Total Syntheses of Clausenawallines A and E.

The first total syntheses of glycoborinine, clausenawalline A, and clausenawalline E were achieved. The key step employed a vanadium-catalyzed oxidative coupling of two hydroxycarbazole monomers. High-throughput experimentation was used to identify conditions favoring selective heterocoupling of these monomers that possess similar redox potentials. A combination of a vanadium catalyst and 4-acetamido-TEMPO gives rise to greatly enhanced cross selectivity relative to the vanadium catalyst alone. Conditions to selectively form homodimer clausenawalline A or heterodimer clausenawalline E as the major product were found.

Quantification of Hydrogen-Bond-Donating Ability of Biologically Relevant Compounds.

Hydrogen bonding is a key factor in the design of ligands for biological binding, including drug targets. Our group previously developed a method for experimentally assessing the hydrogen-bond-donating ability of an analyte using UV-vis titrations with a colorimetric sensor. Using this method, 79 new titrations were performed on weak hydrogen-bond donors, with a focus on heterocycles and pharmaceutically relevant motifs. The hydrogen-bond donating abilities of drug compounds and the substructures of drug compounds were also measured. These titrations will be used to build a database of hydrogen-bond donors.

Hydrogen Bonding Parameters by Rapid Colorimetric Assessment: Evaluation of Structural Components Found in Biological Ligands and Organocatalysts.

Hydrogen bonding is a key molecular interaction in biological processes, drug delivery, and catalysis. This report describes a high throughput UV-Vis spectroscopic method to measure hydrogen bonding capacity using a pyrazinone sensor. This colormetric sensor reversibly binds to a hydrogen bond donor, resulting in a blue shift as additional equivalents of donor are added. Titration with excess equivalents of donor is used to determine the binding coefficient, ln(Keq ). Over 100 titrations were performed for a variety of biologically relevant compounds. This data enabled development a multiple linear regression model that is capable of predicting 95 % of ln(Keq ) values within 1 unit, allowing for the estimation of hydrogen bonding affinity from a single measurement. To show the effectiveness of the single point measurements, hydrogen bond strengths were obtained for a set of carboxylic acid bioisosteres. The values from the single point measurements were validated with full titrations.

Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N, N-Dimethylacetamide.

Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with ß,ß-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized ß-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.