Synthesis and structural analysis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids

Research output: Contribution to journalArticle

Abstract

The first synthesis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids has been achieved by a ten-step sequence starting from N,N-dimethylacetamide (9). Alkylation of 9 with 1-bromohexane gave N,N-dimethyloctanamide (11), which was subjected to aldol condensation with acrolein and afforded the erythro-N,N-dimethyl-3-hydroxy-2-hexyl-4-pentenamide (6) and its threo isomer 7, both of which were subsequently converted to the corresponding 3-oxy(hexanoyl) esters 15 and 16. Stereospecific cyclization of diastereomeric allylic amides (6,7,15 and 16)via iodolactonization gave 3,4,5-trisubstituted γ-butyrolactones (19-25) in satisfactory yields (68-89%) and with high stereoselectivity (at least 6:1), except for the threo amide 16 (2:1). Conversion of the 6-iodo-group of the major iodolactones 23 and 24 to the corresponding 6-hydroxy lactones 31 and 32 through a wet Prévost reaction also resulted in 4-hydroxy lactones 30 and 33, and a mechanism for this reaction is proposed. Further phosphorylation of 4- or 6-hydroxy lactones 30, 31 and 32 with diphenyl chlorophosphate gave the corresponding diphenyl phosphoric acid lactone esters 34, 35 and 36, whereas 33 underwent an elimination reaction under formation of a C(3)-C(4) double bond. Hydrogenolysis of the diphenyl groups of esters 34, 35 and 36 over Adams' catalyst [platinum(IV) oxide] yielded the corresponding phosphoric acid lactone esters 38, 39 and 40, which were finally treated with choline tetraphenylborate to afford the desired lactone phospholipids 41, 42 and 43 in overall yields of 9, 30 and 18%, respectively. The structures of all new compounds were unambiguously assigned by analysis of their1H and13C one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectra obtained on a 300 MHz NMR spectrometer, and the structures were confirmed by low or high resolution mass spectrometry as well as elemental analysis. The stereoisomeric purity of the final products (98.2, 99.0 and 98.5% for 41, 42 and 43, respectively) was determined by high-performance liquid chromatography.

Original languageEnglish
Pages (from-to)211-224
Number of pages14
JournalLipids
Volume29
Issue number3
DOIs
StatePublished - 1 Mar 1994

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Lactones
Structural analysis
Phospholipids
Esters
Organophosphates
Amides
Magnetic Resonance Spectroscopy
Magnetic resonance spectrometers
Tetraphenylborate
Nuclear magnetic resonance
Acrolein
Stereoselectivity
Hydrogenolysis
Phosphorylation
Cyclization
Alkylation
High performance liquid chromatography
Choline
Platinum
Isomers

Cite this

@article{d86b9af06cf64e2d93a910c0ac8e5ab0,
title = "Synthesis and structural analysis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids",
abstract = "The first synthesis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids has been achieved by a ten-step sequence starting from N,N-dimethylacetamide (9). Alkylation of 9 with 1-bromohexane gave N,N-dimethyloctanamide (11), which was subjected to aldol condensation with acrolein and afforded the erythro-N,N-dimethyl-3-hydroxy-2-hexyl-4-pentenamide (6) and its threo isomer 7, both of which were subsequently converted to the corresponding 3-oxy(hexanoyl) esters 15 and 16. Stereospecific cyclization of diastereomeric allylic amides (6,7,15 and 16)via iodolactonization gave 3,4,5-trisubstituted γ-butyrolactones (19-25) in satisfactory yields (68-89{\%}) and with high stereoselectivity (at least 6:1), except for the threo amide 16 (2:1). Conversion of the 6-iodo-group of the major iodolactones 23 and 24 to the corresponding 6-hydroxy lactones 31 and 32 through a wet Pr{\'e}vost reaction also resulted in 4-hydroxy lactones 30 and 33, and a mechanism for this reaction is proposed. Further phosphorylation of 4- or 6-hydroxy lactones 30, 31 and 32 with diphenyl chlorophosphate gave the corresponding diphenyl phosphoric acid lactone esters 34, 35 and 36, whereas 33 underwent an elimination reaction under formation of a C(3)-C(4) double bond. Hydrogenolysis of the diphenyl groups of esters 34, 35 and 36 over Adams' catalyst [platinum(IV) oxide] yielded the corresponding phosphoric acid lactone esters 38, 39 and 40, which were finally treated with choline tetraphenylborate to afford the desired lactone phospholipids 41, 42 and 43 in overall yields of 9, 30 and 18{\%}, respectively. The structures of all new compounds were unambiguously assigned by analysis of their1H and13C one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectra obtained on a 300 MHz NMR spectrometer, and the structures were confirmed by low or high resolution mass spectrometry as well as elemental analysis. The stereoisomeric purity of the final products (98.2, 99.0 and 98.5{\%} for 41, 42 and 43, respectively) was determined by high-performance liquid chromatography.",
author = "Xun Li and Rotella, {David P.}",
year = "1994",
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pages = "211--224",
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Synthesis and structural analysis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids. / Li, Xun; Rotella, David P.

In: Lipids, Vol. 29, No. 3, 01.03.1994, p. 211-224.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis and structural analysis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids

AU - Li, Xun

AU - Rotella, David P.

PY - 1994/3/1

Y1 - 1994/3/1

N2 - The first synthesis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids has been achieved by a ten-step sequence starting from N,N-dimethylacetamide (9). Alkylation of 9 with 1-bromohexane gave N,N-dimethyloctanamide (11), which was subjected to aldol condensation with acrolein and afforded the erythro-N,N-dimethyl-3-hydroxy-2-hexyl-4-pentenamide (6) and its threo isomer 7, both of which were subsequently converted to the corresponding 3-oxy(hexanoyl) esters 15 and 16. Stereospecific cyclization of diastereomeric allylic amides (6,7,15 and 16)via iodolactonization gave 3,4,5-trisubstituted γ-butyrolactones (19-25) in satisfactory yields (68-89%) and with high stereoselectivity (at least 6:1), except for the threo amide 16 (2:1). Conversion of the 6-iodo-group of the major iodolactones 23 and 24 to the corresponding 6-hydroxy lactones 31 and 32 through a wet Prévost reaction also resulted in 4-hydroxy lactones 30 and 33, and a mechanism for this reaction is proposed. Further phosphorylation of 4- or 6-hydroxy lactones 30, 31 and 32 with diphenyl chlorophosphate gave the corresponding diphenyl phosphoric acid lactone esters 34, 35 and 36, whereas 33 underwent an elimination reaction under formation of a C(3)-C(4) double bond. Hydrogenolysis of the diphenyl groups of esters 34, 35 and 36 over Adams' catalyst [platinum(IV) oxide] yielded the corresponding phosphoric acid lactone esters 38, 39 and 40, which were finally treated with choline tetraphenylborate to afford the desired lactone phospholipids 41, 42 and 43 in overall yields of 9, 30 and 18%, respectively. The structures of all new compounds were unambiguously assigned by analysis of their1H and13C one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectra obtained on a 300 MHz NMR spectrometer, and the structures were confirmed by low or high resolution mass spectrometry as well as elemental analysis. The stereoisomeric purity of the final products (98.2, 99.0 and 98.5% for 41, 42 and 43, respectively) was determined by high-performance liquid chromatography.

AB - The first synthesis of stereospecific 3,4,5-trisubstituted γ-butyrolactone phospholipids has been achieved by a ten-step sequence starting from N,N-dimethylacetamide (9). Alkylation of 9 with 1-bromohexane gave N,N-dimethyloctanamide (11), which was subjected to aldol condensation with acrolein and afforded the erythro-N,N-dimethyl-3-hydroxy-2-hexyl-4-pentenamide (6) and its threo isomer 7, both of which were subsequently converted to the corresponding 3-oxy(hexanoyl) esters 15 and 16. Stereospecific cyclization of diastereomeric allylic amides (6,7,15 and 16)via iodolactonization gave 3,4,5-trisubstituted γ-butyrolactones (19-25) in satisfactory yields (68-89%) and with high stereoselectivity (at least 6:1), except for the threo amide 16 (2:1). Conversion of the 6-iodo-group of the major iodolactones 23 and 24 to the corresponding 6-hydroxy lactones 31 and 32 through a wet Prévost reaction also resulted in 4-hydroxy lactones 30 and 33, and a mechanism for this reaction is proposed. Further phosphorylation of 4- or 6-hydroxy lactones 30, 31 and 32 with diphenyl chlorophosphate gave the corresponding diphenyl phosphoric acid lactone esters 34, 35 and 36, whereas 33 underwent an elimination reaction under formation of a C(3)-C(4) double bond. Hydrogenolysis of the diphenyl groups of esters 34, 35 and 36 over Adams' catalyst [platinum(IV) oxide] yielded the corresponding phosphoric acid lactone esters 38, 39 and 40, which were finally treated with choline tetraphenylborate to afford the desired lactone phospholipids 41, 42 and 43 in overall yields of 9, 30 and 18%, respectively. The structures of all new compounds were unambiguously assigned by analysis of their1H and13C one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectra obtained on a 300 MHz NMR spectrometer, and the structures were confirmed by low or high resolution mass spectrometry as well as elemental analysis. The stereoisomeric purity of the final products (98.2, 99.0 and 98.5% for 41, 42 and 43, respectively) was determined by high-performance liquid chromatography.

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