Total synthesis of "aliskiren": the first Renin inhibitor in clinical practice for hypertension.
We report a "macrocycle route" toward aliskiren, a drug presently marketed for the treatment of hypertension, using a highly stereocontrolled approach starting from a common "isopropyl chiron". Highlights of the synthesis include a challenging RCM reaction to produce a nine-membered unsaturated lactone, a highly stereoselective catalytic Du Bois aziridination, and a regio- and diastereoselective aziridine ring-opening to a vicinal amino alcohol.
Hanessian
Stephen
S
Department of Chemistry, Universite de Montreal, C.P. 6128, Succ. Centre-Ville, Montreal, Quebec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
Guesné
Sébastien
S
Chénard
Etienne
E
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005650:Fumarates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013237:Stereoisomerism; D013379:Substrate Specificity; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D011480:Protease Inhibitors; D000092502:Renin Inhibitors; C446481:aliskiren