Enantioselective decarboxylative alkylation reactions: Catalyst development, substrate scope, and mechanistic studies

Douglas C. Behenna, Justin T. Mohr, Nathaniel H. Sherden, Smaranda C. Marinescu, Andrew M. Harned, Kousuke Tani, Masaki Seto, Sandy Ma, Zoltán Novák, Michael R. Krout, Ryan M. McFadden, Jennifer L. Roizen, John A. Enquist, David E. White, Samantha R. Levine, Krastina V. Petrova, Akihiko Iwashita, Scott C. Virgil, Brian M. Stoltz

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123 Citations (Scopus)

Abstract

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center. Sly as a PHOX: The development of an enantioselective decarboxylative palladium-catalyzed allylic alkylation reaction, utilizing phosphinooxazoline ligands, is described. The catalyst is applied to a range of allyl enol carbonate, silyl enol ether, and allyl β-ketoester substrates to provide alkylated ketone products in excellent yield and good ee (see scheme). The utility of these products is demonstrated by their use in several asymmetric syntheses. Mechanistic studies are reported suggesting an unusual inner-sphere mechanism.

Original languageEnglish
Pages (from-to)14199-14223
Number of pages25
JournalChemistry - A European Journal
Volume17
Issue number50
DOIs
Publication statusPublished - Dec 9 2011

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Keywords

  • alkylation
  • allylic compounds
  • asymmetric catalysis
  • enolates
  • reaction mechanisms
  • synthetic methods

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

Cite this

Behenna, D. C., Mohr, J. T., Sherden, N. H., Marinescu, S. C., Harned, A. M., Tani, K., Seto, M., Ma, S., Novák, Z., Krout, M. R., McFadden, R. M., Roizen, J. L., Enquist, J. A., White, D. E., Levine, S. R., Petrova, K. V., Iwashita, A., Virgil, S. C., & Stoltz, B. M. (2011). Enantioselective decarboxylative alkylation reactions: Catalyst development, substrate scope, and mechanistic studies. Chemistry - A European Journal, 17(50), 14199-14223. https://doi.org/10.1002/chem.201003383