Preparation of Chiral Bisoxazolines: Observations on the Effect of Substituents

A series of enantiomerically pure 4-substituted bisoxazolines 1a–f, 2c, and 2e was prepared from naturally derived or synthetic amino alcohols and malonyl dichloride derivatives. The formation of the bisoxazolines was accomplished in two stages: (1) preparation of the bis-amides of the malonyl derivatives with the amino alcohols and (2) cyclization of the hydroxy amides 4 by either of two general protocols; (1) heating with thionyl chloride in toluene or (2) formation of the bismesylate and then heating with aqueous or alcoholic base. The latter procedure was found to be more reliable especially for bisoxazolines with bulky substitutents at C(4). The C(4) trityl-substituted hydroxy amide 4f produced the bis(acylaziridine) 10 by cyclization on the nitrogen atom using KOH/MeOH, but afforded the desired bisoxazoline If by the action of SOCl₂/Et₃N. The synthesis of the non-naturally derived amino alcohols using the Evans asymmetric azidation procedure is also described.