Highly Enantioselective, Catalytic Conjugate Addition of Cyanide to α,β-Unsaturated Imides
Glenn M. Sammis and Eric N. Jacobsen*
*Department of Chemistry and Chemical Biology, Harvard University,
Cambridge, Massachusetts 02138, Email:
jacobsen
chemistry.harvard.edu
G. M. Sammis, E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125, 4442-4443.
DOI: 10.1021/ja034635k
Abstract
A (Salen)Al-Cl complex catalyzes the asymmetric conjugate addition of hydrogen cyanide to α,β-unsaturated imides in high yields and enantioselectivities. The cyanide adducts can readily be converted into a variety of useful chiral building blocks, including α-substituted-β-amino acids.
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Details
Researchers Glenn M. Sammis and Eric N. Jacobsen from Harvard University have developed a highly enantioselective, catalytic method for the conjugate addition of cyanide to α,β-unsaturated imides using (salen)AlIII catalysts. This method addresses the lack of asymmetric catalysts for 1,4-additions to α,β-unsaturated carbonyl compounds, providing access to valuable chiral building blocks like β-substituted-γ-aminobutyric acids and α-substituted-β-amino acids. The study found that using TMSCN and 2-propanol to generate HCN in situ significantly improved reactivity and enantioselectivity, achieving up to 97% ee and 90% yield. The methodology was successfully applied to synthesize pregabalin, an anticonvulsant drug, in 96% ee. Mechanistic studies suggest a bimetallic, dual activation mechanism involving cyanide delivery from a (salen)Al-CN complex to an electrophile bound as an imidate complex. This represents the first example of asymmetric catalysis of cyanide conjugate addition reactions, with ongoing efforts to optimize the catalyst system for broader applications. The research was supported by the NIH and NSF, with detailed experimental procedures available online.
Key Words
ID: J48-Y2003-1420
