Direct catalytic asymmetric synthesis of highly functionalized (2-ethynylphenyl)alcohols via Barbas-List aldol reaction: Scope and synthetic applications

Abstract

A high-yielding asymmetric synthesis of functionalized (2-ethynylphenyl) alcohols 5/6 with good diastereo- and enantioselectivities was achieved by Barbas-List aldol (BLA) reaction of 2-alkynylbenzaldehydes 1 with various ketones 2 in the presence of trans-4-OH-l-proline or l-prolinamide derivative 3/4 as catalyst at the ambient temperature or -35 °C. This method also gives first time access to the novel double aldol addition compounds 6, which are of medicinal importance. Chiral functionalized (2-ethynylphenyl)alcohols 5/6 were transformed into acyclic and cyclic 1,4-triazoles 8/9 and cis-1,3-diols 10 in good yields with high selectivity through double click-reaction and Lewis acid-mediated NaBH 4 reduction respectively. Chiral products 8-10 may become good ligands and inhibitors in medicinal chemistry. © 2012 The Royal Society of Chemistry.