A-RING OXYGENATION STUDIES IN BRIDGEHEAD HYDROXYL-SUBSTITUTED TRANS-TRICYCLO[9.3.1.03,8]PENTADECAN-14-ONE CONGENERS OF TAXOL

The ready availability of 5 has prompted examination of a convenient means for carbonyl transposition in its A-ring. Attempts to implement such chemistry directly on 5 and its silyl-protected derivative suffer from a kinetic proclivity for transannular capture of the enolate anion. This undesirable process was circumvented by reduction of the C9 carbonyl following conversion to silyl enol ether 8. Once the resulting 9alpha-alcohol was protected as its MOM ether, the enolates of 10a and 10b could be efficiently oxygenated at C13 by treatment with the Davis sulfonyl oxaziridine despite severe steric congestion in that locale. The resultant alpha-alcohol 11a could be epimerized to the 13beta-isomer by exposure to potassium hexamethyldisilazide. Remarkably, 11a is prone to autoxidation, although the yield of diketone 12 is capricious. A preferred route to this key intermediate involves periodinane oxidation of 11a. Reduction of 12 and its O-silylated derivative has provided the targeted compounds 15 and 16, respectively. The conformational features of various intermediates are discussed in the light of NMR studies and MM2 calculations.