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1.
Molecules ; 27(19)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36234688

RESUMO

The NIS synthetase family of enzymes responsible for the biosynthesis of siderophores is increasingly associated with bacterial virulence. Proteins in this class represent outstanding potential drug targets, assuming that basic biochemical and structural characterizations can be completed. Towards this goal, we have mated an improved synthesis of the non-commercial amino acid N-hydroxy-N-succinylcadaverine (HSC, 6) with an isothermal titration calorimetry (ITC) assay that profiles the iterative stages of HSC trimerization and macrocyclization by NIS synthetase DesD from Streptomyces coelicolor. HSC synthesis begins with multigram-scale Gabrielle and tert-butyl N-(benzyloxy)carbamate alkylations of 1-bromo-5-chloropentane following prior literature, but the end-game reported herein has two advantages for greater material throughput: (1) hydrogenolysis of benzyl ether and Cbz blocking groups is best accomplished with Pearlman's catalyst at 40 psi of H2 and (2) purification of neutral (zwitterionic) HSC is effected by simple flash chromatography over silica gel in MeOH. HSC is subsequently shown to be a substrate for NIS synthetase DesD, which catalyzes three successive amide bond syntheses via adenyl monophosphate ester intermediates. We quantify and present the iterative and overall enzyme kinetic constants associated with formation of the cyclotrimeric siderophore desferrioxamine E (dfoE, 1).


Assuntos
Produtos Biológicos , Sideróforos , Amidas , Aminoácidos , Carbamatos , Ésteres , Éteres , Ácidos Hidroxâmicos , Lactamas , Ligases , Sideróforos/química , Sílica Gel
2.
ACS Omega ; 5(1): 537-546, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31956800

RESUMO

A simple and convergent way to synthesize 2-amino-6-bromonaphthalenes involves condensation of free secondary amines with the corresponding 2-naphthol under Bucherer conditions. The amination protocol relies on common Teflon-capped pressure flasks and has been used to modify the tertiary aminonaphthalene core of DANPY, a biocompatible chromophore shown to be safe and effective for staining a variety of cellular targets. Following a Suzuki reaction with pyridine 4-boronic acid, additional diversity is introduced upon N-alkylation to install the pyridinium cation. New DANPY derivatives and intermediates reported herein reflect the modularity of the dye nucleus, including the addition of groups useful for applications in membrane staining and DNA-based biophotonics.

3.
Org Biomol Chem ; 17(15): 3765-3780, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30887974

RESUMO

Dyes with nonlinear optical (NLO) properties enable new imaging techniques and photonic systems. We have developed a dye (DANPY-1) for photonics applications in biological substrates such as nucleic acids; however, the design specification also enables it to be used for visualizing biomolecules. It is a prototype dye demonstrating a water-soluble, NLO-active fluorophore with high photostability, a large Stokes shift, and a favorable toxicity profile. A practical and scalable synthetic route to DANPY salts has been optimized featuring: (1) convergent Pd-catalyzed Suzuki coupling with pyridine 4-boronic acid, (2) site-selective pyridyl N-methylation, and (3) direct recovery of crystalline intermediates without chromatography. We characterize the optical properties, biocompatibility, and biological staining behavior of DANPY-1. In addition to stability and solubility across a range of polar media, the DANPY-1 chromophore shows a first hyperpolarizability similar to common NLO dyes such as Disperse Red 1 and DAST, a large two-photon absorption cross section for its size, substantial affinity to nucleic acids in vitro, an ability to stain a variety of cellular components, and strong sensitivity of its fluorescence properties to its dielectric environment.


Assuntos
Materiais Biocompatíveis/química , Corantes Fluorescentes/química , Naftalenos/química , Fármacos Fotossensibilizantes/química , Piridinas/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Piridinas/síntese química , Piridinas/farmacologia
4.
Molecules ; 22(7)2017 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-28672821

RESUMO

A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral centers-one of which is quaternary and all-carbon-substituted. Also featured is a highly regioselective diazoalkane-carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton. Therein, the utility of Sc(OTf)3 as a mild catalyst for formal 1C insertion in complex settings is demonstrated.


Assuntos
Diterpenos Clerodânicos/química , Quinonas/síntese química , Sesquiterpenos/síntese química , Catálise , Modelos Químicos , Estrutura Molecular , Quinonas/química , Sesquiterpenos/química , Estereoisomerismo
5.
Top Curr Chem ; 346: 111-62, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24770564

RESUMO

Diazo compounds continue both to challenge and to fascinate practitioners of chemical synthesis. The most strategically powerful and unique type of reactivity observed with these reagents is a formal insertion of the donor-acceptor carbon into C-C or C-H bonds alpha to carbonyl groups. Although the reaction does not involve discrete carbon-metal bonds, it can be catalyzed by metal-based Lewis acids. This chapter investigates both classical and modern developments in diazoalkyl carbon insertion with a special emphasis on nonstabilized nucleophiles.

6.
J Org Chem ; 78(21): 10573-87, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23879715

RESUMO

This work offers a catalytic approach to convergent ketone assembly based upon formal and tandem C-H insertion of diazoalkanes in the presence of limiting amounts of monomeric formaldehyde, which is easily generated as a gas by thermolysis of the inexpensive and abundant paraformaldehyde (∼30 USD/kg). The method forms di-, tri-, and even tetrasubstituted acetones with high efficiency, and it has streamlined a synthesis of (-)-dihydrocuscohygrine in which the absolute stereochemistry of a proline-based starting material is preserved. Assisted by the advent of new protocols for hydrazone oxidation, we also provide full details on handling non-carbonyl-stabilized diazo compounds.


Assuntos
Alcanos/química , Compostos Aza/química , Formaldeído/química , Cetonas/síntese química , Catálise , Cetonas/química , Estereoisomerismo
7.
J Org Chem ; 78(9): 4620-6, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23557187

RESUMO

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.

8.
J Org Chem ; 77(2): 1181-5, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22239678

RESUMO

A new protocol for titrating nonstabilized diazoalkane solutions by quantitative (19)F NMR is reported. An excess of 2-fluorobenzoic acid dissolved in CDCl(3) is treated with the diazoalkane solution at a low temperature, immediately forming the corresponding 2-fluorobenzoate ester upon warming. A significant difference in the (19)F chemical shift between the ester and acid is seen, allowing facile and accurate integration to determine titer. The procedure is safe, rapid, and indicates the active diazoalkane concentration with high precision.

9.
Org Lett ; 13(8): 2004-7, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21401070

RESUMO

Current methods for asymmetric α-arylation require blocking groups to prevent reaction at the α'-carbon, basic conditions that promote racemization, or multistep synthesis. This work records the first catalytic enantioselective examples of the diazoalkane-carbonyl homologation reaction. Medium ring 2-aryl ketones are prepared in one step in up to 98:2 er and 99% yield from the unsubstituted lower homologue by Sc-catalyzed aryldiazomethyl insertion with simple bis- and tris(oxazoline) ligands.

10.
J Org Chem ; 76(6): 1662-72, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21344895

RESUMO

New conditions for the conversion of simple tertiary amides to α-chloroenamines and their use in Zn(II)-catalyzed cycloaddition reactions with commercial α,ß-unsaturated carbonyl compounds allows rapid, regiocontrolled access to 3-acyl cyclobutanones. Reactions take place at ambient temperature without solvent, giving strained [2 + 2] adducts with all-carbon-substituted quaternary carbon atoms. Ab initio calculations of the putative keteniminium intermediate and studies with styrenyl olefins suggest a dual role for Zn(OTf)(2) during catalysis.


Assuntos
Alcenos/química , Aminas/química , Butanonas/química , Butanonas/síntese química , Elétrons , Zinco/química , Catálise , Transporte de Elétrons , Modelos Moleculares , Conformação Molecular , Teoria Quântica
11.
Org Lett ; 12(16): 3598-601, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20669953

RESUMO

Divergent reactivity is uncovered in the homologation of arylcyclobutanones with trimethylsilyldiazomethane. With Sc(OTf)(3) as catalyst, enolsilanes are obtained with a high preference for methylene migration. By contrast, Sc(hfac)(3) gives beta-ketosilanes with both regio- and diastereocontrol. Each adduct affords the cyclopentanone upon hydrolysis.


Assuntos
Técnicas de Química Combinatória , Ciclopentanos/síntese química , Diazometano/análogos & derivados , Compostos de Trimetilsilil/química , Catálise , Ciclopentanos/química , Diazometano/química , Ligantes , Estrutura Molecular , Estereoisomerismo
12.
Org Lett ; 11(15): 3202-5, 2009 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-19588908

RESUMO

Over a century ago, the first reactions of diazomethane with aldehydes delivered methyl ketones. In the interim, aldehydes have been homologated with trimethylsilyldiazomethane, diazoacetates, and aryldiazomethanes, on rare occasion with catalysis. This work describes a mild procedure for convergent ketone assembly from nonstabilized diazoalkanes, including examples of chiral ketone synthesis with disubstituted (internal) nucleophiles. The method's remarkable tolerance to steric crowding is showcased in a simple approach to achyrofuran, a complex dibenzofuran.


Assuntos
Carbono/química , Furanos/síntese química , Hipoglicemiantes/síntese química , Cetonas/química , Catálise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Furanos/química , Hipoglicemiantes/química
13.
J Am Chem Soc ; 131(3): 878-9, 2009 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-19125571

RESUMO

Though volatile, toxic, and unstable, diazomethane is an indispensable one-carbon reagent with manifold uses in chemical synthesis. In this work, known protocols for hydrazone oxidation were adapted to permit facile access to a range of mono- and disubstituted aryl- or alkyldiazomethanes in pure form in solution; such procedures proceed in 30-60% overall yield starting from inexpensive carbonyl compounds. More important is the discovery that commercial Sc(III) salts are efficient catalysts for net insertion of the diazoalkyl carbon in these nucleophiles into the carbonyl C-C bond of simple cycloalkanones. In a single step, these reactions (1) forge two new C-C bonds under mild conditions, (2) produce molecular nitrogen as the sole stoichiometric byproduct, and (3) afford high yields of complex alpha-tertiary and -quaternary cyclic ketones that are typically accessible only through multistep procedures.

14.
J Am Chem Soc ; 127(40): 13813-5, 2005 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-16201801

RESUMO

A new synthetic strategy for the enantioselective synthesis of members of the dolabellane family of marine natural products has been demonstrated for the specific examples beta-araneosene and isoedunol (1 and 2, respectively) by the pathway outlined in Scheme 1. Key steps include (1) diastereoselective alkylation of Seebach's chiral lactate acetal (6) by the iodide derived from 5; (2) Kulinkovich ethylenation of ester 9 to form the cyclopropanol 10; (3) ring expansion of 10 to form 11; (4) pinacol cyclization of keto aldehyde 12 to form 13a; (5) rearrangement of 13b to 14; (6) propenylation of 14 to 2; and (7) reductive pi-transposition to form 1.


Assuntos
Benzopiranos/síntese química , Diterpenos/síntese química , Fungos/química , Moluscos/química , Pironas/química , Animais , Benzopiranos/química , Cristalografia por Raios X , Diterpenos/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
15.
J Am Chem Soc ; 127(12): 4510-7, 2005 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-15783234

RESUMO

Two isotopically and structurally labeled Ru-based carbenes (2-d4 and 13) have been prepared and attached to the surface of monolithic sol-gel glass. The resulting glass-supported complexes (18-dn and 19) exhibit significant catalytic activity in promoting olefin metathesis reactions and provide products of high purity. Through analysis of the derivatized glass pellets used in a sequence of catalytic ring-closing metathesis reactions mediated by various supported Ru carbenes, it is demonstrated that free Ru carbene intermediates in solution can be scavenged by support-bound styrene ether ligands prior to the onset of competing transition metal decomposition. The observations detailed herein provide rigorous evidence that the initially proposed release/return mechanism is, at least partially, operative. The present investigations shed light on a critical aspect of the mechanism of an important class of Ru-based metathesis complexes (those bearing a bidentate styrene ether ligand).

16.
Org Biomol Chem ; 2(1): 8-23, 2004 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-14737653

RESUMO

The discovery and development of a new class of Ru-based catalysts for olefin metathesis is described. These catalysts, particularly those that do not bear a phosphine ligand, have been demonstrated to promote unique levels of reactivity in a variety of olefin metathesis reactions. The design and development of supported and chiral optically pure variants of this class of Ru catalysts for use in enantioselective metathesis are discussed as well. All catalysts are air stable, reusable, and can be employed with unpurified solvents.

17.
J Am Chem Soc ; 124(18): 4954-5, 2002 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-11982348

RESUMO

The synthesis and structure of a new chiral bidentate imidazolinylidene ligand and a derived chiral Ru-based carbene are disclosed. The Ru complex is stereogenic at the metal center; it can be prepared in >98% diastereoselectivity and purified by silica gel chromatography with undistilled solvents. The air-stable Ru complex efficiently catalyzes ring-closing and ring-opening metathesis and is recyclable. The chiral complex is highly effective (0.5-10 mol % loading) in promoting enantioselective ring-opening/cross metathesis reactions (up to >98% ee). These enantioselective transformations can be effected in air, with unpurified solvent and with substrates that would only polymerize with Mo-based catalysts.

18.
Angew Chem Int Ed Engl ; 40(22): 4251-4256, 2001 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-29712112

RESUMO

Glass-bound Ru-based catalysts! Ru-containing glass pellets efficiently promote olefin metathesis reactions and are easily employed in syntheses of compound libraries. These robust catalysts are active in air and commercially available solvents, can be recycled up to 16 times, and removed from reaction mixtures with a simple pair of tweezers (minimal solvent waste).

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