title: The development of a complementary pathway for the synthesis of aliskiren.
abstract: The synthesis of aliskiren (1), a recently marketed drug for the treatment of hypertension, is presented. The focus of our synthetic effort is to develop an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy) benzyl)-N,N,8-trimethylnon-4-enamide (2a), which has been used as the advanced intermediate toward aliskiren. After an extensive investigation of three different strategies designed to construct the E-olefin functionality in 2a by employing the olefin cross-metathesis, Horner-Wadsworth-Emmons (HWE), and Julia-type olefinations, we have established a new protocol for the synthesis of 2a with a substantially improved overall efficiency in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the synthesis of the appropriate chiral intermediates in excellent enantiomeric purity of higher than 97% ee and a modified Julia-Kocienski olefination for the highly selective construction of E-2a with up to 13.6:1 E/Z ratio from the chiral intermediates. Consequently, the results provide an appealing option for the synthesis of aliskiren.
authors.affiliation: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China. fshan@ciac.ac.cn.
authors.forename: Le-Le
authors.initials: LL
authors.lastname: Li
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Ding
authors.forename: Lian-Xun
authors.initials: LX
authors.lastname: Gao
authors.forename: Fu-She
authors.initials: FS
authors.lastname: Han
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D005650:Fumarates / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000577:Amides; D005650:Fumarates; C446481:aliskiren