Synthesis of Oxazinyl Analogues of Fosmidomycin Using RCM Methodology

Sarah Van der Jeught; Christian V. Stevens; Nicolai Dieltiens

doi:10.1055/s-2007-992373

LETTER

Synthesis of Oxazinyl Analogues of Fosmidomycin Using RCM Methodology

Sarah Van der Jeught, Christian V. Stevens*, Nicolai Dieltiens
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: Chris.Stevens@ugent.be;

Abstract

All articles of this category

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

Full Text

References

References and notes

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

<A NAME="RG32307ST-2">2</A> Thayer A. Chem. Eng. News 2005, 83 (October 24): 69

<A NAME="RG32307ST-3">3</A> Missinou M. Borrmann S. Schindler A. Issifou S. Adegnika A. Matsiegui P. Binder R. Lell B. Wiesner J. Baranek T. Jomaa H. Kremsner P. Lancet 2002, 360: 1941

<A NAME="RG32307ST-4">4</A> Lell B. Ruangweerayut R. Wiesner J. Missinou M. Schindler A. Baranek T. Hintz M. Hutchinson D. Jomaa H. Kremsner P. Antimicrob. Agents Chemother. 2003, 47: 735

<A NAME="RG32307ST-5">5</A> Wiesner J. Ortmann R. Jomaa H. Schlitzer M. Angew. Chem. Int. Ed. 2003, 42: 5274

<A NAME="RG32307ST-6">6</A> Tsuchiya T. Ishibashi K. Terakawa M. Nishiyama M. Itoh N. Noguchi H. Eur. J. Drug. Metab. Pharmacokinet. 1982, 7: 59

<A NAME="RG32307ST-7A">7a</A> Kuemmerle HP. Murakawa T. De Santis F. Chemioterapia 1987, 6: 113

<A NAME="RG32307ST-7B">7b</A> Kuemmerle HP. Murakawa T. Sakamoto H. Sato N. Konishi T. De Santis F. Int. J. Clin. Pharmacol. Ther. Toxicol. 1985, 23: 521

<A NAME="RG32307ST-8">8</A> Reuter K. Sanderbrand S. Jomaa H. Wiesner J. Steinbrecher I. Beck E. Hintz M. Klebe G. Stubbs MT. J. Biol. Chem. 2002, 277: 5378

<A NAME="RG32307ST-9">9</A> Reichenberg A. Wiesner J. Weidemeyer C. Dreiseidler E. Sanderbrand S. Altincicek B. Beck E. Schlitzer M. Jomaa H. Bioorg. Med. Chem. Lett. 2001, 11: 833

<A NAME="RG32307ST-10A">10a</A> Ortmann R. Wiesner J. Reichenberg A. Henschker D. Beck E. Jomaa H. Schlitzer M. Arch. Pharm. Chem. Life Sci. 2005, 338: 305

<A NAME="RG32307ST-10B">10b</A> Ortmann R. Wiesner J. Reichenberg A. Henschker D. Beck E. Jomaa H. Schlitzer M. Bioorg. Med. Chem. Lett. 2003, 13: 2163

<A NAME="RG32307ST-11">11</A> Kurz T. Schlüter K. Kaula U. Bergmann B. Walter RD. Geffken D. Bioorg. Med. Chem. 2006, 14: 5121

<A NAME="RG32307ST-12">12</A> Kurz T. Geffken D. Wackendorff C. Z. Naturforsch., B 2003, 58b: 457

<A NAME="RG32307ST-13">13</A> Woo YH. Fernandes RPM. Proteau PJ. Bioorg. Med. Chem. 2006, 14: 2375

<A NAME="RG32307ST-14">14</A> Courtois M. Mincheva Z. Andreu F. Rideau M. Viaud-Massuard M. J. Enz. Inh. Med. Chem. 2004, 19: 559

<A NAME="RG32307ST-15">15</A> Mincheva Z. Courtois M. Andreu F. Rideau M. Viaud-Massuard MC. Phytochemistry 2005, 66: 1797

<A NAME="RG32307ST-16">16</A> Kuntz L. Tritsch D. Grosdemange-Billiard C. Hemmerlin A. Willem A. Bacht TJ. Rohmer M. Biochem. J. 2005, 386: 127

<A NAME="RG32307ST-17">17</A> Devreux V. Wiesner J. Goeman JL. Van der Eycken J. Jomaa H. Van Calenbergh S. J. Med. Chem. 2006, 49: 2656

<A NAME="RG32307ST-18">18</A> Kurz T. Schlüter K. Pein M. Behrendt C. Bergmann B. Walter RD. Arch. Pharm. Chem. Life Sci. 2007, 340: 339

<A NAME="RG32307ST-19">19</A> Haemers T. Wiesner J. Busson R. Jomaa H. Van Calenbergh S. Eur. J. Org. Chem. 2006, 3856

<A NAME="RG32307ST-20A">20a</A> Haemers T. Wiesner J. Van Poecke S. Goeman J. Henschker D. Beck E. Jomaa H. Van Calenbergh S. Bioorg. Med. Chem. Lett. 2006, 16: 1888

<A NAME="RG32307ST-20B">20b</A> Devreux V. Wiesner J. Jomaa H. Rozenski J. Van der Eycken J. Van Calenbergh S. J. Org. Chem. 2007, 72: 3783

<A NAME="RG32307ST-21A">21a</A> Yang Y.-K. Tae J. Synlett 2003, 1043

<A NAME="RG32307ST-21B">21b</A> Miyabe H. Yoshida K. Matsumura A. Yamauchi M. Takemoto Y. Synlett 2003, 567

<A NAME="RG32307ST-21C">21c</A> Koide K. Finkelstein JM. Ball Z. Verdine GL. J. Am. Chem. Soc. 2001, 123: 398

<A NAME="RG32307ST-21D">21d</A> Le Flohic A. Meyer C. Cossy J. Desmurs JR. Tetrahedron Lett. 2003, 44: 8577

<A NAME="RG32307ST-21E">21e</A> Shustov GV. Chandler MK. Wolfe S. Can. J. Chem. 2005, 83: 93

<A NAME="RG32307ST-22">22</A> Van Meenen E. Moonen K. Verwee A. Stevens CV.
J. Org. Chem. 2006, 71: 7903

<A NAME="RG32307ST-23">23</A> Teulade M. Savignac P. Synthesis 1987, 1037

<A NAME="RG32307ST-24">24</A> Albrecht S. Defoin A. Tarnus C. Synthesis 2006, 1635

<A NAME="RG32307ST-25">25</A> Eguchi S. Furukawa Y. Suzuki T. Kondo K. Sasaki T. Honda M. Katayama C. Tanaka J. J. Org. Chem. 1985, 50: 1895

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.

<A NAME="RG32307ST-27">27</A> For a summary of existing methods for removal of Ru species, see: Conrad JC. Fogg DE. Curr. Org. Chem. 2006, 10: 185

<A NAME="RG32307ST-28A">28a</A> Maynard HD. Grubbs RH. Tetrahedron Lett. 1999, 40: 4137

<A NAME="RG32307ST-28B">28b</A> Grubbs RH. Org. React. (N.Y.) 2004, 22: 123

<A NAME="RG32307ST-28C">28c</A> Ahn YM. Yang K. Georg GI. Org. Lett. 2001, 3: 1411

<A NAME="RG32307ST-28D">28d</A> Paquette LA. Schloss JD. Efremov I. Fabris F. Gallou F. Mendez-Andino J. Yang J. Org. Lett. 2000, 2: 1259

<A NAME="RG32307ST-28E">28e</A> McEleney K. Allen DP. Holliday AE. Crudden CM. Org. Lett. 2006, 8: 2663

<A NAME="RG32307ST-28F">28f</A> Galan BR. Kalbarczyk KP. Szczepankiewicz S. Keister JB. Diver ST. Org. Lett. 2007, 9: 1203

<A NAME="RG32307ST-28G">28g</A> Cho JH. Kim BM. Org. Lett. 2003, 5: 531

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.