We are engaged in the development of the first catalytic asymmetric approach to the construction of phosphinate pseudo-dipeptides. These compounds have become increasingly valuable as inhibitors of matrix metalloproteinases implicated in tumor metastasis mechanisms. Our reaction involves a phospha-Michael addition to a variety of α,β-unsaturated substrates, especially acrylates, that proceeds under heterogeneous reaction conditions to exploit the power of asymmetric phase transfer catalysis. Using Cs<sub>2</sub>CO<sub>3</sub> and a quaternary ammonium salt, the reaction is exceptionally mild and general, tolerating a wide range of substitutions on both the phosphinate and the vinyl electrophile components. This method is an alternative to current procedures involving the intermediacy of highly reactive trivalent phosphorous species, which have proven resistant to asymmetric approaches. By contrast, the present reaction has been engineered to work with cinchonidinium salt catalysts, leading to good enantioselectivities. In this presentation, we will also discuss our optimization studies and efforts to elucidate the mechanism of the observed asymmetric induction.

Phase transfer-catalyzed phospha-Michael additions: An asymmetric approach to phosphinate esters

2019 Spring National Meeting

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