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Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems


This protocol describes a new approach for the preparation of stereodefined trisubstituted chiral enolate species, avoiding conventional asymmetric enolization of carbonyl compounds. This protocol was developed as a single-flask synthetic sequence and therefore does not require isolation or purification of intermediate compounds. The sequence starts from a regioselective carbocupration reaction of readily accessible chiral ynamides; this is followed by oxidation of the generated vinylcuprate with a commonly available oxidizing reagent (tert-butyl hydroperoxide) in order to generate an enolate that completely retains its configuration. This synthetic protocol has been applied to the preparation of aldol and Mannich-type adducts. The procedure reported here requires a simple reaction setup commonly available in all synthetic laboratories and takes 6 h for completion and 2 h for isolation and purification. Final products are valuable diastereomerically and enantiomerically enriched building blocks for organic synthesis containing all-carbon quaternary stereocenters in acyclic systems.

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Figure 1: The general method developed for the construction of all-carbon quaternary stereogenic centers in acyclic systems starting from ynamides 3.


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This research was supported by the Israel Science Foundation (administered by the Israel Academy of Sciences and Humanities (140/12)) and by the Fund for Promotion of Research at the Technion. L.L. thanks the Bayer-Stiftung for financial support. I.M. is the holder of the Sir Michael and Lady Sobell Academic Chair.

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Y.M., M.P. and L.L. planned, conducted and analyzed the experiments. I.M. conceived and directed the project and wrote the manuscript with contributions from Y.M. and M.P. All authors contributed to discussions.

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Correspondence to Ilan Marek.

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Minko, Y., Pasco, M., Lercher, L. et al. Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems. Nat Protoc 8, 749–754 (2013).

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