648409-48-7

Upstream product

• 102249-52-5 4-hydroxy-5-phenylpyridin-2(1H)-one 
• 188670-22-6 (S)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate 
• 32265-03-5 6-chloro-4-hydroxy-5-phenyl(1H)-pyridin-2-one 

Downstream Products

• 648409-49-8 (R)-6-[2,4-bis-(tert-butyldimethylsilanyloxy)-5-phenylpyridin-3-yl]-6H-pyran-3-one 
• 648409-52-3 3-((2R,3R,5R)-tetrahydro-3-methyl-5-((R)-6-methyloctyl)-2H-pyran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 
• 792912-92-6 3-((2R,3R,5R)-tetrahydro-3-methyl-5-((S)-6-methyloctyl)-2H-pyran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 
• 648409-51-2 2,4-bis-(tert-butyldimethylsilanyloxy)-3-[(R)-3-methyl-5-((R)-6-methyloctyliden)tetrahydropyran-2-(R)-yl]-5-phenylpyridine 
• 792912-91-5 2,4-bis-(tert-butyldimethylsilanyloxy)-3-[(R)-3-methyl-5-((S)-6-methyloctyliden)tetrahydropyran-2-(R)-yl]-5-phenylpyridine 
• 792912-97-1 2,4-bis-(tert-butyldimethylsilanyloxy)-3-[(R)-3-methyl-5-(tetradecyliden)tetrahydropyran-2-(R)-yl]-5-phenylpyridine 
• 792912-99-3 3-((2R,3R,5R)-tetrahydro-3-methyl-5-tetradecyl-2H-pyran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 
• 792912-96-0 2,4-bis-(tert-butyldimethylsilanyloxy)-3-[(R)-3-methyl-5-(pentyliden)tetrahydropyran-2-(R)-yl]-5-phenylpyridine 

Relevant academic research and scientific papers

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

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.

Total Synthesis and Reassessment of the Phosphatase-Inhibitory Activity of the Antitumor Agent TMC-69-6H

The unexpected selectivity proflie of I (17R)-and (17S)-TMC-69-6H (see formula) suggests that N-hydroxypyridone derivatives constitute a promising new lead structure in the search for selective phosphatase inhibitors. An unprecedented Pd-catalyzed C-C bond formation to a pyranone derivative was a key step in the synthesis of enantiopure (17R)-and (17S)-TMC-69-6H.