Efficient synthesis of the A-ring phosphine oxide building block useful for 1 alpha,25-dihydroxy vitamin D(3) and analogues

• Published in: Journal of organic chemistry Vol. 67; no. 5; pp. 1580 - 1587
• Main Authors: Daniewski, Andrzej R, Garofalo, Lisa M, Hutchings, Stanley D, Kabat, Marek M, Liu, Wen, Okabe, Masami, Radinov, Roumen, Yiannikouros, George P
• Format: Journal Article
• Language: English
• Published: United States 08.03.2002
• Subjects: Catalysis; Chromatography, Thin Layer; Heptanes - chemical synthesis; Heptanes - chemistry; Magnetic Resonance Spectroscopy; Molecular Structure; Monoterpenes; Oxides - chemical synthesis; Oxides - chemistry; Phosphines; Phosphinic Acids - chemical synthesis; Phosphinic Acids - chemistry; Silanes - chemical synthesis; Silanes - chemistry; Stereoisomerism; Terpenes - chemistry; Vitamin A - analogs & derivatives; Vitamin A - chemical synthesis; Vitamin A - chemistry
• ISSN: 0022-3263

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.