Enantioselective Protonation

Significance

Chiral bicyclic guanidine derivative 1 catalyzes a tandem process involving a conjugate addition followed by enantioselective protonation or deuteration. By using thiols as nucleophiles, this Brønsted base catalyzed methodology allows the preparation of enantioenriched d-cysteine analogues by subsequent deprotection of the products. High yields (82-99%) are reported alongside excellent enantioselectivities (er = 92:8 up to 97:3). The cleavage/formation of a bond containing H (or D) is involved in the rate-determining step as a small but significant kinetic isotope effect was found. Furthermore, a tandem conjugate addition-enantioselective protonation reaction of N-substituted itaconimides and secondary phosphine oxides as nucleophiles is reported.

Comment

Deng and co-workers recently reported an enantioselective conjugate addition followed by the diastereoselective protonation of non-adjacent chiral centers catalyzed by cinchona alkaloids for the generation of 1,3-stereocenters (J. Am. Chem. Soc. 2006, 128, 3928; J. Am. Chem. Soc. 2007, 129, 768). Here, a similar methodology is exploited. The reported generation of a transient enolate through a conjugate addition followed by an in situ enantioselective protonation represents an efficient approach to the preparation of chiral carbonyl compounds with an α-stereogenic center.