title: Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates.
abstract: A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.
authors.affiliation: Departamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, 33071-Oviedo, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Díaz
authors.forename: V
authors.initials: V
authors.lastname: Gotor-Fernández
authors.forename: M
authors.initials: M
authors.lastname: Ferrero
authors.forename: S
authors.initials: S
authors.lastname: Fernández
authors.forename: V
authors.initials: V
authors.lastname: Gotor
mesh_terms: D002117:Calcitriol / Q000737:chemistry*; D002254:Carbonates / Q000138:chemical synthesis*; D002762:Cholecalciferol / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013237:Stereoisomerism
chemical_list: D002254:Carbonates; D007659:Ketones; C083611:1,25-dihydroxy-19-norprevitamin D3; D002762:Cholecalciferol; D002117:Calcitriol