The results are reported of a study of catalysis and chiral recognition by designed complexation of transition states in transacylations of amino ester salts. Four chiral hosts were prepared, (S)-and (R)-(HSM)2D(OEOEO)2E (1), (S)-(HSM)2-D(OEOEOCH3)2 (2), (R)(S)-(HSPhOM)2D(OEOEO)2E (5), and (R)(5,)-(HSPhOM)2D(OEOEOCH3)2 (6), in which M is CH2, E is CH2CH2, and D is 1, 1 ʹ-dinaphthyl substituted in its 2, 2ʹ positions by O's and in its 3, 3ʹ positions by Mʹs, and Ph is ortho-substituted phenyl. The pseudo-first-order kinetics were studied for acylation of large excesses of these hosts by the p-nitrobenzoate ester salts of glycine, L-alanine, L-leucine, L-valine, L-proline, and L-and D-phenylalanine. Solvents buffered to pH (referred to water) of 4.3 to 7.0 ranged from 40% H2O-CH3CN (v) to 20% EtOH-CH2Cl2 to 20% MeOH-CHC13 to 0.2% H2O-3% CH3CN-CHCl3 to 0.04% EtOH-3% CH3CN-CHCl3. The rates of appearance of p-nitrophenol were followed by UV spectroscopy at 25 °C. Evidence was obtained that the active nucleophile was RS-. Cycles such as 1 and 5 were strong complexers of monoalkylammonium salts, and noncycles such as 2 and 6 were not. Therefore, kcycle/k noncycle values were used to determine the effect of highly ordered complexation on reaction rates in 20% EtOH-CH2Cl2. Since proline is a secondary amine, its ester salt did not give highly ordered complexes, and as a result 1 and 2 gave kcycle/knoncycle = 0.8. The ester salt of glycine and the L-ester salts of alanine, valine, phenylalanine, and leucine gave ACycieAnoncycie values derived from (S)-1 and (S)-2 of >130, ⪞130, 160, 490, and >1170, respectively. The ester salt of glycine gave a kcycle/knoncycle value of >230 with (R)(S)-5 and (R)(S)-6. The rate enhancements are attributed to transition-state stabilization by complexation. In 20% EtOH in CHC13, k for L-phenylalanine ester salt reacting with (Sʹ)-1 was 560 times k that was observed for the same reaction run in the presence of K+ ion at concentrations [K+]/[RNH3] ~120. Thus K+ acted as a competitive and dominant binder of 1, and eliminated the acceleration caused by structured complexation. The effect of solvent on kCycle/ knoncycle values was determined for the reaction of L-phenylalanine ester salt with (S)-(HSM)2D(OEOEO)2E and (S)-(HSM)2D(OEOEOCH3)2. These values decreased as the solvent became more hydroxylic as follows: 1600, 0.04% EtOH-3% CH3CN-CHCI3; 960, 20% MeOH-CHC13; 490, 20% EtOH-CHCl3; 8.2, 40% H20-CH3CN (v). The hydroxylic solvents appear to be weak competitive inhibitors of complexation, and therefore are rate inhibiting. Comparison in 20% Et0H-CH2Cl2 of the kʹs for reaction of (R)-(HSM)2-D(OEOEO)2E with L-RCH(NH3)CO2Ar normalized to ester salt with R = (CH3)2CH gave the following rate factors for the various R groups: CH3, 290; (CH3)2CHCH2, 46; C6H5CH2, 17; (CH3)2CH, 1. Thus the reaction rates decreased with increasing steric requirements of the R groups at their points of attachment to the ester salts, and the thiol host showed high structural recognition in reacting with the various guests. In 20% EtOH-CH2Cl2, the k values for the reactions of (S)- and (tf)-(HSCH2)2D(OEOEO)2E with L-RCH(NH3+)CO2Ar were determined. Values of (k)s.L/(k)R.L (rate constants for formation of diastereomeric thiol ester products) correlated with the nature of the R groups of the amino ester salts as follows: CH3, 1; (CH3)2CHCH2, 6.4; C6H5CH2, 8.2; (CH3)2CH, 9.2. Both the direction of the chiral bias and the relative values of these chiral recognition factors for complexation in the rate-limiting transition states correlate with expectations based on Corey-Pauling-Koltun molecular models of the diastereomeric ortho intermediates for the transacylation. Similarities and differences are noted between the transacylation reactions of this study and those catalyzed by enzyme systems. © 1979, American Chemical Society. All rights reserved.
