Synthesis of Conformationally Constrained Tryptophan Derivatives

Article abstract of DOI:10.1021/jo00095a015

Methyl 1,3,4,5-tetrahydro-4-<<(phenylmethoxy)carbonyl>amino>-1H-cyclooctindole-4-carboxylate, methyl 3,4,5,6-tetrahydro-6-methylene-4-<<(phenylmethoxy)carbonyl>amino>-1H-cycloheptindole-4-carboxylate, and methyl 3,4-dihydro-6-methyl-4-<<(phenylmethoxy)carbonyl>amino>-1H-cycloheptindole-4-carboxylate are three novel 3,4-fused tryptophan analogues which have been designed and synthesized for use in peptide/peptoid conformation elucidation studies.These derivatives have a ring that bridges the α-carbon and the 4-position of the indole ring, thus limiting the conformational flexibility of the side chain while leaving both amine and carboxylic acid groups free for further derivatization.The synthesis proceeded from 4-bromoindole via methyl 3-(4-bromo-1H-indol-3-yl)-2-(formylamino)-2-propenoate in which the carbon-carbon double bond was selectively reduced in the presence of the aromatic halide and then converted into methyl 4-bromo-N-<(phenylmethoxy)carbonyl>-α-2-propenyl-DL-tryptophan.Palladium-catalyzed cyclization of this α-propenyl tryptophan derivative proceeded smoothly under Heck conditions to give the compounds described above, yielding both the seven- and eight-membered constrained ring analogues.Functionalization of these key materials has been demonstrated.