A Rapid and Highly Diastereoselective Synthesis of Enantiomerically Pure (4R,5R)- and (4S,5S)-Isocytoxazone

Abstract

A three-step protocol for the highly diastereoselective (>98%) synthesis of both (4R,5R)- and (4S,5S)-isocytoxazone from d- or l-tyrosine is reported. The diastereoselection was confirmed by X-ray crystallography. This synthesis is currently the highest yielding approach towards these enantiomerically pure biologically active oxazolidinones.

diastereoselective - cytoxazone - tyrosine - oxazolidin­one - oxidation

References and Notes

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9

O -Methyl- N - tert -butoxycarbonyl-l-tyrosine Methyl Ester (10): A solution of N-tert-butoxycarbonyl-l-tyrosine (8.00 g, 28.5 mmol) in dimethylformamide (80 mL) was cooled using an ice bath, treated with freshly ground KOH (1.72 g, 31.3 mmol), and a cooled solution of iodomethane (1.95 mL, 31.3 mmol) in dimethylformamide (20 mL) was added dropwise over 5 min. The mixture was stirred at r.t. for 30 min, cooled using an ice bath, and additional KOH (1.72 g, 31.3 mmol) and a cooled solution of iodomethane (1.95 mL, 31.3 mmol) in dimethylformamide (20 mL) was added. The mixture was stirred for 3 h, poured onto ice (150 mL), and extracted with EtOAc (3 × 75 mL). The organic layers were washed with H₂O (3 × 50 mL), brine (2 × 50 mL) and dried (MgSO₄). The solvent was removed under reduced pressure to afford a colourless oil. Crystallization was achieved from EtOAc-light petroleum, to give 10 as colourless crystals (6.5 g, 74%); mp 52-53 ºC; [α]^²0 _D +58.9 (c 1.2, CHCl₃), lit.^¹5 [α]^²² _D +59.2 (c 1.8, CHCl₃). IR (film): 2976, 1746, 1716, 1612, 1515, 1391, 1366, 1248, 1175, 1058, 1034 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 1.42 (s, 9 H), 3.01-3.11 (m, 2 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 4.53 (q, 1 H, J = 5.7 Hz), 5.00 (d, 1 H, J = 6.7 Hz), 6.82 (d, 2 H, J = 8.7 Hz), 7.03 (d, 2 H, J = 8.7 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 28.3, 37.6, 52.7, 54.7, 55.3, 79.9, 114.1, 128.1, 130.3, 155.1, 158.8, 172.4. HRMS: m/z calcd for C₁₆H₂₃NO₅: 309.1576; found: 309.1578.

10 Shimamoto K. Ohfune Y. Tetrahedron Lett.  1988,  29:  5177 

11

Methyl (4 S ,5 R )-5-[4-Methoxyphenyl)-1,3-oxazolidin-2-one 4-Carboxylate (11): A solution of O-methyl-N-tert-butoxycarbonyl-l-tyrosine methyl ester (10; 5.00 g, 16.2 mmol) in MeCN (200 mL) was treated with a solution of K₂S₂O₈ (8.75 g, 32.4 mmol) in H₂O (210 mL) and a solution of CuSO₄ (0.52 g, 3.2 mmol) in H₂O (50 mL). The mixture was heated to 70 ºC for 3 h under a blanket of N₂, allowed to cool, and extracted with EtOAc (3 × 150 mL). The combined organic solutions were dried (MgSO₄) and concentrated under reduced pressure to give a dark yellow oil. Column chromatography, eluting with EtOAc-light petroleum (1:10-1:1), afforded a colourless solid, which was recrystallised from EtOAc-light petroleum to give 11 as a colourless crystalline solid (2.10 g, 52%); mp 94-96 ºC; [α]^²0 _D +83.5 (c 1.15, CHCl₃). IR (film): 3316, 2956, 2362, 2337, 1762, 1613, 1515, 1382, 1250, 1224, 1026, 834, 763 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.81 (s, 3 H), 3.83 (s, 3 H), 4.31 (d, 1 H, J = 5.2 Hz), 5.56 (d, 1 H, J = 5.2 Hz), 6.81 (s, 1 H), 6.93 (d, 2 H, J = 4.8 Hz), 7.33 (d, 2 H, J = 4.8 Hz), ^¹³C NMR (100 MHz, CDCl₃): δ = 53.5, 55.7, 61.8, 79.9, 114.7, 127.5, 130.3, 158.6, 160.6, 170.7. HRMS: m/z [M⁺] calcd for C₁₂H₁₃NO₅: 251.0794; found: 251.0794.

12

Crystal data for 11: C₁₂H₁₃NO₅, M = 251.23, monoclinic,
a = 7.0103 (8), b =5.5734 (6), c = 15.6004 (18) Å, U = 602.01 (12) Å^³, space group P2₁, Z = 2, µ = 0.109 mm^-¹, ρ _calc = 1.386 Mg/cm^³. 5035 data (1542 unique, R _int = 0.0157) collected on an Apex II diffractometer at 150 K. Solved by direct methods^¹6 and refined by full-matrix least squares on F ^². R ₁[I > 2σ(I)] = 0.0298 and wR ₂ (all data) = 0.0745. Goodness of fit on F ^² = 1.079. CCDC No. 804096.

13

(4 R ,5 R )-Isocytoxazone ( ent -3): Methyl (4S,5R)-5-[4-methoxyphenyl]-1,3-oxazolidin-2-one 4-Carboxylate (11; 2.20 g, 8.8 mmol) was dissolved in EtOH (25 mL) and the solution was cooled using an ice bath. A solution of NaBH₄ (0.70 g, 19.3 mmol) in EtOH (8 mL) was added dropwise with stirring. After the addition was complete the ice bath was removed and the mixture was stirred for 45 min. The mixture was cooled to 0 ºC and concd HCl (1.5 mL) was added, followed by H₂O (15 mL). The EtOH was removed under reduced pressure and the remaining aqueous solution was extracted with EtOAc (3 × 50 mL). The combined organic solutions were dried (MgSO₄), and the solvents were removed to afford an off-white solid, which was recrystal-lized from EtOAc-light petroleum to give (4R,5R)-iso-cytoxazone (ent- 3) as a colourless crystalline solid (1.75 g, 90%); mp 140-142 ºC; [α]^²0 _D +74.8 (c 1.08, acetone), lit.^³ [α]^²5 _D +70 (c = 0.4, MeOH). IR (nujol): 3239, 1725, 1614, 1514, 1459, 1376, 1251, 1174, 1062, 1016, 828 cm^-¹. ^¹H NMR (250 MHz, acetone-d ₆): δ = 3.71-3.87 (m, 3 H), 3.86 (s, 3 H), 5.35 (d, 1 H, J = 5.3 Hz), 7.01 (d, 2 H, J = 8.6 Hz), 7.41 (d, 2 H, J = 8.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 56.0, 63.1, 64.2, 80.4, 115.4, 128.7, 133.2, 159.6, 161.3. HRMS: m/z [M⁺] calcd for C₁₁H₁₃NO₄: 223.0845; found: 223.0842.

14

See the Supporting Information for the experimental data.

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