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Copyright Syntheticpages ©2001

Formation of N-Acyl Phosphoramidates; Phosphoramidate

SyntheticPage 201 (2002)
Submitted 8th Aug 2002, published 12th Aug 2002

Dr Russell Cox (,
A contribution from the Cox Group, Bristol

Reaction Scheme

Chemicals Used
Carboxylic acid potassium salt, ethyl chloroformate, BuLi, anhydrous CH2Cl2, (EtO)2P(O)NH2,

(2S)-g-N-Diethoxyphosphoryl-aN,aN-bis(tert-butyloxycarbonyl)-L-asparagine tert-butyl ester a-tert-Butyl N,N-bis(tert-butyloxycarbonyl)-L-aspartate potassium salt (515 mg, 1.20 mmol) was dissolved in anhydrous CH2Cl2 (11 mL) with some molecular sieves (4A, 1.6 mm pellets). Ethylchloroformate (855 uL, 970 mg, 8.7 mmol) was added dropwise and the mixture was stirred for 75 min. Some colourless solid was observed to precipitate at this point (KCl). In a second flask, diethylphosphoramidate ((EtO)2P(O)NH2, 1.1 g, 97%, 6.9 mmol) was dissolved in anhydrous CH2Cl2 (5mL), cooled to -78 oC and butyl lithium (2.76 mL, 2.5 M, 6.9 mmol) was added dropwise. The reaction mixture was stirred for 30 min, allowing it to reach RT. The deprotonated phosphoramidate solution was added dropwise to the first reaction mixture and then stirred overnight at RT. Diluted HCl was added to the crude reaction mixture until pH 3 was achieved. The product was extracted with CH2Cl2 (4 x 50 mL), the organic layers were collected together, dried (Na2SO4), filtered and the solvent was evaporated. A pale red oil was obtained (1.27g). The crude mixture was purified by column chromatography (30% EtOAc:70% Petrol (Rf 0.05) as eluent, increasing the ratio of EtOAc up to 100%, Rf 0.61) to give (2S)-g-diethoxyphosphoryl-aN,aN-bis(tert-butyloxycarbonyl)-L-asparagine tert-butyl ester as a colourless oil (310 mg, 588 mmol, 49%);

Author's Comments
This reaction sequence is good for any system in which acid sensitive groups are present - it works well with compounds containing acetals, t-butyl esters or BOC groups. Carbamate protected nitrogens require two protecting groups (e.g. BoC2) and base sensitive groups such as Fmoc are not suitable. The limitation is the solubility of the k salk, although this can be improved in some cases by the use of 18-crown-6. The low yield in this case was probably caused by a poor batch of BuLi - yields of up to 80% have been observed in other systems when the BuLi has been freshly titrated.

[a]D25 -5.0 (c 0.88 in CH2Cl2); IR (oil): nmax = 3122 (CONH, N-H), 2981 (C-H), 2934 (C-H), 2256 (N-CO), 1734 (C=O), 1725 (C=O), 1366 (C(CH3)3, C-H), 1234 (P=O), 1141 (C-O) cm-1; 1H NMR (300 MHz, CDCl3): d = 8.32-8.08 (bs, 1H, HN-P) 5.38 (dd, 1H, 3J(H,H) = 4.5Hz, 3J(H,H) = 7.6Hz, aCH), 4.25-4.05 (m, 4H, 2 x OCH2), 3.29 (dd, 1H, 2J(H,H) = 16.0Hz, 3J(H,H) = 7.6Hz, bCH), 2.6 (dd, 1H, 2J(H,H) = 16.0Hz, 3J(H,H) = 4.5Hz, bCH), 1.34 (m, 6H, 2 x OCH2CH3); 31P NMR (121 MHz, CDCl3, {1H}): d = -1.8 (s); 31P NMR (121 MHz, CDCl3): d = -1.8 to -1.9 (m); 13C NMR (75 MHz, D2O): d = 171.4 (d, 2J(C,P) = 38Hz, CO-NH-P), 168.9 (CO2tBu), 151.9 (tBuCO2N), 83.2 (C(CH3)3), 81.8 (C(CH3)3), 64.0 (d, 2J(C,P) = 6Hz, OCH2), 63.9 (d, 2J(C,P) = 5Hz, OCH2), 55.3 (aCH), 36.3 (d, 3J(C,P) = 9Hz, bCH2), 28.0 (N-(CO2C(CH3)3)2), 27.8 (CCO2C(CH3)3), 16.1 (d, 3J(C,P) = 3Hz, CH3CH2), 16.0 (d, 3J(C,P) = 3Hz, CH3CH2); LCMS (ES+, CH3CN/H2O) RT 16.4 min, m/z (%): 525 (100, [M]H+), 425 (52, [M - Boc + H]H+), 369 (24, [M - Boc - C4H9 + 2H]H+), 325 (5, [M - 2Boc + 2H]H+), 269 (22, [M - 2Boc - C4H9 + 3H]H+); MS (CI+) m/z (%): 525 (1, [M]H+), 425 (12, [M - Boc + H]H+), 369 (74, [M - Boc - C4H9 + 2H]H+), 341 (20, [M - Boc - C4H9 - C2H5 + 3H]H+), 325 (12, [M - 2Boc + 2H]H+), 313 (22, [M - 2Boc - C2H5 + 3H]H+), 269 (20, [M - 2Boc - C4H9 + 3H]H+), 251 (28, [M - 2Boc - C4H9 - C2H5 + 4H]H+), 180 (18, [CONHP(O)(OCH2CH3)2]+). HRMS (CI+) calcd for [M - Boc + H]H+, C17H34N2O8P 425.4041, observed 425.2052.

Lead Reference
L. A. Adams, R. J. Cox. J. S. Gibson, M. B. Mayo-Martin, M. Walter and W. Whittingham, J. Chem. Soc., 2002, in press.

Other References
R. J. Cox, J. S. Gibson and M. B. mayo-Martin, ChemBioChem, 2002, in press.

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