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Reductive Hydrazination of a keto-acid; Hydrazine carboxylic acid

SyntheticPage 192
DOI: 10.1039/SP192
Submitted Mar 15, 2002, published Mar 19, 2002
Dr Russell Cox (r.j.cox@bris.ac.uk)
A contribution from Cox Group, Bristol


			Reaction Scheme: Reductive Hydrazination of a keto-acid

Chemicals Used

Hydrazine hydrate,
Sodium cyanoborohydride,
Methanol,
Water,
Trifluoroacetic acid.

Procedure

To a solution of di-(Ac-Phe-(e-keto)aminopimelate(OLi)-OLi) pentahydrate (61.4mg, 141umol) in HPLC grade CH3OH (2mL) was added hydrazine hydrate (70uL, 72.1mg, 1.44mmol). The solution was acidified to pH 5.0 by the careful addition of CF3CO2H and after 30min NaCNBH3 (89.4mg, 1.42mmol) was added. The reaction was stirred at RT overnight, then acidified by the addition of conc. aq. HCl. Solvent was removed in vacuo and the solid residue dissolved in deionised water (1mL). The solution was applied to the H+ form of a column of Dowex AG50 WX-8 cation exchange resin (2mL bed volume) and eluted with deionised water until the washings were neutral. The desired product was eluted with 1N NH3 in deionised water. Removal of solvent afforded the product as a glassy semi-solid (52.1mg, 132.2umol, 93.8%).

Author's Comments

Addition of water to the methanolic solution of the ketone can aid solubility and does not decrease the yield. The important aspect of the reaction is to get the pH of the solution to ca 5.5 to 5.0 by the careful addition of TFA - use of a microsyringe to add microlitre amounts works well. This procedure also works for reductive amination - in this case ammonium acetate is a convenient ammonia source. This reaction was performed on a small scale conveniently in a 5mL Wheaton vial.

Data

1H(300MHz; D2O) 7.25 (5H, m, Ph), 4.60 (1H, m, CH), 4.15 (1H, m, CH), 3.55 (1H, m, CH), 3.20 (1H, m, phe CH), 2.95 (1H, m, phe CH), 2.20 (1H, m, AP CH), 1.95 (3H, s, CH3), 1.90-1.20 (5H, m, AP + CH2 + CH); m/z (ES+, H2O/D2O) 394 (M)+ 5%, 395 (M-H+D)+ 80%, 396 (M-2H+2D)+ 75%, 397 (M-3H+3D)+ 65%, 398 (M-4H+4D)+ 33%, 399 (M-5H+5D)+ 8%.

Lead Reference

"Synthesis and in vitro enzyme activity of peptide derivatives of bacterial cell wall biosynthesis inhibitors." R. J. Cox, H. Jenkins, J. A. Schouten, R. A. Stentiford and K. J. Wareing, J. Chem. Soc., Perkin Trans. 1, 2000, 2023-2036.

Other References

"Inhibitors of N-Succinyl Diaminopimelic Acid Aminotransferase (DAP-AT) : A Novel Class of Antimicrobial Compounds." Russell J. Cox, James A. Schouten, Rosie A. Stentiford and Katrina J. Wareing, Bio. Med. Chem. Lett., 1998, 8, 945-950. "Synthesis and Evaluation of Novel Substrates and Inhibitors of N-Succinyl-LL-Diaminopimelate Aminotransferase (DAP-AT) From E. coli." R. J. Cox, W. A. Sherwin, L. Lam and J. C. Vederas, J. Am. Chem. Soc. 1996, 118(32), 7449-7460.

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Keywords: Hydrazine, oxidative addition, oxidation, carbonates, isotopically labelled compounds, amino acids, 192

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