Tripeptide catalysis

DR. KENNETH KUSTIN (Brandeis University) Some years ago, you studied reactions of the type MX + Y = MY + X and found some interesting effects, such as chain reactions and phenomena of that sort. You also found that there was autocatalysis of such ligand substitution reactions by, I believe, triglycine. Has that turned up again Are other tripeptides or polypeptides autocatalytic How does that fit in with the base catalysis concept ... 

Amides. Metal ions catalyze the hydrolysis of a variety of amides, including acylamino acids, dipeptides and tripeptides, and amino acid amides. In all these compounds it is possible for a metal ion to complex with one or more ligand groups, either amine or carboxylate ion functions, in addition to the amide group. Thus the structural prerequisites for the metal ion catalysis of amide hydrolysis are the same as those for ester hydrolysis. 

Thermolysin belongs to a class of proteases (called neutral proteases) which are distinct from the serine proteases, sulfhydryl proteases, metal-loexopeptidases, and acid proteases. Neutral proteases A and B from Bacillus subtilis resemble thermolysin in molecular weight, substrate specificity, amino acid content, and metal ion dependence. Since physiological substrates are most likely proteins, it is difficult to design simple experiments that can be interpreted in terms of substrate specificity and relative velocities. Therefore, studies of substrate specificity and other kinetic parameters must be carried out on di- and tripeptides so that details of the mechanism of catalysis can be obtained and interpreted simply. 

The pentapeptide sequences were assembled on a Fmoc-Val-Pepsyn-KA-resin (0.08 mequiv-g 1) using a Biolynx synthesizer. Fmoc(Fmoc-Hmb)N-Gly-OH was incorporated using its pentafluorophenyl ester with HOBt catalysis for 45 min. Fmoc-Ala-OPfp was double coupled to the terminal (Hmb)tripeptide-resin for 2 h. All couplings not involving an Hmb-substituted residue were performed using standard 0.5 mmol scale coupling protocols. 

Asymmetric phase-transfer catalysis with (S,S)-lg can be successfully extended to the stereoselective N-terminal alkylation of Gly-Ala-Phe derivative 61 (i.e., the asymmetric synthesis of tripeptides), where (S,S)-lg turned out to be a matched catalyst in the benzylation of DL-61, leading to the almost exclusive formation of DDL-62. This tendency for stereochemical communication was consistent in the phase-transfer alkylation of DDL-63, and the corresponding protected tetrapeptide DDDL-64 was obtained in 90% yield with excellent stereochemical control (94% de) (Scheme 5.30) [31]. 

The enantioselective total synthesis of (-)-hemiasterlin, a marine tripeptide with cytotoxic and antimitotic activity, was achieved by E. Vedejs and co-workers. The asymmetric Strecker reaction was used to construct the key tetramethyltryptophan subunit. The aldehyde substrate was first converted to the corresponding chiral imine with (R)-2-phenylglycinol under scandium triflate catalysis. The addition of tributyltin cyanide resulted in the formation of a-amino nitriles as an 8 1 mixture of diastereomers. Subsequently the cyano group was converted to a primary amide, and the chiral auxiliary was removed under catalytic hydrogenation conditions. 

This effect has been studied in our group by Kenichi Morigaki in his dissertation. He utilized the hydrophobic tripeptide Z-Phe-His-Leu-NHj (Z = carboben-zyloxy). This compound has been shown before in the literature to display catalytic properties towards the hydrolysis of certain esters. The authors were particularly interested in the stereoselectivity of the process of L- towards D-amino acids and less in the enhancement of catalysis operated by the micelles. The substrate chosen was a very lipophylic ester, nitrophenylpalmitate. Morigaki used oleate vesicles, and later POPC liposomes, obtaining qualitatively similar results. ... 

An interesting example of intramolecular catalysis of type A syntheses is provided by the ready condensation of certain histidylproline peptides. Treatment of the ditrityl derivative of the tripeptide 121 with 50% acetic acid at room temperature results in rapid detritylation followed by cyclization to give the diketopiperazine 122 with elimination of... 

An initial hypothesis to explain these observations was that glutathione (GSH), the prevalent tripeptide thiol in cells, competes effectively for Cu(i), despite the large stability constant of Cu(NC)2 at pH 7.4 of approximately 10, and that it then serves as the site for catalysis of reduction of O2 by thiols, as in Reactions 26-29.However, in unpublished model experiments, it has been shown that catalysis by the reaction mixture of Cu(NC)2 and GSH is much more effective than that by CuSG alone.This has led to a modified model for reaction, in which a glutathione adduct is a key intermediate ... 

Exchange studies with di- and tripeptides (Nielsen et ai, 1960) gave results similar to those obtained in the case of JV-methylacetamide. The rates varied with pD, indicative of acid and base catalysis, and the minimum rates ( 0.6min for glycylglycine and 0.3 min for the JV-terminal peptide group of alanylglycyl-... 

Mechanistic studies performed by Wennemers and coworkers revealed that the presence of water significantly reduces the reaction rate of peptide-catalysed Michael additions. In order to make the reaction water compatible, the group of Wennemers studied the asymmetric Michael addition in aqueous emulsions supported by tripeptides equipped with alltyl moieties that are supposed to provide a hydrophobic environment for catalysis, similar to the behaviour of enzymes. While the parent peptide 15b showed, under these conditions, low conversion rates and a decreased enantiomeric excess of 73%, the insertion of hydrophobic allqrl side ehains improves the catalyst s performance (21, Scheme 13.14c) by shielding the catalytically active peptide from the surrounding water allowing the addition to proceed in a hydrophobic microenviroment, as previously assumed. The prepared addition products were isolated in good yield and with excellent diastereo- and enantioselectivity." " ... 

A recent example has been described by Brown et al. who have studied the KR of p-nitrophenyl esters of the d- and i-N-tert-butoxycarbonyl derivatives of glutamine and phenylalanine with ethanol or methanol promoted by chiral lanthanide complexes, providing enantioselectivities of up to 99% ee [302]. On the other hand, an enantioselective hydrolysis of phenylalanine derivatives was reported in 1986, providing a perfect enantiomer discrimination (s> 1000), as a result of catalysis with a tripeptide [303]. In 2007, Maruoka et al. reported the KR of differently a,a-disubstituted a-siloxy aldehydes based on an asymmetric rearrangement into the corresponding chiral acyloins using axially chiral organoaluminium Lewis acids, which provided selectivity factors of up to 39.5... 

Scheme J4.20 Addition on

---