Cyclohexanediol(F. Hoffmann-La Roche Ltd.)

A short and efficient de novo route to the des-C,D vitamin D₃ derivative (Ro 65-2299), a potential antipsoriatic, has been developed.This route features an assembly strategy so far unexplored in vitamin D chem. involving a modified Julia olefination of the A-ring ketone I and the 2-benzothiazolyl sulfone II.Construction of the A-ring building block was accomplished by an efficient three-step route starting from the meso trans-1,3,5-cyclohexane triol III, which was desymmetrized by a highly selective enzymic mono-hydrolysis of the corresponding triacetate followed by oxidation of the alc. to give the homochiral diacetoxy ketone I (ee=99.5%) in 83% overall yield.Furthermore, we found efficient and practical syntheses of the 5-acetoxy-2-cyclohexenone IV and its enantiomer, both new building blocks useful for natural product synthesis.

For the synthesis of the potentially antipsoriatic vitamin D derivative, Ro 65-2299, an efficient and multiselective enzymic step was developed in which the easily accessible trans-1,3,5-triacetoxy-cyclohexane I (R = R¹ = α-OAc, R² = β-OAc) was selectively monohydrolyzed in the presence of the cis-isomer I (R = R¹ = R² = α-OAc) to give (1R,3R)-1,3-diacetoxy-5-hydroxy-cyclohexane I (R = α-OAc, R¹ = α-OH, R² = β-OAc) in high enantiomeric excess (>99%) and yield (84%).Furthermore, for the synthesis of the enantiomer of Ro 65-2299 a simple and efficient enzymic procedure for the asym. acetylation of cis-1,5-dihydroxy-3-(tert-butyldimethylsilanoxy)-cyclohexane I (R = α-OSiMe₂CMe₃, R¹ = R² = α-OH) in an anhydrous organic solvent providing (1R,3S,5S)-1-acetoxy-3-hydroxy-5-(tert-butyldimethylsilanoxy)-cyclohexane I (R = α-OSiMe₂CMe₃, R¹ = α-OAc, R² = α-OH) in >99% ee and quant. yield was described.