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Synthesis of Oxazolidinone Phosphonate Derivatives, Part II

Bull. Korean Chem. Soc. 2007, Vol. 28, No. 5

821

Synthesis of Oxazolidinone Phosphonate Derivatives, Part II
Jae-Min Hwang, Sung-Ho Yeom, and Kang-Yeoun Jung*
Department of Environmental & Applied Chemistry, College of Engineering, Kangnung National University,
Kangnung 210-702, Korea. *E-mail: kyjung@kangnung.ac.kr
Received February 9, 2007
Several oxazolidinones, a new class of synthetic antibacterial agents, have shown biological activity against
multidrug-resistant gram positive organisms such as staphylococci, streptococci, and enterococci. Previous
results of our studies with benzoxazolidinone phosphonate derivatives have demonstrated very low
antibacterial activity. In the course of our studies directed towards the discovery of noble antibacterial agents,
we have synthesized several new derivatives of oxazolidinone phosphonates prepared efficiently from
commercially available amino acids. These compounds are tested for in vitro antibacterial activity and one of
the compounds showed promising results allowing us to pursue further studies.
Key Words : Oxazolidinone, Oxazolidinone phosphonates, Antibacterial agent

Introduction
Oxazolidinones are a promising new class of totally
synthetic antibacterial agents active against numerous
Gram-positive organisms, including methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant
enterococci (VRE), penicillin- and cephalosporin-resistant
Streptococcus pneumoniae.1 While they share with other
antimicrobials as ribosomal target, the oxazolidinones bind
in a distinct region of 23S rRNA near the peptidyl transferase center and do not exhibit significant cross-resistance
with the existing classes of antibacterials.2
Linezolid,3 1, (Zyvox™, Pharmacia/Pfizer) is the first
compound commercialized world wide from the oxazolidinone class of antibacterials to treat multi-drug resistant
Gram-positive infections.

However, resistance against linezolid has already started
to develop in Enterococcus faecium4,5 and more alarmingly,
in S. aureus, giving rise to linezolid-resistant MRSA strains.6
Therefore, there is an urgent need for the further exploration
of features of the oxazolidinone class and the synthesis of
new compounds, which are more potent and less prone to
resistance development.
In our previous work,7 we described the synthesis of
variously substituted benzoxazolidinone derivatives using
pentacovalent oxaphosphorane chemistry followed by reductive amination with aromatic amine of oxazolidinones.8
None of the synthetic benzoxazolidinone derivatives showed
better biological activity than commercially available linezolid. As part of our ongoing efforts to improve biological

activity, therefore, we have now designed and synthesized a
range of oxazolidinone phosphonate derivatives from commercially available amino acids.
Results and Discussion
To date, many groups have reported the synthesis and
biological activity of novel oxazolidinones since a few of
synthetic oxazolidinone derivatives had shown antibacterial
activity. In most studies, they used the reactions between
oxirane derivatives and variously substituted amines in order
to synthesize various oxazolidinone derivatives.9
In our work, however, we used L-serine and L-threonine
as a starting material for the synthesis of oxazolidinone
derivatives, which allows us to synthesize oxazolidine moiety
more efficiently as shown in Scheme 1.
Two core compounds, 4-(R)-hydroxylmethyloxazolidin-2one (4a)10 and 4-(R)-hydroxylmethyl-5-(R)-methyloxazolidin-2-one (4b),11 were prepared from commercially available L-serine and L-threonine in four steps, respectively.
Protection of amino group with CbzCl followed by esterification under the presence of catalytic amount of TsOH
gave the corresponding compounds 2a-b, and then reduction
of 2a-b and subsequent cyclization of 3a-b afforded the
desired oxazolidinone compounds, 4a-b in reasonable yields.
Selective protection of hydroxyl groups of 4a and 4b with
TBSCl gave the corresponding TBS ethers 5a and 5b in
97% and 82% yields, respectively. Substitution of 5a and 5b
with 2,4-difluoronitrobenzene (1: fluoronitrobenzene substituent, see Scheme 1 for the structure) or 2-chloro-5nitropyridine (2: nitropyridine substituent) in the presence of
K2CO3 in CH3CN gave the N-substituted compounds, 6a1
and 6a2 from 5a, 6b1 and 6b2 from 5b, which were
followed by deprotection of TBS group with TBAF gave Nsubstituted-5-hydroxyloxazolidinone derivatives 7a1-a2 and
7b1-b2 in 70-85% yields.
Oxazolidinone phosphonate products 8a and 8b were
obtained (40-60% yields) from the reaction of 7a and 7b

70 (bs. THF. vi. 53. 22. 3. 0.95 mmol.47 g.42 (m. v.70. p-TsOH. 3.54. All non-aqueous reactions were conducted in flame-dried glassware. 3.11. 25. 2249.17 (dd. 77. Scheme 1.89 (m. This aqueous mixture was extracted with CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4. NaH. 4. R'-X.0 ppm) as internal standards unless otherwise noted. ii.3 equiv. TBAF. H2. No.58 (d. Treatment of diethyl phosphonate groups of 9a and 9b with TMSBr gave the corresponding oxazolidinone phosphonic acids 10a and 10b in 80-92% yields. 4.5. 6H). 64. 1. 23.11 mmol.) was added quickly at the same temperature.38 (d. Imidazole. Synthesis of Oxazolidinone Phosphonic Acids.16 mmol). 25. Cbz-Cl. FT-IR spectra were recorded on a JASCO FR-IR 460 series.65 (d. Soc. All 31P NMR chemical shifts are reported in ppm relative to 85% H3PO4 (external standard). TMSBr. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-5-(R)-methyl2-oxazolidinone (5b). IR (cm−1): 3441.8 Hz. 78% yield). After the solution was stirred for 5 min at room temperature. 50. J = 2. 2928. J = 6. IR . activated imidazole (3. and anhydrous DMF (60 mL). 1. Reagents: i. we have reported that a new series of Nsubstituted oxazolidinone phosphonic acid derivatives. 30. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-2-oxazolidinone (5a). 60.17. iv. J = 1.1291.56 (d. were easily prepared from the commercially available amino acids. J = 6. THF. tert-butyldimethylsilylchloride (4.8 HRFABMS calcd for C10H21NO3Si (M+1)+: 232.40 (t.5 mol % of Pd/C in THF/methanol at room temperature gave N-4-amino-3-fluorophenyl derivatives 9a3 (R = H. 92% yield) and 9b3 (R = Me. Catalytic hydrogenation of nitro groups on the aromatic ring of 8a1 and 8b1 with ammonium formate in the presence of 1. 0. vii. 9H).2 Hz). Under the same conditions. High resolution FAB mass spectra were obtained from the Hybrid LC-Quarapole-TOF Tandem Mass Spectrometer at the Kangnung National University. 18. −5. THF. under an atmosphere of argon.1295.39.3 Hz).7 Hz. After removal of the solvent under reduced pressure. 4.22. Korean Chem.75. x. 1H). 82%) was prepared from the oxazolidinone 4b (1.3 Hz. 64.17 g.01 (s.5 Hz). ix. with TfOCH2P(O)(OEt)2 in the presence of NaH at room temperature. 67. NaBH4. which are expected to show improved antibacterial activity. 1730. 97%): 1H NMR δ 6. −5. H2O. with magnetic stirring. 1H). The desired product 5b (2 g. J = 5. 2. found: 232.03 (s. 83% yield). 1H). 1H). 8a2 and 8b2 were converted into N-5-aminopyridyl derivatives 9a4 (R = H.3. 2007. HCO2NH4. TBSCl.53 (d. 13C NMR δ 160. 0.32 g. 3. 1H). 2H). 76.54 g. 6H). 9H). CH2Cl2.42 (m.85 (s. 1H). NMR spectra were obtained on a JOEL Lamda 300 spectrometer and recorded at 300 MHz for 1H (75 MHz for 13C) with CDCl3 as solvent and (CH3)4Si (1H) or CDCl3 (13C. In summary. 3H). 10. 8.43. Experimental Section General. the crude oil was purified by flash column chromatography with a gradient solvent system using methylene chloride and methanol to give the desired product 5a (5. 28. J = 8.55 mmol. and then quenched with distilled water.16 mmol. J = 8. Dichloromethane and Et3N were distilled from CaH2 immediately prior to use. Vol. 18. 13C NMR δ 159.2 equiv.47 (s. viii.18.63.8.3. The biological activity of the compounds reported here will be studied and reported in the future. TfOCH2PO(OEt)2. 1H). 0.71. tBuOK. iii.06. This reaction mixture was allowed to stir for 5 hrs. CH2Cl2.4 Hz. 4. 20.). 2H).88 (s. MeOH.56 (m. NaHCO3.21 g.822 Bull. A flame-dried 250 mL round-bottom flask under argon atmosphere was charged with oxazolidinone 4a (2. 50% yield) and 9b4 (R = CH3. 5 Jae-Min Hwang et al.07 mmol) following the same procedure as the compound 5a: 1H NMR δ 6.

1.73 (d. 3. 1.48. This reaction mixture was refluxed for 1 hr. 31P NMR δ 19. 17. 119. -5. 128.1 Hz). After the solution was stirred for 5 min at room temperature. 3H).68 (d. 1. 2939. 109. J = 6.35 g. 1. 2H). JC-F = 2.1360.9.1.66 (d.35 (dd.99 g.14 mmol) was converted to the desired product 7b1 (0.90 (d. 1H).70 (d.6. 1531. −0. 1530.6. 119.68.07 (s. 112.2 equiv) was added quickly. After removal of the solvent under reduced pressure.9. 62. 3H).7 Hz).6 mmol. JC-F = 25.4.60.9 Hz).14.47 (d.97 (s.0652.0 Hz). To a suspension of NaH (0. 1037.5 Hz). 149. 28.26 (m.6 Hz. 112.59 (d. 0. IR (cm−1). J = 5.47 g. 1768.69 (m. 1. N-(3-Fluoro-4-nitrophenyl)-4-(R)-hydroxymethyl-5(R)-methyl-2-oxazolidinone (7b1). 6. 4H). 7.8 Bull.42 (d.0 Hz).97 (d. 2H). A flame-dried 100 mL round-bottom flask under argon was charged with oxazolidinone 5a (1. 61. 4.5 equiv. 9H). J = 240.11 g. 61.3. 111. J = 1.17 (m.84 (dd. 13C NMR δ 151. 56. JC-F = 10.3 Hz.) quickly. 25.3. 112. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-N-(3-fluoro4-nitrophenyl)-5(R)-methyl-2-oxazolidinone (6b1).5.8.6. 2894.90. 73. J = 96. 146. 1. 4.30. 119. 1531.03 (m. JC-F = 25. the solution was treated with (diethoxyphosphono)methyltriflate (0. 146.76.09 (s.15 (d. The procedure was the same as the preparation of compound 8a1.51 (d. J = 6.65. The aqueous mixture was extracted with CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4. respectively. 3. JC-F = 2. J = 251.0. 128. 1H).3.5 Hz). JC-F = 252.54.30 (d. The reaction mixture was stirred for 5 hrs and quenched with distilled water followed by aqueous ammonium chloride.9.2 Hz). N-(3-Fluoro-4-nitrophenyl)-4-(R)-hydroxymethyl-2oxazolidinone (7a1).81 mmol) following the same procedure as the compound 6a1: 1H NMR δ 7. J = 8.41 (d. 2293. found: 246.6.0941.57 (d. 1H). 1635.9 Hz.2. JC-F = 11. J = 5. 7.11 (m.24 (d.7 Hz. 142. 1H).9. 4. Hydroxyoxazolidinone 7b1 (0. 1H). JC-F = 22. 155.3. Soc.85 (dd. 2930.65 (t. 1. 112. 3.1. 4. −5.48 (d. 1077. 3H). 120. the crude oil was purified by flash column chromatography with a gradient solvent system using methylene chloride and methanol to give the desired product 7a1 (0. 1. 4.42. 60%): 1H NMR δ 8.0650.6.05 (d.31 (td.34 mmol. IR (cm−1): 3474.66 (d. 1H). 4.61 (m. J = 6.11 mmol. 1. 2007. 3.62. 3. 72.0.2 Hz). No.3 Hz. 4.6 Hz. 155. JC-F = 2.15 mmol) was converted to the desired product 8b1 (0. 2257. JC-F = 3.0.35 g. 1348.3. After removal of the solvent under reduced pressure. 4.88 g.23. Oxazolidinone 6b1 (0. 3. 112.80 (d.7 Hz). 155. JC-F = 10.3 g.2 Hz). 20.89 (dd. 70. This aqueous mixture was extracted with CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4. 128.13 (s. 1. 75%) was prepared from oxazolidinone 5b (1. 25. 128. 5 Hz.31 (m. found: 385. 2858. 2.2 Hz. 1349. 1H). JC-F = 251. .27 (d. 1735.65 (d. 155. J = 3.03 (d.62 (s. IR (cm−1). [N-(3-Fluoro-4-nitrophenyl)-5-(R)-methyl-2-oxo-oxazolidin-4-(R)-yl-methoxymethyl]-phosphonic acid diethyl ester (8b1). JC-F = 10.14 (d.2 Hz). 131.1.22 mmol. 3504.19. 7.63 (m.47 (m.1551. 4.1515. 3. 130.65 (d. To a solution of oxazolidinone 6a1 (0.7.84 (t. 3. J = 8.9.5 Hz).1 Hz).50 (d. J = 7.79 (m. 6H). the crude oil was purified by flash column chromatography with a gradient solvent system using methylene chloride and methanol to afford pure compound 8a1 (0. 136. JC-F = 10.4 Hz). 2H). 0.0495.07 (dd.) quickly in anhydrous THF (10 mL). 4.11 (d. 2H). 119. 62.3 Hz.07 (m. 2985. 6. 64.44 mmol.11 (d.60 (d.0.76 (d. 7. 3.20 (d.35 equiv.36. [N-(3-Fluoro-4-nitrophenyl)-2-oxo-oxazolidin-4-(R)-ylmethoxymethyl]-phosphonic acid diethyl ester (8a1).70 (d.1 Hz. 1H).97 g. 3426.37 g. 1237.82 g. 4H). 1. 1H).1.5 Hz).77 mmol. −0. J = 8. 16.26. 19.39 (d. 7.62 mmol) in freshly distilled Et2O (20 mL) was added tetrabutylammoniumfloride (1.2. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-N-(3-fluoro4-nitrophenyl)-2-oxazolidinone (6a1).8.6 Hz). 4H). J = 5. 3H). 64. J = 7.60 (dd.4 Hz). 3H). J = 3. found: 407. JC-F = 8. 38%): 1H NMR δ 7. 1346. 2H).1361. JC-F = 3. 65.15 (dd.0 (d. 155. J = 8.61.84 mmol) at 0 oC.7.16 (d.6 Hz). 7. 20 equiv.84 mmol. found: 257.06 (s.07 (m.5 Hz). 65%): 1H NMR δ 8. JC-F = 3.7 mmol. 1766. 1H). 3. After 5 min.68 g.) in freshly distilled THF (20 mL) was added hydroxyoxazolidinone 7a1 (0.0.98 (m.9 Hz). 145. 2H).1552. 4. 7. 2.75 (m. This aqueous mixture was extracted with CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4.47 g.61 (m.2. 128.79 (d.05 mmol.53 (d. Vol.Synthesis of Oxazolidinone Phosphonate Derivatives. −0. 4. JC-F = 8.58 (d. JC-F = 25. HRFABMS calcd for C11H23NO3Si (M+1)+: 246. 17. 1346. 3398. J = 9.9.9 Hz). 3.0 Hz). 77%): 1H NMR δ 8.91 (d.45 g.6. J = 2. 145.3 Hz). 2H). 4H).09 (d.0 Hz).4 Hz). J = 5. 64. 2H).66 (m. 13C NMR δ 155. 1H). The procedure was the same as the preparation of compound 7a1.14 (s. 4.2 Hz. 130. Part II (cm−1): 3434.12 (m.5 Hz). 2H).27 (d. HRFABMS calcd for C10H9N2O5F (M+1)+: 257. 1530. 1410. 1H). 64. J = 3. 5. 60.53.93 (d.6 Hz).93 (m.0 Hz).81 (d.0Hz). 122. 70%): 1H NMR δ 8. 1H). 1747. 4. This reaction mixture was allowed to stir for 5 hrs at the same temperature and quenched with distilled water.4 Hz).81 mmol) and activated K2CO3 (0. 2H).25 (d.8 mmol. HRFABMS calcd for C15H20N2O8PF (M+1)+: 407. 4. JC-F = 3.) in anhydrous CH3CN (20 mL). J = 6. 55. 6H).64 mL.0 Hz).6. 3425. HRFABMS calcd for C16H23N2O5FSi (M+1)+: 371. 4.0 (d. 5 823 Hz).2 Hz.9 Hz). 130.0.18 g.0943. Korean Chem.83. 63.5 Hz).18 g. The desired compound 6b1 (1. JC-F = 252. HRFABMS calcd for C11H11N2O5F (M+1)+: 271.0495. 3H). 7. J = 11.3 Hz).4 Hz). 1.90 (d.1.8 Hz).28. 1528.3. 1H).2 Hz). 1H).0.8.92. 1762. J = 6. 3. 66.6 Hz. JC-F = 25.6 Hz). J = 6. J = 9.03 (m.5 Hz). 1. JC-F = 8. 1026. 3H). 130. 1205. JC-F = 25. 145. 13C NMR δ 156.54 mmol.17 (m. found: 271. 1348.0 Hz.7 Hz). 2H).9 Hz).8 Hz). JC-F = 252.03 mL. JC-F = 8.50 (d. 0. JC-F = 8. J = 6. 2857.4-difluoronitrobenzene (0.22 (d. the crude oil was purified by flash column chromatography with a gradient solvent system of methylene chloride and methanol to give the desired product 6a1 (1. JC-F = 2.2.2 Hz). 65. 13C NMR δ 155. JC-F = 3.88 (dd.9. After removal of the solvent under reduced pressure. 5.81 (s. J = 8. −0. 73. found: 371. HRFABMS calcd for C17H25N2O5FSi (M+1)+: 385.2. 13C NMR δ 155.57. JC-F = 2.6 Hz). 1141. 9H).9. JC-F = 10.4 Hz).5 Hz). 13C NMR δ 155.92.39 (d. J = 8. J = 111. IR (cm−1).1517. 4.2.7 Hz. 7. 36. IR (cm−1).3 Hz).3.55 (d.8.43 (d.5. JC-F = 3. 1. and then quenched with distilled water and ammonium chloride.6 (d. 1. JC-F = 2.66 equiv. JC-F = 10. 57. 3H). 60.1 Hz). J = 8.48.20 (d. 20.90 (d.57 (d. 1H).2 Hz). 57. 4. 2.47 (dd. 2930.

2H). 5. 1349. HRFABMS calcd for C15H22N2O6PF (M+1)+: 377. J = 11.67. 112. 2923.015 equiv. J = 8.7.41. −0. To a solution of phosphonated oxazolidinone 9a3 (0. No.00.01 (m. 2. 1518.4.01. 3. 6H). 16.03 (dd.3. 111. 4. 2984. 85%). 4.1096. 2H). J = 17.5 Hz).62.14 (d. 10. 2850.92 (m.3.17 (s.21 (d.1. 25.39 mmol. 4.5 g. 1. 2H). 88. 0. 1753. 144. 112. J = 8.4.0576.2 Hz. IR (cm−1): 2928.77.9.27 (d.09 mg. 0. 16. 70%): 1H NMR δ 9. 139.3.74 (m. 4.73.17 (dd. After being stirred for 24 hrs at room temperature.6.36 mL.7 (d. 2853.8 Hz.6.77 mmol. 65. 0.31 mmol.92 (d.5 Hz). 6. J = 6. 2H).83. −5.58 (t. 66.17 g. 1769.09. 1H NMR δ 9. 1H).8.37.01 (s.53 (m. 70. HRFABMS calcd for C16H22N2O8PF (M+1)+: 421.9 Hz). 1H). J = 10. 3.69 mmol.7. 8. J = 158. 1.011 mmol. 4. J = 245. 1199.53 (t. [N-(4-Amino-3-fluorophenyl)-2-oxo-oxazolidin-4-(R)yl-methoxymethyl]-phosphonic acid diethyl ester (9a3). 1345.9. Phosphonated oxazolidinone 9b3 (0.35 (m.19.13 g.98. Soc.15 (q.51 mmol) was converted to the desired product 10b3 (0. 1474.08.37.0574. 1. 4. the reaction mixture was filtered and concentrated in vacuo to afford the crude product. 134.5 Hz).31.4. JC-F = 22. 1473. 1. IR (cm−1): 2928. 56.10.03 (m. J = 7.38 (d. 1H). 76%): 1H NMR δ 9. 0.59 (m. 3H). 112. 49. Oxazolidinone 6a2 (2. 2H).60.2.0.7 Hz. 4-(R) -Hydroxymethyl-5-(R)-methyl-N-(5-nitro-pyridin2-yl)-2-oxazolidinone (7b2). J = 6.36 mmol) was converted to the desired product 7b2 (0. 1H).6 Hz. 2H). 154.28.5 g. found: 354. 133. 1H). 2254. 4H).03 g. 2007.86 mmol. 62.49 (m.9 Hz. 5 16. 0. 74.26. After 3 hrs. 1514. 145. 4-(R)-Hydroxymethyl-N-(5-nitro-pyridin-2-yl)-2-oxazolidinone (7a2). 1651.) gave the desired product 6b2 (1.0730. −0.42 (dd.26 (dd. 140. 13C NMR δ 158. 110. 62. 3.51 (t. 133. IR (cm−1): 3433.3 Hz).8 Hz.66 mmol. 0. This crude oil was purified by flash column chromatography with a gradient solvent system using ethyl acetate and methanol to give the desired product 9a3 (0. JC-F = 246. 2856.18 g.35 mmol) in distilled CH2Cl2 (30 mL) was added freshly distilled TMSBr (1. IR (cm−1): 3466. 140. 6.47.14 (t. 144.1407.42. 4.48. J = 164. 116.81 mmol) and 2chloro-5-nitropyridine (0. HRFABMS calcd for C9H9N3O5 (M+1)+: 240.21.3 Hz). J = 113.76. 13C NMR δ 156. [N-(4-Amino-3-fluorophenyl)-2-oxo-oxazolidin-4-(R)yl-methoxymethyl]-phosphonic acid (10a3).33. found: 377.50 (d. 1582. 65.6.68. 61.0 Hz). 4. J = 2.83 (s.65. 21.20 (m.07 (m. 8.2.87 (d.1546.91 (d.6. −0. 13C NMR δ 158. 8.3. 3.5 g. 17. 61.29. 1H).69. 1027.02. 4. 1H NMR δ 9. 1768.32 (m. 2H). J = 8.9.48.67 (d.92. 133. J = 7. C11H14N2O6PF (M+1)+: 321.94. J = 8. 1H). 1H).0 Hz).5 Hz). After being bubbled for 30 min with argon.39. 13 C NMR δ 154.7. 62. J = 9.0738.6.19 (d.95 (m.16 (dd. 2984.3.40 (d. 78%): 1H NMR δ 9.25 g.6. 157.46 mmol. J = 4.70 (d.77.60.4 Hz). 4. J = 8. IR (cm−1): 3388.0542. 30 eq).2. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-5(R)-methylN-(5-nitro-pyridin-2-yl)-2-oxazolidinone (6b2). 0.8 Hz). 1H). 71. 113.13 g.96.2 Hz). 8.5 Hz). J = 1. 89%). 7H).74 mmol. 102. IR (cm−1): 3418. 1117. 1H).82 (s. 3H).25.76 (s. 3H).59 mmol) was converted to 9b3 (0. J = 36. 1420. HRFABMS calcd for C15H23N3O5Si (M+1)+: 354. 65. 0. 2H). J = 10.18 (m.5 equiv.80. 8H). [N-(4-Amino-3-fluorophenyl)-5-(R)-methyl-2-oxo-oxazolidin-4-(R)-yl-methoxymethyl]-phosphonic acid (10b3).09.8 Hz. 1H).2.07. 1H).03 (d.5 g.84 (m. 0. −0.1.53.58 (d. 2127. 5.93. 2920. JC-F = 12. 824. Korean Chem. 4.24 g. 1523. J = 3. 9H). 3. 13C NMR δ 154.77. 1.00. 4.29.4. 1239.55.67 (d. 141. found: 421. 4.65 (d. 1.0 Hz. 2H). 70. A solution of oxazolidinone 8a1 (0. 762.2 Hz. 106. J = 2. 100 mL) was treated with ammoniumformate (0. 3H).39 (dd. 21. HRFABMS calcd for C16H25N3O5Si (M+1)+: 368.11 (s.6.9 Hz.82 (dd.36 (dd. 3. 1597.81 (d.03 g.) gave the desired product 6a2 (2. J = 13. 20.75 mmol. JC-F = 12.7.5 Hz). J = 1. 31P NMR δ 21. J = 5. 2938. 1. 3451.13 (s. [N-(4-Amino-3-fluorophenyl)-5-(R)-methyl-2-oxo-oxazolidin-4-(R)-yl-methoxymethyl]-phosphonic acid diethyl ester (9b3).79 (d.2 g. 6.33 (m.08. found: 240.1201. 0.06 (t.7 Hz). The procedure was the same as the preparation of compound 10a3. 156.25 g.4. 62. 4. 1026. 112. 6.49 mmol) and 2-chloro-5-nitropyridine (1.53 (d. 25. Reaction of oxazolidinone 5b (1. 2H). 1H). 1342.1350. 60.81 (d.3 Hz. HRFABMS calcd for C12H16N2O6PF (M+1)+: 335. 2H). J = 8. 144. 5. 18.1357.6. 73.86 (d.19.59.30. HRFABMS calcd for Jae-Min Hwang et al.6. 4.9 Hz). Oxazolidinone 6b2 (0. 1340. JC-F = 10.8 Hz. JC-F = 3.2. 1H).40 (d.19 (d. 8. 1H). J = 237.32 (dt.08 mmol.57 (m. The procedure was the same as the preparation of compound 6a1. 1H). 2H).3. 4 equiv.47 (d.00 Hz.29 g. −5. 4-(R)-(tert-Butyldimethylsilyloxymethyl)-N-(5-nitropyridin-2-yl)-2-oxazolidinone (6a2). 56. 6H). 73. 4. Vol.5. 31P NMR δ 19.2.4 Hz. 65. 31P NMR δ 16. 2252.59 (d.5 Hz).2 Hz).) was added quickly and stirred.3. 13 C NMR δ 154.3. 154.69. 1026. J = 8.62 (d.6. 82%): 1H NMR δ 9. IR (cm−1): 3433.1 Hz). 1.1409.6.92 g. 1H). JC-F = 2. The procedure was the same as the preparation of compound 6a1. 4. 1747.3. 64. 4. 71.29 (dd.4. Pd/ C (catalyst 1. 112. 3H). 1596. 5. J = 1. found: 391.12 g. 1413. J = 5. 0. 57.1. 4.1098. 0.75.824 Bull.03 (d.0 Hz). 4. 2H). J = 10. J = 10. 148. Reaction of oxazolidinone 5a (1.75 mmol) was converted to the desired product 7a2 (1. 1032. 1199.4.38. HRFABMS calcd for C16H24N2O6PF (M+1)+: 391. 1H).7 Hz).2.22 (bs. 1H). 3.3 Hz.52 (d.34.5 mmol.43.64.60. 31P NMR δ 15.16. 155.28 (d. IR (cm−1): 3460. 8.31. 31P NMR δ 20. Oxazolidinone 8b1 (0. 4. 3H).34.10 g. 1743.7 Hz. 92%): 1H NMR δ 7.5 Hz). 9H). J = 5.87. 61. 28.3. JC-F = 2. found: 321.1200. found: 368. found: 335.3. 144.6 Hz. The procedure was the same as the preparation of compound 9a3. J = 8.43 (t.02 (s.95 mmol. 130.4 Hz. JC-F = 9. 1597. 1532.93.51. 1.5 Hz.48 (dd. 154.9 Hz). 112. 133.6 Hz. JC-F = 22. 3H).58 (m. 13C NMR δ 156. 140.6 Hz).08.45 (d.0. 2. 1H).2 Hz). This mixture was concentrated in vacuo and washed with methylene chloride and ether several times to give the desired product 10a3 (0.47 (m. 8.7 Hz). 114.0 Hz.11. JC-F = 245. 1203. 3. J = 18. 154. J = 8.6 Hz). . 0. 6H). 2H). The procedure was the same as the preparation of compound 7a1.6. J = 1.17.5 Hz).38 (m.18 g.2 equiv.93.) at room temperature. 3244. 140. 7. 1.38.5 Hz).47 (m. J = 1.01.1545. 1H). 65. 1.0543. 130.91 (d. 4. 56. 1761.5%): 1H NMR δ 7.63.9. 2.35 (d.4 Hz).93 (m. J = 8. the reaction was diluted with MeOH.71 mmol) in anhydrous THF:MeOH (35:65.7.4 Hz. 1H). 9. The procedure was the same as the preparation of compound 7a1.5.6. 1650.45(d.

6 Hz. Jr. D.31. 63. (b) Brickner.81 (m. 1H). C.68.67. 2007. The procedure was the same as the preparation of compound 9a3..47 (d. Zurenko. 4.19 mmol) was converted to the desired product 10a4 (0. 95.19 mmol) was converted to the desired product 8b2 (0.4. 31P NMR δ 21. J = 9. 1H). 146.12.. The procedure was the same as the preparation of compound 8a1. 6H).87 (d..4. 134. J = 9. 8. 1H). Angew.97 (m.2 Hz).2%). 4. Des. K.5 Hz). [N-(5-Nitro-pyridin-2-yl)-2-oxo-oxazolidin-4-(R)-ylmethoxymethyl]-phosphonic acid diethyl ester (8a2).00.32 mmol) following the same procedure as the compound 10a3: 1H NMR δ 8. J = 2. P. V.39 (dd. 2. IR (cm−1): 3342.99. Renslo. 19.8 (m.47.8 Hz).0988. IR (cm−1): 3443. 1759. Vol.21. 1293. 3. [N-(5-Amino-pyridin-2-yl)-5-(R)-methyl-2-oxo-oxazolidin-4-(R)-yl-methoxymethyl]-phosphonic acid diethyl ester (9b4). 110. Venkatachalam. Pharm. 52.21. 5H). G. Chem.1401. J. Schreckenberger.22 (d. 5. IR (cm−1): 3283.. found: 390. 2360. 1H). Top. Bioorg. C.69 (dd.0.9.6 Hz). 31P NMR δ 21. G.62. Eliopoulos..0620. R.22 (d. M. Curr. G.02. K.9. 6H).1 Hz.9 Hz.18.1. J = 164. Gregory.3 Hz). RTI05-01-02 from the Regional Technology Innovation Program of the Ministry of Commerce. Ferro. J = 2. 4H).67. S. 1. M.7 Hz). References 1. Chem. 146.25 mmol. 0. 4H)... J.0699. A.4. J = 164. 16. 135. M.50. J = 8.77. J = 11. 1H). J = 159. 19. 6.67. C. 6. M.15 g.4. 1025. No. J = 4. 4. 1333.41.75.34 (q.0.7. 5.0. S.58 (d.3 Hz). Wuonola. The procedure was the same as the preparation of compound 9a3.81 (m. J = 10.. 39. P.02. Sakoulas. 9.4.. K. A.0624.19 (m. 50%): 1H NMR δ 7. 8. 8.19. L.13 (dd. IR (cm−1): 3433.19. M. (b) Barbachyn.. Moellering. J = 7. J = 5. J = 7. H. 2985.4. 1H).64 (dd.01. 65.85. 4H).74.27 mmol. J. J = 6. 2H)... 2254. 8. J = 9. (a) Slee.10.4 Hz. P. found: 304.86.. 1H). HRFABMS calcd for C15H24N3O6P (M+1)+: 374.8 Hz. Int.07 g. 1H). 0.4. Gao.15 (m. H.11g. 6.23. Tsiodras.0.8.57. 2006. 4.27 g. 1606. 3. A. A. 1H). 71. 20. 2931.1248. 105. 1. 6.74 (d. K. J = 164. Chem. J = 2. Hendges.9. M.71.71 (m.72 (s.79. 4. M.5. J = 9. 1. 4.84.2 Hz).41...2.. (d) Nilus.77. D.6 Hz. 1987.28 (bs. 134.2 Hz. found: 360. C.4. A. 0.5 Hz).09. [5-(R)-Methyl-N-(5-nitro-pyridin-2-yl)-2-oxo-oxazolidin4-(R)-yl-methoxymethyl]-phosphonic acid diethyl ester (8b2). 71.78.79 (d.. J.8 Hz. 13C NMR δ 154. J = 8. HRFABMS calcd for C10H11N3O5 (M+1)+: 254. 3.13 mmol. W.0986..9.26 g.74 mmol. Forbes. 13C NMR δ 163. G.6. The procedure was the same as the preparation of compound 10a3. 3H).30 (bs.. 13C NMR δ 161.14 mmol. 4. 2978.11 (dd. 1. R. F. [N-(5-Amino-pyridin-2-yl)-2-oxo-oxazolidin-4-(R)-ylmethoxymethyl]-phosphonic acid (10a4).43. 73. Korean Chem. 1025. 5 825 63. T. 1H). 1H).2 Hz). Grega. 7H). 127.45 (d. 65.14. V. abstract No. Tsiodras. I.. 31P NMR δ 17..27 mmol) was converted to the desired product 8a2 (1. IR (cm−1): 3290.34 (q. J = 11.22 (d. 3. 13C NMR δ 161. Venkatraman. 1126. J = 20.54 (m. 1. HRFABMS calcd for C10H14N3O6P (M+1)+: 304.1145. Venkataraman. 2912.37 mmol) was converted to the desired product 9b4 (0. This work was supported by a grant No.54 (d.1404. IR (cm−1): 3303. J = 7.6.48 (s. 1H). P.83 (d..74. 13C NMR δ 161.90 (d.. Ferraro. Abstracts of 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. 149. 3..8 Hz). 1293. 113.44. J = 2. 134. G. 9..82. 7H)..73 (d. 133. 2925. J.43 (d. The desired product 10b4 (0. 78%) was prepared from the phosphonated oxazolidinone 9b4 (0. D. 62. Oct. D. 31P NMR δ 16.. J = 2.7 Hz).2. 144. S.2 Hz. 1.. N. 62.81 (d. Curr. 3. 1H).68. 1606. Zawada. 16.7 Hz). 6. M. A. 160. Quinn. Barbachyn. 146. 1025. 62. 3.2. HRFABMS calcd for C14H22N3O6P (M+1)+: 360.07 (t. R. 1021. P. 2993. S. Eliopoulas. 1003. Wennersten. 1.3. M. Invest. Batholomew. J = 11.05 g.9.. 146. 54. C. 63.8. M. found: 374.9. 8. H. 1501. 65. 2360.6 Hz. 1018. 2.4 Hz.. L. 0. 673. 6. 1233.5.. found: 254.13 (dd. Huband. 72. 1608. M. 825.1246. 28. 131. IR (cm−1): 3418. M. 1206. J = 4. 2003.51. 16.79. D.4 Hz.95 (dd.7. 66. 1294. R. C. 134.. S. Toops. 73.73.84 (m. 132.57. M. 1H NMR δ 8.30 (d.78. S. J.61. J = 6. 3H).6 Hz).. Gonzales.41 (bs.3 Hz). 62. Gómez. Part II 1H). 6H).11. 0. 3. 4. 0.95 (d. 207.2.0777.38. 1H). 65. J = 5.2 Hz.3. Gold.44 (d. R.. 1H). Ford. 133. J = 9.3. 4. 1996.7. 6. J = 4.86. C. 2003. 55. 140. J = 6.4 Hz. 55.42. McRipley.16 (d. Oxazolidinone 8b2 (0.94 (bs. 2253. 145. 107. 136. 31P NMR δ 21.45.04 g. J = 2.57.40 (dd. Moellering. 175. 0.5. B. 3H). 3. 1.08 g.2 Hz. 4. J = 6. 4-7. 135. S.96. For recent reviews. 0.79. The procedure was the same as the preparation of compound 8a1. 6. 71. 8. Hydroxyoxazolidinone 7b2 (0.1 g. 0.29. 2254.3.28 mmol) was converted to the desired product 9a4 (0. 42. Ulanowicz. Manninen. Prasad.5 Hz). Garmon.42.1 Hz. 3H). R.98 (d. 64.3. 16. 83%): 1H NMR δ 8. 1025. J = 6.29. 16. Lett.67.. Jaishankar..Synthesis of Oxazolidinone Phosphonate Derivatives. Industry and Energy (MOCIE).0. J = 8. Oxazolidinone 8a2 (0..97. 61%): 1H NMR δ 8. see: (a) Brickner. Blais.. 1. Opin.. .. Phosphonated oxazolidinone 9a4 (0. 66.54. Chem. 2982. R. 1651.61(m. 2361. 3.1 Hz.29. 6. S. 8. 68. 144. 108. Sakoulas. J = 2. J.4. 1H).59. J. 1. M. 132.93 (dd. Ford. Hutchinson. J = 6. Kelkar. E. 111. 67. 1H).4. S. 48. Soc.67.8 Hz. 1H). 2. 1622.32. 13C NMR δ 152.3 Hz).8 Hz. 62. 1H). 1H). HRFABMS calcd for C15H22N3O8P (M+1)+: 404. Bull.. 357.20 (m. (c) Hutchinson. 0. 62. W.48 (s.4 Hz. Med.02 (d..17. 1H). 2H). S.8. 3.8 Hz). 1H). 3. 2127. J = 5. J = 7. Curr. 1335.56 (dd.48 (d.98 (d.5 Hz. M. found: 318.0771. found: 404. 145. Hydroxyoxazolidinone 7a2 (1. 109. 1H). 3.26 mmol. 1996. R.96 (d. 2010.6 Hz..34 (d.8.7.1140..0.41. 4H). 244.33 (d. 2919.. 2H). R.3. 1025. J = 164. DenBesten.6 Hz). J = 2.69.. Gold. 6. 13C NMR δ 160. 1H). 6H). Drugs 2003. 1660.44 (d.4%): 1H NMR δ 8. 3. 2. 358. 6H). 6. 65.8. HRFABMS calcd for C11H16N3O6P (M+1)+: 318.3 g.34 (q. 51.47 (d. New York.11. 0. 31P NM R δ 21. 6H). 6H). J = 6. K.3 g..7.0698.48 (q. W. 1H). 143. C. [N-(5-Amino-pyridin-2-yl)-2-oxo-oxazolidin-4-(R)-ylmethoxymethyl]-phosphonic acid diethyl ester (9a4).73. J = 8. J.12 g.33 (m. 1H). Med. Graham. Lancet 2001. Wennerstein.2.30 (d. Lancet 2001. 60. [N-(5-Amino-pyridin-2-yl)-5-(R)-methyl-2-oxo-oxazolidin-4-(R)-yl-methoxymethyl]-phosphonic acid (10b4). HRFABMS calcd for C14H20N3O8P (M+1)+: 390.3 Hz.06 (d. 19. Zajac. J = 13.4 Hz). Gordeeva.8.3 Hz.3 Hz.63 (dd.7.02 (d. 134.56. Acknowledgement. 138.1 Hz. J = 8. 763. J = 9. A. Ed. 1. 73.2 Hz.88. Med. 6. 154. 1179.7.15 (m.

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