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N° d'ordre : 4155

THÈSE

Présentée à

L'UNIVERSITÉ BORDEAUX I

ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES

par Dawood Hosni DAWOOD

POUR OBTENIR LE GRADE DE

DOCTEUR

SPÉCIALITÉ : CHIMIE ORGANIQUE *********************

TOWARDS THE SYNTHESIS OF MONOTERPENOIDS INDOLE ALKALOIDS OF THE ASPIDOSPERMATAN AND STRYCHNAN TYPE

*********************

Soutenue le: 17 décembre 2010

Après avis de:

MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur

Devant la commission d'examen formée de :

MM. PIVA Olivier Professeur, Claude Bernard Lyon 1 Rapporteur PALE Patrick Professeur, Louis Pasteur Strasbourg 1 Rapporteur POISSON Jean-François Chargé de recherche, CNRS Examinateur VINCENT Jean-Marc Directeur de recherche, CNRS Examinateur LANDAIS Yannick Professeur, Bordeaux 1 Directeur de thèse ROBERT Frédéric Chargé de recherche, CNRS Codirecteur de thèse

- 2010 -

Abbreviations

∆: reflux °C: celsius degrees Ac: acetyle ALB Aluminium Lithium bis(binaphthoxide) complex AIBN : azobis(isobutyronitrile) aq.: aqueous Ar : aromatic BINAP : 2,2'-bis(diphenylphosphino)-1,1'-binaphthyle BINAPO : 2-diphenylphosphino-2'-diphenylphosphinyl-1,1'-binaphthalene BINOL: 1,1’-bi-2-naphthol Boc: tert-butyloxycarbonyle BOX: Bisoxazoline Bz : benzoyle Bn: benzyle cat. : catalytic DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCC: dicyclohexacarbodiimide dr.: diastereomeric ratio DIBAL-H: diisobutylaluminium hydride DIPEA: diisopropyléthylamine (Hünig ) DMAP: dimethylaminopyridine DME: dimethoxyethane DMF: DMSO: dimethylsulfoxyde dppp : 1,3-bis(diphenylphosphino)propane DTBMP: di-tert-butyl-4-methylpyridine ee. : EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide equiv.: equivalent Et: ethyl

Et2O: diethyl EtOAc: ethyl acetate EWG: electron withdrawing group h: hour HOBt: hydroxybenzotriazole i- pr : iso-propyle IR: infra red KHMDS: Potassium bis() LDA : lithium diisopropylamide M : concentration (mole in littre)

MW : molecular weight NBS : N-bromosuccinimide NR.: no reaction NMR : nuclear magnetic Nu : o- : ortho p- : para PCC: pyridinium chlorochromate (Corey-Suggs reagent) PDC: pyridinium dichromate p-TSA = APTS : para toluenesulfonic Piv : pivaloyle Pyr.: quant : quantitative Rf : fronted repport SES : trimethylsilylethanesulfonyle t- = tert- : tertio r.t. : room temperature TBAF: tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyle TBS=TBDMS: tert-butyldimethylsilyle Tf : triflate = trifluoromethane TFA: trifluoroacetic acid THF: tetrahydrofurane TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxy TMS : trimethylsilyle TMSBr: trimethyl silyl bromide TMSCl: trimethyl silyl chloride TMSTf: trimethylsilyl triflate Ts : tosyle = paratoluenesulfonyle TTMS : Tristrimethylsilane

Table of contents

Introduction ...... 5

Chapter I: Approach and synthesis of Strychnos alkaloids ...... 9 I. Strychnine ...... 9 I.1. General Aspects ...... 9 I.2. Toxicity of strychnine...... 10 I.3. Biosynthesis of strychnine...... 11 I.4. An overview of the previous syntheses of strychnine...... 13 I.4.1. Generation of C7 quaternary center of strychnine...... 15 I.4.1.a. From indole derivatives...... 16 I.4.1.b. From protected anilino derivatives...... 17 I.4.2. Construction of the bridged CDE ring fragment...... 18 I.4.3. Elaboration of the hydroxyethylidene at C20...... 20 I.4.4. Enantioselective synthesis of (-)-strychnine...... 21 I.4.5. Some detailed syntheses of strychnine...... 23 I.4.5.a. Woodward‟s relay synthesis of (-)-strychnine (1954)...... 23 I.4.5.b. Mori‟s total synthesis of (-)-strychnine (2001)...... 24 I.4.5.c. Bodwell‟s formal synthesis of strychnine (2002)...... 27 I.4.5.d. Padwa‟s total synthesis of strychnine (2007)...... 28 I.4.5.e. Andrade‟s total synthesis of (±)-strychnine (2010)...... 30 I.5. Conclusion ...... 32 II. Mossambine ...... 33 II.1. General comments ...... 33 II.2. Kuehne‟s Synthesis of Strychnos alkaloids...... 35 II.2.1. Intramolecular Diels-Alder reactions...... 36 II.2.1.a. Construction of the C, D and E rings in (±)-echitamidine...... 36 II.2.1.b. Reductive cleavage of the C/E ring...... 37 II.2.1.c. Complete synthesis of (±)-echitamidine...... 38 II.2.2. Condensation-sigmatropic rearrangement sequence...... 39 II.2.2.a. Construction of the C and E rings in (±)-echitamidine...... 39 II.2.2.b. Closure of the D ring...... 39 II.2.3. Selective total synthesis of mossambine and epi-mossambine...... 40 II.2.3.a. Construction of the pentacyclic motif...... 40 II.2.3.b. and synthesis of the key cyclization precursor...... 41 II.2.3.c. Radical cyclization reaction...... 43 II.2.4. Enantioselective approach to (-)-mossambine...... 45 III. Conclusion ...... 46

1 Chapter II: Double Michael approach applied to arylcyclohexa-2,5-diene derivatives, and a new route to the synthesis of Büchi’s ketone...... 47 I. Synthesis of Büchi‟s ketone ...... 47 I.1. Bibliography ...... 47 II. Our strategy ...... 50 II.1. Retrosynthetic analysis ...... 50 III. Synthesis of arylcyclohexa-2,5-dienes...... 51 III.1. Overview on the Birch reaction...... 51 III.2. Achievements of our laboratory...... 53 III.3. Synthesis of biaryls...... 56 III.4. Mechanistic considerations...... 58 III.5. The nature of the ...... 61 III.6. Proposed mechanism for the alkylation step...... 63 IV. Desymmetrization processes...... 66 IV.1. Principles and advantages...... 66 IV.2. Desymmetrization of cyclohexa-2,5-dienes...... 67 V. ...... 68 V.1. Bibliography...... 68 V.2. Results...... 72 V.2.1. Preparation of dienone...... 72 V.2.2. Double Michael addition...... 76 V.2.3. Enantioselective version of Michael addition reactions...... 80 VI. Conclusion...... 83

Chapter III: Desymmetrization approach applied to arylcyclohexa-2,5-diene derivatives in presence of metals. A new route to the synthesis of Strychnos alkaloids...... 85 I. Bibliography...... 85 I.1. Oxidative amination reactions...... 85 I.1.1. Halocyclization...... 86 I.1.2. Hydroamination...... 88 I.1.3. Aminopalladation...... 91 I.1.4. Aminocupration...... 97 II. Our strategy ...... 100 II.1. Retrosynthetic analysis...... 100 III. Achievements of our laboratory...... 101 III.1. Construction of B ring...... 102 III.2. Construction of B then C ring...... 103 IV. Results in the desymmetrization step...... 107 IV.1. Construction of rings C and D ( cascade) ...... 107 IV.1.1. Synthesis of the amide precursors...... 107 IV.1.2. Construction of C and D rings...... 109 IV.1.3. Construction of B, C and D rings in one pot...... 110

2 IV.1.4. Conclusion...... 111 V. Application of the palladium oxidative-amination reaction of cyclohexadienes to the synthesis of Strychnos alkaloids...... 111 V.1. Toward the synthesis of (±)-mossambine...... 112 V.1.1. Conclusion ...... 116 V.2. Attempts toward the synthesis of (±)-strychnine...... 117 V.2.1. Functionalization of the acetate group...... 117 V.2.1.a. Using Organocopper/Grignard reagents...... 118 V.2.1.b. Cyanation of allylic acetate catalyzed by a palladium complex...... 119 V.2.1.c. Bromination of the allylic acetate...... 120 V.2.1.d. Ireland-Claisen rearrangement...... 121 V.2.1.e. Intramolecular displacement...... 122 V.2.1.f. Xanthate formation...... 123 V.2.2. Ring C and G cyclizations...... 124 V.2.3. (II)-mediated aminooxygenation...... 127 V.2.4. Hydroamination reaction...... 130 VI. Conclusion...... 131

General conclusion and perspectives ...... 133

Experimental part ...... 137 I. Experimental part for chapter II ...... 139 II. Experimental part for chapter III ...... 157

3

Introduction

Synthesis of natural molecules with important biological activities is a major challenge for synthetic chemists. Indeed, many of these molecules used in medicine and pharmacology, are present only in small amounts in nature. The synthesis or semisynthesis of these natural products is necessary. Among the natural target molecules with interesting biological (analgesic, anticancer, hemostatic ...) and complex structures, there is the large family of Alkaloids1.

Among the natural target molecules, alkaloids are important to consider because of their structures and biological activities. Several definitions of alkaloid have been given since its inception in 1819. W. Meissner2 set alkaloids as substances derived from plants that react as alkalis. This definition is currently very simplistic because the alkaloids are not simply isolated from plant but also from fungi, animals and micro-organisms and may not have a basic character.

In 1983, S. W. Pelletier3 reported that alkaloid is a cyclic containing a atom in a negative oxidation state and has a limited distribution in certain living organisms. This definition is one of the most accurate. It takes into account more systematically the basic character and the presence of an alkaloid in one or many species, although there are also noncyclic alkaloids. Hesse1 in his book defines the alkaloids as organic substances of natural origin containing one or more nitrogen atoms with a basic character. It is estimated that there are more than 10 000 different alkaloids already isolated (or detected) from plant and animal sources or micro-organisms. Proposing a classification for the alkaloids is a difficult task because of the large number of known compounds.

There are five classes of alkaloids divided according to their structural elements: the heterocyclic alkaloids, alkaloids bearing an exocyclic nitrogen atom, the putrescine, spermidine and spermine alkaloids, peptidic alkaloids, and finally the terpene and steroid

1 Hesse, M. Alkaloids. Nature’s Curse or Blessing ? Wiley-VHC, Zürich, 2002, 413 p., ISBN 3-906390-24-1. 2 Meissner, W. J. Chem. Phys. 1819, 25, 379. 3 Pelletier, S. W. Alkaloids, Chemical and Biological Perspectives, Ed. S. W. Pelletier, John Wiley and Sons, New York, 1983.

5 alkaloids. Biomimetic approaches typically use these amino to provide rapid synthetic routes. The heterocyclic alkaloids belong to the most important class of alkaloids. This class is divided into several families according to the heterocyclic compound (, indole, piperidine, tropane, imidazole, isoquinoline ...) and is divided again according to their plant or animal source.

Our laboratory has been interested for several years by several families of heterocyclic alkaloids. We strive to establish a unified access to different families of alkaloids with interesting biological properties, especially Amaryllidaceae alkaloids4 (ex: galanthamine an acetylcholinesterase inhibitor, important for the treatment of Alzheimer's disease), Aspidosperma alkaloids and pseudo Iboga (ex: vindoline, synthetic precursor of vinblastine, a drug used to treat certain cancers),

Morphinans5 (ex: morphine, a potent analgesic in medicine) and the strychnos (ex: strychnine is a powerful poison that affects the central nervous system) (Scheme 1).

Scheme 1. Access to different classes of alkaloids by the synthon arylcyclohexa-2,5-diene.

4 Martin, S. F. The Alkaloids Brossi, A., Ed.; Academic Press, New York, 1987, vol. 30, p. 251-376. 5 Szantay, C.; Dörnyei, G.; Blasko, G. The alkaloids Academic Press, New York, 1994, vol. 45, p. 127-232.

6 Indeed, all these molecules have a quaternary center, substituted by an aromatic ring, an ethylamine chain, and a motif. These different elements are initially present in the arylcyclohexa-2,5-diene synthon. On the basis of these observations, a unified approach to the synthesis of these alkaloids (aspidospermidine, morphine and Strychnos) has been envisaged, using a cyclohexa-2,5-diene motif. The construction of this skeleton has been the subject of numerous studies in our laboratory6.

Since 2004, desymmetrization methodologies7 has been studied in our laboratory and applied on dienes. The most useful is the arylcyclohexa-2,5-diene motif that has been desymmetrized through hydroamination, Michael, Mannich reactions as well as oxidative amidation strategy. For example, hydroamination has been applied for the total synthesis of the epi-elwesine8.

My thesis consisted of the desymmetrization of arylcyclohexa-2,5-diene by Michael reaction for the synthesis of the Büchi‟s ketone intermediate and oxidative amination reaction in presence of metals (Pd, Cu.) for the synthesis of the pentacyclic skeleton of Strychnos alkaloids.

Initially, we will discuss an approach to the synthesis of Strychnos alkaloids from arylcyclohexa-2,5-dienes. In parallel, the Michael reaction is used to access the Büchi‟s ketone intermediate, and finally desymmetrization applied to the arycyclohexa-2,5-diene derivatives in presence of metals will be described for the total synthesis the pentacyclic skeleton of mossambine and strychnine.

6 Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett. 2005, 7, 4557-4560. 7 Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755-4758. 8 Rousseau, G. Ph.D Thesis University of Bordeaux, 2008, N° d‟ordre : 3654.

7

Chapter I: Approach and synthesis of Strychnos alkaloids

Through this chapter, we will provide a survey of the relevant literature in the synthesis of alkaloids of this family, to identify key issues to be addressed in the strategy we have proposed.

I. Strychnine

I.1. General Aspects

The genus Strychnos is the most important genus of the Loganiaceae family which comprises approximately 190 species of trees and lianas growing in the warm regions of Asia, America, and Africa9. In 1819, Pelletier and Caventou reported the isolation of strychnine, in pure form, as the principal toxin from S. nux vomica and S. ignatii 10(Figure 1).

Figure 1. S. ignatii and S. nux vomica.

In 1946, Robinson et al. reported the elucidation of the correct structure of strychnine (Figure 2).11,12 The numbering system and ring labeling based on the biogenetic interrelationship of monoterpene indole alkaloids, as proposed by Le Men and Taylor, is used throughout this chapter13. The X-ray crystallographic analysis were reported by Robertson and Bevers14, and

9 Bosch, J.; Bonjoch, J.; Amat, M. in „„the Alkaloids‟‟, (G. A. Cordell, ed.), Academic Press, New York, 1996, vol. 48, pp. 75–189. 10 Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1819, 10, 142. 11 Briggs, L. H.; Openshaw, H. T.; Robinson, R. J. Chem. Soc. 1946, 903-908. 12 Holmes, H. L.; Openshaw, H. T.; Robinson, R. J. Chem. Soc. 1946, 910-912. 13 Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508-510.

9 Bijvoet in 195015. The absolute stereochemistry of strychnine was established by Peerdeman in 1956 with X-ray crystallographic analysis16 and confirmed by Schmid et al. in 1963 using a chemical method17. Strychnine ranks as one of the most complex natural products of its size

(C21H22N2O5, molecular weight (MW) = 334): only twenty-four skeletal atoms are assembled in seven rings, resulting in six contiguous stereogenic centers (five of them in the core cyclohexane E ring). Therefore, strychnine is recognized as the flagship alkaloids of the family of Strychnos alkaloids.18

Figure 2. Structure of (-)-strychnine

I.2. Toxicity of strychnine.

Strychnine poisoning can be fatal to humans (a lethal dose of strychnine for an adult human is in the range of 30–100 mg), and can be introduced to the body by inhalation, swallowing, or absorption through the eyes or mouth. The toxicity arises from the blocking of postsynaptic inhibition in the spinal cord and lower brain stem, where it acts as a prototypic competitive antagonist of the glycine receptor19. This property has made strychnine very useful as a tool in experimental pharmacology.

14 Robertson, J. H.; Bevers, C. A. Nature. 1950, 165, 690-691. 15 Bokhoven, C.; Schoone, J. C.; Bijvoet, J. M. Acta Crystallogr. 1951, 4, 270-275. 16 Peerdeman, A. F. Acta Crystallogr. 1956, 9, 824. 17 Nagarajan, K.; Weissmann, Ch.; Schmid, H.; Karrer, P. Helv. Chim. Acta. 1963, 46, 1212-1231. 18 Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; In The Chemistry of Heterocyclic Compounds; Taylor E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4; pp 279- 355. 19 Aprison, M. H. In Glycine Neurotransmision; Otterson, O. P., Storm-Mathisen, J. Eds.; Wiley: New York, 1990; pp 1-23.

10 I.3. Biosynthesis of strychnine.

The biogenetic pathway involves, in the initial steps, the enzymatically catalyzed Pictet-Spengler condensation of tryptamine with secologanin to provide strictosidine. Next to be formed is geissoschizine, the common biogenetic intermediate for all monoterpenoid indole alkaloids (Scheme 2). After an oxidative cyclization involving C16, followed by a skeletal rearrangement, the characteristic framework of Strychnos alkaloids appears with dehydropreakuammicine. The unrearranged monoterpenoid unit characteristic of the Corynanthe skeleton (depicted in boldface in geissoschizine, Scheme 2), originally attached to the indole R-carbon (C2), is now bonded to the β-position (C7), and a new bonding between the rearranged unit (C16/C17/C22) and C2 is in place.20 The next step involves the loss of the methoxycarbonyl group from dehydropreakuammicine to give norfluorocurarine, which, upon hydroxylation and reduction, could lead to the Wieland-Gumlich , a biogenetic precursor of the heptacyclic base strychnine, as shown by Heimberger and Scott 21 in 1973. To complete the strychnidine backbone22, two additional are required. Robinson‟s suggestion that they come from acetate was proven by Schlatter in 1969,23 and probably occurs through prestrychnine, formed by an involving acetyl-CoA.

20 (a) Atta-ur-Rahman; Basha, A. In Biosynthesis of Indole Alkaloids; Clarendon Press: Oxford, 1983; pp 45-93. (b) Dewick, P. M. In Medicinal Natural Products. A Biosynthetic Approach; Wiley: Chichester, 1998; pp 324- 334. 21 Heimberger, S. I.; Scott, A. I. J. Chem. Soc., Chem. Commun. 1973, 217-218. 22 Strychnidine is the Chemical Abstracts‟ stereoparent used for strychnine derivatives; therefore, strychnine is 10-oxostrychnidine, see Figure 2. 23 Schlatter, Ch.; Waldner, E. E.; Schmid, H.; Maier, W.; Gröger, D. Helv. Chim. Acta. 1969, 52, 776-789.

11

Scheme 2. Biosynthesis of Strychnine

Meanwhile, various other Strychnos alkaloids were also identified24 and selected representative are shown in Figure 3.

24 Bonjoch, J.; Sole, D. Chem. Rev. 2000, 100, 3455-3482.

12

Figure 3. Examples of Strychnos Alkaloids.

I.4. An overview of the previous syntheses of strychnine.

Owing to the level of complexity of strychnine relative to its size, coupled with its biological activity, strychnine presents a most formidable synthetic challenge25. The first total synthesis, and the most significant achievements in the history of organic synthesis, was reported by Woodward and co-workers in 195426 and it wasn‟t until the early 1990s that a series of other successful syntheses, both racemic and enantioselective began to appear. There are now more than 16 reported total syntheses of strychnine and each of them feature an elegant application of one or more reactions, for example, the combined with a sigmatropic

25 Beifuss, U. Angew. Chem. Int. Engl. 1994, 33, 1144-1149. 26 (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749-4751. (b) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, Tetrahedron. 1963, 19, 247-288.

13 rearrangement (Overman and co-workers,27 Kuehne et al.28), the intermolecular Diels-Alder reaction (Rawal et al.,29 Martin and co-workers30), intermolecular Heck reactions (Rawal et al.29, Bonjoch/Bosch and co-workers31), the cobalt-mediated [2+2+2] cycloaddition (Vollhardt and co-workers32), skeletal rearrangements (Stork,33 and Martin and co-workers30) and transannular oxidative cyclization (Magnus et al.34). Also we note that all these approaches are directed to isostrychnine or the Wieland-Gumlich aldehyde, whose synthetic conversion to strychnine was reported during Woodward‟s first total synthesis of strychnine, (Scheme 3). Isostrychnine, which is the product of a base or acid-induced retro-Michael addition with double-bond migration obtained from strychnine,35 was converted back to strychnine in 20% yield when treated with alcoholic .36

Scheme 3. Reconversion of isostrychnine to strychnine.

The Wieland-Gumlich aldehyde is another degradation product isolated in the course of strychnine chemical investigations37. Its conversion back to strychnine was achieved in 68%

27 Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776- 5788. 28 (a) Kuehne, M. E., Xu, F. J. Org. Chem. 1993, 58, 7490-7497. (b) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427- 9433. 29 Rawal, V. H., Isawa, S. J. Org. Chem. 1994, 59, 2685- 2686. 30 Ito, M.; Clark, C.W.; Mortimore, M., Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003- 8010. 31 (a) Sole, D.; Bonjoch, J.; GarcIa-Rubio, S.; Bosch, J. Chem. Eur. J. 2000, 6, 655-665; (b) Solé, D.; Bonjoch, J.; GarcIa-Rubio, S. ; Peidro, E.; Bosch, J. Angew. Chem. Int. Ed. 1999, 38, 395- 397. 32 Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324- 9337. 33 Stork, G. disclosed at the Ischia Advanced School of (Ischia Porto, Italy), 1992. 34 Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116- 8129. 35 Wieland, H.; Jennen, R. G. Liebigs Ann. Chem. 1940, 545, 99-112. 36 Prelog, V.; Battegay, J.; Taylor, W. I. Helv. Chim. Acta. 1948, 31, 2244-2246. 37 (a) Wieland, H.; Gumlich, W. Liebigs Ann. Chem. 1932, 494, 191-200. (b) Wieland, H.; Kaziro, K. Liebigs Ann. Chem. 1933, 506, 60-76.

14 yield when treated with a mixture of , sodium acetate, and in acetic acid38 (Scheme 4).

Scheme 4. Conversion of Wieland-Gumlich aldehyde into strychnine.

The major synthetic reports in the synthesis of strychnine make a focus on the following three points: (1) the generation of the C7 quaternary carbon center; (2) the assembling of the CDE core ring; and (3) the elaboration of the hydroxyethylidene side chain.

I.4.1. Generation of C7 quaternary carbon center of strychnine.

The quaternary C7 carbon center has been formed by either taking advantage of the indole reactivity or generating this quaternary center without the use of indole derivatives.

38 Anet, F. A. L.; Robinson, R. Chem. Ind. 1953, 245.

15 I.4.1.a. From indole derivatives.

In most cases, the C and E rings were constructed by a one-pot operation with the generation of the C7 quaternary center. Woodward26, Magnus34, Kuehne28, and Fukuyama39 all use the electrophilic attack of an iminium upon a 2,3-disubstituted indole to generate the C7 quaternary center, but they undertake this important step at different stages of the synthesis. So, Woodward has been constructed the quaternary center in the early stages of the synthesis (ABC rings), while Magnus, Kuehne and Fukuyama elaborate the quaternary center at more advanced stages of the process. On the other hand, both Stork33 and Martin30 generate a 3- chloroindolenine to produce the key quaternary center by means of Harley-Mason‟s skeletal rearrangement40 to close the C and E rings (Scheme 5).

Scheme 5. Generation of C7 quaternary carbon center of Strychnine.

Because intramolecular Diels–Alder type cycloaddition is one of the most powerful methods for the formation of six-membered ring systems41, this type of reaction was also utilized for

39 Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246-10247. 40 (a) Dadson, B. A.; Harley-Mason, J.; Foster, G. H. J. Chem. Soc., Chem. Commun. 1968, 1233. (b) Harley- Mason, J. Pure Appl. Chem. 1975, 41, 167. 41 Carruthers, W. in „„Cycloaddition Reactions in Organic Synthesis‟‟ 1990, pp. 140–208. Pergamon, Oxford. Oppolzer, W.; Weinreb, S. M.; Boger, D. L.; Roush, W. R.; Sweger, R. W.; Czarnik, A.W. in

16 strychnine synthesis by Bodwell42, and Padwa43, including Vollhardt‟s [2+2+2] cyclization32 to close the (CEG, CE and EG rings) respectively. Very recently, Andrade et al.44 reported a novel sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman (IABH) protocol for efficiently assembling the ABCE tetracyclic core of strychnine (Scheme 6).

Scheme 6. Diels–Alder cycloaddition and Baylis Hillman Approaches.

I.4.1.b. From protected anilino derivatives.

In contrast, Overman27, Rawal29, Bonjoch31, and Shibasaki45 worked with intermediates having a functionalized phenyl ring that does not participate in the achievement of C7 quaternary center. Overman used a tandem aza-Cope/Mannich rearrangement, Rawal an

„„Comprehensive Organic Synthesis‟‟, (B. M. Trost, ed.), 1992, vol. 5, pp. 315–592. Pergamon Press, New York. 42 Bodwell, G. J.; Li, J. Angew. Chem. Int. Ed. 2002, 41, 3261-3262. 43 Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279-282. 44 (a) Sirasani, G.; Andrade, R. B. Org. Lett. 2009, 11, 2085-2088. (b) Sirasani, G.; Paul, T.; Dougherty, W.; Kassel, S.; Andrade, R. B. J. Org. Chem. 2010, 75, 3529–3532. 45 (a) Ohshima, T.; Xu, Y.; Takita, R..; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546-14547. (b) Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki, M. Tetrahedron, 2004, 60, 9569-9588.

17 intramolecular Diels-Alder reaction, while Bonjoch used a classical Claisen rearrangement to build up the quaternary C7 center.

On the other hand, Shibasaki generates the C ring by connecting the C6 –C7 bond, which was conducted using the intramolecular electrophilic attack of a thionium ion (transannular cyclization). In Mori‟s synthesis46, the C7 quaternary center and B ring formation were accomplished by intramolecular Heck reaction (Scheme 7).

Scheme 7. Generation of C7 quaternary center From Protected Anilino Derivatives.

I.4.2. Construction of the bridged CDE ring fragment.

The assembly of the bridged CDE ring is a critical step in the synthetic approaches to strychnine. The synthetic strategies for the closure of the piperidine D ring, has involved the formation of the C15–C20 bond (Rawal, Bodwell, Vollhardt, Mori, Stork, Bonjoch-Bosch,

46 (a) Nakanishi, M.; Mori, M. Angew. Chem. Int. Ed. 2002, 41, 1934-1936. (b) Mori, M..; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801-9807.

18 Padwa and Andrade), the ring closure being accomplished by the addition of a vinyl organometallic species to a (Scheme 8). Alternatively, the D ring has been closed by the formation of the N4–C21 bond (Woodward, Kuehne) through an attack of a nitrogen (N4) to an electrophilic carbon species (carbonyl, , or tosylate).

Scheme 8. Construction of D ring.

In the other approaches, in which the D ring has already been constructed, the bridged ring fragment and the C7 quaternary center are formed, either by a transannular cyclization of a stemmadenine-type compound (Magnus, C3-C7 bond formed, Fukuyama, C3-C7 bond formed, and Shibasaki, C6-C7 bond formed), or by multistep sequential processes, such as the aza-Cope/Mannich rearrangement (Overman, C5-C6 and C3-C7 bonds formed) or the skeletal rearrangement of a 3-chloroindolenine (Martin, C3-C7 and C2-C16 bonds formed) (Scheme 9).

19

Scheme 9. Construction of the bridged CDE ring fragment.

I.4.3. Elaboration of the hydroxyethylidene side chain at C20.

The elaboration of the hydroxyethylidene side chain at C20 is an important key operation in the synthesis approaches to strychnine. The stereoselective insertion of the (E)-hydroxyethylidene double bond is accomplished during the closure of the piperidine D ring by methods of intramolecular coupling reactions of vinyl halides with (Rawal, Bodwell, Vollhardt, Mori, Stork, Bonjoch-Bosch, Padwa and Andrade). While, Woodward, Magnus, Kuehne and Fukuyama took advantage of the ketone carbonyl at C20 to introduce the hydroxyethylidene side chain in the last steps of the synthesis by either an allylic

20 rearrangement (Woodward) or a Wittig olefination method (Magnus, Kuehne and Fukuyama). On the other hand, both of Overman, Martin and Shibasaki formed the hydroxyethylidene- bearing piperidine ring early on by means of β-elimination reactions in a highly E-selective manner.

I.4.4. Enantioselective synthesis of (-)-strychnine.

Amongst all syntheses of strychnine, two relay syntheses and six enantioselective syntheses have been reported for the natural enantiomer (-)-strychnine. In the Woodward and Magnus syntheses, relay compound 2 and 3 were used for the final transformation into (-)-strychnine, respectively (Scheme 10). From optically pure L-tryptophan methyl , Kuehne succeeded in the total synthesis of (-)-strychnine. Although the C5 stereocenter originating from the chiral source was removed from an intermediate, the highly diastereoselective intramolecular chirality transfer reaction (4 to 5) allowed an asymmetric synthesis47. Bonjoch/Bosch‟s also used an intramolecular chirality transfer strategy; therefore two new stereocenters were constructed by the diastereoselective reductive, double amination reaction (6 to 7)48. The Overman and Fukuyama enantioselective synthesis employed enzymatic desymmetrization and enzymatic kinetic resolution, respectively. Overman used the optically pure monoacetate (+)-9, which was prepared by the enzymatic of 849. While Fukuyama used the enzymatic kinetic resolution of the racemic bromohydrin 10 with lipase provided the desired chiral bromohydrin acetate 11 (46% yield, 99% ee) along with the unreacted enantiomer (50% yield, 99% ee).

47 Parsons, R. L.; Berk, J. D.; Kuehne, M. E. J. Org. Chem. 1993, 58, 7482-7489. 48 Sole, D.; Bosch, J.; Bonjoch, J. Tetrahedron, 1996, 52, 4013-4028. 49 (a) Deardorff, D. R., Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, 27, 1255- 1256. (b) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth. 1995, 73, 25.

21

Scheme 10. Enantioselective synthesis of (-)-strychnine

Recently, the progress in asymmetric has made possible enantioselective synthesis of (-)-strychnine using chiral unnatural catalysts. Mori and his co-workers used the asymmetric allylic amination catalyzed by the Pd–(S)-BINAPO complex50.

In 2002, Shibasaki achieved the total synthesis of (-)-strychnine using the asymmetric Michael 51 reaction catalyzed by the (R)-ALB complex, prepared from LiAlH4 and (R)-BINOL in a

50 Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. Org. Lett. 2001, 3, 1913-1916. 51 Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 15837-15845.

22 ratio of 1:2. The Michael reaction of dimethyl malonate with cyclohexenone 15 thus afforded the enantiomerically pure Michael product 16 (91% yield, >99% ee)52.

I.4.5. Some detailed syntheses of strychnine.

From the various synthesis of strychnine (total or formal) described in the literature, we chose four of the most recent, of which originality has attracted our attention. The first total synthesis, reported by Woodward and co-workers in 1954 was also added.

I.4.5.a. Woodward’s relay synthesis of (-)-strychnine (1954).

Having obtained 2-veratryltryptamine 17 prepared by Fischer indole synthesis, Woodward undertook the first key step of the synthesis (Scheme 11), the generation of the C7 quaternary center. Pictet–Spengler reaction of the corresponding 2-veratryltryptamine 17 with ethyl glyoxylate was induced by 4-toluenesulfonyl chloride (p-TsCl) to give the spiroannulated compound 19 as the sole product. When 19 was treated with ozone in aqueous , the veratryl group was selectively cleaved between the two methoxy groups, affording the resulting pyridone 20. Prior to the E ring formation, the Ts group was changed for an in three steps. Treatment with sodium methoxide induced epimerization at the C3 position, and subsequent Dieckmann cyclization gave ester 21. Deoxygenation at C14, and of the C14–C15 double bond, then epimerization at the C15 position under basic conditions, provided the thermodynamically more stable 22, which was previously prepared by degradation of (-)-strychnine53. The following transformations were performed using this optically pure, first relay compound 22. Introduction of an acetyl group 54 at the C15 position and oxidation of the resulting methyl ketone 23 with SeO2 directly gave the second relay compound 2439. Diastereoselective addition of sodium acetylide to the ketone (C20), conversion to an allylic , reduction of the amide carbonyl (C21), and stereoselective reduction of the pyridone ring by LiAlH4 afforded 25. Finally, rearrangement of the tertiary allylic alcohol to a primary allylic alcohol resulted in isostrychnine, which was then converted to (-)-strychnine, following the previously reported procedure55.

52 Xu, Y., Ohori, K.; Ohshima, T.; Shibasaki, M. Tetrahedron 2002, 58, 2585-2588. 53 Prelog, V.; Kocor, M.; Taylor, W. I. Helv. Chim. Acta. 1949, 32, 1052. 54 King, J. A.;. McMillan, F. H. J. Am. Chem. Soc. 1955, 77, 2814-2816. 55 Prelog, V.; Battegay, J.; Taylor, W. I. Helv. Chim. Acta. 1948, 31, 2244.

23

Scheme 11. Woodward’s relay synthesis of (-)-strychnine.

I.4.5.b. Mori’s total synthesis of (-)-strychnine (2001).

Palladium-catalyzed reactions have been used quite often in the syntheses of natural products56. Indeed, in Mori‟s total synthesis of (-)-strychnine, all cyclizations for the synthesis of (+)-isostrychnine were achieved using Pd-catalyzed reactions, including the first enantioselective allylic substitution57 (Scheme 12). Compound 27, prepared from allylic alcohol 26 acts as the key precursor for the allylic substitution and as a source of the E ring.

56 Tsuji, J. in „„Palladium Reagents and Catalysts,‟‟. Wiley, New York, 1995. 57 (a) Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J. Org. Chem. 1997, 62, 5265. (b) Nishimata, T.; Mori, M. J. Org. Chem. 1998, 63, 7586-7587. (c) Nishimata, T.; Yamaguchi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5713-5716.

24 By treatment of 27 with Pd(0) in the presence of the nucleophile (2-Bromo- benzenesulfonamide), the π-allylpalladium complex 28 could be formed. Because the Pd catalyst has a chiral ligand, the nucleophile should attack preferentially at either the C2 or C3 position. When (S)-BINAPO58 was used as the chiral ligand, 29 was obtained in 84% ee. The B-ring formation was accomplished by intramolecular Heck reaction59 of 30 to give indoline 31 in 87% yield. At this stage, the enantiomeric excess was increased from 84 to 99% by recrystallization. Reduction of the optically pure 31 followed by protection of the resulting gave 32. Then, Pd-catalyzed allylic oxidation60 of 32 gave tetracyclic compound 33 in 77% yield. This cyclization may proceed through the nucleophilic attack of the N4 nitrogen on the Pd(II)-coordinated C3–C14 double bond and β-elimination of the C15 .

Regioselective hydroboration of 33 with 9-BBN, followed by treatment with H2O2 and NaOH, afforded an alcohol, which was oxidized to ketone 34. The ketone was converted to the C15– C16 double bond by regioselective formation of an enol triflate61 and Pd-catalyzed reduction62.

58 Grubbs, B. H.; Devries, R. A. Tetrahedron Lett. 1977, 18, 1879-1880. 59 (a) Heck, R. F. in „„Comprehensive Organic Synthesis‟‟, (B. M. Trost, ed.), vol. 4, pp. 833–863. Pergamon Press, New York, 1992. (b) Meijere, A.; Meyer, F. E. Angew. Chem. Int. Ed. Engl. 1994, 33, 2379. (c) Link, J. T.; Overman, L. E. in „„Metal-Catalyzed Cross Coupling Reactions‟‟, (P. J. Stang, F. Diederick, eds.), Chapter 6. Wiley-VCH, Weinheim, 1998. (d) Link, J. T. Org. React. (N.Y.) 2002, 60, 157. 60 Hansson, S.; Heumann, A.; Rain, T.; Aakermark, B. A. J. Org. Chem. 1990, 55, 975-984. 61 McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982. 62 Cacchi, S.; Morera, E.; Orter, G. Tetrahedron Lett. 1984, 25, 4821-4824.

25

Scheme 12. Mori’s Total Synthesis of (-)-strychnine.

Deprotection of the tosyl amide and treatment with the 36 produced the monoalkylated compound 37. The pentacyclic compound 38 was formed in (46% yield) by the second intramolecular Heck reaction using 37 as a substrate. Finally, isomerization of the C14–C15 double bond, removal of the Boc group, and N4 alkylation28 provided the optically

26 pure 40. Thus, using the procedure of Vollhardt, the alkenyl 40 was converted to (-)-strychnine in four steps32.

I.4.5.c. Bodwell’s formal synthesis of strychnine (2002).

In 2002, Bodwell42 and his group reported the shortest synthesis of strychnine. The Diels– Alder reaction is one of the most important achievements in chemical synthesis63. For the synthesis of strychnine, Rawal already utilized an intramolecular Diels–Alder reaction, which led to E ring formation at the C7–C2 and C3–C14 bonds (Scheme 7). Vollhardt‟s E ring formation at the C2–C16 and C7–C3 bonds can also be categorized as Diels–Alder cyclization (Scheme 6). The critical point in the Bodwell‟s synthesis is the use of a cyclophane64 as a substrate of the key transannular inverse electron demand Diels–Alder reaction (IEDDA) (Scheme 13). Bodwell previously succeeded in the transannular IEDDA of a doubly trimethylene-tethered , affording a carbazole skeleton-containing pentacyclic compound65. His synthesis started with the iodide 43, which was prepared by the reaction of tryptamine 41 with 3,6-diiodopyridazine 4266. The allyl compound 44 was subjected to a sequential hydroboration–intramolecular Suzuki–Miyaura coupling67 to give the cyclophane. Heating the cyclophane 45 in N,N- induced the transannular IEDDA to produce 46. This was followed by expulsion of N2, to afford pentacyclic product 47 in quantitative yield (C, E, and G rings formation, C7 quaternary center). Chemo- and stereoselective reduction of 47 with NaBH4/CF3COOH, followed by oxidation of the tertiary amine to amide with PDC68, and removal of the led to Rawal‟s key intermediate 49. Strychnine was finally synthesized from 49 in four steps as in Rawal‟s synthesis.

63 Oppolzer, W.; Weinreb, S. M.; Boger, D. L.; Roush, W. R.; Sweger, R. W.; Czarnik, A. W. in „„Comprehensive Organic Synthesis‟‟, (Trost, B. M. ed.), vol. 5, pp. 315–592. Pergamon Press, New York, 1992. 64 (a) Bodwell, G. J. Angew. Chem. Int. Ed. Engl. 1995, 35, 2085. (b) In „„‟‟ (Keehn, P. M.; Rosenfeld, S. M. eds.), vols. 1, 2. Academic Press, New York, 1983. (c) Diederich, F. N. in „„Cyclophanes‟‟, Royal Society of Chemistry, London, 1991. (d) Hopf, H. in „„Classics in Chemistry‟‟, Wiley- VCH, Weinheim, 2000. 65 Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127-130. 66 Shin, M. S.; Kang, Y. J.; Chung, H. A.; Park, J. W.; Kweon, D. H.; Lee, W. S.; Yoon, Y. J.; J. Heterocycl. Chem. 1999, 36, 1135. 67 Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4544-4568. 68 Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-402.

27

Scheme 13. Bodwell’s Formal Synthesis of strychnine.

I.4.5.d. Padwa’s total synthesis of strychnine (2007).

Recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels– Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core system of indole alkaloids 69 (Scheme 14). An intramolecular, Pd-catalyzed, -driven, cross-coupling reaction then led to the critical D ring formation. The acylation of 50 with 51, followed by removal of the Boc group and subsequent N-alkylation with 1-bromomethyl-2-methyl gave mono-tethered substrate 5270. The large 2-methylbenzyl group on the N4 amido nitrogen atom was expected to help in the intramolecular Diels–Alder reaction. Indeed, heating the indolyl amidofuran 52 at 150°C in a

69 (a) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189-2192. (b) Padwa, A.;. Ginn, J. D. J. Org. Chem. 2005, 70, 5197-5206. (c) Padwa, A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833-6841. (d) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247-250. 70 Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735-3745.

28 microwave reactor for 30 min in the presence of catalytic amount of MgI2 produced the tetracyclic compound 55 in 95% yield (formation of C7 quaternary center). 55 was then converted to 57 through reduction and removal of the acetyl and 2-methylbenzyl groups. Alkylation of the N4 amine nitrogen with alkenyl bromide 58, protection of the N1 nitrogen atom as a dimethoxybenzylamine, and oxidation of the secondary alcohol using tetrapropylammonium perruthenate (TPAP)71 completed the synthesis of ketone 60. To construct the D ring, Padwa employed an intramolecular, Pd-catalyzed, enolate-driven, cross- coupling reaction72. So, the pentacylic compound 61 was obtained in 56% yield by the coupling reaction of 60 with Pd(PPh3)4 and PhOK. The keto group in 61 was converted to enol ether 63 in 72% yield by using oxide reagent 62. Finally, acidic treatment of 63 provided W-G aldehyde, which was then converted to strychnine using the established procedure with the highest chemical yield (80%).

71 Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis, 1994, 639. 72 Sole, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461-5464.

29

Scheme 14. Padwa’s Total Synthesis of Strychnine.

I.4.5.e. Andrade’s total synthesis of (±)-strychnine (2010).

Very recently, Andrade reported a total synthesis of (±)-strychnine and (±)-akuammicine based on a novel, sequential one-pot spirocyclization/intramolecular aza-Baylis-Hilman reaction (IABH). His group used this protocol for assembling the ABCE tetracyclic framework of Strychnos alkaloids.

30

Scheme 15. Andrade’s Total Synthesis of (±)-akuammicine.

Akuammicine synthesis started with N-Boc-indole-3-carboxaldehyde 64 (Scheme 15). The compound 66 was obtained from condensation of 64 with allylic amine 6573. Treatment of 66 with bromoacetyl chloride 67 and vinyl silyl 68 effected a vinylogous Mannich reaction via the intermediate N-acyliminium species 6974. Termination of the reaction with TFA removed the N-Boc , giving 70 in high yield. The compound 70 was subjected to the sequential one-pot spirocyclization/IABH protocol: AgOTf and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) generated spiroindolenine 71 having the C- ring and subsequent addition of 3 equiv of DBU produced an intramolecular aza-Baylis- Hillman reaction, providing ABCE tetracycle 72 in 63% yield44a. The presence of the vinyl iodide and conjugated ester in 72 inhibited reduction with LiAlH4 or similar reducing agents. To this end, thionation of 72 with Lawesson‟s reagent afforded thiolactam 73 in 76% yield. Alkylation of the resulting thiolactam with Meerwein‟s and reduction of the thioimidate

73 Sole, D.; Urbaneja, X.; Cordero-Vargas, A.; Bonjoch, J. Tetrahedron 2007, 63, 10177-10184. 74 Martin, S. F. Acc. Chem. Res. 2002, 35, 895.

31 with NaBH4 and furnished the tetracycle 74 in a one-pot operation (75% yield). By intramolecular Heck reaction for the 74, akuammicine was obtained in71% yield31b. Also, Andrade reported the concise total synthesis of (±)-strychnine by employing the vinylogous Mannich reaction and a novel sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction. His strychnine synthesis is summarized in Scheme 16.

Scheme 16. Andrade’s Total Synthesis of (±)-Strychnine.

I.5. Conclusion

Through this chapter, the different approaches to the synthesis of Strychnine have been described. These approaches should be highly useful for the synthesis of indole alkaloids and for the synthesis of a variety of natural products. The major synthetic approaches in the

32 synthesis of strychnine make a focus on the following three points: (1) the generation of the C7 quaternary carbon center; (2) the assembling of the CDE core ring; and (3) the elaboration of the hydroxyethylidene side chain. Among the syntheses of strychnine, two relay syntheses and six enantioselective syntheses have been described in this part.

II. Mossambine

II.1. General comments

The Strychnos alkaloids contain an important group of complex compound and widely distributed as monoterpenoid indole alkaloids75. This family can be arranged in two classes, strychnan and aspidospermatan. The strychnan class includes the alkaloids which have unrearranged monoterpenoid unit attached to the indole nucleus by C2/C16 and C7/C3 bonds. The majority of strychnan alkaloids belong to the curan type (Figure 4). The curan alkaloids contain the pentacyclic alkaloids of the akuammicine group76.

Figure 4. Structure of some Curan Alkaloids

75 Sapi, J.; Massiot, G. in Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4, pp 279-355. 76 The numbering system and ring labeling (ABCDE) based on the biogenetic interrelationship of indole alkaloids is used throughout this work: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508-510.

33 In the last few years, the strychnan alkaloids have been the subject of synthetic investigations. Much of this investigation has focused on the synthesis of the heptacyclic alkaloid strychnine. By looking at the structure of curan alkaloids (Figure 4), the key points that will guide the synthesis of this family are installing the quaternary center at C7 in the last synthetic steps77, and those bonds around C7 which are made at the initial stages of the synthesis78. In the remainder of this part, we will mention the synthetic strategies in the total synthesis of the curan alkaloids (Scheme 17). We can also note that the enantioselective synthesis of curan 79 80 alkaloids has been little studied ‟ .

77 (a) Amat, A.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299- 6312. (b) Kuehne, M. E.; Frasier, D. A.; Spitzer, T, D. J. Org. Chem. 1991, 56, 2696-2700. (c) Kuehne, M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J. Org. Chem. 1994, 59, 5977-5982. (d) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc. 1996, 118, 9804-9805. 78 (a) Formation of C20/C21 bond: Kuehne, M. E.; Xu, F.; Brook, C. S. J. Org. Chem. 1994, 59, 7803-7806. (b) Formation of C15/C20 bond: Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873-7881. (c) Closure of the indole ring from protected or from nitro derivatives. (d) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966-3977. 79 Amat, M.; Coll, M.-D.; Bosch, J.; Espinosa, E.; Molins, E. Tetrahedron: Asymmetry 1997, 8, 935-948. 80 Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873-7881.

34

Scheme 17. Synthetic Strategies for the Curan alkaloids synthesis.

II.2. Kuehne’s Synthesis of Strychnos alkaloids.

Kuehne developed two alternative strategies for the synthesis of Strychnos alkaloids (85, R = , R‟ = H), the first strategy namely the intramolecular Diels-Alder cyclization reaction of indoloacrylate (86, disconnection A, Scheme 18), and a condensation-sigmatropic rearrangement sequence (87, disconnection B, Scheme 18). The key point in these reactions was a generation of the vinylogous urethane function that is found in the majority of the pentacyclic strychnos alkaloids skeleton. Apart from these strategies, we will report herein the synthesis of (±)-echitamidine and mossambine.

35

Scheme 18. Alternative Strategies for the Strychnos alkaloids synthesis by Kuehne.

II.2.1. Intramolecular Diels-Alder reactions.

Intramolecular Diels-Alder reactions (the first strategy) provided total syntheses of the echitamidine alkaloids 9081. This method required the diene precursor 88 for these syntheses. This precursor was derived from tetracyclic intermediate 89 by reductive cleavage of the C/E ring (Scheme 19).

Scheme 19. Construction of C, D and E rings by Intramolecular Diels-Alder Reactions (Kuehne).

II.2.1.a. Construction of the C, D and E rings in (±)-echitamidine.

The glycol derived ketal 93 was generated in one step (92% yield) by condensation of the N-benzylindoloazepine 91 with the ketal 92 (Scheme 20). The ketal function was

81 Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115, 2064-2065.

36 advantageous for the secodine-type [2 + 4]-cyclization step, leading to the tetracyclic product 93. Having a protected ketone at C19 seemed also useful for the later steps of the synthesis. In contrast, the ketal proved to be incompatible with the reductive opening of the tetracycle 93 to an indoloazonine. The ketal group in 93 was resistant to hydrolysis with hot aqueous HCl, but it could be removed with formic and trifluoroacetic acids to give the ketone 94 (100%). Reduction of this ketone with in methanol led to two C19 epimeric 95a and 95b (1:2, 91%). With addition of CeC13 in the reduction step, only the major epimer 95b was obtained (96%), while a reduction of the ketone 94 with lithium or L-Selectride provided equal amounts of the epimeric alcohols 95a and 95b. (The stereochemical for these alcohols were determined by X-ray analysis). The relative configuration of C19, C20 in the epimer 95a corresponds to the relative configuration of those centers in echitamidine 90.

Scheme 20. Synthesis of tetracyclic alcohol.

II.2.1.b. Reductive cleavage of the C/E ring.

Two C16 epimeric indoloazonine 96a and 97a were obtained (l: l, 94%), when the tetracyclic 95a was subjected to reductive cleavage by the sodium borohydride in hot acetic acid (Scheme 21). The relative configuration at C16 and C20 could be obtained from the characteristic difference in chemical shifts and coupling constants of the C16 H (96a δ 5.1, d;

37 97a δ 5.6, dd)82. By heating in toluene with DBU, the N-benzylamine 96a was converted to its epimer 97a. Using the debenzylation conditions with the C16 epimer 97a, t-Boc protection of the diamine 98a, and acetylation of the resulting alcohol 99a with acetic anhydride produced the acetate 100a in 82% overall yield.

Scheme 21. Reductive cleavage of the C/E ring

II.2.1.c. Complete synthesis of (±)-echitamidine.

Achieving the chlorination of the indole ring of the acetate 100a with tert-butyl hypochlorite and triethylamine, followed by dehydrohalogenation with DBU, produced the indoloacrylate 101a with (45-53% yields). Deprotection of the diene 97a with TMSOTf (100%) produced diamine 102a, the key substrate for introduction of the central two carbon bridge of the Strychnos alkaloid ring system. The amine 102a was treated by the vinyl acetate, to give pentacyclic product 103a in modest yields (5-20%). On heating this product in methanol at 150 °C, it was equilibrated to (±)-echitamidine.

82 Kuehne, M. E.; Frasier, D. A.; Spitzer, T. J. Org. Chem. 1991, 56, 2696-2700.

38 II.2.2. Condensation-sigmatropic rearrangement sequence.

II.2.2.a. Construction of the C and E rings in (±)-echitamidine.

For some synthesis of Strychnos alkaloids, the condensation-sigmatropic rearrangement sequence (the second strategy) has been also applied83. In the synthesis of echitamidine alkaloids according Kuehne, the ketal 92 was converted to its vinylog 104 by a Wittig reaction (Scheme 22). When heating this unsaturated aldehyde with tryptamine derivative 105 in the presence of BF3-etherate, the tetracyclic ketal 106 was obtained in 30% yield as a single diastereomer. Debenzylation, by hydrogenolysis with ammonium formate and Pd/C, provided the secondary amine 107.

II.2.2.b. Closure of the D ring.

The elaboration of ring D of the Strychnos alkaloid skeleton was carried out using the iminium-ketal intermediate 108, issued from the condensation of the crude amine 107 with formaldehyde in the presence of HCl84. Cyclization and hydrolysis of the ketal produced the ketone 109 in 83% overall yield from the tetracyclic ketal 106. Thus, the pentacyclic Strychnos alkaloid skeleton, was obtained in a three-pot operation from the aldehyde 104 and the tryptamine derivative 105 in 25% overall yield. Epimerization of the ketone 109 at C20 with sodium methoxide provided the ketone 110. Stereoselective reduction of the ketone 110 with sodium borohydride produced (±)-echitamidine85.

83 Parsons, R. P.; Berk, J. D.; Kuehne, M. E. J. Org. Chem. 1993, 58, 7482-7489. 84 Intramolecular alkylation of ketals by imonium intermediates was first described by Wenkert (Wenkert, E. Acc. Chem. Res. 1968, 1, 78 and used for the synthesis of iboxyphylline (Kuehne, M. E.; Pitner, J. B. J. Org. Chem. 1989, 54, 4553-4569. 85 Kuehne, M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J. Org. Chem. 1994, 59, 5977-5982.

39

Scheme 22. Synthesis of (±)-echitamidine using Condensation-sigmatropic rearrangement sequence reactions (Kuehne).

II.2.3. Selective total synthesis of mossambine and epi-mossambine.

Kuehne has used the same biomimetic approaches and strategies (Scheme 7) to achieve the synthesis of Mossambine and epi-Mossambine. He has also developed its strategy in an asymmetric version.

II.2.3.a. Construction of the pentacyclic ketone motif.

Kuehne‟s group has used the vinyloguos urethane function that is found in the majority of the pentacyclic Strychnos alkaloids skeleton (Scheme 23). However, to achieve his goal of

40 keeping the vinylogous urethane function of the pentacycle 85, it seemed clear that at the imine 111 oxidation level, a tautomerization to a conjugated enamine 112 had to be avoided (e.g., 111, X = Y # H). A carbonyl, or protected at C14, suggested itself as a good blocking group for keeping the imine and acrylate functionalities of a cyclization precursor 111, and mossambine.

II.2.3.b. Alkylation and synthesis of the key cyclization precursor.

The indoloazepine ester 113 (obtained in three steps from tryptamine with 43% overall yield), used as starting material by Kuehne in so many of his alkaloid syntheses, was alkylated on nitrogen by (Z)-1-bromo-2- iodobut-2-ene, then produced a 70% yield of the allylic amine 114 (Scheme 24).86,87 of the formed azepine in refluxing toluene, in the presence of 2- acetoxyacetaldehyde, led to the generation of the enamine acrylate 115. The tetracyclic acetate 116 was formed in 93% yield by stereoselective cyclization.88 The acetate group in compound 40 was hydrolyzed to the corresponding alcohol 117 in good yield (95%). The generation of the imino-enone 118 (the key cyclization precursor) required oxidation of the vinylogous urethane. The oxidation with phenylseleninic anhydride89 provided the imino enone 118 (63%). This key cyclization precursor could also be obtained, in better overall yield, by Swern oxidation of the alcohol 117 (87%) and reaction of ketone 119 with tert-butyl hypochlorite and triethylamine (100%).

86 Kuehne, M. E.; Bohnert, J. C.; Bornmann, W. G.; Kirkemo, C. L.; Kuehne, S. E.; Seaton, P. J.; Zebovitz, T. C. J. Org. Chem. 1985, 50, 919-924. 87 (a) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47, 404-408. (b) For methodology see: Corey, E. J.; Kirst, H. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1970, 92, 6314-6320. 88 For methodology see: Kuehne, M. E.; Kuehne, S. E. J. Org. Chem. 1993, 58, 4147-4148. 89 (a) Danieli, B.; Lesma, G.; Palmisano, G.; Riva, R. J. Chem. Soc., Chem. Commun. 1984, 909. (b) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52, 347-353. (c) Danieli, B.; Lesma, G.; Palmisano, G.; Passarella, D.; Silvani, A. Tetrahedron 1994, 50, 6941-6954.

41

Scheme 23. General strategy for synthesis of (±)-mossambine by Kuehne.

In a third method to generate the imino enone 118, Kuehne and his co-workers suggested that the tetracyclic amine 12090 could be alkylated with (Z)-1-bromo- 2-iodo-2-butene (75%). The resulting vinylogous urethane 121, by the reaction with phenylseleninic anhydride, then led to oxygenation at C14 and formation of the imino enone 118 in poor yield (35%).

90 Kuehne, M. E.; Matsko, T. H.; Bohnert, J. C.; Motyka, L.; Oliver- Smith, D. J. Org. Chem. 1981, 46, 2002- 2009.

42

Scheme 24. Construction of imino-enone motif.

II.2.3.c. Radical cyclization reaction.

Kuehne and his co-workers, affords another example of the formation of a vital ring (D ring) by a radical cyclization reaction, an approach which was first introduced in a synthesis of vincadifformine and related alkaloids. The imino enone 118 reacted with tri-n-butyltin hydride in refluxing benzene. The pentacyclic vinylogous urethane product was obtained in 51%yield as a 1.5-1.8:1 E:Z mixture of olefin 122E and 122Z, from which E-122 could be obtained pure by crystallization of chromatographically enriched fractions (Scheme 25).

43

Scheme 25. Radical cyclization reaction.

The synthesis of (±)-mossambine was then completed by reduction of the major ketonic olefin 122E by ceric chloride and sodium borohydride. Some hydroxyl epimer (14-epi- mossambine) was also formed in a ratio of 5:1 (96%), which could be obtained exclusively from 122E by reduction with L-selectride. The relative stereochemistry of the hydroxyl function in the (±)-mossambine and 14-epi-mossambine epimers was established by NMR nOe experiments.47 of the synthetic product was then performed. The racemic unsaturated pentacyclic keto ester 122E was resolved via its condensation product with (R)-(N-methylphenylsulfonimidoyl) (Johnson‟s method), which gave a mixture of two diastereoisomers, 14(R),S(R) and 14(S),S(R). Selective pyrolysis of the 14(R),S(R) 123 isomer in the mixture gave (-)-122E, which on completion of the synthesis gave natural (-)-mossambine.

44 II.2.4. Enantioselective approach to (-)-mossambine.

In 2001, Kuehne and his co-workers developed the (+)-(R)-1,2-(α-(R)-mesyloxy-β-dimethyl- tetramethylene)-ferrocene as a chiral that could be introduced onto an amine function group at an advanced stage of a synthetic sequence and could be simply removed under very mild conditions,91 to give the corresponding secondary in >99% ee. Then alkylation of the secondary amine product with (Z)-1-bromo-2-iodobut-2-ene gave the key intermediate (-)- 127 (70%, ee > 99%) for cyclization to (-)-mossambine92 (Scheme 26).

Scheme 26. Enantioselective approach to (-)-mossambine.

91 Kuehne, M. E.; Bandarage, U. K. J. Org. Chem. 1996, 61, 1175-1179. 92 Kuehne, M. E.; Bandarage, U. K.; Hammach, A.; Li, Y.-L.; Wang, T. J. Org. Chem. 1998, 63, 2172-2183.

45 When looking at the structure of the pentacyclic alkaloids of the akuammicine-group, it appears that the key points that guide the synthesis of this family are the installation of the quaternary center at C7 and the construction of the C and D rings. These two points are also key points of the strategy proposed in this thesis.

III. Conclusion

This chapter present an overview of the different approaches proposed in the synthesis of Strychnos alkaloids. In most cases, the C and E rings were constructed by a one-pot operation with the generation of the C7 quaternary center. Two of them culminated with three-ring formation (Bodwell and Fukuyama syntheses). The polycyclization reactions utilized for strychnine synthesis are classified according to the reaction type. Magnus and Fukuyama employed the transannular cyclization of similar iminium ion intermediates, leading to two ring (C, E) and three-ring (C, D, E) formation, respectively. In Stork‟s and Martin‟s syntheses, Harley-Mason‟s skeletal rearrangement strategy was used to close the C and E rings. Domino cyclizations developed by Overman and Kuehne involve both [3,3] sigmatropic rearrangement and the Mannich reaction. Intramolecular Diels–Alder type cycloaddition reaction was also utilized for strychnine synthesis by Rawal, Bodwell, and Padwa, including Vollhardt‟s [2+2+2] cyclization. In any event, one-pot polycyclization processes made it possible to reduce the number of steps in the synthesis. In our strategy, the common precursor of this family is the arylcyclohexa-2,5-diene 1, having many benefits from what we have seen throughout this chapter. It incorporates the rings A and E, and the quaternary carbon center C7 which is difficult to install. The arylcyclohexa-2,5-diene 1, also has an ethylamine chain which will form the C ring in this family. In that context, we wish to propose a new pathway to synthesis of Strychnos alkaloids (strychnine and mossambine). Our approach is based on the desymmetrization process of arylcyclohexa-2,5-diene by Michael reaction, for the synthesis of the Büchi‟s ketone intermediate and oxidative amination reaction in presence of metals (Pd, Cu...) for the synthesis the pentacyclic skeleton of Strychnos alkaloids.

46 Chapter II: Double Michael approach applied to arylcyclohexa- 2,5-diene derivatives, and a new route to the synthesis of Büchi’s ketone.

The synthesis of pentacyclic skeleton of the Aspidosperma and Strychnos alkaloids was the first objective of this thesis. The arylcyclohexa-2,5-diene motif which was developed in our laboratory was used as a precursor for this synthesis. We also developed a cascade reaction strategy to achieve this objective.

I. Synthesis of Büchi’s ketone

I.1. Bibliography

The first study on the synthesis of ketone 130, the core of the Aspidosperma and Strychnos alkaloids families was carried out by Büchi93 in 1971. In his synthesis, condensation of 1-methyltryptamine with 1-chloro-3-ketobutene in an solution containing triethylamine provided the hydrogen bonded cis-enamino ketone 128 (92%). All attempts to cyclize this amine failed, but heating the N-acetyl trans-enamino ketone 129, prepared by acetylation (acetic anhydride-triethylamine in hot benzene) in BF3-Et2O at 90°C gave the Büchi ketone 130 (38%) and the tetrahydro-β-carboline 131 (20%). The latter was isolated from the nonbasic portion of the reaction mixture (Scheme 27). Exposure of the indole 131 to boron trifluoride under identical conditions gave a maximum of 8% of the indoline 130. This result demonstrates that the indoline is formed directly from its precursor 129 by electrophilic C3 substitution, followed by nucleophilic enol addition to C2 of the resulting indolenine.

93 (a) Büchi, G.; Matsumoto, K.; Nishimura, H. J. Am. Chem. Soc. 1971, 93, 3299-3301. (b) Ando, M.; Büchi, G.; Ohnuma, T. J. Am. Chem. Soc. 1975, 97, 6880-6881.

47

Scheme 27. Synthesis of Büchi’s ketone.

In 1990, Winkler et al. developed the photocycloaddition approach94 outlined in Scheme 28 that could solve the chemical problems encountered in the earlier studies by Büchi.

Scheme 28. Retrosynthesis of Büchi’s ketone according to Winkler.

In his retrosynthesis, the Büchi ketone 130 could be obtained by ring-closure of 132 through a Mannich reaction. In turn, the keto imine 132 was issued from a retro-Mannich fragmentation of photoadduct 133, which would in turn be derived from the intramolecular

94 Winkler, J. D.; Muller, C. L.; Scott, R. D.; Williard, G. J. Am. Chem. Soc. 1990, 112, 8971-8975.

48 photocycloaddition between the secondary vinylogous amide and the moiety of an indole, as found in 134, where R would necessarily be an electron withdrawing group95. Winkler envisioned that both absolute and relative stereochemical control might be achieved via the intramolecular photocycloaddition96, starting with a component 135, which could be prepared from an α-amino acid, in this case, L-tryptophan. In the end, Winkler realized the synthesis of Büchi ketone 130 in homochiral form in 14 steps (7% overall yield from L- tryptophan).

In 2005, Marko et al. described an efficient and diastereoselective method that allows the rapid construction of the tetracyclic core of the Aspidosperma and Strychnos alkaloid families97. His approach was based on two key steps: a one-pot silica gel/tBuOK polycyclization cascade and an oxidative decarboxylation-Michael addition reaction (Scheme 29).

Scheme 29. Oxidative decarboxylation-Michael addition reaction.

95 (a) Ikeda, M.; Ohno, K.; Mohri, S.; Takahashi, M.; Tamura, Y . J. Chem. Soc., Perkin Trans. I 1984, 405. (b) Julian, D.: Foster, R. J. Chem. Soc. Chem. Comm. 1973, 311. 96 (a) Winkler. J. D.: Hershberger, P. M.; Springer, J. P. Tetrahedron Lett. 1986. 5177-5180. (b) Winkler, J. D.; Hershberger, P. M. J. Am. Chem. Soc. 1989, 111 , 4852-4856. 97 (a) Marko, I. E.; Southern, J. M.; Adams, H. Tetrahedron Lett. 1992, 33, 4657-4660. (b) Solberghe, G.; Marko, I. E. Tetrahedron Lett. 2002, 43, 507-509. (c) Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett. 2005, 7, 5245-5248.

49 II. Our strategy

II.1. Retrosynthetic analysis

Indole alkaloids, such as strychnine, vindoline, and vindorosine have attracted great attention over the years, due to their biological activities. For example vindoline, is the key component in the preparation of the antitumor drugs vincristine and vinblastine98. These alkaloids share the same tetracyclic core, known as the Büchi ketone 130. Our strategy to synthesize Büchi ketone 130 is based on the desymmetrization of dienone 142 through a cyclization process (Scheme 30). Firstly, a Birch reductive alkylation of a biaryl such as 140 followed by an oxidation of the corresponding arylcyclohexa-2,5-diene 141 would give the dienone 142. A desymmetrization via a double Michael addition would then allow an access to Büchi ketone 130, a key intermediate in several approaches to these alkaloids. Further cyclizations will give the pentacyclic skeleton of Aspidosperma and Strychnos alkaloids. This strategy is concise and fast. Ultimately, it is planned to form three cycles B, C and D in one-pot, depending on the nature of R and R‟ groups.

Scheme 30. Synthetic strategy toward the Aspidosperma alkaloids.

98 (a) Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N. Y. Acad. Sci. 1958, 76, 882. (b) Svoboda, G. H.; Neuss, N.; Gorman, M. J. Am. Pharm. Assoc. Sci. Ed. 1959, 48, 659.

50 The precursor of the double Michael addition is a symmetrical cyclohexa-2,5-diene, which was prepared in our laboratory by Birch reductive alkylation reaction99.

III. Synthesis of arylcyclohexa-2,5-dienes.

A symmetrical arylcyclohexadiene bearing an ethylamino group at the benzylic center would constitute a common skeleton for all the alkaloids described above. Birch reductive alkylation reaction has been extensively studied on simple arenes100. In contrast, just a few studies have been conducted on biaryls. The Birch reductive alkylation strategy brings up two main problems: (1) the issue during the reduction of aryl moieties, which mainly depend on the nature of the on both aromatic groups and (2) the competition between alkylation and reduction of aryl moieties, which depends on the basicity vs nucleophilicity of the formed anion in the . In the arenes, the regioselectivity of the Birch reduction is easily predictable.

III.1. Overview on the Birch reaction.

The reaction was discovered by Birch, Wooster and Godfrey in 1937, but its real development was made by A. J. Birch101. This reaction allows the synthesis of a wide variety of organic compounds by reduction of aromatic and conjugated diene systems. The alkali metals used are lithium, sodium, potassium, or less commonly, calcium and magnesium. They are dissolved in liquid ammonia to form a solution of intense blue color.

Birch reduction of biaryls bearing various substituents including Me, SiMe3, F, CO2H, and

CO2R has been investigated. Interestingly, few studies have been performed on Birch

99 (a) Lebeuf, R.; Robert, F.; Landais, Y. Org. Lett. 2005, 7, 4557-4560. (b) Lebeuf, R.; Berlande, M.; Robert, F.; Landais, Y. Org. Synth. 2009, 86, 1-10. (c) Lebeuf, R.; Dunet, J.; Beniazza, R.; Ibrahim, D.; Bose, G.; Berlande, M.; Robert, F.; Landais, Y. J. Org. Chem. 2009, 74, 6469-6478. 100 (a) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334. (b) Schultz, A. G. Chem. Commun. 1999, 1263-1271. (c) Rabideau, P. W. Tetrahedron 1989, 45, 1579-1603. 101 Birch, A. J. J. Chem. Soc. 1944, 430.

51 102 reduction of electron-rich biaryls (substituted only by OMe, NR2, etc.) . In substituted biaryls, the control of the regioselectivity is based on the nature of the substituents and their position relative to the biaryl bond. Substituents interesting for the synthesis of alkaloids are electron-donating groups (OMe, OR, NHR,...). Reduction of p-methoxybiphenyl 143 produced various regioisomers and over-reduced products, indicating that regioselectivity may not be so easy to predict in this case (Scheme 31).

Scheme 31. Birch reduction and Birch reductive alkylation of biaryls.

The first investigations on the Birch reductive alkylation of biaryls were carried out by Harvey103. His studies on the Birch reductive of biphenyl 148 showed that

102 (a) Birch, A. J.; Nadamuni, G. J. Chem. Soc., Perkin Trans. 1 1974, 545-552. (b) Tanaka, H.; Shibata, M.; Ito, K. Chem. Pharm. Bull. 1984, 32, 3271–3272. (c) Tanaka, H.; Takamura, Y.; Shibata, M.; Ito, K. Chem. Pharm. Bull. 1986, 34, 24-29. 103 (a) Lindow, D. F.; Cortez, C. N.; Harvey, R. G. J. Am. Chem. Soc. 1972, 94, 5406-5412. (b) Lindow, D. F.; Harvey, R. G. J. Am. Chem. Soc. 1971, 93, 3786-3787.

52 alkylation mainly takes place at the benzylic position (Scheme 31)104. When Na is used as a reducing agent, polyalkylation products were observed, probably due to the higher solubility of NaNH2 (compared to LiNH2 or CaNH2). Polyalkylation results from deprotonation of the bis-allylic position by the highly basic formed upon reaction.

Müller has conducted the reaction using lithium as metal and several electrophiles105. Good results are obtained with chloroacetonitrile and methyl chloroacetate. However, when a is present on one of the two rings, the regioselectivity is greatly affected and differs depending on the position of the substituent (Scheme 32).

Scheme 32. Birch reductive alkylation of biaryls having a methyl group.

III.2. Achievements of our laboratory.

Our laboratory has been interested to study the Birch reductive alkylation of substituted biaryls (with electron-rich substituents), owing to the lack of information on the regioselectivity of such reductions and the few results on the Birch reductive alkylation of biaryls. Preliminary results have shown that the process is applicable to a variety of biarylic systems and is readily amenable to large-scale synthesis.

Birch reductive alkylation of biaryl 159 led to the formation of two inseparable regioisomers 160 and 161 in good overall yield (Scheme 33). The formation of 160 as the major isomer indicates that the reduction occurs on the most electron-rich aromatic ring, in good agreement

104 Rabideau, P. W.; Peters, N. K.; Huser, D. L. J. Org. Chem. 1981, 46, 1593-1597. 105 (a) Müller, P. M.; Pfister, R. Helv. Chim. Acta 1983, 66, 771-779. (b) Müller, P. M.; Pfister, R.; Urban, R. European Patent 12801 1980, Chem. Abstract. 93, 185839.

53 with the observed relative reduction rates on simple arenes, which follow the order ArOMe > ArH > ArOH.101,106 Birch reductive alkylation of 162 having two methoxy groups meta to the biaryl linkage produces arylcyclohexadienes 163 or 164 in good yield and complete regiocontrol.

Scheme 33. Birch reductive alkylation of biaryls bearing m-OMe groups.

The reductive reaction carried out on biaryl 165 provided only the reduced product 166, along with non purified over-reduced byproducts. It was interesting to notice that the biaryl 165 was reduced only in one position with the combined effects of methoxy substituents. The group, led to a good regioselectivity but only to reduction, without a trace of the alkylated product (Scheme 34).

Scheme 34. Birch reductive alkylation of biaryls bearing OH group.

Although the amount of lithium was raised to 3.6 equiv., the presence of over-reduced products seems to indicate that either the phenol is not deprotonated under the present conditions or more likely that the ammonium phenolate (formed by reaction between the phenol and NH3) acts as a proton source, ultimately competing with the alkylation process. It was then necessary to deprotonate the phenol before the alkylation takes place. The n-BuLi

106 For instance, is reduced 3.3 times faster than benzene; see: Krapcho, A. P.; Bothner-By, A. A. J. Am. Chem. Soc. 1959, 81, 3658-3666.

54 was chosen to avoid a source of different cation in the reaction medium. When the reduction was carried out on the polysubstituted biaryl 165 (Scheme 35), the corresponding diene 167 was formed in excellent yields indicating that a careful choice of the nature of the substituents on the aromatic ring allowed the alkylation to take place selectively on the 3,5-substituted arene (as in 163 and 164, Scheme 33). The temperature is an important factor in the Birch reaction process. When the temperature was raised above -50°C, a large amount of the reduced product was formed at the expense of the desired alkylated compound, indicating that at higher temperature, protonation is favored over alkylation.

Scheme 35. New conditions for Birch reductive alkylation of phenolic biaryls.

Looking at the nature of the alkaloids targets outlined in (Scheme 1), an ortho amino group could be important in the context of developing a gateway to synthesis of Aspidosperma and Strychnos alkaloids. Preliminary experiments carried out on the 2-aminobiphenyl, have produced only reduced products. Therefore, it was necessary to protect the nitrogen with an electron withdrawing group (Scheme 36).

Scheme 36. Birch reductive alkylation of biaryls bearing o-amino substituents.

55 In most cases, reduced products are also observed, but in rather low amounts. The better acceptors on nitrogen could improve the yield of the alkylation by limiting the N-Li repulsion. A (170 and 171, Scheme 36) protected amino group afforded the best results of the alkylation. In contrast, the reduction of electron-richer analogues such as 176, bearing an additional m-OMe group, produced the diene 177 as a single product (Scheme 37). This result is indicative of the strong electronic effect of the m-OMe group on the regioselectivity of the process.

Scheme 37. Birch reductive alkylation of electron-richer analogue 176.

We also extended the reduction to electron-richer analogues such as 178 having an additional OMe group in the ortho position. Surprisingly, we observed the formation of diene 180 in low yield (11%) with the loss of the o-OMe group, resulting from the reduction and alkylation of the aminophenyl ring (Scheme 38).

Scheme 38. Birch reductive alkylation of more electron-rich analogue 178.

III.3. Synthesis of biaryls.

Concerning to the families of Strychnos and Aspidosperma alkaloids, two different substrates have been used. For these families the biaryls 170 and 171 were synthesized directly from commercial 2-aminobiphenyl 181 through the introduction of a sulfonamide protected group (Scheme 39).

56

Scheme 39. Synthesis of biaryls 170 and 171.

A considerable number of biaryl substrates were synthesized, for instance through the development of organometallic catalysis. The coupling reaction between two sp2 centers is very important in the synthesis and production of biaryls. For example the biaryls 176 was obtained by such an organometallic coupling (Scheme 40).

Scheme 40. Formation of 166 by a Suzuki coupling reaction.

Similarly, the biaryl tert-butyl-2-iodo-3-methoxyphenylcarbamate 188 was coupled with the phenylboronic acid through a Suzuki coupling, leading to the corresponding biaryl 178 in good yield (Scheme 41).

57

Scheme 41. Formation of 178 by Suzuki coupling reaction.

III.4. Mechanistic considerations.

The mechanism of Birch reaction has received much attention. The Birch reductive alkylation of arenes involves an initial electron-transfer process from the metal to the arene followed by 107 the alkylation of the resulting anion (Scheme 42). The electron transfer from Li in NH3 to the biaryl provides the radical anion 189108. As the Birch reductive alkylation is run in absence of proton source (e.g. an alcohol), a second electron transfer can then lead to a dianion (190 and 191). At this stage, the dianion is really basic and protonates on the solvent (ammonia). The protonation generally occurs at the terminal position leading to a 1,4-cyclohexadienyl system, thus controlling the regioselectivity of the whole process. Subtle substituent effects were shown to alter the basicity of monoanion 192 and modify its lifetime in the medium, leading in certain cases to larger amount of reduced products 193 through protonation of 192 by ammonia (as illustrated in Scheme 44). If the basicity of 192 is weaker, it can persist in the

107 (a) Harvey, R. G. Synthesis 1970, 2, 161-172. (b) Harvey, R. G.; Arzadon, L. Tetrahedron 1969, 25, 4887- 4894. (c) Rabideau, P. W.; Burkholder, E. G. J. Org. Chem. 1978, 43, 4283-4288. (d) Rossi, R. A.; Camusso, C. C.; Madoery, O. D. J. Org. Chem. 1974, 39, 3254-3258. (e) Rabideau, P. W.; Harvey, R. G. J. Org. Chem. 1970, 35, 25–30. 108 (a) Müllen, K.; Huber, W.; Neumann, G.; Schnieders, C.; Unterberg, H. J. Am. Chem. Soc. 1985, 107, 801- 807. (b) Müllen, K. Angew. Chem., Int. Ed. Engl. 1987, 26, 204-217.

58 environment and be alkylated after the addition of electrophile species. A dialkylated product 195 may be observed in some cases. Its formation could arise either from an alkylation of the dianion 190 still present, or by the deprotonation of the alkylated product 194 by the still present in the medium.

Scheme 42. Mechanism of the Birch reductive alkylation of biaryls.

It was previously shown that substituents on biaryls can influence the regioselectivity and sometimes prevent the alkylation. Concerning the elimination of methoxy groups in ortho, this could be explained through several reaction intermediates. Rabideau et al. have explained defluorination at the intermediate radical-anion stage.109 In our case, this elimination could occur at the stage of the monoanion, after protonation. The radical anion 196 may change into his resonance structure 197 and the elimination could take place as before. It could also take place at the stage of monoanion 199, after isomerization of the double bond, proceeding from the elimination of 200 (Scheme 43).

109 Jessup, D. W.; Paschal, J. W.; Rabideau, P. W. J. Org. Chem. 1977, 42, 2620-2621.

59

Scheme 43. Possible mechanism for elimination of a in ortho position.

The difference in reactivity between phenol in the ortho and para positions must come from repulsion between the negatively charged phenolate formed during the first deprotonation with n-BuLi and benzyl anion formed during the reaction. The repulsion is much stronger when the phenoxide is ortho. In this case the benzyl anion is more basic and thus more quickly protonated by ammonia (Scheme 44).

Scheme 44. Difference in reactivity of the ortho and para phenolate.

Another explanation could be that the presence of an ortho substituent prevents the two rings from being coplanar and thus decreases the stability of the benzylic anion. But in this case, it should be the same for any ortho substituents. Now, as regards the ortho-substituted biaryls with a nitrogen group, the anionic intermediate should react as 202, yet these biaryls are alkylated. The explanation could be that the anion carried by the nitrogen can be delocalized by resonance onto the protecting group (EWG: Electron Withdrawing Group), which decreases the repulsion with the benzylic anion (Figure 45).

60

Scheme 45. Delocalization of the negative charge over the nitrogen protecting group.

Indeed the SO2Et is a better withdrawing group than Boc, so the negative charge of the nitrogen is probably more delocalized with the sulfonyl (203c and 204, Scheme 45) than with the carbonyl of the carbamate.

III.5. The nature of the electrophile.

Several like alkyl halides were tested in order to generalize the method. Alkyl halides were chosen because they are stable in ammonia, which can play the role of a base or a nucleophile. The dialkylation study of anthracene has been used to compare the alkyl halides110. Harvey showed that the reaction is selective and gives good yields with methyl bromide and ethyl chloride. In addition, a difference was observed between the chloro, bromo and iodomethane. The use of methyl chloride leaves the starting material unchanged and iodomethane tends to react with ammonia to give the methylamine and ammonium iodide, causing the presence of reduced product. The results observed in our laboratory are not always in agreement with these observations. The chloroacetonitrile and ethyl chloroacetate gave better yields than their brominated derivatives. The reductions were carried out generally on biphenyl and were extended to other biaryls if the results were interesting. Various electrophiles were tested in order to enrich our approach and extend it forward to other applications (Scheme 46).99c

110 Harvey, R. G.; Arzadon, L. Tetrahedron, 1969, 25, 4887-4894.

61

Scheme 46. Birch reductive alkylation with different electrophiles.

These examples have shown that the nature of the on the electrophiles may have a strong effect on the reaction outcome. Indeed, the reactions that lead to products 207 and 208 were tested with the corresponding brominated electrophiles and gave the corresponding dienes but with lower yields. In contrast, with simple alkyl halides such as allyl bromide (product 206), the chlorinated derivatives are less reactive than their brominated analogues. Other electrophiles including α-chloroamide and dimethoxy bromo provided the desired alkylated products in satisfying yields (products 207 and 209, Scheme 46).

Aziridines were found to be good electrophiles under the Birch reductive conditions as reported by the reductive alkylation of biaryls 205 and 170, which produced respectively the dienes 211 and 212 having two orthogonally protected amino groups. This one-pot formation of a precursor of aspidosperma alkaloids is worthy of note and shortens to a significant extent the access to this class of alkaloids.

Increasing the steric bulk on the electrophile modified the regioselectivity of the alkylation process. In this context, alkylation of biaryl 170, using tert-butyl α-chloroacetate led to the alkylated product at the 3-position, as indicated by the formation of 213 (Scheme 47).

62

Scheme 47. Birch reductive alkylation with aziridine and butyl bromide as electrophiles.

III.6. Proposed mechanism for the alkylation step.

By looking at the above results, the α-chloronitrile and esters were used as electrophiles, providing a straightforward manner to install the ethylamino group found in alkaloids (Scheme 1). The most probable mechanism for the alkylation with alkyl halides is a nucleophilic substitution (SN2), the SN1 mechanism through a carbocation being unlikely in an ammonia solution.

The reductive alkylation was carried out on biphenyl 148 to introduce a t-Bu group at the benzylic position (Scheme 48) using tert-butyl bromide as an electrophile. A SN2 mechanism is now unlikely to explain the introduction of the t-Bu group, which is probably better illustrated as a single-electron-transfer (SET) mechanism111 (Scheme 49).

Scheme 48. Birch reductive alkylation with t-BuBr as electrophiles.

111 (a) Garst, J. F. Acc. Chem. Res. 1971, 4, 400-406. (b) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R. J. Am. Chem. Soc. 2000, 122, 3344-3350. (c) Hazimeh, H.; Mattalia, J. M.; Marchi-Delapierre, C.; Barone, R.; Nudelman, N. S.; Chanon, M. J. Phys. Org. Chem. 2005, 18, 1145-1160.

63 The yield of this reaction (25%) was estimated using 1H NMR. The alkylated product 214 and the biphenyl 148 are nonpolar and hence very difficult to separate.

Scheme 49. Possible mechanism for electron-transfer (ET).

To confirm the mechanism of (SET), “radical clock” alkylating agents were used. We thus synthesized the bromomethyl-2,3-diphenylcyclopropane112 and used it as an electrophile (Scheme 50).

Ph R Ph Ph Ph R Br Ph R Ph Ph Ph

Scheme 50. Proposed mechanism for the cyclopropane ring-opening.

The reductive alkylation of biphenyl 148 was accomplished using the “radical clock” alkylating agent (bromomethyl-2,3-diphenylcyclopropane). The alkylated diene 218 was formed in a good yield, without a trace of the cyclopropane ring-opening product 219 (expected product) (Scheme 51).

112 (a) Merlic, C. A.; Walsh, J. C.; Tantillo, D.J.; Houk, K. N. J. Am. Chem. Soc. 1999, 121, 3596-3606. (b) Kim, A.; Hong, J. H. E. J. Med. Chem. 2007, 42, 487-493.

64

Scheme 51. Birch reductive alkylation with bromomethyl-2,3-diphenylcyclopropane.

Similarly, reductive alkylation of biaryl 165 with cyclopropylmethyl bromide (Scheme 52), led to the alkylated product 220 in moderate yield (34%).

Scheme 52. Birch reductive alkylation with cyclopropyl bromide as an electrophile.

This was intriguing as cyclopropyl bromide is also frequently used as a radical clock, with cyclopropyl ring-opening rate constant as high as 6.7×107 M-1s-1.113 Cyclopropane from bromomethyl-2,3-diphenylcyclopropane (Scheme 50) exhibits an even higher ring-opening rate constant, e.g. > 2×1010 M-1s-1.114 Cyclopropylmethyl bromides may thus react through an

SN2-type mechanism, while tertiary alkyl electrophiles would react through a radical mechanism as the polar mechanism is not accessible due to steric hindrance. A single electron transfer mechanism followed by radical recombination in a "solvent cage" may also be envisioned as an alternative pathway to explain the formation of 218 and 220.115

113 (a) Newcomb, M. In Radical in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1; pp 317-336. (b) Newcomb, M.; Choi, S. Y.; Horner, J. H. J. Org. Chem. 1999, 64, 1225–1231. 114 (a) Castellino, A. J.; Bruice, T. C. J. Am. Chem. Soc. 1988, 110, 1313-1315. (b) Castellino, A. J.; Bruice, T. C. J. Am. Chem. Soc. 1988, 110, 7512-7519. (c) Adam, W.; Heil, M.; Castellino, A. J.; Bruice, T. C. J. Am. Chem. Soc. 1991, 113, 1730-1736. 115 (a) Ashby, E. C. Acc. Chem. Res. 1988, 21, 414-421. (b) Houmam, A. Chem. Rev. 2008, 108, 2180-2237.

65 In summary, a quick overview of our achievements on the synthesis of arylcyclohexa-2,5- diene 1 has been presented. The precursors for the synthesis of Aspidosperma and Strychnos alkaloids are thus accessible. The mechanism of alkylation step has also been illustrated. We thus prepared a series of symmetrical dienes, with an alkyl chain and an arene functionalized with an ortho-substituted nitrogen group. These substrates have all the qualities required to be precursors of alkaloids in a desymmetrization approach.

IV. Desymmetrization processes.

Desymmetrization reactions have seen considerable use in organic synthesis.116 The important advantage of these reactions is that a readily accessible symmetrical precursor can be converted in a single step into a stereochemically complex product, often with the formation of several stereogenic centers.

IV.1. Principles and advantages.

The chirality of our molecules will be set up by a desymmetrization process. The molecule 221 has a prochiral center as two atoms or groups are identical. The selective modification of one of the two enantiotopic atoms or groups would lead to one enantiomer of a chiral molecule. This process is called desymmetrization (Scheme 53).

Scheme 53. Concept of desymmetrization.

116 (a) Anstiss, M.; Holland, J.M.; Nelson, A.; Titchmarsh, J.R. Synlett, 2003, 1213-1220. (b) Willis, M. C. J. Chem. Soc. Perkin Trans.1 1999, 1765-1784. (c) Spivey, A. C.; Andrews, B. I. Angew. Chem., Int. Ed. 2001, 40, 3131-3134. (d) Kramer, R.; Brückner, R. Synlett, 2006, 33-38. (e) Rahman, N. A.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369-1395. (f) Studer, A.; Schleth, F. Synlett 2005, 20, 3033-3041.

66 IV.2. Desymmetrization of cyclohexa-2,5-dienes.

In the context of desymmetrization, we recall here the important features of the cyclohexa-2,5- diene precursors: • It is symmetrical and easily accessible by a limited number of steps (by Birch reductive alkylation for instance). • The quaternary center is already installed. • It includes the two nitrogen atoms present in Aspidosperma and Strychnos alkaloids. • Both faces of cyclohexadiene, because of the plane of symmetry, are diastereotopic, and the two olefins are enantiotopic as shown in Scheme 54.

Scheme 54. Characteristic features of cyclohexa-2,5-dienes.

The desymmetrization of symmetrical cyclohexadienes is a very efficient process to prepare, in one pot, useful building blocks. In a single operation, at least two, in most cases more than two, new stereogenic centers are formed. Desymmetrizations are accomplished using chiral reagents (enantioselective desymmetrization). On the other hand, the differentiation of the two double bonds in cyclohexadienes can be performed using a preexisting stereogenic center covalently bound to the cyclohexadiene (diastereoselective desymmetrization) (Scheme 55)116f. These reactions are categorized as diastereotopic group-selective processes.

Scheme 55. Differentiation of the double bonds in cyclohexadienes.

67 V. Michael reaction.

The desymmetrization of cyclohexadiene by double Michael addition reaction has been developed in our laboratory117. Initially, the object of this thesis was to apply this methodology to the synthesis of the pentacyclic skeleton of the Aspidosperma and Strychnos alkaloids to demonstrate the usefulness and effectiveness of this process.

V.1. Bibliography.

In 1887, Arthur Michael118 defined the Michael addition as an addition of enolate (ketone or aldehyde) to α,β-unsaturated carbonyl compounds. Michael addition is now commonly used to describe the 1,4-addition (or conjugate addition) of resonance-stabilized onto the electrophilic center of the Michael acceptor (Scheme 56). The Michael reaction is a very effective reaction for the formation of C-C bonds.

Scheme 56. Michael addition reaction.

Many have been used; the most common being malonates. The development of conjugate addition (Michael) reactions for stereoselective generation of C-C bonds remains an important challenge in organic synthesis.119 Lewis acid-based120 and organocatalytic strategies have led to many successes.121 For example, Michael additions of highly activated

117 Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais. Y. Org. Lett. 2007, 9, 3913-3916. 118 Michael, A. J. Prakt. Chem. 1887, 35, 349-356. 119 Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992 120 For reviews, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (b) Yamaguchi, M. In Comprehensive Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin- Heidelberg, Germany, 1999; Chapter 31.2. 121 (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-5175. (b) List, B. Tetrahedron 2002, 58, 5573-5590. (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481-2495.

68 nucleophiles, such as malonates122 or nitroalkanes123 to simple enones, have been reported. Alternatively, the unactivated or have been used with highly activated Michael acceptors, such as nitroalkenes.124 C-O and C-N bonds can be both created by the Michael addition reaction. The synthesis of the Sceletium alkaloid mesembrine is an example for the application of this reaction. Ogasawara et al. reported an asymmetric route to the synthesis of (-)-mesembrine starting from an achiral starting material.125 Allylic oxidation of 223 gave cyclohexanone 224, which was decarbamoxylated to give the (-)-mesembrine by cyclization of the intermediate amino enone 224 via the aza-Michael addition (Scheme 57).

Scheme 57. Syntheses of (-)-mesembrine by Ogasawara.

Other alkaloids have also been synthesized with this method, in particularly the Manzamine126and Amaryllidaceae127 alkaloids. Hart126 reported that cyclization of amino- cyclohexadienone 227 after deprotection of SES group occurs with a high level of diastereoselection to afford perhydroindole 228 (Scheme 58). The cyclization of 227 to 228 is

122 (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955-4957. (b) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661-665. (c) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975-2978. (d) Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805-8808. 123 (a) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331-8338. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257-4259. (c) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520-3530. 124 (a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369-1371. (b) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558-9559. (c) Betancort, J. M.; Barbas III, C. F. Org. Lett. 2001, 3, 3737-3740. (d) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559-2561. (e) Enders, D.; Seki, A. Synlett 2002, 26. 125 Yamada, O.; Ogasawara, K. Tet. Lett. 1998, 39, 7747-7750. 126 (a) Bland, D.; Hart, D. J.; Lacoutiere, S. Tetrahedron 1997, 53, 8871-8880. (b) Bland D.; Chambournier, G.; Dragan, V.; Hart, D. J. Tetrahedron 1999, 55, 8953-8966. 127 (a) Martin, S. F.; Davidsen, S. K.; Puckette, T.A. J. Org. Chem. 1987, 52, 1962-1972. (b) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184-3190.

69 related to diastereoselective cyclization of 1,4-cyclohexadienes described by Wipf and Curran.128

Scheme 58. Syntheses of perhydroindole Core of Manzamine Alkaloids.

The Michael reaction is fairly common in the field of total synthesis of natural products. There are also some examples of double Michael addition. Marino used this strategy for his aspidospermidine and aspidophytine syntheses. 129 The tricyclic structure 230 was furnished by an intramolecular conjugate addition under basic conditions. The second cyclization to get the compound 232 was performed by deprotection-conjugate addition under acidic conditions (Scheme 59).

128 (a) Wipf, P.; Kim, Y. Tet. Lett. 1992, 33, 5477-5480. (b) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106-11112; (d) Curran, D. P.; Qi, H.; DeMello, N. C.; Lin, C. H. J. Am. Chem. Soc. 1994, 116, 8430-8431. 129 (a) Marino, J. P.; Laborde, E.; Paley, R. S. J. Am. Chem. Soc. 1988, 110, 966-968; (b) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios, A. J. Am. Chem. Soc. 2002, 124, 13398-13399. (c) Marino, J. P.; Cao, G. Tet. Lett. 2006, 47, 7711-7713.

70

Scheme 59. Syntheses of (+)-aspidospermidine via double Michael addition reaction.

The last example that is much closer to our proposed strategy has been reported by Guillou130 and co-workers during their formal total syntheses of Aspidosperma alkaloids. This was completed by reaction of anilide 233 with methyl amine to provide the tricyclic compound 234 by a Michael addition and tetracyclic compound 235 by a double Michael addition. The tricyclic skeleton was subjected to basic cyclization in the presence of sodium hydride or to afford only the tetracyclic product 235 as outlined in Scheme 60. The construction of nitrogen cycles by Michael addition reaction seems to be an interesting approach. It can be done using several different conditions, with different substituted amines and .

Scheme 60. Syntheses of Aspidosperma alkaloids via Double Michael addition reaction.

130 (a) Bru, C.; Thal, C.; Guillou, C. Org. Lett. 2003, 5, 1845-1846. (b) Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043-9048. (c) Pereira, J.; Barlier, M.; Guillou, C. Org. Lett. 2007, 9, 3101-3103.

71 V.2. Results.

V.2.1. Preparation of dienone.

To achieve the alternative approach using a double Michael addition process, we firstly turned our attention to the synthesis of the dienone that could preform both nitrogen rings in a single operation. The compound 174 (Scheme 36) was chosen as a precursor for the synthesis of the corresponding dienone to complete our syntheses. Therefore, it was necessary to reduce the group and then protect the corresponding primary amine (Scheme 61).

Scheme 61. Synthesis of diene 237 having two orthogonally protected amino groups.

The allylic oxidation131 of diene 237 was carried out using manganese(III) acetate132. For the mechanistic studies proposed by the authors, the pH value dropped gradually during the reaction (after 6h the pH was about 5). The acidity increased to pH 4 after 36h. A plausible explanation is that an acetate unit in Mn3O(OAc)9 (active form of Mn(OAc)3) was displaced by a t-BuOOH molecule to give in situ acetic acid which is responsible for the mild acidic conditions of the reaction (Scheme 62).

131 Page, P. C. B.; McCarthy, T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 7, p 83. 132 (a) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149-3151; (b) Dunet, J. Ph.D Thesis University of Bordeaux, 2009, N° d‟ordre: 3879.

72

Scheme 62. Proposed Catalytic Cycle of Allylic oxidation by manganese (III) acetate.

In our hands, the allylic oxidation of the diene 237 by manganese(III) acetate in the presence of 5 equivalents of t-BuOOH, interestingly led to the corresponding peroxide 238, instead of the expected dienone (Scheme 63, conditions A). We observed that dihydrate Mn(OAc)3 in the presence of molecular sieves produced the best yields. Using instead the hexahydrate, various amounts of a mono-1,4-addition product (having the sulfonamide group) were detected that could not be separated from minor byproducts.

Scheme 63. Allylic oxidation of diene 237.

The presence of mono-addition product is interesting and prompted us to search for other conditions. The more reproducible results were obtained following Corey‟s method133 using a mixture of Pd/C and t-BuOOH (Scheme 63, conditions B). Under these conditions, we observed a single product, the peroxide 238. It is worth noticing that with the allylic oxidation using the above conditions, Corey observed directly the formation of α,β-enones. But the allylic oxidation by the t-BuOOH/Pd(OAc)2/K2CO3/CH2Cl2 system produced the allylic

133 Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727-2730.

73 tert-butylperoxy as major products (Scheme 64). Surprisingly, the difference between these two reactions is only due to the use of different source of palladium.

Scheme 64. Allylic oxidation of olefin 239 by Corey.

The initiating t-BuOO˙ radical appears to be formed by homolysis of L2Pd(OOt-Bu)2, which leads also to L2Pd(OOt-Bu), a species that can provide a second t-BuOO group by either radical transfer or dissociation. Oxidation of L2Pd by t-BuOOH regenerates the key reactant

L2Pd(OOt-Bu)2 (Scheme 65). In the case of Pd(OAc)2, this species can be formed by exchange of the ligand OAc with OOt-Bu, and release of acetic acid.

Scheme 65. Catalytic cycle of Pd-catalyzed allylic oxidation.

Several decompositions of the peroxide bond are possible. According to Kornblum and De la Mare134, tert-butyl peroxide can be decomposed under basic condition (NaOH, KOH, sodium ethoxide, piperidine ...). In the proposed mechanism, the base could abstract the α-proton from the peroxide, leading to the formation of a carbonyl and the expulsion of t-BuO¯.

134 Kornblum, N.; De la Mare, H. E. J. Am. Chem. Soc. 1951, 73, 880-881.

74 Theoretically, it is possible to use a catalytic amount of base, since the t-BuO¯ is regenerated 135 in each cycle. The reactions performed by Corey were carried out in the presence of K2CO3.

The base concentration is less pronounced in the case of using Pd(OAc)2 due to formation of acetic acid, which could explain the difference in the observed results. Another possibility 0 would be the insertion of Pd in the O-O bond. In the case of using Pd(OAc)2, the amount of Pd0 in the reaction mixture is too small to decompose the peroxide. And in this case only the peroxide 241 is observed (Scheme 66).

Scheme 66. Possible mechanisms for decomposition of the peroxide.

Surprisingly, the same reaction conditions applied to the compound 247136 and 249137 led to the enone 248 and 250 with an excellent yield, and in a shorter time (Scheme 67).

135 Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12658-12659. 136 The reaction was carried out by Redouane Beniazza during his master II. 137 Levin, J. I.; Turos, E.; Weinreb, S. M. Synthetic communication 1982, 12, 989-993.

75

Scheme 67. Allylic oxidation of the model compounds.

The above results indicate that, the sulfonamide group (NHSO2Et) seems to play a role in the stability of the obtained peroxide, may be due to the coordination of palladium by the sulfonamide group or to the more acidic NH proton that could react with K2CO3. After these results on the allylic oxidation, we will turn our attention on the study of the double Michael reaction.

V.2.2. Double Michael addition.

The mentioned examples in literature reported that the Michael addition of a secondary amine would be done under basic conditions. Various attempts to convert peroxide 238 into the desired dienone were then carried out. We have seen that the conditions were favorable to this reaction. But, when the peroxide was subjected to the NaH and t-BuOK, only degradation was observed. In our case, the abstracted bis-allylic proton could be relatively acidic; therefore a strong base as NaOH as described by Kornblum134 will be not necessary. It was finally found that the use of DBU (2 equiv) seemed interesting, since it is relatively non-nucleophilic and still a strong base. The use of DBU in refluxing THF are the optimal conditions to transform peroxide 238 into double Michael product 251, whose structure was unambiguously assigned through X-Ray (Scheme 68). The reflux is necessary for the formation the C ring.

76

Scheme 68. Double Michael reaction.

Finally, the diene oxidation-double Michael addition sequence could be carried out in a single- pot operation. The tetracyclic compound 251 was obtained by sequential addition of reagents in one pot, with overall yields of 54% and 60% respectively. The oxidation reaction was performed at first, then once completed (through monitoring by TLC), the DBU was added and the reaction mixture was refluxed, which led to the double 1,4-addition product 251, an analogue of Büchi‟s ketone with 54% overall yield (Scheme 69).

Scheme 69. Allylic oxidation and Double Michael in one-pot.

Concerning the objective of this thesis, the construction of Büchi‟s ketone 130 required the deprotection of SO2Et protective group, followed by the methylation of the resulting tetracyclic amine. The deprotection of the SO2Et group is usually difficult and requires hard conditions. Therefore, we turned our attention to the SES analogue 175 which is obtained also in three steps from commercial 2-aminobiphenyl 181. Encouraged by the above results, it was envisaged that the nitrile group in the precursor 175 could be reduced and then the corresponding primary amine 252 protected with acetate to provide the diene 253 (Scheme 70).

77

Scheme 70. Synthesis of Diene 253.

The allylic oxidation of diene 253 was carried out using the Corey‟s method. Interestingly, under these conditions, we observed a mixture of the peroxide product 254 and 25% of the separable mono-1,4-addition product 255 (Scheme 71). The same results were obtained using a mixture of Pd(OAc)2 and t-BuOOH.

Scheme 71. Allylic oxidation of compound 253 by Corey’s method.

The use of DBU (2 eq) in refluxing THF transformed peroxide 254 through a 1,4-double additions into product 256 in 70% overall yield (Scheme 72).

Scheme 72. Double Michael reaction.

The tetracyclic compound 256 could be obtained by sequential addition of the reagents in a single-pot operation as outlined in Scheme 73. Interestingly, the cyclohexadienone 257 was formed firstly but reacted spontaneously to provide the double Michael addition product 256 in 60% overall yield.

78

Scheme 73. Allylic oxidation and Double Michael in one-pot.

At this stage, all that remained to be done to complete the synthesis of the tetracyclic core of the Aspidosperma and Strychnos alkaloid families was the methylation of the tetracyclic compound 256. This methylation can be accomplished after deprotection of the 138 function of 256, realized by using n-Bu4NF (TBAF) (Scheme 74).

Scheme 74. Deprotection of the aniline function of 256.

The indolino nitrogen of 258 was methylated using excess methyl iodide and potassium carbonate in refluxing acetonitrile (Scheme 75).97

Scheme 75. Methylation step in the syntheses of Büchi’s ketone.

In order to restrict the number of steps and do all the reactions in cascade, the deprotection- methylation sequence was performed in a single pot operation. The Büchi‟s ketone 130 was

138 Gao, Y.; Lan-Bell, P.; Vederas, J. C, J. Org. Chem. 1998, 63, 2133-2143.

79 obtained by sequential addition of TBAF in THF then excess methyl iodide at room temperature, with 59% overall yield (Scheme 76).

Scheme 76. Deprotection and methylation in one-pot.

This sequential cascade process thus provides a useful intermediate, e.g. 130, in the synthesis of the Aspidosperma and Strychnos alkaloids in only six steps (Protection, Birch reductive alkylation, Reduction, Protection, Cascade sequence and Protection/Methylation sequence) and 17% overall yield from commercially available 2-aminobiphenyl.

V.2.3. Enantioselective version of Michael addition reactions.

After studying the Michael addition reaction in a racemic version, we then turned our attention to an asymmetric version of this reaction. Indeed, the DBU used for this reaction could possibly be replaced by chiral amines used in the context of , as well as organometallic reagents or Lewis acids (Scheme 77). Cinchona alkaloids were found to catalyze enantioselective Michael addition reactions. Chiral quaternary ammonium salts derived from quinine are known to be effective in Michael reactions under phase transfer catalysis.139 Other derivatives could be synthesized from quinine and could be adapt to achieve our objective. Herein, we have employed compounds 248 and 250 as substrates in asymmetric Michael addition reactions.

139 (a) Zhang, F. Y.; Corey, E. J. Org. Lett. 2001, 3, 639-641. (b) Zhang, F. Y.; Corey, E. J. Org. Lett. 2000, 2, 1097-1100. (c) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222-4266. (d) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679-697.

80

Scheme 77. Organocatalysis and Lewis acid screened in this study.

The compound 248 obtained in our laboratory (Scheme 67) was chosen as the first model substrate in this reaction, the results for the optimization of the reaction conditions are summarized in Table 1. The cyclization of cyclohexadiene 248 was first carried out using Lewis acids such as titanium (table 1, entries 1-3) in the presence of binaphthol derivatives as chiral ligand. Surprisingly, nor basic or acidic titanium complexes failed to react with the dienone. But an accidental addition of Ti(Oi-Pr)4 in a Ti(NEt2)4 experiment gave the tricyclic compound 259 in high yield, but with no enantiomeric excess (entry 3).

81

Table 1. Screening of the optimal reaction conditions for the cyclization of compound 248.

Subsequently, we proposed to study this reaction with cyclohexadiene 250 obtained in our laboratory (Scheme 67). The results for the optimization of the reaction conditions are summarized in Table 2. The cyclization of cyclohexadiene 250 was first carried out using various organocatalysts, basic or acidic (table 2, entries 1-4), Phase Transfert Catalyst (table 2, entry 5) or organometallic complexes (table 2, entries 6-9). Despite very slow reactions, the tricyclic compound 260 was obtained in excellent yield in most cases, but again with no enantiomeric excess. When the cyclization was accomplished using titanium derivatives as Lewis acid (table 2, entries 7-9) in the presence of chiral ligands, the mixture of both titanium salts Ti(Oi-Pr)4 and Ti(NEt2)4 discovered fortiously, gave again the best result. The tricyclic compound 260 was thus formed in high yield (87%), albeit with a very low but significant enantiomeric excess (14% ee, entry 8). The potential use and the mechanistic aspects of this "magic mixture" have not been explored further due to lack of time.

82

Table 2. Screening of the optimal reaction conditions for the cyclization of compound 250.

In conclusion, the use of chiral ligands on the metal, especially titanium, might provide an entry toward enantioselective double Michael reaction. Several catalytic system have been tested, but without success. The tricyclic compound is generally obtained in good yield but the enantiomeric excesses did not exceed 14% with the use of titanium in the presence of BINOL (Table 2, entry 8). Based on the resulting (table 2, entry 8), much more have to be done to have a good desymmetrization method for our cyclohexadienones.

VI. Conclusion.

In this chapter we have presented a rapid overview of the achievements of our laboratory for the synthesis of arylcyclohexa-2,5-dienes through the Birch reductive alkylation reaction. The mechanism of alkylation step has also been illustrated. We have also described an efficient

83 approach to the tetracyclic core of Aspidosperma and Strychnos alkaloids based on a double Michael addition reaction. The general synthetic strategy is straightforward due to the cascade process. This sequential cascade process thus provides a useful racemic intermediate, i.e. 130, in the synthesis of the Aspidosperma and Strychnos alkaloids in only six steps (Protection, Birch reductive alkylation, Reduction, Protection, Cascade sequence and deprotection/Methylation sequence) and 17% overall yield from commercially available 2-aminobiphenyl 181 (Scheme 78). Various attempts at performing the enantioselective version of the Michael addition reaction by chiral amines or Lewis acids were effective in terms of the yield but failed in terms of enantioselectivity.

Scheme 78. General synthesis of Büchi’s Ketone.

84 Chapter III: Desymmetrization approach applied to arylcyclohexa-2,5-diene derivatives in presence of metals. A new route to the synthesis of Strychnos alkaloids.

As part of the overall desymmetrization strategy of our laboratory to access several large families of alkaloids from arylcyclohexa-2,5-dienes, initially, the objective of this thesis was to apply this methodology to the synthesis of pentacyclic core of Strychnos alkaloids, to demonstrate the usefulness and effectiveness of this process. Strychnos alkaloids, belonging to the curane type, constitute an important group of architecturally complex and widely distributed monoterpenoid indole alkaloids9.

I. Bibliography.

I.1. Oxidative amination reactions.

The synthetic strategy consists in an electrophile-promoted cyclization of a nitrogen group to an olefin (Scheme 79)140. One of the first problems that appear is the compatibility between this nitrogen function and the electrophile. Therefore, the primary amine is preferably protected by an electron withdrawing group, to decrease its nucleophilicity.

Scheme 79. Electrophile-promoted cyclization olefins.

140 (a) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, pp 411-454. (b) Frederickson, M.; Grigg, R. Org. Prep. Proc. Int. 1997, 29, 63-115. (c) Wirth, T. Angew. Chem., Int. Ed. 2000, 39, 3740-3749.

85 Effective electrophiles range from strong Brønsted acids to main-group (e.g., selenium, halogens) and transition-metal reagents (, gold, copper and palladium).141 The reactions generally proceed via an intramolecular nucleophilic attack on an electrophile- activated olefin intermediate, 262 (Scheme 79). The use of transition-metal electrophiles in these reactions is effective because facile cleavage of the metal-carbon bond often enables the metal electrophile to be regenerated and used catalytically. Moreover, the use of chiral ligands around the metal center may render the reaction asymmetric.

I.1.1. Halocyclization.

The intramolecular cyclization of nitrogen derivatives on olefins by various halogen agents such as I2, Br2, NBS, NIS and PhSeBr were highly developed. The amides are special cases because they cyclized generally by their rather than by their nitrogen atom.142 Ganem et al, described the bromocyclization of a cyclohexa-2,5-diene using an amide substituted by a (264, Scheme 80).143 The obtained product 265 can be rearomatized quantitatively, releasing the 266 under mild conditions.

Scheme 80. Bromocyclization of cyclohexa-2,5-diene.

The influence of the protecting group on the nitrogen atom in iodocyclization has been shown by Tamaru and Yoshida in their study on the synthesis of pyrrolidines (Scheme 81)144

141 (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471-1474. (b) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070-1071. (c) Zhang, J.; Yang, C. G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798- 1799. (d) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042-6043. (e) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179- 4182. (f) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747-1749. 142 Review : Rousseau, G. Tetrahedron 1998, 54, 13681-13736. 143 Biloski, A. J.; Wood, R. D.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 3233-3235. 144 Tamaru, Y.; Kawamura, S.-I.; Bando, T.; Tanaka, K.; Hojo, M.; Yoshida, Z.-I. J. Org. Chem. 1988, 53, 5491- 5501.

86

Scheme 81. Influence of the protecting group on amine in the iodocyclization reaction.

The diastereoselective iodocyclization reaction of oxygenated group on the cyclohexadiene moiety has been developed by Elliot et al.145 (Scheme 82).

Scheme 82. Diastereoselective iodocyclization.

145 Butters, M.; Elliott, M. C.; Hill-Cousins, J.; Paine, J. S.; Walker, J. K. E. Org. Lett. 2007, 9, 3635-3638.

87 Using standard reaction conditions (3 equivalents of , or sodium hydrogen carbonate as base in acetonitrile). The cyclohexadiene diol 273 give predominantly the expected 5-exo cyclization product 274, in accordance with the transition state B. The other approach is unfavorable with the axial position of the tert-, inducing a strong 1,3-diaxial interaction. The reaction is also highly regioselective. Depending on the substituants on the stereogenic center, the compound issued from a 6-endo cyclization is achieved with a maximum of 6% yield. The 6-exo and 7-endo cyclization reactions have also been studied and, although the regioselectivity is lower, the diastereocontrol is total.

The asymmetric iodolactamization reaction continues to be actively pursued. Only three separate examples of substrate-controlled asymmetric iodolactamization have been reported146. For example, Li141c reported an efficient model for chiral-auxiliary induced asymmetric iodolactamization. With LiH as the base and the appropriate oxazolidine such 277 as the both γ and δ-lactams can be achieved in high yield with good to excellent diastereoselectivity (Scheme 83).

Scheme 83. Diastereoselective iodolactamization.

I.1.2. Hydroamination.

Hydroamination reactions allow easy access to different and elegant secondary or tertiary amines147. The hydroamination is formally the direct addition of an N-H bond on a C-C multiple bond. Indeed, all atoms except those belonging to the catalyst used in catalytic amount, come into play in the reaction. The hydroamination is now one of the most attractive

146 (a) Takahata, H.; Yamazaki, K.; Takamatsu, T.; Yamazaki, T.; Momose, T. J. Org. Chem. 1990, 55, 3947- 3950. (b) Knapp, S.; Gibson, F. S. J. Org. Chem. 1992, 57, 4802-4809. (c) Shen, M.; Li, C. J. Org. Chem. 2004, 69, 7906-7909. 147 Jayasree, S.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795-813.

88 reactions to synthesize amines, present in many natural products, pharmaceutical agents but also in fine chemistry. However, the direct nucleophilic addition of an amine on a C-C multiple bonds is difficult.

Different kinds of activation can be used to overcome these difficulties. The olefins, for example, can be substituted by an electron-withdrawing group, like a ketone, ester, nitrile, or nitro, to increase their electrophilicity. The hydroamination reaction is then rather called a Michael-type reaction of the amine on the olefin. The obtained product in this case is anti-Markovnikov.

The reaction can also be activated by an acid and cause the formation of a carbocation intermediate. Under these conditions, the Markovnikov product is obtained. Zeolithes have been widely used for this type of catalysis, but conversions are often weak148. A recent example is the formation of pyrrolidines of type 280 catalyzed by triflic or (Scheme 84)149.

Scheme 84. Acid-catalyzed hydroamination.

The reaction involves the addition of tosylamines and N-phenylamides on terminal olefins or arenes. This example shows the activation of the double bond. The proposed mechanism involves first the protonation of tosylamine 281 on the nitrogen or oxygen, followed by intramolecular transfer of this proton to the olefin to form the carbocation 283, which will then be trapped by tosylamine. The product 285 is formed after abstraction of a proton on the sulfonamide to complete the catalytic cycle (Scheme 85).

148 (a) Lequitte, M.; Figueras, F.; Moreau, C.; Hub, S. J. Catal. 1996, 163, 255-261. (b) Mizuno, N.; Tabata, M.; Uematsu, T.; Iwamoto, M. J. Catal. 1994, 146, 249-256. 149 Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471-1474.

89

Scheme 85. Proposed mechanism for the acid activation.

In 2006, our group has developed an intramolecular hydroamination reaction using the diene 286 having an amino chain substituted by an auxiliary chiral (Scheme 86)150.

Scheme 86. Diastereoselective intramolecular hydroamination.

The amine 286 thus led to the cyclized product 287 in excellent yield as a single isomer. The formation of an allylic amine 287 as the only isomer indicates that isomerization of the olefinic system must occur at some stage, i.e., either on the starting diene or on the olefin formed after hydroamination.151 It was reasoned that isomerization of the olefin left after addition of the amine across the first double bond should be difficult under these mild reaction conditions. Therefore, isomerization should occur before cyclization.

150 Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755-4758. 151 (a) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744-8745. (b) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785-14803.

90 It is difficult to differentiate olefins by electrophilic cyclization involving halogenated compounds and metals such as Ag, Cu and others. The fact that the chiral metallic center is not involved directly in the activation of olefins does not allow a good differentiation. Therefore, we turned out attention toward electrophilic cyclization involving transition-metal reagents (palladium, copper...).

I.1.3. Aminopalladation.

The aminooxidative reaction is similar to that used for several years in the Wacker process,152 discovered by Smidt and co-workers in the late 1950s. This process allows the oxidation of ethylene double bond using palladium(II) (Scheme 87).

Scheme 87. Wacker oxidation.

The complete catalytic cycle of the Wacker process is illustrated in scheme 88. This process involves the coordination of palladium with the olefin and then the external nucleophile (H2O for example) attacks the activated olefin. After β-elimination, the obtained enol can be isomerized to the corresponding ketone and reductive elimination of HX forms Pd(0). The optimization work done on this process has mainly been centered on the reoxidation process of Pd(0) to Pd(II).

152 (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176-182. (b) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80 – 88.

91

Scheme 88. Overall catalytic cycle of the Wacker process.

Indeed, the challenge in the effective reoxidation of Pd(0), the limiting factor of this reaction, is usually the precipitation of the Pd(0) as a “black palladium” versus the reoxidation. The direct reoxidation of palladium (0) by oxygen is difficult. Many different conditions have been tried to facilitate this transformation. This could be achieved for example by adding copper chloride (CuCl2), used in catalytic amount. Other nucleophiles may react with palladium- olefin complex. The most common are alcohols, and weakly basic amines such as those substituted by the tosyl or carbamate groups.

The Wacker process is important not only in its own right, but because it also opened up the field of catalytic palladium chemistry153. Palladium(II) catalysis has been widely, mainly because of the industrial interest in the Wacker reaction that converts ethylene to acetaldehyde in the presence of water152. Unlike water, amines form complexes with palladium and thus inhibit the reaction. In general the amines must be protected.

The palladium(II)-catalyzed addition of nitrogen nucleophiles to olefin is a well developed process to form C-N bonds.154 Palladium(II) activates the olefin via the coordination complex

153 Handbook of Organopalladium Chemistry for Organic Synthesis (Ed.: E. Negishi), Wiley-Interscience, New York, 2002. 154 (a) Hosokawa, T. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, pp 2211-2225. (b) Tamaru, Y.; Kimura, M. Synlett 1997, 749.

92 288. The aminopalladated intermediate 289 commonly undergoes β-hydride elimination to produce oxidative amination products such as 290. However, a number of alternative products, such as 291-293 (Scheme 89), can be prepared by modifying the reaction conditions155.

Scheme 89. Intramolecular Aminopalladation of olefins.

The need to use protected amines and reoxidation problems has not prevented the emergence of several syntheses of heterocycles, also in an asymmetrical version. The pioneering work on aminopalladation process was made by Hegedus on ortho-allylanilines such 294 to form indoles (Scheme 90)156.

Scheme 90. Construction of indoles by aminopalladation reaction.

155 (a) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z.-I. J. Am. Chem. Soc. 1988, 110, 3994-4002. (b) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690-7691. (c) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-4247. 156 (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am.Chem. Soc. 1978, 100, 5800-5807. (b) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc. 1980, 102, 3583-3587. (c) Hegedus, L. S.; McKearin, J. M.; J. Am. Chem. Soc. 1982, 104, 2444-2451.

93 This allowed to concentrate research toward the major difficulty of the reaction, the reoxidation of palladium(0). Solving the problem of reoxidation of Pd(0) into Pd(II) has been crucial for all catalytic reactions based on palladium(II). The dioxygen is the ideal oxidant, producing no residue in the reaction mixture except the intermediate and finally water157,158. Regarding to the amination reactions, the use of dioxygen as reoxidant has been described by Bäckvall et al.159 independently in the presence of DMSO (Scheme 91).

Scheme 91. Different catalytic systems for the Aminopalladation.

160 Subsequently, Stahl demonstrated the usefulness of the Pd(OAc)2/Pyridine (1:2) system in xylenes as one of the most efficient catalyst available for intramolecular oxidative amination of olefins (Scheme 92).

Scheme 92. Pd(OAc)2/pyridine system for aminopalladation reaction.

157 Stahl, S.S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188-7189. 158 Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420. 159 Rönn, M.; Bäckvall, J. E.; Anderson, P. G. Tetrahedron lett. 1995, 36, 7749-7752. 160 Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41, 164- 166.

94 Stoltz and co-workers later modified this catalyst system, using Pd(O2CCF3)2 and pyridine

(1:4) with 3 Å molecular sieves and Na2CO3, to promote several different heterocyclization reactions, including oxidative aminations161. Stahl suggested a possible catalytic cycle for the oxidative amination reactions: aminopalladation of the olefin is followed by a β-hydride elimination generating the heterocyclic product 302 and a reduced Pd catalyst (steps I and II, Scheme 93). The reduced Pd is then oxidized directly by molecular oxygen to regenerate the Pd(II) catalyst (steps III and IV).

Scheme 93. Catalytic cycle for dioxygen-coupled Pd-catalyzed oxidative amination of olefins.

Aminopalladation of the olefin forms a new stereocenter adjacent to the nitrogen atom (step I, Scheme 88), and this stereocenter is retained in the product if β-hydride elimination proceeds away from this center, as in the formation of 302 (step II). In contrast to the well-developed asymmetric Pd(0)-catalyzed cyclization reactions,162 much less attention has been paid to investigate the origin of enantioselectivities in Pd(II)-catalyzed asymmetric nucleopalladation of alkenes163. If several examples are described with the use of 164 165 166 as nucleophiles ‟ ‟ there are very few with nitrogen derivatives.

161 (a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (b) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778-17788. 162 (a) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533. (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945. 163 (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328-6335. 164 Use of ortho-allylphenol: (a) Hosokawa, T.; Uno, T.; Inui, T; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318-2323. (b) Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J. Org. Chem. 1985, 50, 1282-1287. (c) Uozumi,

95 Only one successful example of asymmetric Pd-catalyzed aerobic oxidative amination of alkenes has been identified. Yang and co-workers reported that the Pd(O2CCF3)2/sparteine and t Pd(OAc)2/ Bu-QUOX systems catalyze tandem oxidative bicyclization reactions as shown in 167 168 Scheme 94. ‟

Scheme 94. Asymmetric Pd-catalyzed aerobic oxidative amination of olefins.

The conditions for these reactions resemble those reported previously by Stoltz et al. for related oxidative heterocylizations of phenol substrates (Scheme 95)153,155,156.

Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071-5075. (d) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063-5064. (e) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozomi, Y. J. Am. Chem. Soc. 2004, 126, 3036-3037. 165 Use of primary alcohol: Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907- 2908. 166 Asymmetric Wacker: (a) El-Qisairi, A. K.; Hamed, O.; Henry, P. M. J. Org. Chem. 1998, 63, 2790-2791. (b) Hamed, O.; Henry, P. M. Organometallics 1998, 17, 5184-5189. (c) El-Qisairi, A. K.; Henry, P. M J. Organomet. Chem. 2000, 603, 50-60. (d) El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M J. Organomet. Chem. 2002, 656, 167-175.(e) Shinohara, T.; Arai, M. A.; wakita, K.; Arai, T.; Sasai, H. Tetrahedron letters, 2003, 44, 711-714. 167 Yip, K. T.; Yang, M.; Law, K. L.; Zhu, N. Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130-3131. 168 He, W.; Yip, K. T.; Zhu, N. Y.; Yang, D. Org. Lett. 2009, 11, 5626-5628.

96

Scheme 95. Oxidative heterocylizations of phenol 309.

I.1.4. Aminocupration.

Wacker-type experimental procedures were initially adopted, wherein a catalytic amount of expensive , e.g., PdII or PtII, could be used in conjunction with less expensive stoichiometric CuII salts (commonly used to reoxidize Pd0 to PdII).

Chemler et al. found that the CuII oxidants are themselves capable of inducing additions of heteroatom‟s to double bonds169. For examples tosyl-o-allylaniline 311 has been cyclized into

312 with Cu(OAc)2 (3 eq) and Cs2CO3 in CH3CN or DMF at 120 °C. This transformation represents a highly concise heterocycle formation. In contrast, when the olefin 311 was treated with catalytic amounts (0.1 eq) of Pd(OAc)2 in the presence of Cu(OAc)2, the indole product 313 (the result of aminopalladation and subsequent β-hydride elimination), was obtained, similarly to the results reported by Hegedus and others (Scheme 96)154.

Scheme 96. Cu and Pd mediated oxidative amination.

169 Sherman, E.S.; Chemler, S. R.; Tan, T.B.; Gerlits, O. Org. Lett. 2004, 6, 1573-1575.

97 Chemler suggested a possible mechanism for this reaction as shown in Scheme 97. Thus, one- electron oxidation of the nitrogen (311 to 314) followed by 5-exo-trig intramolecular ring closure generates 315. Subsequent addition of the primary carbon-based radical onto the aromatic ring, followed by an oxidation and rearomatization, would provide 312. An alternative mechanism would involve nitrogen-copper(II) bond formation (317) followed by intramolecular and subsequent addition to the aromatic ring, possibly via a radical process.

Scheme 97. Proposed reaction mechanism.

More recently, Chemler reported that the organic soluble copper salt, Cu(II) neodecanoate II [Cu(ND)2] was shown to be more reactive than Cu(OAc)2. Also, the Cu 2-ethylhexanoate is more reactive than any copper carboxylates owing to its high solubility in organic solvents170.

170 (a) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72, 3896-3905. (b) Fuller, P.H.; Chemler, S. R. Org.Lett. 2007, 9, 5477-5480. (c) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079. (d) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.

98 The catalytic asymmetric aminooxygenation of olefin is a clear challenge for these reactions and has been realized rarely160,161. A successful example of copper(II)-catalyzed asymmetric aminooxygenation reaction that involves intramolecular addition of arylsulfonamides across terminal olefins has been reported by Chemler and co-workers (Scheme 98)171.

Scheme 98. Enantioselective aminooxygenation and transition-state model.

The observed stereochemistry is consistent with transition state 320 (Scheme 98), where the substrate‟s N-substituent is on the opposite face to that of the phenyl substituent172.

Recently in 2008, Chemler added 2,2,6,6-tetramethylpiperidine-N-oxy radical (TEMPO) (3 eq), a standard carbon radical trapping agent, in the optimal catalytic enantioselective aminooxygenation reaction, instead of the stoichiometric oxidant MnO2. The product formed does not contain the second cycle resulting from the addition on the sulfonyl aromatic ring, but instead the TEMPO adduct. This oxidant also improved both the yield and the enantioselectivity (Scheme 99)173.

171 Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948-12949. 172 Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. 173 Fuller, P. H.; Kim, J.W.; Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638-17639.

99

Scheme 99. Enantioselective aminooxygenation in the presence of TEMPO.

From the previous examples, we found that the oxidative amination of olefins and 1,3-dienes catalyzed by PdII or CuII has recently received a great deal of attention as an atom-economical process. The absence of aminopalladation reaction on cyclohexa-2,5-dienes and the emergence of asymmetric versions prompted us to apply this reaction onto these systems. Aminopalladation reactions allow the addition of a protected amine to olefin with generation of an unsaturation through the β-elimination. In this way, it should be possible to build two five-membered rings of the Aspidosperma and Strychnos alkaloids.

II. Our strategy

II.1. Retrosynthetic analysis.

The proposed strategy to access some of these pentacyclic-targets, like mossambine and strychnine, is based on the desymmetrization of cyclohexa-2,5-diene intermediate 323 having two orthogonally protected amino groups, accessible from a simple biaryl 323 through Birch reductive alkylation. The key desymmetrization process is an oxidative amination of cyclohexadiene 324 catalyzed by metals (Pd, Cu…), that allows the elaboration of ring B and C in a one pot operation. This strategy would provide an access to several natural products, belonging to the Aspidosperma and Strychnos alkaloids (Scheme 100).

100

Scheme 100. Desymmetrization of an arylcyclohexa-2,5-diene new access to Strychnos alkaloids.

The symmetrical nature of 324 also implies that the Pd cascade may in principle be extended to an enantioselective series. It should be noted that the cycles B, C, D in aspidospermidine could be generated in one pot by oxidative addition of palladium (II) species.

III. Achievements of our laboratory.

Pioneered by Bäckvall157,174, the addition of an amino group across the double bond of a 1,3- diene is known to generate a new C-N bond along with an allylic system. On the basis of these studies, we investigated the possible extension of the aminopalladation process to our 1,4- diene system.

The first attempt in our laboratory showed that monocyclization of 1,4-dienes was feasible by treating readily available model compounds 325-328 with 10% Pd(OAc)2 and NaOAc (2 eq) (Scheme 101)175. In DMSO under an oxygen stream, the 1,3-dienes 329-332 were obtained in moderate yields showing that alkaloids C ring could be elaborated efficiently by this way.

174 (a) Bäckvall, J.-E.; Andersson, P. G. J. Am. Chem. Soc. 1990, 112, 3683-3685. (b) Verboom, R. C.; Persson, B. A.; Bäckvall, J.-E. J. Org. Chem. 2004, 69, 3102-3111. 175 Lebeuf, R. Ph.D Thesis University of Bordeaux1, 2006, N° d‟ordre: 3276.

101

Scheme 101. Construction of the C ring through the oxidative amination reaction.

Despite the different conditions used, the reaction is not quantitative and the best isolated 150 yields were obtained by using the system DMSO/O2 . The major side product is issued from the overoxidation of the diene (enones have been isolated in some cases). To test the feasibility of the Aspidosperma D ring synthesis, the product 328 was subjected to the oxidative amination conditions mentioned above. We hoped that a Heck type cyclization of the resulting π-allyl-Pd on the acrylamide olefin would take place (Scheme 101). Not surprisingly, only the oxidative amination product 331 was obtained in 60% yield, the β- elimination being faster than the Heck reaction. However, this result encouraged us to consider formation of the B and C rings of alkaloids in a single-pot operation by the oxidative amination reaction, but on substrates where the β-elimination would be impossible.

III.1. Construction of B ring.

Construction of ring B looked more challenging with the synthesis of a cyclohexa-2,5-diene 324, having an ortho-substituted phenyl substituent. Formation of ring B through oxidative amination using PdII-catalyzed conditions was then investigated varying the nature of solvent and co-oxidant. Oxyamination of precursor 174 thus provided the cyclized product 333 (Scheme 102)117. Without additives, the cyclized product was obtained but in moderate yield (entry 1).

102

Scheme 102. PdII-catalyzed oxidative amination of diene 174.

The best results were obtained when using NaOAc as a base under a stream of oxygen (entry 2). Other additives such as pyridine156 and CuOAc led to no improvement (entries 3 and 4). It was observed that oxygen concentration was a critical factor, indicating that Pd0 reoxidation is 158 176 0 II the turnover limiting step of the process ‟ . Inefficient reoxidation of Pd into Pd leads to aggregation of Pd0 and precipitation of Pd metal. Charcoal (noted as C in Scheme 102) was thus added to the mixture to prevent the Pd0 aggregation177. This resulted in a significant improvement of the yield and also allowed a reduction of Pd loading (entries 5 and 6). It was noted that the presence of stoichiometric NaOAc as a base often enhances the yield of these reactions. These findings resemble those reported previously by Larock et al 178.

Encouraged by the efficiency of the conditions mentioned above as well as the possible formation of the B ring, we then turned our attention to the construction of the C ring.

III.2. Construction of B then C ring.

The compound 333 possesses a conjugated diene, which should favor the oxidative amination and possibly another Heck-type reaction in tandem, β-elimination being impossible in this

176 Gligorich, K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2006, 45, 6612-6615. 177 (a) Mahaim, C.; Carrupt, P.-A.; Hagenbuch, J-P.; Florey, A.; Vogel, P. Helv. Chim. Acta 1980, 63, 1149. (b) Steunenberg, P.; Jeanneret, V.; Zhu, Y.-H.; Vogel, P. Tetrahedron: Asymmetry 2005, 16, 337. 178 Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585.

103 case. This synthesis was performed from the product 333 in two steps. The first is a reduction of the nitrile function to the primary amine 334, performed in good yield. The second step is the acylation of the amine by which leads to the desired precursor 335 in 86% yield (Scheme 103).117

Scheme 103. Synthesis the precursor diene 335.

When compound 336 was subjected to the conditions above (Scheme 102) to construct the ring C (and eventually the D ring), we found that these conditions did not provide to the pentacyclic product, but only a tetracyclic product, with insertion of an acetate function (product 337), whose structure was secured through X-Ray crystallography. Despite the impossibility of a β-hydride elimination, the D-ring has not been formed which could be explained by the unfavorable position of Pd as compared to that of the double bond (Scheme 104) or the low nucleophilicity of the allyl Pd-complex for the Heck reaction.

Scheme 104. Construction of ring C.

The insertion of the acetate function has already been highlighted by Bäckvall159b on conjugated diene 338 as shown in Scheme 105.

104

Scheme 105. PdII-catalyzed intramolecular 1,4-oxidation with alcohols.

In our case, this insertion can be done in two positions and by a migration of the acetate from the palladium acetate complex (red, Scheme 106) or through an external anti attack by AcONa (blue, Scheme 106).

Scheme 106. Regioselectivity for the insertion of the acetate function.

In the case of the amide compound 336, we proposed the tentative rational for the PdII-Pd0 cascade and the acetate insertion as cited in Scheme 107.

Scheme 107. Tentative rational for the PdII-Pd0 cascade and the acetate insertion.

The C ring formation leaves a PdII allyl complex on the opposite side of the acrylamide (thus preventing the D ring formation). The acetate insertion would thus come from an internal delivery at C4, away from the bulky sulfonamide. It is important noticing that only one of the four possible diastereomers is formed.

105 In conclusion, we have shown that the formation of ring B followed by ring C by oxidative amination is possible. Since these two cycles are formed under the same conditions, it became essential to consider the formation of these two cycles in a one pot operation.

II.2.3. Construction of B- and C-rings in one pot.

Encouraged by the results obtained using conditions mentioned above, we turned our attention to the consecutive formation of rings B and C in the same time. Precursors 341, 342 bearing orthogonal protecting groups, were first prepared through reduction of the nitrile and conversion of the resulting primary amine into the desired amides (Scheme 108) 117.

Scheme 108. Oxidative amination cascade of 1,4-dienes 341 and 342.

Diene 341, led after double oxidative-amination in a single-pot operation, to tetracyclic compound 343 having four new stereogenic centers, as a single regio-and stereoisomer.

With our objective to construct the B, C and D rings in a “one pot‟‟ process, the study was then extended to a model compound having a suitably disposed unsaturated system that could eventually trap the allyl-Pd intermediate. This was tested on precursor 342 bearing an acrylamide moiety. Unfortunately, the PdII-cascade led as above to the tetracyclic allylic acetate 337 identical to the one formed through the stepwise approach (Scheme 100). The X-Ray crystallography led us establishing the relative configuration of 337 (1H NMR) and proved the regiochemistry of the acetate incorporation117. The formation and the stereochemistry of the tetracyclic skeleton of 343 and 337 may be tentatively explained as cited in Scheme 107.117

Formation of ring B probably occurs first due to the higher acidity of the NHSO2Et group. Thus ring B is formed with subsequent β-elimination of a hydrido-Pd species to generate a

106 1,3-diene analogue of 333 (Scheme 103).179 Pd0 is then reoxidized by oxygen into PdII, which can catalyze the second oxidative amination with the amido group approaching anti relative to ring B to form a π-allyl-Pd acetate 340 (Scheme 107). Assuming an anti amino-palladation step during the formation of ring C, 337 is then generated with the stereochemistry as shown and thus delivers, during reductive elimination, the acetate group bound to palladium on the bottom face and at the less-hindered C4 site to give 342 and 337 as single regio and stereoisomers180.

In summary, the previous results showed that B and C rings could be formed using the same conditions (palladium oxidative amination conditions). We developed a methodology for the formation of the B and C rings in a one pot operation in good yields. Our main aim was then to construct the C and D rings or the B, C and D rings of Aspidosperma alkaloids consecutively in a single pot. The application of this method for the synthesis of Strychnos alkaloids has been considered.

IV. Results in the desymmetrization step.

IV.1. Construction of rings C and D (nucleophilic addition cascade)

IV.1.1. Synthesis of the amide precursors.

In order to survive the highly oxidative conditions (Pd(II) + oxygen), the nitrogen on the ethylamino chain has to be protected by an electron withdrawing group. Amides are the most logical and simplest protecting groups that could allow the construction of C and D rings in one pot. However, the amide formation using acid chloride derivatives in the presence of triethylamine and DMAP was shown troublesome. It was therefore necessary to perform a direct peptide type coupling of an acid with the primary amine. The coupling agents widely used for peptide coupling are carbodiimides such as dicyclohexylcarbodiimide (DCC), the first to be reported by Sheehan181. The problem with the use of DCC is that the resulting product in the end of the reaction, dicyclohexylurea, is soluble in organic solvents and often inseparable

179 Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274-7276. 180 Stahl proposed that oxidative amination of olefins with tosylamine occurred through a syn pathway. See: Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328-6335. 181 Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067-1068.

107 from the final products. Other carbodiimides such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC)182 which is sold as its HCl salt, are soluble in water and are removed during work up. These coupling agents are often used in the presence of additives (nucleophiles) such as hydroxybenzotriazole (HOBt). The carboxylic acids used in the coupling were chosen because they possess an additional nucleophilic center that could attack the π-allyl-palladium complex to form the desired pentacycle.

The coupling of 334 with different acids has been achieved with EDC and HOBt in the presence of Hünig‟s base. The desired amides were obtained with modest to good yields as shown in Scheme 109.

Scheme 109. Peptide type coupling of primary amine 327 with different carboxylic acids.

182 (a) Sheehan, J. C.; Hlavka, J. J. J. Org. Chem. 1956, 21, 439-441. (b) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org. Chem. 1961, 26, 2525-2528.

108 In entry 6 we observed an elimination of PhSO2H and the eliminated product 349 is finally obtained with 54% yield (Scheme 109).

IV.1.2. Construction of C and D rings.

The application of the palladium oxidative amination conditions, as mentioned in Scheme 102, on the resulting amides 344-348 (entries 1-5, Scheme 109) was then tested. Unfortunately, this reaction afforded unsatisfactory results; only degradation products have been observed, probably due to over-oxidation. Only amide 349 has led to the tetracyclic product 350, albeit in low yield, with insertion of the acetate function at C4 (Scheme 110). We also observed several compounds that have not been identified.

Scheme 110. PdII-catalyzed oxidative amination of compound 349.

Consequently, the last attempt to construct two rings in one pot was carried out using the precursor 352. At first, the cyclohexa-2,5-diene 175, obtained via a regioselective Birch reductive-alkylation was subjected to the palladium oxidative amination conditions, producing the tricyclic compound 351 in 78% yield. The reduction of the nitrile functional group into a primary amine, followed by treatment of the crude amine with an isocyanate led to the desired precursor 352 in 73% overall yield (Scheme 111)183.

183 Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 5039-5042.

109

Scheme 111. Synthesis the diene 352.

The compound 352 was used in this investigation without further purification, and led after palladium oxidative amination to a pentacyclic compound 353 as a single isomer in 53% yield (Scheme 112).

Scheme 112. Construction of C and D cycles by PdII-catalyzed oxidative amination.

Having found a nucleophile that could stand the highly oxidative conditions, we thus proved that C and D rings could be formed in one pot operation under the conditions of the palladium oxidative amination developed in our laboratory. It then became essential to consider the formation of these three rings in one pot operation.

IV.1.3. Construction of B, C and D rings in one pot.

We have already shown that a double bond on an acrylamide such as 337 cannot participate in a Heck reaction, probably due to the large distance between the double bond and the Pd- complex that are localized on opposite faces. Thus, a nucleophile that would attack anti relative to the π-allyl Pd(II) intermediate as in 352 would possess greater chance of success. Amido- 354, prepared through reduction of the nitrile and conversion of the resulting amine into the desired amide, was subjected to the conditions above (Scheme 102). 354 led after palladium oxidative amination, to the pentacyclic compound 355 as a single regio-and stereoisomer and in excellent yield (Scheme 113).

110

Scheme 113. One-pot elaboration of the pentacyclic core of an “aza-aspidosperma Alkaloid”.

IV.1.4. Conclusion.

We have described an efficient approach toward the tetracyclic core of Aspidosperma and Strychnos alkaloids based on the desymmetrization process achieved by a palladium oxidative amination reaction. A pentacyclic system is also at hand by adding a supplementary nucleophile, giving rise after oxidative amination to the pentacyclic core of what we called an “aza-aspidosperma alkaloid”. With this method, three rings have been formed in a one pot operation. The starting dienes were easily at hand from commercially available 2-aminobiphenyl using a regioselective Birch reductive alkylation developed in our laboratory. More work has still to be done in order to find a suitable all carbon amide that could form the D ring present in Aspidosperma alkaloids.

V. Application of the palladium oxidative-amination reaction of cyclohexadienes to the synthesis of Strychnos alkaloids.

Mossambine and strychnine differ from Aspidosperma alkaloids by the different connections of the D ring. These alkaloids cannot be made by a tricyclization approach. Nevertheless we thought that the use of the allylic acetate formed after the double cyclization would be useful for the completion of the synthesis.

111 V.1. Toward the synthesis of (±)-mossambine.

As already described in chapter I, the first total synthesis of mossambine and epi-mossambine was reported by Kuehne et al., who developed two strategies (see Scheme 7) to achieve this synthesis. An asymmetric version has also been described. In these previous studies, the key point that has guided the synthesis of these compounds was the installation of the quaternary center at C7 in the last synthetic steps79, and of the bonds around C7 which are made at the initial stages of the synthesis.80

As for the synthesis of Aspidosperma, our approach is based on palladium oxidative amination of an arylcyclohexadiene. But in this case, we wish to use the allylic acetate obtained after the double cyclization to complete the synthesis.

Scheme 114. Proposed retrosynthetic analysis of mossambine.

As illustrated in Scheme 114, our retrosynthetic analysis of mossambine involves closure of the D-ring by an intramolecular Heck cyclization reaction of vinyl iodide 357. A critical step of our synthetic plan relies upon the efficient construction of the tetracyclic substructure found in 356 by PdII-mediated oxidative amination reaction.

With this background in mind, our synthetic approach toward (±)-mossambine began by the protection of 2-aminobiphenyl 181 with 2-(trimethylsilyl)ethanesulfonyl chloride in pyridine. The Birch reduction was thus tested on the commercially available 2-aminobiphenyl, protected with this electron-withdrawing group (Scheme 115).

112

Scheme 115. Synthesis of tetracyclic core of Mossambine.

Indeed, intermediate 360 should be available from 175 following two pathways. A stepwise approach started by the palladium oxidative amination reaction of the cyclohexadiene 175 that gave cyclic product 351 followed by the reduction of the nitrile group and protection of the resulting crude amine by di-tert-butyl dicarbonate in hot THF. Then, the resulting amide 361, subjected to the Pd(II)-oxidative amination, effectively provided the tetracyclic skeleton 360 in 72% yield. The sequence has then been shortened (path B) by prior reduction of the nitrile and protection of the primary amine. The di-amide 358 led after double oxidative amination to the same tetracyclic compound 360 in 68% overall yield. We used the Boc protective group due to its easy cleavage by TFA, under standard conditions, and its known stability under the palladium oxidative amination conditions. Similarly, the di-amide 359 led after double oxidative amination reaction, to the tetracyclic compound 362 in 68% overall yield

Removal of the Boc protective group by TFA in DCM at 0°C furnished 363. This was followed by N-Alkylation of indole 363 with (Z)-1-bromo-2-iodobut-2-ene184, which afforded the vinyl iodide compound 364 in 72% yield (over 2 steps) (Scheme 116).

184 For the preparation of Z-1-bromo-2-iodobut-2-ene, see: Gamez, P.; Ariente, C.; Gore, J.; Cazes, B. Tetrahedron 1998, 54, 14825-14834.

113

Scheme 116. Approach toward Heck/carbonylation reaction.

Most surprisingly, our attempts to induce D-ring closure by subjecting tetracycle 364 to the 185 Jeffery modification of the Heck conditions [Pd(OAc)2, K2CO3, cat. n-Bu4NCl, DMF, 60°C] did not lead to the expected product but to several compounds that have not been identified. As other groups have found troublesome the presence of the nitrogen protecting group in similar Heck reactions186, we decided to remove the SES protective group first. This was done 187 by using CsF in refluxed CH3CN, which afforded the amine 365 in 58% yield (Scheme 116).

The intramolecular Heck reaction,188 using a palladium catalyst, was then carried out on the iodo amine 365. Gratifyingly, the reaction effectively provided the pentacyclic imine 366 in 44% yield (Scheme 116). In parallel, we also tried to introduce directly the one-carbon substituent at C16 after the cyclization, using a Heck/carbonylation reaction189 onto the iodo amine 365. This reaction was explored by using Pd(OAc)2 as a palladium source, PPh3 as a ligand, Bu4NBr as an additive, and triethylamine as the base (Scheme 117). This reaction was heated in a 2:1 mixture of DMA and MeOH under a balloon atmosphere of CO. Unfortunately,

185 (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287. (b) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667- 2670. (c) Jeffery, T. Synthesis 1987, 70. 186 Rawal, V. H.; Michoud, C. J. Org. Chem. 1993, 58, 5583-5584. 187 (a) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P. Tetrahedron Lett. 1986, 27, 2099–2102. 188 (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030-3031. 189 Gerald, D.; Artman, III.; Weinreb, S. M. Org. Lett. 2003, 5, 1523-1526.

114 this reaction did not lead to the expected product 367 but instead to the ester 368 in low yield (31%) along with some degradation products.

Scheme 117. Intramolecular Heck reaction.

Starting from 366, the selective introduction of the carbomethoxy group at C16 was necessary in order to complete the synthesis of Mossambine. We took advantage of the cyanomethyl formate (Mander‟s reagents)190, which is known to be a “soft” acylating agent able to promote C-acylation over N-acylation. The deprotonation of 366 was carried out by treatment with LDA in THF followed by a quick injection of Mander‟s reagent182. Unfortunately, the reaction did not work, but led to recovered starting imine acetate 366, even when using (4 eq) of LDA and (3 eq) of the Mander‟s reagent (Scheme 118).

Scheme 118. Introduction of the CO2Me group at C16.

Many attempts to introduce the ester group at C16 were fruitless, probably due to the lack of reactivity at this position. The presence of the acetate function that may be deprotonated with LDA might also prevent the second deprotonation. Thus, the imine function was then

190 (a) Mander, L. N. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 5, pp 3466-3469. (b) Crabtree, S. R.; Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256- 264. (c) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V.H. J. Am. Chem. Soc. 2002, 124, 4628-4641.

115 transformed into the N-methoxycarbonyl enamine 370 by treatment of 366 with methyl in the presence of NaH in 44% yield (Scheme 119).

Scheme 119. Synthesis of the N-methoxycarbonyl enamine 370.

With the N-methoxycarbonyl enamine 370 in hand, a photoisomerization, described during the synthesis of similar compounds191, hydrolysis of the acetate with concomitant inversion of the configuration at C4, should complete the synthesis of mossambine. Unfortunately, due to a lack of time and insufficient quantities of material, we were not able to complete the total synthesis (Scheme 120).

Scheme 120. Prospective studies to complete the total synthesis of Mossambine.

V.1.1. Conclusion

Cyclohexadiene 175 has proved to be a particularly useful building block for assembling the tetracyclic ABCE ring system of Mossambine alkaloid. The central step in the synthesis consists of a double palladium oxidative amination reaction of arylcyclohexadiene compounds. This reaction reported here provided the formation of rings B and C in a single pot operation. After generation of the iodoamine 365, the closure of the bridged piperidine D ring (with the C15-C20 bond formed) has been accomplished by an intramolecular Heck cyclization reaction. The N-methoxycarbonyl enamine 370 was obtained in 10 steps and 2% overall yield from commercially available 2-aminobiphenyl 181.

191 Bonjoch, J.; Sole, D.; Rubio, S. G.; Bosch, J. J. Am. Chem. Soc. 1997, 119, 7230-7240.

116 V.2. Attempts toward the synthesis of (±)-strychnine.

Strychnine, a well-known poison found in large quantities in Indian nuts, has a long and rich history as one of the more notorious members of the Strychnos alkaloid family9. Over the years, strychnine has attracted considerable attention from the synthetic community mainly due to its complex heptacyclic structure, containing 24 skeletal atoms and six contiguous stereogenic centers.

V.2.1. Functionalization of the acetate group.

The functionalization of the acetate group and the selective introduction of the nucleophile at C16 were necessary at this stage in order to complete the synthesis of strychnine. Our first attempts toward this synthesis based on the introduction of external nucleophiles are outlined in scheme 121 below.

Scheme 121. Functionalization of the allylic acetate.

117 V.2.1.a. Using Organocopper/Grignard reagents.

192 Bäckvall et al reported the functionalization of allylic acetates by SN2'-substitution reactions using Grignard reagents and catalytic amounts of Cu(I). The careful choice of the copper(I) catalyst, the reaction temperature, the solvent, and the careful addition of the are important parameters that influence the regioselectivity of the addition to produce either α- or γ-product (scheme 122).

Scheme 122. Copper(I)-mediated substitution reactions.

For this purpose, we choose the allylic acetate 343 as a model compound to achieve this study. Different conditions were tried (Scheme 123) but in all cases starting allylic acetate 343 was recovered unchanged.

Scheme 123. Organocopper SN2` substitution reactions using Grignard reagent.

192 (a) Bäckvall, J.-E.; Sellen, M. J. Chem. Soc., Chem. Commun. 1987, 827. (b) Bäckvall, J.-E.; Sellen, M.; Grant, B. J. Am. Chem. Soc. 1990, 112, 6615-6621. (c) Persson, E. S. M.; van Klaveren, M.; Grove, D. M.; Bäckvall, J.-E.; van Koten, G. Chem. Eur. J. 1995, 1, 351. (d) Barsantai, P.; Calo, V.; Lopez, L.; Marchese, G.; Naso, F.; Pesce, G. J. Chem. Soc., Chem. Commun. 1978, 1085. (e) Trost, B.M.; Lautens, M. J. Am. Chem. Soc. 1983, 105, 3343. (f) Corey, E. J.; Boaz. N. W. Tetrahedron Lert. 1984, 3063.

118 V.2.1.b. Cyanation of allylic acetate catalyzed by a palladium complex.

Also, we turned our attention to cyanation of the allylic acetate in the presence of palladium complexes as catalysts. The cyanation of allylic esters catalyzed by a palladium complex was reported previously by Tsuji et al193 (Scheme 124). In this reaction, trimethylsilyl 194 (Me3SiCN) is very efficient as a cyanide source and provides β,γ-unsaturated carbonitriles195.

Scheme 124. Cyanation of the Allylic esters.

A possible catalyst cycle for the present cyanation would consist of three representative steps: (1) oxidative addition of the allylic ester to a palladium(0) catalyst species, (2) transmetalation of the allylpalladium species with Me3SiCN, and (3) reductive elimination to afford the product.

Our allylic acetate 343 was thus subjected to the conditions of Tsuji195 but it did not convert to the desired product, even with the addition of CuCN along with trimethylsilyl cyanide (Scheme 125).

193 (a) Tsuji, Y.; Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.; Tanaka, S.; Ebihara, M.; Kawamura, T. Organometallic 1998, 17, 4835-4841. (b) Tsuji, Y.; Yamada, N.; Tanaka, S. J. Org. Chem. 1993, 58, 16-17. 194 (a) Weber, W. P. Silicon Reagents for Organic Synthesis; Springer-Verlag: Berlin, 1983; pp 6-20. (b) Colvin, E. W. Silicon in Organic Synthesis; Butterworth: London, 1981; pp 296-298 195 (a) Tsuji, J.; Ueno, H.; Kobayashi, Y.; Okumoto, H. Tetrahedron Lett. 1981, 22, 2573-2578. (b) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988-2995. (c) Araki, S.; Minami, K.; Butsugan, Y. Bull. Chem. Soc. Jpn. 1981, 54, 629.

119

Scheme 125. Cyanation of allylic acetate catalyzed by a palladium complex.

V.2.1.c. Bromination of the allylic acetate.

In the course of the acetate group functionalization, trimethylsilyl bromide (TMSBr) was examined as a reagent. We thought that this reagent should allow the bromination of allylic acetate196. The substrate 343 has been reacted with TMSBr in the presence of several Lewis acids, including ZnI2 or Sc(OTf)3 (Scheme 126). Unfortunately, this reaction did not yield the desired compound and the allylic acetate 343 was recovered unchanged.

Scheme 126. Bromination of the Allylic acetate 343.

196 (a) Seltzman, H.H.; Moody, M. A.; Begum, M.K. Tet.Lett. 1992, 33, 3443-3446. (b) Wuts, P. G. M.; Duda, N. Synlett. 2007, 14, 2185-2188.

120 In summary, all of our attempts to functionalize the acetate group or to introduce a nucleophile at C16 did not provide the expected products. Only, the starting material was recovered unchanged, may be due to steric hindrance of the protecting groups on both nitrogen atoms.

V.2.1.d. Ireland-Claisen rearrangement.

The possibility that the allylic acetate could undergo a Claisen-type rearrangement197 under basic conditions has been explored in order to introduce the carbon substituent at C16 in the strychnine skeleton. For this purpose, the allylic acetate 343 was treated with LDA in THF at - 78°C for 30 min. We observed that the starting allylic acetate was consumed, but the desired product 374 did not formed under these conditions. Surprisingly, the allylic alcohol 375 was recovered instead in 48% isolated yield (Scheme 127).

Scheme 127. The Ireland-Claisen rearrangement.

The same product 375 was formed in 85% yield through saponification of the acetate group 130 using 3 equiv. of K2CO3 in a 2:1 mixture of MeOH/H2O. Other groups have also observed that this rearrangement caused problems on polycyclic acetates under basic conditions. The locked conformation of the 6-membered ring is suspected to prevent the required orbital alignment between the enolate and the alkene framework.

197 Ireland , R. E.; Mueller, R. H. J. Am. Chem. Soc, 1972, 94, 5897-5898.

121 V.2.1.e. Intramolecular displacement.

Based on the previous failures, we then tried to introduce an on the indole nitrogen in order to form the G ring through an intramolecular SN2' type cyclization.

Scheme 128. Synthesis of bromo-acryloyl carboxylate 376.

Deprotection of the SES group of 360 followed by acylation with 3-bromoacryloyl chloride198 in the presence of triethylamine gave 376 in 40% overall yield (Scheme 128).

With bromoacryloyl acetate 376 in hand, we thus tried to elaborate the strychnine G-ring. Interestingly, Mori used the Heck reaction to build the G-ring from a similar compound, lacking the acetate group47. It has been shown that β-aceto-elimination is possible199. Unfortunately, application of the same conditions on 376 did not lead to the expected product, but to several non identified compounds and degradation products (Scheme 129).

198 Ge, C. S.; Hourcade, S.; Ferdenzi, A.; Chiaroni, A.; Mons, S.; Delpech, B.; Marazano, C. Eur. J. Org. Chem. 2006, 4106-4114. 199 Pan, D.; Jiao, N. Synlett. 2010, 11, 1577-1588.

122

Scheme 129. Attempts toward the construction of the G-ring of strychnine.

200 We then turned our attention to SN2' type reactions using cuprates or zincates. For instance, metalation of 376 with MgCl2 and addition of CuCN as a catalyst (Scheme 129) did not afford the pentacyclic compound 38. Only the starting material was recovered unchanged, indicating that the intermediate Grignard reagent was not formed. We also tried to investigate the reaction of allylic acetate compound 376 with n-BuZnBr.LiBr201, prepared from n-BuLi and

ZnBr2 to afford the pentacyclic compound 38. Again, this reaction did not produce the desired product, but only degradation was observed.

In conclusion, all of our attempts to construct the G-ring did not provide the expected product. In most cases, degradation was observed.

V.2.1.f. Xanthate formation.

We then turned our attention to the useful xanthate chemistry, in order to construct the G-ring through a radical cyclization, which would give intermediate 38 already described by Mori50. First, the OAc group in 360 was removed by saponification. The resulting allylic alcohol was then converted to the xanthate compound 378 in 83% isolated yield. The propiolic acid was

200 Kobayashi, Y.; Nakata, K.; Ainai. T. Org. Lett. 2005, 7, 183-186. 201 Nakata, K.; Kiyotsuka, Y.; Kitazume, T.; Kobayashi, Y. Org. Lett. 2008, 10, 1345-1348.

123 chosen for the acylation step, as it is the direct precursor of 38. Coupling with the resulting xanthate amine was then achieved under the Sheedan conditions182. Although the coupling was effective, the purification of 379 proved to be much more difficult. Indeed, the purification on silica gel resulted in product degradation and partial deprotection of the (Scheme 130).

Scheme 130. Xanthate formation and prospective radical cyclization.

It was difficult at this stage to consider the end of the synthesis of the pentacyclic compound 38, through the use of fragile intermediate 379.

V.2.2. Ring C and G cyclizations.

The allylic acetate being quite impossible to functionalize, we decided to move one step backward. The diene obtained after the first oxidative amination could also be a template for a double cyclization to build rings C and G (Scheme 131).

Scheme 131. Ring C and G cyclizations.

124 The generation of an anion or a radical on the nitrogen should allow this cascade reaction. For this purpose, the nitrile group in 351 was reduced and the resulting amine protected by treatment with p-TsCl in pyridine as a solvent to afford the sulfonyl amide 380 in 74% overall yield (Scheme 132).

Scheme 132. Synthesis of sulfonyl amide 380.

The removal of the SES protecting group was found problematic at this stage, probably due to the acidic NH of the tosylamine (Scheme 133). The best result was obtained by using TBAF (6 equiv.) in 1,3-dimethyltetrahydropyrimidin-2(1H)-one (DMPU) as a solvent at room temperature. The tosyl amine compound 382 is then formed in 73% isolated yield as a single product.

Scheme 133. Deprotection of the SES group.

Surprisingly, product 381 was also formed when CsF was used to deprotect the SEM group. This intriguing tetracyclic skeleton could come from a 1,5-sigmatropic shift, followed by an enamine-imine isomerization, completed by the attack of the tosylamine on the imine. This

125 product has an interesting backbone that can be found in other alkaloids of the akuammiline family like minfiensine202 (Scheme 134).

Scheme 134. Tentative rationale for the formation of compound 381.

The coupling of the amine 382 with (Z)-3-(trimethylsilyl)acrylic acid203 has been achieved with EDC and HOBt (Scheme 135), and the desired coupling product was obtained in 57% yield.

Scheme 135. Peptide coupling of amine 382 with (Z)-3-(trimethylsilyl).

Then different conditions were tested to achieve the construction of the C and G rings of the Strychnine from 383 (scheme 135). Initially, the compound 383 was subjected to the PdII-catalyzed oxidative amination as mentioned above, it thus appeared that the tetracyclic compound 384 was formed in low

202 (a) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A.D. J. Am. Chem. Soc. 2008, 130, 5368- 5377. (b) Jones, S. B.; Simmons, B.; MacMillan, D. W.C. J. Am. Chem. Soc. 2009, 131, 13606-13607. (c) Shen, L.; Yi Wu, M. Z.; Qin, Y. Angew. Chem. Int. Ed. 2008, 47, 3618-3621. 203 (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 2547-2549. (b) Cunico, R.F.; Clayton, F. J. J. Org. Chem. 1976, 41, 1480-1482.

126 quantity (18% yield), along with degradation, but no trace of a pentacyclic product issued from a Heck reaction via the π-allyl palladium complex (scheme 136).

Scheme 136. Toward the construction of the C and G rings in Strychnine.

Submitting product 384 to Pd(0) to form again the π-allyl-Pd complex led either to starting material and/or degradation whatever the conditions. This approach is thus not suitable to access the G-ring.

V.2.3. Copper(II)-mediated aminooxygenation.

We then turned our attention to the conditions reported by Chemler et al170, 204, who recently reported a copper(II)-catalyzed amination, which is followed by the trapping of the radical intermediate by TEMPO (Scheme 137). TEMPO also is used for copper turnover [Cu(I) to Cu(II)].

Scheme 137. Putative mechanism of aminooxygenation and trapping of the radical intermediate by TEMPO.

204 Sherman, E. S.; Chemler, S. R. Adv. Synth. Catal. 2009, 351, 467-471.

127 The model compound 385 (prepared by reduction of the nitrile group of cyclohexadiene 236 then protection of the resulting amine by a SO2Et group) was reacted with Cu(OAc)2 (3 equiv.) in DMF (Scheme 138). 1,3-Diene 386 was obtained in reasonable yield showing that ring C could be elaborated efficiently through this method, without the need for expensive palladium catalysis.

Scheme 138. CopperII-mediated Aminocupration.

Formation of B and C rings looked more challenging with the synthesis of a cyclohexa-2,5- diene 387, having two orthogonally protected amino groups. The construction of B and C rings through oxidative amination of 387 using CuII-catalyzed conditions was then investigated. Oxyamination of 387 thus provided a monocyclized product with insertion of TEMPO in C16 position, but in moderate yield (Scheme 139). This result indicated that the reaction was stopped at this point (formation of the B-ring).

Scheme 139. Formation of B-ring by CuII-catalyzed.

Then, we tried to perform this reaction under a stream of oxygen, decreasing the quantity of TEMPO. Unfortunately, the reaction did not produce the desired product and only degradation was observed.

We turned our attention to copper(II) 2-ethylhexanoate, another source of copper, more soluble in DMF and thus more active. The diene 359 was subjected to the Cu(EH)2 as a source of copper, in the presence of TEMPO. Unfortunately, we observed the same result as that obtained with the diene 387 (Scheme 139). The formation of the C-ring appears more difficult

128 to form. For instance, the resulting TEMPO adduct 389 was subjected to the palladium oxidative amination conditions mentioned above to construct the C-ring. Surprisingly, only degradation was observed (Scheme 140).

Scheme 140. Aminocupration and Aminopalladation.

Because the aminooxygenation reaction of 359 using catalytic amounts of Cu(II) salts (Scheme 140) was stopped at the formation of B-ring, we turned our attention to the formation of the C-ring. We thus started with a model compound 390, in which the B-ring had already been obtained by the palladium oxidative amination. Thus, the diene 390 was treated by

Cu(EH)2 as a source of copper, in DMF at 150°C. Although the construction of C-ring is effective, as shown by 1H NMR of the crude reaction mixture, the purification of the product proved to be very difficult, the purification on silica gel resulting in product degradation (Scheme 141).

Scheme 141. CuII-catalyzed construction of the C-ring.

To avoid any degradation during purification, the crude TEMPO adduct 391 was treated by zinc in hot methanol in the presence of ammonium chloride. Unfortunately, only degradation was observed.

As the product 391 is formed, the formation of the C- ring is thus possible. Hence, we thought to use this condition in a double ring C/ring G cyclization.

129 Running such a reaction on our diene 383 would produce an allylic radical that could add onto the enamide to form the G ring along with the C ring. For this purpose, triene 383 was then submitted to copper(II)ethylhexanoate and TEMPO but none of the expected pentacyclic product was formed. Once again only degradation was observed (Scheme 142).

Scheme 142. Construction of C and G rings.

V.2.4. Hydroamination reaction.

The last approach consisted in an attack of a lithium amide onto the diene that would generate an allylic anion able to add in a 1,4-fashion onto the enamide. The removal of a on an amine mediated by Li in NH3 was expected to provide a lithium amide that would then react with the diene system. Such an hydroamination has already been documented in alkaloid synthesis205. Unfortunately, the reduction of the tosyl group on 383 by lithium in ammonia produced only degradation products and none of the cyclized products could be detected from the reaction mixture (Scheme 143).

Scheme 143. Reduction of the tosyl group on 383.

205 (a) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688-9689. (b) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449-455.

130 VI. Conclusion.

In chapter II we have described the desymmetrization of cyclohexadienes by double Michael addition reactions. This work was followed by a description of the desymmetrization of cyclohexadienes by the oxidative amination reaction catalyzed by metals (Pd, Cu). The B, C and D rings of the Aspidosperma and Strychnos alkaloids have been formed in one pot operation by the palladium oxidative amination reaction. The tetracyclic core for the synthesis of Mossambine alkaloid has been synthesized and we have reached the N-methoxycarbonyl enamine 370 in 10 steps and with 2% overall yield from commercially available 2- aminobiphenyl 181. Photoisomerization and hydrolysis of the OAc group remain to be done to complete the synthesis of Mossambine (Scheme 114). On the other hand, we have described different approaches toward the synthesis of Strychnine. These different approaches were accomplished using precursors 343, 360 and 383 developed in our laboratory. But all the attempts failed. These reactions did not produce the expected product. We have observed that the oxidative amination was possible using the CuII-catalyzed reaction. However, the formation of the C-ring appeared very difficult to realize under our conditions. With the high temperature (150°C) we observed the formation of the tetracyclic compound with insertion of TEMPO at C16, but the purification of the product proved quite difficult. However, these conditions are of interest as they allow the cyclization to be performed without the need for palladium catalysis.

Several Heck-type reactions have been attempted but with little success. However Heck reaction on vinyl bromide 376 certainly deserves more attention as β-aceto-elimination is possible although only few examples have been described in the literature. The lack of time and little quantity of material did not allow us to perform several attempts. This would provide a pentacyclic intermediate 38, already prepared by Mori that directly leads to strychnine in a few steps. The success of this cyclization is crucial as it would provide us with the shortest total synthesis of strychnine.

131

General conclusion and perspectives

In the course of this PhD thesis, we have first extended the scope of the Birch reductive alkylation of biaryls. This reaction had found little interest before we started our investigations. In that context, we have described the use of various electrophiles in order to understand the mechanism of the alkylation step. From the results obtained using radical clocks, we were able to propose two mechanisms for this alkylation step depending on the nature of the alkylating agents. The most likely mechanism is a SN2 mechanism for primary alkylating agents and an electron transfer mechanism must also be considered for bulkier alkylating agents such as tertiary halides.

During the second part of our project, cyclohexa-2,5-dienes obtained through the Birch reductive alkylation have been successfully desymmetrized leading to a unified approach to several alkaloids.

On one hand, we have completed the desymmetrization methodology based on a double Michael addition reaction. This work led to an efficient approach to the tetracyclic core of Aspidosperma and Strychnos alkaloids. It is important noticing that during this reaction, three stereogenic centers were created and only one diastereoisomer was obtained during this transformation. This methology, based on an efficient cascade led to a valuable racemic substrate 130, known as the Büchi ketone, a key-intermediate in the synthesis of Aspidosperma and Strychnos alkaloids. 130 was prepared in only six steps and 17% overall yield from commercially available 2-aminobiphenyl 181 (Scheme 144).

Scheme 144. Synthesis of Büchi ketone.

Various attempts to perform an enantioselective version of this double Michael addition reaction by chiral amines or Lewis acids were unsuccessful. In most cases, while yields were

133 generally good, enantioselectivity level remained very low. Interestingly, a recent report by You et al this year described a rather efficient enantioselective oxo-Michael process on cyclohexadienones, structurally close to those described in this manuscript.206

On the other hand, we developed the desymmetrization of cyclohexadiene by oxidative- amination catalyzed by palladium or copper. The B, C and D rings of the Aspidosperma alkaloids were formed in a single-pot operation by PdII-catalyzed oxidative amination. Using this method, the tetracyclic core of mossambine alkaloid has been synthesized. We have reached the N-methoxycarbonyl enamine 370 in 10 steps and 2% overall yield from commercially available 2-aminobiphenyl 181. One of the most promising perspectives for this synthesis would be the photoisomerization and hydrolysis of the OAc group which should allow the completion of the synthesis of mossambine (Scheme 145).

Scheme 145. Achievements and perspectives towards the synthesis of Mossambine.

In parallel, and using again the PdII-oxidative amination process, we have described three different approaches towards the synthesis of strychnine from precursors 336, 353 and 377. Unfortunately, all attempts to complete the total synthesis have, so far, been unsuccessful. Therefore, the synthesis of natural alkaloids such as Strychnine would require further studies, Heck reaction starting from an advanced intermediate bearing a vinyl bromide being one of the possible pathways that should be investigated further.

206 Gu, Q. ; Rong, Z.-Q. ; Zheng, C. ; You, S.-L. J. Am. Chem. Soc. 2010, 132, 4056-4057.

134 We have also observed that oxidative amination could also be performed using a CuII catalyst. The B-ring was easily formed using this method, but the formation of the C-ring was found to be more difficult. At the high temperature (150°C), we observed the tetracyclic compound with insertion of TEMPO at C16 position, but isolation of this advanced intermediate was problematic. To date, the synthesis of Aspidosperma and Strychnos type of alkaloids by our method has not been totally successful, but our investigations on the mechanism of the alkylation during Birch reductive alkylation of biaryls and the studies on desymmetrization processes (Michael addition and oxidative amination) have opened the way for a straightforward construction of complex monoterpenoid indole alkaloids, an objective that will be pursued in the group.

135

Experimental part

137 Notation

: Chemical shift in ppm approx: approximately calcd. : calculated d: doublet EI: electronic impact ESI: electrospray ionization g: gram Hz: Hertz HRMS: High resolution mass spectroscopy IR: infrared J: coupling constant in hertz m: multiplet mg: milligram MHz: mega hertz mL: milliliter mmol: millimole Mp: MS: mass spectroscopy NMR: Nuclear Magnetic Resonance ppm: part per million q: quadruplet s: singlet SIMS: Secondary Ion Mass Spectrometry t: triplet RT: retention time

General remarks All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous conditions. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials. Commercial reagents were used without purification, unless otherwise stated. Macherey Nagel silica gel 60M (230-400 mesh ASTM) was used for flash chromatography. In some cases, silica gel was preliminary deactivated by mixing with 5% (v/v) of triethylamine. CH2Cl2 and (i-Pr)2NH were distilled under CaH2. THF and Et2O were distilled from sodium and benzophenone. Toluene was distilled from sodium. was distilled over calcium sulfate. Ethanol and methanol was dried over magnesium turnings activated by iodine. In some cases, THF, Et2O, CH2Cl2, MeOH, and toluene were dried on a MB SPS-800. For Birch reductions, lithium wire (3.2 mm diameter, 0.01% sodium) was cut into small pieces and hammered before use. NH3 gas was dried by passing through potassium hydroxide pellets. 1H NMR and 13C NMR were recorded on Brüker DPX-200 FT (1H: 200 MHz, 13C: 50.2 MHz), Brüker AC-250FT (1H: 250 MHz, 13C: 62.9 MHz), Brüker Avance- 300FT (1H: 300 MHz, 13C: 75.5 MHz) and Brüker DPX-400FT (1H: 400 MHz, 13C: 100.2 MHz) apparatus using CDCl3 as internal reference unless otherwise indicated. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz respectively. Mass spectra were recorded on a Nermag R10-10 C. High resolution mass spectra were recorded on a FT- IRC mass spectrometer Brüker 4.7T BioApex II. InfraRed (IR) spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR spectrophotometer. Melting points were not corrected and determined by using a Büchi-Totolli apparatus and Stuart Scientific apparatus (SMP3).

138 I. Experimental part for chapter II

Only are reported the products I have done. For the others products in the synthesis of arylcyclohexa-2,5-dienes, see: Lebeuf, R.; Dunet, J.; Beniazza, R.; Ibrahim, D.; Bose, G.; Berlande, M.; Robert, F.; Landais, Y. J. Org. Chem. 2009, 74, 6469-6478.

N-(Biphenyl-2-yl) ethanesulfonamide (170)

To a solution of 2-aminobiphenyl 181 (8.0 g, 47 mmol, 1 eq) in dry CH2Cl2 (50 mL) were added pyridine (7.7 mL, 94 mmol, 2 eq) and EtSO2Cl (5.4 mL, 56 mmol, 1.2 eq) at room temperature under nitrogen. The stirring was continued for 12 h at the same temperature. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate 95:5) to provide 170 (12.208 g, 46.7 mmol, 99%) as a white solid. Mp = 82.2-82.9°C.

Rf = 0.51 (Petroleum Ether/EtOAc: 80/20). IR (solid, KBr):  = 3250, 1482, 1401, 1337, 1155, 909, 754, 699 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.68-7.65 (m, 1H, aromatic CH), 7.50-7.33 (m, 6H, 6 aromatic CH), 7.24-7.11 (m, 2H, 2 aromatic CH), 6.56 (broad s, 1H, NH), 2.98 (q, 2H, J =

7.1 Hz, CH2, SO2Et), 1.12 (t, 3H, J = 7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 137.4 (aromatic C), 133.9 (saromatic C), 133.2 (aromatic C), 130.6 (aromatic CH), 129.3 (2 aromatic CH), 128.9 (2 aromatic CH), 128.8

(aromatic CH), 128.3 (aromatic CH), 124.6 (aromatic CH), 120.0 (aromatic CH), 46.2 (CH2,

SO2Et), 7.8 (CH3, SO2Et). MS (ESI) m/z (%): 284 [M+Na]+ (100), 262 [M+H]+ (36). + HRMS (ESI): [M+Na] C14H15NO2NaS: calcd. 284.0721, found 284.0708.

2-Trimethylsilanyl-ethanesulfonic acid biphenyl-2-ylamide (171)

To a solution of 2-aminobiphenyl 181 (2 g, 11.83 mmol, 1 eq) in dry CH2Cl2 (50 mL) were added pyridine (3.84 mL, 47.32 mmol, 4 eq) and 2-Trimethylsilanyl-ethanesulfonyl chloride

139 (5 mL, 26.03 mmol, 2.2 eq) at room temperature under nitrogen. The stirring was continued for 12 h at the same temperature. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (Pentane/ethyl acetate 98:2) to provide 171 (3.879 g, 11.63 mmol, 98%) as a yellow oil.

Rf = 0.2 (Petroleum Ether/EtOAc: 95/5). IR (film, NaCl):  = 3357, 2952, 1581, 1481, 1396, 1250, 1147, 841, 754, 567 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.73-7.71 (m, 1H, aromatic CH), 7.56-7.49 (m, 3H, 3 aromatic CH), 7.43-7.38 (m, 3H, 3 aromatic CH), 7.32-7.26 (m, 2H, 2 aromatic CH), 5.57

(broad s, 1H, NH), 2.94-2.88 (m, 2H, CH2, SES), 0.82-0.75 (m, 2H, CH2, SES), 0.0003 (s, 9H,

SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 139.7 (aromatic C), 136.2 (aromatic C), 135.1 (aromatic C), 132.8 (aromatic CH), 131.6 (2 aromatic CH), 131.1 (2 aromatic CH), 130.5

(aromatic CH), 126.8 (saromatic CH), 122.2 (2 aromatic CH), 50.2 (CH2, SES), 12.2 (CH2,

SES), -0.001 (3CH3, SiMe3). MS (ESI) m/z (%): 356 [M+Na]+ (100). + HRMS (ESI): [M+Na] C17H23NO2NaSiS: calcd. 356.1111, found 356.1112.

Ethanesulfonic acid (3-methoxy-biphenyl-2-yl)-amide (176)

To a solution of 3-methoxy-biphenyl-2-ylamine (0.332 g, 1.667 mmol, 1 eq), pyridine (0.264 g, 3.334 mmol, 2 eq), catalyitic amount of DMAP in CH2Cl2 (5 mL), Ethanesulfonyl chloride (0.235 g, 1.833 mmol, 1.1 eq) was added. Stirring was continued for 12h at the room temperature. The reaction was stopped by addition of water (50 mL) and extracted with

EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified through silica gel chromatography (petroleum ether/ethyl acetate 90:10) to provide 176 (360 mg, 1.236 mmol, 74%) as a white solid. Mp = 90.7 – 91.2 °C.

Rf = 0.17 (Petroleum Ether/EtOAc: 80/20). IR (solid, KBr):  = 3262, 1572, 1472, 1323, 1262, 1140, 1117, 909, 760 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.39-7.27 (m, 3H, 3 aromatic CH), 7.22-7.17 (m, 2H, 2 aromatic CH), 6.88-6.85 (m, 2H, 2 aromatic CH), 5.81 (broad s, 1H, NH), 3.83 (s, 3H,

OMe), 2.46 (q, 2H, J = 7.5 Hz, CH2, SO2Et), 1.12 (t, 3H, J = 7.1 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 154.8 (C=O, OMe), 140.1 (aromatic C), 139.1 (aromatic C), 129.8 (2 aromatic CH), 128.4 (2 aromatic CH), 127.7 (aromatic CH), 126.5

140 (aromatic CH), 123.4 (aromatic C), 123.1 (aromatic CH), 110.5 (aromatic CH), 56.1 (CH3,

OMe), 48.4 (CH2, SO2Et), 8.3 (CH3, SO2Et). + + MS (ESI) m/z (%):314 [M+Na] (62), 199 [(M+H)-SO2Et] (100) + HRMS (ESI): [M+Na] C15H17NO3NaS: calcd. 314.0821, found 314.0808.

(6-Methoxy-biphenyl-2-yl)-carbamic acid tert-butyl ester (178)

In a 25 mL two-necked flask equipped with a condenser were introduced product 184 (300 mg, 0.86 mmol, 1 eq), Phenyl boronic acid (126 mg, 1.032 mmol, 1.2 eq) and a 2M aqueous solution of Na2CO3 (1 mL) in DME (6 mL). Dioxygene was extruded by three freeze-pump- thaw cycles. Palladium (tetrakistriphenylphosphine) (50 mg, 0.043 mmol, 0.05 eq) was added under nitrogen. The mixture was warmed to 90 °C for 14 h. The reaction mixture was filtered over celite. The solution was extracted with ethyl acetate, dried over Na2SO4, and evaporated under vacuum. The residue was purified through silica gel chromatography (petroleum ether/ethyl acetate 95:5) to to provide 178 (218 mg, 0.729 mmol, 85%) as a white solid. Mp = 98.7 – 101.4 °C.

Rf = 0.75 (Petroleum Ether/EtOAc: 80/20). IR (solid, KBr):  = 1733, 1591, 1522, 1494, 1472, 1434, 1258, 1156, 1047 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.73-7.71 (m, 1H, aromatic CH), 7.42-7.38 (m, 2H, 2 aromatic CH), 7.34-7.31 (m, 1H, aromatic CH), 7.24-7.15 (m, 3H, 3 aromatic CH), 6.61- 6.58 (m, 1H, aromatic CH), 6.14 (broad s, 1H, NH), 3.60 (s, 3H, OMe), 1.34 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 156.8 (C=O, OMe), 152.6 (C=O, Boc), 136.8 (aromatic C), 133.6 (aromatic C), 130.5 (2 aromatic CH), 128.8 (2 aromatic CH), 128.7 (aromatic CH), 127.7 (aromatic CH), 119.8 (aromatic C), 111.7 (aromatic CH), 105.4

(aromatic CH), 80.3 (Cq, Boc), 55.7 (CH3), 28.1 (3CH3, Boc). MS (ESI) m/z (%): 322 [M+Na]+ (100), 200 [(M+H)-Boc]+ (86). + HRMS (ESI): [M+Na] C18H21NO3Na: calcd. 322.1413, found 322.1398.

(2-Iodo-6-methoxy-phenyl)-carbamic acid tert-butyl ester (184)

A solution of (2-methoxy-phenyl)-carbamic acid tert-butyl ester 183 (2.179 g, 9.76 mmol, 1 eq) in dry Et2O (30 mL) under a nitrogen atmosphere was cooled to - 20°C and a solution of t- butyl lithium (1.2 M in pentane, 19.3 mL, 24.4 mmol, 2.5 eq) was added dropwise. The

141 solution was then stirred for 3 h at -10°C, after which time a pale yellow suspension was present. The reaction was quenched by the addition of 1,2-diiodoethane (8.25 g, 29.28 mmol,

3 eq) in Et2O (15 mL), followed by warming to room temperature over 2 h. The brown suspension was diluted with ether (100 mL), washed with 10% sodium thiosulphate solution, water, brine, and dried over sodium sulphate. The solvent was evaporated under vacuum. The residue was purified through silica gel chromatography (petroleum ether/ethyl acetate 80:20) to provide 184 (2.45 g, 7.019 mmol, 72%) as a white solid. Mp = 106.4 – 107.1°C.

Rf = 0.38 (Petroleum Ether/EtOAc: 80/20). IR (solid, KBr):  = 3311, 2976, 1703, 1583, 1489, 1366, 1249, 1163, 820, 771cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.37-7.34 (m, 1H, aromatic CH), 6.88-6.78 (m, 2H, 2 aromatic CH), 5.92 (broad s, 1H, NH), 3.74 (s, 3H, OMe), 1.43 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 155.3 (C=O, OMe), 153.4 (C=O, Boc), 130.7 (aromatic CH), 128.9 (aromatic CH), 128.5 (aromatic C), 111.4 (aromatic CH), 100.3

(aromatic C), 80.4 (Cq, Boc), 55.9 (sCH3), 28.3 (3CH3, Boc). MS (ESI) m/z (%): 372 [M+Na]+ (17), 250 [(M+H)-Boc]+ (100) + HRMS (ESI): [M+Na] C12H16NO3NaI: calcd. 372.0067, found 372.0054.

(3-Methoxy-biphenyl-2-yl)-carbamic acid tert-butyl ester (185)

In a 25 mL two-necked flask equipped with a condenser were introduced product 184 (100 mg, 0.286 mmol, 1 eq), Phenyl boronic acid (42 mg, 343 mmol, 1.2 eq) and a 2M aqueous solution of Na2CO3 (0.5 mL) in DME (4 mL). Dioxygene was extruded by three freeze-pump- thaw cycles. Palladium (tetrakistriphenylphosphine) (16.5 mg, 0.0143 mmol, 0.05 eq) was added under nitrogen. The mixture was warmed to 90 °C for 14 h. The reaction mixture was filtered over celite. The solution was extracted with ethyl acetate, dried over Na2SO4, and evaporated under vacuum. The residue was purified through silica gel chromatography (petroleum ether/ethyl acetate 95:5) to to provide 185 (76 mg, 0.254 mmol, 89%) as a white solid. Mp = 80.4 – 81.6°C.

Rf = 0.41 (Petroleum Ether/EtOAc: 80/20). IR (solid, KBr):  = 3582, 2837, 1709, 1586, 1498, 1366, 1254, 1164, 1050, 798 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.38-7.23 (m, 1H, aromatic CH), 7.23-7.18 (m, 2H, 2 aromatic CH), 7.16-7.13 (m, 2H, 2 aromatic CH), 6.89-6.80 (m, 2H, 2 aromatic CH), 5.82 (broad s, 1H, NH), 3.79 (s, 3H, OMe), 1.19 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 154.5 (s, C=O, OMe), 153.7 (C=O, Boc), 140.1 (aromatic C), 128.6 (2 aromatic CH), 128.1 (2 aromatic CH), 126.9 (aromatic CH), 123.5

142 (aromatic C), 122.5 (aromatic CH), 110.1 (aromatic CH), 79. (Cq, Boc), 55.8 (CH3), 28.1

(3CH3, Boc). MS (ESI) m/z (%): 322 [M+Na]+ (22), 200 [(M+H)-Boc]+ (100) + HRMS (ESI): [M+Na] C18H21NO3Na: calcd. 322.1413, found 322.1419.

General procedure for Birch reductive alkylation: In an oven dried three-necked round bottom flask equipped with a dry-ice condenser was introduced, under nitrogen, the biarylic precursor (1 eq) in THF (0.03 M). In case the starting material is a phenol or a biaryl with an amino substituent, n-BuLi (2.5-2 M solu. in , 1.1 eq) was added dropwise at -20°C and the solution was stirred for 15 min. The flask was then cooled to -78°C and ammonia (0.07 M) was condensed. Lithium wire (2.5 eq) was added. The media turned rapidly brown and finally brick red. The solution was stirred either at -78 °C for 30 minutes in case of "activated" biaryls (e.g. containing a 3,5-dimethoxyphenyl ring or amino substituent) or stirred at -33°C (refluxing NH3) for 1h for biphenyl. The red mixture was then cooled to -78°C and electrophile (3 eq) in THF (3M) was added in one portion. The mixture turned immediately brown. After 10 min., ammonia was let to evaporate and a half-saturated aqueous ammonium chloride solution was added. After extraction with

EtOAc or Et2O, the reaction media was washed with brine, dried over Na2SO4 and the organic solvents were concentrated under vacuum to provide a brown or yellow paste. The crude product was then submitted to silica gel flash chromatography (Petroleum ether/EtOAc mixtures).

N-(2-(1-(cyanomethyl)cyclohexa-2,5-dienyl)phenyl)ethanesulfonamide (174)

Synthesized according to the general procedure from N-(biphenyl-2-yl)ethanesulfonamide 170 (3 g, 11.48 mmol, 1 eq), THF (50 mL), n-BuLi (2.1M, 6.01 mL, 12.628 mmol, 1.1 eq), ammonia (approx 100 mL), lithium (201 mg, 28.7 mmol, 2.5 eq) and chloroacetonitrile (2.3 mL, 34.44 mmol, 3 eq) in THF (11 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 95/5 then 80/20) afforded 174 (1.902 g, 6.29 mmol, 55 %) as a yellow solid. Mp = 124.5-125.1°C. IR (solid, KBr):  = 2953, 1718, 1522, 1431, 1346, 1196, 975, 756, 661 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.60-7.49 (m, 1H, aromatic CH), 7.35-7.25 (m, 1H, aromatic CH), 7.18-7.12 (m, 3H, 3 aromatic CH), 6.31-6.18 (m, 2H, 2 vinylic CH), 5.70-5.58

(m, 2H, 2 vinylic CH), 3.13 (q, 2H, J = 7.5 Hz, CH2, SO2Et), 3.01-2.95 (m, 2H, CH2CN), 2.93

(s, 2H, bisallylic CH2), 1.31 (t, 3H, J = 7.1 Hz, CH3, SO2Et).

143 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 137.2 (aromatic C), 130.1 (aromatic C), 129.3 (aromatic CH), 128.8 (2 vinylic CH), 128.3 (2 vinylic CH), 125.3 ( aromatic CH), 124.2

(aromatic CH), 119.8 (aromatic CH), 117.0 (CN), 46.9 (CH2, SO2Et), 41.2 (vinylic C), 30.6

(CH2CN), 26.0 (bisallylic CH2), 8.1 (CH3, SO2Et). MS (ESI) m/z (%): 325 [M+Na]+ (100). + HRMS (ESI): [M+Na] C16H18N2O2NaS: calcd. 325.0987, found 325.0977 (8.5 ppm).

N-(2-(1-(cyanomethyl)cyclohexa-2,5-dienyl)phenyl)-2-(trimethylsilyl)ethanesulfonamide (175)

Synthesized according to the general procedure from product 171 (1.7 g, 5.10 mmol, 1 eq) in THF (40 mL). n-BuLi (2 M solution in hexane, 2.75 ml, 5.61 mmol, 1.1 eq), ammonia (approx 80 mL), lithium (89 mg, 12.75 mmol, 2.5 eq) and chloroacetonitrile (1.155 g, 15.30 mmol, 3 eq) in THF (10 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 90/10  80/20) afforded 175 (1.14 g, 3.04 mmol, 60%) as a yellow oil.

Rf = 0.46 (Petroleum Ether/EtOAc: 80/20). IR (film, NaCl):  = 3347, 2953, 1581, 1495, 1410, 1337, 1251, 1170, 842, 758 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.54 (d, 1H, J = 7.9 Hz, aromatic CH), 7.34-7.18 (m, 1H, aromatic CH), 7.17-7.13 (m, 2H, 2 aromatic CH), 6.25-6.22 (m, 2H, 2 vinylic CH), 5.64

(d, 2H, J = 7.9 Hz, 2 vinylic CH), 3.07-2.95 (m, 6H, 3CH2), 1.03-0.97 (m, 2H, CH2), 0.0004

(s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 139.4 (aromatic C), 132.1 (aromatic C), 131.2 (aromatic CH), 130.7 (2 vinylic CH), 130.3 (2 vinylic CH), 127.3 (aromatic CH), 126.1

(aromatic CH), 121.8 (aromatic CH), 118.9 (CN), 50.9 (CH2), 43.2 (aromatic C), 32.6

(CH2CN), 27.9 (bisallylic CH2), 12.2 (CH2), -0.06 (3CH3, SiMe3). MS (ESI) m/z (%): 397 [M+Na]+ (100). + HRMS (ESI): [M+Na] C19H26N2O2NaSSi: calcd. 397.1376, found 397.1373.

N-(6-(cyanomethyl)-2-methoxy-6-phenylcyclohexa-1,4-dienyl)ethanesulfonamide (177)

Synthesized according to the general procedure from product 176 (0.5 g, 1.71 mmol, 1 eq), THF (10 mL), n-BuLi (2M, 1.881 mmol, 1.1 eq), ammonia (approx 20 mL), lithium (29.8 mg,

144 4.27 mmol, 2.5 eq) and chloroacetonitrile (0.387 g, 5.13 mmol, 3 eq) in THF (10 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20) afforded 177 (343 mg, 1.0327 mmol, 60%) as a colorless oil.

Rf = 0.18 (Petroleum Ether/EtOAc: 70/30). IR (film, NaCl):  = 3263, 2941, 1687, 1494, 1316, 1238, 1135, 888, 763, cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.38-7.28 (m, 2H, 2 aromatic CH), 7.23-7.19 (m, 2H, 2 aromatic CH), 6.89-6.85 (m, 1H, aromatic CH), 5.94-5.88 (m, 1H, vinylic CH), 5.64-

5.61 (m, 1H, vinylic CH), 4.46 (s, 1H, NH), 3.62 (s, 3H, OMe), 3.27-3.10 (m, 2H, CH2,

CH2CN), 3-2.91 (m, 2H, bisallylic CH2), 2,48 (q, 2H, J = 4.5 Hz, CH2, SO2Et), 1.24 (t, 3H, J

=7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 149.9 (C=O, OMe), 141.1 (aromatic C), 130.8 (vinylic CH), 129.1 (2 aromatic CH), 127.8 (aromatic CH), 127.2 (2 aromatic CH), 122.5 (s, vinylic CH), 117.9 (s, CN), 112.8 (aromatic C), 55.1 (CH3, OMe), 48.4 (aromatic C), 48.3

(CH2, SO2Et), 27.1 (bisallylic CH2), 26.6 (CH2, CH2CN), 8.4 (CH3, SO2Et). + + MS (ESI) m/z (%) 355 [M+Na] (100), 200 [C13H13NO+H] (20). + HRMS (ESI): [M+Na] C17H20N2O3NaS: calcd. 355.1086, found 355.1082.

Tert-butyl 5-methoxy-6-phenylcyclohexa-1,4-dienylcarbamate (179)

Synthesized according to the general procedure from product 178 (629 g, 2.102 mmol, 1 eq), THF (10 mL), n-BuLi (2 M solution in hexane, 1.5 ml, 2.312 mmol, 1 eq), ammonia (approx 20 mL), lithium (4 mg, 5.255 mmol, 2.5 eq) and chloroacetonitrile (476 mg, 6.306 mmol, 3 eq) in THF (10 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20) afforded 179 (103 mg, 0.3419 mmol, 16 %) as a white solid M.p = 94.5 – 95.7 °C.

Rf = 0.46 (Petroleum Ether/EtOAc: 90/10). IR (solid, KBr):  = 3344, 2976, 1730, 1514, 1454, 1367, 1227, 1158, 956, 870, 755 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.23-7.16 (m, 5H, 5 aromatic CH), 6.11 (s, broad, 1H, NH ),, 5.25 (s, 1H, vinylic CH), 4.69-4.67 (m, 1H, vinylic CH), 3.81 (t, 1H, J = 6.03 Hz,

CH), 3.34 (s, 3H, OMe), 2.98-2.89 (m, 2H, bisallylic CH2), 1.31 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 152.8 (C=O, Boc), 152.1 (C=O, OMe), 140.1 (aromatic C), 130.4 (aromatic C), 127.5 (2 aromatic CH), 127.4 (aromatic CH), 126.2 (2 aromatic CH), 107.6 (vinylic CH), 89.9 (vinylic CH), 78.8 (Cq, Boc), 53.3 (CH3, OMe), 46.6

(aromatic CH), 27.2 (3CH3, Boc), 24.3 (bisallylic CH2). MS (ESI) m/z (%): 324 [M+Na]+ (100), 302 [M+H]+ (12). + HRMS (ESI): [M+Na] C18H23NO3Na: calcd. 324.1570, found 324.1562.

145 Tert-butyl 2-(1-(cyanomethyl)cyclohexa-2,5-dienyl)phenylcarbamate (180)

Synthesized according to the general procedure from product 178 (629 mg, 2.102 mmol, 1 eq), THF (10 mL), n-BuLi (2M, 1.5 ml, 2.312 mmol, 1.1 eq), ammonia (approx 20 mL), lithium (4 mg, 5.255 mmol, 2.5 eq) and chloroacetonitrile (476 mg, 6.306 mmol, 3 eq) in THF (10 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20) afforded 180 (73 mg, 0.2385 mmol, 11%) as a colorless oil.

Rf = 0.16 (Petroleum Ether/EtOAc: 90/10). IR (film, NaCl):  = 3411, 2976, 1727, 1583, 1449, 1392, 1233, 1158, 931, 753 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.30-7.19 (m, 4H, 4 aromatic CH), 7.04-7.02 (d, 1H, J= 4.4Hz, aromatic CH), 6.13-6.07 (m, 2H, 2 vinylic CH), 5.54-5.51 (m, 2H, 2 vinylic CH), 2.95-2.84 (m, 4H, 2CH2), 1.39 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 153.1 (C=O, Boc), 137.6 (aromatic C), 129.7 (aromatic C), 128.6 (aromatic CH), 128.4 (aromatic CH), 127.5 (2 vinylic CH), 126.9 (2 vinylic CH), 125.2 (aromatic CH), 124.1 (aromatic CH), 117.3 (CN), 80.1 (Cq), 41.2

(aromatic C), 28.3 (3CH3, Boc), 26.1 (bisallylic CH2). MS (ESI) m/z (%) 333 [M+Na]+ (100), 211 [M-Boc]+ (75). + HRMS (ESI): [M+Na] C19H22N2O2Na: calcd. 333.1573, found 333.1571.

(1-Allylcyclohexa-2,5-dienyl)benzene (206)

Synthesized according to the general procedure from biphenyl 148 (1 g, 6.5 mmol, 1 eq), THF (20 mL), ammonia (approx 40 mL), lithium (114 mg, 16.25 mmol, 2.5 eq) and Allyl bromide (2.36 g, 19.5 mmol, 3 eq) in THF (5 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate 98/2) afforded 206 (1.01 g, 5.15 mmol, 79%) as a colorless oil.

Rf = 0.9 (Petroleum Ether/EtOAc: 95/5). IR (film, NaCl):  = 3059, 2920, 2815, 1638, 1597, 1482, 996, 913, 738 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.40-7.20 (m, 5H, 5 aromatic CH), 5.88-5.83 (m, 2H, 2 vinylic CH), 5.76 (m, 1H, allylic CH), 5.73-5.66 (m, 2H, 2 vinylic CH), 5.10-5.02 (m,

2H, CH2), 2.68-2.61 (m, 2H, CH2). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 147.5 (aromatic C), 135.3 (allylic CH), 132.5 (2 vinylic CH), 128.3 (aromatic CH), 126.6 (aromatic CH), 125.9 (aromatic CH), 123.5 (2 vinylic CH), 116.9 (CH2), 44.8 (CH2), 43.7 (aromatic C), 26.1 (CH2).

146 MS (ESI) m/z (%): 303 [M+Ag]+ (23). + HRMS (ESI): [M+Ag] C15H16Ag: calcd. 303.0297, found 303.0308.

N,N-diethyl-2-(1-phenylcyclohexa-2,5-dienyl)acetamide (207)

Synthesized according to the general procedure from biphenyl 148 (1 g, 6.5 mmol, 1 eq), THF (20 mL), ammonia (approx 40 mL), lithium (114 mg, 16.25 mmol, 2.5 eq) and 2- chloro-N, Ndiethyl acetamide 97% (2.23 mL, 16.25 mmol, 2.5 eq) 2.5 eq) in THF (5 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate 80/20) afforded 207 (1.048 g, 3.89 mmol, 60%) as a brown oil.

Rf = 0.52 (Petroleum Ether/EtOAc: 70/30). IR (film, NaCl):  = 2973, 1644, 1446, 1427, 1379, 1221, 1096, 765, 731 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.38-7.27 (m, 4H, 4 aromatic CH), 7.19-7.16 (m, 1H, aromatic CH), 5.98-5.93 (m, 2H, 2 aromatic CH), 5.87-5.82 (m, 2H, 2 aromatic CH),

3.36 (q, 4H, J = 8.7 Hz, 2CH2), 2.89 (s, 2H, CH2), 2.68-2.65 (m, 2H, CH2), 1.17 (t, 3H, J =

8.4 Hz, CH3), 1.06 (t, 3H, J = 8.4 Hz, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 169.3 (C=O), 147.5 (aromatic C), 132.3 (2 aromatic CH), 128.4 (2 CH vinylic), 126.3 (2 aromatic CH), 125.9 (aromatic CH), 123,4 (2

CH, vinylic), 43,3 (CH2), 43,2 (aromatic C), 42.6 (CH2), 39.9 (CH2), 25.9 (CH2), 14,4 (CH3),

12.98 (CH3). + + MS (ESI) m/z (%):270 [M+H] (100), 292 [M+Na] (50). + HRMS (ESI): [M+H] C18H24NO: calcd. 270.1857, found 270.1859.

N-(2-(1-(2,2-Dimethoxyethyl)cyclohexa-2,5-dienyl)phenyl)ethanesulfonamide (209)

Synthesized according to the general procedure from N-(biphenyl-2-yl) ethanesulfonamide 170 (3 g, 11.5 mmol, 1 eq), THF (60 mL), n-BuLi (6.02 mL, 12.65 mmol, 1.1 eq), ammonia (approximately 120 mL), lithium (200 mg, 28.7 mmol, 2.5 eq), 2-bromo-1,1-dimethoxyethane (5.83 mg, 34.5 mmol, 3 eq), and THF (15 mL). Purification by flash chromatography (silica gel, petroleum ether/EtOAc 90/10) afforded 209 (2.45 g, 6.980 mmol, 60%) as ayellow oil

Rf = 0.64 (Petroleum Ether/EtOAc: 80/20).

147 IR (film, NaCl):  = 2940, 1718, 1664, 1486, 1342, 1153, 996 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.58-7.56 (m, 1H, aromatic CH), 7.36- 7.33 (m, 1H, aromatic CH), 7.25-7.22 (m, 1H, aromatic CH), 7.11 7.08 (m, 1H, aromatic CH), 6.09-6.02 (m, 2H, 2 vinylic CH), 5.56-5.53 (m, 2H, 2vinylic CH), 4.43 (t, 1H, J = 4.5 Hz, CH(2OMe),

3.30 (s, 6H, 2OMe), 3.10 (q, 2H, J = 7.5Hz, CH2, SO2Et), 2.95-2.87 (m, 2H, bis allylic CH2),

2.23 (d, 2H, J = 4.1Hz, CH2), 1.29 (t, 3H, J = 7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 137.8 (aromatic C), 132.5 (aromatic C), 131.0 (2 vinylic CH), 128.5 (aromatic CH), 126.3 (aromatic CH), 125.3 (2 vinylic CH), 124.0

(aromatic CH), 119.3 (aromatic CH), 102.7 (CH(2OMe)), 53.1 (2CH3, 2OMe), 46.4 (aromatic

C), 43.6 (CH2, SO2Et), 41.1 (CH2), 25.7 (bisallylic CH2), 8.1 (CH3, SO2Et). MS (ESI) m/z (%):374 [M+Na]+ (100). + HRMS (ESI): [M+Na] C18H25NO4NaS: calcd. 374.1402, found 374.1399.

N-(2-(1-allylcyclohexa-2,5-dienyl)phenyl)ethanesulfonamide (210)

Synthesized according to the general procedure from N-(biphenyl-2-yl)ethanesulfonamide 170 (1 g, 3.83 mmol, 1 eq), THF (20 mL), n-BuLi (2 M, 4.213 mmol, 1.1 eq), ammonia (approx 40 mL), lithium (67 mg, 9.6 mmol, 2.5 eq) and Allyl bromide (1.4 g, 11.5 mmol, 3 eq) in THF (10 mL). Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 90/10 then 80/20) afforded 210 (550 mg, 1.8144 mmol, 47 %) as a colorless oil.

Rf = 0.25 (Petroleum Ether/EtOAc: 90/10). IR (film, NaCl):  = 3341, 1714, 1580, 1493, 1335, 1285, 1147, 1113, 921, 713, 573 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.53-7.46 (m, 2H, 2 aromatic CH), 7.33 (d, 1H, J = 7.9 Hz, aromatic CH), 7.26-7.18 (m, 1H, aromatic CH), 7.05-7.02 (m, 1H, aromatic CH), 6.00-5.95 (m, 2H, 2 vinylic CH), 5.78-5.64 (m, 1H, allylic CH), 5.44 (d, 2H, J = 10.2 Hz, 2 vinylic CH), 5.05-5.00 (m, 2H, allylic CH2), 3.07 (q, 2H, J = 7.5 Hz, SO2Et), 2.87-2.70 (m,

2H, bisallylic CH2), 2.600 (d , 2H, J = 7.14 Hz, CH2), 1.25 (t, 3H, J = 7.5 Hz, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 137.7 (aromatic C), 133.6 (allylic CH), 132.8 (aromatic C), 130.8 (2 vinylic CH), 128.3 (aromatic CH), 127.1 (aromatic CH), 125.9 (2 vinylic CH), 123.7 (aromatic CH), 119.1 (aromatic CH), 118.2 (allylic CH2), 46.3 (CH2,

SO2Et), 44.1 (CH2), 42.4 (aromatic C), 25.8 (bisallylic CH2), 7.9 (CH3, SO2Et ). + + + MS (ESI) m/z (%): 211 [(M+H)-SO2Et] (18), 195 [(M+H)-NHSO2Et] (9), 326 [M+Na] (100). + HRMS (ESI): [M+Na] C17H21NO2NaS: calcd. 326.1187, found 326.1187.

148 (3-((1-Phenylcyclohexa-2,5-dienyl)methyl)cyclopropane-1,2-diyl)dibenzene (218)

Synthesized according to the general procedure from biphenyl 148 (0.4 g, 2.6 mmol, 1 eq), THF (10 mL), ammonia (approx 20 mL), lithium (40 mg, 5.72 mmol, 2.2 eq) and Trans-2,3- diphenyl-trans-1-bromomethylcyclopropane (1.56 g, 5.2 mmol, 2.1 eq) in THF (10 mL). Purification by silica gel chromatography (pentane 100%) afforded 218 (656 mg, 1.811 mmol, 70%) as a colorless oil.

Rf = 0.74 (Petroleum Ether/EtOAc: 90/10). IR (film, NaCl): = 1081, 1653, 1063, 871, 755, 692, 668, 616, 576, cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.36-7.18 (m, 15H, 15 aromatic CH), 5.91-5.64 (m,

4H, 4 vinylic CH), 2.68-2.60 5 (m, 1H, cyclopropane CH), 2.52-2.47 (m, 2H, CH2), 2.30 (t, 1H, J= 5.3Hz, cyclopropane CH), 2.16-2.11 (m, 1H, cyclopropane CH), 1.66-1.53 (m, 2H, bisallylic CH2). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 147.9 (aromatic C), 143.1 (aromatic C), 138.8 (aromatic C), 132.8 (aromatic, CH), 132.4 (aromatic, CH), 128.9 (aromatic CH), 128.5 (aromatic CH), 128.2 (2 vinylic CH), 128.2 (2 vinlyic CH), 128.1 (aromatic CH), 126.6 (aromatic CH), 126.1 (2 aromatic CH), 125.9 (2 aromatic CH), 125.9 (aromatic CH), 125.4 (2 aromatic CH), 123.7 (aromatic CH), 123.4 (aromatic CH), 44.4 (aromatic C), 39.3 (CH2), 31.6 (cyclopropane CH), 30.1 (cyclopropane CH), 26.7 (cyclopropane CH), 25.9 (bisallylic

CH2). MS (ESI) m/z (%)469 [M+Ag]+(2) + HRMS (ESI): [M+Ag] C28H26Ag: calcd. 469.1079, found 469.1080.

N-Methyl-2-(1-phenylcyclohexa-2,5-dienyl)acetamide (249)

To a solution of product 208 (1 g, 4.386 mmol, 1 eq) in dry toluene (40 mL) was added dimethylamine hydrochloride derived aluminum amide (0.941 g, 8.772 mmol, 13.65 mL, 2 eq). The solution was heated under nitrogen until no starting ester was observed by TLC (2- 12h). The reaction mixture was cooled to room temperature and was carefully quenched with 5% HCl. The organic layer was extracted three times with ethyl acetate. The organic extracted was combined, dried over MgSO4 and concentrated under vacuum. The crude product was

149 purified by silica gel chromatography (petroleum ether/ ethyl acetate, 50/50 then ethyl acetae, 100%) afforded 249 (0.757 g, 3.33 mmol 76% yield) as a white solid. Mp = 134.1-135.9°C.

Rf = 0.48 (EtOAc: 100%). IR (solid, KBr)  = 3342, 3029, 2812, 1639, 1557, 1446, 1367, 1272, 886 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.22-7.13 (m, 4H, 4 aromatic CH), 7.11-7.08 (m, 1H, aromatic CH), 5.84-5.78 (m, 2H, 2 vinylic CH), 5.72-5.67 (m, 2H, 2 vinylic CH), 5.45

(broad s, 1H, NH), 2.67 (s, 2H, bisallylic CH2), 2.59- 2.56 (m, 2H, CH2), 1.49 (s, 3H, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 171.1 (C=O), 146.6 (aromatic C), 131.4 (2 vinylic CH), 128.5 (2 aromatic CH), 126.4 (aromatic CH), 126.2 (2 aromatic CH), 124.4 (2 vinylic

CH), 47.9 (CH2), 42.5 (aromatic C), 26.3 (bisallylic CH2), 25.8 (CH3). MS (ESI) m/z (%): 250 [M+Na]+ (100). + HRMS (ESI): [M+Na] C15H17NONa: calcd. 250.1207, found. 250.1209.

N-Methyl-2-(4-oxo-1-phenylcyclohexa-2,5-dienyl)acetamide (250)

In 250 ml round bottom flask, equipped with a magnetic stirrer, was placed Pd/C (0.0365 g,

0.0103 mmol), CH2Cl2 (5 mL), tBuOOH (0.4 ml, 2.07 mmol), K2CO3 (1.0142 g, 0.103 mmol), and product 249 (0.1 g, 0.414 mmol) under N2. The mixture was stirred at 0 °C and monitored by TLC until starting material had been consumed (12h). The reaction mixture was then further stirred for 3 h at 23 °C and filtered through a short pad of silica gel washing with

CH2Cl2. the solvent evaporated in vacuo. The crude product was purified through column chromatography, (Silica gel, EtOAc 100%) to afford the desired product (83 mg, 0.343 mmol, 83% yield) as a yellow solid.

Rf = 0.33 (EtOAc: 100%). IR (solid, KBr)  = 3306, 1661, 1493, 1446, 1255, 1166, 857, 756 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.33-7.21 (m, 5H, 5 aromatic CH), 7.14 (d, 2H, J = 10.2 Hz, 2 vinylic CH), 6.29 (d, 2H, J = 10.2 Hz, 2 vinylic CH), 5.76 (broad s, 1H, NH), 2.91

(s, 2H, CH2), 2.65 (d, 3H, J = 4.9 Hz, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 185.9 (C=O), 169.1 (C=O), 153.1 (2 aromatic CH), 139.1 (aromatic C), 129.4 (2 vinylic CH), 128.4 (2 aromatic CH), 128.1 (aromatic CH), 126.4

(2 vinylic CH), 47.1 (aromatic C), 45.1 (CH2), 26.5 (CH3). MS (ESI) m/z (%): 242 [M+H]+ (75), 264 [M+Na]+ (100). + HRMS (ESI): [M+H] C15H16NO2: calcd. 242.1181, found. 242.1183.

150 N-(2-(1-(2-aminoethyl)cyclohexa-2,5-dienyl)phenyl)-2-(trimethylsilyl)ethanesulfonamide (252)

In a 100 ml two-necked round bottom flask, AlCl3 (1.54 g, 11.55 mmol, 3 eq) was dissolved in Et2O (25 mL) at 0°C, then LiAlH4 (0.58 g, 15.40 mmol, 4 eq) was added. The reaction mixture is stirred at room temperature for 30 min. Product 175 (1.440 g, 3.85 mmol, 1 eq) was dissolved in Et2O (15 mL) and THF (8 mL), and added dropwise at 0°C. The reaction mixture is stirred at room temperature for 18h then the reaction was stopped by addition of ice then NaOH 10% (40 mL) was added and the reaction mixture was stirred for 1h. Ether was added. The reaction mixture was filtered through celite and extracted with DCM. The combined organic layers were washed with brine, drying over sodium sulfate and concentrated under vacuum. Purification by silica gel chromatography (Silica gel deactivated CH2Cl2: MeOH 95:5) afforded 252 (577 mg, 1.5257 mmol, 40%) as a yellow oil.

Rf = 0.23 (CH2Cl2: MeOH 95:5). IR (film, NaCl):  = 3347, 2952, 1493, 1336, 1251, 1169, 1147, 889, 758 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.57-7.55 (m, 1H, aromatic CH), 7.45-7.35 (m, 1H, aromatic CH), 7.30-7.25 (m, 1H, aromatic CH), 7.15-7.09 (m, 1H, aromatic CH), 6.10 (d, 2H, J = 10.17 Hz, 2 vinylic CH), 5.54 (d, 2H, J = 10.17 Hz, 2 vinylic CH), 3.63 (broad s, 3H, NH and NH2), 3.07-3.01 (m, 2H, CH2), 2.94-2.88 (m, 2H, CH2), 2.86-2.78 (m, 2H, CH2), 2.19-

2.11 (m, 2H, CH2), 1.04-0.98 (m, 2H, CH2), -0.0006 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 137.5 (aromatic C), 132.5 (aromatic C), 130.3 (2 vinylic CH), 128.2 (aromatic CH), 126.1 (2 vinylic CH), 125.9 (aromatic CH), 123.6

(aromatic CH), 119.1 (aromatic CH), 48.3 (CH2), 41.9 (aromatic C), 41.6 (CH2), 37.5 (CH2),

25.6 (bisallylic CH2), 9.9 (CH2), -2.3 (3CH3, SiMe3). MS (ESI) m/z (%): 379 [M+H]+ (100). + HRMS (ESI): [M+H] C19H31N2O2SSi: calcd. 379.1870, found 379.1873.

N-(2-(1-(2-(2-(trimethylsilyl)ethylsulfonamido)phenyl)cyclohexa-2,5-dienyl)ethyl) acetamide (253)

Product 252 (671 mg, 1.78 mmol, 1 eq) was dissolved in dichloromethane (25mL). The triethylamine (0.27 g, 2.67 mmol, 1.5 eq) was added dropwise at 0°C followed by the acetic

151 anhydride (0.22 g, 2.136 mmol, 1.2 eq). The solution was stirred over night at r.t. NH4Cl saturated was added then the reaction mixture was extracted with dichloromethane. The organic layers were washed with brine then dried over Na2SO4. The solvent was evaporated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30 then EtOAc 100%) afforded 253 (366 mg, 0.870 mmol, 51% (2 step)) as a yellow oil.

Rf = 0.35 (Petroleum Ether/EtOAc: 80/20). IR (Film, NaCl):  = 3340, 2952, 1651, 1548, 1335, 1251, 1146, 842, 758 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.56-7.53 (m, 1H, aromatic CH), 7.41-7.36 (m, 2H, 2 aromatic CH), 7.30-7.24 (m, 1H, aromatic CH), 7.13-7.08 (m, 1H, aromatic CH), 6.12-6.09 (m, 2H, 2 vinylic CH), 5.98 (broad s, 1H, NH), 5.54-5.51 (m, 2H, 2 vinylic CH), 3.37-3.30

(m, 2H, CH2), 3.07-3.01 (m, 2H, CH2), 2.94-2.88 (m, 2H, CH2), 2.16-2.11 (m, 2H, CH2), 1.99

(s, 3H, CH3), 1.01-0.98 (m, 2H, CH2), 0.0001 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 172.3 (C=O), 139.8 (aromatic C), 134.6 (aromatic C), 132.4 (2 vinylic CH), 130.5 (aromatic CH), 128.6 (2 vinylic CH), 127.1 (aromatic CH),

125.9 (aromatic CH), 121.4 (aromatic CH), 50.6 (CH2), 43.8 (aromatic C), 40.9 (CH2), 37.9

(CH2), 27.9 (bisallylic CH2), 25.4 (CH3), 12.2 (CH2), 0.003 (3CH3, SiMe3). MS (ESI) m/z (%): 443 [M+Na]+ (100), 421 [M+H]+ (53) . + HRMS (ESI): [M+Na] C21H32N2O3NaSSi: calcd. 443.1795, found 443.1789.

N-(2-(4-(tert-butylperoxy)-1-(2-(2-(trimethylsilyl)ethylsulfonamido)phenyl)cyclohexa- 2,5-dienyl)ethyl)acetamide (254)

To a suspension of 3% Pd/C (0.0319 g, 0.009 mmol, 0.025 eq) in CH2Cl2 (3 mL) K2CO3 (0.0124 g, 0.09 mmol, 0.25 eq) and tert-butyl in decane (5M) (0.4 mL, 1.8 mmol, 5 eq) were added at 0°C. Product 253 (0.150 g, 0.36 mmol, 1 eq) was dissolved in

CH2Cl2 (2 mL) and then added to the reaction media. The mixture was stirred at 0°C during 8h and then at r.t overnight. The mixture was filtered through a pad of silica gel washing with

CH2Cl2 to remove the excess of tert-butyl hydroperoxide. Silica was then washed with ethyl acetate. The solvent was concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate 100%) afforded 254 (85 mg, 0.870 mmol, 47%) as a colorless oil.

Rf = 0.25 (EtOAc 100%). IR (Film, NaCl):  = 3354, 2953, 1658, 1548, 1453, 1336, 1251, 1195, 1146, 860 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.29-7.27 (m, 3H, 3 aromatic CH), 7.24-7.14 (m, 1H, aromatic CH), 7.12-7.09 (m, 1H, aromatic CH), 6.32-6.27 (m, 2H, 2 vinylic CH), 6.19 (broad s, 1H, NH), 5.91-5.88 (m, 2H, 2 vinylic CH), 5.12 (s, 1H, aromatic CH), 3.36 (q, 2H, J

= 6.4 Hz, CH2), 3.06-3.00 (m, 2H, CH2), 2.26 (t, 2H, J = 6.7 Hz, CH2), 1.93 (s, 3H, CH3),

1.28 (s, 9H, t-Bu), 1.01-0.98 (m, 2H, CH2), -0.0005 (s, 9H, SiMe3).

152 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 172.1 (C=O), 139.3 (aromatic C), 139.1 (2 vinylic CH), 133.2 (aromatic C), 130.8 (aromatic CH), 129.1 (aromatic CH), 127.8 (2 vinylic CH), 126.6 (aromatic CH), 122.1 (aromatic CH), 82.8 (aromatic C), 74.7 (CH, CHOOt-Bu), 51.2

(CH2), 45.6 (aromatic C), 39.1 (CH2), 37.9 (CH2), 28.5 (3CH3, OOt-Bu), 25.4 (CH3), 12.3

(CH2), 0.02 (3CH3, SiMe3). MS (ESI) m/z (%):531 [M+Na]+ (100), 419 [(M+H)-OOt-Bu]+ (53). + HRMS (ESI): [M+Na] C25H40N2O5NaSSi: calcd. 531.2324, found 531.2324.

N-(2-((4aS,9aS)-2-oxo-9-(2-(trimethylsilyl)ethylsulfonyl)-2,4a,9,9a-tetrahydro-1H- carbazol-4a-yl)ethyl)acetamide (255)

To a suspension of 3% Pd/C (319 mg, 0.009 mmol, 0.025 eq) in CH2Cl2 (3 mL) K2CO3 (124 mg, 0.09 mmol, 0.25 eq) and tert-butyl hydroperoxide in decane (5M) (0.4 mL, 1.8 mmol, 5 eq) were added at 0°C. Product 253 (150 g, 0.36 mmol, 1 eq) was dissolved in CH2Cl2 (2 mL) and then added to the reaction media. The mixture was stirred at 0°C during 8h and then at r.t overnight. The mixture was filtered through a pad of silica gel washing with CH2Cl2 to remove the excess of tert-butyl hydroperoxide. Silica was then washed with ethyl acetate; the solvent was concentrated under vacuum. Purification by silica gel chromatography (ethyl acetate 100%) afforded 255 (40 mg, 0.09 mmol, 25%) as a colorless oil.

Rf = 0.20 (EtOAc 100%). IR (film, NaCl):  = 3350, 2948, 1652, 1456, 1347, 1148, 860, 757 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.23-7.18 (m, 1H, aromatic CH), 7.17-7.06 (m, 2H, 2 aromatic CH), 7.04-7.01 (m, 1H, aromatic CH), 6.70 (d, 1H, J = 10.2 Hz, vinylic CH), 6.02 (d, 1H, J = 10.2 Hz, vinylic CH), 5.82 (broad s, 1H, NH), 4.75 (t, 1H, J = 5.2 Hz, aromatic

CH), 3.28-3.11 (m, 2H, CH2), 3.05-2.96 (m, 2H, CH2), 2.91-2.78 (m, 2H, CH2), 2.05-1.99

(m, 2H, CH2), 1.85 (s, 3H, CH3), 1.06-0.98 (m, 2H, CH2), 0.0002 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 195.8 (C=O), 170.1 (C=O), 148.2 (vinylic CH), 140.7 (aromatic C), 132.5 (aromatic C), 129.1 (aromatic CH), 127.6 (vinylic CH), 123.9 (aromatic CH), 123.4 (aromatic CH), 114.8 (aromatic CH), 64.6 (aromatic CH), 50.3

(aromatic C), 47.9 (CH2), 40.1 (CH2), 37.7 (CH2), 35.5 (CH2), 22.9 (CH3), 9.8 (CH2), -2.1

(3CH3, SiMe3). MS (ESI) m/z (%):457 [M+Na]+ (100), 435 [M+H]+ (22). + HRMS (ESI): [M+Na] C21H30N2O4NaSSi: calcd. 457.1587, found 457.1589.

153 (3aS,6aS,11a1R)-3-acetyl-7-(2-(trimethylsilyl)ethylsulfonyl)-2,3,3a,4,6a,7-hexahydro-1H- pyrrolo[2,3-d]carbazol-5(6H)-one (256)

To a suspension of 3% Pd/C (93 mg, 0.03 mmol, 0.025 eq) in CH2Cl2 (14 mL), K2CO3 (41 mg, 0.3 mmol, 0.25 eq) and tert-butyl hydroperoxide in decane (5M) (1.04 mL, 5.2 mmol, 5 eq) were added at 0°C. Product 254 (0.435 g, 1.04 mmol, 1 eq) was dissolved in CH2Cl2 (5 mL) and then added to the reaction media. The mixture was stirred for 8h at 0°C, and then at r.t overnight. DBU (0.31 mL, 2.08 mmol, 2 eq) was added and the mixture was heated for 20h at reflux. After cooling at r.t, the reaction mixture was filtered through a pad of silica gel and the residue was washed with CH2Cl2 to remove the excess of tert-butyl hydroperoxide. Silica was then washed with a mixture of AcOEt/methanol (96/4). The organic solvents were removed under vacuum. Purification by silica gel chromatography (ethyl acetate / methanol, 99/1) afforded 256 (270 mg, 0.6218 mmol, 60%) as a white solid. Mp = 230.1 – 231.8 °C.

Rf = 0.37 (EtOAc 100%). IR (solid, KBr) : = 3354, 2918, 1722, 1643, 1414, 1348, 1250, 1150, 843, 759 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.34-7.27 (m, 2H, 2 aromatic CH), 7.06-7.04 (m, 2H, 2 aromatic CH), 4.55-4.50 (m, 1H, CH), 4.46-4.42 (m, 1H, CH), 3.77-3.74 (m, 2H,

CH2), 3.05-2.94 (m, 2H, CH2), 2.60-2.51 (m, 2H, CH2), 2.43-2.39 (m, 2H, CH2), 2.36-2.26

(m, 2H, CH2), 2.13 (s, 3H, CH3), 1.19-0.97 (m, 2H, CH2), -0.0038 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 207.5 (C=O), 171.6 (C=O), 141.7 (s, aromatic C), 137.1 (aromatic C), 131.5 (aromatic CH), 126.4 (aromatic CH), 125.1 (aromatic CH), 116.6

(aromatic CH), 67.7 (aromatic CH), 61.1 (aromatic CH), 54.5 (aromatic C), 50.6 (CH2), 47.5

(CH2), 45.7 (CH2), 43.4 (CH2), 39.8 (CH2), 24.6 (CH3), 11.9 (CH2), -0,2 (3CH3, SiMe3). MS (ESI) m/z (%):457 [M+Na]+ (100), 435 [M+H]+ (21). + HRMS (ESI): [M+Na] C21H30N2O4NaSSi: calcd. 457.1587, found 457.1586.

(3aS,6aS,11a1S)-3-acetyl-2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazol-5(6H)-one (258)

To a solution of product 256 (151 mg, 0.35 mmol, 1 eq) in THF (4 mL) was added a 1 M solution of n-Bu4NF (TBAF) in THF (737 µL, 1.4 mmol, 4 eq). The resulting solution was

154 stirred for 15 min and then diluted with Et2O (18 mL). The organic layer was washed with water followed by saturated aqueous NaHCO3 (10 mL), dried, and concentrated in vacuo. Purification by silica gel chromatography (Dichlorimethane / methanol, 95/5) afforded 258 (63 mg, 0.2332 mmol, 67%) as a yellow solid. Mp = 62.3 – 64.1°C.

Rf = 0.43 (DCM/MeOH: 95:5). IR (solid, KBr): = 3354, 2924, 1716, 1635, 1486, 1417, 1362, 1261, 749 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.06-6.95 (m, 2H, 2 aromatic CH), 6.73-6.68 (m, 1H, aromatic CH), 6.59-6.56 (m, 1H, aromatic CH), 4.17-4.13 (m, 1H, CH), 4.04-4.02 (m,

1H, CH), 4.01-3.92 (s, broad 1H, NH), 3.73-3.61 (m, 2H, CH2), 2.86-2.77 (m, 2H, CH2),

2.65-2.52 (m, 2H, CH2), 2.50-2.38 (m, 2H, CH2), 2.04 (s, 3H, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 210.2 (C=O), 172.1 (C=O), 151.6 (aromatic C), 133.6 (aromatic C), 131.1 (aromatic CH), 125 (aromatic CH), 121.6 (aromatic CH), 112.1

(aromatic CH), 65.8 (aromatic CH), 64.5 (aromatic CH), 55.1 (aromatic C), 49.1 (CH2), 45.5

(CH2), 42.1 (CH2), 39.6 (CH2), 25.3 (CH3). MS (ESI) m/z (%): 293 [M+Na]+ (100), 271 [M+H]+ (10). + HRMS (ESI): [M+Na] C16H18N2O2Na: calcd. 293.1260, found 293.1258.

(3aR)-1-Methyl-3a-phenyl-3,3a-dihydro-1H-indole-2,6(7H,7aH)-dione (260)

In 25 ml round bottom flask, equipped with a magnetic stirrer, was added product 250 (100 mg, 0.422 mmol, 1 eq) in THF (5 mL), then DBU (1, 8-diazabicyclo (5.4.0) undec-7en 98%) (0.128 g, 0.844 mmol, 2 eq) was added to the solution. Stirring was continued for 12h. The reaction mixture was filtered through celite, and then washed with ethyl acetate. The solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate, 100%) afforded 260 (79 mg, 0.320 mmol, 76%) as a white solid. Mp = 129.3-130.6°C.

Rf = 0.50 (EtOAc: 100%). IR (solid, KBr)  = 2918, 1684, 1396, 1250, 961, 765, 702 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.38-7.28 (m, 5H, 5 aromatic CH), 6.68 -6.64 (m,

1H, vinylic CH), 6.19-6.16 (m, 1H, vinylic CH), 4.04 (s, 1H), 3.17 (d, 2H, J = 16.9 Hz, CH2),

2.75 (s, 3H, CH3) 2.66- 2.59 (m, 2H, CH2). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 194.9 (C=O), 171.6 (C=O), 150.4 (vinylic CH), 139.3 (aromatic C), 129.2 (vinylic CH), 128.9 (2 aromatic CH), 128.1 (aromatic CH), 126.5

(2 aromatic CH), 65.2 (aromatic CH), 45.9 (aromatic C), 43.9 (CH2), 36.3 (CH2), 27.1 (CH3). MS (ESI) m/z (%): 242 [M+H]+ (100). + HRMS (ESI): [M+H] C15H16NO2: calcd. 242.1181, found 242.1183.

155 (3aS,6aS,11a1S)-3-Acetyl-7-methyl-2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazol- 5(6H)-one (130)

To a mixture of product 258 (74 mg, 0.272 mmol, 1eq) and potassium carbonate (31 mg, 0.0272 mmol, 0.1 eq) in acetonitrile (3 mL) was added MeI (0.08 mL, 1.632 mmol, 6 eq) in one portion. The reaction mixture was stirred at reflux for 20h then diluted with dichloromethane (20 mL) and quenched by addition of water (20 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over MgSO4, evaporated under vacuum. Purification by silica gel chromatography (Dichloromethane / methanol, 50/1) afforded 130 (46 mg, 0.1618 mmol, 60%) as a white solid. Mp = 186.3 – 187.7 °C.

Rf = 0.52 (DCM/MeOH; 95:5). IR (solid, KBr):  = 2924, 1716, 1646, 1488, 1362, 1296, 1261, 1233, 1111, 756 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.14 (t, 1H, J = 7.9 Hz, aromatic CH), 6.99-6.97 (m, 1H, aromatic CH), 6.73 (t, 1H, J = 7.5 Hz, aromatic CH), 6.47-6.44 (m, 1H, aromatic CH),

4.10 (t, 1H, J = 4.1 Hz, CH), 3.78-3.64 (m, 1H, CH), 3.62-3.52 (m, 2H, CH2), 3.03-2.95 (m,

1H, CH), 2.70-2.69 (m, 1H, CH), 2.63 (s, 3H, CH3), 2.58-2.52 (m, 2H, CH2), 2.49-2.42 (m,

1H, CH), 2.09-2.07 (m, 1H, CH), 2.03 (s, 3H, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 208.1 (C=O), 170.1 (C=O), 152.1 (aromatic C), 131.3 (aromatic C), 129.4 (aromatic CH), 122.6 (aromatic CH), 119.1 (aromatic CH), 108.3

(aromatic CH), 71.1 (aromatic CH), 63.2 (aromatic CH), 52.4 (aromatic C), 47.3 (CH2), 39.9

(CH2), 39.3 (CH2), 37.8 (CH2), 33.3 (CH3), 23.4 (CH3). MS (ESI) m/z (%): 307 [M+Na]+ (100), 285 [M+H]+ (13). + HRMS (ESI): [M+Na] C17H20N2O2Na: calcd. 307.1416, found 307.1404.

156

II. Experimental part for chapter III

Dimethyl 2-(2-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a- yl)ethylamino)-2-oxoethyl)malonate (344)

Product 334 (100 mg, 0.328 mmol, 1 eq) was dissolved in CH2Cl2 (4 mL), then 2- methoxycarbonyl- 1-methyl ester (1.1 eq), EDAC (1.5 eq), HOBt (1.3 eq) were added to this mixture. Then the base (DIPEA, 0.16 ml, 3 eq) was added. The reaction mixture was stirred 30h at room temperature. Then the reaction was stopped by addition of NaHCO3 (10 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30) afforded 344 (70 mg, 0.1470 mmol, 45% over 2 steps) as a colorless oil.

Rf = 0.79 (EtOAc: 100%). IR (film, NaCl): = 2951, 1783, 1707, 1596, 1476, 1346, 1235, 1153, 757 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.41-7.02 (m, 5H, 5 aromatic CH), 6.03 (d, 1H, J = 3 Hz, vinylic CH), 5.94-5.89 (m, 1H, vinylic CH), 5.70-5.67 (m, 1H, vinylic CH), 5.05 (s, 1H,

CH), 3.96 (t, 1H, J = 3 Hz, NH), 3.75 (s, 6H, 2CO2Me), 3.28 (d, 1H, J = 3.4 Hz, CH), 3.20-

3.11 (m, 2H, CH2, SO2Et), 2.74-2.71 (m, 2H, CH2), 2.06-2.02 (m, 2H, CH2), 1.89-1.81 (m,

2H, CH2), 1.39 (t, 3H, J = 4.14 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 169.6 (C=O), 169.3 (2C=O, 2CO2Me), 140.7 (aromatic C), 136.8 (aromatic C), 130.2 (aromatic CH), 128.2 (2 vinylic CH), 124.7 ( aromatic CH), 124.1 (aromatic CH), 123.5 (vinylic CH), 121.3 (aromatic CH), 114.3 (vinylic

CH), 65.4 (CH), 52.9 (2CH3, 2CO2Me), 47.6 (CH, CHCO2Me), 46.7 (CH2, SO2Et), 45.9

(aromatic CH), 41.7 (CH2), 35.7 (CH2), 34.8 (CH2), 7.8 (CH3, SO2Et). MS (ESI) m/z (%):499 [M+Na]+ (100), 477 [M+H]+ (18). + HRMS (ESI): [M+Na] C23H28N2O7NaS: calcd. 499.1520, found 499.1520.

157 N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-3,4,5- trimethoxybenzamide. (345)

Product 334 (100 mg, 0.328 mmol, 1 eq) was dissolved in CH2Cl2 (4 mL), then 3,4- dimethoxy-benzoic acid, (1.1 eq), EDAC (1.5 eq), HOBt (1.3 eq) were added to this mixture. Then the base (DIPEA, 0.16 ml, 3 eq) was added. The reaction mixture is stirred for 30h at room temperature. Then the reaction was stopped by addition of NaHCO3 (10 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30 then 50/50) afforded 345 (75 mg, 0.15 mmol, 46% over 2 steps) as a white solid. M.p = 74.2-75.9 °C.

Rf = 0.86 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 2924, 1638, 1583, 1498, 1338, 1234, 1127, 697 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.32 (d, 1H, J = 7.9 Hz , aromatic CH), 7.07-7.04 (m, 2H, 2 aromatic CH), 6.96-6.87 (m, 3H, 3 aromatic CH), 6.27 (t, 1H, J = 3 Hz, NH), 5.97- 5.96 (m, 2H, 2 vinylic CH), 5.90- 5.84 (s, 1H, vinylic CH), 5.69 (d, 1H, J = 9.4 Hz, vinylic

CH), 5.09 (d, 1H, J = 3 Hz, CH), 3.81 (s, 9H, 3OMe), 3.49-3.35 (m, 2H, CH2), 3.12 (q, 2H, J

= 7.1 Hz, CH2, SO2Et), 2.11-1.95 (m, 2H, CH2), 1.33 (t, 3H, J=7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 167.2 (C=O), 153.1 (2C=O, 2OMe), 140.5 (aromatic CH), 136.8 (aromatic CH), 130.4 (C=O, OMe), 129.7 (2 vinylic CH), 128.1 (aromatic CH), 124.7 (aromatic CH), 123.8 (aromatic CH), 123.8 (aromatic CH), 123.5 (vinylic CH), 121.2 (aromatic CH), 114.2 (vinylic CH), 104.2 (2 aromatic CH), 65.3 (CH),

60.9 (CH3, OMe), 56.2 (2CH3, 2OMe), 46.7 (aromatic CH), 46.3 (CH2, SO2Et), 41.5 (CH2),

36.1 (CH2), 7.8 (CH3, SO2Et). MS (ESI) m/z (%):521 [M+Na]+ (100), 499 [M+H]+ (45). + HRMS (ESI): [M+Na] C26H30N2O6NaS: calcd. 521.1716, found 521.1721.

158 N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-2-(4- methylphenylsulfonamido)acetamide (346).

In a 25 ml two-necked round bottom flask, (toluene-4-sulfonylamino)-acetic acid, EDAC, HOBt were dissolved in DCM (8 mL) and stirred for 1h at 0°C. The crude amine 334 (250 mg, 0.822 mmol) was added to the reaction mixture and DIPEA (0.425 mL, 3 eq). The reaction mixture was stirred for 30h at room temperature. Then the reaction was stopped by addition of NaHCO3 (10 mL), extracted with DCM. The combined organic layers were washed with brine, drying over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20 then 50/50) afforded 346 (349 mg, 0.6774 mmol, 82 % over 2 steps) as a white solid. M.p = 143.4-144.1°C.

Rf = 0.48 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 2284, 1658, 1458, 1339, 1152, 763 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.92-7.89 (m, 2H, 2NH), 7.70 (d, 2H, J= 8.1 Hz, 2 aromatic CH, Ts), 7.39-7.32 (m, 4H, 4 aromatic CH), 7.24 (t, 1H, J= 6.8 Hz, aromatic CH), 7.11 (t, 1H, J= 14.8 Hz, aromatic CH), 6.06-6.01 (m, 1H, vinylic CH), 5.96-5.85 (m, 3H, 3 vinylic CH), 5.10 (d, 1H, J= 3.4 Hz, CH), 3.36 (d, 2H, J= 7.1 Hz, CH2), 3.24-3.12 (m, 2H,

CH2, SO2Et), 3.09-2.53 (m, 2H, CH2), 2.34 (s, 3H, Ts), 2.01-1.91 (m, 1H), 1.70-1.60 (m, 1H),

1.27 (t, 3H, J= 7.3 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 162.1 (C=O), 140.6 (aromatic C), 139.8 (aromatic CH, Ts), 138.7 (aromatic C), 136.6 (vinylic C), 134.4 (vinylic C), 133.9 (aromatic CH, Ts), 130.1 (aromatic CH), 129.7 (2 aromatic CH, Ts), 128.3 (vinylic C), 128.2 (2 aromatic CH, Ts), 124.8 (vinylic C), 124.1 (aromatic CH), 123.9 (aromatic CH), 123.6 (vinylic C), 121.5

(aromatic CH), 114.3 (vinylic C), 65.4 (CH), 46.7 (aromatic C), 46.3 (CH2, SO2Et), 41.2

(CH2), 36.1 (CH2), 7.9 (CH3, SO2Et). MS (ESI) m/z (%): 538 [M+Na]+ (100), 615 [M+H]+ (56). + HRMS (ESI): [M+Na] C25H29N3O5NaS2: calcd. 538.1446, found 538.1452.

159 N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)furan-3- carboxamide. (347)

Product 334 (250 mg, 0.822 mmol, 1 eq) was dissolved in CH2Cl2 (10 mL), then furan-2- carboxylic acid (1.1 eq), EDAC (1.5 eq), HOBt (1.3 eq) were added to this mixture. Then the base (DIPEA, 0.41 ml, 3 eq) was added. The reaction mixture is stirred 30h at room temperature. Then the reaction is stopped by addition of NaHCO3 (20 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30 then 50/50) afforded 347 (174 mg, 0.4370 mmol, 53 % over 2 steps) as a white solid. M.p = 52.2-54.5 °C.

Rf = 0.48 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 3370, 2928, 1651, 1528, 1476, 1343, 1170, 1009, 722, 697 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = .43-7.42 (m, 2H, 2 aromatic CH), 7.27-7.15 (m, 2H, 2 aromatic CH), 7.09-7.02 (m, 2H, 2 furan CH), 6.52-6.48 (m, 2H, NH and furan CH), 6.07- 6.06 (s, 2H, 2vinylic CH), 5.97-5.94 (m, 1H, vinylic CH), 5.74 (d, 1H, J = 9.4 Hz, vinylic

CH), 5.10 (s, 1H, CH), 3.50 (q, 2H, J = 7.1 Hz, CH2), 3.22-3.12 (m, 2H, CH2, SO2Et), 2.23-

1.95 (m, 2H, CH2), 1.42 (t, 3H, J =7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 158.4 (C=O), 147.8 (furan C), 143.9 (furan CH), 140.7 (aromatic C), 136.7 (aromatic C), 130.2 (aromatic CH), 128.2 (vinylic CH), 124.7 (vinylic CH), 123.9 (aromatic CH), 123.9 (aromatic CH), 123.5 (furan CH), 121.3 (aromatic CH), 114.2 (vinylic CH), 114.1 (vinylic CH), 112.1 (furan CH), 65.4 (CH), 46.7 (aromatic

C), 45.8 (CH2, SO2Et), 41.8 (CH2), 35.1 (CH2), 7.8 (CH3, SO2Et). MS (ESI) m/z (%):399 [M+H]+ (100), 421 [M+Na]+ (54). + HRMS (ESI): [M+H] C21H23N2O4S: calcd. 399.1373, found 399.1380.

160 N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-1H-indole-3- carboxamide. (348)

Product 334 (149 mg, 0.489 mmol, 1 eq) was dissolved in CH2Cl2 (6 mL), then the 1H- indole-3-carboxylic acid, (1.1 eq), EDAC (1.5 eq), HOBt (1.3 eq) were added to this mixture. Then the base (DIPEA, 0.24 ml, 3 eq) was added. The reaction mixture is stirred for 30h at room temperature. Then the reaction was stopped by addition of NaHCO3 (10 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30 then 50/50) afforded 348 (105 mg, 0.2348 mmol, 48% over 2 steps) as a white solid. M.p = 126.6-127.7 °C.

Rf = 0.65 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 3401, 1618, 1542, 1457, 1339, 1150, 1009, 749 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 9.77 (s, 1H, NH), 7.94-7.91 (m, 1H, aromatic CH), 7.62 (s, 1H, indol CH), 7.29-7.25 (m, 2H, 2 aromatic CH), 7.09-7.01 (m, 3H, 3 aromatic CH), 6.88-6.86 (m, 2H, 2aromatic CH), 6.46-6.42 (t, 1H, J = 5.3 Hz, NH), 5.84-5.83 (m, 2H 2 vinylic CH), 5.74-5.70 (m, 1H vinylic CH), 5.50 (d, 1H, J = 9.4 Hz, vinylic CH), 5.04-5.03 (s,

1H, CH), 3.34-3.32 (m, 2H, CH2), 3.10-2.97 (m, 2H, CH2, SO2Et), 2.03-1.79 (m, 2H, CH2),

1.21 (t, 3H, J = 7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 166.1 (C=O), 140.4 (aromatic C), 137.1 (aromatic C), 136.5 (aromatic C), 130.2 (aromatic CH), 128.1 (indol CH), 127.9 (vinylic CH), 125.1 (aromatic C), 124.7 (vinylic CH), 124.1 (aromatic CH), 123.8 (aromatic CH), 123.6 (aromatic

CH), 122.8 (s, aromatic CH), 121.5 (aromatic CH), 121.1 (vinylic CH), 120.2 (aromatic CH), 114.2 (vinylic CH), 112.2 (aromatic CH), 111.5 (aroamtic C), 65.5 (CH), 46.8 (aromatic C),

45.8 (CH2, SO2Et), 42.2 (CH2), 35.4 (CH2), 7.7 (CH3, Et). MS (ESI) m/z (%): 470 [M+Na]+ (100), 448 [M+H]+ (50), + HRMS (ESI): [M+Na] C25H25N3O3NaS: calcd. 470.1662, found 470.1662.

161 (E)-N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-3- (phenylsulfonyl)acrylamide (349).

In a 25 ml two-necked round bottom flask, 3,3-Bis-benzenesulfonyl-, EDAC, HOBt were dissolved in DCM (5 ml) and stirred for 1h at 0°C. The crude amine 334 (220 mg, 0.723 mmol) was added to the reaction mixture and DIPEA (0.374 mL, 3 eq). The reaction mixture was stirred for 30h at room temperature. Then the reaction was stopped by addition of

NaHCO3 (10 ml), extracted with DCM. The combined organic layers were washed with brine, drying over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20 then 50/50) afforded 349 (195 mg, 0.3915 mmol, 54 % (2 step)) as a white solid. M.p = 147.1-148.9°C.

Rf = 0.48 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 3231, 1671, 1476, 1343, 1148, 656 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.55 (d, 2H, J= 7.5 Hz, 2 aromatic CH), 7.33-7.30 (m, aromatic CH), 7.25-7.20 (m, 2H, 2 aromatic CH), 7.04 (d, 1H, J= 8.1 Hz, vinylic CH), 6.94-6.82 (m, 2H, 2 aromatic CH), 6.80 (t, 1H, J= 8.1 Hz, aromatic CH), 6.71-6.67 (m, vinylic CH), 6.64-6.58 (m, aromatic CH), 6.33 (t, 1H, J= 5.4 Hz, NH), 5.66-5.58 (m, 2H, vinylic CH), 5.55-5.53 (m, vinylic CH), 5.33 (d, 1H, J= 9.6 Hz, vinylic CH), 4.69 (d, 1H, J=

2.6 Hz, CH), 3.06-2.97 (m, 2H, CH2), 2.84-2.72 (m, 2H, CH2, SO2Et), 1.83-1.69 (m, 1H, CH),

1.58-1.49 (m, 1H, CH), 1.05 (t, 3H, J= 7.3 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 162.1 (C=O), 140.6 (aromatic C), 139.8 (aromatic

CH, SO2Ph), 138.7 (aromatic C), 136.6 (vinylic C), 134.4 (vinylic C), 133.9 (aromatic CH,

SO2Ph), 130.1 (aromatic CH), 129.7 (2 aromatic CH, SO2Ph), 128.3 (vinylic C), 128.2 (2 aromatic CH, SO2Ph), 124.8 (vinylic C), 124.1 (aromatic CH), 123.9 (aromatic CH), 123.6

(vinylic C), 121.5 (aromatic CH), 114.3 (vinylic C), 65.4 (CH), 46.7 (aromatic C), 46.3 (CH2,

SO2Et), 41.2 (CH2), 36.1 (CH2), 7.9 (CH3, SO2Et). + + MS (ESI) m/z (%):521 [M+Na] (100), 499 [M+H] (11). + HRMS (ESI): [M+Na] C25H26N2O5NaS2: calcd. 521.1175, found 521.1192.

162 (3aR,4R,6aS,11a1R)-7-(ethylsulfonyl)-3-((E)-3-(phenylsulfonyl)acryloyl)-2,3,3a,4,6a,7- hexahydro-1H-pyrrolo[2,3-d]carbazol-4-yl acetate (350).

Starting material 349 (1 eq.) and sodium acetate (2.0 eq.) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (0.1 eq.) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80:20) afforded 350 (49 mg, 0.0881 mmol, 26 % yield) as an oil product.

Rf = 0.48 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2981, 1739, 1648, 1420, 1348, 1151, 671 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.69-7.64 (m, 2H, 2 aromatic CH), 7.57-7.52 (m, 1H, aromatic CH), 7.44-7.38 (m, 2H, 2 aromatic CH), 7.33-7.26 (m, 3H, 3 aromatic CH), 7.03 (t, 1H, J = 7.5 Hz, vinylic CH), 6.80 (d, 1H, J = 7.7 Hz, aromatic CH), 6.34 (d, 1H, J = 10.3 Hz, vinylic CH), 5.84 (d, 1H, J = 7.7 Hz, vinylic CH), 3.30 (d, 1H, J = 10.3 Hz, CH), 5.22 (d, 1H, J = 8.6 Hz, CH), 4.65 (s, 1H, CH), 4.11-4.01 (m, 1H, CH), 3.94 (d, 1H, J = 9.03 Hz,

CH), 3.75-3.68 (m, 1H, CH), 3.16 (q, 2H, J = 7.3 Hz, CH2, SO2Et), 2.40-2.20 (m, 2H, CH2),

2.08 (s, 3H, OAc), 1.42 (t, 3H, J = 7.3 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.3 (C=O, OAc), 161.9 (C=O), 141.6 (aromatic

CH, SO2Ph), 140.2 (aromatic C), 138.8 (aromatic C), 135.2 (vinyl C), 134.4 (vinyl C), 131.1

(aromatic CH, SO2Ph), 129.9 (aromatic CH), 129.7 (2 aromatic CH, SO2Ph), 128.3 (2 aromatic CH, SO2Ph), 128.2 (aromatic CH), 127.7 (vinyl C) 125.1 (aromatic CH), 123.1 (vinyl C), 114.7 (aromatic CH), 70.1 (CH), 65.1 (CH), 64.1 (CH), 52.1 (aromatic C), 44.8

(CH2), 43.8 (CH2, SO2Et), 36.3 (CH2), 21.1 (CH3), 7.8 (CH3, SO2Et). MS (ESI) m/z (%): 579 [M+Na]+ (100). + HRMS (ESI): [M+Na] C27H28N2O7NaS2: calcd. 579.1230, found 579.1244.

163 2-((4aS,9aS)-9-(2-(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a- yl)acetonitrile (351)

Product 175 (1.8 g, 4.813 mmol, 1 eq) and sodium acetate (0.790 g, 9.63 mmol, 2.0 eq) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (110 mg, 0.4813 mmol, 0.1 eq) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether/ ethyl acetate: 80/20) afforded 351 (1.40 g, 3.762 mmol, 78%) as a white solid. Mp = 92.4-93.3°C

Rf = 0.16 (petroleum ether/ ethyl acetate: 90/10). IR (solid, KBr) : = 2958, 1595, 1478, 1342, 1250, 1152, 984, 838, 738, 650 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.42-7.39 (m, 1H, aromatic CH), 7.25-7.20 (m, 2H, 2 aromatic CH), 7.08-7.04 (m, 1H, aromatic CH), 6.07 (s, 2H, 2 vinylic CH), 6.01-5.97 (m, 1H, vinylic CH), 5.74 (d, 1H, J = 9.4 Hz, vinylic CH), 5.00 (s, 1H, CH), 3.17-2.97 (m, 2H,

CH2), 2.82 (ABsystem, 2H, JAB = 25.59 Hz, CH2), 1.11-1.04 (m, 2H, CH2), 0.0002 (s, 9H,

SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 141.5 (aromatic C), 133.2 (aromatic C), 129.3 (vinylic CH), 127.7 (aromatic CH), 124.4 (vinylic CH), 124.2 (vinylic CH), 123.6 (aromatic CH), 123.6 (aromatic CH), 122.6 (aromatic CH), 116.4 (Cq, CN), 114.3 (vinylic CH), 65.4

(CH), 48.2 (aromatic C), 45.6 (CH2), 29.4 (CH2), 9.7 (CH2), -1.9 (3CH3), SiMe3. MS (ESI) m/z (%): 395 [M+Na]+ (100). + HRMS (ESI): [M+Na] C19H24N2O2NaSiS: calcd. 395.1219, found 395.1224.

164 4-methyl-N-(2-((4aS,9aS)-9-(2-(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-carbazol- 4a-yl)ethylcarbamoyl)benzenesulfonamide (352)

In a 100 ml two-necked round bottom flask, AlCl3 (1.142 g, 8.56 mmol, 3 eq) was dissolved in Et2O (12 mL) at 0°C, then LiAlH4 (433 mg, 11.42 mmol, 4 eq) was added. The reaction mixture is stirred at room temperature for 30 min. product 351 (1.062 g, 2.855 mmol, 1 eq) was dissolved in Et2O (3 mL) and THF (3 mL), and added dropwise at 0°C. The reaction mixture is stirred at room temperature for 18h then the reaction was stopped by addition of ice then NaOH 10% (40 mL) was added and the reaction mixture was stirred for 1h. Ether was added. The reaction mixture was filtered through celite and extracted with DCM. The combined organic layers were washed with brine, drying over sodium sulfate and concentrated in vacuum afforded the amine 351b as a yellow oil.

To a solution of the crude amine 351b (703 mg, 1.869 mmol, 1eq) in CH2Cl2 (20 mL) at 0°C was added the p-toluene sulfonyl isocyante (368 mg, 1.869 mmol, 1eq). The reaction was wormed to r.t and stirred while monitoring the consumption of the amine by TLC (2-16h). The reaction mixture was evaporated directly without extraction. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30) afforded 352 (786 mg, 1.371 mmol, 73% over 2 steps) as a white solid. M.p = 86.8-88.1°C.

Rf = 0.58 (petroleum ether/ ethyl acetate: 70/30). IR (solid, KBr):  = 3353, 2950, 1672, 1547, 1345, 1250, 698 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 8.75 (broad s, 1H, NH), 7.77 (d, 2H, J = 8.3 Hz, 2 aromatic CH, Ts), 7.38 (d, 1H, J = 8.1 Hz, aromatic CH), 7.30-7.16 (m, 2H, 2 aromatic CH), 7.14-7.09 (m, 2H, 2 aromatic CH), 7.02-6.97 (m, 1H, aromatic CH), 6.54-6.52 (m, 1H, NH), 6.03(d, 2H, J = 3.4 Hz, 2 vinylic CH), 5.93-5.87 (m, 1H, vinylic CH), 5.65 (d, 1H, J = 9.6

Hz, vinylic CH), 5.00 (s, 1H, CH), 3.28-3.20 (m, 2H, CH2), 3.08-2.99 (m, 2H, CH2), 2.40 (s,

3H, CH3, Ts), 2.12-2.02 (m, 1H, CH), 1.87-1.77 (m, 1H, CH), 1.08-0.99 (m, 2H, CH2), -0.01

(s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.9 (C=O), 144.9 (Cq, Ts), 141.2 (aromatic C), 136.8 (aromatic C), 136.2 (Cq, Ts), 130. (vinyl CH), 130.1 (2 aromatic CH, Ts), 128.3 (aromatic CH), 127.1 (2 aromatic CH, Ts), 125.3 (aromatic CH), 123.7 (vinyl CH,), 123.6 (aromatic CH), 123.3 (vinyl CH), 121.4 (aromatic CH), 114.1 (vinyl CH), 65.2 (CH), 49.2

(aromatic C), 46.6 (CH2, SES), 41.4 ( CH2), 36.2 (CH2), 21.8 (CH3, Ts), 9.9 (CH2, SES), -1.9

(3CH3, SiMe3). MS (ESI) m/z (%): 596 [M+Na]+ (100). + HRMS (ESI): [M+Na] C27H35N3O5NaSiS2: calcd. 596.1679, found 596.1683.

165 Compound (353)

Starting material 352 (1 eq.) and sodium acetate (2 eq.) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (0.1 eq.) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 90/10) afforded 353 (80 mg, 0.140 mmol, 53% (2steps) as a white solid. M.p = 239.3-241.1°C.

Rf = 0.63 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2924, 1737, 1478, 1348, 1164, 840, 663 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.98 (d, 2H, J = 8.3 Hz, aromatic CH, Ts), 7.29 (m, 4H, 4 aromatic CH), 7.10-7.09 (m, 1H, aromatic CH), 7.08-7.06 (m, 1H, aromatic CH), 6.10- 5.97 (m, 2H, 2 vinylic CH), 4.92-4.88 (m, 1H, CH), 4.61 (d, 1H, J = 8.3 Hz, CH), 4.40 (s, 1H,

CH), 3.51-3.37 (m, 2H, CH2), 3.11-3.05 (m, 2H, CH2), 2.47-2.41 (m, 1H, CH), 2.40 (s, 3H,

CH3, Ts), 2.23-1.11 (m, 1H, CH), 1.10-1.04 (m, 2H, CH2), 0.02 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.7 (C=O), 144.8 (Cq, Ts), 140.5 (aromatic C), 136.6 (aromatic C), 131.7 (Cq, Ts), 130.3 (vinyl CH), 129.7 (aromatic CH), 129.6 (2 aromatic CH, Ts), 128.2 (2 aromatic CH, Ts), 124.5 (vinyl CH), 124.3 (aromatic CH,), 122.9 (aromatic

CH), 114.8 (aromatic CH), 62.7 (CH), 57.4 (CH), 52.1 (s, CH), 50.2 (aromatic C), 49.6 (CH2,

SES), 42.8 (CH2), 41.9 (CH2), 21.8 (CH3, Ts), 10.3 (CH2, SES), -1.9 (3CH3, SiMe3). MS (ESI) m/z (%): 594 [M+Na]+ (100), 572 [M+H]+ (8) . + HRMS (ESI): [M+Na] C27H35N3O5NaSiS2: calcd. 594.1523, found 594.1546.

N-(2-(1-(2-(ethylsulfonamido)phenyl)cyclohexa-2,5-dienyl)ethylcarbamoyl)-4- methylbenzenesulfonamide (354)

In a 100 ml two-necked round bottom flask, AlCl3 (966 mg, 7.25 mmol, 3 eq) was dissolved in Et2O (20 mL) at 0°C, then LiAlH4 (365 mg, 9.64 mmol, 4 eq) was added. The reaction mixture is stirred at room temperature for 30 min. product 174 (700 mg, 2.41 mmol, 1 eq) was dissolved in Et2O (5 mL) and THF (5 mL), and added dropwise at 0°C. The reaction mixture

166 is stirred at room temperature for 18h then the reaction was stopped by addition of ice then NaOH 10% (40 mL) was added and the reaction mixture was stirred for 1h. Ether was added. The reaction mixture was filtered through celite and extracted with DCM. The combined organic layers were washed with brine, drying over sodium sulfate and concentrated in vacuum afforded the amine 236 as a viscous oil.

To a solution of crude amine 236 (1 eq) in CH2Cl2 (20 mL) at 0°C was added the p-toluene sulfonyl isocyante (1 eq). The reaction was wormed to r.t and stirred while monitoring the consumption of the amine by TLC (2-16h). The reaction mixture was evaporated directly without extraction. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30) afforded 354 (376 mg, 0.747 mmol, 70% over 2 steps) as a white solid. M.p = 92.1-93.4°C.

Rf = 0.26 (petroleum ether/ ethyl acetate: 70/30). IR (solid, KBr):  = 3347, 1672, 1453, 1335, 1148, 1090, 887 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 8.48 (broad s, IH, NH), 7.45 (d, 2H, J = 8.3 Hz, 2x aromatic CH, Ts), 7.23 (d, 1H, J = 7.9 Hz, aromatic CH), 7.02-6.90 (m, 5H, 4 aromatic CH and NH), 6.35 (t, 1H, J= 5.7 Hz, NH), 5.77 (d, 2H, J = 10.2 Hz, 2 vinylic CH), 5.15 (d, 2H, J

= 10.2 Hz, 2 vinylic CH), 3.01-2.93 (m, 2H, CH2), 2.81 (q, 2H, J = 7.3 Hz, CH2, SO2Et),

2.65 (AB system, 2H, JAB = 8.3 Hz, CH2), 2.08 (s, 3H, Ts), 1.75-1.70 (m, 2H, CH2), 0.99 (t, 3H,

J = 7.3 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.9 (C=O), 144.9 (Cq, Ts), 137.6 (s, Cq, Ts), 136.8 (aromatic C), 132.4 (aromatic C), 130.1 (2 vinyl CH), 130.1 (2 aromatic CH, Ts), 128.6 (aromatic CH), 126.9 (2 aromatic CH, Ts), 126.8 (2 vinyl CH), 126.2 (aromatic CH,), 123.9

(aromatic CH), 119.3 (aromatic CH), 46.5 (CH2, SO2Et), 41.7 (aromatic C), 38.8 (CH2), 36.7

(CH2), 25.8 (CH2), 21.7 (CH3, Ts), 8.1 (CH3, SO2Et). MS (ESI) m/z (%): 526 [M+Na]+ (100), 504 [M+H]+ (6) . + HRMS (ESI): [M+Na] C24H29N3O5NaS2: calcd. 526.1440, found 526.1450.

Compound (355)

Starting material 354 (1 eq.) and sodium acetate (2.0 eq.) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (0.1 eq.) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 90/10) afforded 355(107 mg, 0.214 mmol, 72%) as a white solid.

167 M.p = 217.7-219.1°C.

Rf = 0.48 (petroleum ether/ ethyl acetate: 50/50). IR (solid, KBr):  = 2972, 1734, 1478, 1384, 1154, 763, 663 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.87 (d, 2H, J = 8.3 Hz, 2 aromatic CH, Ts), 7.28- 7.18 (m, 4H, 4 aromatic CH), 7.15-7.10 (m, 1H, aromatic CH), 7.04 (t, 1H, J = 7.3 Hz, aromatic CH), 6.01 (t, 2H, J = 14.3 Hz, 2 vinylic CH), 4.84-4.81 (m, 1H, CH), 4.55 (d, 1H, J

= 8.3 Hz, CH), 4.33 (s, 1H, CH), 3.43-3.29 (m, 2H, CH2), 3.16 (q, 2H, J = 7.4 Hz, CH2,

SO2Et), 2.40-2.38 (m, 1H, CH), 2.35 (s, 3H, Ts), 2.21-2.10 (m, 1H, CH), 1.36 (t, 3H, J = 7.3

Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 151.6 (C=O), 144.8 (Cq, Ts), 140.2 (aromatic C), 136.7 (aromatic C), 131.7 (Cq, Ts), 130.4 (vinyl CH), 129.7 (2 aromatic CH, Ts), 129.6 (aromatic CH), 128.2 (2 aromatic CH, Ts), 124.5 (vinyl CH), 124.3 (aromatic CH,), 123.1 (aromatic CH), 114.8 (aromatic CH), 62.7 (CH), 57.5 (CH), 52.1 (CH), 50.1 (aromatic C),

47.2 (CH2, SO2Et), 43.1 (CH2), 41.8 (CH2), 21.7 (CH3, Ts), 8.2 (CH3, SO2Et). MS (ESI) m/z (%): 522 [M+Na]+ (100), 500 [M+H]+ (10) . + HRMS (ESI): [M+Na] C24H25N3O5NaS2: calcd. 522.1127, found 522.1144.

Tert-butyl 2-(1-(2-(2-(trimethylsilyl)ethylsulfonamido)phenyl)cyclohexa-2,5- dienyl)ethylcarbamate. (358)

To a solution of product 175 (380 mg, 1.005 mmol, 1 eq) in THF (10 mL), was added (t-

Boc)2O (263 mg, 1.206 mmol, 1.2 eq) and the resulting solution was refluxed at 80°C for 12 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80:20) afforded 358 (275 mg, 0.5750 mmol, 57% over 2 steps) as a white solid. M.p = 58.3-60.5 °C.

Rf = 0.51 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 3350, 2954, 1713, 1495, 1336, 1251, 1147, 861, 757 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.58-7.55 (m, 1H, aromatic CH), 7.42-7.39 (m, 1H, aromatic CH), 7.30-7.25 (m, 1H, aromatic CH), 7.15-7.12 (m, 1H, aromatic CH), 6.12 (d, 2H, J = 9.4 Hz, 2 vinylic CH), 5.55 (d, 2H, J = 9.78 Hz, 2x vinylic CH), 4.70 (broad s, 2H, 2NH),

3.22- 3.20 (m, 2H, CH2), 3.07-3.01 (m, 2H, CH2), 2.94-2.80 (m, 2H, bisallylic CH2), 2.14-

2.09 (m, 2H, CH2), 1.47 (s, 9H, Boc) 1.04-0.98 (m, 2H, CH2), -0.0005 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 158.1 (C=O, Boc), 139.8 (aromatic C), 134.7 (aromatic C), 132.4 (2 vinylic CH), 130.4 (aromatic CH), 128.5 (2 vinylic CH), 128.3 ( aromatic CH), 125.9 (aromatic CH), 121.4 (aromatic CH), 81.4 (Cq, Boc), 50.5 (CH2), 43.7

168 (aromatic C), 41.3 (CH2), 38.9 (CH2), 30.5 (3CH3, Boc), 27.8 (bisallylic CH2), 12.1 (CH2), -

0.0001 (3CH3, SiMe3). MS (ESI) m/z (%):501 [M+Na]+ (100), 479 [M+H]+ (46), 379 [(M+H)-Boc]+ (73). + HRMS (ESI): [M+Na] C24H38N2O4NaSSi: calcd. 501.2361, found 501.2361.

4-Methyl-N-(2-(1-(2-(2-(trimethylsilyl)ethylsulfonamido)phenyl)cyclohexa-2,5- dienyl)ethyl)benzenesulfonamide. (359)

TsCl (278 mg, 1.458 mmol, 1.1 eq) was dissolved in pyridine (2.5 mL). The mixture was stirred at 0°C. Product 175 (0.5 g, 1.326 mmol, 1 eq) was dissolved in pyridine (2.5 mL), and then was added to the reaction mixture. The reaction was stirred at r.t for 24h. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with a lot HCl (0.1M). The solvent was removed under vacuum. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 60:40) afforded 359 (421 mg, 0.7910 mmol, 60% over 2 steps) as a white solid. M.p = 60.4-61.7°C.

Rf = 0.39 (petroleum ether/ ethyl acetate: 70/30). IR (solid, KBr):  = 3313, 2953, 1599, 1494, 1409, 1333, 1251, 860, 661 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.63 (d, 2H, J = 8.3 Hz, 2 aroamtic CH), 7.56-7.49 (m, 1H, aroamtic CH), 7.36-7.24 (m, 4H, 4 aromatic CH), 7.11-7.05 (m, 1H, aromatic CH), 6.06-6.02 (m, 2H, 2 vinylic CH ), 5.43 (d, 1H, J = 10.2 Hz, CH), 5.06 (t, 1H, J = 6 Hz, NH),

3.09-3 (m, 4H, 2CH2), 2.89 (d, 2H, AB system, JAB = 4.2 Hz, bisallylic CH2), 2.46 (s, 3H, Ts),

2.13-2.08 (m, 2H, CH2), 1.02-0.96 (m, 2H, CH2), -.0001 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.6 (Cq, Ts), 137.7 (Cq, Ts), 137.1 (aromatic C), 132.2 (aromatic C), 130.1 (2 aromatic CH, Ts), 129.8 (2 vinylic CH), 128.6 (aromatic CH), 127.2 (2 vinylic CH), 126.8 (2 aromatic CH, Ts), 126.1 (aromatic CH), 123.9 (aromatic CH),

119.4 (aromatic CH) 48.6 (CH2), 41.6 (aromatic C), 39.6 (CH2), 38.9 (CH2), 25.8 (bisallylic

CH2), 21.6 (CH3, Ts), 10.1 (CH2), -1.9 (3CH3, SiMe3). MS (ESI) m/z (%):533 [M+H]+ (100), 555 [M+Na]+ (90). + HRMS (ESI): [M+Na] C26H36N2O4NaSiS2: calcd. 555.1778, found 555.1796.

169 (3aR,4R,6aS,11a1R)-tert-butyl 4-acetoxy-7-(2-(trimethylsilyl)ethylsulfonyl)-3a,4,6a,7- tetrahydro-1H-pyrrolo[2,3-d]carbazole-3(2H)-carboxylate (360)

Product 361 (1.070 g, 2.248 mmol, 1 eq) and sodium acetate (0.368 g, 4.496 mmol, 2 eq) were dissolved in DMSO (0.1M) and the solution was flushed with dioxgen. Pd(OAc)2 (505 mg, 0.225 mmol, 0.1 eq) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate 90:10) to provide 360 (0.880 mg, 1.647 mmol, 72%) as a colorless oil.

Rf = 0.41 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl):  = 3354, 2814, 1668, 1478, 1171, 1055, 844, 766 cm-1 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.32-7.22 (m, 2H, 2 aromatic CH), 7.05-6.99 (m, 2H, 2 aromatic CH), 6.27-6.16 (m, 1H, vinylic CH), 6.10-6.04 (m, 1H, vinylic CH), 5.52 (s,

1H, CH), 4.61 (s, 1H, CH), 4.21 (s, 1H, CH), 3.63 (broad s, 2H, CH2), 3.03-2.97 (m, 2H, CH2,

SES), 2.16-2.07 (m, 2H, CH2,), 1.62 (s, 3H, CH3, OAc), 1.50 (s, 9H, 3CH3, Boc), 1.06-1.01

(m, 2H, CH2, SES), 0.0001 (s, 9H, 3CH3, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 169.8 (C=O, OAc), 154.4 (C=O, Boc), 154.1 (aromatic C), 141.4 (aromatic CH), 137.9 (aromatic C), 137.3 (vinylic C), 128.8 (aromatic CH), 123.9 (aromatic CH), 122.3 (vinylic C), 113.7 (aromatic CH), 80.4 (Cq, Boc), 68.7

(CH), 67.5 (CH), 60.1 (CH), 53.7 (aromatic C), 47.8 (CH2, SES), 43.8 (CH2), 40.3 (CH2),

28.5 (3CH3, Boc), 20.30 (CH3, OAc), 9.9 (CH2, SES), -2.05 (3CH3, SiMe3). MS (ESI) m/z (%): 557 [M+Na]+(100). + HRMS (ESI): [M+Na] C26H38N2O6 Na SSi: calcd.557.2112, found 557.2108.

Tert-butyl 2-((4aS,9aS)-9-(2-(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-carbazol- 4a-yl)ethylcarbamate (361)

To a solution of crude amine 351b (1.180 g, 3.138 mmol, 1 eq) in THF (15 mL), (Boc)2O (0.822 g, 3.766 mmol, 1.1 eq) was added and the resulting solution was refluxed at 80°Cf or

170 12 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. Purification by silica gel chromatography (petroleum ether/ ethyl acetate: 80/20) afforded 361 (1.280 g, 2.687 mmol, 86% over 2 steps) as colourless oil.

Rf = 0.41 (Petroleum Ether/EtOAc: 80/20). IR (film, NaCl): = 3404, 2953, 1705, 1505, 1476, 1345, 1249, 1167, 893, 752 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.40 (d, 1H, J= 7.9 Hz, aromatic CH), 7.13-7.10 (m, 2H, 2 aroamtic CH), 7.02-6.99 (m, 1H, aroamtic CH), 6.02-6.01 (s, 2H; 2 vinylic CH), 5.92- 5.86 (m, 1H, vinylic CH), 5.68 (d, 1H, J = 9.4 Hz, vinylic CH), 5.02 (s, 1H, CH), 4.76 (s, 1H,

NH), 3.17-2.98 (m, 4H, 2CH2), 2.11-1.86 (m, 2H, CH2), 1.41 (s, 9H, 3CH3, Boc), 1.09-1.01

(m, 2H, CH2), -0.0001 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 157.8 (C=O), 142.9 (aromatic C), 138.7 (aromatic C), 132.6 (aromatic CH ),130.1 (vinylic CH), 126.7 (aromatic CH), 125.7 (vinylic CH), 125.6 (vinylic CH), 125.5 (vinylic CH), 123.1 (aromatic CH), 115.9 (aromatic CH), 81.2 (Cq, Boc),

67.4 (CH), 49.9 (aromatic C), 48.6 (CH2), 44.1 (CH2), 38.4 (CH2), 30.4 (3CH3, Boc), 11.8

(CH2), -0.003 (3CH3), SiMe3. MS (ESI) m/z (%):499 [M+Na]+ (100), 377 [(M+H)-Boc]+ (28), 477 [M+H]+ (15). + HRMS (ESI): [M+Na] C24H36N2O4NaSiS: calcd. 499.2057, found 499.2070.

(3aR,4R,6aS,11a1S)-3-tosyl-7-(2-(trimethylsilyl)ethylsulfonyl)-2,3,3a,4,6a,7-hexahydro- 1H-pyrrolo[2,3-d]carbazol-4-yl acetate (362)

Starting material 359 (1 eq.) and sodium acetate (2.0 eq.) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (0.1 eq.) was added and the resulting solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 90/10) afforded 362 (46 mg, 0.07820 mmol, 62%) as a white solid

Rf = 0.43 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2925, 1746, 1477, 1351, 1232, 1028, 843, 661 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.84 (d, 2H, J= 7.9 Hz, 2 aromatic CH, Ts), 7.46 (d, 2H, J= 7.9 Hz, 2 aromatic CH, Ts), 7.25-7.21 (m, 1H, aroamtic CH), 7.14 (t, 1H, J= 7.5 Hz, aromatic CH), 6.62 (t, 1H, J= 7.5 Hz, aromatic CH), 6.20 (d, 1H, J= 10.2 Hz, aromatic CH), 5.71 (d, 1H, J= 10.2 Hz, vinylic CH), 5.47 (d, 1H, J= 7.5 Hz, vinylic CH), 5.08 (d, 1H, J= 9.03 Hz, CH), 4.14 (d, 1H, J= 9.06 Hz, CH), 4.03 (s, 1H), 3.71-3.66 (m, 1H), 3.36-3.27 (m,

171 1H), 2.98 (m, 2H, CH2), 2.52 (s, 3H, CH3, Ts), 2.14 (s, 3H, OAc), 2.01-1.84 (m, 2H, CH2),

1.07-1.01 (m, 2H, CH2), -0.01 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.5 (C=O, OAc), 144.4 (aromatic C, Ts), 140.1 (aromatic C), 137.1 (aromatic C), 133.6 (aromatic C, Ts), 131.8 (aromatic CH), 130.2 (2 aromatic CH, Ts), 129.2 (aromatic CH), 128.1 (2 aromatic CH, Ts), 127.7 (vinylic C), 124.8 (vinylic C), 122.6 (aromatic CH), 117.2 (aromatic CH), 70.2 (CH), 69.9 (CH), 60.9 (CH),

54.22 (aromatic C), 48.9 (CH2, SES), 47.1 (CH2), 40.1 (CH2), 21.6 (CH3, Ts), 21.2 (CH3,

OAc), 9.9 (CH2, SES), -1.9 (3CH3, SiMe3). MS (ESI) m/z (%): 611 [M+Na]+ (100), 612 [M+Na+H]+ (28). + HRMS (ESI): [M+Na] C28H36N2O6 Na S2Si: calcd. 611.1676, found 611.1689.

(3aR,4R,6aS,11a1R)-3-((Z)-2-iodobut-2-enyl)-7-(2-(trimethylsilyl)ethylsulfonyl)- 2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3-d]carbazol-4-yl acetate (364)

To a solution of product crude 363 (160 mg, 0.37 mmol, 1 eq) in CH3CN (6 mL) were added anhydrous K2CO3 (110 mg, 0.74 mmol, 2 eq) and (Z)-1-bromo-2-iodo-2-butene (193 Mg, 0.74 mmol, 2 eq). The mixture was stirred at r.t for 3 h. The solvent was removed under vacuum, and the residue was partitioned between H2O and CH2Cl2. The dried organic extracts were concentrated under vacuum. Purification by silica gel chromatography (Hexane / ethyl acetate: 8/2) afforded 364 (164 mg, 0.267 mmol, 72% over 2 steps) as a white solid. M.p = 134.3-135.6°C

Rf = 0.65 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2950, 1731, 1476, 1340, 1232, 1100, 970, 840, 698 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.33-7.25 (m, 1H, aroamtic CH), 7.16-7.11 (m, 1H, aroamtic CH), 7.05-7.00 m, 1H, aroamtic CH), 6.08-6.04 (m, 1H, vinylic CH), 5.90 (q, 1H, J = 6.03 Hz, vinylic CH), 5.81-5.76 (m, 1H, vinylic CH), 5.23 (s, 1H, CH), 4.59 (s, 1H, CH),

3.93 (AB system, 2H, JAB = 140.1 Hz, CH2), 3.29 (d, 1H, J = 3.8 Hz, CH), 3.20-3.12 (m, 1H,

CH), 3.09-3.02 (m, 2H, CH2), 2.69-2.61 (m, 1H, CH), 2.10-1.91 (m, 2H, CH2), 1.85 (s, 3H,

OAc), 1.77 (d, 3H, J = 6.4 Hz, CH3), 1.10-1.04 (m, 2H, CH2), -0.0004 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.4 (C=O, OAc), 140.1 (s, aromatic C), 135.8 (aromatic C), 130.9 (aromatic CH), 130.2 (vinylic CH), 128.6 (aromatic CH), 125.7 (aromatic CH), 123.8 (vinylic CH), 123.6 (vinylic CH), 114.3 (aromatic CH), 109.4 (Cq, CI), 67.9

(CH), 66.5 (CH), 66.4 (CH2), 66.1 (CH), 51.4 (aromatic C), 50.1 (CH2), 48.4 (CH2), 40.1

(CH2), 21.6 (CH3, OAc), 20.9 (CH3) 10.1 (CH2), -1.9 (3CH3, SiMe3). MS (ESI) m/z (%):615 [M+H]+ (100), 637 [M+Na]+ (70). + HRMS (ESI): [M+H] C25H36IN2O4SSi: calcd. 615.1209, found 615.1216.

172 (3aR,4R,6aS,11a1S)-3-((Z)-2-iodobut-2-enyl)-2,3,3a,4,6a,7-hexahydro-1H-pyrrolo[2,3- d]carbazol-4-yl acetate. (365)

CsF (1.854 g, 13.9 mmol, 15 eq) was added to a solution of product 364 (0.5 g, 0.814 mmol, 1 eq) in CH3CN (40 mL). The resulting suspension was heated at 80 °C for 30 h. After cooling to r.t, the solvent was removed under vacuum. Purification by silica gel chromatography (Silica gel deactivated, Dichloromethane / methanol: 95/5) afforded 365 (214mg, 0.475 mmol, 58%) as brown oil.

Rf = 0.26 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl):  = 3368, 1731, 1606, 1484, 1369, 1238, 1022, 969, 743 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.10-7.06 (m, 2H, 2 aromatic CH), 6.77 (t, 1H, J = 7.5 Hz, aromatic CH), 6.68 (d, 1H, J = 7.8 Hz, aromatic CH), 5.97 (q, 1H, J = 6.4 Hz, vinylic CH), 5.79-5.70 (m, 2H, 2x vinylic CH ), 5.30 (s, 1H, NH), 4.01 (s, 1H, CH), 3.95 (d, 1H, J = 14.3 Hz, CH), 3.89 (s, 1H, CH), 3.51 (d, 1H, J= 14.3 Hz, CH), 3.23 (d, 1H, J = 4.1 Hz, CH), 3.14-3.07 (m, 1H, CH), 2.72-2.64 (m, 1H, CH), 2.16-2.07 (m, 2H), 1.96 (s, 3H,

OAc), 1.82 (d, 3H, J= 6.4 Hz, CH3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.8 (C=O, OAc), 148.7 (aromatic C), 133.9 (aromatic C), 131.52 (aromatic CH), 130.6 (vinylic CH), 128.05 (vinylic CH), 125.5 (vinylic CH), 123.7 (aromatic CH), 119 (aromatic CH) 110.2 (Cq, CI), 109.9 (aromatic CH), 69.7

(CH), 67.1 (CH), 66.7 (CH2), 62.1 (CH), 52.7 (aromatic C), 50.3 (CH2), 38.7 (CH2), 21.7

(CH3), 21.3 (CH3, OAc). MS (ESI) m/z (%):451 [M+H]+ (100), 473 [M+Na]+ (12), 391 [(M+H)-OAc]+ (11). + HRMS (ESI): [M+H] C20H24IN2O2: calcd. 451.0877, found 451.0882.

Compound (366)

A solution of product 365 (190 mg, 0.422 mmol, 1 eq), Pd(OAc)2 (9 mg, 0.0411 mmol, 0.1 eq), K2CO3 (284 mg, 2.055 mmol, 5 eq) and Bu4NCl (1165 mg, 0.419 mmol, 1 eq) in DMF (4 mL) was warmed at 60 °C for 3 h. After cooling to room temperature, Et2O was added and the organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum.

173 Purification by silica gel chromatography (Diethyl ether /triethylamine: 98/2) afforded 366 (60 mg, 0.186 mmol, 44%) as a yellow soild. M.p = 104.7 – 105.9 °C.

Rf = 0.48 (Diethyl ether /triethylamine: 95/5). IR (solid, KBr):  = 3368, 1731, 1606, 1484, 1369, 1238, 1022, 969, 743 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.55 (d, 1H, J = 7.9 Hz, aromatic CH), 7.32-7.28 (m, 2H, 2 aromatic CH), 7.20-7.15 (m, 1H, aromatic CH), 5.49 (q, 1H, J = 6.8 Hz, vinylic CH), 5.09 (t, 1H, J = 3.4 Hz, CH), 4.17 (d, 1H, J = 2.6 Hz, CH), 3.80 (d, 1H, J = 15.5 Hz,

CH), 3.43 (s, 1H, CH), 3.39-3.19 (m, 4H, 2CH2), 2.81 (d, 1H, J = 13.5 Hz, CH), 2.26-2.17

(m, 1H, CH), 2.12-2.03 (m, 1H, CH), 1.69 (d, 3H, J = 6.8 Hz, CH3), 1.42 (s, 3H, OAc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 187.2 (Cq), 169.5 (C=O, OAc), 154.5 (aromatic C), 144.2 (aromatic C), 139.4 (Cq), 127.4 (aromatic CH), 124.9 (aromatic CH), 120.9 (aromatic

CH), 120.6 (aromatic CH), 119.6 (CH) 69.2 (CH), 67.2 (CH), 63.2 (aromatic C), 55.2 (CH2),

52.9 (CH2), 35.9 (CH2), 34.1 (CH), 33.4 (CH2), 19.8 (CH3), 12.8 (CH3, OAc). MS (ESI) m/z (%):345 [M+Na]+, 323 [M+H]+, 263 [M-Ac+H]+. + HRMS (ESI): [M+Na] C20H22N2O2Na: calcd. 345.1579, found 345.1600.

(Z)-methyl 2-(((3aR,4R,6aS,11a1S)-4-acetoxy-3a,4,6a,7-tetrahydro-1H-pyrrolo[2,3- d]carbazol-3(2H)-yl)methyl)but-2-enoate (368)

Pd(OAc)2 (2.5 mg, 0.0111 mmol, 0.1 eq), PPh3 (8.7 mg, 0.0333 mmol, 0.3 eq), Bu4NBr (74 mg, 0.22866 mmol, 2.06 eq) and TEA (0.074 mL, 0.5328 mmol, 4.8eq) were added to product 365 (50 mg, 0.111 mmol, 1eq) in DMA (2 mL) and MeOH (1 mL). The reaction flask was equipped with a balloon of , flushed three times with CO and heated under an atmosphere of CO for 12 h. The reaction mixture was cooled to r.t and saturated aqueous

NaHCO3 (10 mL) was added. The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined extracts were dried over MgSO4. The volatile organics were removed under vacuum. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 5/1) afforded 368 (13 mg, 0.0340 mmol, 31%) as a brown oil.

Rf = 0.63 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl):  = 2972, 1721, 1456, 1315, 1238, 832, 677 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.06-7.00 (m, 3H, 2 aromatic CH , NH), 6.75 (t, 1H, J = 7.3 Hz, aromatic CH), 6.64 (d, 1H, J = 7.9 Hz, aromatic CH), 6.16 (q, 1H, J = 7.1 Hz, vinylic CH), 5.75-5.66 (m, 2H, 2 vinylic CH), 5.27 (s, 1H, CH), 3.97-3.92 (m, 2H, CH2), 3.70

(s, 3H, CO2Me), 3.28 (d, 1H, J = 13.9 Hz, CH), 3.14 (d, 1H, J = 3.9 Hz, CH) 3.07-3.02 (m,

174 1H, CH), 2.66-2.58 (m, 1H, CH), 2.10-2.01 (m, 2H, CH2), 1.97 (d, 3H, J = 7.3 Hz, CH3), 1.91 (s, 3H, OAc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.8 (C=O, OAc), 168.2 (C=O, CO2Me), 148.7

(aromatic C), 136.6 (vinylic C), 133.9 (Cq, C-CO2Me), 131.6 (aromatic C), 131.3 ( aromatic CH), 128.1 (vinylic C), 125.2 (aromatic CH), 123.7 (aromatic CH), 119.1 (vinylic C), 110.1

(aromatic CH) 68.9 (CH), 67.2 (CH), 61.9 (CH), 58.1 (CH2), 52.5 (aromatic C), 51.3 (CH3,

CO2Me), 50.7 (CH2), 38.6 (CH2), 21.2 (CH3, OAc), 15.4 (CH3). + + + MS (ESI) m/z (%): 323 [(M+H)-CO2Me] (100), 383 [M+H] (85), 405 [M+Na] (55). + HRMS (ESI): [M+H] C22H27N2O4: calcd. 383.1965, found 383.1731.

Compound (370)

To a solution of NaH (7.5 mg, 0.3105 mmol, 2 eq.) in THF (2 mL) cooled at 0°C was added dropwise a solution of the imine 366 (50 mg, 0.1552 mmol, 1 eq) in THF (1 mL) over 25 min. After 40 min, methyl chloroformate (0.02 mL, 0.0.465 mmol, 3 eq)) was added over 5 min. The resulting mixture was stirred at -20°C for 12h and then poured into brine (20 mL). The organic layer was separated, and the aqueous layer was extracted with ether. The combined extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (diethyl ether/triethylamine 99:1 then 95:5) to provide 370 (26 mg, 0.0686 mmol, 44%) as white solid. M.p = 143.4-144.7°C.

Rf = 0.41 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr) = 3456, 2962, 1733, 1474, 1360, 1230, 1059, 757, 603 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.75 (d, 1H, J = 5.85 Hz, aromatic CH), 7.07-7.01 (m, 1H, aromatic CH), 7.01 (d, 1H, J = 4.74 Hz, aromatic CH), 6.99 (t, 1H, J = 4.74 Hz, aromatic CH), 6.07 (d, 1H, J = 6.06 Hz, vinylic CH), 5.45-5.39 (q, 1H, J = 5.13 Hz, vinylic CH), 5.25 (t, 1H, J = 2.64 Hz, CH), 4.17-4.16 (m, 1H, CH), 3.91 (s, 3H, OMe), 3.61 (d, 2H, J

= 11.19 Hz, CH2), 3.57-2.96 (m, 1H, CH), 2.95-2.93 (m, 1H, CH), 2.82-2.75 (m, 1H, CH),

2.26-2.20 (m, 1H, CH), 1.82-1.75 (m, 1H, CH), 1.70 (d, 3H, J = 5.13 Hz, CH3), 1.46 (s, 3H, OAc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.4 (C=O, OAc), 153.2 (aromatic C), 145.5 (C=O, OMe), 140.7 (aromatic C), 135.7 (aromatic C), 134.3 (aromatic C), 127.3 (vinylic C), 123.7 (aromatic CH), 121.8 (vinyl C), 119.8 (aromatic CH), 115.2 (aromatic CH), 108.5

(CH), 69.1 (CH), 60.2 (CH), 52.9 (CH3, OMe), 52.8 (aromatic C), 52.4 (CH2), 52.1 (CH2),

41.1 (CH2), 35.7 (CH), 20.57 (CH3, OAc), 13.2 (CH3). MS (ESI) m/z (%): 381[M+H]+(100). + HRMS (ESI): [M+H] C22H25N2O4: calcd. 381.1808, found 381.1808.

175 1-((3aR,4R,6aS,11a1R)-7-(ethylsulfonyl)-4-hydroxy-3a,4,6a,7-tetrahydro-1H- pyrrolo[2,3-d]carbazol-3(2H)-yl)ethanone (375)

To a stirring solution of product 343 (100 mg, 0.245 mmol, 1 eq) in MeOH (4 mL) ,water (1 mL) and K2CO3 (3 eq) were added. The reaction mixture was stirred and the completion of the hydrolysis was monitored by TLC (EtOAc 100%). After 3h the reaction was quenched by addition of water. The two layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate, 100%) afforded 375 (75 mg, 0.207 mmol, 85 %) as a white solid. Mp = 80.1-82.7 °C.

Rf = 0.23 (ethyl acetate, 100%). IR (solid, KBr):  = 3401, 1616, 1420, 1342, 1149, 1039, 952, 722 cm-1 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.33-7.30 (m, 1H, aroamtic CH), 7.21-7.16 (m, 1H, aroamtic CH), 7.00-6.95 (m, 1H, aroamtic CH), 6.85-6.82 (m, 1H, aroamtic CH), 5.96-5.91 (m, 1H, vinylic CH), 5.87-5.82 m, 1H, vinylic CH), 5.73 (s, 1H, OH), 4.51 (s, 1H, CH), 4.09

(d, 1H, J = 8.3 Hz, CH), 3.96 (d, 1H, J = 8.3 Hz, CH), 3.75-3.69 (m, 2H, CH2), 3.08 (q, 2H, J

= 7.5 Hz, CH2, SO2Et), 2.21 (s, 3H, CH3), 2.22-2.10 (m, 2H, CH2), 1.34 (t, 3H, J = 7.5 Hz,

CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 173.5 (C=O), 139.6 (aromatic C), 136.5 (aromatic C), 133.1 (aromatic CH), 129.4 (vinylic CH), 126.8 (aromatic CH), 124.6 (aromatic CH), 122.9 (vinylic CH), 114.7 (aromatic CH), 71.1 (CH), 67.5 (CH), 66.3 (CH), 51.2 (aromatic

C), 45.7 (CH2, SO2Et), 45.3 (CH2), 38.6 (CH2), 22.6 (CH3), 7.9 (CH3, SO2Et). MS (ESI) m/z (%):385 [M+Na]+ (100), 363 [M+H]+ (56), 345 [M-OH]+ (15). + HRMS (ESI): [M+Na] C18H22N2O4NaS: calcd. 385.1192, found 385.1194.

(3aR,4R,6aS,11a1S)-tert-butyl 4-acetoxy-7-((Z)-3-bromoacryloyl)-3a,4,6a,7-tetrahydro- 1H-pyrrolo[2,3-d]carbazole-3(2H)-carboxylate (376)

3-bromoacryloyl chloride (206 mg, 1.216 mmol, 1.5 eq) was added to the crude product 360

(300 mg, 0.810 mmol, 1 eq) in CH2Cl2 (10 mL), then triethylamine (1.5 eq), EDAC (1.5 eq) was added to this mixture. The reaction mixture was stirred for 6h at room temperature. Then

176 the reaction was stopped by addition of H2O (20 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate 70:30) to provide 376 (162 mg, 0.3226 mmol, 40%) as yellow solid. M.p = 92.9-94.6°C.

Rf = 0.41 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr): 2976, 1739, 1696, 1480, 1391, 1239, 1170, 932, 753, 659 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.72 (d, 1H, J = 9.6 Hz, aromatic CH), 7.28-7.24 (m, 2H, aromatic, vinylic CH), 7.10-7.02 (m, 3H, 2 aromatic, vinylic CH), 5.92 (s, 2H, 2 vinylic CH), 5.50 (s, 1H, CH), 4.72 (s, 1H, CH), 4.06 (s, 1H, CH), 3.76 (s, 1H, CH), 3.50 (s, 1H,

CH), 2.16 (s, 2H, CH2), 1.94 (s, 3H, OAc), 1.48 (s, 9H, Boc). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 170.5 (C=O, OAc), 161.8 (C=O, acryloyl), 155.2 (C=O, Boc), 140.22 (aromatic C), 136.5 (aromatic C), 129.4 (aromatic CH), 128.9 (aromatic CH), 128.6 (2 vinyl C), 126.6 (2 vinyl C), 125.4 (aromatic CH), 122.9 (aromatic CH), 80.6

(Cq, Boc), 69.03 (CH), 64.02 (CH), 63.3 (CH), 52.1 (aromatic C), 45.03 (CH2), 38.7 (CH2),

28.6 (3CH3, Boc), 21.1 (CH3, OAc). + HRMS (ESI): [M+Na] C24H27N2O5 Br Na: calcd. 525.1001, found 525.0997.

(3aR,4R,6aS,11a1R)-tert-butyl 4-hydroxy-7-(2-(trimethylsilyl)ethylsulfonyl)-3a,4,6a,7- tetrahydro-1H-pyrrolo[2,3-d]carbazole-3(2H)-carboxylate (377)

To a solution of product 360 (84 mg, 0.157 mmol, 1 eq) in MeOH (4 mL), ,water (1 mL) and

K2CO3 (65 mg, 0.474 mmol, 3 eq). The reaction mixture was stirred and the completion of the hydrolysis was monitored by TLC (EtOAc 100%). After 3h the reaction was quenched by addition of water. The two layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate, 100%) afforded 377 (62 mg, 0.1218 mmol, 78 %) as a white solid. Mp = 154.2-155.9 °C.

Rf = 0.32 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 3368, 2954, 1668, 1478, 1399, 1149, 1055, 844, 752 cm-1 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.37-7.34 (m, 1H, aroamtic CH), 7.26-7.24 (m, 1H, aroamtic CH), 7.05-7.03 (m, 1H, aroamtic CH), 6.93-6.91 (m, 1H, aroamtic CH), 5.99 (d, 1H, J = 10.5 Hz, vinylic CH), 5.90 (d, 1H, J = 10.2 Hz, vinylic CH), 5.52 (s, 1H, OH), 4.57 (s,

1H, CH), 4.17 (d, 1H, J = 7.9 Hz, CH), 3.73 (d, 1H, J = 8.3 Hz, CH), 3.61-3.60 (m, 2H, CH2),

3.06-3.01 (m, 2H, CH2), 2.16-2.11 m, 2H, CH2), 1.54 (s, 9H, Boc), 1.07-1.00 (m, 2H, CH2),

0.0005 (s, 9H, SiMe3).

177 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 157.6 (C=O), 139.8 (aromatic C), 137.1 (aromatic C), 132.9 (saromatic CH), 129.2 (vinylic CH), 127.1 (aromatic CH), 124.5 (aromatic CH), 123.2 (vinylic CH), 114.5 (aromatic CH), 81.7 (Cq, Boc), 71.4 (CH), 67.1 (sCH), 66.7 (CH),

51.7 (aromatic C), 47.8 (CH2), 44.1 (CH2), 38.6 (CH2), 28.5 (3CH3, Boc), 10.1 (CH2), -1.9

(3CH3, SiMe3). + + + MS (ESI) m/z (%):515 [M+Na] (100), 493 [M+H] (43), 419 [(M+H)-SiMe3] (65). + HRMS (ESI): [M+Na] C24H36N2O5NaSSi: calcd. 515.2006, found 515.2017.

(3aR,4R,6aS,11a1R)-tert-butyl4-(ethylthiocarbonothioyloxy)-7-(2 (trimethylsilyl)ethylsulfonyl)-3a,4,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazole-3(2H)- carboxylate (378)

Sodium hydride (4 mg, 0.0.165 mmol and 1.4 eq) was suspended in dry THF (4 mL) at 0 °C and product 377 (58 mg, 0.118 mmol, 1 eq) was added. The solution was stirred at r.t for 1h. Carbon (0.06 mL, 0.944 mmol, 8 eq) was slowly added and the solution was stirred for 2 h. Ethane iodide (0.06 mL, 708 mmol, 6 eq) was added and the solution stirred for 4 h.

The reaction was quenched with saturated NH4Cl (20 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic phase was dried over MgSO4, and the solvent was removed in vacuo. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ethyl acetate 95:5) to provide 378 (59 mg, 0.0972 mmol, 83%) as a white solid. M.p = 142-144 °C.

Rf = 0.78 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr) = 3447, 2925, 1692, 1478, 1399, 1200, 1152, 751, 579 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.38-7.35 (m, 1H, aromatic CH), 7.27-7.22 (m, 1H, aromatic CH), 7.05-7.04 (m, 2H, 2 aromatic CH), 6.36-6.32 (m, 1H, vinylic CH), 6.06 (broad s, 1H, vinylic CH), 4.66 (s, 1H, CH), 4.08 (broad s, 1H, CH), 3.89 (broad s, 1H, CH), 3.48-

3.39 (m, 2H, CH2), 3.06-2.93 (m, 4H, 2CH2, SO2Et, SES), 2.27-2.17 (m, 2H, CH2), 1.47 (s,

9H, 3CH3, Boc), 1.25-1.21 (m, 3H, CH3, SEt), 1.01-0.88 (m, 2H, CH2), 0.0004 (s, 9H,

SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 156.6 (C=S), 142.4 (C=O), 137.1 (aromatic C), 132.6 (aromatic C), 131.3 (aromatic CH), 128.9 (aromatic CH), 126.3 (aromatic CH), 125.4 (d, 2 vinylic C), 116.05 (aromatic CH), 82.7 (Cq, Boc), 67.4 (CH), 65.3 (CH), 53.8 (CH), 49.3

(aromatic C), 46.02 (CH2, SES), 41.1 (CH2), 32.2 (CH2), 30.4 (3CH3, Boc), 25.9 (CH2, SEt),

15.3 (CH3, SEt),11.9 (CH2, SES), 0.0012 (3CH3, SiMe3). + + MS (ESI) m/z (%): 419 [M+H-t-Bu-OCS2Et] (100), 475 [M-OCS2Et] (24), 619 [M+Na]+(34). + HRMS (ESI): [M+Na] C27H40N2O5 Na S3Si: calcd. 619.1760, found 619.1779.

178 4-Methyl-N-(2-((4aS,9aS)-9-(2-(trimethylsilyl)ethylsulfonyl)-9,9a-dihydro-4aH-carbazol- 4a-yl)ethyl)benzenesulfonamide. (380)

TsCl (0.56 g, 2.93 mmol, 1.1 eq) was dissolved in Pyridine (4.5 mL), the mixture was stirred at 0°C. The crude amine 351 (1 g, 2.66 mmol, 1eq) was dissolved in pyridine (4.5 mL) and then was added to the reaction mixture. The reaction was stirred at r.t for 24h. The mixture was diluted with Ethyl acetate and the organic layer was washed a lot of time with HCl 1M. The solvent was removed under vacuum. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 70/30 then 60:40) afforded 380 (1.042 g, 1.966 mmol, 74% over 2 steps) as a white solid. M.p = 59.8 - 62.1°C.

Rf = 0.29 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2972, 1597, 1476, 1335, 1152, 842, 696 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.71 (d, 2H, J = 6.2 Hz, 2 aromatic CH, Ts), 7.37 (d, 1H, J = 6.06 Hz, aromatic CH), 7.30 (d, J = 6.06 Hz, 2 aromatic CH), 7.16-7.12 (m, 1H, aromatic CH), 7.05-6.97 (m, 2H, 2 aromatic CH), 6.01-5.95 (m, 2H, 2 vinylic CH), 5.89-5.85 (m, 1H, vinylic CH), 5.59 (d, 1H, J = 7.2 Hz, vinylic CH), 4.91 (d, 1H, J = 2.5 Hz, CH), 4.84

(t, 1H, J = 4.7 Hz, NH), 3.06-2.91 (m, 4H, 2CH2), 2.42 (s, 3H, Ts), 2.12-2.07 (m, 1H, CH),

1.92-1.85 (m, 1H, CH),1.11-0.96 (m, 2H, CH2), -.0001 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.6 (aromatic C), 141.1 (Cq, Ts), 136.7 (aromatic C), 136.1 (Cq, Ts), 130.5 (aromatic CH), 129.9 (2 aromatic CH,Ts), 128.3 (vinylic CH), 127.1 (2 aromatic CH,Ts), 125.1 (aromatic CH), 123.6 (aromatic CH), 123.5 (vinylic

CH), 123.4 (vinylic CH) 121.4 (aromatic CH), 113.9 (vinylic CH), 65.2 (CH), 48.9 (CH2),

46.6 (aromatic C), 41.9 (CH2), 38.9 (CH2), 21.6 (CH3, Ts), 9.9 (CH2), -1.9 (3CH3, SiMe3). MS (ESI) m/z (%):213 [(M+H)-Ts and SES]+ (100), 553 [M+Na]+ (26) . + HRMS (ESI): [M+Na] C26H34N2O4NaSiS2: calcd. 553.1621, found 553.1623.

1,6,7,13,14,25-Hexahydro-14-tosylpyrrolo[3,2-8]carbazole. (381)

CsF (4.21 g, 27.7 mmol, 15 eq) was added to a solution of product 380 (0.979 g, 1.847 mmol,

1 eq) in CH3CN (40 mL). The resulting suspension was heated at 80 °C for 30 h. After cooling to r.t, the solvent was removed under vacuum, Purification by silica gel

179 chromatography (Silica gel deactivated, Dichloromethane / methanol: 95/5) afforded 381 (278 mg, 0.759 mmol, 41%yield) as a white solid. M.p = 172.4-174.1°C.

Rf = 0.89 (petroleum ether/ ethyl acetate: 70/30). IR (solid, KBr):  = 3414, 2373, 1465, 1317, 1153, 1027, 725, 660 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.57 (d, 2H, J = 6.2 Hz, 2 aromatic CH, Ts), 7.13 (d, 2H, J = 5.8 Hz, 2 aromatic CH), 6.93-6.91 (m, 2H, 2 aromatic CH), 6.62-6.60 (m, 1H, aromatic CH), 6.46 (d, 1H, J = 6.06 Hz, aromatic CH), 5.63-5.55 (m, 2H, 2 vinylic CH), 5.06 (s, 1H, NH), 3.36-3.31 (m, 1H, CH), 2.94-2.88 (m, 1H, CH), 2.73-2.68 (m, 1H, CH), 2.29 (s,

3H, CH3, Ts), 2.26-2.24 (m, 1H, CH), 2.20-2.14 (m, 1H, CH), 2.03-1.95 (m, 1H, CH), 1.91-

1.81 (m, 2H, CH2). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 147.8 (aromatic C), 142.9 (Cq, Ts), 137.2 (Cq, Ts), 131.5 (aromatic C), 129.5 (2 aromatic CH, Ts), 129.3 (aromatic CH), 128.3 (aromatic CH), 127.1 (2 aromatic CH, Ts), 125.8 (vinylic CH), 122.6 (aromatic CH), 119.2 (aromatic CH),

109.8 (vinylic CH), 90.3 (aromatic C), 56.6 (aromatic C), 46.9 (CH2), 34.7 (CH2), 30.9 (CH2),

22.9 (CH2), 21.4 (CH3, Ts). MS (ESI) m/z (%):213 [(M+H)-Ts]+ (100), 367 [M+H]+ (6), 389 [M+Na]+ (4). + HRMS (ESI): [M+H] C21H23N2O2S: calcd. 367.1480, found 367.1486.

N-(2-((4aS,9aS)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-4-methylbenzenesulfonamide. (382)

TBAF (1.523 g, 5.824 mmol, 5 eq) was added to a solution of product 380 (0.772 g, 1.4561 mmol, 1 eq) in DMPU (10 mL). The resulting suspension was stirred at r.t for 4h. The solvent was removed under vacuum. Purification by silica gel chromatography (Silica gel deactivated, Dichloromethane / methanol: 95/5) afforded 382 (391 mg, 1.0678 mmol, 73%) as a brown oil.

Rf = 0.27 (petroleum ether/ ethyl acetate: 70/30). IR (film, NaCl):  = 3421, 2951, 1578, 1469, 1157, 666 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.61 (d, 2H, J = 6.02 Hz, 2 aromatic CH, Ts), 7.19 (d, 2H, J = 6.06 Hz, 2 aromatic CH), 6.91-6.82 (m, 2H, 2 aromatic CH), 6.66-6.62 (m, 1H, aromatic CH), 6.56 (d, 1H, J = 5.6 Hz, aromatic CH), 5.83-5.75 (m, 2H, 2 vinylic CH), 5.64- 5.61 (m, 1H, vinylic CH), 5.43 (d, 1H, J = 7.2 Hz, vinylic CH), 5.05 (t, 1H, J= 4.7 Hz, NH),

4.16 (d, 1H, J = 3.6 Hz, CH), 2.90- 2.77 (m, 2H, CH2), 2.33 (s, 3H, CH3, Ts), 1.99-1.92 (m, 1H, CH), 1.76-1.69 (m, 1H, CH). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 149.5 (aromatic C), 143.3 (Cq, Ts), 136.9 (aromatic C), 134.1 (Cq, Ts), 131.4 (vinylic CH), 129.6 (2 aromatic CH, Ts), 127.5 (vinylic CH), 126.9 (2 aromatic CH, Ts), 124.6 (aromatic CH), 124.2 (aromatic CH), 123.1 (aromatic

180 CH), 121.5 (vinylic CH), 119.8 (aromatic CH), 110.4 (vinylic CH), 60.9 (CH), 47.4

(aromatic C), 40.6 (CH2), 38.9 (CH2), 21.5 (CH3, Ts). MS (ESI) m/z (%):367 [M+H]+ (100), 389 [M+Na]+ (73), 213 [(M+H)-Ts]+ (31). + HRMS (ESI): [M+H] C21H23N2O2S: calcd. 367.1480, found 367.1481.

4-Methyl-N-(2-((4aS)-9-((Z)-3-(trimethylsilyl)acryloyl)-9,9a-dihydro-4aH-carbazol-4a- yl)ethyl)benzenesulfonamide. (383)

Product 382 (280 mg, 0.773 mmol, 1 equiv.) was dissolved in CH2Cl2 (15 mL), then (E)-3- (trimethylsilyl)acrylic acid (1.1 equiv.), EDAC (1.5 equiv.), HOBt (1.3 equiv.) were added to this mixture. The reaction mixture is stirred 30h at room temperature. Then the reaction was stopped by addition of NaHCO3 (10 mL), extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column-chromatography (silica gel, Ep: EtOAc 80:20 then 50:50) to afford the desired product 383 (216 mg, 0.4388 mmol, 57% yield (2 step)) as a yellow solid. M.p = 74.4-.75.6°C.

Rf = 0.29 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr): = 3445, 2955, 1634, 1477, 1395, 1157, 868, 756, 551 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.44 (d, 2H, J = 7.5 Hz, 2 aromatic CH, Ts), 7.13 (s broad, 1H, CH), 7.03-6.97 (m, 4H, 4 aromatic CH), 6.79 (s, 2H, aromatic CH, Ts), 6.53 (s broad, 1H, CH), 5.65 (s, 3H, 3 vinylic CH), 5.40 (s broad, 1H, NH), 5.02 (s, 1H, CH), 4.45 (s,

1H, vinylic CH), 2.74 (s, 2H, CH2), 2.18 (s, 3H, CH3, Ts), 1.67-1.57 (m, 2H, CH2), -0.03 (s,

9H, SiMe3). GC/MS (RT = 30.32 min) , m/z: 492.3.

(3aR,11a1S)-3-tosyl-7-((E)-3-(trimethylsilyl)acryloyl)-2,3,3a,4,6a,7-hexahydro-1H- pyrrolo[2,3-d]carbazol-4-yl acetate. (384)

Starting material 383 (1 eq.) and sodium acetate (2.0 eq.) were dissolved in DMSO (0.1M) and the solution was flushed with dioxygen. Pd(OAc)2 (0.1 eq.) was added and the resulting

181 solution was stirred for 24h at 55°C. The reaction mixture was diluted with a large volume of water and was extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 80/20) afforded 362 (10 mg, 0.0181 mmol, 18%) as a colorless oil.

Rf = 0.41 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl): = 3245, 2985, 1653, 1397, 1395, 1157, 878, 756, cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.92 (d, 2H, J = 12.1 Hz, 2 aromatic CH, Ts), 7.51 (d, 2H, J = 11.7 Hz, 2 aromatic CH, Ts), 7.30 (broad s, 1H, vinylic CH), 7.17 (t, 1H, J = 11.8 Hz, 1 aromatic CH), 6.93 (broad s, 1H, vinylic CH), 6.60 (s, 2H, 2 aromatic CH), 6.12 (broad s, 1H, vinylic CH), 5.77 (broad s, 1H, vinylic CH), 4.30 (s, 1H, CH), 3.66 (broad s, 1H, CH),

3.3 (broad s, 1H, CH), 2.57 (s, CH3, Ts), 2.13-2.04 (m, 2H, CH2), 1.65 (broad s, 2H, CH2),

1.45( s, CH3, OAc), 0.19 (s, 9H, SiMe3). GC/Ms (RT = 9.80 min) , m/z: 550.3.

N-(2-(1-phenylcyclohexa-2,5-dienyl)ethyl)ethanesulfonamide (385)

Product 236 (190 mg, 0.96 mmol, 1 eq) was dissolved in CH2Cl2 (10 mL), pyridine (152 mg, 1.92 mmol, 2 eq) and ethyl sulfonyl chloride (136 mg, 1.056 mmol, 1.1 eq) were added. Stirring was continued for 12h at the room temperature. The reaction was stopped by addition of water (50 mL) and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purification by silica gel chromatography (Petroleum ether / ethyl acetate: 8/2) afforded 385 (148 mg, 0.508 mmol, 53% over 2 steps) as a colourless oil.

Rf = 0.34 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl):  = 3291, 2879, 1420, 1319, 1144, 1080, 914, 766, 699 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.20-7.16 (m, 4H, 4 aromatic CH), 7.11-7.05 (m, 1H, aroamtic CH), 5.79-5.75 (m, 2H, 2 vinylic CH), 5.51-5.47 (m, 2H, 2 vinylic CH), 4.38 (t,

1H, J = 6.04 Hz, NH), 3.05-3.02 (m, 2H, CH2), 3.02 (q, 2H, J = 1.14 Hz, CH2, SO2Et), 2.88

(s, 2H, bisallylic CH), 1.99-1.95 (m, 2H, CH2), 1.22 (t, 3H, J = 7.3 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 147.2 (aromatic C), 131.7 (2 vinylic CH), 128.5 (2 aromatic CH), 126.4 (2 vinylic CH), 124.5 (aromatic CH), 124.7 (2 aromatic CH), 46.8 (CH2,

SO2Et), 43.1 (aromatic C), 40.7 (CH2), 40.2 (CH2), 26.1 (CH2) 8.4 (CH3, SO2Et). MS (ESI) m/z (%): 314 [M+Na]+ (100). + HRMS (ESI): [M+Na] C16H21NO2NaS: calcd. 314.11907, found 314.1192.

182 (3aR,7aS)-1-(ethylsulfonyl)-3a-phenyl-2,3,3a,7a-tetrahydro-1H-indole (386)

Product 385 (70 mg, 0.241 mmol, 1 eq) in a glass pressure tube equipped with a magnetic stir bar was treated with Cs2CO3 (78 mg, 0.41 mmol, 1 eq) and the given copper acetate (0.723 mmol, 3 eq) in DMF (3 mL) under N2. The tube was capped and the mixture was heated, stirring, for the indicated time in an oil bath. The reaction mixture was allowed to cool to r.t., and diluted with Et2O (20 mL). This mixture was then washed with sat. aq. EDTANa2 (10 mL). The organic layer was dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (ethyl acetate / Hexane: 20/80) afforded 386 (43 mg, 0.1487 mmol, 53% over 2 steps) as a colourless oil.

Rf = 0.34 (petroleum ether/ ethyl acetate: 80/20). IR (film, NaCl):  = 2940, 1495, 1329, 1238, 1147, 967, 759, 699 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.30-7.17 (m, 5H, 5 aromatic CH), 6.00-5.93 (m, 3H, 3 vinylic CH), 5.62 (d, 1H, J =9.8 Hz, vinylic CH), 4.56 (d, 1H, J = 4.1 Hz, CH), 3.66-

3.60 (m, 1H, CH), 3.27-3.19 (m, 1H, CH), 2.78-2.70 (m, 2H, CH2,, SO2Et), 2.59-2.52 (m, 1H,

CH), 2.50-2.18 (m, 1H, CH), 1.14 (t, 3H, J = 7.5 Hz, CH3, SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.5 (aromatic C), 133.6 (vinylic CH), 128.7 (2 aromatic CH), 127.3 (vinylic CH), 125.9 (2 aromatic CH), 125.8 (aromatic CH), 124.2

(vinylic CH), 122.3 (vinylic CH), 62.5 (CH), 50.4 (aromatic C), 47.4 (CH2, SO2Et), 46.5

(CH2), 37.7 (CH2) 7.9 (CH3, SO2Et). MS (ESI) m/z (%): 290 [M+H]+ (100). + HRMS (ESI): [M+Na] C16H20NO2S: calcd. 290.1209, found 290.1218.

N-(2-((4aS,9aR)-9-(ethylsulfonyl)-1-(2,2,6,6-tetramethylpiperidin-1-yloxy)-2,4a,9,9a- tetrahydro-1H-carbazol-4a-yl)ethyl)-4-methylbenzenesulfonamide. (388)

Product 387 (70 mg, 0.152 mmol, 1 eq) in a glass pressure tube equipped with a magnetic stir bar was treated with Cs2CO3 (49 mg, 0.152 mmol, 1 eq) and the given copper acetate (0.456 mmol, 3 eq), TEMPO (5eq) in DMF (3 mL) under N2. The tube was capped and the mixture was heated, stirring, for the indicated time in an oil bath. The reaction mixture was allowed to cool to r.t., and diluted with Et2O (20 mL). This mixture was then washed with sat. aq.

EDTA.Na2 (10 mL). The organic layer was dried over Na2SO4, and concentrated under

183 vacuum. The resulting oil was purified by silica gel chromatography (ethyl acetate / Hexane: 20/80) afforded 388 (42 mg, 0.0682 mmol, 45%) as a colorless oil.

Rf = 0.37 (petroleum ether/ ethyl acetate: 70/30). IR (film, NaCl):  = 3294, 2930, 1598, 1458, 1347, 1170, 1093, 815, 713, 662 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.63 (d, 2H, J= 8.3 Hz, 2 aromatic CH, Ts ), 7.25- 7.19 (m, 3H, 3 aroamtic CH), 7.13-7.08 (m, 1H, aromatic CH), 6.98-6.90 (m, 2H, 2 aromatic CH), 5.63-5.58 (m, 2H, 2 vinylic CH), 4.75 (s, 1H, NH), 4.24 (d, 1H, J =7.9 Hz, CH), 4.07-

4.06 (m, 1H, CH), 3.23-3.16 (m, 2H, CH2, SO2Et), 2.94-2.90 (m, 2H, CH2), 2.56-2.50 (m,

1H), 2.34 (s, 3H, Ts) 2.12-2.06 (m, 1H), 1.85-1.79 (m, 2H, CH2), 1.37 (t, 3H, J = 7.5 Hz, CH3,

SO2Et), 1.18-0.98 (m, 6H, 3CH2, TEMPO), 0.84-0.81 (m, 12H, 4CH3, TEMPO). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.4 (aromatic C), 139.9 (aromatic C, Ts), 138.6 (aromatic C), 136.7 (aromatic C, Ts), 129.7 (vinylic CH), 128.9 (2 aromatic CH), 128.2 (2 aromatic CH), 127.1 (vinylic CH), 125.7 (aromatic CH), 124.4 (aromatic CH), 123.1

(aromatic CH), 116.8 (aromatic CH), 77.6 (CH), 69.1 (CH), 50.1 (aromatic C), 46.2 (CH2),

40.5 (CH2, SO2Et), 39.5 (CH2), 39.4 (2CH2) 27.2 (CH2), 21.5 (CH3, Ts), 17.3 (CH2), 7.9 (CH3,

SO2Et). MS (ESI) m/z (%):616 [M+H]+ (70), 638 [M+Na]+ (38). + HRMS (ESI): [M+H] C32H46N3O5S2: calcd. 616.2873, found 616.2878.

4-Methyl-N-(2-((4aS,9aR)-1-(2,2,6,6-tetramethylpiperidin-1-yloxy)-9-(2 (trimethylsilyl)ethylsulfonyl)-2,4a,9,9a-tetrahydro-1H-carbazol-4a- yl)ethyl)benzenesulfonamide. (389)

Product 359 (100 mg, 0.1879 mmol, 1 eq) in a glass pressure tube equipped with a magnetic stir bar was treated with Cs2CO3 (61.2 mg, 0.1879 mmol, 1 eq) and the given copper ethylhexanoate (0.5637mmol, 3 eq), TEMPO (5eq) in DMF (3 mL) under N2. The tube was capped and the mixture was heated, stirring, for the indicated time in an oil bath. The reaction mixture was allowed to cool to r.t., and diluted with Et2O (20 mL). This mixture was then washed with sat. aq. EDTANa2 (10 mL). The organic layer was dried over Na2SO4, and concentrated under vacuum. The resulting oil was purified by silica gel chromatography (ethyl acetate / Hexane: 25/75) afforded 389 (67 mg, 0.0975 mmol, 52%) as a white solid. M.p = 122.2-123.6°C.

Rf = 0.39 (petroleum ether/ ethyl acetate: 80/20). IR (solid, KBr):  = 2930, 1598, 1458, 1336, 1251, 1094, 842, 752 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.67 (d, 2H, J = 8.3 Hz, 2 aromatic CH, Ts), 7.25- 7.10 (m, 4H, 4 aromatic CH), 7.01-6.93 (m, 2H, 2 aromatic CH), 5.68-5.62 (m, 2H, 2 vinylic

184 CH), 4.68 (s, 1H, NH), 4.35 (d, 1H, J = 8.3 Hz, CH), 4.11-4.04 (m, 1H, CH), 3.32-2.93 (m,

4H, 2CH2), 2.60-2.52 (m, 1H, CH), 2.37 (s, 3H, Ts) 2.15-2.06 (m, 1H, CH), 1.95-1.77 (m, 2H,

CH2), 1.45-1.25 (m, 6H, 3CH2, TEMPO), 1.09-1 (m, 12H, 4CH3, TEMPO), 0.91-0.84 (m, 2H,

CH2), 0.001 (s, 9H, SiMe3). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.4 (aromatic C), 140.3 (Cq, Ts), 139.1 (aromatic C), 136.9 (Cq, Ts), 129.8 (2 aromatic CH, Ts), 129.2 (aromatic CH), 128.2 (aromatic CH), 127.3 (2 aromatic CH), 125.9 (vinylic CH), 124.5 (vinylic CH), 123.1

(aromatic CH), 117.2 (aromatic CH), 77.6 (CH), 69.2 (CH), 50.5 (aromatic C), 49.6 (CH2),

40.6 (CH2), 39.7 (2CH2), 39.4 (CH2) 27.5 (CH2), 21.7 (CH3, Ts), 17.4 (CH2), 9.9 (CH2), -1.7

(3CH3, SiMe3). MS (ESI) m/z (%):688 [M+H]+ (100), 710 [M+Na]+ (28). + HRMS (ESI): [M+H] C35H54N3O5SiS2: calcd. 688.3268, found 688.3341.

N-(2-((4aS,9aS)-9-(ethylsulfonyl)-9,9a-dihydro-4aH-carbazol-4a-yl)ethyl)-4- methylbenzenesulfonamide. (391)

TsCl (394 mg, 2.06 mmol, 1.1 eq) was dissolved in pyridine (2 mL). The mixture was stirred at 0°C. Crude amine 334 (572 mg, 1.88 mmol, 1 eq) was dissolved in pyridine (2 mL), and then was added to the reaction mixture. The reaction was stirred at r.t for 4h. The mixture was diluted with ethyl acetate and the organic layer was washed with a lot of HCl (0.1M). The solvent was removed under vacuum. Purification by silica gel chromatography (petroleum ether/ ethyl acetate, 60:40) afforded 391 (412 mg, 0.8995 mmol, 48% over 2 steps) as a white solid. M.p = 55.4 – 57.1°C.

Rf = 0.25 (petroleum ether/ ethyl acetate: 70/30). IR (solid, KBr):  = 3289, 2940, 1597, 1477, 1341, 1235, 1154, 1093, 815, 664 cm-1. 1 H NMR (CDCl3, 300 MHz): δ (ppm) = 7.72 (d, 2H, J = 8.3 Hz, 2 aroamtic CH), 7.39 (d, 1H, J = 8.3 Hz, aromatic CH), 7.31-7.28 (m, 2H, 2 aromatic CH), 7.17-7.12 (m, 1H, aromatic CH), 7.05-7 (m, 2H, 2 aromatic CH), 5.97-5.84 (m, 3H, 3 vinylic CH), 5.61 (d, 1H, J = 9.4

Hz, vinylic CH), 5.13 (t, 1H, J = 6 Hz, NH), 4.90 (s, 1H, CH), 3.14-2.90 (m, 4H, 2CH2),

2.43 (s, 3H, CH3, Ts), 2.14-2.04 (m, 1H),1.91-1.81 (m, 1H), 1.38 (t, 3H, J= 7.5 Hz, CH3,

SO2Et). 13 C NMR (CDCl3, 75.5 MHz): δ (ppm) = 143.6 (aromatic C), 140.6 (aromatic C, Ts), 136.6 (aromatic C), 136.4 (aromatic C, Ts), 129.8 (2 aromatic CH, Ts), 128.2 (vinylic CH), 127.1 (2 aromatic CH, Ts), 124.6 (aromatic, CH), 123.9 (2 aromatic CH), 123.8 (vinylic CH), 123.5 (vinylic CH), 121.4 (aromatic CH) 114.1 (vinylic CH), 65.3 (CH), 46.5 (aromatic C), 45.8

(CH2, SO2Et), 42.2 (CH2), 38.9 (CH2), 21.5 (CH3, Ts), 7.8 (CH3, SO2Et). MS (ESI) m/z (%):481 [M+Na]+ (100), 459 [M+H]+ (55).

185

Towards the Synthesis of Monoterpenoids Indole Alkaloids of the Aspidospermatan and Strychnan Type.

Résumé: L'objectif de ce travail était d'accéder au squelette des alcaloïdes de type Aspidosperma et Strychnos à partir d'arylcyclohexa-2,5-diènes. Ces derniers sont d'abord synthétisés par réaction de Birch alkylante, puis ont été désymétrisés dans un premier temps par des réactions de Michael. Cette réaction fournit la cétone de Büchi, le noyau tétracyclique des alcaloïdes Aspidosperma en seulement en 6 étapes et un rendement global de 17%. Dans un second temps, la réaction d'amination oxydante catalysée par des métaux (Pd, Cu) a été développée. Cette réaction a permis un accès rapide au squelette pentacyclique d’aza-aspidospermanes et au squelette tétracycliques des alcaloïdes de type Strychnos. En parallèle, nous avons décrit une approche vers le squelette pentacyclique de la mossambine et la strychnine.

Mots clés : Synthèse d'alcaloïdes, Aspidosperma, Strychnos, Cétone de Büchi, Réaction de Birch alkylante, Désymétrisation, Addition de Michael, Amination oxydante.

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Abstract: The aim of this work was to access the skeleton of the Aspidosperma and the Strychnos alkaloids using arylcyclohexa-2,5-dienes as common synthetic precursors. Initially, these arylcyclohexadienes were synthesized through Birch reductive alkylation reactions. The desymmetrization of these cyclohexadienes was developed via the Michael addition reaction, providing the Büchi ketone, the tetracyclic core of Aspidosperma alkaloids, in only 6 steps and 17% overall yield. On the other hand, we described the oxidative amination reaction catalyzed by metals (Pd, Cu). The palladium oxidative amination reaction allowed a fast access to the pentacyclic framework of aza-aspidospermanes and the tetracyclic framework of the strychnos. In parallel, we have described an approach toward the pentacyclic skeleton of mossambine and strychnine.

Key words: Alkaloid synthesis, Aspidosperma, Strychnos, Büchi ketone, Birch reductive alkylation, Desymmetrization, Michael addition, Oxidative amination.

Discipline: Sciences Chimiques

Institut des Sciences Moléculaires UMR 5255 CNRS 351 cours de la libération 33405 TALENCE Cedex. France