UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthetic studies of indole alkaloids McKague, Allan Bruce


Two synthetic approaches to the Aspidosperma and Iboga classes of indole alkaloids are described. Section A discusses a possible synthetic route to the nine-membered ring alkaloid quebrachamine (93a). Nicotinic acid (75) was reduced to nipecotic acid hydrochloride (76), which was esterified to yield methyl nipecotate (77). Attempted preparation of 3-carbomethoxy-3-ethylpiperidine (67) by alkylation of (77) or of its p-bromobenzamide derivative (78) was unsuccessful„ The substituted piperidine (67) was then prepared by another synthetic sequence. Alkylations of methyl cyanoacetate led to methyl 3-chloropropylethylcyanoacetate (83). Catalytic reduction of the latter nitrile to the corresponding amine allowed cyclization to 3-carbomethoxy-3-ethylpiperidine (67). Reaction of 67 with 2-carboethoxy-3-(β-chloroethyl)-indole (66) provided 2-carboethoxy-3-[β-(3-carbomethoxy-3-ethyl-N-piperidyl)-ethyl]-indole (68). Attempted acyloin condensation of the latter to a nine-membered ring compound (69) was unsuccessful and led only to hydrolysis products. Section B describes the first total synthesis of the nine-membered ring compounds 4α- and 4β- dihydrocleavamine (152) and (153), isomeric with quebrachamine. Conversion of 2-ethyl 1,3-propanediol (106) to the monobenzyl ether (107) followed treatment with thionyl chloride provided 3-benzyloxy-2-ethyl- propyl chloride (108). Alkylation of malonic ester with the latter afforded diethyl 3-benzyloxy-2-ethylpropylmalonate (109 ). A second alkylation of 109 with ethyl bromoacetate yielded diethyl 2-(2-benzyloxymethylbutyl)-2-carboethoxysuccinate (113 ). Hydrolysis, decarboxylation and re-esterification of this triester provided the substituted succinic ester (71a) in high yield. The succinic ester (71a) was also prepared but in low yield by hydrolysis, decarboxylation and re-esterification of the malonic ester (109) followed by alkylation with ethyl iodoacetate,, Condensation of the succinic ester (71a) with tryptamine provided the succinimide (130) which was reduced with lithium aluminum hydride to the tertiary amine (131) in high yield. Mercuric acetate oxidation of the latter afforded a mixture of isomeric cyclized compounds one of which was the desired benzyl ether 72a. Catalytic debenzylation yielded the corresponding aminoalcohol (149) which was converted to the quaternary mesylate (73a) by treatment with methanesulfonyl chloride. Reductive cleavage of 73a with sodium in liquid ammonia yielded 4α- and 4β- dihydrocleavamine. The synthesis of the isomeric dihydrocleavamines coupled with other synthetic work provides a general entry into the Aspidosperma and Iboga alkaloids.

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