We propose the synthesis of highly substituted crown ether compound 1, to be used as a mimic of the sulfhydryl proteases (or acyl transferases) such as papain. The compound was designed with the help of Corey-Pauling-Koultun (CPK) models to efficiently bind alpha-amino acid ester hydrobromides, and enhance the solvolysis of these. The crown ether bears six substituents (two CH2OCH2CH2SH groups; two hydroxymethyls; two methyls) attached to six chiral carbons of known absolute configuration. Four of the substituents are functional: the CH2OCH2CH2SH groups bear the nucleophilic sulfur atom to attack the carbonyl of bound substrate; the hydroxymethyls are so placed to provide hydrogen bonding possibilities with the presumed transition states leading to the tetrahedral intermediates. All six substituents assist in making the uncomplexed crown ring less conformationally mobile than less substituted crowns, perhaps providing a degree of preorganization to 1.
The aims of this proposal are to prepare 1 and assess its ability to mimic the sulfhydryl proteases (or at least acyl transferases). Several less substituted crown ethers (2-4) related to 1 will also be synthesized. These are necessary to help determine the contribution(s) which the various side chains in 1 make in the efficacy of this compound as an enzyme mimic. A comparison of the rates of solvolysis of alpha-amino acid RHO- nitrophenyl ester hydrobromides in the presence of each of the crowns 1-5 will be done. The new synthetic methodology developed as a consequent of this project will allow for the future elaboration of more precise enzyme mimics and the consequent better understanding of the nature of enzyme - substrate interactions.
