Enantioselective Synthesis of 2,3,4,5-Tetra(hydroxyalkyl)pyrrolidines through 1,3-Dipolar Cycloadditions

1,3-Dipolar cycloadditions were conducted starting from azomethine ylides and enantiomerically pure sugar-derived dihydropyranones. The ylide intermediates were generated from imines obtained by condensation of glycine or L-alanine esters and 2,2-dimethoxyacetaldehyde. This aldehyde was employed as precursor of a dimethoxymethyl group attached to the pyrrolidine ring, instead of the usual aryl group derived from aromatic aldehydes. Under silver catalysis the cycloaddition was highly regio- and diastereoselective, affording good yields of the 2,5-cis cycloadducts, with the endo configuration strongly prevailing. The enantioselectivity was controlled by the acetal stereocenter of the pyranone: the (S)-isomer gave a pyrrolidine with a defined configuration for the four asymmetric ring carbons, while the (R)-dihydropyranone gave the enantiomeric ring. A sequence of reactions applied to the cycloadducts derived from (S)-enone afforded the target 2,3,4,5-tetra(hydroxyalkyl)pyrrolidines. The enantiomers were obtained from cycloadducts synthesized from the (R)-enone. The pyrrolidines were evaluated as inhibitors of the beta-galactofuranosidase from Penicillium fellutanum.

Automated summary

This study investigates the 1,3-dipolar cycloadditions starting from azomethine ylides and enantiomerically pure sugar-derived dihydropyranones. The reaction shows high regio- and diastereoselectivity under silver catalysis, resulting in the formation of pyrrolidine compounds with specific configurations.