Abstract
A procedure for the enantioselective synthesis of α-substituted glutamates and pyroglutamates via a cyclopropenimine-catalyzed Michael addition of amino ester imines is described. Enantioselectivities of up to 94% have been achieved, and a variety of functional groups were found to be compatible. The impact of the catalyst structure and imine substitution is discussed. Compared to other methods, this protocol allows for a broader and more enantioselective access to pyroglutamate derivatives.
Highlights
Introduction αSubstituted glutamates have value as synthetic building blocks and as a common substructure in a number of biologically active molecules [1,2,3,4,5]
We describe the use of cyclopropenimine catalysis for the enantioselective catalytic Michael reaction of α-substituted amino ester imines
We found that the previously reported cyclopropenimine 4 catalyzed this transformation with 90% conversion and 84% ee in 24 hours at ambient temperature (Table 1, entry 1)
Summary
Introduction αSubstituted glutamates have value as synthetic building blocks and as a common substructure in a number of biologically active molecules [1,2,3,4,5]. One of the most straightforward approaches to α-substituted glutamate derivatives is via the Michael addition of α-amino ester enolates to acrylate acceptors. The use of substituted amino ester derivatives for the enantioselective α-alkylation has been achieved [31], Michael reactions with these nucleophiles have met with limited success [32,33,34,35,36,37,38,39].
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