RESUMO
The iboga alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C-H functionalization procedures leading to the core seven-membered ring of the iboga skeleton, a cyclization that proved to be highly challenging. The electrophilic palladium salt Pd(CH3CN)4(BF4)2 was effective for the cyclization of diverse N-(2-arylethyl)isoquinuclidines with yields of 10-35%. A two-step, bromination-reductive Heck reaction protocol was also effective for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C-H functionalization provided the benzofuran analogues of ibogamine (74%) and epi-ibogamine (38%). Although each approach suffers from significant shortcomings, in combination, the methods described provide practical routes to diverse ibogamine analogues.
Assuntos
Alcaloides/síntese química , Alcenos/química , Compostos Heterocíclicos/química , Tabernaemontana/química , Alcaloides/química , Catálise , Ciclização , Estrutura Molecular , Compostos Organometálicos/química , Paládio/químicaRESUMO
An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products.
Assuntos
Alcenos/química , Benzamidas/síntese química , Ródio/química , Benzamidas/química , Catálise , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
We report a new catalytic protocol for highly selective C-H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO(2), CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C-H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C-H bond) in combination with steric effects (sensitivity to bulky substituents).
Assuntos
Piridinas/química , Elétrons , Estrutura Molecular , EstereoisomerismoRESUMO
The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper.
Assuntos
Aminas/química , Compostos de Anilina/química , Indóis/síntese química , Paládio/química , Catálise , Ciclização , Indóis/química , Estrutura Molecular , OxirreduçãoRESUMO
Herein, we report a urea derived directing group for mild and highly selective oxidative C-H bond olefination. Subsequent intramolecular Michael addition affords dihydroquinazolinones in good yields. The N-O bond of the urea substrate exhibits superior oxidative behaviour compared to a variety of other external oxidants.
RESUMO
A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.
RESUMO
A novel protocol for palladium-catalyzed intermolecular formal [4 + 2] annulation of 2-phenylbenzoic acids with alkynes is described. Acridine is shown to be essential for the high reaction efficiency. Phenanthrene derivatives are formed in moderate to good yields without coupling (pseudo)halides or organometallic species.
RESUMO
A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp(3) C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R(3) = CO(2)R). Alternatively, in some cases (R(3) = CN), the enamine can be utilized for a vinylic sp(2) C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.