First Total Synthesis of (+)-Gelsedine

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First total synthesis of (+)-gelsedine

Beyersbergen van Hen, W.G.

Publication date 1999

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Citation for published version (APA): Beyersbergen van Hen, W. G. (1999). First total synthesis of (+)-gelsedine.

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Download date:01 Oct 2021 CHAPTER 1

INTRODUCTION

1.1 The Gelsemium Alkaloids

The genus Gelsemium belongs to the plant family Loganiaceae and consists of three species, viz. Gelsemium elegans Benth., Gelsemium sempervirens Ait., and Gelsemium rankinii Small.1 G. elegans Benth. (in Chinese: Kou-Wen or Hu-Men-Teng) is distributed over southeastern Asia, and has been used in traditional Chinese medicine, as well as a remedy for certain kinds of skin ulcers, and more recently as an analgesic for the palliation of various acute cancer pains.lb G. sempervirens (yellow jasmine) is indigenous to southeastern United States and the highlands of central America. Although this plant causes death and abortion in livestock that feed upon its leaves, it has been used in the treatment of neuralgia and migraine, and spasmodic disorders such as asthma and whooping cough.1* The extracts of this plant are still sold by Vogel as a homeopathic medicine under the name of 'Gelsemium D6 drops' for the treatment of headaches and fever.2 G. rankinii Small also grows in southeastern United States. These three species have all been extensively investigated for the presence of alkaloids since more than a century.

Scheme 1.1 /=\ HO

Me 3 ((+)-gelsemine)

OMe OMe OMe 4 ((+)-humentenine) 5 ((+)-gelselegirie) 6 ((-)-gelsedine)

The alkaloids isolated from these plants have highly compact polycyclic structures and can be classified into six groups based on their skeletal types.la These are the sarpagine-, koumine-, gelsemine-, humentenine-, gelselegine-, and gelsedine-types. Examples of these Chapter 1

types of alkaloids are depicted in Scheme 1.1. The indole alkaloid koumidine (1) belongs to the sarpagine-type. The other five oxindole alkaloids bear the name of the type that they belong to. This thesis deals with the total synthesis of one of these structures, viz. gelsedine (6). Additional examples of the gelsedine-type of the Gelsemium alkaloids are depicted in Scheme 1.2.3The alkaloid gelsedine was isolated as a minor constituent from G sempervirens in 1953 by Schwarz and Marion4' and was later also found to occur in G. elegans.ih The structure of 6 was elucidated by Wenkert5 in 1962 on the basis of a spectroscopic comparison with the 11- methoxy analogue gelsemicine (7), which structure was already determined in 1961 through X- ray crystallography by Przybylska and Marion.6 Gelsedine and gelsemicine have, as can be expected from their structural resemblance, 25 comparable specific rotations [gelsedine: [a] D = -159 (c = 1.35, CHC13), m.p. 172.5-174 °C 25 and gelsemicine: [a] D = -142 (c = 0.95, CHC13), m.p. 171-172 °C], Although the biological activity of gelsedine has not been determined, gelsemicine is thought to constitute the active component in G. sempervirens, from which it was isolated in 1931.7 Gelsemicine proved to be far more toxic (MLD 0.05-0.06 mg/kg in rabbits, intravenous injection) than the principal alkaloid gelsemine (3) (MLD 180 mg/kg).lb

OMe OMe OMe 6 ((-)-gelsedine, R = H) 8 (14-hydroxygelsedine, R = H) 10 (gelsenicine, R = H) 7 ((-)-gelsemicine, R = OMe) 9 (14-hydroxygelsemicine, R = OMe) 11 (14-hydroxygelsenicine, R = OH)

More recently, the 14-hydroxy analogue of gelsedine (8)8 was isolated from both G. sempervirens and G. elegans. The alkaloids 14-hydroxygelsemicine (9)9, gelsenicine (10)10 and 14-hydroxygelsenicine (ll)10a11 were solely found in G. elegans. How these characteristic 14- hydroxy analogues evolve biogenetically is not yet known. Nevertheless, a tentative explanation for the biosynthesis of gelsedine is described in the next section.

1.2 Biogenetic Considerations

Although the transformation of [6-I4C]-strictosidine into gelsemine in Gelsemium sempervirens with 0.47% incorporation has been reported, the exact biosynthetic pathway for

10 Introduction the Gelsemium alkaloids is still vague.12 It is envisioned that the biosynthesis starts with the condensation of tryptamine (12) and secologanin (13) followed by a Pictet-Spengler cyclization to give strictosidine (14) (Scheme 1.3).la Hydrolysis of the glycoside bond furnishes aldehyde 15. An intramolecular C-C bond formation between C-5 and C-16 in 15 would provide intermediate 16, the precursor for the sarpagine-type alkaloids, viz. koumidine (1). By C/D ring-cleavage and simultaneous ether linkage formation between C-3 and the primary alcohol at C-17 in 1, anhydrovobasinediol (17), also a sarpagine-alkaloid, would be generated.

Scheme 1.3

OHC vOGIc NH2 W // + H" Me0 C ,£>Glc H 2 12 (tryptamine) 13 (secologanin) H Me02C 14 (strictosidine)

O 17 (anhydrovobasinediol) 4 (humentenine) 6 (gelsedine)

Subsequent enzymatic oxidation of anhydrovobasinediol (17) would first provide the humantenine-type oxindole alkaloids having the S-configuration at the C-7 spiro-center, viz. 4. Ring contraction of the six-membered ring through the elimination of the C-21 carbon would furnish the gelsedine-type alkaloids, viz. 6. The conversion from koumidine into gelsedine is illustrated in Section 1.4 by the biomimetic synthesis of gelselegine, gelsenicine and gelsedine by Sakai.

11 Chapter 1

1.3 Total Syntheses of Koumine and Gelsemine

Total syntheses of Gelsemium alkaloids are of relatively recent date. In 1990, Magnus reported the first total synthesis of (+)-koumine.13 En route, the two related alkaloids (+)- koumidine14 and (+)-taberpsychine15 were also synthesized. All these synthetic alkaloids were antipodal to the natural compounds, although both antipodes were accessible.

NMe NMe

3 ((+)-koumine) 1 ((+)-koumidine) 18 ((+)-taberpsychine)

The biomimetic synthesis of (+)-koumine started from (S)-tryptophan, which was converted in four steps into N,N'-dibenzyltryptophan methyl ester 20 (Scheme 1.4). By using Cook's16 improvement of the Pictet-Spengler condensation 20 was treated with 2-ketoglutaric acid/benzene at reflux with provision for the removal of water. The resulting acids (67%) were esterified to give a mixture of diastereomeric methyl esters (ca. 2:1 in 80%). The major trans diastereomer 21 was isolated in 58% by fractional crystallization from methanol on a larger scale. The minor cis diastereomer could be isolated in pure form by chromatography of the mother liquors. The synthesis was continued with the more readily available trans diastereomer 21 to give eventually the antipodes of naturally occurring koumidine, taberpsychine and koumine.

Scheme 1.4

?X02H >C02Me H2OC^-"~-CO2H C02Me 4 steps 67%; W // NHBn NBn 62% N MeOH, Me3SiCl, Bn 58% 19 ((-)-tryptophan) 21 \^C02Me 22% 7 steps pyrrolidine, W // •£> TFA, 68% N N Bn C02Me Bn X. = C0 Me 23 22 2

First, 21 was transformed into the unsaturated acetylenic ester 22 in seven steps. Treatment of 22 with pyrrolidine and trifluoroacetic acid in benzene at reflux gave a mixture

12 Introduction of E- and Z-quinuclidines by reaction of the intermediate enamine with the a,ß-unsaturated acetylenic ester. The minor Z-isomer (12%) was converted into (+)-koumidine in five steps. The major E-isomer 23 (68%) was transformed into allylic alcohol 24 in four steps (Scheme 1.5). At this stage (+)-taberpsychine was synthesized in three steps from intermediate 24. (+)-Koumine was also synthesized from 24 by applying the sequence described in Scheme 1.5.

Fragmentation of 24 by treatment with methyl chloroformate in CH2C12 gave methyl carbamate

26, presumably via the extended iminium ion 25. Reduction with LiAlH4 in THF furnished (+)-18-hydroxy-taberpsychine 27, which is not, as yet, a natural product. When 27 was exposed to Mitsunobu conditions (diethyl azodicarboxylate/Ph3P/imidazole/NaH in THF at reflux) it was converted into (+)-koumine (3) in an intramolecular SN2' reaction. A total number of 21 steps was needed starting from (S)-tryptophan and the overall yield was 0.18%.

Scheme 1.5

4 steps 31% * C02Me

61% Me02CCl

NMe

DEAD, Ph3P NaH, 34% ,vH OH

C02Me 3 ((+)-koumine) 26 R C 25 LiAlH4,78/o|-TiAlH 78°/ r ( = °2Me . ) 27 7fR=(R =M Me)

The second Gelsemium alkaloid to be synthesized via total synthesis was gelsemine. Three syntheses were reported in 1994 by our17 and other groups18 and later other total syntheses of gelsemine were completed by Fukuyama19" and Overman.I9b However, no enantioselective synthesis has appeared to date. The synthesis of our group will be detailed here since it was one of the first to appear (Scheme 1.6). The synthesis started with a Diels-Alder reaction of E-hex-3,5-dien-l-ol20 28 with N- methylmaleimide 29 affording selectively the endo-adduct, imide 30, in excellent yield. Then 30 was converted in five steps into ethoxylactam 31 (E:Z 3:1).21 Subsequent subjection of 31 to BF,OEt, resulted in a highly stereospecific N-acyliminium ion cyclization via intermediate 32 to give aldehyde 33 as a separable 3:1 mixture of isomers at C-5. After elaboration of 33

13 Chapter 1 toward

Scheme 1.6 TIPSO + 28 PhMe, 5 steps_ reflux 22% 0' ^N^Jr\ ° 95% Me 29 BF3-OEt2

TDS = dimethylthexylsilyl S OTf /\-T-""A L-selectride, 0=\ y -* JHF, -78 °C o 3 steps o N .. / 'OoTDS "then PhNTf2 OTDS 40% Me 65% f*b"TIPS 35 34 32 V^

The vinyl triflate 35 served as a suitable functional handle to introduce the spiro- oxindole moiety present in gelsemine and was transformed into anilide 36 in two steps via a Pd-catalyzed aminocarbonylation/protection sequence (Scheme 1.7).

Scheme 1.7 O SEM S OTf Br S V-N , Pd(aba)2 teps LT Vi Et3N' toluene, Q reflux Me ^ ,NlC^OTDS Me 56% 35 36 s, 62%

2 steps 45%

Protection was necessary because Heck cyclizations of such unprotected amides give 223 poor results. Standard Heck cyclization (Pd(OAc),, PPh3, Et3N, MeCN, reflux, 3 days) gave

14 Introduction a single oxindole product possessing the opposite spiro stereochemistry to that required. However, reaction under modified Heck cyclization conditions first reported by Overman22b furnished desired 37 in 56% yield together with 28% of the spiroepimer. Then 37 was converted in three steps into tetrahydropyran 38. After deprotection of the oxindole and selective reduction of the lactam moiety racemic gelsemine 3 was obtained. A total number of 19 steps was needed starting from E-hex-3,5-dien-l-ol and the overall yield was 0.29%. In 1992, the synthesis of the enantiopure alcohol 40, an intermediate in our total synthesis, starting from (S)-malic acid was reported by our group (Scheme 1.8).23 More recently, we have completed the synthesis of the enantiopure a,ß-unsaturated ketone 34, also an intermediate in our total synthesis, starting from (R)-pyrrolinone 4124 using a different approach.20 This synthesis of 34 features a number of improvements compared to the previously discussed synthesis. Both intermediates, 40 and 34, should, in principle, allow the total synthesis of enantiopure gelsemine.

Scheme 1.8 /=\ C02Et HO )—s 5 steps \—( 4 steps H„.)—f„H

H02C C02H -^ ,pr0XXo (S)-malic acid

}*^- ^""0/Pr 3 stePs, TMS / 10 steps 0-^NNl' 73% „„„ 14% 0= 'O/Pr , j '0 OTDS 41 Me 34

1.4 Semisynthesis of Gelsedine

In 1994, a semisynthesis of gelsedine based on a biomimetic approach was reported by Sakai.26 The synthesis started with the conversion of (-)-gardnerine (41), readily available from Gardneria nutans Sieb. (Loganiaceae),27a into (-)-(19E)-koumidine (42) in six steps (Scheme 1.9).27b Treatment of 42 with TrocCl (2,2,2-trichloroethyl chloroforma te) in the presence of MgO in aqueous THF gave ring-opened compound 43. Because of the higher susceptibility to Os04 oxidation of the ethylidene moiety than the indole function, two equivalents of OsOj were used to transform indole 43 into oxindole 44. The stereochemistry of the oxindole at the C-7 spiro-center was confirmed to have the S-configuration by comparison

15 Chapter 1

of the CD spectrum with that of the humantenine-type alkaloids.28 The ethylidene side chain was reformed in a three step procedure. Treatment with Nal and TMSC1 in MeCN effected the double-bond migration in 45 to provide enamide 46, which was converted to the diol 47 in two steps.

Scheme 1.9 /=r\ HO R °sC\ \ OH OH 52% O R 44 41 ((-)-gardnerine, R = OMe) 1 74% 3 steps 6 ste s 62 42 ((19E)-(-)-koumidine, R = H)-i P - '" R = Troc

O -, TMSC1, Nal, U 94% HN- O R 45

At this stage, the N-methoxyoxindole function, which is one of the characteristics of many Gelsemium alkaloids, was introduced in three steps (Scheme 1.10). Treatment of 48 with

TMAD (N^N^N'-tetramethylazodicarboxamide) and n-Bu3P (a modified Mitsunobu reaction)29 gave epoxide 49 after deprotection of the amine.

Scheme 1.10 O

MeO 7 (gelsedine) 11 (gelsenicine) 6 (gelselegine)

16 Introduction Upon standing for 5 days 49 was gradually transformed into gelselegine (6). It appears that the primary amine regioselectively attacked C-20 with complete inversion. By analogy with the biogenetic speculation, the C-21 carbon of 6 was oxidatively cleaved with NaI04 in aqueous MeOH to afford gelsenicine (11). Furthermore, catalytic reduction of the imine function of 11 furnished gelsedine (7) in quantitative yield. Since (+)-(19£)-koumidine has been synthesized by Magnus13 starting from (S)- tryptophan in 19 steps, the Sakai approach constitutes a formal total synthesis of gelselegine, gelsenicine and gelsedine.

1.5 Approaches toward Gelsedine

Apart from the semisynthesis by Sakai, several synthetic approaches have been reported, but none of these approaches resulted in a total synthesis. Hamer synthesized compound 50, which consists of the skeleton of gelsedine, but still lacks the ethyl and oxindole moieties and the functionalities to introduce them.30a Compound 51 was synthesized by Baldwin in a different approach and is comparable to 50.30b This structure has an extra ketone function, which in principle can be elaborated to an oxindole moiety. However, accounts on further work have not appeared in both cases.

MeN--\__y

N-OMe 50

Compound 52 was synthesized by Kende and resembles gelsedine more closely in that it has an oxindole moiety in place.31 The synthesis of this structure will be detailed because it constitutes an elegant approach in which the skeleton is made in one of the last steps. Commencing with the Michael-Dieckmann route for the synthesis of 3-pyrrolidinones32, the ethyl ester of 4-ferf-butoxycrotonic acid was allowed to react with the ethyl ester of N- methoxycarbonylglycine by using NaH in benzene at reflux temperature to give the 3- pyrrolidinone ester 55 (Scheme 1.11). Lactonization and reaction with (carbo-ferf- butoxymethylene)rriphenylphosporane afforded lactone 56, which was converted in four steps into aldehyde 57.

17 Chapter 1

Scheme 1.11

H /\ X02Me O N NaH/ Et02C O U p /7— C02/Bu 53 benzene UJ5)—fy 2 steps Q ^—( 4 steps H" reflux 55%

Et02C' X>/Bu 42% H *t Bu0 ° C02Me 54 C02Me 55

(KBu)2BOTf, /"^^

O (îPr)2NEt/ [l ! 7—OB(nBu)2 57 — \^~N CH2CI2, CH2C12, JH OMe -78 "C OMe -70 'C \—( C02Me 58 59 f> 42% W^--N 60 OMe

The known N-methoxyindole 5833 was now prepared for condensation with aldehyde 57. Thus, reaction of 58 with di-n-butylboron triflate at -78 °C in the presence of diisopropylethylamine gave vinyloxyborane 59 in nearly quantitative yield.34 This was allowed to react directly with 57 to afford after work-up and silica gel chromatography a mixture of Z-and E-olefins 60 (8:1).

Scheme 1.12

;- .; , " Me02C C02Me N 62 MeÓ

53%|TFAA/TFA(1:1) 1 CHCI3, rt

O TMSI, toluene ,. _ _/N -. Me02C N-OMe reflux OMe 61% 52 (R = H) 64 (R = 4-PhBz)

18 Introduction Reduction of the double bond with 5% palladium on carbon and reduction of the lactone with lithium-sec-butylborohydride furnished lactol 61 as a mixture of C-7 and C-3 epimers, which was of no consequence in view of the subsequent enolization step (Scheme 1.12). After treatment of 61 with a 1:1 mixture of trifluoroacetic acid-trifluoroacetic anhydride in chloroform 63 was obtained as a single product. The carbamate was selectively cleaved with in situ prepared trimethylsilyl iodide to give amine 52. Although the spiro-stereochemistry of the oxindole was initially thought to be the desired one, it was later proven to be the unnatural isomer by X-ray crystallographic analysis of the protected amine 64. Our group has worked previously on the total synthesis of gelsedine following a strategy similar to that of Kende. This approach, however, did not culminate in a total synthesis of gelsedine.35

1.6 Purpose of the Investigation

The main goal of this investigation is the preparation of enantiopure gelsedine via total synthesis. The reasons for this project are three-fold, (a) The compact structure of the molecule poses a real synthetic challenge, emphasized by the fact that despite the activities of a number of renowned research groups gelsedine has not succumbed to a total synthesis, (b) Gelsedine is probably one of the most biologically active representatives of the Gelsemium alkaloids, (c) The synthetic potential of N-acyliminium ion chemistry and expertise of our group in this area are expected to be highly benificial in this synthetic endeavor.

1.7 Outline of this Thesis

This thesis deals with the various aspects involved in developing the methodology required to arrive at gelsedine. The N-acyliminium ion chemistry developed in the group of Hiemstra/Speckamp will play a crucial role in this venture. In Chapter 2 a detailed retrosynthetic analysis and the synthesis of the advanced intermediate 67 will be described (Scheme 1.13). The bicyclic skeleton 66 was formed via an N-acyliminium ion cyclization of aliène 65. Unfortanately the total synthesis could not be completed via 67 because insuperable problems were encountered. Chapter 3 and 4 reveal our new approach and vinyl iodide 68 served as a new opening for our projected synthesis. Chapter 3 mainly deals with the introduction of the oxindole and tetrahydropyran moieties to lead to compound 69. Finally, in Chapter 4 the introduction of the two-carbon fragment and the last part of the synthesis from 69 toward e«i-gelsedine (70) are detailed. Parts of this thesis have been published36 or will be published in the near future.37

19 Chapter 1

Scheme 1.13 // HO HO ^/ MeOzC, ^ — r\ .0 H02C C02H Et0XNX0 (S)-malic acid 65 k 66 Ph

OMe

68 69 70 (enf-gelsedine)

1.8 References and Notes

1. For reviews on Gelsemium alkaloids, see: (a) Takayama, Hv Sakai, S. in Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1995; Vol 15, p 465. (b) Liu, Z.-J.; Lu, R.-R. in The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1988; Vol 33, p. 83. (c) Saxton, J. E. in The alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1965; Vol 8, p. 93. 2. Internet: http://www.avogel.nl/vr/pr/191363/index.html. 3. In this thesis, stereochemical assignments in the structural drawings are made with emboldened or dashed wedges for non-racemic compounds with known absolute configuration. Emboldened or dashed lines are used for indicating relative stereochemistry. Waving lines indicate a mixture of diastereomers. wedges: | or = lines: or = wave: \

4. (a) Schwarz, H.; Marion, L. Can. ]. Chem. 1953, 31, 958. (b) Jin, H. L.; Xu, R. S. Acta Chim. Sinica 1982, 40, 1129. 5. Wenkert, E.; Orr, J. C; Garratt, S.; Hansen, J. H.; Wickberg, B.; Leicht, C. L. ]. Org. Chem. 1962, 27, 4123. 6. (a) Przybylska, M.; Marion, L. Can. J. Chem. 1961, 39, 2124. (b) Przybylska, M. Acta Crystallogr. 1961,14, 694. (c) Przybylska, M. Acta Cnjstallogr. 1962, 15, 301. 7. Chou, T. Q.; Chin. J. Physiol. 1931, 5, 131. 8. (a) Ponglux, D.; Wongseripipatana, S.; Subhadhirasakul, S.; Takayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C; Aimi, N.; Sakai, S. Tetrahedron 1988, 44, 5075. (b) Schun, Y.; Cordeil, G. A. /. Nat. Prod. 1985, 48, 788.

20 Introduction 9. (a) Wichtl, M.; Nikiforov, A.; Schulz, G.; Sponer, S.; Jentzsch, K. Monatsh. Chem. 1973, 104, 87. (b) Wichtl, M.; Nikiforov, A.; Schulz, G.; Sponer, S.; Jentzsch, K. Monatsh. Chem. 1973,104, 99. 10. (a) Yan, J. S.; Chen, Y. W. Acta Pharm. Sinica 1983, 18, 104. (b) Du, X. B.; Dai, Y. H.; Zhang, C. L.; Lu, S. L.; Liu, Z. G. Acta Chim. Sinica 1982, 40, 1137. 11. Yan, J. S.; Chen, Y. W. Acta Pharm. Sinica 1984,19, 437. 12. Nagakura, N; Ruffer, M.; Zenk, M. H. ƒ. Chem. Soc, Perkin Trans. 1,1979, 2308. 13. Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. ƒ. Am. Chem. Soc. 1990,112, 5220. 14. (-)-Koumidine was first isolated from G. elegans: Jin, H. L.; Xu, R. S. Acta Chim. Sinica 1982, 40, 112. The geometry of the ethylidene group was recently corrected by Cordell. Schun, Y.; Cordell, G. A. Photochemistry 1987, 24, 2875. 15. (-)-Taberpsychine or (-)-(19E)-anhydrovobasinediol was isolated from Tabernaemontana psychotrifolia: (a) Biemann, K.; Spiteller, R. ƒ. Am. Chem. Soc. 1962, 84, 4578. Its structure was reported in 1969 under the name of anhydrovobasinediol and it was partially synthesized from vobasine. (b) Dugan, J. J.; Hesse, M.; Renner, U.; Schmid, H. Helv. Chim. Acta 1969, 52, 701. (c) Burnell, R. H.; Medina, J. D. Can. ƒ. Chem. 1971, 49, 307. 16. (a) Yu, P.; Wang, T.; Yu, F.; Cook, J. M. Tetrahedron Lett. 1997, 38, 6819. (b) Zhang, L. H.; Cook, J. M. Heterocycles 1988, 27, 1357. 17. (a) Newcombe, N. J.; Fang, Y.; Vijn, R. J.; Hiemstra, H.; Speckamp, W. N. ƒ. Chem. Soc, Chem. Commun. 1994, 767. (b) Verhaar, M. T., Report, University of Amsterdam, 1994. 18. (a) Atarashi, S.; Choi, J.-K.; Ha, D.-C; Hart, D. J.; Kuzmich, D.; Lee, C.-S.; Ramesh, S.; Wu, S. C. J. Am. Chem. Soc. 1997,119, 6226. (b) Dutton, J. K.; Steel, R. W.; Tasker, A. S.; Popsavin, V.; Johnson, A. P. ƒ. Chem. Soc, Chem. Commun. 1994, 765. (c) Kuzmich, D.; Wu, S. C; Ha, D.-C; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi, J.-K.; Hart, D. J. ]. Am. Chem. Soc. 1994,116, 6943. 19. (a) Fukuyama, T.; Gang, L. J. Am. Chem. Soc. 1996, 118, 7426. (b) O'Donnell, C. J.; Earley, W. G.; Jacobsen, J. E.; Madin, A.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Book of Abstracts, Division of Organic Chemistry, 217th ACS National Meeting, Anaheim, CA, USA, March 21-25, 1999; Abstract 036. 20. Hoye, T. R.; Magee, A. S.; Trumper, W. S. Synth. Commun., 1982,12, 183. 21. Hiemstra, H; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1988, 53, 3882. 22. (a) Abelman, M. M.; Oh, T.; Overman, L. E. ƒ. Org. Chem. 1987, 52, 4130. (b) Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33, 4859. 23. Koot, W. -J.; Hiemstra, H. Speckamp, W. N. /. Org. Chem. 1992, 57, 1059. 24. (a) Van der Deen, H.; Cuiper, A. D.; Hof, R. P.; Van Oeveren, A.; Feringa, B. L.; Kellogg, R. M.; ƒ. Am. Chem. Soc. 1996,118, 3801. (b) Cuiper, A. D.; Kellogg, R. M.; Feringa, B. L. ƒ. Chem. Soc, Chem. Commun. 1998, 655.

21 Chapter 1

25. Dijkink, J.; Cintrât, J.-C; Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40, 5919. 26. Takayama, H.; Tominaga, Y.; Kitajama, M.; Aimi, N.; Sakai, S. ƒ. Org. Chem. 1994, 59, 4381. 27. (a) Sakai, S.; Kubo, J.; Haginiwa, J. Tetrahedron Lett. 1969, 10, 1485. (b) Takayama, H.; Sakai, S. Chem. Pharm. Bull. 1989, 37, 2256. 28. Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai, S. Tetrahedron 1989, 45, 1327. 29. (a) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994, 539. (b) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639. 30. (a) Hamer, N. K. ƒ. Chem. Soc, Chem. Commun. 1990, 102. (b) Baldwin, S. W.; Doll, R. J. Tetrahedron Lett. 1979, 20, 3275. 31. (a) Kende, A. S.; Luzzio, M. J.; Mendoza, J. S. ƒ. Org. Chem. 1990, 55, 918. (b) Luzzio, M. J., PhD thesis, University of Rochester (USA), 1987. We thank Professor A. S. Kende of the University of Rochester (USA) for sending us a copy of this thesis. 32. (a) Rozing, G. P.; De Koning, H.; Huisman, H. O. Heterocycles 1977, 7, 123. (b) Rozing, G. P.; De Koning, H; Huisman, H. O. Heterocycles 1976, 5, 325. (c) Kuhn, R.; Osswald, G. Chem. Ber. 1956, 89, 1423. 33. Wright, W. B.; Collins, K. H. ƒ. Am. Chem. Soc. 1956, 78, 221. 34. (a) Mukaiyama, T.; Inoue, T. Buil. Chem. Soc. Jpn. 1980, 53, 174. (b) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 559. 35. Niekel, R. S., Report, University of Amsterdam, 1990. 36. (a) Beyersbergen van Henegouwen, W. G.; Hiemstra, H. ƒ. Org. Chem. 1997, 62, 8862. (b) Hiemstra, H.; Beyersbergen van Henegouwen, W. G.; Karstens, W. F. ].; Moolenaar, M. ].; Rutjes, F. P. J. T. in Current Trends in Organic Synthesis; Kluwer/Plenum: Dordrecht, New York, 1999; p. 267. 37. Beyersbergen van Henegouwen, W. G.; Fieseler, R. M.; Rutjes, F. P. J. T.; Hiemstra, H. Angew. Chem. Int. Ed. Engl. 1999, 38, in press.