Mechanistic Investigations of the ZnCl2-Mediated Tandem Mukaiyama Aldol Lactonization: Evidence for Asynchronous, Concerted Transition States and Discovery of 2-Oxopyridyl Ketene Acetal Variants

The ZnCl2-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted beta-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl2-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cydoaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama open or Zimmerman-Traxler chair-like transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl2 and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated beta-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to beta-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.