Synthetic studies on taxane skeleton, taxol and its derivatives

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Taxol【○!R】 (paclitaxel), a typical taxane diterpene, is one of the most attractive synthetic targets in organic chemistry because of its unique structural features, as well as its antileukemic and tumor inhibiting activity. Recently, the total synthesis of taxol has been accomplished by six groups in succession, however, the efforts for developing an efficient synthetic method of taxanes are continuously being made. We now report a new synthetic route for the taxane skeleton using a fragmentation reaction and an intramolecular nitrile oxide cyclization reaction as key steps.First, we have confirmed the viability of intramolecular nitrile oxide cyclization for the construction of A/B ring system. The cyclization reaction of a model compound, 4-(5'-nitropentyl) cyclohexene derivative, promoted by p-chlorophenyl isocyanate and a catalytic amount of triethl amine was found to form directly the A/B ring system which has a bridgehead double bound in A ring and an oxime group in B ring.Next, the synthesis of the key intermediate consisting of A/C ring and its intramolecular cyclization to produce the taxane skeleton were investigated. The C ring unit was constructed by the fragmentation reaction of bicyclo [2.2.2] octane derivative prepared from D-mannitol in stereoselective manner. Connection of the C ring moiety with 4,6,6-trimethyl-2,4-cylohexadienyl group provided A/C ring system, which was easily converted into the key intermediate. The crucial cyclization reaction of the compound with p-chlorophenyl isocyanate gave the taxane skeleton in optically active form.