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1.
Org Lett ; 25(9): 1547-1552, 2023 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-36827601

RESUMO

Xyloketal B is a pentacyclic fungal marine natural product that has shown potential for the treatment of diseases such as Alzheimer's disease and atherosclerosis. Herein, we describe the first asymmetric synthesis of this natural product, which relies on a chemoenzymatic strategy. This approach leverages a biocatalytic benzylic hydroxylation to access to an ortho-quinone methide intermediate which is captured in a [4 + 2] cycloaddition to stereoselectively yield a key cyclic ketal intermediate enroute to (+)-xyloketal B. The relative configuration of this intermediate was rapidly confirmed as the desired stereoisomer using MicroED. To complete the synthesis, a second ortho-quinone methide was accessed through a reductive approach, ultimately leading to the stereoselective synthesis of (+)-xyloketal B.


Assuntos
Indolquinonas , Piranos , Estereoisomerismo
2.
Chem Soc Rev ; 49(22): 8137-8155, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-32701110

RESUMO

Catalytic C-H oxyfunctionalization reactions have garnered significant attention in recent years with their ability to streamline synthetic routes toward complex molecules. Consequently, there have been significant strides in the design and development of catalysts that enable diversification through C-H functionalization reactions. Enzymatic C-H oxygenation reactions are often complementary to small molecule based synthetic approaches, providing a powerful tool when deployable on preparative-scale. This review highlights key advances in scalable biocatalytic C-H oxyfunctionalization reactions developed within the past decade.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Oxigenases/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Biocatálise , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química
3.
J Am Chem Soc ; 141(51): 20269-20277, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31840992

RESUMO

Generation of reactive intermediates and interception of these fleeting species under physiological conditions is a common strategy employed by Nature to build molecular complexity. However, selective formation of these species under mild conditions using classical synthetic techniques is an outstanding challenge. Here, we demonstrate the utility of biocatalysis in generating o-quinone methide intermediates with precise chemoselectivity under mild, aqueous conditions. Specifically, α-ketoglutarate-dependent non-heme iron enzymes, CitB and ClaD, are employed to selectively modify benzylic C-H bonds of o-cresol substrates. In this transformation, biocatalytic hydroxylation of a benzylic C-H bond affords a benzylic alcohol product which, under the aqueous reaction conditions, is in equilibrium with the corresponding o-quinone methide. o-Quinone methide interception by a nucleophile or a dienophile allows for one-pot conversion of benzylic C-H bonds into C-C, C-N, C-O, and C-S bonds in chemoenzymatic cascades on preparative scale. The chemoselectivity and mild nature of this platform is showcased here by the selective modification of peptides and chemoenzymatic synthesis of the chroman natural product (-)-xyloketal D.


Assuntos
Indolquinonas/biossíntese , Ferroproteínas não Heme/metabolismo , Indolquinonas/química , Estrutura Molecular , Monascus/enzimologia , Ferroproteínas não Heme/química , Penicillium/enzimologia , Estereoisomerismo
4.
Chem Biol Drug Des ; 93(6): 1207-1213, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30485666

RESUMO

Technologies enabling new enzyme discovery and efficient protein engineering have spurred intense interest in the development of biocatalytic reactions. In recent years, whole-cell biocatalysis has received attention as a simple, efficient, and scalable biocatalytic reaction platform. Inspired by these developments, we have established a whole-cell protocol for oxidative dearomatization of phenols using the flavin-dependent monooxygenase, TropB. This approach provides a scalable biocatalytic platform for accessing gram-scale quantities of chiral synthetic building blocks.


Assuntos
Biocatálise , Fenóis/metabolismo , Escherichia coli/genética , Flavinas/metabolismo , Oxigenases de Função Mista/metabolismo , Oxirredução
5.
J Org Chem ; 82(24): 13656-13662, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29172511

RESUMO

The convergent synthesis of bicyclo[2.2.2]diazaoctane structures using an intermolecular Diels-Alder cycloaddition between a pyrazinone and commercially available fumarate or maleate precursors is reported. High reactivity and stereoselection is observed with both dienophile substrates. Structure validation was achieved by conversion of cycloadducts into known [2.2.2]diazabicyclic compounds or into crystalline derivatives suitable for X-ray analysis. The cycloadduct derived from reaction of pyrazinone and maleic anhydride underwent selective anhydride ring opening and intersected an established precursor in the synthesis of brevianamide B.


Assuntos
Alcaloides/química , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Alcaloides/síntese química , Reação de Cicloadição , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química
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