De Novo Approaches to Monosaccharides and Complex Glycans

Abstract

Over the years, considerable effort has been made toward the development of new synthetic routes to monosaccharides [1]. This interest came primarily from the medicinal chemistry community, as these new routes often provided access to unnatural sugars, which could be of use in structure–activity relationship (SAR) studies. In addition, the synthesis of monosaccharides, and in particular hexoses, has served as a challenge and ameasuring stick to the synthetic organic community. Of particular interest are the routes to hexoses that start from achiral starting materials, where asymmetric catalysis is used to install the stereochemistry. In the synthetic organic community, these routes are described as ‘‘de novo’’ or ‘‘de novo asymmetric’’ routes to carbohydrates, whereas in the carbohydrate community, the term de novo takes up other meanings. For the purposes of this review, the term de novo asymmetric synthesis refers to the use of catalysis for the asymmetric synthesis of carbohydrates from achiral compounds [2]. This then precludes the inclusion of de novo process that produced sugars frommolecules with preexisting chiral centers (e.g., Seeberger and Reisig) [3, 4]. The challenge of a de novo synthetic approach to carbohydrates has been met by many groups (Scheme 1.1). These approaches begin most notably with the seminal work by Masamune and Sharpless [5] (2 to 5), which utilized iterative asymmetric epoxidation of allylic alcohols to prepare all eight possible hexoses. More recently, Danishefsky [6] demonstrated the power of asymmetric heteroDiels–Alder reaction for the synthesis of several glycals (3 and 4 to 5), which inspired further studies toward oligosaccharide synthesis. Johnson and Hudlicky [7] turned to the use of enzyme catalysis for the oxidation/desymmetrization of substituted benzene rings to achieve hexopyranoses (1 to 5). Alternatively, Wong and Sharpless [8] used a combination of transition metal catalysis (asymmetric dihydroxylation) and an enzyme-catalyzed aldol reaction for the synthesis of several 2-keto-hexoses. More recently, this challenge has been engaged by MacMillan who utilized an iterative aldol reaction approach (a proline-catalyzed aldol followed by a subsequent diastereoselective aldol reaction) to produce various hexoses