Dehydropeptides

S)-2,2-Dimethyl-cyclopro-panecarbox-amide 13 Cilastatin Dehydropeptide inhibitor Hydrolysis Comononas acidivorans and recombinant E. coli One-pot, two-step processes [7]... 

Dehydropeptides were reduced (Scheme 3.9) on a preparative scale in two-phase systems with catalysts prepared in situ from [ RhCl(COD) 2] and chiral water-soluble ligands 35, 36, and 37 (Ch.2). The highest (87%) diastereoselectivity was obtained with [ RhCl(COD) 2] + tetrasuhbnated 2,4-bis(diphenylphosphino)pentane, BDPPTS, 36 [121]. 

This enzyme [EC 3.5.1.14] (also referred to as histozyme, hippuricase, benzamidase, dehydropeptidase II, amino-acylase I, and acylase I) catalyzes the hydrolysis of an A-acyl-L-amino acid to yield a fatty acid anion and an L-amino acid. The enzyme has a wide specificity for the amino acid derivative. It will also catalyze the hydrolysis of dehydropeptides. 

Therefore, suitable unsaturated oxazolones can be used as intermediates to prepare dehydropeptides wherein the synthetic strategy used will depend on the position of the double bond in the final compound. If the double bond is located in the N-terminal amino acid, ring opening of the oxazolone 516 with the appropriate amino acid or peptide generates the desired dehydropeptide 517 directly. 

This synthetic strategy has been used to prepare some interesting dehydropeptides such as chromophoric dehydro analogues of leucine enkephalin/ potential angiotensin-converting enzyme inhibitors/ and dehydropeptides substituted with a p-lactam moiety. " ... 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

Synthesis of Peptides by Hydrogenation of Dehydropeptides. In addition to the interest in dehydropeptides in their own right, these compounds are also used to prepare non-proteinogenic peptides by simple reduction. For example, the electrochemical reduction of dehydropeptides derived from 2,3-dimethoxybenzaldehyde has been described. ... 

Synthetically, amino acid esters react with a 4-(indol-3-ylmethylene)-5(4//)-oxazolone 406 to afford dehydropeptides 816 as shown in Scheme 7.251. ... 

Dehydropeptides (21) were employed for the asymmetric hydrogenation, catalyzed by chiral rhodium complexes of the hydroxyproline derivative (13). It was reported that the stereoselectivity is satisfying (ds = 90-95 %)50). 

While investigating the biomimetic formation of cysteine, Schmidt et al. 2331 added thiolates to N-protected chiral a-aminoacrylic acid derivatives (dehydropeptides). (235) was obtained in optical yields up to 90 %. 

Azlactone oxidation Azlactones derived from dipeptides are more readily dehydrogenated than the dipeptides. This route to dehydropeptides has been examined with several reagents. Halogenation dehydrohalogenation is possible, but yields at best are 50%. Various oxidation procedures are about as effective. The most satisfactory method is oxidation of the corresponding trimethylsilyl enol ether with DDQ. However, this oxidation is limited to aryl azlactones. 

An alternative to the azlactone procedure for the preparation of short-chain dehydropeptides 19 is offered by the direct condensation of an a-oxo acid 17 on heating with one equivalent of a carboxylic acid amide or by the treatment of an a-oxo acid 17 with a nitrile in the presence of dry HC1 gas (Scheme 6). If the former reaction proceeds with the condensation of two molecules of amide per molecule of a-oxo acid, then the corresponding a,a-bis(acylamino) aliphatic acid 18 is formed, which on warming with acetic acid results in partial deamidation with formation of the corresponding dehydropeptide 19. 

If benzyl carbamate is used as the amide component in the reaction with a-oxo acids 23 then the Na-benzyloxycarbonyl-DHA 24 is obtained directly (Scheme 8). Shin and et al.[77 84l widely exploited the above method in the synthesis of various a, 3-didehydropeptides (Table 3). In presence of 3 M thionyl chloride and acetyl chloride, 24 gave the A-carboxy-DHA anhydride ANCA 25, which could be conveniently converted into dehydropeptides.[77 84 Compared with the common saturated A-carboxy-a-amino acid anhydrides (NCAs), ANCAs were found to be stable at room temperature for several months. 

This procedure may be employed for the synthesis of most of the a-haloacyl-DHAs. Ammonolysis with aq NH3 yields the respective a-aminoacyl-DHA. More specifically, a-haloacyl-DHA (20 g) was dissolved in 28% aq NH3 (200 mL) and the mixture kept at 37 °C for 36 h. The soln was then concentrated in vacuo at 35 °C, the residue dissolved in H20 (50 mL) and the resulting soln treated with abs EtOH (200 mL). The dehydropeptide was obtained as solid mass, which was filtered, washed with alcohol and Et20, and dried (P205). 

Table 4 Dehydropeptides Prepared by Dehydration of (3-Hydroxy-a-amino Acids 961...

Properties and synthesis of a,/3-dehydropeptides including penicillin and antibiotics 91WCH689. 

Pieroni O, Fissi A, Pratesi C, Temussi PA, Ciardelh F. Reversible screw sense inversion of the 3io-helix in a dehydropeptide. J. Am. Chem Soc. 1991 113 6338-6340. 

Pieroni O, Fissi A, Jain RM, Chauhan VS. Solution structure of dehydropeptides a CD investigation. Biopolymers 1996 38 97-108. 

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