Synthesis of Plasmalogen via 2,3-Bis-O-(4‘-methoxybenzyl)-sn-glycerol

The synthesis of the O-vinyl ether phospholipid plasmalogen 1 from 2,3-bis-O-[p-methoxybenzyl (PMB)]-sn-glycerol (13) is described. Treatment of 13 with potassium hydride, trichloroethylene, and n-butyllithium gave a 1-O-alkynyl glycerol derivative, which was alkylated with 1-iodohexadecane to afford the long-chain O-alkynyl ether 14. The latter was quantitatively converted to cis-enol ether 15 (Z/E ratio between 35:1 and 100:1) with Lindlar catalyst in hexane/EtOAc 1:1 containing quinoline. The PMB groups of 15 were removed by Birch reduction (Na, NH3), giving 1-O-[1‘-(Z)-octadecenyl]-sn-glycerol (2) in 95% yield. Regioselective silylation of 2 followed by palmitoylation provided 1-O-[1‘-(Z)-octadecenyl]-2-O-palmitoyl-3-(tert-butyldiphenylsilyl)-sn-glycerol (17). Desilylation with Bu4NF/imidazole at −23 °C followed by phosphocholine insertion (using 2-chloro-2-oxo-1,3,2-dioxaphospholane with 2 equiv of pyridine in benzene at 4 °C and then trimethylamine in benzene/MeCN 1:3 at 70 °C) completes the synthesis of plasmalogen (1).