Synthesis of Enantiostructured Triacylglycerol Prodrugs Constituting an Active Drug Located at Terminal <i>sn</i>-1 and <i>sn</i>-3 Positions of the Glycerol Backbone

The current paper reports the asymmetric synthesis of a focused library of enantiostructured triacylglycerols (TAGs) constituting a potent drug of the NSAID type (ibuprofen or naproxen) along with a pure bioactive n-3 polyunsaturated fatty acid (EPA or DHA) intended as a novel type of prodrugs. In this second category TAG prodrugs one of the terminal sn-1 or sn-3 positions of the glycerol skeleton is acylated with a single saturated medium-chain fatty acid (C6, C8, C10 or C12), the remaining one with the drug entity, and the PUFA located in the sn-2 position. This was accomplished by a six-step chemoenzymatic approach, two of which promoted by a lipase, starting from enantiopure (R)- and (S)-solketals. The highly regioselective immobilized Candida antarctica lipase (CAL-B) played a crucial role in the regiocontrol of the synthesis. The most challenging key step involved the incorporation of the drugs activated as oxime esters by the lipase exclusively into the terminal position of glycerol protected as a benzyl ether. All combinations, the total of 32 such prodrug TAGs, were prepared, isolated and fully characterized, along with 40 acylglycerol intermediates, obtained in very high to excellent yields in majority of cases.