Total Synthesis of Archaeal 36-Membered Macrocyclic Diether Lipid

Total synthesis of archaeal 36-membered macrocyclic diether lipid 2 is reported. The synthesis is based upon stereoselective preparation of functionalized isoprenoid chains, ether-linkage formation between the isoprenoid chains with a glycerol derivative, and the ultimate intramolecular dicarbonyl coupling using low-valent titanium known as McMurry coupling. This synthetic method has successfully provided the first practical route to chemically defined archaeal macrocyclic membrane lipids, which were not available because of the lack of synthetic access. Also described is a highly stereoselective and convenient synthesis of stereochemically homogeneous archaeal biphytanyl glycerol lipid 1.