Predicting hydration propensities of biologically relevant α-ketoamides.

Quantum chemical calculations coupled to experiments were used to predict covalent hydration propensities of biologically relevant α-ketoamides. Experimentally determined hydration equilibrium constants for related ketones and aldehydes were compared to computationally determined values to develop a method for predicting hydration equilibrium constants. This method was used on six newly synthesized α-ketoamides to experimentally verify computational predictions. A correlation between calculation and experiment was observed and applied to models of several pertinent APIs. Our results indicate that the keto form is favored for practically all α-ketoamides in biological environs.

Delocalization of charge and electron density in the humulyl cation­implications for terpene biosynthesis.

The stabilizing features of a macrocyclic sesquiterpene-derived cation were explored using quantum mechanical calculations. The monocyclic humulyl cation, the product of 11,1-cyclization of farnesyl diphosphate, is the product of the first committed step in the enzymatic synthesis of a range of structurally diverse sesquiterpenes, including humulene (monocyclic); caryophyllene (bicyclic); and protoilludene, pentalenene, and isocomene (tricyclic). These natural products are formed via carbocation cascades that are directed in part by the conformation of the humulyl cation. Understanding the mechanistic details of product formation requires an understanding of the conformational preferences of this fundamental intermediate. Replacing the carbocation with borane (preserving π-accepting capabilities), ammonium (preserving positive charge), and methylene (preserving neither π-accepting capabilities nor charge) provides a systematic method to distinguish electrostatic and orbital effects on structure and internal stabilization. Several modes of internal stabilization­hyperconjugation, transannular π(alkene)···C(+) and transannular C-H···C(+) interactions­were uncovered, confirming and extending previous studies on this and similar systems.