Synthesis of Chiral Diether and Tetraether Phospholipids: Regiospecific Ring Opening of Epoxy Alcohol Intermediates Derived from Asymmetric Epoxidation

David H. Thompson, Chris B. Svendsen, Ciro Di Meglio, Valerie C. Anderson

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32 Scopus citations


Diether and tetraether phospholipids have been synthesized using chiral epoxy alcohol starting materials (e.g. glycidol 3-nitrobenzenesulfonate esters or tert-butyldiphenylsilyl ethers). These chiral precursors provide control over the stereochemistry, substitution patterns, and steric properties of the phosphoglycerol backbone. Configuration at the sn-2 glycerol carbon was controlled by asymmetric epoxidation of allyl alcohol followed by acid-catalyzed, regioselective opening of the oxirane ring using excess aliphatic n-alcohols to give mono-O-alkylated glycerol intermediates in good yields. Nucleophilic attack at the less-hindered carbon of the oxirane ring was highly favored over attack at the sterically less accessible site, typically proceeding with regioselectivities of >10:1 and >95% ee's. Triflic acid, boron trifluoride etherate, toluenesulfonic acid, and tropylium tetrafluoroborate, all at 10 mol %, proved to be the most-effective catalysts compared with 10% cesium fluoride, 10% magnesium chloride, or 20% DDQ based on (i) comparison of initial rates of product formation, (ii) regioselectivity of attack on the glycidol nucleus, and (iii) isolated yields of 3-O-alkyl-sn-glycerol 1-(3′-nitrobenzenesulfonates). Ether linked phospholipids, produced by alkylation of O-alkylglycerol sulfonates with excess n-alkyl triflates in the presence of equimolar 1,8-bis(dimethylamino)-naphthalene, were isolated in 43–49% overall yields (from glycidol 3-nitrobenzenesulfonate) after tetrabutylammonium hydroxide deprotection and phosphorylation; treatment of the 3-O-alkylglycerol sulfonates with tetrabutylammonium hydroxide prior to alkylation at the sn-2 center led to internal displacement and oxirane ring reformation, rather than hydrolysis to 3-O-alkylglycerol as described in J. Chromatogr. 1990, 506, 611. 3,3′-O-Polymethylene diglycerol phospholipids (bolaamphiphiles) were also prepared by this route using glycidol 3-nitrobenzenesulfonate and bifunctional α,ω-diols as nucleophiles. Synthesis of sterically demanding ether lipids, via Sharpless epoxidation of cyclopentene- 1-methanol, produced materials that exhibited larger molecular areas than the analogous 1,2-di-O-alkyl phosphatidic acids in monolayer experiments, confirming the restricted conformational flexibility of the cyclopentyl derivative at the air-water interface. Bolaamphiphiles adopted a U-shaped conformation at the air-water interface. Elution-mode HPLC of racemic 3-O-hexadecyl-2-O-[(3′,5′-dinitrophenyl)carbamoyl]glycerol 1-(3′-nitrobenzenesulfonate) on chiral naphthylalanine phases suggests that displacement-mode HPLC (Camacho-Torralba, P. L.; Vigh, G.; Thompson, D. H.; J. Chromatogr. 1993, 641, 31; 1993,646, 259) may be used to obviate semipreparative chiral syntheses of alkyl glycerol ethers such as platelet activating factors, the antitumor agent ET-18-OCH3, and other biologically active ether lipids.

Original languageEnglish (US)
Pages (from-to)2945-2955
Number of pages11
JournalJournal of Organic Chemistry
Issue number11
StatePublished - Jun 1 1994

ASJC Scopus subject areas

  • Organic Chemistry


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