RESUMO
We report that Ru(bpz)32+ is an excellent sensitizer for the photooxygenation of aryl cyclopropanes upon irradiation with visible light. The effectiveness of this photocatalyst enables the synthesis of a range of five-membered endoperoxides in excellent yield with quite low (0.5 mol%) catalyst loadings even when standard household light sources are utilized.
RESUMO
The C(5)-hydroperoxyenals (C(5)-HPALDs) are a newly-recognized class of multi-functional hydrocarbons produced during the hydroxyl radical (OH)-initiated oxidation of isoprene. Recent theoretical calculations suggest that fast photolysis of these compounds may be an important OH source in high-isoprene, low-NO regions. We report experimental constraints for key parameters of photolysis, OH reaction and ozone reaction of these compounds as derived from a closely-related, custom-synthesized C(6)-HPALD. The photolysis quantum yield is 1.0 ± 0.4 over the range 300-400 nm, assuming an absorption cross section equal to the average of those measured for several analogous enals. The yield of OH from photolysis was determined as 1.0 ± 0.8. The OH reaction rate constant is (5.1 ± 1.8) × 10(-11) cm(3) molecule(-1) s(-1) at 296 K. The ozone reaction rate constant is (1.2 ± 0.2) × 10(-18) cm(3) molecule(-1) s(-1) at 296 K. These results are consistent with previous first-principles estimates, though the nature and fate of secondary oxidation products remains uncertain. Incorporation of C(5)-HPALD chemistry with the above parameters in a 0-D box model, along with experimentally-constrained rates for C(5)-HPALD production from isomerization of first-generation isoprene hydroxyperoxy radicals, is found to enhance modeled OH concentrations by 5-16% relative to the traditional isoprene oxidation mechanism for the chemical regimes of recent observational studies in rural and remote regions. This enhancement in OH will increase if C(5)-HPALD photo-oxidation products also photolyze to yield additional OH or if the C(5)-HPALD production rate is faster than has been observed.
RESUMO
Structurally novel endoperoxides can be sythesized by the photocatalytic cyclotrimerization of bis(styrene) substrates with molecular oxygen. The optimal catalyst for this process is Ru(bpz)(3)(2+), which is a markedly more efficient catalyst for these photooxygention reactions than conventional organic photosensitizers. The 1,2-dioxolane products are amenable to synthetic manipulation and can be easily processed to 1,4-diols and γ-hydroxyketones. An initial screen of the biological activity of these compounds reveals promising inhibition of cancer cell growth.
Assuntos
Álcoois/síntese química , Antineoplásicos/síntese química , Peróxidos/síntese química , Álcoois/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Catálise , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oxigênio/química , Peróxidos/química , Peróxidos/farmacologia , Processos FotoquímicosRESUMO
The synthesis and biological evaluation of potent and selective anaplastic lymphoma kinase (ALK) inhibitors from a novel class of 2,4-diaminopyrimidines, incorporating 2,3,4,5-tetrahydro-benzo[d]azepine fragments, is described. An orally bioavailable analogue (18) that displayed antitumor efficacy in ALCL xenograft models in mice was identified and extensively profiled.
Assuntos
Benzazepinas/química , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Benzazepinas/farmacocinética , Benzazepinas/uso terapêutico , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.
Assuntos
Éteres/síntese química , Toxinas Marinhas/síntese química , Oxocinas/síntese química , Alquilação , Ciclização , Éteres/química , Toxinas Marinhas/química , Estrutura Molecular , Oxocinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process followed by methylenation.
Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Aldeídos/química , Alcenos/química , Toxinas Marinhas/química , Oxirredução , Oxocinas/química , Especificidade por SubstratoRESUMO
[reaction: see text] A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation, ring-closing metathesis, and Hosomi-Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which were united through a Horner-Wadsworth-Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.