Molecular Library Synthesis Using Complex Substrates: Expanding the Framework of Triterpenoids

Ignatenko, Vasily A.; Han, Yong; Tochtrop, Gregory P.

doi:10.1021/jo302211f

Cited by 26 publications

(32 citation statements)

References 45 publications

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“…Tetraketone 1 was prepared according to our previously published method 18 from doubly-protected bryonolic acid in two steps by oxidation of the Δ8,9 double bond with ruthenium tetroxide under Sharpless conditions. Early analysis of the bichromophoric structure of tetraketone 1 revealed that the ‘bowsprit’ hydrogen H-5 is in γ-position to the keto groups at C-8 and C-11.…”

Section: Resultsmentioning

confidence: 99%

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Approach for Expanding Triterpenoid Complexity via Divergent Norrish-Yang Photocyclization

Ignatenko

Tochtrop

2013

J. Org. Chem.

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Triterpenoids comprise a very diverse family of polycyclic molecules that is well-known to possess a myriad of medicinal properties. Therefore, triterpenoids constitute an attractive target for medicinal chemistry and diversity-oriented synthesis. Photochemical transformations provide a promising tool for the rapid, green and inexpensive generation of skeletal diversity in the construction of natural product-like libraries. With this in mind, we have developed a diversity-oriented strategy, whereby the parent triterpenoids bryonolic acid and lanosterol are converted to the pseudo-symmetrical polyketones by sequential allylic oxidation and oxidative cleavage of the bridging double bond at the B/C-ring fusion. The resultant polyketones were hypothesized to undergo divergent Norrish-Yang cyclization to produce unique 6/4/8-fused triterpenoid analogs. The subtle differences between parent triterpenoids led to dramatically different spatial arrangements of reactive functionalities. This finding was rationalized through conformational analysis to explain unanticipated photoinduced pinacolization, as well as the regio- and stereochemical outcome of the desired Norrish-Yang cyclization.

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Section: Resultsmentioning

confidence: 99%

“…14–16 In this regard, the increase in structural complexity of triterpenoid-like molecules through alteration of their carbocyclic core skeleton can be viewed as a promising tool to study the chemical biology and medicinal chemistry of this natural product family. 17–18 …”

Section: Introductionmentioning

confidence: 99%

Approach for Expanding Triterpenoid Complexity via Divergent Norrish-Yang Photocyclization

Ignatenko

Tochtrop

2013

J. Org. Chem.

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“…[47] Tw ot ypes of chemical approaches were applied to the di-and triketones 45-47, which were generated from acylated bryonolic acid or its derivatives by oxidative cleavage of the double bond between the steroidal Ba nd Cr ings using ruthenium chloride (Scheme 4a). First, the phototransformation potential of bis-(ketones) 46 and 52 was exploited in aN orrish-Yang reaction to form the novel scaffolds 51, 53,and 54.Second, transannular aldol reactions under different reaction conditions were expediently performed on these polycarbonyl substrates to afford molecules with NP-derived scaffolds (48-50, 55;S cheme 4a).…”

Section: Methodsmentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

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“…5). The pH values of the culture media were measured after cultivation of A. oryzae (OE::pksCH-2), [11][12][13][14][15] . c, Diversity-oriented semi-synthetic process that combines heterologous biosynthesis and artificial diversification (this work).…”

Section: Resultsmentioning

confidence: 99%

“…To conduct a successful screening of promising drug leads and biological probes, a compound library should be developed that is diverse with regard to the molecular framework. One strategy for expanding the diversity of natural-product-related scaffolds is to make good use of readily available natural products as starting points [11][12][13][14][15] . Although this semi-synthetic approach has great potential to expand the chemical space of natural products, the limited number of natural products that fulfil the availability and reactivity requirements has hindered the emergence of successful examples.…”

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confidence: 99%

Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides

et al. 2015

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The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.

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Molecular Library Synthesis Using Complex Substrates: Expanding the Framework of Triterpenoids

Cited by 26 publications

References 45 publications

Approach for Expanding Triterpenoid Complexity via Divergent Norrish-Yang Photocyclization

Approach for Expanding Triterpenoid Complexity via Divergent Norrish-Yang Photocyclization

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides

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