Synthetic studies of indole alkaloids
Creators: name: Abdurahman, Nizam
Publisher: name: University of British Columbia
Year: 2011

description: Novel transannualr cyclisation reactions of nine-membered ring compounds like quebrachamine, dihydrocleavamine and carbomethoxydihydrocleavamine, previously described in this laboratory, provide an attractive entry into the Aspidosperma, Vinca and Iboga alkaloids. In this thesis two approaches to the synthesis of the nine-membered ring alkaloid, quebrachamine, are described. The first section of this thesis discusses the synthesis of model compounds suitable for evaluating the acyloin condensation for the synthesis of this alkaloid. For this purpose, 3-carbomethoxypiperidine (98) was prepared by three different routes. In sequence (a), nicotinic acid (109) was methylated to give methyl nicotinate (110), which on catalytic hydrogenation yielded (98). In sequence (b), nicotinic acid was reduced in the presence of dilute aqueous ammonia and 5% rhodium on charcoal to provide nipecotic acid (111). Esterification with diazomethane provided the desired piperidine (98). In sequence (c), the desired material was prepared by an esterification reaction of nipecotic acid hydrochloride (111,a). The formation of the intermediate arylhydrazone (108,a) was accomplished via a Japp-Klingemann reaction from diethyl ૪-chloropropylmalonate (108) and benzene-diazonium chloride. The arylhdrazone (108,a) was then treated under the conditions of the Fischer indole synthesis to provide 2-carboethoxy-3-(β-chloroethyl)-indole (97,a). Transesterification with methanol provided 2-carbomethoxy-3-(β-chloroethyl)-indole (97,b). The piperidine derivative (98) was coupled with (97,a) and (97,b) to provide the coupling products (99,R=Et) and (99,R=Me). Attempted acyloin condensations of these latter compounds to provide the nine-membered ring compound (100) are described. The second section of this thesis describes a new total synthesis of (dl)-quebrachamine via a completely different sequence. Diethyl ૪-benzyloxypropylethylmalonate (144) was prepared by the condensation between diethyl ethylmalonate and 1-chloro-3-benzyloxypropane (143.). Alkaline hydrolysis of (144) provided ૪-benzyl-oxpropylethyl malonic acid (145), whichwas decarboxylated to give 2-(૪-berizyloxypropyl)-butarioic acid (146). Esterification of (146) provided ethyl 2-(૪-benzyloxy-propyl)-butanoate (147), which by subsequent alkylation with triphenylmethyl sodium and ethyl bromoacetate gave ethyls[formula omitted]-(૪-benzyloxyprqpyl)–[formula omitted]-ethylsuccinate (148). Condensation of (148) with tryptamine provided N-β[-(3-indolyl)-ethyl]-[formula omitted]-(૪-benzyloxypropyl)-[formula omitted]-ethylsuccinimide (123), which was reduced with lithium aluminum hydride to yield N-[β-(3-indolyl)-ethyl]-3-(૪-benzyloxy-propyl)-3-ethylpyrrolidine (124). Thy uncyclised benzyl etheramine (124) was treated with an excess of mercuric acetate to provide a crude product which was immediately reduced with sodium borohydride to give a mixture of the isomeric cyclic benzyl ether amines (125). Catalytic debenzylation provided three separable aminoalcohols (164) A, B and C. The relatively abundant aminoalcohol B was converted to the quaternary ammonium salt (126) by treatment with methanesulfonyl chloride in pyridine. Ring cleavage of (126) with sodium and liquid ammonia yielded (dl)-quebrachamine (1).