Ready access to fluorinated phosphonate mimics of secondary phosphates. Synthesis of the (α,α-Difluoroalkyl)phosphonate analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine

David B Berkowitz, Marijean Eggen, Quanrong Shen, Richard K. Shoemaker

Research output: Contribution to journalArticle

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Abstract

In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary inflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78°C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant α,α-difluoro-β-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (α,α-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their 1H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (α,α-difluoroalkyl)phosphonate analogues of L-phosphoserine (≥96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.

Original languageEnglish (US)
Pages (from-to)4666-4675
Number of pages10
JournalJournal of Organic Chemistry
Volume61
Issue number14
StatePublished - Jul 12 1996

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Phosphothreonine
Phosphoserine
Organophosphonates
Esters
Phosphates
Alcohols
Hydrides
Serine
Amino Alcohols
Stereochemistry
Oxalates
Ac-Nal(1)-Cpa(2)-Pal(3,6)-Arg(5)-Ala(10)-lHRH
Lithium
Aldehydes
Anions
Condensation
Substitution reactions
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{f9528e168dcc4b3eaf4de3ed5748be97,
title = "Ready access to fluorinated phosphonate mimics of secondary phosphates. Synthesis of the (α,α-Difluoroalkyl)phosphonate analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine",
abstract = "In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary inflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78°C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99{\%}), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85{\%}), and the Garner ester derived from D-serine (15, 77{\%}). Expeditious treatment of the resultant α,α-difluoro-β-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (α,α-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their 1H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (α,α-difluoroalkyl)phosphonate analogues of L-phosphoserine (≥96{\%} ee) and L-phosphoallothreonine (93{\%} ee) from D-serine and of L-phosphothreonine (91{\%} ee) from L-glycerate, respectively.",
author = "Berkowitz, {David B} and Marijean Eggen and Quanrong Shen and Shoemaker, {Richard K.}",
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T1 - Ready access to fluorinated phosphonate mimics of secondary phosphates. Synthesis of the (α,α-Difluoroalkyl)phosphonate analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine

AU - Berkowitz, David B

AU - Eggen, Marijean

AU - Shen, Quanrong

AU - Shoemaker, Richard K.

PY - 1996/7/12

Y1 - 1996/7/12

N2 - In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary inflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78°C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant α,α-difluoro-β-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (α,α-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their 1H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (α,α-difluoroalkyl)phosphonate analogues of L-phosphoserine (≥96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.

AB - In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary inflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78°C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant α,α-difluoro-β-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (α,α-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their 1H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (α,α-difluoroalkyl)phosphonate analogues of L-phosphoserine (≥96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.

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