RESUMO
Bicyclic carbocycles containing a high fraction of Csp3 have become highly attractive synthetic targets because of the multiple applications they have found in medicinal chemistry. The formal cycloaddition of bicyclobutanes (BCBs) with two- or three-atom partners has recently been extensively explored for the construction of bicyclohexanes and bicycloheptanes, but applications to the synthesis of medium-sized bridged carbocycles remained more limited. We report herein the formal [4+2] cycloaddition of BCB ketones with silyl dienol ethers. The reaction occurred in the presence of 5 mol% aluminium triflate as a Lewis acid catalyst. Upon acidic hydrolysis of the enol ether intermediates, rigid bicyclo[4.1.1]octane (BCO) diketones could be accessed in up to quantitative yields. This procedure tolerated a range of both aromatic and aliphatic substituents on both the BCB substrates and the dienes. The obtained BCO products could be functionalized through reduction and cross-coupling reactions.
RESUMO
Peptide and protein bioconjugation sees ever-growing applications in the pharmaceutical sector. Novel strategies and reagents that can address the chemo- and regioselectivity issues inherent to these biomolecules, while delivering stable and functionalizable conjugates, are therefore needed. Herein, we introduce the crosslinking ethynylbenziodazolone (EBZ) reagent JW-AM-005 for the conjugation of peptides and proteins through the selective linkage of cysteine residues. This easily accessed compound gives access to peptide dimers or stapled peptides under mild and tuneable conditions. Applied to the antibody fragment of antigen binding (Fab) species, JW-AM-005 delivered rebridged proteins in a one-pot three-reaction process with high regioselectivity, outperforming the standard reagents commonly used for this transformation.
Assuntos
Cisteína , Iodo , Cisteína/química , Reagentes de Ligações Cruzadas/química , Iodo/química , Proteínas/química , Peptídeos , Indicadores e ReagentesRESUMO
Azepanes are important seven-membered heterocycles, which are present in numerous natural and synthetic compounds. However, the development of convergent synthetic methods to access them remains challenging. Herein, we report the Lewis acid catalyzed (4+3) annulative addition of aryl and amino donor-acceptor cyclopropanes with 2-aza-1,3-dienes. Densely substituted azepane derivatives were obtained in good to excellent yields and with high diastereoselectivity. The reaction occurred under mild conditions with ytterbium triflate as the catalyst. The use of copper triflate with a trisoxazoline (Tox) ligand led to an enantioselective transformation. The obtained cycloadducts were convenient substrates for a series of further modifications, showing the synthetic utility of these compounds.
RESUMO
A Pd-catalyzed method based on the use of a molecular tether is described for olefin difunctionalization. Enabled by an easily introduced trifluoroacetaldehyde-derived tether, a simultaneous introduction of oxygen and nitrogen heteroatoms across unsaturated carbon-carbon bonds was achieved under oxidative conditions, most probably via high-valent Pd intermediates. Good yields and high diastereoselectivity were obtained with aryl-substituted alkenes, whereas nonterminal alkyl-substituted olefins gave aza-Heck products. Tether cleavage under mild conditions provided fast access to functionalized ß-amino alcohols.
RESUMO
We report an organophotocatalytic 1,2-oxyalkynylation of ene-carbamates and enol ethers using Ethynyl BenziodoXolones (EBXs). 1-Alkynyl-1,2-amino alcohols and diols were obtained in up to 89% yield. Photocatalytic formation of radical cations led to Umpolung of the innate reactivity of the alkenes, enabling addition of a nucleophilic benzoate followed by radical alkynylation.
RESUMO
Alkynyl sulfoxides are important building blocks with a unique reactivity in organic chemistry, but only a few reliable methods have been reported to synthesize them. A novel route to access alkynyl sulfoxides is reported herein by using ethynyl benziodoxolone (EBX) reagents to trap sulfenate anions generated in situ, via a retro-Michael reaction. The reaction takes place under metal-free and mild conditions. It is compatible with aryl, heteroaryl, and alkyl sulfoxides with up to 90% yield. This practical access to alkynyl sulfoxides is expected to facilitate the application of these useful building blocks in organic synthesis.
RESUMO
Azides are building blocks of increasing importance in synthetic chemistry, chemical biology, and materials science. Azidobenziodoxolone (ABX, Zhdankin reagent) is a valuable azide source, but its safety profile has not been thoroughly established. Herein, we report a safety study of ABX, which shows its hazardous nature. We introduce two derivatives, tBu-ABX and ABZ (azidobenziodazolone), with a better safety profile, and use them in established photoredox- and metal-mediated azidations, and in a new ring-expansion of silylated cyclobutanols to give azidated cyclopentanones.
RESUMO
Fine-tuned organic photoredox catalysts are introduced for the metal-free alkynylation of alkylnitrile radicals generated via oxidative ring opening of cyclic alkylketone oxime ethers. The redox properties of the dyes were determined by both cyclic voltammetry and computation and covered an existing gap in the oxidation potential of photoredox organocatalysts.
RESUMO
The one-step synthesis of the bench-stable hypervalent iodine reagents IndoleBX and PyrroleBX using mild Lewis acid catalyzed conditions is reported. The new reagents are stable up to 150 °C and were applied in the C-H arylation of unactivated arenes using either rhodium or ruthenium catalysts. A broad range of heterocyclic systems of high interest for synthetic and medicinal chemistry was accessed in high yields. The developed C-H functionalization could not be achieved using reported reagents or methods, highlighting the unique reactivity of Indole- and Pyrrole-BX.
RESUMO
A versatile synthesis of azidolactones through azidation and cyclization of carboxylic acids onto alkenes has been developed. Based on either photoredox or palladium catalysis, (1,1) and (1,2) azido lactones can be selectively synthesized. The choice of catalyst and benziodoxol(on)e reagent serving as azide source was essential to initiate either a radical or Lewis acid mediated process with divergent outcome. These transformations were carried out under mild conditions using a low catalyst loading and gave access to a large scope of azido lactones.
RESUMO
Tetrahydrofurans and pyrrolidines are among the most important heterocycles found in bioactive compounds. Cyclization-functionalization domino reactions of alcohols or amines onto olefins constitute one of the most efficient methods to access them. In this context, oxy- and aminoalkynylation are especially important reactions, because of the numerous transformations possible with the triple bond of acetylenes, yet these methods have been limited to the use of silyl protected acetylenes. Herein, we report the first palladium-catalyzed oxy- and aminoalkynylation using aliphatic bromoalkynes, which proceeded with high diastereoselectivity and functional group tolerance. A one-pot hydrogenation of the triple bond gave then access to alkyl-substituted tetrahydrofurans and pyrroldines. Finally, a detailed study of the side products formed during the reaction gave a first insight into the reaction mechanism.
Assuntos
Alcenos/química , Alcinos/química , Aminas/química , Furanos/química , Paládio/química , Pirrolidinas/química , Catálise , Ciclização , Hidrogenação , Estrutura MolecularRESUMO
The first Pd(0)-catalyzed intramolecular oxy- and aminoalkynylation of nonactivated olefins is reported. The reaction gives access to important tetrahydrofuran and pyrrolidine heterocycles with high diastereoselectivity. The unique synthetic potential of acetylenes is further exploited to access key building blocks for the synthesis of bioactive natural products.
Assuntos
Alcenos/química , Alcinos/química , Furanos/síntese química , Paládio/química , Pirrolidinas/síntese química , Catálise , Técnicas de Química Combinatória , Furanos/química , Estrutura Molecular , Pirrolidinas/químicaRESUMO
One of the major challenges faced by organic chemistry is the efficient synthesis of increasingly complex molecules. Since October 2007, the Laboratory of Catalysis and Organic Synthesis (LCSO) at EPFL has been working on the development of catalytic reactions based on the Umpolung of the innate reactivity of functional groups. Electrophilic acetylene synthons have been developed using the exceptional properties of ethynyl benziodoxolone (EBX) hypervalent iodine reagents for the alkynylation of heterocycles and olefins. The obtained acetylenes are important building blocks for organic chemistry, material sciences and chemical biology. The ring-strain energy of donor-acceptor cyclopropanes was then used in the first catalytic formal homo-Nazarov cyclization. In the case of aminocyclopropanes, the method could be applied in the synthesis of the alkaloids aspidospermidine and goniomitine. The developed methods are expected to have a broad potential for the synthesis and functionalization of complex organic molecules, including carbocycles and heterocycles.
Assuntos
Alcinos/síntese química , Ciclopropanos/química , Hidrocarbonetos Iodados/química , Alcinos/química , Catálise , Estrutura Molecular , TermodinâmicaAssuntos
Alcinos/química , Amidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Organometálicos/química , Paládio/química , Alcaloides de Pirrolizidina/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Estrutura Molecular , Alcaloides de Pirrolizidina/química , EstereoisomerismoRESUMO
In the last decades, hypervalent iodine reagents have raised from chemical curiosities to mainstream reagents in organic synthesis. The use of benziodoxole-derived reagents has been especially successful in oxidation methods, whereas non-cyclic iodinanes have been used both for oxidation and atom-transfer reactions. On the other hand, the exceptional properties of benziodoxole reagents for atom-transfer reactions have only started to attract the attention of the synthetic community more recently. In this review, progress in the use of these compounds for C-X and C-C bond formations will be presented. In particular, recent breakthroughs in trifluoromethylation and alkynylation reactions have been realized since 2006 based on benziodoxole-derived reagents and these results are the main focus of this article.
Assuntos
Alcinos/química , Hidrocarbonetos Iodados/química , Indicadores e Reagentes/química , Iodobenzoatos/química , Alcinos/síntese química , Iodobenzenos , Metilação , OxirreduçãoRESUMO
The first example of intramolecular oxyalkynylation of nonactivated alkenes using oxidative Pd chemistry is reported. Both phenol and aromatic or aliphatic acid derivatives could be used under operator-friendly conditions (room temperature, technical solvents, under air). The discovery of the superiority of benziodoxolone-derived hypervalent iodine reagent 3d as an alkyne transfer reagent further expands the rapidly increasing utility of hypervalent iodine reagents in catalysis and is expected to have important implications for other similar processes.