title: Enantiospecific total synthesis of the important biogenetic intermediates along the ajmaline pathway, (+)-polyneuridine and (+)-polyneuridine aldehyde, as well as 16-epivellosimine and macusine A.
abstract: The first stereospecific synthesis of polyneuridine aldehyde (6), 16-epivellosimine (7), (+)-polyneuridine (8), and (+)-macusine A (9) 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 (13). This alkaloid was available in enantiospecific fashion in seven reaction vessels in 27% overall yield from d-(+)-trytophan methyl ester (14) via a combination of the asymmetric Pictet-Spengler reaction, Dieckmann cyclization, and a stereocontrolled intramolecular enolate-driven palladium-mediated cross-coupling reaction. A new process for this stereocontrolled intramolecular cross-coupling has been developed via a copper-mediated process. The initial results of this investigation indicated that an enolate-driven palladium-mediated cross-coupling reaction can be accomplished by a copper-mediated process which is less expensive and much easier to work up. An enantiospecific total synthesis of (+)-polyneuridine aldehyde (6), which has been proposed as an important biogenetic intermediate in the biosynthesis of quebrachidine (2), was then accomplished in an overall yield of 14.1% in 13 reaction vessels from d-(+)-tryptophan methyl ester (14). Aldehyde 13 was protected as the N(a)-Boc aldehyde 32 and then converted into the prochiral C(16)-quaternary diol 12 via the practical Tollens' reaction and deprotection. The DDQ-mediated oxidative cyclization and TFA/Et(3)SiH reductive cleavage served as protection/deprotection steps to provide a versatile entry into the three alkaloids polyneuridine aldehyde (6), polyneuridine (8), and macusine A (9) from the quarternary diol 12. The oxidation of the 16-hydroxymethyl group present in the axial position was achieved with the Corey-Kim reagent to provide the desired beta-axial aldehydes, polyneuridine aldehyde (6), and 16-epivellosimine (7) with 100% diastereoselectivity.
authors.affiliation: Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Yin
authors.forename: M Shahjahan
authors.initials: MS
authors.lastname: Kabir
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.forename: Sundari K
authors.initials: SK
authors.lastname: Rallapalli
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000404:Ajmaline / Q000737:chemistry*; D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: C518016:16-epi-vellosimine; D000447:Aldehydes; D026121:Indole Alkaloids; C518014:polyneuridine; C518013:polyneuridine aldehyde; D000404:Ajmaline; C518015:macusine A
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