New synthesis of sn-1,2-and sn-2,3-O-diacylglycerols application to the synthesis of enantiopure phosphonates analogous to triglycerides: A new classof inhibitors of lipases

Phosphonate compounds mimic the first transition state occurring during enz ymatic carboxyester hydrolysis of natural substrates by forming a covalent bond with the catalytic serine. However, until now the organophosphorus com pounds used in the inhibition studies more or less resembled a natural trig lyceride substrate. In order to elucidate the interfacial activation and th e mechanism of action of lipases, specific inhibitors need to be prepared. To achieve this goal, enantiomerically pure sn-1,2- and sn-2,3-O-didecanoyl glycerol compounds were prepared - starting from a C-4 chiral synthon, 3-bu ten-1,2-diol - and treated with n-pentylphosphonic dichloride and p-nitroph enol to afford the corresponding diastereomeric phosphonates, which were ac ylglycerol analogs. Subsequent separation of each of the phosphonate diaste reomers A/B or ent-A/ent-B, performed by HPLC, led to four enantiopure ster eoisomers that will be investigated as inhibitors of Human Pancreatic Lipas e (HPL) and Human Gastric Lipase (HGL) using the monomolecular film techniq ue.