β-ketochlorohydrins as iminosugar building blocks for medicinal chemistry applications

Readily available, achiral acetaldehyde derivatives and ketones are easily converted into chlorohydrin building blocks enantio- and diastereoselectively via a one-pot, proline-catalyzed tandem α-chlorination/aldol reaction (αCAR). Using these chlorohydrins, rapid construction of the pyrrolidine scaffolds can be achieved by diastereoselective reductive amination and cyclization. The application of these chlorohydrin building blocks in library synthesis is demonstrated. Design and synthesis of novel chlorohydrins with diversifiable functional groups for library construction are reported. This methodology was then applied to the automated synthesis of a 30-member hydroxypyrrolidine library via a one-pot, multi-step procedure. These building blocks can also be effectively implemented in target-oriented synthesis. Optimization of the synthesis of stereoisomeric pyrrolizidines using a pyrrolidine-first synthetic route relying on a similar diastereoselective reductive amination and cyclization of a chlorohydrin building block was achieved.