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DOI: 10.1055/s-0037-1611530
Synthesis of 1-Palmitoyl-2-((E)-9- and (E)-10-nitrooleoyl)-sn-glycero-3-phosphatidylcholines
Publication History
Received: 08 March 2019
Accepted after revision: 06 April 2019
Publication Date:
08 May 2019 (online)
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Dedicated to Prof. Dr. Hans-Ulrich Reißig on the occasion of his 70th birthday
Abstract
Extensive investigation of nitrated phospholipids in connection with various biologically important processes requires reliable access to suitable material. A selective chemical synthesis introducing a defined nitrofatty acid at the sn-2 position of a 2-lyso sn-glycero-3-phosphatidylcholine was developed. Given that the nitroalkene moiety of both reactant nitrofatty acid derivative and the product esters is characterised by particular sensitivity to nucleophile addition and, depending on the intermediate, subsequent olefin isomerisation and retro-Henry-type reaction, a reliable two-step ester formation was introduced. The activation of the nitrofatty acid succeeded after reaction with trichlorobenzoyl chloride, and the mixed anhydride could be isolated via extractive work-up. Subsequent reaction with 1-palmitoyl-2-lyso-sn-glycero-3-phosphatidylcholine enabled the sn-2 esterification to be achieved with high yield by using a minimum of reagents, avoiding the formation of side products and facilitating final isolation and purification.
Key words
nitrooleic acid - nitro phospholipid - nitrooleoyl glycero 3-phosphatidylcholine - ester formation - mixed anhydrideSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611530.
- Supporting Information
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According reported procedures, more or less complete consumption was achieved by using short-chain saturated nitroalkanes and aldehydes, see:
The DCC/DMAP methodology had been successfully applied to introduce ω-functionalized fatty acid substituents including acetals, silyl ethers, protected amines, etc.25a–e An excess of DCC was always used, acid/PPC 3 ratios involved varied from 1:1 to 3:1, yields of up to 95% were given. Further publications showed that short reaction times and high yields of sn-2 esters often required acid/PPC 3 ratios of up to 10:1.25f–i Alternatively, excess of PPC 3 has been used to react with peptide-type acid derivatives.
For DCC/DMAP and alternative procedures, see:
Significant rate enhancement was reported, supporting the DCC/DMAP esterification by glass bead addition and sonication. Nearly complete ester formation was achieved after hours at ambient temperature, but again excess of acid proved to be necessary (PPC 3/acid = 1:2–5) to afford high yields (up to 95%)
Successful PPC sn-2 ester formations have been reported using carboxylic acids activated in situ involving the Yamaguchi methodology (mixed anhydrides). Originally, work-up problems using the standard DCC/DMAP procedure were avoided. Furthermore, enone substituted carboxylic acids (Michael acceptors) have been successfully reacted in PPC sn-2 esterifications. Standard PPC/acid ratios used varied from 1:1 to 1:2–3, and high yields were reported. For DCB/Me-imidazole, see:
For TCB, see:
For acylation of carbohydrates, see:
For data of 24 see the Supporting Information. Several 1,3-diacyl glycero-2-phosphatidylcholines are known as artificial compounds. In general, such compounds can be obtained via chemical syntheses. Biological data are rare in the literature.
According the literature, cyclic, homo and mixed anhydrides have been employed in PPC sn-2 ester formations. Several authors reported high yields upon running such conversions, but the less pronounced reactivity of the anhydrides often required the use of an excess of the acid derivative and long reaction times; lower yields of 40 to 80% can be regarded as standard. The use of mixed anhydrides promised the best compromise with respect to stability and reactivity of the nitrooleic acid derivative. For cyclic anhydrides, see:
For homo anhydrides, see:
For mixed anhydrides, see:
For imides, see:
For DCC/HOBt, see: