Regio- and Enantioselective Monofunctionalization of Diols via Hemiboronic Acid Catalysis

Abstract

Polyhydroxylated compounds such as carbohydrates, glycerols and diols play an important role in biological chemistry and as pharmaceutical agents. Furthermore, diols are often useful starting materials and intermediates to prepare stereochemically complex molecules. However, hydroxy group site-selectivity in the functionalization of diols remains an important unmet challenge. Traditional methods toward diol functionalization include multi-step protection/deprotection strategies and the use of stoichiometric activation. These processes are inefficient from an atom economy standpoint and can often result in the production of hazardous waste. More recently, diol functionalization via catalysis has become an emerging approach to overcome these challenges. Chapter 1 is a summary of common methods to functionalize diol-containing compounds. Various catalytic transformations have been developed in the regioselective derivatization of carbohydrates. Asymmetric catalysis has also been a common approach toward the preparation of optically active compounds from achiral diols, however few methods provide high enantioselectivities for a wide range of substrates and transformations. Boronic acids have emerged as attractive catalysts toward diol functionalization because of their ability to undergo reversible interactions with hydroxy functional groups to form boronic esters. Diol activation is achieved upon formation of a tetrahedral adduct by enhancing the nucleophilicity of the oxygen atoms in the boronic ester. Chapter 2 describes the use of a bench-stable hemiboronic acid catalyst in the regioselective monofunctionalization of polyol substrates. Evidence for the formation of an active tetrahedral adduct, without the use of a Lewis base, is described. The stability of the catalyst is a considerable iii improvement to current borinic acid catalyzed methods. Mechanistic considerations and efforts to control regioselectivity are discussed. Chapter 3 summarizes the discovery of a novel chiral variant of the aforementioned hemiboronic acid toward the catalytic enantioselective desymmetrization of 1,3-diols. Reaction optimization and catalyst design leads to the synthesis of optically active alcohols from symmetrical diols with good enantioselectivity. In the end, a mild and practical method is a unique way to prepare useful, chiral building blocks. Favourable characteristics of the developed reaction, such as catalyst recyclability and use of a weak base, is discussed.