A Facile Synthesis of a Difluoromethylene Analog of β-Aspartyl Phosphate as an Inhibitor of l-Aspartate-β-semialdehyde Dehydrogenase

Shoufa Han; Roger A. Moore; Ronald E. Viola

doi:10.1055/s-2003-38743

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Synlett 2003(6): 0845-0846
DOI: 10.1055/s-2003-38743

LETTER

A Facile Synthesis of a Difluoromethylene Analog of β-Aspartyl Phosphate as an Inhibitor of l-Aspartate-β-semialdehyde Dehydrogenase

Shoufa Han, Roger A. Moore, Ronald E. Viola*
University of Toledo, Department of Chemistry, Toledo, Ohio 43606, USA
Fax: +1(419)5301583; e-Mail: ron.viola@utoledo.edu;

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Publication History

Received 24 January 2003
Publication Date:
17 April 2003 (online)

Abstract
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Abstract

An efficient and high yield procedure for the synthesis of the difluoromethylene analog of β-aspartyl phosphate, β-aspartyl difluoromethylenephosphonate (βAFP), is described. Preincubation of βAFP with l-aspartate-β-semialdehyde dehydrogenases from several infectious microorganisms leads to potent time-dependent enzyme inactivation.

Key words

l-aspartate-β-semialdehyde dehydrogenase - difluoromethylenephosphonate - antibacterial - β-aspartylphosphate - time-dependent inhibition

References

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18

Analytical Data of Compound 3: R_f 0.49 (hexanes-EtOAc, 2:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.29 (m, 10 H), 5.92 (d, 1 H, J = 8.4 Hz), 5.06 (s, 2 H), 5.10 (s, 2 H), 4.73 (m, 1 H), 4.21 (q, 4 H, J = 6.8 Hz), 3.4 (dd, 2 H, J = 8.0 Hz), 1.3 (t, 6 H, J = 6.8 Hz). ¹⁹F NMR (188.2 MHz, CDCl₃): δ =
-119.1 (d, J _F-P = 95.4 Hz).

19

Analytical Data of βAFP: TOF-ES MS [C₅H₈F₂NPO₆]H⁺: Calcd: 248.0674. Found: 248.0156. ¹H NMR (400 MHz, D₂O): δ = 3.9 (m, 1 H), 3.4 (t, 2 H, J = 3.4 Hz). ¹³C NMR (100.6 MHz, D₂O): δ = 205.2, 175.9, 120.6 (dt, J _C-F = 270.5 Hz, J _C-P = 156.4 Hz), 51.9, 33.0. ¹⁹F NMR (188.2 MHz, D₂O): δ = -119.1 (d, ² J _F-P = 74.9 Hz), -124.5 (d, ² J _F-P = 78.7 Hz). ³¹P NMR (81.0 MHz, D₂O): δ = 2.35 (t, ² J _F-P = 75.6 Hz). Elemental analysis [C₅H₆F₂NPO₆(NH₄)₃Cl]: Calcd: C, 17.98%; H, 5.41%; N, 16.74%. Found: C, 18.14%; H, 5.19%; N, 16.34%.