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1.
J Med Chem ; 66(7): 4659-4670, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36932954

RESUMO

After acute myocardial infarction, early reperfusion is the most effective strategy for reducing cardiac damage and improving clinical outcome. However, restoring blood flow to the ischemic myocardium can paradoxically induce injury by itself (reperfusion injury), with microvascular dysfunction being one contributing factor. α2B adrenergic receptors have been hypothesized to be involved in this process. To assess α2B-related pharmacology, we identified a novel α2B antagonist by HTS. The HTS hit showed limited α2A selectivity as well as low solubility and was optimized toward BAY-6096, a potent, selective, and highly water-soluble α2B antagonist. Key aspects of the optimization were the introduction of a permanently charged pyridinium moiety to achieve very good aqueous solubility and the inversion of an amide to prevent genotoxicity. BAY-6096 dose-dependently reduced blood pressure increases in rats induced by an α2B agonist, demonstrating the role of α2B receptors in vascular constriction in rats.


Assuntos
Adrenérgicos , Ratos , Animais
2.
Chem Rev ; 122(2): 2907-2980, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34558888

RESUMO

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.


Assuntos
Disciplinas das Ciências Biológicas , DNA , DNA/química
3.
Angew Chem Int Ed Engl ; 59(13): 5248-5253, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32030865

RESUMO

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.

4.
Acc Chem Res ; 48(3): 619-27, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25699585

RESUMO

Synthetic organic chemistry underpins many scientific disciplines. The development of new synthetic methods proceeds with the ultimate intention of providing access to novel structural motifs or providing safer, increasingly efficient, or more economical chemical reactions. To facilitate the identification and application of new methods in solving real synthetic problems, this Account will highlight the benefits of providing a fuller picture of both the scope and limitations of new reactions, with a primary focus on the evaluation of functional group tolerance and stability of a reaction using intermolecular screens. This Account will begin with a discussion on reaction evaluation, specifically considering the suitability of a given reaction for application in target-oriented synthesis. A comparison of desirable and essential criteria when choosing a reaction is given, and a short discussion on the value of negative and qualitative data is provided. The concept of intermolecular reaction screening will be introduced, and a direct comparison with a traditional substrate scope highlights the benefits and limitations of each and thus the complementary nature of these approaches. In recent years, a number of ad hoc applications of intermolecular screens to evaluate the functional group tolerance of a reaction or the stability of functional groups to a given set of reaction conditions have been reported, and will be discussed. More recently, we have developed a formal high-throughput intermolecular screening protocol that can be utilized to rapidly evaluate new chemical reactions. This simple and rapid protocol enables a much broader evaluation of a reaction in terms of functional group tolerance and the stability of chemical motifs to the reaction conditions than is feasible with a typical reaction scope. The development, evaluation, and application of this method within our group will be discussed in detail, with both the potential benefits and limitations highlighted and discussed. In addition, we will discuss more recent applications of intermolecular screens from both industrial and academic groups. Modifications in protocols and applications will be highlighted, including problem based evaluations, assessment of biomolecule compatibility, establishment of relative rate data, and the identification of new reactivity. Such screens have been applied in diverse chemistries including C-H functionalization reactions, frustrated Lewis-pair-catalyzed hydrogenations, heterogeneous catalysis, photoredox catalysis, enantioselective organocatalysis, and polymer science. We feel that the application of intermolecular screens to such a diversity of reactions highlights the practical simplicity of such screens. A summary of the applications and potential utility of intermolecular reaction evaluation is provided.

5.
Chem Sci ; 6(3): 1816-1824, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29308135

RESUMO

A highly selective arylation of a number of polyaromatic hydrocarbons (PAHs) with aryliodonium salts and Pd/C as the only reagent is reported. The first C-H functionalization of triphenylene is explored, and proceeds at the most sterically hindered position. This non-chelate assisted C-H functionalization extends the reactivity profile of Pd/C and provides controlled access to π-extended PAHs, an important aspect of work towards the preparation of nanographenes. Mechanistic studies suggest in situ formation of catalytically active insoluble nanoparticles, and that the reaction likely proceeds via a Pd(0)/Pd(ii) type reaction manifold.

6.
Nat Chem ; 6(10): 859-71, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25242480

RESUMO

New organic reactivity has often been discovered by happenstance. Several recent research efforts have attempted to leverage this to discover new reactions. In this Review, we attempt to unify reported approaches to reaction discovery on the basis of the practical and strategic principles applied. We concentrate on approaches to reaction discovery as opposed to reaction development, though conceptually groundbreaking approaches to identifying efficient catalyst systems are also considered. Finally, we provide a critical overview of the utility and application of the reported methods from the perspective of a synthetic chemist, and consider the future of high-throughput screening in reaction discovery.


Assuntos
Preparações Farmacêuticas/síntese química , Catálise , Técnicas de Química Combinatória , Reação de Cicloadição , DNA/química , DNA/metabolismo , Ensaios de Triagem em Larga Escala , Imunoensaio , Compostos Orgânicos/síntese química , Compostos Orgânicos/química , Preparações Farmacêuticas/química , Técnicas de Síntese em Fase Sólida , Especificidade por Substrato
7.
Nat Protoc ; 9(6): 1348-53, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24833173

RESUMO

This protocol provides a rapid method for evaluating the tolerance of a given set of reaction conditions to a wide range of functional groups, as well as the stability of functional groups to the reaction conditions. This information is highly desirable when considering the application of a given protocol in the preparation of complex compounds, including natural products or biologically active molecules. By using a contemporary Rh(III)-catalyzed C-H activation protocol for the preparation of indole derivatives as a demonstrative example, here we describe a simple process that uses batch reaction preparation, small-scale parallel reaction techniques, simplified gas chromatography (GC) calibration techniques and GC analysis to undertake this evaluation in a rapid and cost-effective manner. This analysis provides quantitative data for a large number of functional groups and heterocycles, and it is readily adaptable to investigate structural motifs of choice, such as common moieties or functional groups within a given medicinal or agrochemical project or within a family of natural products. Twenty chosen additives plus controls can be evaluated in ∼3 d depending on the reaction time, with actual reaction setup and analysis taking 12-24 h depending on the reaction.


Assuntos
Engenharia Química/métodos , Técnicas de Química Sintética/métodos , Compostos Orgânicos/química , Catálise , Indóis/química , Cinética , Estrutura Molecular
8.
Chem Commun (Camb) ; 50(34): 4459-61, 2014 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-24652405

RESUMO

An experimentally simple additive-free Rh(III)-catalysed direct alkynylation of alkenes has been developed. This protocol employs commercially available TIPS-EBX as the alkyne source, giving access to conjugated terminal enynes following a simple silyl-deprotection. This method has also been applied to arenes.

9.
Chemistry ; 20(13): 3800-5, 2014 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-24550131

RESUMO

An experimentally simple method has been developed to rapidly establish the stability of widely utilized silyl, acetal, and carbamate protecting groups to a given set of reaction conditions. Assessment of up to twelve protecting groups in a single experiment has been demonstrated. Evaluation of this protocol in two unrelated synthetic transformations suggests that this method can be used to select appropriate protecting groups in the design of synthetic routes.

10.
Angew Chem Int Ed Engl ; 53(7): 1809-13, 2014 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24505001

RESUMO

The completely C3-selective arylation of thiophenes and benzo[b]thiophenes was achieved by using Pd/C as a heterogeneous catalyst without ligands or additives under mild reaction conditions. The practicability of this transformation is demonstrated by notable functional group tolerance and the insensitivity of the reaction to H2 O and air. This method is also applicable to nitrogen- and oxygen-containing heterocycles, yielding the corresponding C2-arylated products. Three-phase tests along with Hg-poisoning and hot-filtration tests suggest that the catalytically active species is heterogeneous in nature.

11.
Angew Chem Int Ed Engl ; 52(47): 12430-4, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24123602

RESUMO

[3]DendrAl(l)ene! A new synthesis of [3]dendralenes is based on a Rh(III) -catalyzed alkenyl CH activation and coupling reaction with allenyl carbinol carbonates (see scheme; DG=directing group). A variety of [3]dendralenes with diverse substitution patterns are accessible with good efficiency. The reaction is highly stereoselective and compatible with different directing groups and numerous functional groups.

12.
Beilstein J Org Chem ; 9: 1443-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23946841

RESUMO

Studies on SmI2-mediated spirocyclisation and lactone reduction culminate in a telescoped sequence in which additives are used to "switch on" individual steps mediated by the electron transfer reagent. The sequence involves the use of two activated SmI2 reagent systems and a silicon stereocontrol element that exerts complete diastereocontrol over the cyclisation and is removed during the final stage of the sequence by Peterson elimination. The approach allows functionalised cyclopentanols containing two vicinal quaternary stereocentres to be conveniently prepared from simple starting materials.

13.
Nat Chem ; 5(7): 597-601, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23787750

RESUMO

In contrast to the rapidity with which scientific information is published, the application of new knowledge often remains slow, and we believe this to be particularly true of newly developed synthetic organic chemistry methodology. Consequently, methods to assess and identify robust chemical reactions are desirable, and would directly facilitate the application of newly reported synthetic methodology to complex synthetic problems. Here, we describe a simple process for assessing the likely scope and limitations of a chemical reaction beyond the idealized reaction conditions initially reported. Using simple methods and common analytical techniques we demonstrate a rapid assessment of an established chemical reaction, and also propose a simplified analysis that may be reported alongside new synthetic methodology.


Assuntos
Química Orgânica
14.
J Am Chem Soc ; 135(20): 7450-3, 2013 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-23647450

RESUMO

The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.


Assuntos
Tiofenos/síntese química , Catálise , Estrutura Molecular , Paládio/química , Estereoisomerismo , Tiofenos/química
15.
Org Biomol Chem ; 10(30): 5820-4, 2012 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-22367284

RESUMO

Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI(2)-H(2)O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.


Assuntos
Iodetos/química , Lactonas/química , Samário/química , Água/química , Transporte de Elétrons , Especificidade por Substrato
16.
Org Lett ; 12(23): 5446-9, 2010 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-21049913

RESUMO

The use of a silicon stereocontrol element in cyclobutanol and cyclopentanol-forming cyclizations mediated by SmI(2) results in excellent diastereocontrol. The C-Si bond in the products of cyclization provides a versatile handle for further manipulation. An asymmetric route to cyclization substrates involving copper-catalyzed silyl transfer has also been developed.


Assuntos
Carbono/química , Iodetos/química , Samário/química , Silício/química , Ciclização , Modelos Moleculares , Estrutura Molecular , Oxirredução , Estereoisomerismo
17.
Chemistry ; 16(33): 10240-9, 2010 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-20645340

RESUMO

SmI(2)/H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.


Assuntos
Dioxanos/química , Ésteres/química , Hidroxiácidos/síntese química , Substâncias Redutoras/química , Ésteres/síntese química , Radicais Livres , Iodetos/química , Samário/química , Água/química
18.
J Am Chem Soc ; 131(21): 7214-5, 2009 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-19422232

RESUMO

SmI(2)-H(2)O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over-reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters and esters. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron transfer to the ester carbonyl and the anomeric stabilization of the resulting radical-anion intermediate. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes.


Assuntos
Ésteres/química , Substâncias Redutoras/química , Radicais Livres , Hidroxiácidos/síntese química , Iodetos/química , Samário/química , Água/química
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