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The Hancock Alkaloids (−)-Cuspareine, (−)-Galipinine, (−)-Galipeine, and (−)-Angustureine: Asymmetric Syntheses and Corrected ¹H and ¹³C NMR Data

Davies, Stephen G., Fletcher, Ai M., Houlsby, Ian T. T., Roberts, Paul M., Thomson, James E., Zimmer, David
Journal of natural products 2018 v.81 no.12 pp. 2731-2742
alkaloids, enantiomers, lithium, nuclear magnetic resonance spectroscopy, propionic acid
The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl-N-(α-methyl-p-methoxybenzyl)amide to 5-(o-bromophenyl)-N-methoxy-N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald–Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (−)-cuspareine, (−)-galipinine, (−)-galipeine, and (−)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-(o-bromophenyl)propanoic acid in all cases. Unambiguously corrected ¹H and ¹³C NMR data for the originally isolated samples of (−)-cuspareine, (−)-galipinine, and (−)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.