Stereoselective yeast-mediated reduction of trans-5-(1'-oxo-3'-methylbutyl)-3-methyldihydrofuran-2-one: production of chiral intermediates for the synthesis of β-secretase inhibitors

Abstract

Objective: To investigate the usefulness of yeast strains to the production of chiral hydroxylactones, important synthons in the synthesis of β-secretase inhibitors.

Results: Strains Rhodotorula glutinis KCh 242, Rhodotorula rubra KCh 82, Rhodotorula marina KCh 77 and Saccharomyces cerevisiae KCh 464 reduced racemic trans-5-(1'-oxo-3'-methylbutyl)-3-methyldihydrofuran-2-one (4) according to the Prelog's rule to afford preferentially the stereoisomers with S configurations at C-1'. R. marina KCh 77 and R. glutinis KCh 242 exhibited selectivity towards 3S, 5R enantiomer of the substrate, whereas R. rubra KCh 82 and S. cerevisiae KCh 464 preferred the reduction of its antipode. The highest yield of 3R,5S,1'S-hydroxylactone 3c (78 %) was obtained with R. rubra KCh 82.

Conclusions: Different stereoisomers of trans-5-(1'-hydroxy-3'-methylbutyl)-3-methyldihydrofuran-2-one and its 5-substituted analogues are produced as important intermediates in the synthesis of drugs for the therapy of Alzheimer's disease.

Keywords: Bio-reductions; Hydroxylactones; Lactones; Rhodotorula spp.; Saccharomyces cerevisiae; β-Secretase inhibitors.