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 tetra‐butylammonium 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°C with Bu4NF 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 Et3N, as base to avoid acyl migration; the dioxaphospholane triester intermediate was subsequently cleaved with Me3N 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.