title: X-ray and deuterium labeling studies on the abnormal ring cleavages of a 5 beta-epoxide precursor of formestane.
abstract: A new convergent synthesis of the antitumor steroid formestane (4-OHA) 5 has been performed from the easily available epimeric mixture of 5 alpha- and 5 beta-androst-3-en-17-one 1a and 1b in order to attempt a yield improvement. A two-step oxidative route followed by base-catalyzed isomerization was applied to the 5 alpha- and 5 beta-epimers 1a and 1b, either as a mixture or separately, leading to the title compound 5. From epimer 1a an efficient process was attained to prepare the desired aromatase inhibitor formestane. Epimer 1b led to the formation of the same compound 5. Additionally, 1b have also been converted in 5 beta-hydroxyandrostane-3,17-dione 12 and androst-4-ene-3,17-dione 13, revealing an unexpected reactivity of the 3 beta,4 beta-epoxy-5 beta-androstan-17-one intermediate 6 formed from 1b during the first oxidative step with performic acid. Cleavage of the epoxide 6 led to the trans-diaxial and the trans-diequatorial vic-diols 7 and 8 and to the 1,3-diol 9. The formation of the abnormal products 8 and 9 were investigated through X-ray and deuterium labeling studies. Diol 8 was formed through a trans-diequatorial epoxide ring opening and the 1,3-diol 9 was formed through an intramolecular rearrangement involving a 1,2-hydride shift. All the vic-diols 3, 7 and 8 formed, proved to be good precursors for the synthesis of the target compound 5.
authors.affiliation: Centro de Estudos Farmacêuticos, Lab. Química Farmacêutica, Fac. de Farmácia, Univ. de Coimbra, 3000-295 Coimbra, Portugal. etavares@ci.uc.pt
authors.forename: Elisiário J Tavares
authors.initials: EJ
authors.lastname: da Silva
authors.forename: Fernanda M F
authors.initials: FM
authors.lastname: Roleira
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Sá e Melo
authors.forename: André S Campos
authors.initials: AS
authors.lastname: Neves
authors.forename: José A
authors.initials: JA
authors.lastname: Paixão
authors.forename: Maria J
authors.initials: MJ
authors.lastname: de Almeida
authors.forename: Manuela R
authors.initials: MR
authors.lastname: Silva
authors.forename: Lourdes C R
authors.initials: LC
authors.lastname: Andrade
mesh_terms: D000732:Androstanols / Q000737:chemistry; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D000736:Androstenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D047072:Aromatase Inhibitors; D003903:Deuterium; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D007536:Isomerism; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D014965:X-Rays
chemical_list: D000732:Androstanols; D000736:Androstenes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D000735:Androstenedione; D003903:Deuterium; C014594:formestane