Resolution of Pentafluorophenyl
Active Esters Using (S)-4-Phenyloxazolidin-2-thione

Najla Al Shaye; Tom W. Broughton; Elliot Coulbeck; Jason Eames

doi:10.1055/s-0028-1088218

LETTER

Resolution of Pentafluorophenyl Active Esters Using (S)-4-Phenyloxazolidin-2-thione

Najla Al Shaye, Tom W. Broughton, Elliot Coulbeck, Jason Eames*
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull, HU6 7RX, UK
Fax: +44(1482)466410; e-Mail: j.eames@hull.ac.uk;

Abstract

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Abstract

A series of structurally related racemic pentafluorophenyl active esters were resolved using an equimolar amount of (S)-4-phenyloxazolidin-2-thione. The levels of diastereocontrol were found to be excellent (>86% de at ˜30% conversion).

Key words

chiral auxiliaries - chiral resolution - molecular recognition - stereoselectivity

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References

References and Notes

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For reviews, see:

<A NAME="RD40208ST-3A">3a</A> Eames J. Angew. Chem. Int Ed. 2000, 39: 885

<A NAME="RD40208ST-3B">3b</A> Eames J. In Organic Synthesis Highlights Vol. 5: Wiley-VCH; Weinheim: 2003. Chap. 17. p.151

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<A NAME="RD40208ST-4A">4a</A> Coumbarides GS. Dingjan M. Eames J. Flinn A. Motevalli M. Northen J. Yohannes Y. Synlett 2006, 101

<A NAME="RD40208ST-4B">4b</A> Boyd E. Chavda S. Eames J. Yohannes Y. Tetrahedron: Asymmetry 2007, 18: 476

<A NAME="RD40208ST-5A">5a</A> Coumbarides GS. Dingjan M. Eames J. Flinn A. Northen J. Yohannes Y. Tetrahedron Lett. 2005, 46: 2897

<A NAME="RD40208ST-5B">5b</A> Yohannes Y. PhD Thesis University of London; UK: 2004.

<A NAME="RD40208ST-6">6</A> Chavda S. Coulbeck E. Dingjan M. Eames J. Flinn A. Northen J. Tetrahedron: Asymmetry 2008, 19: 1536

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The relative configuration of this adduct was determined through stereospecific synthesis.

For oxazolidin-2-thione (S,S)-anti-5, the PhCHN double doublet appeared at δ = 5.51 ppm (1 H, dd, J = 8.3, 3.0 Hz). Whereas, for oxazolidin-2-thiones (R,S)-syn-5, the PhCHN double doublet appeared at δ = 5.62 ppm (1 H, dd, J = 9.2, 6.1 Hz).

<A NAME="RD40208ST-10">10</A> Eames J. Chavda S. Coumbarides GS. Dingjan M. Flinn A. Northen J. Chirality 2007, 19: 313

<A NAME="RD40208ST-11">11</A> Boyd E. Chavda S. Coulbeck E. Coumbarides GS. Dingjan M. Eames J. Flinn A. Motevalli M. Northen J. Yohannes Y. Tetrahedron: Asymmetry 2007, 18: 2515

The ee was determined through hydrolysis of the active ester and derivatization of the parent 2-phenylpropionic acid. For further information, see ref. 15.

For the mutual kinetic resolution of active ester (rac)-2 with 4-phenyloxazolidin-2-thione (rac)-4, gave the corresponding (RS,SR)-(rac)-syn-5 in 55% yield with 96% de. For further information, see ref. 6.

This lower diastereocontrol was not due to in situ racemization of active ester (rac)-15 nor epimerization of the resulting oxazolidin-2-thione (R,S)-syn-16 as this adduct can be made stereospecifically by addition of (R)-15 to the lithiated 4-phenyloxazolidin-2-thione (S)-4-Li.

The ee was determined by derivatisation with (R)-1-phenylethanol using a DMAP-mediated DCC coupling procedure.

Representative Experimental Procedure:(2 R ,4 S )-3-(2-Phenylpropionyl)-4-phenyloxazolidin-2-thione [( R , S )- syn -5]
n-Butyllithium (0.36 mL, 2.5 M in hexane, 0.90 mmol) was added to a stirred solution of 4-phenyloxazolidin-2-thione (S)- 4 (0.15 g, 0.84 mmol) in THF (5 mL) at -78 ˚C. After stirring for 1 h, a solution of pentafluorophenyl 2-phenyl-propionate [(rac)-2, 0.26 g, 0.84 mmol] in THF (1 mL) was added. The resulting mixture was stirred for 2 h at -78 ˚C. The reaction was quenched with H₂O (10 mL). The organic layer was extracted with CH₂Cl₂ (2 × 10 mL), dried (MgSO₄), and evaporated under reduced pressure to give a mixture of diastereomeric oxazolidin-2-thiones syn-5 and anti-5 (ratio 94:6 syn/anti). The crude residue was purified by flash chromatography on SiO₂ eluting with light PE (bp 40-60 ˚C)-Et₂O (7:3) to give the oxazolidin-2-thione (R,S)-syn-5 (77 mg, 30%) as a white solid and the pentafluoro-phenyl 2-phenylpropionate (S)-2 (0.123 g, 47%) as a colorless liquid.
Oxazolidin-2-thione (R,S)-syn-5: R _f = 0.67 [light PE (bp
40-60 ˚C)-Et₂O, 1:1]; mp 87-89 ˚C [lit.⁶ (S,R) 84-86 ˚C]; [α]_D ^²0 +66.1 (c 3.6, CHCl₃) [lit. (S,R) [α]_D ^²0 -58.3 (c 4.0, CHCl₃)]. IR (CHCl₃): ν_max = 1708 (C=O), 1216 (C=S) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.20-7.08 (6 H, m, 6 × CH, Ph^A and Ph^B), 6.94 (2 H, dt, J = 6.9, 1.8 Hz, 2 × CH, Ph^A), 6.88 (2 H, dt, J = 7.0, 1.8 Hz, 2 × CH, Ph^B), 5.98 (1 H, q, J = 6.9 Hz, PhCHCH₃), 5.62 (1 H, dd, J = 9.2, 6.1 Hz, PhCHN), 4.68 (1 H, t, J = 9.2 Hz, CH _AH_BO), 4.20 (1 H, dd, J = 9.2, 6.1 Hz, CH_A H _BO), 1.35 (3 H, d, J = 6.9 Hz, PhCHCH ₃). ^¹³C NMR (100 MHz, CDCl₃): 185.2 (C=S), 174.8 (C=O), 139.1 and 136.9 (2 × i-C; 2 × Ph), 128.8,^² 128.7,^¹ 128.5,^² 128.3,^² 127.1^¹ and 126.4^² (10 × CH, 2 × Ph), 73.6 (CH₂O), 62.6 (PhCHN), 43.9 (PhCHCH₃), 18.7 (PhCHCH₃). HRMS: m/z calcd for C₁₈H₁₈NO₂S [MH⁺]: 312.1053; found: 312.1054.
Pentafluorophenyl 2-phenylpropionate (S)-2: R _f = 0.63 [light PE (40-60 ˚C)-Et₂O, 9:1]; [α]_D ^²0 +40.8 (c 4.6, CHCl₃) {ca. 55% ee based on lit.^¹0 (S) [α]_D ^²0 +74.5 (c 4.9, CHCl₃); lit.^¹¹ (R) [α]_D ^²0 -75.0 (c 3.3, CHCl₃)}. IR (film): ν_max = 1784 (C=O) cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.41-7.28 (5 H, m, 5 × CH, Ph), 4.07 (1 H, q, J = 7.2 Hz, CH₃CH), 1.64 (3 H, d, J = 7.2 Hz, CH ₃CH). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.6 (OC=O), 141.1 [142.40 and 139.90, 2 C, ddt, ^¹ J _C,F = 251.3 Hz, ^² J _C,F = 12.2 Hz, ^³ J _C,F = 3.8 Hz, C(2)-F], 139.4 [140.70 and 138.18, 1 C, dtt, ^¹ J _C,F = 253.2 Hz, ^² J _C,F = 13.4 Hz, ^³ J _C,F = 4.2 Hz, C(4)-F], 138.7 (i-C, Ph), 137.8 [139.05 and 136.58, 2 C, dtdd, ^¹ J _C,F = 249.1 Hz, ^² J _C,F = 14.5 Hz, ^³ J _C,F = 5.7 Hz, ⁴ J _C,F = 3.1 Hz, C(3)-F], 128.9, 127.8, 127.5 (3 × CH, Ar), 125.2 (1 C, tdt, ^² J _C,F = 14.2 Hz, ⁴ J _C,F = 4.2 Hz, ^³ J _C,F = 2.0 Hz, i-CO, OC₆F₅), 45.1 (PhCH), 18.5 (CH₃CH). ^¹9F NMR (378 MHz, CDCl₃):
δ = -152.6 (2 F, d, ^³ J _F,F = 20.9 Hz, F_ortho), -157.9 (1 F, t, ^³ J _F,F = 20.9 Hz, F_para), -162.3 (2 F, t, ^³ J _F,F = 20.9 Hz, F_meta). HRMS: m/z calcd for C₁₅H₉F₅O₂ [M⁺]: 316.0517; found: 316.0514.