A Combined DFT and NMR
Investigation of the Zinc Organometallic
Intermediate Proposed in the <i>Syn</i>-Selective Tandem
Chain Extension–Aldol Reaction of β-Keto Esters
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Abstract
The tandem chain extension–aldol (TCA) reaction
of β-keto
esters provides an α-substituted γ-keto ester with an
average <i>syn</i>:<i>anti</i> selectivity of
10:1. It is proposed that the reaction proceeds via a carbon–zinc
bound organometallic intermediate potentially bearing mechanistic
similarity to the Reformatsky reaction. Evidence, derived from control
Reformatsky reactions and a study of the structure of the TCA intermediate
utilizing DFT methods and NMR spectroscopy, suggests the γ-keto
group of the TCA intermediate plays a significant role in diastereoselectivity
observed in this reaction. Such coordination effects have design implications
for future zinc mediated reactions