Peptides catalyst design

Successful representative catalysts for asymmetric acylations include phosphine catalysts, chiral pyridine derivatives, other N-heterocycles " and peptide-based catalysts. Miller and coworkers designed peptide catalysts with -turns, a common feature within proteins and enzymes, in order to obtain secondary structure in which the catalytically active residues can be incorporated. During their initial work on asymmetric acylation reactions peptides were employed containing the catalytic histidine moiety to serve as nucleophile in a series of j0-tum type small peptides for the kinetic resolution of trans-1,2 acetamidocyclohexanol (- -/-)146 (Figure 53a). 

Design of catalysts mimicking the catalytic principles of enzymes is among the great challenges of modern chemistry (9, 10). Catalytic antibodies are examples of semisynthetic artificial enzymes (11-14). Fully synthetic molecules also have been designed as enzyme mimics by using either peptidic (15, 16) or nonpeptidic (17-24) molecules. 

Unsaturated half acid esters such as 1 are readily prepared by Stobbe condensation between dialkyl succinate and an aldehyde. Johannes G. de Vries of DSM and Floris P. J. T. Rutjes of Radboud University Nijmegen observed (Adv. Synth. Catal. 2008, 350, 85) that these acids were excellent substrates for enantioselective hydrogenation. Kazuaki Kudo of the University of Tokyo designed Organic Lett. 2008,10,2035) a resin bound peptide catalyst for the transfer reduction of unsaturated aldehydes such as 3, using 4 as the net donor. Note that 5 was produced with high enantiocontrol from 3 that was a 2 1 mixture of geometric isomers. 

A wide range of small organic molecules, mainly secondary amines such as proline derivatives, promote asymmetric aldol reactions through enamine catalysis [6]. List, Reymond, Gong, and others reported the first examples of peptidic catalysts for aldol reactions [7]. In their report, Reymond and coworkers [7a] developed two classes of peptides, following two different designs. In the first peptide class a primary amine is present as a side chain residue (similar to the natural type I aldolase) or as free N-terminus in the second a secondary amine or a proHne residue is present at the N-terminus of the peptide, which incorporated at least one free carboxyhc function (Figure 5.3). 

Catalyst Design from Theoretical Principles Chemzymes for Peptide Synthesis from Theozyme Blueprints... 

The first designed catalyst where there was some understanding of the relationship between structure and function was oxaldie 1, a 14-residue peptide that folds in solution to form helical bundles [11] (Fig. 12). Oxaldie 1 was designed to catalyze the decarboxylation of oxaloacetate, the a-keto acid of aspartic acid, via a mechanism where a primary amine reacts with the ketone carbonyl group to form a carbinolamine that is decarboxylated to form pyruvate. The reaction is piCj dependent and proceeds faster the lower the piC of the primary amine if the reaction is carried out at a pH that is lower than the piCj, of the reactive amine. The sequence contains five lysine residues that in the folded state form... 

Miller and co-workers have taken a totally different approach to design an efficient catalyst for enantioselective acylation. Their strategy relied on the use of a pep-tide-based backbone incorporating a 3-(l-imidazolyl)-(5)-alanine unit as the catalytic core. Upon treatment with an achiral acyl source these biomimetic enantioselective acyl transfer catalysts allow the formation of an acyl imidazolium ion in proximity to the chiral environment generated by the folding of the peptide [3, 159-174]. 

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004,126, 10558) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2. 

The design of the peptide implies that interaction of the catalyst with its substrate relies heavily on hydrogen bonding. Initial studies indeed revealed that, in particular, N-acyl amino alcohols such as 25 and ent-25 were efficiently differentiated whereas both enantiomers of l-(l-naphthyl)ethanol were acetylated at identical rates [28]. Catalyst 23b, shown in Scheme 12.12, was the most efficient from a series of ten peptides. For best performance, proper matching of the sense of chirality of all three chiral amino acids is necessary, and the type of amino acid present at the carbon terminus enables further tuning (for example, L-Phe was found to be better than, e.g., L-Val, selectivity factor 21) [29]. 

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