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Acylation and Cbz hydrogenolysis; (S)-2-(2’,2’-dimethylpropionylamino)-5-aminopentanoic acid

SyntheticPage 492
DOI: 10.1039/SP492
Submitted Apr 15, 2011, published May 23, 2011
David Fox (d.j.fox@warwick.ac.uk)
A contribution from Fox Group, Warwick University


			Reaction Scheme: <img src="/images/empty.gif" alt="" /><img src="/images/empty.gif" alt="" /><img src="/images/empty.gif" alt="" />Acylation and Cbz hydrogenolysis<img src="/images/empty.gif" alt="" /><img src="/images/empty.gif" alt="" /><img src="/images/empty.gif" alt="" />

Chemicals Used

Nω-CBz-L-Ornithine
Potassium hydroxide
Trimethylacetyl chloride
Hydrogen
palladium hydroxide (20% on carbon)

Procedure

Nω-CBz-L-Ornithine (31.92 g, 120 mmol) was added to a mixture of KOH (6.72 g, 120 mmol), water (200 ml) and THF (100 ml) at 0 ºC. Trimethylacetyl chloride (12.3 ml, 100 mmol) was added dropwise keeping the internal temperature below 10 ºC. The reaction was stirred for 14 hours. The mixture was then extracted with 1:1 EtOAc / 40-60 petroleum ether (2 × 200 ml). Aqueous HCl (6 M) was then added until the solution was pH 2. The mixture was then extracted with ethyl acetate (4 × 200 ml), and the combined extracts were dried over Na2SO4 and then reduced in vacuo to give a thick colourless oil. This oil was dissolved in MeOH (650 ml), palladium hydroxide (20% on carbon, 400 mg) was added, and the mixture was stirred at ambient temperature under hydrogen (1 atm.) for 14 hours. The mixture was then filtered through a pad of celite and the solvent was removed in vacuo to give the target compound as a white solid (14.9 g, 69%).

Author's Comments

The lower price, or increases ease of synthesis, of Nω-Cbz-ornithine and lysine compared to Nω-Boc-ornithine and lysine can make them preferable starting materials for the synthesis of ornithine or lysine Nα-mono-amides. The decreased water solubilities of Cbz-amide intermediates compared to Boc-amide intermediates also result in increase yields for the first step. Importantly however the un-acylated Cbz ornithine or lysine is water soluble enough at low pH to be extracted into aqueous acid (or pH 2 aqueous sulfate buffer, 0.5 M Na2SO4 / 0.5 M NaHSO4). This extraction allows the use of excess protected amino-acid starting material. In turn this ensures complete reaction of the acid chloride and clean pre-hydrogenolysis intermediate. The Cbz removal by hydrogenolysis is simple to perform, and after filtration and reduction in vacuo results in analytically clean product as a neutral molecule. Acid-mediated Boc removal usually results in the formation of a ammonium salt product which has be subjected to another procedure (e.g. ion exchange chromatography) to generate the overall-neutral product. The ability to generate very clean material, at the expense of a slight reduction is yield, can be very important, especially if the reaction is being performed on large scale where chromatography is not practical or crystallisation not possible.

Data

δH(400MHz, D2O) 4.14 (1H, dd J 7, 5, CHN), 2.93 (2H, t, J 7 CH2N), 1.87-1.76 (1H, m, CH2), 1.73-1.54 (3H, m, CH2), 1.13 (9H, s, (CH3)3) (NH and OH missing).

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Keywords: amides, amines, amino acids, carbamates, hydrogenolysis deprotection, peptides, substitution

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