[reaction: see text] A diversity-oriented protocol has been developed for the assembly of densely hydroxylated cycloheptane amino acids via succession of a vinylogous Mukaiyama aldol reaction (VMAR), a Morita-Baylis-Hillman reaction (MBHR), and an intramolecular pinacol coupling reaction (IPCR). The plan utilizes D- or L-configured glyceraldehyde derivatives as "chiral" surrogates of glyoxal and N-[(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyl)oxy]pyrrole as the synthetic equivalent of the alpha,gamma-dianion of gamma-aminobutanoic acid. The parallel, asymmetric syntheses of four cycloheptane representatives proceed with high diastereocontrol and virtually complete enantioselectivity in ten steps and overall yields of 15-37%.
An efficient, stereocontrolled synthesis of (6S,7S,8S,8aR)-6,7,8-trihydroxyindolizidine (alias 1-deoxy-7,8-di-epi-castanospermine) (14) has been developed, which exploits an asymmetric vinylogous Mukaiyama aldol reaction (VMAR) between N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)pyrrole (1) and 2,3-O-isopropylidene-D-glyceraldehyde (2) to construct the initial pyrrolidine building block 3, and an ene-ene ring closing metathesis reaction (RCM) (9 to 10) to install the indolizidine skeleton. The synthetic sequence was 13 steps, proceeding in 19.5% overall yield. The configurational and conformational structure of 14 was ascertained unambiguously and confronted to previously published assignments of rac-14 and ent-14.
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