J. Craig Ruble

Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors

ABSTRACT QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (−)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst; application to natural product synthesis

A planar-chiral DMAP derivative is shown to serve as an effective catalyst for the kinetic resolution of allylic alcohols; to illustrate its practical utility, the catalyst is applied to the resolution of two alcohols that have been employed as intermediates in recent natural product total syntheses.

Additives promote Noyori-type reductions of a β-keto-γ-lactam: asymmetric syntheses of serotonin norepinephrine reuptake inhibitors.

Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.

A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald–Hartwig Amination

Transition-metal catalysis has revolutionized organic synthesis, but difficulties can often be encountered when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery collections that are enriched in substances possessing less desirable properties (high lipophilicity, low polar surface area). Masking groups are often employed to circumvent this problem, which is in opposition to the inherent ideality of these methods for green chemistry and atom economy. A general screening methodology, related to robustness screening described by Glorius et al., builds a broad understanding of the impact of individual functional groups on the success of a transformation under various conditions and provides a simple framework for identifying new conditions that tolerate challenging functional groups. Application of this approach to profile the conditions for the Buchwald-Hartwig amination and rapidly identify bespoke conditions for challenging substrate classes is described.