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1.
Chem Sci ; 14(18): 4745-4758, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37181769

RESUMO

The complete account of the total syntheses of scabrolide A and yonarolide is disclosed. This article describes an initial approach involving a bio-inspired macrocyclization/transannular Diels-Alder cascade, which ultimately failed due to undesired reactivity during macrocycle construction. Next, the evolution of a second and third strategy, which both involve an initial intramolecular Diels-Alder reaction followed by a late-stage closure of the seven-membered ring of scabrolide A are detailed. The third strategy was first validated on a simplified system, but problems were encountered during a key [2 + 2] photocycloaddition on the fully elaborated system. An olefin protection strategy was employed to circumvent this problem, ultimately leading to the completion of the first total synthesis of scabrolide A and the closely related natural product yonarolide.

2.
J Org Chem ; 87(21): 14115-14124, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36269312

RESUMO

We utilize ab initio quantum mechanics calculations to evaluate a range of plausible mechanistic pathways for the unexpected formation of a [6-4-4] ring system from an enone-olefin photocycloaddition in the synthesis of (-)-scabrolide A, previously reported by our group. We present a mechanistic analysis that is consistent with all current experimental observations, including the photoexcitation, the C-C bond formation, and the associated chemo- and diastereoselectivity.


Assuntos
Teoria Quântica
3.
J Am Chem Soc ; 144(44): 20232-20236, 2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36287147

RESUMO

The first total synthesis of the furanobutenolide-derived cembranoid diterpenoid havellockate is disclosed. Our convergent strategy employs a Julia-Kocienski olefination to join two enantioenriched fragments to produce a diene that is subsequently used in a propiolic acid esterification/Diels-Alder cascade. This sequence generates the fused carbocyclic core of the natural product in short order. A challenging Zn-mediated Barbier allylation then forges the final C-C bond and also establishes two vicinal stereogenic centers. Finally, a Cu-catalyzed aerobic oxidation facilitates the formation of the ß-hydroxybutanolide to complete the total synthesis.


Assuntos
Diterpenos , Estereoisomerismo
4.
J Am Chem Soc ; 142(19): 8585-8590, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32223255

RESUMO

The first total synthesis of the norcembranoid diterpenoid scabrolide A is disclosed. The route begins with the synthesis of two chiral pool-derived fragments, which undergo a convergent coupling to expediently introduce all 19 carbon atoms of the natural product. An intramolecular Diels-Alder reaction and an enone-olefin cycloaddition/fragmentation sequence are then employed to construct the fused [5-6-7] linear carbocyclic core of the molecule and complete the total synthesis.

5.
J Am Chem Soc ; 139(30): 10196-10199, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28721734

RESUMO

An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late-stage C-H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C-H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/síntese química , Engenharia de Proteínas , Diterpenos/química , Diterpenos/metabolismo , Oxirredução , Estereoisomerismo
6.
Org Lett ; 17(21): 5160-3, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26501770

RESUMO

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.


Assuntos
Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Paládio/química , Alquilação , Catálise , Ligantes , Estrutura Molecular , Estereoisomerismo
7.
J Org Chem ; 78(23): 12189-93, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24180591

RESUMO

Neoglycosylations are increasingly being employed in the synthesis of natural products, drug candidates, glycopeptide mimics, oligosaccharide analogues, and other applications, but the efficiency of these reactions is usually limited by slow reaction times. Here, we show that aniline derivatives such as 2-amino-5-methoxybenzoic acid enhance the rate of acid-catalyzed neoglycosylation for a range of sugar substrates up to a factor of 32 relative to the uncatalyzed reaction.


Assuntos
Compostos de Anilina/química , Glicosídeos/síntese química , Configuração de Carboidratos , Catálise , Glicosídeos/química , Concentração de Íons de Hidrogênio
8.
J Org Chem ; 78(4): 1670-6, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23368752

RESUMO

The amphimedosides, discovered in 2006, are the first examples of naturally occurring glycosylated alkoxyamines. We report syntheses of amphimedosides A-C that feature a stereoselective oxyamine neoglycosylation and found that these alkaloids display modest cytotoxicity toward seven diverse human cancer cell lines, exhibiting IC(50) values ranging from 3.0 µM to greater than 100 µM.


Assuntos
Alcaloides/química , Amino Açúcares/síntese química , Antineoplásicos/síntese química , Alcaloides/farmacologia , Alcaloides/toxicidade , Amino Açúcares/química , Amino Açúcares/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glicosilação , Humanos , Concentração Inibidora 50 , Estereoisomerismo
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