Stereoselective Synthesis of Acortatarins A and B

Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol side chain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde side chain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A

Solvent-Dependent Divergent Functions of Sc(OTf)₃ in Stereoselective Epoxide-Opening Spiroketalizations

A stereocontrolled synthesis of benzannulated spiroketals has been developed using solvent-dependent Sc­(OTf)₃-mediated spirocyclizations of <i>exo</i>-glycal epoxides having alcohol side chains. In THF, the reaction proceeds via Lewis acid catalysis under kinetic control with inversion of configuration at the anomeric carbon. In contrast, in CH₂Cl₂, Brønsted acid catalysis under thermodynamic control leads to retention of configuration. The reactions accommodate a variety of aryl substituents and ring sizes and provide stereochemically diverse spiroketals

Stereoselective Synthesis of Acortatarins A and B

Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol side chain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde side chain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A

General Platform for Systematic Quantitative Evaluation of Small-Molecule Permeability in Bacteria

The chemical features that impact small-molecule permeability across bacterial membranes are poorly understood, and the resulting lack of tools to predict permeability presents a major obstacle to the discovery and development of novel antibiotics. Antibacterials are known to have vastly different structural and physicochemical properties compared to nonantiinfective drugs, as illustrated herein by principal component analysis (PCA). To understand how these properties influence bacterial permeability, we have developed a systematic approach to evaluate the penetration of diverse compounds into bacteria with distinct cellular envelopes. Intracellular compound accumulation is quantitated using LC-MS/MS, then PCA and Pearson pairwise correlations are used to identify structural and physicochemical parameters that correlate with accumulation. An initial study using 10 sulfonyladenosines in <i>Escherichia coli</i>, <i>Bacillus subtilis</i>, and <i>Mycobacterium smegmatis</i> has identified nonobvious correlations between chemical structure and permeability that differ among the various bacteria. Effects of cotreatment with efflux pump inhibitors were also investigated. This sets the stage for use of this platform in larger prospective analyses of diverse chemotypes to identify global relationships between chemical structure and bacterial permeability that would enable the development of predictive tools to accelerate antibiotic drug discovery

Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization–Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding

Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl₂/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-<i>exo</i> Markovnikov regioselectivity. Mechanistic and computational studies support an <i>anti</i>-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization

Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics

A stereoselective synthesis has been developed to provide all four side-chain stereoisomers of difluoroindanediol <b>2</b>, the mixture of which was previously identified as an inhibitor of the <i>o</i>-succinylbenzoate-CoA synthetase MenE in bacterial menaquinone biosynthesis, having promising in vitro activity against methicillin-resistant <i>Staphylococcus aureus</i> and <i>Mycobacterium tuberculosis</i>. Only the (1<i>R</i>,3<i>S</i>)-diastereomer inhibited the biochemical activity of MenE, consistent with computational docking studies, and this diastereomer also exhibited in vitro antibacterial activity comparable to that of the mixture. However, mechanism-of-action studies suggest that this inhibitor and its diastereomers may act via other mechanisms beyond inhibition of menaquinone biosynthesis

Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics

A stereoselective synthesis has been developed to provide all four side-chain stereoisomers of difluoroindanediol <b>2</b>, the mixture of which was previously identified as an inhibitor of the <i>o</i>-succinylbenzoate-CoA synthetase MenE in bacterial menaquinone biosynthesis, having promising in vitro activity against methicillin-resistant <i>Staphylococcus aureus</i> and <i>Mycobacterium tuberculosis</i>. Only the (1<i>R</i>,3<i>S</i>)-diastereomer inhibited the biochemical activity of MenE, consistent with computational docking studies, and this diastereomer also exhibited in vitro antibacterial activity comparable to that of the mixture. However, mechanism-of-action studies suggest that this inhibitor and its diastereomers may act via other mechanisms beyond inhibition of menaquinone biosynthesis

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene <b>10</b> and cyclopentadiene <b>11</b>. A second Diels–Alder reaction features the first use of an azepinone dienophile (<b>8</b>), with high diastereofacial selectivity achieved via rational design of siloxydiene component <b>36</b> with a sterically demanding bromine substituent. Subsequent Mannich-type <i>N</i>-acyl­iminium and radical cyclizations provide complete hexacyclic skeleton <b>33</b> of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate <b>45</b> and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene <b>10</b> and cyclopentadiene <b>11</b>. A second Diels–Alder reaction features the first use of an azepinone dienophile (<b>8</b>), with high diastereofacial selectivity achieved via rational design of siloxydiene component <b>36</b> with a sterically demanding bromine substituent. Subsequent Mannich-type <i>N</i>-acyl­iminium and radical cyclizations provide complete hexacyclic skeleton <b>33</b> of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate <b>45</b> and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene <b>10</b> and cyclopentadiene <b>11</b>. A second Diels–Alder reaction features the first use of an azepinone dienophile (<b>8</b>), with high diastereofacial selectivity achieved via rational design of siloxydiene component <b>36</b> with a sterically demanding bromine substituent. Subsequent Mannich-type <i>N</i>-acyl­iminium and radical cyclizations provide complete hexacyclic skeleton <b>33</b> of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate <b>45</b> and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures