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

Abstract

The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-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(2)-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(2) 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.

Transition-metal mediated carbon–sulfur bond activation and transformations

“…The analogues of ketene dithioacetals, i.e., O,S-ketene acetals 167, reacted with aldehydes at ambient temperature through a ZnCl 2 -mediated tandem Mukaiyama aldol lactonization pathway to afford highly diastereoselective 1,2-disubstituted b-lactones 168 (eqn ( 60)). 132 Mechanistic and theoretical studies reveal that both efficiency of this process and high diastereoselectivity are highly dependent on the type of ketene acetals employed but independent of ketene acetal geometry. The precoordination between ZnCl 2 and thiopyridyl ketene acetal to form adducts 169 prior to aldehyde addition benefits the process.…”

Approach to the Core Structure of 15-epi-Exiguolide

“…In the 1 H NMR spectrum of 26, the coupling constant J = 15.4 Hz between the olefinic protons indicated formation of the trans double bond. We also tried to form β-lactone 25 from the corresponding 2-pyridyl thioester in a domino Mukaiyama aldol reaction/lactonization (LiTMP, THF, TESCl, -78 °C, 2 h, addition of ZnCl 2 , r.t., 2 h, then addition of 9, 50 °C, 3 d); 25 however, the expected 25 was not formed. Continuing with the synthesis, the primary alcohol function was deprotected by acid-catalyzed transetherification to give alcohol 27.…”

Tailored Synthesis of Skeletally Diverse Stemona Alkaloids through Chemoselective Dyotropic Rearrangements of β‐Lactones

“…Since its first discovery in the late of 1970s, [19] this unique reaction has been explored intermittently by different groups, mostly on a methodological level [20] . Despite a seemingly useful method for the access of multisubstituted γ‐butyrolactones, its synthetic potential has remained underdeveloped, particularly in natural product synthesis, [20o,q] This is partially because its complicated reactivity and selectivity issues, which are largely dependent on substrate structures as well as reaction conditions, make it less predictable and controllable in practice. In recent years, our group has been striving to unearth the synthetic potential of this class of reactions [21] .…”