Synthesis of (-)-Tetrahydrolipstatin

Significance

(-)-Tetrahydrolipstatin is used for the treatment of obesity under the trade name ­Orlistat. It inhibits gastric and pancreatic lipases resulting in slow hydrolysis of triglycerides into free fatty acids. It is also known as a potent inhibitor of fatty acid synthase, an enzyme responsible for fatty acid synthesis in many human carcinomas. The pivotal anti-aldol segment I is synthesized via a nonaldol route involving a Lewis acid catalyzed diastereoselective ring opening of THF F to afford styrene derivative G as a key step.