Efficient Synthesis of the A-Ring Phosphine Oxide Building Block Useful for 1α,25-Dihydroxy Vitamin D₃and 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.

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

“…Tert -butyldimethylsilyl protection of 6a gave 6b in 96% yield. Side-chain degradation on 6b by Daniewski's method [40] afforded alcohol 7a (71%), which was protected to 7b in the usual way (91%). Epoxide 7b was converted in 77% yield to dibromide 8b by the two-step sequence: 1) oxidative cleavage with periodic acid; 2) Corey-Fuchs side-chain extension [41].…”

Pd‐Mediated Reactions of Epoxides

“…[101] Moreover, the dienol isolated from the Z substrate was the E isomer. This contrasted markedly with the isomerization of (E)-and (Z)-diene epoxide nitriles, which occurred with preservation of the stereochemistry of their C=C bonds [Equation (69)].…”

“…[101] In the course of the synthesis of ingenane diterpenes, Rigby and co-workers isomerized α-alkenyl epoxides [102] on the basis that stereospecific anti-elimination of a HPdXL n fragment from an η 3 -allylpalladium intermediate could be effected in the presence of base. [103] These eliminations can proceed efficiently, leading to the dienols depicted in Equation (70), but are very sensitive to the substitution at C-9.…”

Difluoromethyl analogs of the natural hormone 1α,25-dihydroxyvitamin D3: Design, synthesis, and preliminary biological evaluation

“…Enantiomerically pure phosphine oxide (−)-22 [17] and CD-ring ketone 21, were separately azeotropically dried with anhydrous benzene (4× 5 mL) on a rotary evaporator and held under vacuum (ca. 0.1 mm Hg) for at least 48 h prior to use.…”