Efficient synthesis of the A-ring phosphine oxide building block useful for 1α,25-dihydroxy vitamin D3 and analogues

The 1alpha-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 3beta-alcohol 11 and the highly chemo- and stereoselective isomerization of dieneoxide ester (E)-7 to the 1alpha-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 1alpha-hydroxy epimers complements our previously reported synthesis of the corresponding 1beta-epimers, thus producing all stereoisomers of these versatile building blocks efficiently from carvone.