This article reports rate constants for thiol-thioester exchange (k (ex)), and for acid-mediated (k (a)), base-mediated (k (b)), and pH-independent (k (w)) hydrolysis of S-methyl thioacetate and S-phenyl 5-dimethylamino-5-oxo-thiopentanoate-model alkyl and aryl thioalkanoates, respectively-in water. Reactions such as thiol-thioester exchange or aminolysis could have generated molecular complexity on early Earth, but for thioesters to have played important roles in the origin of life, constructive reactions would have needed to compete effectively with hydrolysis under prebiotic conditions. Knowledge of the kinetics of competition between exchange and hydrolysis is also useful in the optimization of systems where exchange is used in applications such as self-assembly or reversible binding. For the alkyl thioester S-methyl thioacetate, which has been synthesized in simulated prebiotic hydrothermal vents, k (a) = 1.5 × 10(-5) M(-1) s(-1), k (b) = 1.6 × 10(-1) M(-1) s(-1), and k (w) = 3.6 × 10(-8) s(-1). At pH 7 and 23°C, the half-life for hydrolysis is 155 days. The second-order rate constant for thiol-thioester exchange between S-methyl thioacetate and 2-sulfonatoethanethiolate is k (ex) = 1.7 M(-1) s(-1). At pH 7 and 23°C, with [R″S(H)] = 1 mM, the half-life of the exchange reaction is 38 h. These results confirm that conditions (pH, temperature, pK (a) of the thiol) exist where prebiotically relevant thioesters can survive hydrolysis in water for long periods of time and rates of thiol-thioester exchange exceed those of hydrolysis by several orders of magnitude.

This paper describes a systematic study of the thermodynamics of association of bovine carbonic anhydrase II (BCA) and para-substituted benzenesulfonamides with chains of oligoglycine, oligosarcosine, and oligoethylene glycol of lengths of one to five residues. For all three of these series of ligands, the enthalpy of binding became less favorable, and the entropy less unfavorable, as the chain length of the ligands increased. The dependence on chain length of the enthalpy was almost perfectly compensated by that of the entropy; this compensation resulted in dissociation constants that were independent of chain length for the three series of ligands. Changes in heat capacity were independent of chain length for the three series and revealed that the amount of molecular surface area buried upon protein-ligand complexation did not increase with increasing chain length. Taken together, these data refute a model in which the chains of the ligands interact hydrophobically with the surface of BCA. To explain the data, a model is proposed based on decreasing "tightness" of the protein-ligand interface as the chain length of the ligand increases. This decreasing tightness, as the chain length increases, is reflected in a less favorable enthalpy (due to fewer van der Waals contacts) and a less unfavorable entropy (due to greater mobility of the chain) of binding for ligands with long chains than for those with short chains. Thus, this study demonstrates a surprising example of enthalpy/entropy compensation in a well-defined system. Understanding this compensation is integral to the rational design of high-affinity ligands for proteins.

This paper describes a calorimetric study of the association of a series of seven fluorinated benzenesulfonamide ligands (C6HnF5−nSO2NH2) with bovine carbonic anhydrase II (BCA). Quantitative structure–activity relationships between the free energy, enthalpy, and entropy of binding and pKa and log P of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two independent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different structural interactions between the ligand and BCA: the ZnII cofactor–sulfonamide bond (≈65 % of the free energy of binding), the hydrogen bonds between the ligand and BCA (≈10 %), and the contacts between the phenyl ring of the ligand and BCA (≈25 %). Calorimetry revealed that all of the ligands studied bind in a 1:1 stoichiometry with BCA; this result was confirmed by 19F NMR spectroscopy and X‐ray crystallography (for complexes with human carbonic anhydrase II).

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.

Two synthetic routes to a series of structurally novel kinase inhibitors containing a cis-1,3-disubstituted cyclobutane are described. The first route utilized addition of 3-aminocyclobutanol to 1,4-dinitroimidazole 5 as the crucial step in preparing 1, whereas the second route employed a novel 1,4-addition of 4-nitroimidazole 18 to in situ generated cyclobutenone 17 as the key reaction. This allowed for a stereoselective and shorter synthesis that eliminated the use of potentially explosive 1,4-dinitroimidazole 5. [structure: see text]