Oxyanion hole mimics

Several research groups have studied the function of oxyanion holes by generating small-molecule mimics of the key components. In the following discussion, selected examples of oxyanion hole mimics are discussed. 

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Scheme 4.12 Oxyanion hole mimics developed by Zhu and Drueckhammer [94],...

Kim, Chin, and co-workers have described a highly interesting oxyanion hole mimic that transforms L-amino acids to D-amino acids [97]. The mechanism involves stabilization of the enolate intermediate by an internal hydrogen bond array generated by urea group (Scheme 4.14). In the presence of an external base, such as triethylamine, the receptors readily promote the epimerization of a-amino acids, favoring the D-amino acids due to unfavorable steric interactions in the receptor-L-amino acid complex. These receptors can also be viewed as chiral mimics of pyridoxal phosphate [98]. 

Mimics of Enzymatic Oxyanion Holes and Similar Systems... 

In 1989, Rebek and co-workers reported a simple system based on Kemp s triacid that served as a mimic of an enolizing enzyme [86]. This early mimic, however, had the enolizing substrate covalently attached to the triacid skeleton. In addition, the mimic did not possess any oxyanion hole functionalities. However, 2 years later the Rebek group reported a true enolizing catalyst that hosted a carboxylic acid as the oxyanion hole component (Scheme 4.8) [87]. The rate of enolization of the quinuclidone substrate was enhanced by a factor of 10 in the presence of 2.5 mM of the receptor (R = n-Pr). 

Phosphonates (Fig. 8) and sulfonates represent a third class of covalent irreversible inhibitors. These inhibitors adopt a stable tetrahedral geometry and are covalently bound transition-state analogs. They often have a peptide-like specificity element, and the electrophilicity of the leaving groups can be modified to mne the reactivity of the inhibitor. These inhibitors are specific for serine proteases, because the serine protease active site has a well-defined oxyanion hole, which stabilizes the transition-state mimic. 

For a comprehensive review of oxyanion holes in catalysis, see Pihko P, Raptikko S, Wierenga RK (2009) Oxyanion Holes and Their Mimics In Pihko PM (ed) Hydrogen Bonding in Oiganic Synthesis, Wiley-VCH, Weinherm, Germany p 43... 

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