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 Anderson

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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
Volume59
Issue number11
StatePublished - 1994

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glycidol
Epoxidation
Ethylene Oxide
Glycerol
Phospholipids
Alcohols
Ether
Regioselectivity
Alkylation
Glyceryl Ethers
Carbon
Lipids
Cyclopentanes
Phosphatidic Acids
Nucleophiles
Stereochemistry
Phosphorylation
Magnesium Chloride
Acids
Ethers

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of chiral diether and tetraether phospholipids : Regiospecific ring opening of epoxy alcohol intermediates derived from asymmetric epoxidation. / Thompson, David H.; Svendsen, Chris B.; Di Meglio, Ciro; Anderson, Valerie.

In: Journal of Organic Chemistry, Vol. 59, No. 11, 1994, p. 2945-2955.

Research output: Contribution to journalArticle

Thompson, David H. ; Svendsen, Chris B. ; Di Meglio, Ciro ; Anderson, Valerie. / Synthesis of chiral diether and tetraether phospholipids : Regiospecific ring opening of epoxy alcohol intermediates derived from asymmetric epoxidation. In: Journal of Organic Chemistry. 1994 ; Vol. 59, No. 11. pp. 2945-2955.
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abstract = "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.",
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TY - JOUR

T1 - Synthesis of chiral diether and tetraether phospholipids

T2 - Regiospecific ring opening of epoxy alcohol intermediates derived from asymmetric epoxidation

AU - Thompson, David H.

AU - Svendsen, Chris B.

AU - Di Meglio, Ciro

AU - Anderson, Valerie

PY - 1994

Y1 - 1994

N2 - 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.

AB - 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.

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