Asymmetric synthesis of H1 receptor antagonist (R,R)-clemastine.

The first asymmetric synthesis of (R,R)-clemastine (1) has been accomplished by the coupling of (R)-tertiary alcohol 2 and (R)-chloroethylpyrrolidine 3 via O-alkylation. (R)-Tertiary alcohol 2 was synthesized by stereoselective alkylation of chiral α-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 with L-homoserine lactone, in which racemization-minimized N-allylation and ring-closing metathesis were involved as key steps.

Stereoselective synthesis of (-)-hydroxyclemastine as a versatile intermediate for the H1 receptor antagonist clemastine.

Hydroxyclemastine was targeted as a versatile analogue of clemastine with H1 receptor antagonist activity. Stereoselective synthesis of (-)-hydroxyclemastine was performed in which the key step was chelation-controlled diastereoselective 1,2-addition of Grignard reagent to alpha-alkoxyketone.