Unveiling the Reaction Mechanism of the Das/Chechik/Marek Synthesis of Stereodefined Quaternary Carbon Centers

Pedro J Silva,Carlos E P Bernardo

doi:10.3390/app11115002

Abstract

The reaction mechanism of the Cu+-catalyzed introduction of two all-carbon-substituted stereocenters in an ynamide system using a Grignard reagent, a zinc carbenoid, and an aldehyde, was investigated using density-functional theory. In contrast to the formation of an organocopper(I) compound and subsequent carbocupration reaction, previously postulated as the initial step, the reaction proved to instead proceed through an initial complexation of the substrate alkyne bond by the Cu+-catalyst, which primes this bond for reaction with the Grignard reagent. Subsequent addition of the zinc carbenoid then enables the nucleophilic attack on the incoming aldehyde, which is revealed as the rate-limiting step. Our computations have also identified the factors governing the regio- and setereoselectivity of this interesting reaction, and suggest possible paths for its further development.

Highlights

Introduction theDas/Chechik/Marek Synthesis ofTen years ago, Chechik, Das, and Marek developed a simple method to generate stereodefined quaternary all-carbon-substituted carbon centers in acyclic systems [1]
Our computations characterized the precise nature of the different transition states, identified the rate-determining step, and showed that, instead of the proposed pathway, the initial carbo-metalation event proceeds through the formation of a π-complex between CuI and the alkyne, followed by direct methylation of the alkyne bond by the unmodified Grignard reagent
Our DFT computations showed that CuCH3 synthesis from THFcomplexed CuI and CH3 MgBr is exergonic by 11.8 kcal·mol−1 and that it proceeds readily with a barrier of only 9.6 kcal·mol−1

Summary

Introduction

Introduction theDas/Chechik/Marek Synthesis ofTen years ago, Chechik, Das, and Marek developed a simple method to generate stereodefined quaternary all-carbon-substituted carbon centers in acyclic systems [1]. 2 is instead reacted with the Simmons–Smith–Furukawa zinc carbenoid (ICH2 ZnCH2 I), yielding a much more reactive allylzinc compound 3 which is susceptible to addition of a carbonyl compound to provide the last substituent at the quaternary center This step is stereocontrolled, presumably through the formation of a Zimmerman–Traxler transition state (a six-membered ring transition state adopting a chair conformation) involving an interaction between the carbonyl oxygen and the zinc atom. This reaction has been extensively cited since, and was subsequently modified to yield stereo-defined tri-substituted enolates [2]. Our computations characterized the precise nature of the different transition states, identified the rate-determining step, and showed that, instead of the proposed pathway, the initial carbo-metalation event proceeds through the formation of a π-complex between CuI and the alkyne, followed by direct methylation of the alkyne bond by the unmodified Grignard reagent

Methods

Results

Conclusion