title: Stereoselective reduction of C-20 ketone of vitamin D CD-ring and a new synthetic approach to maxacalcitol.
abstract: Stereoselective reduction of C-20 ketone of vitamin D CD-ring precursor using Corey's CBS reagents, (R)-(+)-2-methyl-CBS-oxazaborolidine and (S)-(-)-2-methyl-CBS-oxazaborolidine, led to the (20S)-alcohol 5 and (20R)-epimer 4 in approximately 17:1 selectivity. A new synthetic approach to the 22-oxa-25-hydroxy Grundmann's ketone 11 was developed through the Williamson etherification of (20S)-alcohol 5 with 1-bromomethyl-2,2-dimethyloxirane, followed by regioselective reductive epoxide ring opening with LiAlH4, the removal of the silyl protecting group by TBAF, and the environmentally benign TEMPO-mediated oxidation using inexpensive Oxone as a co-oxidizing agent. The preparation of drug maxacalcitol was achieved on gram scale by the convergent Lythgoe coupling via Wittig-Horner reaction of the A-ring phosphine oxide synthon with the CD-ring fragment.
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Zhao
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China. Electronic address: liuzhaop@sdu.edu.cn.
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D007659:Ketones / Q000737:chemistry*; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D007659:Ketones; D002117:Calcitriol; C051883:maxacalcitol
keywords: CBS reagents; KH-1060; Maxacalcitol; Stereoselective reduction; Vitamin D; Wittig–Horner reaction