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Part One. Synthesis of Optically Active Tryptophan Derivatives with Potential Activity as Indoleamine 2,3-dioxygenase Inhibitors: An Approach Via Asymmetric Catalytic Hydrogenation. Part Two. Design, Synthesis and Pharmacology of Selective Ligands for Alpha1-containing GABA(A)/benzodiazepine Receptor Subtypes: SAR Studies of Beta-carbolines at Positions -3 and -6 and Their Corresponding Bivalent Ligands. Part Three. First Enantiospecific Total Synthesis of the Important Biogenetic Intermediates, (+)-polyneuridine and (+)-polyneuridine Aldehyde, as Well as 16-epi-vellosimine and Macusine A.

Part III. The first stereospecific total synthesis of (+)-polyneuridine aldehyde 17, 16-epivellosimine 19, (+)-polyneuridine 22 and macusine A 23 has been accomplished from commercially available D-(+)-tryptophan methyl ester. D-(+)-Tryptophan has served here both as the chiral auxiliary and the starting material for the synthesis of the common intermediate, (+)-vellosimine 27. This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from D-(+)-tryptophan methyl ester 28 via a combination of the asymmetric Pictet-Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. An enantiospecific total synthesis of (+)-polyneuridine aldehyde 17, which was proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine 6, was then accomplished in an overall yield of 14.1% in 13 reaction vessels from D-(+)-tryptophan ethyl ester 28. Aldehyde 27 was protected as the Na-Boc aldehyde 63, and then converted into the prochiral C (16)-quaternary diol 64 via the practical Tollens' reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et3SiH reductive cleavage served as protection/deprotection step to provide a versatile entry into the three alkaloids, polyneuridine aldehyde 17, polyneuridine 22 and macusine A 23 from quarternary diol 26. The chemospecific and regiospecific oxidations of the 16-hydroxymethyl group contained in the axial position in contrast to the equatorial hydroxymethyl group was achieved with the Corey-Kim reagent to provide the desired aldehydes, polyneuridine aldehyde 17 and 16-epi-vellosimine 19 with absolute diastereoselectivity.

Objectives and synthetic approach The unique and complex architecture of the
above-mentioned indole alkaloids, coupled with their largely unexplored
potential in medicine or as tools for biological studies, make these compounds
attractive ...