Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

Abstract

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp3‐hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis‐phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation‐stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.

Kinetic resolution of racemic tertiary allylic alcohols through SN2′ reaction using a chiral bisphosphoric acid/silver(i) salt co-catalyst system

“…¶ Before considering the substituent effect of the catalyst, we summarize the intriguing features of these transition states, as follows: Two phosphoric acid units interact with each other through a hydrogen bond. 14 These two phosphoric acid units have specific roles and their involvement in the bond recombination sequence is essential. One phosphoric acid forms a hydrogen bond between the phosphoryl oxygen P O and the hydroxy proton of the tertiary alcohol.…”

“…Recently, we have developed an enantioselective intramolecular S N 2′ reaction using a co-catalyst system composed of chiral bisphosphoric acid catalyst ( R )- 1a 12 c ,14 and arylboronic acid (or silver carbonate) as a weakly Lewis acidic additive (Scheme 2a). 12 c In the reported co-catalyst system, achiral tertiary allylic alcohols 2 having a normal ring structure (five- or six-membered ring) at the allylic position and trichloroacetimidate as the leaving group ( LG ) underwent an intramolecular S N 2′ reaction smoothly, giving rise to enantioenriched diene monoepoxides ( R )- 3 as multifunctional products for further manipulation.…”

Chiral Bisphosphoric Acids and Their Applications in Asymmetric Catalysis

“…Employing BisPA‐2 b as the chiral Brønsted acid, Terada and coworkers successfully developed an enantioconvergent propargylic substitution reaction of racemic secondary propargylic alcohols with thiols to give propargyl thioether with up to 99 % ee (Scheme 9). [27] The sulfur functional group at the alkynyl terminus, which could stabilize the propargylic cation, is crucial for the reaction. Switching the leaving group from OH to benzoyl groups gave the chiral product 22 with similar levels of enantioselectivities, indicating the generation of a common cationic intermediate.…”

The Two Faces of Carbenium Ions: Intermolecular Trapping of Prochiral Carbocations with Stereocontrol

“…A related work to the benzylic system from the Terada laboratory was reported in the following year [37] . Secondary propargylic alcohols were treated with a strong chiral diphosphoric acid developed by the same group, and the cationic intermediate was captured by thiols (Scheme 16, top).…”