Mechanistic Investigations
of the ZnCl<sub>2</sub>-Mediated Tandem Mukaiyama Aldol Lactonization:
Evidence for Asynchronous,
Concerted Transition States and Discovery of 2-Oxopyridyl Ketene Acetal
Variants
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Abstract
The ZnCl<sub>2</sub>-mediated tandem Mukaiyama aldol
lactonization
(TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides
a versatile, highly diastereoselective approach to <i>trans</i>-1,2-disubstituted β-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 ZnCl<sub>2</sub>-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] cycloaddition 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 ZnCl<sub>2</sub> and thiopyridyl ketene
acetals prior to aldehyde addition for optimal reaction rates. Our
previously proposed, silylated β-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 β-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