Efficient stereoselective synthesis of plasmenylcholines

The first practical total chemical synthesis of a plasmenylcholine (1-O-1'-(Z)-hexadecenyl-2-hexadecanoyl-sn-glycero-3-phosphocholine) with pure (Z) olefin stereochemistry is reported. Monopalmitin was doubly protected as the 3-TBDPS-2-TBDMS ethers (tert-butyldiphenylsilyl-, tert-butyldimethylsilyl-) and converted to the corresponding 1-O-1'-(Z)-hexadecenyl-2-TBDMS-3-TBDPS-glyceryl ether (by the method of ref. [43]). Clean deprotection with tetrabutylammonium fluoride in the presence of imidazole gave 1-O-1'-(Z)-hexadecenylglycerol in >90% yield. Resilylation with TBDPSCl followed by acylation of the sn-2 alcohol with palmitoyl chloride and deprotection of the resulting 3-TBDPS-2-hexadecanoyl-1-O-1'-(Z)-hexadecenylglycerol at -20 degrees C with Bu(4)NF gave 2-hexadecanoyl-1-O-1'-(Z)-hexadecenylglycerol in 86% yield. The 3-phosphocholine group was attached by phosphorylating the free hydroxyl with 2-chloro-2-oxo-1,3,2-dioxaphospholane in the presence of pyridine, instead of Et(3)N, as base to avoid acyl migration; the dioxaphospholane triester intermediate was subsequently cleaved with Me(3)N to give 1-O-1'-(Z)-hexadecenyl-2-hexadecanoyl-sn-glycero-3-phosphocholine in 18% overall yield from monopalmitin. The efficiency and flexibility of this route makes it well-suited to the preparation of a wide variety of 1-, 2-, and 3-substituted as well as isotopically labeled plasmenylcholines for biophysical and biochemical studies.