RESUMO
We report a novel and environmentally friendly method for the ipso-bromination of arylboronic acids by exploiting the oxone/KBr system. We discovered that CuBr can catalyze the reaction and increase the yield from 63 to 97%. We believe that CuBr might catalyze the in situ generation of HOBr from oxone/KBr. The mild reaction condition permits tolerance of a diverse array of functional groups with exclusive regio- and chemoselectivity and allows low-cost large-scale reaction without explosion risk.
RESUMO
Aspidosperma and uleine alkaloids belong to the large family of monoterpene indole alkaloids with diverse biological activities and thus have attracted extensive synthetic interest. Reported is the development of a new synthetic strategy that allows direct C3-C2' linkage of indoles with functionalized 2-hydroxypiperidines to construct the core common to all aspidoserma and uleine alkaloids. Such indole-piperidine linkage is enabled by coupling aza-Achmatowicz rearrangement (AAR) with indoles via an intermolecular aza-Friedel-Crafts (iAFC) reaction. This AAR-iAFC reaction proceeds under mild acidic conditions with wide tolerance of functional groups (33 examples). The synthetic application of the AAR-iAFC method was demonstrated with collective total syntheses of 3 uleine-type and 6 aspidosperma alkaloids: (+)-3-epi-N-nor-dasycarpidone, (+)-3-epi-dasycarpidone, (+)-3-epi-uleine, 1,2-didehydropseudoaspidospermidine, 1,2-dehydroaspidospermidine, vincadifformine, winchinine B, aspidospermidine, and N-acetylaspidospermidine. We expect that this AAR-iAFC strategy is applicable to other monoterpene indole alkaloids with the C3-C2' linkage of indoles and piperidines.
RESUMO
Every year, dengue virus (DENV) affects millions of people. Currently, there are no approved drugs for the treatment of DENV infection. Autophagy is a conserved degradation process that was shown to be induced by DENV infection and required for optimal DENV replication. The modulation of autophagy is, therefore, considered an attractive target to treat DENV infection. This study carried out a high-content image screen analysis using Crispr-Cas9 GFP-LC3 knocked-in HeLa cells of a compound library synthesized from or inspired by natural products and their biocongener precursors to discover novel autophagy inhibitors. The screen identified Ka-003 as the most effective compound for decreasing the number of autophagic vacuoles inside cells upon autophagy induction. Ka-003 could inhibit autophagy in a dose-dependent manner at low micromolar concentrations. More importantly, Ka-003 demonstrated the concentration-dependent inhibition of DENV production in Crispr-Cas9 GFP-LC3 knocked-in THP-1 monocytes. The core structure of Ka-003, which is a methyl cyclohexene derivative, resembles those found in mulberry plants, and could be synthetically prepared in a bioinspired fashion. Taken together, data indicate that Ka-003 hampered autophagy and limited DENV replication. The low cytotoxicity of Ka-003 suggests its therapeutic potential, which warrants further studies for the lead optimization of the compound for dengue treatment.
Assuntos
Vírus da Dengue , Dengue , Humanos , Vírus da Dengue/fisiologia , Células HeLa , Autofagia/fisiologia , Replicação ViralRESUMO
An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14â steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.
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ortho-Quinone methides (o-QMs) underwent formal [4 + 2]-cycloaddition reactions with arylallenes regioselectively at the styrenyl olefin to furnish the corresponding 3-methylene-2-arylchromans in moderate to good yields (up to 88%). When R ≠ H, the reactions also proceeded with moderate stereoselectivity (up to 5:1) which was governed by the nature of the R group. The 3-methylene-2-arylchromans could serve as common intermediates for further functionalization including epoxidation, oxidative cleavage/Baeyer-Villiger oxidation, Riley oxidation, acid-catalyzed rearrangement, and Pd-catalyzed cross-coupling reactions to furnish the corresponding derivatives in moderate to good yields.
Assuntos
Cromanos , Indolquinonas , Reação de Cicloadição , OxirreduçãoRESUMO
ortho-Quinone methides (o-QMs) generated from the corresponding benzyl acetate precursors chemoselectively underwent the formal [4 + 2]-cycloadditions with the olefin of styrene, stilbene, or cinnamate derivatives by using different transition metal salts or Brønsted acids. Such selectivity was obtained when these olefins either separately acted as the dienophiles or were simultaneously present on the same dienophiles. Complete selectivity was also achieved between the stilbene olefin and acetylene to furnish the key chroman intermediate for the subsequent ring-closing metathesis (RCM), affording the corresponding tetracyclic 5H-dihydronaphtho[1,2-c]chromene.
RESUMO
In four steps from the tricyclic core, palodesangren B trimethyl ether and palodesangren D dimethyl ether could be synthesized in 29 and 18% overall yields, respectively. A reaction sequence comprising the regioselective MgCl2-mediated Casnati-Skattebøl ortho-formylation of phenol, Wittig methylenation, acryloylation, and Ru(II)-catalyzed ring-closing metathesis (RCM) led to the formation of the final 2H-pyran-2-one ring of the desired tetracyclic core.