The influence of acceptor acidity on hydrogen bond mediated aglycone delivery (HAD) through the picoloyl protecting group

Abstract

The outcome of glycosylation reactions heavily relies on the specific protecting group patterns employed on both the donor and acceptor molecules. The picoloyl (Pico) protecting group stands out as it can steer the stereoselectivity in a glycosylation reaction through hydrogen bond‐mediated aglycone delivery (HAD). This provides syn‐stereoselectivity, with respect to the stereochemistry of the Pico group, by forming a hydrogen bond between the incoming acceptor and the picoloyl ring nitrogen. We here probe how acceptor acidity influences the stereodirecting effect of the picoloyl protecting group. A set of 3‐O‐functionalized glucosyl and mannosyl donors, each bearing different protecting groups (picolinate, nicotinate, isonicotinate, and benzoate), were synthesized for systematic evaluation. For the 3‐O‐picoloyl‐glucose series, the picoloyl group exhibited minimal influence on stereoselectivity, with only weak nucleophiles showing a modest shift in selectivity for the 3‐O‐Pico protected glucosyl donor in comparison to the other C‐3‐acyl glucosides. In contrast, in the 3‐O‐picoloyl‐mannose series a much stronger β‐directing effect was observed, wherein more acidic acceptors led to increased β‐selectivity. The results provide insights into the complex interplay of acceptor acidity and glycosylation stereoselectivity mediated by the picoloyl protecting group.

Influence of remote carbamate protective groups on the β-selectivity in rhamnosylations

“…16 The HAD approach can be very effective, but also limited by the nature of acceptors used. 17,18 Other stereo-directing groups, e.g. 2-(diphenylphosphinoyl)acetyl, have also been introduced.…”