Synthesis of Oxazinyl Analogues of Fosmidomycin Using RCM Methodology

Abstract

Fosmidomycin is a promising antimalarial compound with a novel mode of action, the inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase, a key enzyme in the biosynthesis of isoprenoids through the nonmevalonate pathway. This paper describes the synthesis of a series of analogues in which the hydroxamate moiety is incorporated in a ring structure, leaving the complexation with the enzyme up to the oxygen lone pairs instead of the free hydroxyl group. The antimalarial activities of the different analogues are currently under investigation.

Key words

fosmidomycin - oxazinyl analogues - 1-deoxy-d-xylulose 5-phosphate reductoisomerase - ring-closing metathesis - heterogeneous ruthenium catalysis

References and notes

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1

Aspirant of the Fund for Scientific Research, Flanders (FWO, Vlaanderen), Belgium.

26

Preparation of Diethyl 1-Phenyl-3-(4-methyl-3-oxo-3,6-dihydro-2 H -1,2-oxazin-2-yl)propylphosphonate (10b): A solution of 9b (1 g, 2.53 mmol) in anhyd CH₂Cl₂ (30 mL) was brought under a N₂ atmosphere. The mixture was stirred at reflux temperature and Grubbs’ second-generation catalyst (0.1073 g, 0.126 mmol) was added. After 6 h of refluxing, the solvents were evaporated under vacuum to yield the product 10b as a crude oil. Purification by column chromatography was necessary to remove the traces of the ruthenium catalyst, yielding 10b (0.70 g, 1.90 mmol, 75%). ¹H NMR (300 MHz, CDCl₃): δ = 1.08 (t, J = 7.0 Hz, 3 H, OEt), 1.29 (t, J = 7.0 Hz, 3 H, OEt), 1.88 (q, J = 1.7 Hz, 3 H, CMe), 2.22-2.35 (m, 1 H, CH_AH_BCHP), 2.40-2.54 (m, 1 H, CH_AH_BCHP), 3.11 (ddd, J = 3.1, 11.2, 23.1 Hz, 1 H, CHP), 3.46 (ddd, J = 6.7, 6.8, 14.0 Hz, 1 H, CH_AH_BN), 3.59 (ddd, J = 7.2, 7.2, 14.0 Hz, 1 H, CH_AH_BN), 3.66-4.11 (m, 4 H, 2 × OEt), 4.35 (ddq, J = 1.7, 3.5, 15.4 Hz, 1 H, OCH_AH_BCH=C), 4.44 (ddq, J = 1.7, 3.5, 15.4 Hz, 1 H, OCH_AH_BCH=C), 6.35 (tq, J = 1.7, 3.5 Hz, 1 H, OCH₂CH=C), 7.23-7.37 (m, 5 H, CH_arom). ¹³C NMR (75 MHz, CDCl₃, ref. CDCl₃): δ = 15.70 (CMe), 16.27, 16.35, 16.45, 16.54 (2 × OEt), 27.78 (J _C-P = 2.3 Hz, CH₂CHP), 42.33 (J _C-P = 138.5 Hz, CHP), 45.14 (J _C-P = 18.5 Hz, CH₂N), 61.97 (J _C-P = 6.9 Hz, OEt), 62.81 (J _C-P = 6.9 Hz, OEt), 67.54 (OCH₂CH=C), 77.13 (CDCl₃), 127.44 (J _C-P = 2.3 Hz, CH_arom), 128.67 (J _C-P = 2.3 Hz, 2 × CH_arom), 129.40 (J _C-P = 6.9 Hz, 2 × CH_arom), 129.67 (CMe), 132.92 (OCH₂CH=C), 135.48 (J _C-P = 6.9 Hz, C_q,arom), 166.46 (CO). ³¹P NMR (109 MHz, CDCl₃): δ = 28.92. IR (NaCl): 1674, 1635 (C=O, C=C), 1242 (P=O), 1058, 1028 (PO) cm^-1. MS (ESI, +ve mode, %): m/z = 368.3 (100) [M + H⁺]. Chromatography (PE-EtOAc, 1:4): R _f = 0.18.

29

Preparation of Diammonium 1-Phenyl-3-(4-methyl-3-oxo-3,6-dihydro-2 H -1,2-oxazin-2-yl)propylphos-phonate (1b): To a solution of 10b (0.50 g, 1.36 mmol) in anhyd MeCN at r.t. was added dropwise TMSBr (13.6 mmol) and this mixture was stirred at r.t. for 24 h. The solvents and traces of TMSBr were removed under reduced pressure and under high vacuum. The residual oil was dissolved in H₂O and the pH was adjusted with a 5% NH₄OH solution to pH 8-9. Lyophilization of the solution resulted in a solid and purification was performed by column chromatography on Whatman CF11 cellulose. The solvent used was MeCN-aq 1 M NH₄OH (5:1) and the fractions were analyzed on cellulose TLC with the use of UV light to visualize the spots after dipping the plates in a pinacryptol yellow solution (0.1% in H₂O) and drying with hot air. The desired fractions were again lyophilized, yielding 1b as a pale brown hygroscopic solid (0.31 g, 0.88 mmol, 65%). ¹H NMR (300 MHz, CDCl₃): δ = 1.72 (d, J = 1.7 Hz, 3 H, CMe), 2.14-2.42 (m, 2 H, CH₂CHP), 2.93 (ddd, J = 3.0, 11.8, 22.0 Hz, 1 H, CHP), 3.50 (t, J = 6.5 Hz, 2 H, CH₂N), 4.31 (ddd, J = 1.9, 3.6, 15.7 Hz, 1 H, OCH_AH_BCH=C), 4.44 (ddq, J = 1.9, 3.4, 15.7 Hz, 1 H, OCH_AH_BCH=C), 4.79 (D₂O), 6.45 (tq, J = 1.7, 1.7 Hz, 1 H, OCH₂CH=C), 7.19-7.35 (m, 5 H, 5 × CH_arom). ¹³C NMR (75 MHz, CDCl₃, ref. MeCN): δ = 1.47 (ref. MeCN), 15.20 (CMe), 28.13 (J _C-P = 2.3 Hz, CH₂CHP), 44.79 (J _C-P = 129.2 Hz, CHP), 45.94 (J _C-P = 17.3 Hz, CH₂N), 68.24 (OCH₂CH=C), 119.69 (ref. MeCN), 127.17 (J _C-P = 2.3 Hz, CH_arom), 128.36 (CMe), 129.00 (J _C-P = 2.3 Hz, 2 × CH_arom), 129.69 (J _C-P = 6.9 Hz, 2 × CH_arom), 135.26 (OCH₂CH=C), 139.14 (J _C-P = 6.9 Hz, C_q,arom), 166.73 (CO). ³¹P NMR (109 MHz, CDCl₃): δ = 22.91. IR (NaCl): 1668 (C=O, C=C), 1033 (PO) cm^-1. MS (ESI, -ve mode, %): m/z = 310.3 (100) [M - ⁺NH₄ - NH₃]. Chromatography (MeCN-1 M NH₄OH, 5:1): R _f = 0.16.