Archaebacteria including methanogens, extreme halophiles, extreme thermophiles and thermoacidophiles grow under rather extraordinary conditions and have structurally unique membrane lipids to adapt the extreme environments. The lipids are consisted of hydrophobic isoprenoid chains linked to glycerol with the ether bonds, which are well contrast to the ester linkage of the eubacterial and eukaryotic membrane lipids. The second feature is the stereochemistry of the glycerol portion in the archaebacterial lipids, i.e., the hydrophobic phytanyl groups are attached to the hydroxyl groups at the sn-2- and 3-positions of glycerol. The third and most striking feature of the archaebacterial ether lipid is found in the macrocyclic (36- or 72-membered) ring structures 1 and 2. These unusual lipids have been interested in connection with the physicochemical properties based on the lipid bilayer structure. Our interest in these lipids focuses on the biochemical significance of the macrocyclic molecular structures. Prerequisite is to develop synthetic methods of the macrocyclic lipids, because it is difficult to obtain significant amount of the archaebacterial lipids in pure form from natural sources. Here, we will describe the first synthesis of a 36-membered model compound 3 and the natural archaebacterial cyclic lipid 2 isolated from extreme thermophile Methanococcus jannaschii by the direct closure of the macrocyclic ring using the McMurry coupling. Also described is the synthesis of desmethylated analogs of archaebacterial 72-membered tetraether lipids. The McMurry coupling reaction under high dilution conditions of the dialdehyde 27 and 30 yielded successfully the 72-membered macrocyclic products 28 and 31 in 27 and 36% yileld, respectively. We have developed a highly efficient synthetic method of the macrocyclic lipid based on the McMurry coupling. The properties of the synthesized lipid are currently under study.
