title: Efficient synthesis of the A-ring phosphine oxide building block useful for 1 alpha,25-dihydroxy vitamin D(3) and analogues.
abstract: The 1 alpha-hydroxy A-ring phosphine oxide 1, a useful building block for vitamin D analogues, was synthesized from (S)-carvone in nine synthetic operations and a single chromatographic purification in 25% overall yield. The synthesis features two novel efficient synthetic transformations: the Criegee rearrangement of alpha-methoxy hydroperoxyacetate 10 in methanol to obtain directly the desired secondary 3 beta-alcohol 11 and the highly chemo- and stereoselective isomerization of dieneoxide ester (E)-7 to the 1 alpha-allylic alcohol with an exocyclic double bond (E)-8. Further insight into the selectivity control of the latter rearrangement was obtained from the reactions of (Z)-epimeric substrates. The new synthetic approach leading to the 1 alpha-hydroxy epimers complements our previously reported synthesis of the corresponding 1 beta-epimers, thus producing all stereoisomers of these versatile building blocks efficiently from carvone.
authors.affiliation: Chemical Synthesis - Process Research, Non-Clinical Development, Pre-Clinical Research and Development, Hoffmannminus signLa Roche, Inc., Nutley, New Jersey 07110, USA.
authors.forename: Andrzej R
authors.initials: AR
authors.lastname: Daniewski
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Garofalo
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Hutchings
authors.forename: Marek M
authors.initials: MM
authors.lastname: Kabat
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Masami
authors.initials: M
authors.lastname: Okabe
authors.forename: Roumen
authors.initials: R
authors.lastname: Radinov
authors.forename: George P
authors.initials: GP
authors.lastname: Yiannikouros
mesh_terms: D002384:Catalysis; D002855:Chromatography, Thin Layer; D000081005:Cyclohexane Monoterpenes; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D039821:Monoterpenes; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry; D010720:Phosphines; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D012821:Silanes / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013729:Terpenes / Q000737:chemistry; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C452446:1alpha-hydroxy A-ring phosphine oxide; D000081005:Cyclohexane Monoterpenes; D006536:Heptanes; D039821:Monoterpenes; D010087:Oxides; D010720:Phosphines; D010721:Phosphinic Acids; D012821:Silanes; D013729:Terpenes; D014801:Vitamin A; C006923:carvone