Efficient Fluorination with Tetrabutylammonium Dihydrogen Trifluoride in a Novel Approach toward 1-alpha-Fluoro-25-hydroxy-vitamin D(3) Analogues.

The known, but hardly accessible, A-ring phosphine oxide 20, a building block for 1-alpha-fluoro-25-hydroxy-vitamin D(3), was prepared by a new route in gram amounts from (S)-(+)-carvone in 20 steps and 0.6% overall yield. Fluorine was introduced at an early stage by the completely regio- and stereoselective trans-diaxial opening of key-epoxide 5 with neat tetrabutylammonium dihydrogen trifluoride at 95 degrees C. The required 2-carbon chain extension of cyclohexanol 13 was accomplished in moderate yield via S(N)' substitution with cesium phenylselanyl acetate followed by Ireland-Claisen rearrangement of the resulting ester 15. Spontaneous elimination of the derived phenyl selenoxide led stereorandomly to a 1:1 mixture of dienoates E/Z-17, which was transformed into 20 as previously described.