Chemical synthesis of lipids

There is by and large no need for the chemical synthesis of many of the phospholipids that make up macromolecular lipid assemblies in cells, since these are readily available from natural sources and are purified from these by HPLC. In effect, biological syntheses of lipids dominate chemical syntheses. However, there is some value in illustrating the general method 

---

The initial target for our chemical synthesis of lipid I was phosphomuramyl pentapeptide 9. At the outset, we were confident in our ability to prepare the monosaccharyl pentapeptide core structure, but were unsure of our ability to install the anomeric phosphate with the desired a-stereochemistry. We were also concerned about the timing for introduction of the anomeric phosphate since solubility and anomeric selectivity could be strongly influenced by the presence or absence of the peptapeptide side chain. In addition, we had not settled on a method for... 

In summary, we were able to develop a chemically robust synthetic route to lipid I, the penultimate intermediate utilized in bacterial cell wall biosynthesis. The identification of a method for stereoselective introduction of the anomeric phosphate and a protocol to enable diphosphate coupling were pivotal to our success and ultimately provided the precedent for our chemical synthesis of lipid II detailed in the sections that follow. 

Chemical Synthesis of Lipid A for the Elucidation of Structure-Activity Relationships... 

Rasmussen JAM, Hermetter A (2008) Chemical synthesis of fluorescent glycero- and sphingolipids. Prog Lipid Res 47 436-460... 

LPS immunotherapy was the first immunotherapy for cancers assayed in patients in spite of its toxicity. The standardisation of animal models of cancer, the discovery of the LPS composition and of lipid A activity, the discovery of lipid A structure leading to its chemical synthesis, and the synthesis of lipid A derivatives far less toxic than the natural lipids A, restarted research in this field. At the same time, advances in immunology allowed a better understanding of the mechanisms of action of LPS and lipids A in whole organisms. 

In recognition of the difficulty in obtaining the lipid intermediates in quantities to facilitate detailed mechanistic study of the peptidoglycan biosynthetic enzymes, we initiated an effort directed toward a chemical synthesis of both lipid I and lipid II. As was the case with the fermentation/isolation protocols, we anticipated several technical challenges that would need to be addressed in order to reach the target compounds. These challenges, and their solutions, will be discussed in the sections that follow. 

Galanos, C., Luderitz, O., Kusumoto, S., and Shiba, T. (1983). The chemistry of bacterial lipopolysaccharides with emphasis on the structure and chemical synthesis of their lipid A component. In Handbook of Natural Toxins, Vol II, Bacterial Toxins (Tu, Habig and Hardegree, eds.) Marcel Dekker, Inc., New York. 

We then focused on the synthesis of lipid A analogs which contain 3-hydroxy fatty acids. For this purpose, sufficient amount of (R)-3-hydroxytetradecanoic acid ( ), which is the commonest hydroxy acid in Salmonella lipid A, was first prepared by means of an asymmetric reduction of the corresponding keto ester, i. ., methyl 3-oxotetradecanoate (j ) (7). Catalytic hydrogenation of 21 in the presence of Raney Ni modified with (R, R)-tartaric acid foaBr (8) afforded the crude (R)-ester in 85% enantiomeric excess. After saponification, the resultant acid was purified through its dicyclohexylammonium salt to give the optically and chemically pure (R)-acid In a yield of 61% from... 

Attempting to improve transfection efficiency, the inclusion of enzyme, pH or redox susceptible chemical groups in the cationic lipid structure has been investigated [126-129] with, for example the synthesis of lipid moieties connected through ester bonds sensitive to intracellular esterases [64, 70, 71, 126]. 

Paltauf, F. (1983) Chemical synthesis of ether lipids, in Ether Lipids. Biochemical and Biomedical Aspects, H. K. Mangold and F. Paltauf, editors, Academic Press, New York, pp. 49-84. 

D. V. Yashunsky, V. S. Borodkin, M. A. J. Ferguson, and A. V. Nikolaev, The chemical synthesis of bioactive glycosylphosphatidylinositols from Trypanosoma cruzi containing an unsaturated fatty acid in the lipid, Angew. Chem. Int. Ed. Engl., 45 (2006) 468—474. 

A. K. Das and A. K. Hajra, A novel chemical synthesis of l-O-hexadecyl-rac-[2-3H] glycero-3-phosphorylethanolamine and a simple assay for plasmanyl desaturase, J. Lipid Res., 1996, 37, 2706-2714. 

At 25° C, elemental Hg has a water solubility of 5.6><10 g/L. Mercuric chloride is considerably more soluble, having a solubility of 69 g/L at 20° C. In comparison, an organic Hg compound, such as methylmercury chloride, is much less water soluble, having a solubility of 0.100 g/L at 21° C. Dimethylmercury, a veiy toxic by-product of the chemical synthesis of MeHg (Nierenberg et al. 1998), also has a relatively low water solubility (1.0 g/L at 21° C). Due to its low water solubihty, MeHg chloride is considered to be relatively lipid soluble. As discussed later in this chapter, the solubility of the different forms of Hg might play a role in their differential toxicity. 

The discovery of split inteins further advanced the scope of EPL into the realm of conditional protein splicing. As outlined above, certain inteins can be split into two halves. An advantage for a general applicability concerns the observation that the split site is asymmetric. This opens an access to chemical synthesis of the smaller intein half and hence an easy route to C-terminal modification of proteins with, e.g., fluorophores, lipid anchor, or other posttranslational modifications of proteins. 

---