Synthesis and evaluation of the antitumor agent TMC-69-6H and a focused library of analogs

• Published in: Tetrahedron Vol. 60; no. 43; pp. 9543 - 9558
• Main Authors: Fürstner, Alois, Feyen, Fabian, Prinz, Heino, Waldmann, Herbert
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 18-10-2004
• Subjects: Heterocycles; Julia–Kocienski olefination; N-oxidation; Palladium; Phosphate inhibitors; Heterocycles; N-oxidation; Julia–Kocienski olefination; Palladium; Phosphate inhibitors
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2004.06.139

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)MoO
5(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.
Graphical Abstract