RESUMO
Titanium alkoxide-based alkyne-alkyne reductive coupling mediated by in situ generated arylamidate is described. A high level of regioselectivity is achieved in 37 examples, where (E,E)-dienes are exclusively formed. To the best of our knowledge, this study represents the first example of an apparent amide and carbamate directing effect in metal-mediated reductive coupling.
RESUMO
A modular and diastereodivergent synthesis of tetrahydro-1 H-pyrrolo[1,2 d]diazepine-(2,5)-diones is presented. The tetrahydropyrrolodiazepinedione scaffold is obtained via a base-mediated three-step isomerization/tandem cyclization of amino acid-coupled homoallylic amino esters. Diastereoselectivity of the process is mediated by the interplay of a kinetic cyclization event and a propensity for thermodynamic epimerization at two labile chiral centers, giving rise to two distinct major diastereomers dependent on starting material stereochemistry and reaction conditions selected. Herein, we present a synthetic and computational study for this tandem process on a variety of amino ester substrates.
Assuntos
Lactamas/química , Pirróis/química , Pirróis/síntese química , Técnicas de Química Sintética , Ciclização , Cinética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , TermodinâmicaRESUMO
Six kava analogues of the structural type 3-oxocyclohex-1-en-1-yl benzoates (and corresponding benzamides) were synthesized and evaluated for their affect on periodontal deconstruction in collagen anti-body primed oral gavage model of periodontitis. The compounds were prepared through an acylation or amidation of the enolizable cyclic 1,3-diketone. We have learned that three of the analogues are responsible for the reduction of inflammatory cell counts within soft tissue. These novel kava-like molecules where the lactone is replaced by an α,ß-unsaturated ketone show promise in the prevention and treatment of inflammation and alveolar bone loss associated with periodontitis.
Assuntos
Benzamidas/farmacologia , Benzoatos/farmacologia , Cicloexanonas/farmacologia , Kava/química , Doenças Periodontais/tratamento farmacológico , Animais , Benzamidas/síntese química , Benzamidas/química , Benzoatos/síntese química , Benzoatos/química , Cicloexanonas/síntese química , Cicloexanonas/química , Macrófagos/efeitos dos fármacos , Camundongos , Doenças Periodontais/microbiologia , Porphyromonas gingivalis/patogenicidade , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Complete details of an asymmetric synthesis of (+)-isatisine A (1) are described. The synthesis highlights the use of a highly diastereoselective Mukaiyama-type [3 + 2]-annulation of allylsilane 5 with the unsaturated aldehyde 9a to assemble the functionalized tetrahydrofuran core of isatisine A. A convergent route to the framework of the natural product was established that employed a substrate-controlled indole coupling that was followed by a late-stage intramolecular copper(I)-mediated amidation to complete the assembly of the tetracyclic framework of (+)-isatisine A. In addition, the scope of the [3 + 2]-annulation was evaluated and enhanced utilizing diastereomeric allylsilanes anti-5 and syn-5 to establish an efficient route to stereochemically well-defined tetrahydrofurans.
Assuntos
Alcaloides Indólicos/síntese química , Isatina/análogos & derivados , Silanos/química , Alcaloides Indólicos/química , Isatina/síntese química , Isatina/química , Estrutura Molecular , EstereoisomerismoRESUMO
An organosilane-directed alkyne-alkene reductive coupling of readily available propargylsilanes is used to access densely functionalized chiral allylsilanes. The divergent reactivity of the allylsilanes can be controlled to afford a range of novel carbocyclic ring systems through an intramolecular allylation, [3+2] annulation, and Sakurai-like homodimerization.
Assuntos
Alcenos/química , Alcinos/química , Hidrocarbonetos Cíclicos/síntese química , Silanos/química , Alcenos/síntese química , Alcinos/síntese química , Compostos Alílicos/síntese química , Compostos Alílicos/química , Ciclização , Dimerização , Hidrocarbonetos Cíclicos/química , Oxirredução , Silanos/síntese química , EstereoisomerismoRESUMO
A stereoselective synthesis of the antibiotic (-)-virginiamycin M(2) is detailed. A convergent strategy was utilized that proceeded in 10 steps (longest linear sequence) from enantioenriched silane (S)-15. This reagent, which was prepared via a Rh(II)- or Cu(I)-catalyzed carbenoid Si-H insertion, was used to introduce the desired olefin geometry and stereocenters of the C1-C5 propionate subunit. A modified Negishi cross-coupling or an efficient alkoxide-directed titanium-mediated alkyne-alkyne reductive coupling strategy was utilized to assemble the trisubstituted (E,E)-diene. An underutilized late-stage SmI(2)-mediated macrocyclization was employed to construct the 23-membered macrocycle scaffold of the natural product.
Assuntos
Antibacterianos/síntese química , Cobre/química , Ródio/química , Silanos/química , Silício/química , Virginiamicina/análogos & derivados , Alcenos/química , Alcinos/química , Catálise , Cromatografia Líquida de Alta Pressão , Ciclização , Humanos , Hidrogênio/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Estereoisomerismo , Virginiamicina/síntese químicaRESUMO
A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).
Assuntos
Antineoplásicos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/síntese química , Quinonas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas/química , Linhagem Celular Tumoral , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Fenóis/síntese química , Quinonas/química , Quinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Actinas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Piranos/síntese química , Piranos/farmacologia , Acetamidas/química , Actinas/química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Anhydrous FeCl3 in the presence of 2,6-lutidine promotes the substrate-controlled enantioselective [4 + 2]-cycloaddition and crotylation reaction between an enantioenriched ( S, E)-crotyl silane and in situ generated ortho-quinone methides ( oQMs). The reaction produces both the chiral chroman and crotylation products in a ratio reflective of the electronic nature of the parent oQM with overall combined yields up to 96%. A ring-opening and elimination sequence was subsequently developed to provide direct access to the crotylation products, containing two contiguous tertiary carbon stereocenters, in good yields and enantioselectivities.
Assuntos
Indolquinonas/química , Silanos/química , Reação de Cicloadição , Estrutura Molecular , EstereoisomerismoRESUMO
Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis ( http://ftmap.bu.edu/ ). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Lactamas Macrocíclicas/farmacologia , Lactonas/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/metabolismo , Lactonas/síntese química , Lactonas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
An enantioselective synthesis of the Hsp90 inhibitor geldanamycin was achieved in 20 linear steps and 2.0% overall yield from 2-methoxyhydroquinone. The synthesis is highlighted by a regio- and stereoselective hydroboration reaction; a Sc(OTf)(3)/Et(3)SiH-mediated pyran ring-opening reaction; an enantioselective crotylation to simultaneously install the C8-C9 (E) -trisubstituted olefin, the C10 and C11 stereocenters; a chelation-controlled asymmetric metallated acetylide addition; and an intramolecular copper(I)-mediated aryl amidation reaction to close the 19-membered macrolactam.
Assuntos
Benzoquinonas/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Hidroquinonas/química , Lactamas Macrocíclicas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Catálise , Cobre/química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , EstereoisomerismoRESUMO
A convergent enantioselective synthesis of herboxidiene/GEX 1A (1) is described that features a double stereodifferentiating crotylation, [4 + 2] annulation, and a silicon-based sp2-sp2 cross-coupling to assemble the conjugated diene.
Assuntos
Antineoplásicos/síntese química , Álcoois Graxos/síntese química , Piranos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Estrutura Molecular , Piranos/química , Piranos/farmacologia , Estereoisomerismo , Streptomyces/químicaRESUMO
A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-component, Lewis acid mediated additions to in situ generated oxonium ions, resulting in enantioenriched homopropargylic ethers.
Assuntos
Alcadienos/química , Alcadienos/síntese química , Pargilina/análogos & derivados , Pargilina/síntese química , Silanos/química , Silanos/síntese química , Aldeídos/química , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Cinética , Lipase/química , Solventes , EstereoisomerismoRESUMO
An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product. [structure: see text].
Assuntos
Acetamidas/síntese química , Piranos/síntese química , Acetamidas/química , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
[structure: see text] The stereocontrolled synthesis of pyridooxazinones by Mg(OTf)2-promoted epoxide ring-opening with use of chiral pipecolates as nucleophiles is described. Pyridooxazinone products derived from azido-epoxides can be further rearranged to seven-membered pyridodiazepinones by azide reduction. The sequence of functional group interconversions generates diversity through topological and stereochemical variation.
Assuntos
Ésteres/química , Ácidos Pipecólicos/química , Compostos Aza/química , Catálise , Compostos de Epóxi/química , Ésteres/síntese química , Estrutura Molecular , Oxazinas/química , EstereoisomerismoRESUMO
Alkylidene indane and ring-expanded scaffolds have been prepared using an enantioselective crotylation/Heck cyclization sequence. Further diversification using consecutive cyclopropanation-Cope rearrangement affords novel chemotypes including spiroindane frameworks.
Assuntos
Indanos/química , Indanos/classificação , Alquilação , Compostos Azo/síntese química , Compostos Azo/química , Ciclização , Indanos/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Estereoisomerismo , Compostos de Vinila/síntese química , Compostos de Vinila/químicaRESUMO
Suitably functionalized tetrahydropyridines (methyl pipecolates) have been used as conformationally biased templates for radical cyclizations to access benzoisoquinuclidines and linearly fused indenopiperidines. Variation of skeletal types is determined by location of a radical-initiating element.
Assuntos
Hidrogênio/química , Piridinas/síntese química , Alquilação , Carbono/química , Ciclização , Radicais Livres/química , Hidantoínas/química , Modelos Moleculares , Estrutura Molecular , Piridinas/químicaRESUMO
Iron(III) salts promote the condensation of aldehydes or acetals with electron-rich phenols to generate ortho-quinone methides that undergo Diels-Alder condensations with alkenes. The reaction sequence occurs in a single vessel to afford benzopyrans in up to 95% yield. The reaction was discovered while investigating a two-component strategy using 2-(hydroxy(phenyl)methyl)phenols to access the desired ortho-quinone methide in a Diels-Alder condensation. The two-component condensation also afforded the corresponding benzopyran products in yields up to 97%. Taken together, the two- and three-component strategies using ortho-quinone methide intermediates provide efficient access to benzopyrans in good yields and selectivities.
Assuntos
Indolquinonas/química , Compostos Férricos , Estrutura Molecular , FenóisRESUMO
Porphyromonas gingivalis (P.g.)-induced TNF-α can be affected by muramyl dipeptide (MDP) in a biphasic concentration-dependent manner. We found that in P.g.-exposed macrophages, treatment with 10 µg/mL of MDP (MDP-low) up-regulated TNF-α by 29%, while 100 µg/mL or higher (MDP-high) significantly decreased it (16% to 38%). MDP-high was found to affect the ubiquitin-editing enzyme A20 and activator protein 1 (AP1). An AP1 binding site was found in the promoter region of A20. A20 promoter activity was up-regulated after transfection of AP1 cDNA in cells. Four analogues of MDP (3-6) were prepared through a convergent strategy involving the synthesis of two unique carbohydrate fragments, 7a and 7b, using the peptide coupling reagents, EDCI and HOAt. Analogue 4 improved MDP function and P.g.-induced activities. We propose a new signaling pathway for TNF-α induction activated after exposing macrophages to both P.g. and MDP-high or analogue 4.