Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles via decarboxylative asymmetric allylic alkylation
An enantioselective synthesis of diverse N4-Boc-protected α,α-disubstituted piperazin-2-ones using the palladium-catalyzed decarboxylative allylic alkylation reaction has been achieved. Using a chiral Pd-catalyst derived from an electron deficient PHOX ligand, chiral piperazinones are synthesized in high yields and enantioselectivity. The chiral piperazinone products can be deprotected and reduced to valuable gem-disubstituted piperazines. This reaction is further extended to enable the enantioselective synthesis of α,α-disubstituted tetrahydropyrimidin-2-ones, which are hydrolyzed into corresponding chiral β^(2,2)-amino acids.
© 2018 The Royal Society of Chemistry. Open Access Article. Published on 31 October 2018. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. All publication charges for this article have been paid for by the Royal Society of Chemistry. The article was received on 06 Sep 2018, accepted on 29 Oct 2018 and first published on 31 Oct 2018. The NIH-NIGMS (R01GM080269) and Caltech are thanked for support of our research program. Additionally, A. W. S. thanks the NIH-NIGMS for a predoctoral fellowship (Ruth L. Kirschstein Institutional National Research Service Award F30GM120836) and a UCLA-Caltech Medical Scientist Training Program Fellowship (T32GM008042). S. N. H. thanks the Bayer Foundation for an Otto Bayer Scholarship. Dr David VanderVelde is thanked for assistance with structural assignments via NMR analysis. Dr Scott Virgil, Dr Marchello Cavitt, Dr Brendan O'Boyle, Dr Justin Hilf, Dr Corey Reeves, and Kevin Yang are thanked for helpful discussions.
Published - c8sc03967d.pdf
Supplemental Material - c8sc03967d1.pdf