Hydrolytic cleavage of p-nitrophenyl esters of N-protected amino acids in the presence of cyclodextrins : transition state stabilization

• Main Author: Loncke, Paul G
• Format: Others
• Published: 1998
• Online Access: http://spectrum.library.concordia.ca/424/1/MQ39956.pdf; Loncke, Paul G <http://spectrum.library.concordia.ca/view/creators/Loncke=3APaul_G=3A=3A.html> (1998) Hydrolytic cleavage of p-nitrophenyl esters of N-protected amino acids in the presence of cyclodextrins : transition state stabilization. Masters thesis, Concordia University.

The kinetics of cleavage of p-nitrophenyl esters of N-tert-butyloxycarbonyl amino acids (BOC-Esters) and N-benzyloxycarbonyl amino acids (CBZ-Esters) in basic solution containing $\alpha$-cyclodextrin, $\beta$-cyclodextrin, or $\gamma$-cyclodextrin, ($\alpha$-CD, $\beta$-CD, or $\gamma$-CD) were studied. Most of the cleavage reactions occur through conventional 1:1 (ester:CD) complexes. In some cases, a second cleavage process involving two CD molecules is evident. Also, an additional process involving the formation of non-productive 1:2 complexes is apparent in two cases. In order to determine the dominant mode of binding for the esters in the 1:1 complexes, variations in the kinetic parameters with structure were examined, along with circular dichroism studies. Also, the extent to which the three stabilize the transition states of the normal ester cleavage reactions was estimated, and used to probe the structures of the transition state complexes. Cleavage of the p-nitrophenyl esters of BOC-Asn, CBZ-Asn, BOC-Gln, and CBZ-Gln in basic aqueous solution involves intramolecular nucleophilic attack by ionized internal amide groups. In the presence of CDs, moderate rate enhancements were observed in most cases due to reaction within 1:1 complexes. However, cleavage of BOC-Asn and CBZ-Asn in the presence of $\beta$-CD is initially retarded due to the formation of very stable non-productive 1:1 complexes, and then enhanced due either to reaction between the non-productive 1:1 complexes and unbound CD molecules, or to reaction within weak productive 1:2 complexes. Finally, modest enantioselectivity was observed for cleavage of pairs of p-nitrophenyl esters of N-protected amino acid enantiomers in the presence of CDs. Similar results were seen for cleavage of a pair of N-hydroxysuccinimide esters of BOC-Pro enantiomers. The selectivity observed was shown to be almost entirely due to stronger transition state binding of the L-ester