The Chemistry of the Taxane Diterpene: Stereoselective Reductions of Taxanes

Stereoselective reductions of taxanes are detailed. Chelation-controlled reductions employing SmI2 are described for the stereoselective reduction of the 9-keto functionality of the diterpene moiety of several taxanes. In all cases the 9 beta-hydroxy stereochemistry was obtained exclusively. In addition to C9 reduction, partial C10-deoxygenation via beta-elimination was observed. Lower reaction temperatures favored the reduction pathway without beta-elimination. Acetic acid as the proton source gave higher yields and cleaner reaction products. This chemistry provided access to taxanes with 9 beta-hydroxy, 10 beta-hydroxy stereochemistry. Evidence is presented, suggesting that chelation of samarium with the 7 beta-hydroxyl group is required for the reduction of the C9 ketone moiety. The synthesis of paclitaxel analogues, possessing the 9 alpha-hydroxy, 10 alpha-hydroxy stereochemistry was also achieved. Reduction of the 10-ketone group of 10-oxopaclitaxel employing NaBH4 produced 10-deacetyl-10-epipaclitaxel stereoselectively. Using an excess of NaBH4 in this reaction gave exclusively the 9 alpha-hydroxy, 10 alpha-hydroxy paclitaxel analogue.