Total synthesis of (S)-forphenicinol via asymmetric organocatalysis

Practical asymmetric synthesis of (S)-forphenicinol, the active ingredient of immunomodulator and anticancer drug Forfenimex (R), 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 gamma-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%).

Automated summary

A practical asymmetric synthesis method of (S)-forphenicinol, the active ingredient of immunomodulator and anticancer drug Forfenimex (R), from commercially available 2-hydroxy-dimethylterephthalate has been developed. The key steps of the synthesis involve a stereogenic-center-forming enantioselective organocatalytic Mannich reaction and oxidative transformation of the gamma-pyrone fragment, resulting in a significantly higher total yield compared to known methods.