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1.
J Org Chem ; 81(4): 1333-57, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26796481

RESUMO

Full details on the evaluation and application of an easily feasible and generally useful method for configurational assignments of isolated methyl-bearing stereocenters are reported. The analytical tool relies on a bioinformatic gene cluster analysis and utilizes a predictive enoylreductase alignment, and its feasibility was demonstrated by the full stereochemical determination of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain. Furthermore, a full account of our strategies and tactics that culminated in the total synthesis of ajudazol B, the most potent and least abundant of these structurally unique class of myxobacterial natural products, is presented. Key features include an application of an asymmetric ortholithiation strategy for synthesis of the characteristic anti-configured hydroxyisochromanone core bearing three contiguous stereocenters, a modular oxazole formation, a flexible cross-metathesis approach for terminal allyl amide synthesis, and a late-stage Z,Z-selective Suzuki coupling. This total synthesis unambiguously proves the correct stereochemistry, which was further corroborated by comparison with reisolated natural material. Finally, 5-lipoxygenase was discovered as an additional molecular target of ajudazol B. Activities against this clinically validated key enzyme of the biosynthesis of proinflammatory leukotrienes were in the range of the approved drug zileuton, which further underlines the biological importance of this unique natural product.


Assuntos
Araquidonato 5-Lipoxigenase/química , Produtos Biológicos/síntese química , Cumarínicos/síntese química , Hidroxiureia/análogos & derivados , Araquidonato 5-Lipoxigenase/biossíntese , Produtos Biológicos/química , Biologia Computacional , Cumarínicos/química , Humanos , Hidroxiureia/química , Hidroxiureia/farmacologia , Estereoisomerismo
2.
Nat Prod Rep ; 31(4): 456-67, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24362363

RESUMO

This review presents recent advances in sequential catalytic methods developed in our group for the rapid and stereoselective synthesis of key structural features of complex polyketides. These include a novel domino reaction, based on a combination of a nucleophilic addition and a Tsuji-Trost reaction, an innovative sequence relying on an oxidative diyne cyclization and regioselective opening, as well as sequential cross coupling strategies. The design and scope of these methods are discussed and applications in complex target syntheses presented.


Assuntos
Produtos Biológicos/síntese química , Policetídeos/síntese química , Produtos Biológicos/química , Catálise , Ciclização , Estrutura Molecular , Policetídeos/química , Estereoisomerismo
3.
Org Lett ; 21(6): 1939-1942, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30840465

RESUMO

The enantioselective total synthesis of (+)-salimabromide was accomplished by a concise two-step conversion of the fully functionalized dibromo-tetraline core, involving a one-pot Baeyer-Villiger/allylic oxidation by an innovative radical reagent combination. This route unequivocally resolves the stereochemistry and reveals the highly unusual, almost racemic nature of natural salimabromide.

4.
Org Lett ; 17(12): 2956-9, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26020357

RESUMO

A concise synthesis of the tricyclic core 2 of the structurally unique marine myxobacterial natural product salimabromide has been developed. Compound 2 contains the tetraline subunit including the two quaternary centers and the eight-membered ring of salimabromide. Major features for its synthesis include a Lewis base catalyzed Denmark-crotylation for stereoselective construction of the highly hindered quaternary stereocenter, an innovative iodine/selectfluor induced endo-carbocylization, and a unique chemoselective carbonylative lactonization of the eight-membered ring.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
5.
Org Lett ; 15(4): 964-7, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23391209

RESUMO

A concise total synthesis of dysidavarone A possessing the new "dysidavarane" carbon skeleton has been accomplished by a convergent strategy, involving a stereoselective reductive alkylation of a Wieland-Miescher type ketone under Birch conditions and an advantageous intramolecular palladium-catalyzed α-arylation of a sterically hindered ketone. Dysidavarone A showed potent antimicrobial and antiproliferative activities based on characteristic morphological changes of treated cells.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Paládio/química , Quinonas/síntese química , Quinonas/farmacologia , Sesquiterpenos/síntese química , Sesquiterpenos/farmacologia , Compostos de Espiro/química , Alquilação , Animais , Antibacterianos/química , Antineoplásicos/química , Catálise , Dysidea/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Quinonas/química , Sesquiterpenos/química , Estereoisomerismo
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