A new chemoenzymatic approach to the synthesis of latanoprost and bimatoprost

Bimatoprost (1) and Latanoprost (2) are prostaglandin analogues widely used for glaucoma treatment. We have developed a new chemoenzymatic synthesis for 1 and 2, which utilizes a highly stereoselective sequence of biotransformations catalyzed by enzymes belonging to a single microorganism (the non-conventional yeast Pichia anomala). The original synthesis, starting from (–)-Corey lactone benzoate (3aR,4R,5R,6aS)-3, was modified by replacing three synthetic steps (C=C reduction, stereoselective C=O reduction and hydrolysis/deprotection of the benzoate ester) with a one-pot, three-enzymes conversion. Starting from substrate (3aR,4R,5R,6aS)-4 the use of Pichia anomala allows for the obtainment of Lactondiol B (3aR,4R,5R,6aS,3’S)-6 or Lactondiol L (3aR,4R,5R,6aS,3’R)-7, depending on the co-substrate employed: Lactondiol B (3aR,4R,5R,6aS,3’S)-6 was obtained with 68-70% yield using glucose, whereas the use of fumaric acid gave 87% yield of Lactondiol L (3aR,4R,5R,6aS,3’R)-8 in a simple one-pot, three-step biotransformation. In both cases the reactions were also highly stereoselective, with enantiomeric eccesses of products >97%. Different strategies of reaction optimization and improvement, including cells/enzyme immobilization and continuous flow reactor process implementation, will be also discussed.