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First Total Synthesis of (+)-Gelsedine

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First Total Synthesis of (+)-Gelsedine UvA-DARE (Digital Academic Repository) First total synthesis of (+)-gelsedine Beyersbergen van Hen, W.G. Publication date 1999 Link to publication Citation for published version (APA): Beyersbergen van Hen, W. G. (1999). First total synthesis of (+)-gelsedine. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) 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.
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