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Abstract

A concise, efficient and flexible total synthesis of the potent antitumor agent TMC-69-6H (2) is described. Key steps involve the palladium catalyzed regioselective addition of 4-hydroxy-2-pyridone 5 to pyranyl acetate 6 which is accompanied by a spontaneous 1,4-addition of the phenolic –OH group to the emerging enone to give the tricyclic product 7 in excellent yield. When this reaction is carried out with optically enriched (S)-6 (conveniently prepared by a lipase catalyzed kinetic dynamic resolution) in the presence of the chiral ligand (S,S)-12 and allylpalladium chloride dimer, the ensuing matched situation delivers the key building block (−)-7 in 96% ee. Its further elaboration into 2 involves a Julia–Kocienski olefination with tetrazolylsulfone 19 and a final N-oxidation effected by the peroxomolybdenum complex [(pyridine)MoO₅(HMPA)] to form the hydroxamic acid motif. The flexibility inherent to this route allows for the preparation of a focused library of analogues for biochemical evaluation. The results obtained show that N-hydroxy-2-pyridone derivatives constitute a promising new class of selective phosphatase inhibitors. In contrast to previous reports in the literature, however, TMC-69-6H and congeners are found to exhibit pronounced activities against the tyrosine protein phosphatase PTB1B, the dual specific phosphatase VHR, and the serine/threonine phosphatase PP1, while being only weak inhibitors for the dual specific phosphatases Cdc25 A and B. Two key intermediates of the synthesis route have been characterized by X-ray crystallography.