Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

Mizoguchi, Haruki; Oikawa, Hideaki; Oguri, Hiroki

doi:10.1038/nchem.1798

Cited by 210 publications

(96 citation statements)

References 53 publications

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“…For instance, 1,4‐dihydropyridine is employed as medicine for calcium channel blocker, hypertension, cardiovascular, Alzheimer's diseases, and multidrug‐resistant cancers . Also, 1,2‐dihydropyridine is an important intermediate in the synthesis of natural products and pharmaceutical targets . The traditional methods for synthesis of these compounds have various weak points such as the use of expensive catalyst, harsh reaction conditions, and poor chemoselectivity and regioselectivity .…”

Section: Introductionmentioning

confidence: 99%

Theoretical prediction of Ni(I)‐catalyst for hydrosilylation of pyridine and quinoline

2019

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Catalytic synthesis of dihydropyridine by transition‐metal complex is one of the important research targets, recently. Density functional theory calculations here demonstrate that nickel(I) hydride complex (bpy)NiIH (bpy = 2,2′‐bipyridine) 1 is a good catalyst for hydrosilylation of both quinoline and pyridine. Two pathways are possible; in path 1, substrate reacts with 1 to form stable intermediate Int1. After that, N3─C1 bond of substrate inserts into Ni─H bond of 1 via TS1 to afford N‐coordinated 1,2‐dihydroquinoline Int2 with the Gibbs activation energy (ΔG°‡) of 21.8 kcal mol−1. Then, Int2 reacts with hydrosilane to form hydrosilane σ‐complex Int3; this is named path 1A. In the other route (path 1B), Int1 reacts with phenylsilane in a concerted manner via hydride‐shuttle transition state TS2 to afford Int3. In TS2, Si atom takes hypervalent trigonal bipyramidal structure. Formation of hypervalent structure is crucial for stabilization of TS2 (ΔG°‡ = 17.3 kcal mol−1). The final step of path 1 is metathesis between Ni─N3 bond of Int3 and Si─H bond of PhSiH3 to afford N‐silylated 1,2‐dihydroproduct and regenerate 1 (ΔG°‡ = 4.5 kcal mol−1). In path 2, 1 reacts with hydrosilane to form Int5, which then forms adduct Int6 with substrate through Si–N interaction between substrate and PhSiH3. Then, N‐silylated 1,2‐dihydroproduct is produced via hydride‐shuttle transition state TS5 (ΔG°‡ = 18.8 kcal mol−1). The absence of N‐coordination of substrate to NiI in TS5 is the reason why path 2 is less favorable than path 1B. Quinoline hydrosilylation occurs more easily than pyridine because quinoline has the lowest unoccupied molecular orbital at lower energy than that of pyridine. © 2019 Wiley Periodicals, Inc.

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Section: Introductionmentioning

confidence: 99%

Theoretical prediction of Ni(I)‐catalyst for hydrosilylation of pyridine and quinoline

2019

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“…Although DOS has emerged as an indispensable tool to promote the unbiased screening of compounds and their interactions with diverse biological targets, one of the key challenges in this field is the identification of appropriate chemical structures that will exhibit improved biological relevance and high molecular diversity. To address this issue, synthetic community has been developing many DOS-based approaches for the generation of compound libraries embodying core scaffolds of natural products or its mimetics7891011. Natural products have inherent bioactivity and high bioavailability; thus, the natural product-inspired DOS libraries with biological relevance could be of great value for the identification of bioactive compounds121314.…”

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confidence: 99%

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

et al. 2016

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Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

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“…The biosynthesis of the cancer drug vinblastine in the plant Catharanthus roseus provides a remarkable example in which a single precursor (dehydrosecodine [ 15 ]) is cyclized to two different products (catharanthine [ 16 ] and tabersonine [ 17 ]) by two chemo and stereoselective [4+2] cyclases (Scheme A). Decades of biomimetic chemical investigation support the notion that divergent Diels‐Alder cyclisations of the hypothetical intermediate dehydrosecodine ( 15 ) could provide the two distinct scaffolds, catharanthine ( 16 ) and tabersonine ( 17 ), by an inverse‐ and a normal‐electron‐demand Diels–Alder reaction, respectively. Through a combination of in planta silencing, bioinformatics and recombinant assays, the enzymes controlling this crucial branch point have finally been identified .…”

Section: Controlling (Stereo)selectivitymentioning

confidence: 97%

Biocatalytic Strategies towards [4+2] Cycloadditions

Lichman

O’Connor

Kries

2019

Chemistry A European J

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Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understanding are underway by means of crystallography and computational modelling. This Minireview aims to shed light on the catalytic strategies that this highly diverse family of enzymes employs to accelerate and direct the course of [4+2] cycloadditions with reference to small‐molecule catalysts and designer enzymes. These catalytic strategies include oxidative or reductive triggers and lid‐like movements of enzyme domains. A precise understanding of natural cycloaddition catalysts will be instrumental for customizing them for various synthetic applications.

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Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

Cited by 210 publications

References 53 publications

Theoretical prediction of Ni(I)‐catalyst for hydrosilylation of pyridine and quinoline

Theoretical prediction of Ni(I)‐catalyst for hydrosilylation of pyridine and quinoline

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Biocatalytic Strategies towards [4+2] Cycloadditions

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