Intermolecular Michael addition of substituted Amines to a sugar-derived α,β-Unsaturated Ester: synthesis of 1-deoxy-d-gluco- and -l-ido-homonojirimycin, 1-deoxy-castanospermine and 1-deoxy-8a-epi-castanospermine

Abstract

The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin 3a, 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and 1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular Michael addition of benzylamine to α,β-unsaturated ester 1, derived from d-glucose, which afforded diastereomeric mixture of β-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5, respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The β-amino esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a and 6b, individually, gave β-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation gave 3a and 3b, respectively. On the other hand, the β-amino ester 6a was converted to γ-amino ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate gave γ-lactam 14a. The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good yield. The same sequence of reactions was applied to β-amino ester 6b, which afforded 1-deoxy-8a-epi-castanospermine 5b.