Total synthesis of ( S )-forphenicinol via asymmetric organocatalysis

Practical asymmetric synthesis of ( S )-forphenicinol, the active ingredient of immunomodulator and anticancer drug Forfenimex®, from commercially available 2-hydroxy-dimethylterephthalate has been developed. Key steps of the synthesis are a stereogenic-center-forming enantioselective organocatalytic Mannich reaction of protected arylcarbaldimine with a kojic acid derivative and oxidative transformation of the γ-pyrone fragment into the carboxylic group. The total yield of ( S )-forphenicinol hydrochloride (99% ee) via the proposed nine-step synthetic scheme (17%) is significantly higher than those attained by known methods (4.6% and 0.8%).