Tandem asymmetric propargylic amination/carboxylative cyclization reaction to chiral 5-methylidene-2-oxazolidinones using CO2 as C1 synthon

Abstract

We report a tandem asymmetric Cu-catalyzed propargylic animation (ACPA)/Ag-catalyzed carboxylative cyclization (SCC) with CO₂ to 5-methylidene-2-oxazolidinones, even with tetrasubstituted stereocenters. By varying pyridine bisoxazoline (PYBOX) ligands, a general and highly enantioselective ACPA of unprecedentedly broad scope of secondary propargylic acetates and primary amines is achieved. Both α-aryl and α-aliphatic propargylic acetates could react with either aromatic or aliphatic primary amines to give the corresponding N-aryl or N-aliphatic ethynylamines with α-aliphatic or α-aryl groups in over 90% ee for use in the next step. The key to developing this one-pot sequence is to use a chelator triethylenetetramine (TETA) to mask the copper ion, to avoid its negative effect on Ag-catalyzed cyclization, whilst releasing PYBOX to activate the silver catalyst. With the methylidene moiety, these oxazolidinones can be readily elaborated. The value of the sequence is further shown by the catalytic enantioselective total synthesis of (−)-cytoxazone and the potent ezetimibe analogue.