RESUMO
Transition metal catalysis has contributed to the discovery of novel methodologies and the preparation of natural products, as well as new chances to increase the chemical space in drug discovery programs. In the case of marine drugs, this strategy has been used to achieve selective, sustainable and efficient transformations, which cannot be obtained otherwise. In this perspective, we aim to showcase how a variety of transition metals have provided fruitful couplings in a wide variety of marine drug-like scaffolds over the past few years, by accelerating the production of these valuable molecules.
Assuntos
Organismos Aquáticos , Produtos Biológicos , Elementos de Transição , Catálise , Produtos Biológicos/síntese química , Produtos Biológicos/química , Elementos de Transição/química , Descoberta de Drogas/métodos , AnimaisRESUMO
Herein, we present a novel C(sp3)-C(sp3) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules.
RESUMO
In this perspective, we showcase the benefits of continuous flow chemistry and photochemistry and how these valuable tools have contributed to the synthesis of organic scaffolds from the marine environment. These technologies have not only facilitated previously described synthetic pathways, but also opened new opportunities in the preparation of novel organic molecules with remarkable pharmacological properties which can be used in drug discovery programs.
Assuntos
Descoberta de Drogas , Tecnologia , Química FarmacêuticaRESUMO
A convenient regioselective synthesis of allyl- and vinylsilyl alcohols, from a common precursor, was described, by selecting the appropriate reaction conditions. Allyl- and vinylsilyl alcohols were tested in silyl-Prins cyclizations for the preparation of disubstituted oxygenated heterocycles in a one-pot sequential reaction. The methodology was sensitive to the structure of the starting alkenylsilyl alcohol and reaction conditions, with competitive pathways observed (particularly for allylsilyl alcohols), such as Peterson elimination and oxonia-Cope reactions. However, the use of vinylsilyl alcohols allowed the preparation of differently disubstituted cis-2,6-dihydropyrans in moderate to good yields. Computational studies support the proposed mechanism.
RESUMO
Coumarin and its derivatives have significantly attracted the attention of medicinal chemists and chemical biologists due to their huge range of biological, and in particular, pharmacological properties. Interesting families of coumarins have been found from marine sources, which has accelerated the drug discovery process by inspiring innovation or even by the identification of analogues with remarkable biological properties. The purpose of this review is to showcase the most interesting marine-derived coumarins from a medicinal chemistry point of view, as well as the novel and useful synthetic routes described to date to achieve these chemical structures. The references that compose this overview were collected from PubMed, Mendeley and SciFinder.
Assuntos
Produtos Biológicos , Descoberta de Drogas , Cumarínicos/farmacologia , Cumarínicos/química , Química Farmacêutica , Produtos Biológicos/farmacologia , Produtos Biológicos/químicaRESUMO
This perspective scrutinizes flow chemistry as a useful tool for medicinal chemists to expand the current chemical capabilities in drug discovery. This technology has demonstrated his value not only for the traditional reactions used in Pharma for the last 20 years, but also for bringing back to the lab underused chemistries to access novel chemical space. The combination with other technologies, such as photochemistry and electrochemistry, is opening new avenues for reactivity that will smoothen the access to complex molecules. The introduction of all these technologies in automated platforms will improve the productivity of medicinal chemistry labs reducing the cycle times to get novel and differentiated bioactive molecules, accelerating discovery cycle times.
Assuntos
Química Farmacêutica , Descoberta de Drogas , Compostos Orgânicos/química , Estrutura MolecularRESUMO
Formation of all-carbon-substituted quaternary carbons is a key challenge in organic and medicinal chemistry. We report a cobalt-catalyzed C(sp3)-C(sp3) cross-coupling that allows for the introduction of benzyl, heteroarylmethylzinc and allyl groups to halo-carbonyl substrates. The cross-coupling reaction is selective for C(sp3)-over C(sp2)-halides, in contrast to most used catalytic metals, and allows access to novel scaffolds of pharmaceutical interest. NMR mechanistic studies suggest the presence of Co(0) complexes as catalytic species.
RESUMO
Gold-catalysis has enabled new synthetic opportunities in the chemistry of vinyldiazo compounds. Herein, we report the gold-catalyzed reaction of stabilized vinyldiazo compounds with pinacol alkenylboronates to provide boryl-functionalized cyclopentene derivatives through a formal [3+2] carbocycloaddition reaction, a very unusual pathway in alkenylboronate chemistry. This reaction proceeds with high regio- and stereoselectivity. The synthetic usefulness of the resulting borylated cyclopentene derivatives toward the synthesis of densely functionalized cyclopentanoids is also demonstrated.
RESUMO
The reaction of para-hydroxybenzyl alcohols with ferrocene in the presence of a catalytic amount of InCl3 provided ferrocenyl phenol derivatives, an interesting class of organometallic compounds with potential applications in medicinal chemistry. This transformation exhibited a reasonable substrate scope delivering the desired products in synthetically useful yields. Evidence of involvement of a para-quinone methide intermediate in this coupling process was also provided. Preliminary biological evaluation demonstrated that some of the ferrocene derivatives available by this methodology exhibit significant cytotoxicity against several cancer cell lines with IC50 values within the range of 1.07â»4.89 µM.
Assuntos
Compostos Ferrosos/química , Indolquinonas/química , Metalocenos/química , Fenol/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The reaction of vinylazides with alkenyldiazo compounds in the presence of [Cu(CH3 CN)4 ][BF4 ] provided cyclopentene derivatives with retention of the azide functionality. This process likely involves a sequence comprising: 1)â decomposition of the diazo component with generation of a copper alkenylcarbene species; 2)â stepwise regioselective [3+2] cycloaddition; 3)â allylic azide rearrangement. This method is compatible with a broad range of substrates. We also show that the azide-containing cycloadducts can be efficiently converted into the corresponding amine and triazole derivatives.
RESUMO
The reaction of ferrocene and ruthenocene with aryldiazo acetates in the presence of gold catalysts produced new functionalized metallocenes resulting from a C-H bond functionalization process. This process is believed to proceed through initial decomposition of the diazo component and formation of an electrophilic gold-carbene intermediate, which is subsequently involved in an electrophilic aromatic substitution. The gold-catalyzed functionalization of ruthenocene exhibited a broad scope and a notable functional-group tolerance. Interestingly, the functionalized ferrocene derivatives were found to react with molecular oxygen to yield α-aryl-α-ferrocenyl-α-hydroxyacetates. Adsorption on silica gel was found to be essential for this dioxygen activation/C(sp3 )-H bond functionalization sequence. The methodologies reported herein provide a simple and efficient approach to functionalized metallocene derivatives that are difficult to access through conventional organic functional group transformations.
RESUMO
Transition metal-catalyzed transformations of vinyldiazo compounds have become a versatile tool in organic synthesis. Although several transition metals have been investigated for this purpose, this field has been mainly dominated by dirhodium catalysts. Remarkable levels of chemo-, regio-, diastereo- and enantioselectivity have been reached in some of these rhodium-catalyzed transformations. In the last few years coinage metals have also emerged as useful catalysts in transformations involving vinyldiazo compounds. In some cases, highly efficient catalyst-dependent protocols arising from divergent mechanistic pathways have been reported. In this Personal Account, we aim to showcase recent advances in metal coinage catalyzed transformations of vinyldiazoacetates, an exciting field of research to which our group has actively contributed in the last few years.
RESUMO
The reaction of electronically unbiased allenes with alkenyldiazo compounds in the presence of gold catalysts provided alkylidenecyclopentene derivatives resulting from a formal intermolecular (3+2) carbocyclization. A stepwise mechanism involving initial activation of the diazo component and subsequent formation of an allyl cation intermediate has been proposed. This process represents the first intermolecular gold-catalyzed cycloaddition involving non-activated allenes.
RESUMO
Transition metal-catalyzed C-H bond functionalizations of ferrocene derivatives have emerged in the last few years as a versatile tool in synthetic organometallic chemistry. These protocols offer significant advantages over more traditional approaches for the synthesis of functionalized ferrocene derivatives in terms of both atom- and step-economy. In this Perspective, we aim to showcase the state of the art in this field, with special emphasis on recent asymmetric methodologies.
RESUMO
A rhodium-catalyzed carbene transfer to alkynes is reported. Easily available enynones served as the carbene source replacing diazocompounds. The overall process involved a cyclization-cyclopropenation-ring enlargement sequence.