Convergent and stereoselective synthesis of nonulosonic acid (NulO) scaffolds via imine/aldehyde reductive coupling

Abstract

Nonulosonic acids (NulOs) represent an important class of monosaccharides, which have received increasing interest due to their biological roles and potential in vaccine development. As they are only sparsely found in nature, their chemical synthesis is key to exploiting their full potential. In this work, we describe a building-block approach starting from the abundant natural products glucose and threonine. With a few simple modifications, these can serve as coupling partners in an SmI₂-mediated reductive coupling, where two new stereocenters are constructed together with the C9 backbone. The approach is easily modified to access the desired diastereomer, and we demonstrate, by the synthesis of 7 NulOs, how both naturally occurring and unknown NulOs can be synthesized in a few steps from the available building blocks. The stereochemistry of the newly established stereocenters was carefully studied by transforming the NulO derivatives into their pyranoses, followed by NMR studies. The assignment of stereochemistry is furthermore supported by a crystal structure and a model for the coupling reaction, allowing us to propose rules for the stereochemical outcome, making this approach predictable.