Maria Angelica Linton

Effect of water solvation on the lipophilicity of isomeric pyrimidine-carboxamides.

Incorporation of nitrogen is a common medicinal chemistry tactic to reduce logD values. Neighboring group participation influences logD, so the results are isomer dependent. The logD and logP differences observed between isomeric pyrimidines 1, 2 and 3 presumably result when the carbonyl or ether lone pairs are in close proximity to a heterocyclic nitrogen lone pair, recruiting water to bridge between the electron rich atoms. Various lipophilicity calculators did not discriminate between 1 (logD=2.6) and 3 (logD=1.0), but solvation energies using Poisson-Boltzmann and 3D-RISM methods rationalize the observed differences in lipophilicity among pyrimidine carboxamide isomers.

Reductive Condensation between β-KetoEsters and Aldehydes: Preparation of Novel Carbon-Linked DihydropyroneInhibitors of Hepatitis C Virus Polymerase

The route for the preparation of carbon-linked pyrone libraries involving an optimized one-step reductive condensation between active methylene compounds and aldehydes is described. The initial synthesis ofthese analogues utilizing conventional alkylation methods proved to be unsuitable for singleton or library application. The chemistry was not only low-yielding but presented serious purification challenges. The optimized route reported herein utilizes a Lewis base-borane complex that acts in situ first as a catalyst for the condensation, then as a mild reducing agent to cleanly yield the desired product in a one-pot reaction.