Modular Total Syntheses of the Alkaloids Discoipyrroles A and B, Potent Inhibitors of the DDR2 Signaling Pathway

The title natural product <b>1</b> has been synthesized by treating the 1,2,3,5-tetrasubstituted pyrrole <b>23</b> with oxoperoxymolybdenum­(pyridine) (hexamethylphosphoric triamide) (MoOPH). Compound <b>23</b> was itself prepared in seven steps from parent pyrrole using Ullmann–Goldberg and Suzuki–Miyaura cross-coupling, Vilsmeier–Haack formylation, electrophilic bromination, and Wittig olefination reactions as key steps. Related chemistry has been used to prepare discoipyrrole B (<b>2</b>)

Total Synthesis of the Cyclic Carbonate-Containing Natural Product Aspergillusol B from d‑(−)-Tartaric Acid

A total synthesis of compound <b>3</b> from d-(−)-tartaric acid is reported, thereby establishing that the structure, including relative stereochemistry, originally assigned to the cyclic carbonate-containing natural product aspergillusol B is correct

A Unified Approach to the Isomeric α‑, β‑, γ‑, and δ‑Carbolines via their 6,7,8,9-Tetrahydro Counterparts

A cross-coupling/reductive cyclization protocol has been employed in a unified approach to all four carbolines. So, for example, the 2-nitropyridine <b>8</b>, which is readily prepared through an efficient palladium-catalyzed Ullmann cross-coupling reaction, is reductively cyclized under conventional conditions to give 6,7,8,9-tetrahydro-α-carboline that is itself readily aromatized to give α-carboline (<b>1</b>)

A Unified Approach to the Isomeric α‑, β‑, γ‑, and δ‑Carbolines via their 6,7,8,9-Tetrahydro Counterparts

A cross-coupling/reductive cyclization protocol has been employed in a unified approach to all four carbolines. So, for example, the 2-nitropyridine <b>8</b>, which is readily prepared through an efficient palladium-catalyzed Ullmann cross-coupling reaction, is reductively cyclized under conventional conditions to give 6,7,8,9-tetrahydro-α-carboline that is itself readily aromatized to give α-carboline (<b>1</b>)

A Total Synthesis of (±)-3‑<i>O</i>‑Demethylmacronine through Rearrangement of a Precursor Embodying the Haemanthidine Alkaloid Framework

A total synthesis of the racemic modification, (±)-<b>2</b>, of the tazettine-type alkaloid 3-<i>O</i>-demethyl­macronine is described. The key steps are an intramolecular Alder-ene (IMAE) reaction and a lactam-to-lactone rearrangement of tetracycle <b>13</b>, a compound that embodies the haemanthidine alkaloid framework

A Unified Approach to the Isomeric α‑, β‑, γ‑, and δ‑Carbolines via their 6,7,8,9-Tetrahydro Counterparts

A cross-coupling/reductive cyclization protocol has been employed in a unified approach to all four carbolines. So, for example, the 2-nitropyridine <b>8</b>, which is readily prepared through an efficient palladium-catalyzed Ullmann cross-coupling reaction, is reductively cyclized under conventional conditions to give 6,7,8,9-tetrahydro-α-carboline that is itself readily aromatized to give α-carboline (<b>1</b>)

A Unified Approach to the Isomeric α‑, β‑, γ‑, and δ‑Carbolines via their 6,7,8,9-Tetrahydro Counterparts

A cross-coupling/reductive cyclization protocol has been employed in a unified approach to all four carbolines. So, for example, the 2-nitropyridine <b>8</b>, which is readily prepared through an efficient palladium-catalyzed Ullmann cross-coupling reaction, is reductively cyclized under conventional conditions to give 6,7,8,9-tetrahydro-α-carboline that is itself readily aromatized to give α-carboline (<b>1</b>)

A Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Route to the Carbazole Natural Products 3‑Methyl‑9<i>H</i>‑carbazole, Glycoborine, Glycozoline, Clauszoline K, Mukonine, and Karapinchamine A

The title natural products <b>2</b>–<b>7</b> have been prepared by reductive cyclization of the relevant 2-arylcyclohex-2-en-1-one (e.g. <b>20</b>) to the corresponding tetrahydrocarbazole and dehydrogenation (aromatization) of this to give the target carbazole (e.g. <b>4</b>). Compounds such as <b>20</b> were prepared using a palladium-catalyzed Ullmann cross-coupling reaction between the appropriate 2-iodocyclohex-2-en-1-one and <i>o</i>-halonitrobenzene

Studies on the Photochemical Rearrangements of Enantiomerically Pure, Polysubstituted, and Variously Annulated Bicyclo[2.2.2]octenones

A series of enantiomerically pure bicyclo[2.2.2]­octenones, including the lactone-annulated system <b>26</b>, has been prepared by engaging derivatives of an enzymatically derived and homochiral <i>cis</i>-1,2-dihydrocatechol in inter- or intra-molecular Diels–Alder reactions. Systems such as <b>26</b> readily participate in photochemically promoted oxa-di-π-methane rearrangement or 1,3-acyl migration processes to give products such as diquinane <b>34</b> or mixtures of cyclobutanone <b>36</b> and cyclopropane <b>38</b>, respectively

Structure of an Insecticide Sequestering Carboxylesterase from the Disease Vector <i>Culex quinquefasciatus:</i> What Makes an Enzyme a Good Insecticide Sponge?

Carboxylesterase (CBE)-mediated metabolic resistance to organophosphate and carbamate insecticides is a major problem for the control of insect disease vectors, such as the mosquito. The most common mechanism involves overexpression of CBEs that bind to the insecticide with high affinity, thereby sequestering them before they can interact with their target. However, the absence of any structure for an insecticide-sequestering CBE limits our understanding of the molecular basis for this process. We present the first structure of a CBE involved in sequestration, Cqestβ2¹, from the mosquito disease vector <i>Culex quinquefasciatus</i>. Lysine methylation was used to obtain the crystal structure of Cqestβ2¹, which adopts a canonical α/β-hydrolase fold that has high similarity to the target of organophosphate and carbamate insecticides, acetylcholinesterase. Sequence similarity networks of the insect carboxyl/cholinesterase family demonstrate that CBEs associated with metabolic insecticide resistance across many species share a level of similarity that distinguishes them from a variety of other classes. This is further emphasized by the structural similarities and differences in the binding pocket and active site residues of Cqestβ2¹ and other insect carboxyl/cholinesterases. Stopped-flow and steady-state inhibition studies support a major role for Cqestβ2¹ in organophosphate resistance and a minor role in carbamate resistance. Comparison with another isoform associated with insecticide resistance, Cqestβ1, showed both enzymes have similar affinity to insecticides, despite 16 amino acid differences between the two proteins. This provides a molecular understanding of pesticide sequestration by insect CBEs and could facilitate the design of CBE-specific inhibitors to circumvent this resistance mechanism in the future