Clemastine (1) is an H1-receptor antagonist with excellent antihistaminic activity. Clemastine has two chiral centers, and is marketed as the (R, R)-enantiomer. These chiralities have a significant influence on potency. However, asymmetric synthesis of (R,R)-clemastine has not been reported to date.
The first asymmetric synthesis of (R,R)-clemastine (1) has been accomplished by coupling of (R)-tertiary alcohol 2 and (R)-chloroethylpyrrolidine 3 via O-alkylation. (R)-Tertiary alcohol 2 was synthesized by stereoselective alkylation of chiral a-benzyloxy ketone with Grignard reagent via chelation-controlled 1,4-asymmetric induction. In the reaction, chiral benzyl group acts as a chiral auxiliary as well as a protecting group. (R)-chloroethylpyrrolidine 3 was prepared by asymmetric transformation starting from L-homoserine lactone, in which racemization-minimized N-allylation and ring-closing metathesis were involved as key steps.