An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
The synthesis of isokidamycin, which represents the first total synthesis of a bis-C-aryl glycoside natural product in the pluramycin family, has been completed. The synthesis features the use of a silicon tether as a disposable regiocontrol element in an intramolecular Diels−Alder reaction between a substituted naphthyne and a glycosyl furan and a subsequent O→C-glycoside rearrangement.
Silicon tethers were employed to control the regiochemistry of Diels−Alder reactions between substituted benzynes and glycosyl furans as a key step in the syntheses of unsymmetrical representatives of three major groups of C-aryl glycosides. The cycloaddition precursors were readily prepared by O-alkylation of substituted phenols with various sugar-substituted furylsilane derivatives. Selective deprotonation on the benzene ring of these ethers led to a benzyne that underwent an intramolecular Diels−Alder reaction to give bridged cycloadducts. Fluoride-induced removal of the silicon tether and acid-catalyzed ring opening of the oxabicycloheptadiene subunit yielded the desired C-aryl glycosides as single isomers.
The significance of the proposed PSM changes could be to greatly expand coverage of processes in order to include many not currently covered by the PSM regulation. New chemicals will likely be added to Appendix A, and reactive chemicals (a definition will be needed) also may be covered. What exactly will be the definition of a reactive chemical is unclear at this time, although definitions used in New Jersey in the TCPA Act may guide OSHA. It is likely that atmospheric storage of flammable liquids will be included more specifically and the exemption of these tanks eliminated. In applying RAGAGEP, sites may be required to apply the most recent codes and standards to covered processes, perhaps at the time of PHA auditing: A narrowing of the PSM exemption for retail facilities could bring many of them under the PSM regulation at some level. Process safety management practices should be applied to all facilities that store and process hazardous materials that have fire, explosion, reactivity, and toxic properties. If changes are made to the PSM regulation, many new sites will be covered and will need to formally adopt PSM as defined in the OSHA regulation. The addition of reactive chemicals to the PSM regulation will greatly expand the number of processes covered by the regulation. Keeping up with the most current codes, standards, and legislative changes is a daunting task that may require the support of specialists. The results of the proposed legislation will be an increase in the level of process safety excellence throughout the chemical industries.
Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.
A formal, enantioselective synthesis of the antitumor antibiotic (+)−FR900482 (1) has been completed using an approach that featured the ring-closing metathesis of the diene 37 to give the key intermediate benzazocine 38. Although several initial protecting-group strategies unexpectedly failed at various stages of the endeavor, the successful approach to 1 involved the conversion of commercially available 5-nitrovanillin (10) into the prochiral diol 24. The manipulations of the residues on the aromatic ring of 10 were straightforward, and the diol array in 24 was introduced by the hydride reduction of the malonate 23, which was in turn prepared by a nucleophilic substitution of the triflate 12. Adjustment of alcohol-protecting groups to give 27 and refunctionalization of the aromatic nitro group led to the protected N-allylamine 36. Elaboration of the diol array via a highly stereoselective Grignard addition furnished the diene 37. Ring-closing metathesis of 37 using the Grubbs catalyst 34 cleanly afforded the benzazocine 38. A tactic originally conceived for preparing 42 by introduction of the aziridine ring onto 38 was impractical because the iodo cyclization of the allylic tosylcarbamate 39 was neither efficient nor selective to give 40. Hence, 38 was transformed into 49, which was a key intermediate in Fukuyama's elegant synthesis of racemic FR900482, thereby completing a formal synthesis of the alkaloid. The prochiral diol 24 was enzymatically desymmetrized using Pseudomonas species lipase to give 25 in 94% enantiomeric excess. Inasmuch as subsequent adjustment of the alcohol-protecting groups gave the intermediate 26 (cf the racemic analogue 27) in enantiomerically pure form, an enantioselective synthesis of (+)−FR900482 has also been completed in a formal sense.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)