Organocatalytic Asymmetric Conjugate Addition to Allenic Esters and Ketones

Abstract

The first example of an organocatalytic enantioselective conjugate addition of cyclic beta-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral beta,gamma-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for beta-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic beta-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active alpha-vinyl-substituted alpha-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (gamma-lactames).

Recent Developments in Asymmetric Phase‐Transfer Reactions

“…[106] The highly enantioselective conjugate addition of b-ketoesters to electron-deficient allenes was also developed to obtain conjugate adducts such as 139 (Scheme 83). [107] Jørgensen and co-workers also reported the asymmetric conjugate addition of b-ketoester 123 to 140, which has a sulfone as a leaving group. The reaction was promoted by catalyst 1 g to give product 141 arising from a conjugate addition and subsequent elimination of sulfone (Scheme 84).…”

Methylene‐Bridged Bis(imidazoline)‐Derived 2‐Oxopyrimidinium Salts as Catalysts for Asymmetric Michael Reactions

“…Corey et al first reported the conjugate addition of 1 to acrylates and enones with notable enantioselectivity (>90 % ee ) in the presence of an N-alkylated cinchonidine salt 4. Subsequently, the scope of the reaction was expanded with other modified cinchona alkaloids5 as well as new catalysts, comprising largely of quaternary bis(ammonium) and N-spiro ammonium moieties derived from tartrates,6 axially-chiral 1,1′-biaryl units,5f, 7 inositol-derived crown ethers,8 and a calix[4]arene amino acid 9. The use of these pH-neutral catalysts requires strong bases to generate the nucleophile, thus very low temperatures (typically −40 to −78 °C) were necessary to suppress competitive reactions.…”

Cinchona‐Catalyzed Nucleophilic Conjugate Addition to Electron‐Deficient CC Double Bonds

“…Very recently, the use of the electron-deficient allenic esters and ketones 50 as acceptors was also reported by the same group [14]. Under PTC conditions (42a (3 mol%), o-xylene/CHCl 3 , K 2 CO 3 aq), the cyclic b-ketoester 49 underwent an addition to the electron-deficient allenic esters and ketones 50, giving the corresponding b,g-unsaturated (isolated alkene) carbonyl compounds 51 with excellent enantioselectivity (up to 96% ee, Scheme 9.16).…”