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

• Published in: Archives of pharmacal research Vol. 38; no. 12; pp. 2131 - 2136
• Main Authors: Lee, Sun Young, Jung, Jung Wha, Kim, Tae-Hyun, Kim, Hee-Doo
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01.12.2015; 대한약학회
• Subjects: alcohols; alkylation; antagonists; Chemistry, Pharmaceutical - methods; Clemastine - chemical synthesis; Histamine H1 Antagonists - chemical synthesis; Medicine; Pharmacology/Toxicology; Pharmacy; Receptors, Histamine H1 - chemistry; Research Article; Stereoisomerism; 약학; Asymmetric synthesis; Asymmetric transformation; (; H; Clemastine; ,; receptor antagonist; (R,R)-Clemastine; H1 receptor antagonist
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-015-0641-4

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.