Enzyme mimics: acyl transfers

Acyl transfer processes are of immense strategic and synthetic importance in synthesis and biology. In Fignre 12, the ability of peptidases snch as chymotrypsin to cleave amide bonds using a nncleophilic serine-195 residne to generate an activated acyl-enzyme intermediate was described. Numerous supramolecular structures have been designed that mimic these natural enzymatic acyl transfer processes, such as Lehn s crown ether/ammonium ion complexation... 

There have been numerous synthetic supramolecular structures created to mimic the various aspects of the natural enzymes that catalyze acyl transfers. Here, we only show two with their respective binding geometries and electron pushing for the nucleophilic attack. The first shown below was developed by Lehn, and uses the well precedented binding between crown ethers and ammonium ions to form a complex between the catalyst and the substrate. The second example was developed by Bres-low, where cyclodextrin (the toroid see Chapter 4) is used to drive hydrophobic binding of the substrate to the catalyst. These two examples do indeed catalyze their respective acyl transfers, but with orders of magnitude lower... 

Enzymatic Acyl Transfers I The Catalytic Triad 604 Enzymatic Acyl Transfers II Zn(II) Catalysis 605 Enzyme Mimics for Acyl Transfers 606 Peptide Synthesis—Optimizing Acyl Transfer 606... 

We saw in Section 12.3.1 the use of the cyclodextrins as mimics for transacylases, a well-understood class of enzymes that perform the task of transferring an acyl group from one substrate to another (e.g. from an ester to water). Transacylase chemistry has also been addressed by Cram,5 who used chiral corands, such as 12.11, related to 3.106 bearing thiolate nucleophiles situated above and below the plane of the macrocycle. An acyclic analogue 12.12 was also prepared for comparison. The salient features of 12.11 are shown diagrammatically in Figure 12.4. 

Cram s group, like that of Lehn, is attempting to imitate enzyme catalysis via kinetic acceleration through host-guest complexation. A series of transacylase mimics have been synthesized [44] which contain the complexing site, the proton transfer catalyst and the nucleophile found in the chymotrypsin active site. Relatively rapid rates of acylation were observed. It is obvious, however, that additional information will have to be acquired and more model compounds synthesized before the mode of action of an enzyme such as chymotrypsin can be clarified. 

The transfer of acyl groups is commonly encountered in biology, and catalyzed by the acyltransferase family of enzymes. For example, acetylcholinesterase hydrolase hydrolyzes excess acetylcholine after nerve impulses. Many chemical models built to mimic the enzymatic function of acyltransferases have been developed, classically employing cyclodextrins which form hydrophobic complexation intermediates. ... 

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