Synthesis of Enantioenriched 2-((Hetera)cyclo)alkylchromanols and their Spirocyclic Analogs through Enzymatic Resolution

Abstract

An efficient approach to the multigram synthesis of 2-((hetera)cyclo)alkylchromanols and their spirocyclic analogs based on enzymatic resolution is described. It is shown that enzymatic acylation could be used for the preparation of enantioenriched title compounds with primary alkyl substituents at the C-2 position. Meanwhile, enzymatic hydrolysis of the corresponding acetates was optimal for the preparation of the target alcohols when significant steric hindrance is present, e.g., due to the α-branching. The latter factor was demonstrated to be crucial for the enzymatic reaction rate in both cases. The synthetic utility of the obtained chiral alcohols was demonstrated through Mitsunobu configuration inversion, as well as by preparation of the corresponding primary amines – valuable sp3-enriched building blocks for medicinal chemistry.