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Total Synthesis and Comparative Analysis of Orlistat, Valilactone, and a Transposed Orlistat Derivative: Inhibitors of Fatty Acid Synthase

2006; American Chemical Society; Volume: 8; Issue: 20 Linguagem: Inglês

10.1021/ol061651o

1523-7060

Gil Ma, Manuel Zancanella, Yatsandra Oyola, Robyn D. Richardson, Jeffrey W. Smith, Daniel Romo,

Lipid metabolism and biosynthesis

Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol−lactonization (TMAL) process as a key step. This process allows facile modification of the α-side chain. Versatile strategies for modifying the δ-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.