Peptide-catalysed alcohol

In this chapter, remarkable advances in the research devoted to peptide catalysed alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxida-tion are discussed. 

Miller and coworkers demonstrated a successful application of a peptide-catalysed kinetic resolution in the total synthesis of (-)-mitosane, which is a key intermediate for mitomycin C synthesis. A pentapeptide was found to effect kinetic resolution via acylation of a racemic alcohol with a A ei of 27. ° To expand the scope of applications of peptide catalysts to substrates lacking additional hydrogen-bond donors and acceptors, the group of Miller initiated a screening of a peptide library containing potential catalysts (resin bound. 

In addition to kinetic resolution processes, the previously described peptide-catalysed acylation reaction of alcohols can be applied to desymmetrisation of meso compounds. In 2005, Miller and coworkers published the desymmetrisation of prochiral glycerol derivatives via enantioselective acylation of one primaiy alcohol function. A (3-tum histidine-based pentapeptide was identified as the most promising catalyst from a peptide libraiy and afforded the monoacylated product with up to 97% enantiomeric excess. One year later Miller and Hansen successfully demonstrated the desymmetrisation of a meso bis-phenol compound, which was found to be challenging because of the large distance between the two OH groups as well as between the desired site of functionalisation and the prochiral stereogenic centre of the substrate. The nucleophilic N-methylhistidine containing peptide 9 was identified as a powerful tool for monoacylation via extensive libraiy... 

A practical enzymatic procedure using alcalase as biocatalyst has been developed for the synthesis of hydrophilic peptides.Alcalase is an industrial alkaline protease from Bacillus licheniformis produced by Novozymes that has been used as a detergent and for silk degumming. The major enzyme component of alcalase is the serine protease subtilisin Carlsberg, which is one of the fully characterized bacterial proteases. Alcalase has better stability and activity in polar organic solvents, such as alcohols, acetonitrile, dimethylformamide, etc., than other proteases. In addition, alcalase has wide specificity and both l- and o-amino acids that are accepted as nucleophiles at the p-1 subsite. Therefore, alcalase is a suitable biocatalyst to catalyse peptide bond formation in organic solvents under kinetic control without any racemization of the amino acids (Scheme 5.1). 

Lipase-catalysed transesterification of the racemic alcohol 67 has been used effectively to produce (5)-(+)-67 (LipaseQL, 0-5 °C, 4h 47% yield >99% ee), which was then converted to a chiral precursor required for the synthesis of the non-peptide vasopressin Vi receptor agonist, OPC-51803 [02H635]. The chiral synthesis of a 1-benzazepine-based antagonist (OPC-41061) at this receptor has also been described [02H123],... 

An improved approach to enzyme-catalysed peptide synthesis stems from a thorough understanding of the kinetics and mechanism of action of proteinases. Many proteinases function by the Ping Pong Bi Bi mechanism (Roberts, 1977) and hydrolysis of an V-protected amino acid or peptide ester involves the acylation of a Ser or Cys side-chain by the ester with the liberation of the relevant alcohol or amino component and the formation of a covalent O- or S-acylated enzyme. The latter is hydrolysed in a second step ... 

Normally, an alcoholic group such as that on serine is not a good nucleophile. However, there is usually a histidine residue close by to catalyse the reaction. For example, the mechanism by which chymotrypsin hydrolyses peptide bonds is shown in Fig. 4.20. 

Scheme 13.1 Kinetic resolution of racemic acetamido alcohols catalysed by peptides 1-3.

Scheme 13.3 Kinetic resolution of secondary alcohols catalysed by peptide 4.

Since the introduction of the first peptide organocatalyst in the 1980s, a considerable number of new peptide frameworks have been developed that are able to effectively catalyse several important transformations including alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxidation are discussed. A few successful examples of solid-supported peptides and reactions in ball milling under solvent-free conditions have been demonstrated. These methods combine the advantages of being economically and environmentally friendly processes. 

One of the most studied classes of enzymes that cleave the peptide bond is the peptidases, of which chymotrypsin is one of the best known. The nucleophile in the reaction catalysed by this enzyme is from the alcohol group on the side chain of serine-195. The reaction is base-catalysed from the adjacent side chain, histidine-57. A stable intermediate is formed due to the hydrogen bonding occurring in the cavity, known as the oxy-anion packet. The leaving-group departure occurs from an acid-catalysed reaction (Scheme 2.21). 

Apart from being specific for a particular reaction, enzjmies show varying degrees of substrate specificity. This ranges from the absolute specificity shown by urease, which has urea as its one and only substrate, to group specificity in which an enzyme will act upon a general type of substrate, e.g. alcohols, esters or peptide bonds. The lipases have a broad specificity and will act on the esters of most fatty acids, while hexokinase catalyses the phosphorylation of a variety of aldohexoses. 

Similarly, this laboratory has recently described the synthesis of constrained peptidomimetics (118, Scheme 11.14) via intramolecular palladium-catalysed cinnamylation of a variety of amino acid side chains containing heteroatom nucleophiles (117, XH = amine, imidazole, phenol, carbo y). This procedure is remarkable for its scope and efficiency, proceeding rapidly and in high yield independent of the nature of the residues and chain length of the peptide. Further, protection of guanidine, alcohol and amide side chains was not required. These and similar templates would appear to be quite suitable for library investigations. 

---