Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones.

Herein, we report the palladium-catalyzed decarboxylative asymmetric allylic alkylation of α-enaminones. In addition to serving as valuable synthetic building blocks, we exploit the α-enaminone scaffold and its derivatives as probes to highlight structural and electronic factors that govern enantioselectivity in this asymmetric alkylation reaction. Utilizing the (S)-t-BuPHOX ligand in a variety of nonpolar solvents, the alkylated products are obtained in up to 99% yield and 99% enantiomeric excess.

Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates.

We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and -retentive preparation of allyloxycarbonyl-trapped fully substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand.

Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase.

Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs-from a library of 183 derivatives-that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC50s of 47-170 nM) but do not alter the enzyme's ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.

Enantioconvergent catalysis.

An enantioconvergent catalytic process has the potential to convert a racemic starting material to a single highly enantioenriched product with a maximum yield of 100%. Three mechanistically distinct approaches to effecting enantioconvergent catalysis are identified, and recent examples of each are highlighted. These processes are compared to related, non-enantioconvergent methods.

Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ.

The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross-species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3.

Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology.

Antibiotics targeting DNA gyrase have been a clinical success story for the past half-century, and the emergence of bacterial resistance has fueled the search for new gyrase inhibitors. In this paper we demonstrate that a new class of gyrase inhibitors, the gyramides, are bacteriostatic agents that competitively inhibit the ATPase activity of Escherichia coli gyrase and produce supercoiled DNA in vivo. E. coli cells treated with gyramide A have abnormally localized, condensed chromosomes that blocks DNA replication and interrupts chromosome segregation. The resulting alterations in DNA topology inhibit cell division through a mechanism that involves the SOS pathway. Importantly, gyramide A is a specific inhibitor of gyrase and does not inhibit the closely related E. coli enzyme topoisomerase IV. E. coli mutants with reduced susceptibility to gyramide A do not display cross-resistance to ciprofloxacin and novobiocin. The results demonstrate that the gyramides prevent bacterial growth by a mechanism in which the topological state of chromosomes is altered and halts DNA replication and segregation. The specificity and activity of the gyramides for inhibiting gyrase makes these compounds important chemical tools for studying the mechanism of gyrase and the connection between DNA topology and bacterial cell division.

Enantioselective synthesis of isotopically labeled homocitric acid lactone.

A concise synthesis of homocitric acid lactone was developed to accommodate systematic placement of carbon isotopes (specifically (13)C) for detailed studies of this cofactor. This new route uses a chiral allylic alcohol, available in multigram quantities from enzymatic resolution, as a starting material, which transposes asymmetry through an Ireland-Claisen rearrangement.

Catalytic Alkene Cyclization Reactions for the Stereoselective Synthesis of Complex "Terpenoid-like" Heterocycles.

A new catalytic synthesis of densely-substituted tetrahydroquinolines is described. This reaction forms up to two rings, three bonds, and three stereogenic centers with excellent stereo- and regiocontrol in a single step. Although control experiments demonstrate that the active catalyst is protic acid, Sc(OTf)3 serves as an effective and practical pre-catalyst. The scope of this reaction is demonstrated with 21 monocyclizations and 14 bicyclization reactions.

The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives of Totarol.

The synthesis and antimicrobial activity heterocyclic analogs of the diterpenoid totarol are described. An advanced synthetic intermediate with a ketone on the A-ring is used to attach fused heterocycles and a carbon-to-nitrogen atom replacement is made on the B-ring by de novo synthesis. A-ring analogs with an indole attached exhibit, for the first time, enhanced antimicrobial activity relative to the parent natural product. Preliminary experiments demonstrate that the indole analogs do not target the bacterial cell division protein FtsZ as had been hypothesized for totarol.

Comparison of small molecule inhibitors of the bacterial cell division protein FtsZ and identification of a reliable cross-species inhibitor.

FtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin's function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross-comparison of reported FtsZ inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two side chains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively, these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.