Modular assembly of chiral multisubstituted tetrahydropyrans through a cascade asymmetric aldehyde allylboration/oxa-cyclization by a chiral phosphoric acid

Abstract

Considering the structural importance of 2,6-disubstituted and 2,2,6-trisubstituted tetrahydropyran motifs, two novel types of cascade reactions have been developed to address the challenges of synthetic efficiency, high stereoselectivity and construction of a diaryl quaternary stereogenic carbon center. A single BINOL-derived chiral phosphoric acid catalyst enabled the asymmetric aldehyde-allylboration and subsequent intramolecular oxa-Michael addition or intermolecular variant of oxa-Pictet–Spengler reactions with high to excellent yields (up to 93%), diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to 99% ee). The origin of the stereochemical induction was understood via chair-like 6-membered transition states and DFT calculations, which suggested that the thermodynamically favored 2,2,6-trisubstituted THPs were obtained through the kinetically controlled attack of indole on the Si-face of the oxocarbenium ion intermediate.