Efficient Synthesis of the A-Ring Phosphine Oxide Building Block Useful for 1α,25-Dihydroxy Vitamin D3 and Analogues

• Published in: Journal of organic chemistry 2002-03, Vol.67 (5), p.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: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Chemistry; Exact sciences and technology; Organic chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0161577

The 1α-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 α-methoxy hydroperoxyacetate 10 in methanol to obtain directly the desired secondary 3β-alcohol 11 and the highly chemo- and stereoselective isomerization of dieneoxide ester (E)- 7 to the 1α-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 1α-hydroxy epimers complements our previously reported synthesis of the corresponding 1β-epimers, thus producing all stereoisomers of these versatile building blocks efficiently from carvone.