6B 0,.0 CX 34,.00 CY 16,.00 FI 150 .065P n - 6 .956P HZ/CH WO .476 PPH/CM 4 ,618 sa *4049 .5 3 Figure 21: ^ NMR spectrum of 240 (63 MHz, CDClg) cn o> .« C « A » .0 0 > ÎÎJII5TÜ" 241 % ;:L w 50Q09.000 I f i n I J j r-| ■! » I'"' f I'T'I > »1»'1 I I I I I % *T*'I I 1 I* t iW I r I I I' [- 1* M -,' I , I > I i 'tW f i »' t > i j i i i i' i i J.S Ï.0 15 ».0 7.S 7.0 6.5 6.0 5.5 5.0 4.5 4.0 5.5 5.0 5.5 5.0 1.5 1.0 .5 0.0 Figure 22: ^ H NMR spectrum of 241 (300 MHz, CDClg) cn vj aDflOePT.Or w tihI ÎkoΔ I f o 5y” 7S.” °'*^® ÎÏ PV 1 # 241 no 0 .0 AO .« 1 9 RG 1600 KS 660 16 ; o : W 4 6 0 0 .0 0 0 HZ/CX W 2 .6 9 3 PPK/CM 7 ,0 5 9 SA -1 4 0 2 .6 6 01 .4 0 0 0 0 0 0 S I 20H P9 9 6 .0 0 02 .0 0 3 7 0 0 0 S2 16H no 0 .0 PW S . 60 06 3 3 .6 0 KS 960 OS 0 S3 OH PS 2 4 .2 0 pfl 4 9 .4 0 PI 5 .2 0 PO 3 8 .3 0 P2 1 0 .4 0 310 Figure 23: ^ ^C NMR spectrum of 241 (75 MHz, CDCI3 ) C l 00 .CpgMe N M 4,9 M 0 .0 1 r 02 »000.000 M::;« I"' ' •’ « I I I ' '"' I J » I I • I I r-j'i'T-i . , . . . . I I I I I I I 'i-r-i-|'i I't-i I M I I I I ri^ i' Figure 24: ^ H NMR spectrum of 244 (300 MHz, CDCI3 ) Ü1 CO CHI 287 88 AH-250.1 I \ l Hsj^^C02Me CHI2B7.C DATE 28-6-90 TIKE 8:05 62,896 93.0 2600.000 32760 32768 14705.682 H2/PTI .698 2 4 4 PH RD l.î AO I Ao)'" FW 16400 02 4350.000 DP 20H CPO 16 .100 GB 0.0 ex 34.00 CY 15.00 FI 158.757P F2. 20.859P HZ/CH 255.096 PPH/CH 4.056 SR -4040.63 ,*-WW4 150 140 130 120 110 100 90 60 70 60 50 40 30 PPM Figure 25: ^ NMR spectrum of 244 (63 MHz, CDCI3 ) O) O NO. FIOI O U E 25-3-■93 2 4 6 SF 250.,133 s r 6 3 .0 01 4104,,552 SI 32768 TO 32760 SM 3 496.,503 H2/PT ,213 PH 8.0 RD 0.,0 AO 4.,686 RG 4 KS 32 TE 303 FH 4400 02 50000,.000 OP 30U PO LB 0..0 GB 0..0 CX 34..00 CY 0,.0 FI 12,.OOOP F2 -1,.COOP H2/CH 95.,639 PPH/CH .362 SR 2871..26 11.0 9.0 7.0 6 .0 5.0 3.0 2.0 PPM Figure 26: NMR spectrum of 246 (250 MHz, CDCij) O I 5 p NO. FIOI DATE: 25-3-•93 SF 62..896 sr 93.0 01 2200,.000 SI 3276B 2 4 6 TO 32768 sw 14705,.862 HZ/PT PK 7,.0 RD 0,.0 AQ 1, 114 RG 800 HS 806 TE 303 FW 18400 02 4100,.000 OP 20H CPO LB 0.,0 CB 0,.0 CX 34..00 CY 0 .0 FI 160..O05P F2 5..OlOP HZ/CH 206,.723 PPH/CH 4 .559 SR -4041 .79 150 140 130 120 110 100 90 ^^^60 70 60 50 40 30 20 O) ro Figure 27: ^ 3q ^IVIR spectrum of 246 (63 MHz, CDCig) DATE 15-1-93 TIKE 11:44 SF 300.133 SFO 300.130 SF02 300,130 sr 210.0 ÏÏ HZ/PT^^®®,230 PK i:5 ;g 4.194 40 I il§ 02 50000.000 HZ/CH 92.689 PPH/CH .309 SA ' 3368.61 9.0 8.0 5.0 3.0 2.0 0.0 PPM Figure 28: "* H NMR spectrum of 245 (300 MHz, CDCI3 ) 05 CO CMI292 Cta 68 AXO 0£PT AH-25Q-2 a g Çîii iSTj;” ifô îîtSoo Iy®*$S 01 2500.000 S t 32768 TO 32768 KZ/PT .8 8 8 % 1:1 S§m 1000 T£ 309 02 4430.000 H7/CX 282.129 PPH/CH 4.486 2 4 5 SA -4043.53 1000 Figure 29: "* NMR spectrum of 245 (63 MHz, CDCI3 ) O) 4^ T s DATE 15-1-93 TIME 17; 44 SF 300.133 SFO 300.130 SF02 300.130 sr 210.0 TO 32768 2 4 7 HZ/PT .238 PK 3:8 I 303 02 50000.000 HZ/CH 92.689 9.0 ... 6.0 ... " P P H 3.0 0.0 Figure 30: NMR spectrum of 247 (300 MHz, CDCig) O) Ol CKH007 Cl) 68 U O K P 1 AH«250*2 a i t CM7.M4 TIhI îSTot*’ |,„ p . i L K : K S:? êS ?l ‘iSI 02 4450.000 KZ/CK 2 8 0 .4 4 0 PPH/CM 4 .4 5 9 M -4 0 4 1 .7 3 2 4 7 140 130 120 110 100 SO 80 70 60 50 ' 40 30 20 10 Figure 31: ^ ^MR spectrum of 247 (63 MHz, CDCIg) O) O) 2 4 9 ÎÇ w T-"' Il É î r ” S ?:S 1 r n 4400 02 60000.000 DP 3QL PO L$ 0 .0 8 4:1" t ' ' ^ 1 ■ I ‘ ' ■ I ' ■ ■ I ' ' ' I ' ' ' ' I ' ' I ^ ' ' * I ' ' ■ » 1 ■ » ' ' I 1 n I I r * i ’ I* I *1 1* I ' i ~ i 1 *1 I n ' 4 **f ' V 1 ■»*'! 'r* > ' ; ^ -T T -r" i i-i « - 1 i r - 9.5 9,0 5.6 5.0 7.5 7.0 6.5 6.0 5,5 8.0 4.S 4.0 3.5 3.0 2.5 2.0 1.5 1.0 .5 0.0 Figure 32: ^ H NMR spectrum of 249 (250 MHz, CDCIg) G) •vj C H U . 004 es *N0 DEPT AH-250.2 £ £ 1 1 CI.004 AU PR06; B8DEC.a u S. DATE 13-7-90 TIKE 13:10 sINg-"" 32768 14705.882 IHZ/PT .898 pw 1.5 RD 0.0 2 4 9 AQ 1.114 RG 400 NS 6308 TE 303 FH 16400 02 4450.000 DP 20H CPO LB 1.500 GB 0.0 CX 34.00 CY 15.00 FI 153.84GP F2 4.847P HZ/CH 275.635 PPH/CM 4.302 SR -4044.42 150 140 130 120 110 100 90 80 70 60 50 40 20 10 PPM Figure 33: ^ NMR spectrum of 249 (63 MHz, CDCIg) O) 00 ?îïi SF 300,133 SFO 300.130 i î HZ/PT^’®®.236 PW I lU 02 50000.000 H7/CK 92.609 PPK/CM .309 SR 3360.01 / / , u 1.0 0.0 Figure 34: ^ H NMR spectrum of 250 (300 MHz, CDCIg) o> CO a s B3to£pr Î V CHlMAC.eOl Mea^T.on Pflos: Ifo ll;l?§ Si kS/p” ’'*.«5< PV LQ M 9 .0 T .0 4 9 R6 1600 H$ 250 Te ’ s Sj 02 4 4 9 0 .0 0 0 HZ/CH 4 4 9 .9 6 3 PPH/CH 7 .0 5 9 SA -4 0 4 9 .5 3 01 .6 0 0 0 0 0 0 SJ 20H Pfl 5 5 .0 0 02 .0 0 3 7 0 0 9 32 30H AD 0 .0 J i " I ■i Figure 35: ^ ^C NMR spectrum of 250 (63 MHz, CDCIg) O VKIIZ124 t i k I SFO i o o l l i o SF02 200.130 SV 200.0 01 3740.000 260 SI 32700 TO, 32768 HZ/PT .220 Eg kî î ;L ÏI J 02 50000.000 HZ/CH 55.921 PPH/CH .279 SR 2334.22 7.5 7.0 6.5 5.5 <4.5 4.0 3.5 3.0 2.5 2.0 1.5 0.0 PPM Figure 36: NMR spectrum of 260 (200 MHz, CDCIg) CH-IY-117 C13 03 ANC OEPI AH-J50-3 CH.OOA AU PHOG: BBDEPT.0F2 NH Mo sr 93. îi H°/pP®“.95< PK NO. Î8 3:: 260 400 I 303 02 4450.000 HZ/CH 303.633 PPH/CH 4.828 SR -4037.80 D: .8000000 SI 20H P9 85.00 02 .0037000 S2 20H PO 0.0 PW 1.50 DE 42.50 NS 400 OS 0 53 OH P6 8.50 P8 17.00 PI 4.50 PO 12.80 P2 8.00 "T"' "■T.. I j ” ""T" 130 120 110 90 80 70 40 PPM 30 20 Figure 37: "* NMR spectrum of 260 (63 MHz, CDCIg) PO SOgPh EW" Kl- 1 W1 8COOO.OOO K:# 8 .9 0 .0 4 .0 2 .0 PPM 0 .0 Figure 38: ‘‘ h NMR spectrum of 261 (300 MHz, CDCIg) •vj CO CHIV112 C13 80 AKO OEPT AH-2S0-2 CHH.004 TiSi i!rfi°® SF 62.896 \( SFO 62.900 SOjPh ïi H°/PT^'®®.898 gg AQ l:S R6 ÏI 02 4450,000 SR -«<1.73 150 K O 130 120 n o 100 30 80 70 60 50 PPM ■40 30 20 10 Figure 39: ^ NMR spectrum of 261 (63 MHz, CDCIg) 4k PhOgS OEftC.OOl DATE 20-2"■93 SF 250..133 SY 83.0 01 4104,,552 SI 32760 TO 32768 SW 3496.,503 KZ/PT .213 PK B..0 RO 0..0 AO 4..686 RG 20 NS 44 TE 303 FK 4400 02 60000..000 OP SOL PO L8 0,.0 GB 0 .0 CX 34,.00 CY 0 .0 FI 9 .OOOP F2 .499P HZ/CH 69 .685 PPH/CH .279 SR 2652 .69 vj ...... 7.5 3.0 0.0 PPU c n Figure 40 : ^ H NMR sp ec tru m ot 262 (250 MHz, C D C I g ) CH-IV-121 C13 es AND OEPT AH-250-2 CHI.004 d a t e 22-2-93 1 TIME 14:33 |F02^3 250.130 01 2600.000 SI 32768 TO 32766 HZ/PT .698 Pk RO l:§ AO 40*-'" I NO. 02 4450.000 262 HZ/CH 295.962 PPH/CH 4.706 SR -4040.83 150 130 120 100 90 PPM 40 Figure 41: 1 3q spectrum of 262 (63 MHz, CDCIg) 07 PhO gS # îlrJj” ot 4060.701 KZ/PT j:L 02 60000.000 “ ;I5I M 9 9 6 0 .9 7 1 .9 7 .9 7.0 4 .0 9 .0 2.0 0.0 Figure 42: NMR spectrum of 258 (300 MHz, CDCIg) •vj -si i 5 = Z ; p: 2 Ï CH.004 / ?«i !i1 i” :F, #:ggg i™2„.«0.130 Ü a - W » PhOpS H?/PT^'®°,esa PK RO l:S AQ 5845 I 303 02 4450.000 NH, 258 TIo" Tso" n o 100 so 80 70 40 PPH 30 20 Figure 43: "* ^c NMR spectrum of 258 (63 MHz, CDCIg) Vj 00 CHIV126.010 DATE 0-3-93 TIKE 13:00 SF 300.133 SFO 300.130 ÎÏ H2/PT*^®®.a38 gg M !;5- RG ¥i i 02 50000.000 HZ/CH 63.860 PPH/CH .279 SA 3390.03 8.0 7.5 6.5 3.5 3.0 2.5 2.0 1.5 1.0 PPH 0.0 Figure 44: ^ H NMR spectrum of 263 (300 MHz, CDCIg) -s i CO CHII12J C13 88 AND OEPT AM-250 P h O ÿ J . , , ^ ^ CHI,004 AU PR06: OBOEC.AU DATE 16-1-fll 3#gg'«" U705.88: HZ/PTi KS *0 !:L 400 12000 I 303 18400 4450.000 ; 20H CPO kg {jg'" g =g:2" FI 1S4.376P HZ/CN Z ^ V . Î W PPH/CH 3.837 SB -4044.42 v i w ' ■ » T— ■ M ■ ■ "~'l" ■ 150 140 130 120 100 00 PPH Figure 45: ^ NMR spectrum of 263 (63 MHz, CDCIg) 00 o DATE J8-1J-92 TXKE X 4 : 12 SF 300.133 SFO 300.130 SF02 300.130 SY 210.0 01 4668.701 SI 32768 TO, 32768 HZ/PT .230 PH 4.5 RO 0.0 2 7 9 AO 4.194 RG 20 02 50000.000 HZ/CH 83.660 PPH/CH .279 SR 3359.99 7.5 5.5 3.5 2.5 2.0 0.0 PPH Figure 46: ^ H NMR spectrum of 279 (300 MHz, CDCIg) O i i 11 \( GN C K.004 ?}ii îi’jr ” NO SOCVCNT C0CJ3 2 Iy «3.” *"®® 01 2600.000 2 7 9 fo M7G0 pw 2 . 0 RO 0, 0 AO 1. 114 AS 4 0 0 KS 800 TE 303 fw 18400 0 2 4450.,000 0? 20H CPO LB 1,.500 68 0,,0 CX 3 4 , . 0 0 c r 16,. 0 0 f l 159,.799P f2 3,.634P HZ/CK 288 . 8 8 7 PPH/CH 4 .593 SR > 4 0 3 6 .35 00 Figure 47: ■* NMR spectrum of 279 (63 MHz, CDCI3 ) ro OHO 280 NOPP .001 DATE 9-1-93 SF 250. 133 sr 63.0 OJ 4104. 552 SI 32766 TO 32768 sw 3496. 503 HZ/PT 213 PM 6. 0 RO 0.0 AO 4. 686 RG 10 MS 24 TE 303 FM 4400 02 50000..000 OP 30L PO LB 0..0 GB 0 .0 CX 34 .00 cy 0 .0 FI 10 .OOlP F2 .499P HZ/CH 77 .248 PPH/CH .309 SR 2645 .65 9.0 8.5 5.05.5 3.5 PPM Figure 48: ^ H NMR spectrum of 280 (250 MHz, CDCI3 ) C» CO 280 HOP.QOI OKIE 9-1-93 62.696 2200.000 H705.882 K2/PT .090 PH 1.,5 PO 0.,0 AQ i . .114 RG 400 NS 1184 T£ 303 FH 18400 02 4100..000 DP 20H CPD LB 0..0 08 0..0 CX 34 .00 CY 0 .0 FI 210 .OlOP F2 5,.024P HZ/CH 379 .199 PPH/CH 6 .029 SR -4041 .79 200 190 J80 170 160 160 UO 130 120 110^^ ICO 90 80 70 60 50 40 30 Figure 49: ^ NMR spectrum of 280 (63 MHz, CDCio) CO A p o p o .o o i N ^ ^ P h DATE lO-G-92 TIKE 7:36 SF 3 0 0X33 o SFO 300.130 î\ TO, 32768 N O o HZ/PT .238 282 PM 4.5 RD 0.0 AO 4.194 RG 10 N3 40 TE 303 02 50000.000 HZ/CH 03.860 PPH/CH .279 SR 3376.59 7.5 5.0 4.0 PPM Figure 50: ^ H NMR spectrum of 282 (300 MHz, CDCig) 00 Ü1 BBOEPÎ.OfZ ÎÎÜ i§Tlî“ IfO 62:900 IfOÎSY 93,0 250.130 01 2609.090 N"^ ^P h W»,. PU 1.5 ROAO0 1.049 .0 RO 1600 NS I t 30)923 02 4439.000 HZ/CM 443.963 PPK/CH 7.039 sn 4036 «3 OS 282 ss 20K.6000000 P9 63.00 02 .0037000 S2 20H RO 0.0 PM 1.50 0£ 42.50 NS OS 923 S3 OH ® P8P6 17.00 9.90 PI 4.50 P2PO 12.60 9.00 Figure 51: ^ ^C NMR spectrum of 282 {63 MHz, CDCI3 ) 00 05 'OMg t r 300.133 SI 5Î5IS-’'‘ NO. % ::L 299 % ,« 02 50000.000 K i ; *,J , 1,* # I, f-Y I I I T I . .'1 I I 1-1 . -I J T-I I—I «-I I |-| II »-i-f-r r I i“« |-r'i-t-i-j-« i-i-i-1'r-i M-r"i"r 1.9 1.0 7.5 7.0 6.5 6.0 5 5 5.0 4.5 _ 4.0 3.5 3.0 2.5 2.0 1.9 l.O .5 0.0 F igure 52; NMR sp ec tru m of 299 (300 MHz, CDCIg) 03N 'OMe 8B2.DF ?}JI K!" Ifo H;lfS NO2 01 «000.000 2 9 9 i P L . PW . « o ' : ' " "S5§ 02 4600.000 HZ/CH 932.693 PPH/CH 7.058 SR -1396.7$ OS .4000000 SS 20H P9 96.00 02 .0037000 S2 I6M RO 0 .0 PW i.e o DC 33.90 NS 23040 OS 0 S3 OH P6 24.20 P0 48.40 PS 5.20 PO 35.30 P2 10.40 PPK z to 200 180180 170 160 ISO SODItO Figure 53: ^ NMR spectrum of 299 (75 MHz, CDCI3 ) 03 00 J035C.O O » ?}if tîi” tro loSlîio K'L,.!"'"y c PW O M e S:L TE J 02 8 0 0 0 0 .0 0 0 NH 300 [■ I" I (-1-1-1'T-r I I I «M I I # 5 # :0 7 ' , i 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 .5 0.0 CO Figure 54: '•h NMR spectrum of 300 (250 MHz, CDCig) CO CH>H1>230 Ct3 es ANO OCPT AC-300 d Ai CM.004 tikI irSi”* BÎ. Jiiri!. LPi:: BO 'I’oo il N"^ ^OMe ?l SSI 02 4900.000 S 3 l r 300 ISO 140 120 110 100 ^^^90 00 70 ”'cO ' 50 ' TÔ 30 Figure 55: ^ NMR spectrum of 300 (75 MHz, CDCIg) to o 6 0 fP .0 0 2 t ik I 'O M e sro j?S:î!o s{ 'rS i:t iî C O g M e U 3 0 J 02 80000.000 307 IR 3 / /] i - l — X- j L “T-f-j -1 ■T'|-»-r I I I' !■*-» I N 'l •- r ' 1 1 ] 1* I . -I'l I I p-i-'i , • ' I* I I I I I I I r ' ' ' ‘l-J—«-1-T I I* f I I 1"J I 1 I - I' I I I -T-T—{■ I I I I I I I »■ « I ■ m -V ’i-T- 8.9 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 J.5 2 .0 1.5 i.o .5 o.o Figure 56: NMR spectrum of 307 (250 MHz, CDCI3 ) (Û CHIY020 C13 08 AND OEPT AH-250-2 CH.004 GATE 9-12-92 TIME 17:41 SF 62.89S SFO 62.900 |F02^^|50.130 01 2600.000 SI 32768 TO^ 32768 HZ/PT .898 PH RO I:? AO 1.114 RG 400 3535 ÏI 303 02 4450.000 HZ/CH 268.613 PPH/CH 4.271 SR -4043.53 3 0 7 140 130 120 110 100 90 80 70 60 50 40 30 20 10 PPM Figure 57: ^ ^ m r spectrum of 307 (63 MHz, CDCIg) CO to AUH0CCK2.0P2 PftOR ■OMe 6 in-Mi 01 4000.000 S I 16304 KZ/PT” “ .4flfl t i l ,!•»« Ï1 II! 02 2767.576 318 1%%, " I I I SR 2 0 1 7 .2 2 D4 .0575000 RSA W 0 .0 DE isoioo El "I 07 3.6000000E3 KZ 4 D1 .0050000 S3 861 03 .0050000 02 KOELIST.004 1 3 7 4 5 .1 1 7 a 3738.770 3 3 7 3 7 .7 9 3 5 3 7 3 ll6 B 9 ? 1111:111 9 U) ^ÎST.OOl S ex> P I 1 0 .4 0 06 .0000030 P2 2 0 .6 0 09 .0000794 DS I . 0500000 1 0 4 T * " | ” * ' i " i ' »■ J “ i " f T " f \ I . I ■ . I ■ ■ . . ■ ...... t ' I . r 'i I I I I I i I 1.0 7.3 7.0 6.5 6.0 5.5 5.0 4.5^^ 4,0 3.5 3.0 % 5 Figure 58: ‘‘ h NMR spectrum of 318 at 370 K (250 MHz, toiuene-dg) (O 00 CH-lV-025 C13 00 *N0 OEPr AK-250-2 CH.004 AU PROG: BBDEPT.0F2 DATE 6-9-82 'O M e TIKE 9:51 SOLVENT C0C13 62.895 83.0 2600.000 32768 32768 I 15625.000 H Z / P T . 9 5 4 PH 1.5 MeOpC no 0.0 AO 1.049 RG 1600 318 NS 9760 TE 303 FH 19600 02 4450.000 DP 20H CPD LB 1.500 GB 0.0 CX 34.00 CY 0.0 FI 161.044P F2 17.590P HZ/CH 265.374 PPH/CH 4.219 SR -3689.56 150 90 PPM 30 20 Figure 59: ^ XMR spectrum of 318 at 370 K (63 MHz, DMSO-dg) CO A. I!. 324 Lpi;::: £0“ i:î 1 i “ 02 50000.000 Figure 60: ^ H NMR spectrum of 324 (300 MHz, DMSO-dg) co en Cm-J v- \ E ■ X : ; : y * B CM.004 DATEtike 28-10-921^47 SOCVEHT C0C13 „ 1 " " 92768 I 470 9 .6 8 2 5?/pf 324 5;? III FW 18400 445 9 .0 0 0 P 20H CPD 18 'Î %A -3719.46 ISO 140 T PPM Figure 61: ^ NMR spectrum of 324 (63 MHz, DMSO-dg) (O O) 325 6H3CN12.003 DATE 21-3-93 250.134 63.0 5264.000 32758 32768 SHI 3496.503 HZ/PT .213 PW 8..0 flO 0..0 AO 4..685 RG 40 NS 165 TE 303 FH 4400 02 50000..000 OP 30L PO LB 0,.0 GB 0 .0 CX 34 .00 CY 0 .0 FI 10.• OOlP F2 .500P HZ/CH 77 .248 PPH/CH .309 SR 4040 .57 9.5 9.0 5.5 4.54.0 3.5 3.0 2.5 2.0 PPM Figure 62: H NMR spectrum of 325 at 313 K (250 MHz, DMSO-dg) CO N AUC X.004 PflQG; Ç îilii” I f o li^Soo 01 2600.000 81 32768 HZ/Pt” ®®,854 I %: 02 5600.000 HZ/CH 2 9 0 .7 8 7 01 .8000000 51 20H P i 6 5 .0 0 02 .0037000 52 20H 325 I '# PS 8 .5 0 Eî '1:11 II 'l:ll 150 140 130 120 no 100 90 80 70 60 50 40 30 20 10 Figure 63: ^ NMR spectrum of 325 at 313 K (63 MHz, DMSO-dg) CO 00 CH.OOO ?iîl ifo K'Lo.i""' 303 02 50000.000 ^ /V 9 .0 0 1 .5 0 6.00 7.50 7 .0 0 6 .5 0 6.00 5 .5 0 S . 00 2 .0 0 Figure 64: ^ H NMR spectrum o? 327 at 343 K (300 MHz, DMSO-dg) (0 CO CM-jr-os/ cosrpfCQ êtj/jr àc-jop CMC5.SKX f i PflOJ: jU , 5 W C0SP0Q4R.DF T i l l I fo 3 oo!» 3o E . . m SI l35S-=” S IZ 2048 S I l 2048 ITO 2040 W /P T 1 .0 3 4 PW flD 0 .0 AO .4 8 3 RG 200 KS 32 TE 303 DC 2 9 7 .5 DR 12 ow 236 fW 2700 02 50000.000 W0W2 0 WOMl 0 SSS2 3 SS81 3 KC2 R SR 4 7 9 1 .2 } SR2 4 7 9 1 .2 0 6 SRI 4 7 8 1 .2 0 6 PS 1 0 .4 0 01 1 .0 0 0 0 0 0 0 PJ 1 0 .4 0 03 .0 0 0 0 0 2 0 00 .00 0 0 0 1 0 02 .00 0 0 0 3 0 05 .0003200 06 .46 4 0 0 0 0 KE 554 IK .00 0 4 7 2 0 3 .0 MeOgC 327 Figure 65: ^ H NMR COSY spectrum of 327 at 343 K (300 MHz, DMSO-dg) CKC.OOl AU PflOG; CCO.OF ÎÎSI Sÿ-oi^ S f • 7 5 .4 6 9 SFO 7 3 .4 7 0 SF02 Î00.1W ST 7 9 .0 01 6 0 0 0 .0 0 0 SI 32750 TO 32750 HZ/PT 1.221 PW 1 .9 PO 0 .0 ÂQ .6 1 9 AS 600 ws 6577 TC 303 02 6 1 0 0 .0 0 0 HZ/CH 5 1 0 .5 4 1 PPH/CH 6 .7 5 5 327 SA 01 .4 0 0 0 0 0 0 S ! SON P9 9 6 .0 0 02 .00 3 7 0 0 0 52 I6H AO 0 .0 PW 1 .9 0 OE 3 3 .8 0 MS 6577 OS i4w iYMsW'*h*\<4W^W,''/*6wiW'W^iA4#»^^ 11 « ...... - PPM...... Figure 66: ^ ^C NMR spectrum of 327 at 343 K (75 MHz, DMSO-dg) ro o H 58t .0 0 1 DATE 3 3 -1 0 -6 2 TIKC 1 6 :3 0 S f 3 0 0 .1 3 3 sro 3 0 0 .1 3 0 i F O i 3 0 0 .1 3 0 S t 1 1 0 .0 01 46 6 6 .7 0 1 S I 32766 32 768 HZ/PT 238 4 .5 RO 0 .0 40 4 .1 9 4 RO 40 MS T£ 393 344 02 50000.000 HZ/CH 0 3 .6 6 0 PPH/CH ,2 7 9 SR 3 3 7 1 .4 3 I U Figure 67: ^ H NMR spectrum of 344 (300 MHz, CDCI3 ) ro o ro CH-iv-e24 e u eo ikj oept ak- 25o -2 T : CH.004 04TC Î-Ï-92 TINE 17 :5 3 SOtVEHT C0CJ3 SF 6 ? .8 9 6 s r 9 3 .0 2 5 0 0 .0 0 0 !i HZ/py'^^iesa PH I;§ RG «I 3 4 4 Ï! *44 5 0 .0 0 0 20H CPO , i ! r PPH/CHL:;iË 4.136 SR -4 0 4 3 .5 3 150 140 pp« •« ?0 «0 50 40 3 0 20 ro Figure 6 8 : NMR spectrum of 344 (63 MHz, CDCI3 ) o CO OMCS.SHX TIME Jriz'”® I f o aoollao 10 32768 HZ/PT .2 3 8 1 2 3 KS oM JS ?l 3?S 02 59000.000 HZ/CM 6 3 .6 6 0 PPH/CH .279 SR 3 3 6 0 .9 4 Figure 69: NMR spectrum of 123 (300 MHz, CDCI3 ) ro o M CURSOR FREQUENCY FPM INTENSITY MUl. l 2686 1 1 8 0 8,550 189,0193 1 .408 S 2 4967 9 7 1 3 .1 5 0 154.4321 1 .0 3 3 S 3 5649 9 0 6 3 .3 7 0 144.1010 1 .087 s 5785 89 3 5 .3 4 0 142.0336 1.961 5 5 6728 80 3 3 .7 0 3 1 27.7 3 0 0 2 .9 6 5 D 6 6891 78 7 8 .6 0 3 1 25.2653 2.8 1 4 D 7 7157 7624.830 121.2294 2 .9 9 8 D 8 7246 7 5 3 9 .5 9 2 119.8740 2 .7 9 9 D 9 7268 7518.967 119.5461 2 .7 7 9 ü 10 10041 4874.609 77.5027 2 .2 7 0 11 10074 4042.766 2 .3 : 6 123 12 10108 481 0 .6 2 5 76.4855 2 .2 5 6 13 10755 4193.497 h 6 .6730 2 .9 ? 7 D 14 10839 4113.356 65.39S4 1.7:,': 15 3 4 9 2 .6 6 0 55.53vH 2 .7 0 7 1 16 11612 3376.219 53.6794 2 . 7 8 9 V 17 12701 226] .245 35.9521 2.9 0 7 T 18 12838 2207.265 35.0939 '2. 706 T 19 13157 1902.809 2.9 9 7 0 20 13478 1596.635 25 .3 8 5 3 2 .9 6 5 T 21 14305 8 0 7 .0 9 6 12.04 50 2.60" 0 PPM 99 Figure 70: ^ NMR spectrum of 123 (63 MHz, CDCI3 ) ro o tn LINE#HEIGHT HSIGMTIL) FREOIHZ)PPM I 5 5 0 . 0 0 5 5 0 . : 2 2 0 1 1 . 4 5 4 . 0 2 1 31 1 . 9 9 3 1 1 . '1 9 1 8 9 5 . 9 7 3 . 7 9 0 3 3 6 2 . 8 9 3 6 3 . .6 1 6 0 0 . 4 5 3 . 7 5 9 2 8 7 . 8 2 2 8 7 . ;13 1 7 0 2 . 9 2 3 . 4 0 4 5 2 9 5 . 8 1 2 9 5 . 9 1 1698.49 3.396 6 2 5 9 . 2 8 2 5 9 . 7 4 1 6 9 5 . 8 6 3 . 3 9 0 7 6 5 4 . 6 5 6 5 9 . 4 1 1 6 9 2 . 0 7 3 . 3 6 3 a 3 3 3 . 9 6 3 3 4 . 3 6 1 6 8 4 . 4 6 3 . 3 6 7 9 5 3 3 . 0 0 5 3 7 . 6 9 1 6 8 2 . 4 6 3 . 3 6 3 10 4 3 5 . 7 4 4 3 6 . 3 1 1677.61 3.354 1 1 3 2 6 . 6 3 3 2 6 . 6 0 1 6 7 1 . 6 9 3 . 3 4 2 12 6 5 2 . 5 4 6 5 2 . 7 8 1 6 6 6 . 8 7 3 . 3 3 2 13 6 7 0 . 2 1 6 7 0 . 3 0 1 6 6 5 . 4 7 3 . 3 3 0 1 4 3 0 4 . 9 2 3 0 6 . 4 5 1 6 5 8 . 9 0 3 . 3 1 6 15 3 4 7 . 8 4 3 4 8 . 0 2 1654.00 3.307 16 2 2 0 . 1 0 2 3 1 . 3 0 1647.61 3. 294 17 3 9 9 . 3 6 399.52 1616.44 3 . 2 3 1 l a 2 7 4 . 5 7 2 7 4 . 5 7 1611.39 3.221 13 3 1 9 . 9 5 3 2 0 . 0 4 3 . 2 0 8 2 0 6 6 6 . 6 6 6 6 9 . 4 4 1 5 9 4 .6 1 3 . 1 8 8 21 6 0 1 . 7 3 6 0 3 . 3 3 1579.13 3. 157 2 2 5 6 2 . 3 9 5 6 4 . 5 3 1 3 6 7 . 4 5 2 . 7 3 4 1 3 5 2 . 0 0 2 . 7 0 3 2 4 1 9 7 . 4 5 1 9 9 . 7 6 1 1 3 6 . 0 2 2 . 2 7 5 3 3 9 . 13 1 1 3 1 .3 1 2 . 2 6 2 2 6 4 2 0 . 3 3 4 2 3 . 9 1 1 1 2 4 . 8 2 2 . 2 4 9 2B 2 7 6 . 5 4 2 7 6 . 6 2 1 1 1 1 . 3 7 2 . 2 2 2 2 9 2 7 1 . 8 2 3 0 5 2 2 . 0 1 5 2 1 . 9 6 1 0 7 0 . 5 7 2 . 1 4 0 SÎ;*ïSS' P 4 5 7 . 61 2 . 1 2 7 3 2 3 6 7 . 4 1 3 7 3 . 2 7 1 0 5 7 . 5 0 2 . 1 1 4 1 0 5 1 . 0 2 2 . l O l lÉ li'-' #& ro o PPM O) H NMR sp ec tru m of D ehydrotublfoline, p rovided by Dr. L, E. Overm an p p [NE# HEIGHT HEIGHT(L) FREQ(HZ) PPM 1 82. 21 82.64 23781.64 189.083 2 81. 63 87. 10 19423.37 154.431 3 62. 14 63. 90 18122.67 144.090 4 80. 15 90. 22 17842.22 141.860 5 223.04 304.53 16086.00 127.897 6 245.76 260.12 15777.39 125.443 7 206.IS 249.16 15270.32 121.411 8 362.79 408.22 15091.03 119.986 9 57. 23 57. 28 9727.66 77.343 10 3053.74 3102.24 9716.44 77.253 1 1 118.79 119.05 9703.97 77.154 12 99. 64 99. 69 9696.38. 77.094 13 3113.05 3183.47 9684.52 77.000 14 94. 1 1 94. 34 9667.44 76.864 15 101.41 104.38 9663.49 76.832 16 3046.17 3139.58 9652.56 76.745 17 77. 54 79. 35 9637.53 76.626 18 209.27 24 4.16 8380.77 66.634 19 84. 26 85. 56 8229.45 65.431 20 222.03 225.44 6982.86 55.519 21 238.25 252.77 6756.15 53.717 22 225.43 269.65 4541.07 36.105 23 206.88 211.52 4423.06 35.167 24 245.31 246.87 3810.95 30.300 ■ffS— i 91.36 37 34.04 -----e9r-6S8- 26 230.41 231.00 3200.73 25.448 27 ------171.80 1635.96 13.007 jJ * t 1— I—r “ T I T" I I I I I I I I I I I rT ~| I I I I I I I I I I I— I— I— I— I— I— I— I— r 200 180 160 140 120 100 80 60 40 20 0 ro o 1 3 C NMR spectrum of Dehydrotublfoline, provided by Dr. L. E. Overman