Controlling pyramidal nitrogen chirality by asymmetric organocatalysis.

Abstract

Chirality is central to life, and controlling the formation of one of a pair of mirror-image molecules (enantiomers) is a central tenet of synthetic chemistry. Although controlling stereogenic carbon^1-3, silicon^4,5, phosphorus^6,7 and sulfur^8,9 centres is commonplace, nitrogen centres in amines are not typically stable. Limited achievements in the enantioselective construction of nitrogen chirality have primarily been established in quaternary ammonium salts^10-12 and bridged bicyclic amines^13-17, which have a restricted pyramidal configuration. The asymmetric synthesis of non-bridged pyramidal nitrogen-chirogenic compounds suffers from a super-stoichiometric chiral source and exhibits poor stereoselectivity^18-24. Here we present a catalytic enantioselective strategy for construction of acyclic nitrogen stereocentres via a chiral Brønsted acid-catalysed chlorination reaction. We designed a stereospecific intramolecular reaction to overcome the structural and configurational instabilities of nitrogen-chlorinated hydroxylamines. The resulting 2-alkoxy-1,2-oxazolidines showed good enantiopurities, and density functional theory calculations confirmed successful enantiocontrol of nitrogen chirality during the chlorination process. Furthermore, this strategy has been applied successfully to synthesize the enantioselective N-chloroaziridines with a configurationally stable nitrogen stereogenic centre. Control experiments provide evidence for an S_N2 pathway for the intramolecular nucleophilic substitution event.