A Predictive Model for the Pd‐Catalyzed Site‐Selective Oxidation of Diols

Abstract

A predictive model, shaped as a set of rules, is presented that predicts site-selectivity in the mono-oxidation of diols by palladium-neocuproine catalysis. For this, the factors that govern this site-selectivity within diols and between different diols have been studied both experimentally and with computation. It is shown that an electronegative substituent antiperiplanar to the CÀ H bond retards hydride abstraction, resulting in a lower reactivity. This explains the selective oxidation of axial hydroxy groups in vicinal cis-diols. Furthermore, DFT calculations and competition experiments show how the reaction rate of different diols is determined by their configuration and conformational freedom. The model has been validated by the oxidation of several complex natural products, including two steroids. From a synthesis perspective, the model predicts whether a natural product comprising multiple hydroxy groups is a suitable substrate for site-selective palladium-catalyzed oxidation.

Total synthesis of dissectol A, using an enediolate-based Tsuji–Trost reaction

“…Therefore, we opted for a palladium-catalysed site-selective oxidation, a reaction we have studied intensively. 20–22 Provided we could maintain the catalyst entirely in its Pd( ii ) form, this oxidation reaction should be compatible with the allylic function which obviously is sensitive to Pd(0).…”

Practical Site-selective Oxidation of Glycosides with Pd(OAc)2/Neocuproine

“…Site-selective oxidation of the secondary hydroxy groups in unprotected carbohydrates is considerably more challenging, 11,12 but significant progress has been made over the past ten years. Waymouth and co-workers were able to selectively oxidize glycerol with the catalyst [(neocuproine)PdOAc] 2 (OTf) 2 and 1,4-benzoquinone (BQ) or oxygen as a terminal oxidant (Scheme 1A).…”