Syntheses of strychnan- and aspidospermatan-type alkaloids. 10. An enantioselective synthesis of (-)-strychnine through the Wieland-Gumlich aldehyde

Article abstract of DOI:10.1021/jo9813989

Condensations of L-tryptophan-derived 2-[(methoxycarbonyl)methyl]-3- [2(S)-(benzyloxycarbonyl)-2-(N(b)-benzylamino)ethyl]indole (6) with 4,4- dimethoxyacrolein or with 2,4-hexadienal, followed by removal of the tryptophanyl ester function, respectively gave the tetracyclic acetal (-)- methyl (2S,-3aS,5R,11bR)-3-benzyl-2,3,3a,4,5,7-hexahydro-5- (dimethoxymethyl)-1H-pyrrolol[2,3-d]carbazole-6-carboxylate (10) or the tetracyclic olefin (-)-methyl (2S,3aS,5R,11bR)-3-benzyl-2,3,3a,4,5,7- hexahydro-5-(1-propenyl)-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (14). Their respective hydrolysis or oxidation provided, enantioselectively, the tetracyclic aldehyde (-)-methyl (2S,3aS,5R,11bR)-3-benzyl-2,3,3a,4,5,7- hexahydro-5-formyl-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (5). Its reaction with tri-n-butyl-1-(ethoxy)ethoxymethyltin and n-butyllithium, followed by oxidation of the resultant alcohol (-)-methyl (2S,3aS,5R,11bR)-3-benzyl- 2,3,3a,4,5,7-hexahydro-5-(1ξ-hydroxy-2-((1-ethoxy-ethoxy))ethyl-1H- pyrrolo[2,3-d]carbazole-6-carboxylate (16) and cyclization furnished the pentacyclic ketone (-)-methyl (2S,3aS,SR,11bR)-3-benzyl-2,3,3a,4,5,7- hexahydro-3,5-ethano-12-oxo-1H-pyrrolo-[2,3-d]carbazole-6-carboxylate (15). A Horner-Emmons condensation led to the unsaturated esters (-)-methyl (2S,3aS,5R,11bR)-3-benzyl-2,3,3a,4,5,7-hexahydro-3,5-ethano-12-(E and Z)- [(methoxycarbonyl)-methylene]-1H-pyrrolo[2,3-d]carbazole-6-carboxylates (19 and 20) with 17:1 E/Z selectivity. Reductions of the ester and vinylegous urethane functions in 19 led to the Wieland-Gumlich aldehyde 3 as a 6:1 anomeric hemiacetal mixture. Its condensation with malonic acid provided (- )-strychnine (1) in 5.3% overall yield and 14 steps from the tryptophan derivative 6.