Synthesis of again natural products and synthetic rocaglate derivatives

The enantioselective total syntheses and absolute configuration assignments of (+)-ponapensin and (+)-elliptifoline have been achieved via enantioselective [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. The resulting cyclopenta[b,c]benzopyran was reduced through a reagent-controlled, diastereoselective reduction. Amidation was accomplished through direct ester-amide exchange mediated by trimethylaluminum, and diastereoselective N-acyliminium cyclization was observed likely due to stereoelectronic stabilization of one face of the N-acyliminium. The total syntheses revealed the absolute configuration to be opposite of what was hypothesized. These observations led to an interesting biosynthetic hypothesis in which a kinetic resolution/parallel kinetic resolution may be taking place. Through testing this conjecture, an asymmetric transfer hydrogenation kinetic resolution methodology was developed and applied to the first enantioselective total syntheses of (+)-aglaiastatin and (-)-aglaroxin C. The total syntheses confirmed the absolute configuration of these metabolites, and the natural enantiomers were found to be the most biologically active. Chiral urea, thiourea, trifluoroethanols, and TADDOLs have been evaluated as catalysts in the asymmetric [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate. Chiral trifluoroethanols such as Pirkle's alcohol promoted [3+2] photocycloaddition between 3-hydroxyflavone and methyl cinnamate with enantioselectivities up to 40% ee with 20 mol% loading. These additives may be interacting with 3-hydroxyflavone through an excited state double proton transfer mechanism. The synthesis, unexpected light-driven di-epimerization, and biological evaluation of a novel rocaglate-derived β-lactone and β-lactone analogs have been achieved. In addition to in vitro inhibition of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone enantiomer was found to inhibit ABHD10 in PC3 cells, suggesting that derivatives of this β-lactone may serve as valuable chemical probes. The mechanism of the photochemical di-epimerization was investigated and may be occurring through photochemical electron transfer. Biotinylated rocaglate derivatives have been synthesized and evaluated in a streptavidin pull down assay to determine the molecular target of rocaglates. eIF4G was pulled down as the molecular target for one of the biotinylated analogs, but eIF4A was not pulled down by any of the biotinylated analogs

Chemical proteomics approaches for identifying the cellular targets of natural products.

Covering: 2010 up to 2016. Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied "in situ" - in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide-alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss 'competitive mode' approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed

Enantioselective Photocycloaddition of 3‑Hydroxyflavones: Total Syntheses and Absolute Configuration Assignments of (+)-Ponapensin and (+)-Elliptifoline

We have previously reported development of biomimetic, asymmetric [3 + 2] photocycloadditions between 3-hydroxyflavones and cinnamate dipolarophiles to access (−)-rocaglamide and related natural products. Herein, we describe enantioselective syntheses of aglain cycloadducts leading to the first total syntheses and absolute configuration assignments of the aglain natural products (+)-ponapensin and (+)-elliptifoline

Remodeling Natural Products: Chemistry and Serine Hydrolase Activity of a Rocaglate-Derived β‑Lactone

Flavaglines are a class of natural products with potent insecticidal and anticancer activities. β-Lactones are a privileged structural motif found in both therapeutic agents and chemical probes. Herein, we report the synthesis, unexpected light-driven di-epimerization, and activity-based protein profiling of a novel rocaglate-derived β-lactone. In addition to <i>in vitro</i> inhibition of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone enantiomer was also found to inhibit these enzymes, as well as the serine peptidases CTSA and SCPEP1, in PC3 cells

Enantioselective Photocycloaddition of 3‑Hydroxyflavones: Total Syntheses and Absolute Configuration Assignments of (+)-Ponapensin and (+)-Elliptifoline

We have previously reported development of biomimetic, asymmetric [3 + 2] photocycloadditions between 3-hydroxyflavones and cinnamate dipolarophiles to access (−)-rocaglamide and related natural products. Herein, we describe enantioselective syntheses of aglain cycloadducts leading to the first total syntheses and absolute configuration assignments of the aglain natural products (+)<b>-</b>ponapensin and (+)<b>-</b>elliptifoline

A New Chiral Anthracene for the Asymmetric Diels−Alder/Retro-Diels−Alder Sequence

(−)-(R)-9-(1,2-Dimethoxyethyl)anthracene (8) is successfully employed as a chiral template in the Diels−Alder/retro-Diels−Alder sequence for the preparation of α,β-unsaturated lactams. The cycloadditions proceed with complete diastereoselectivity, and regioselectivity in subsequent transformations of the carbonyl groups is also excellent. Flash vacuum pyrolysis accomplishes the cycloreversion

Biomimetic Kinetic Resolution: Highly Enantio- and Diastereoselective Transfer Hydrogenation of Aglain Ketones To Access Flavagline Natural Products

We have previously reported asymmetric syntheses and absolute configuration assignments of the aglains (+)-ponapensin and (+)-elliptifoline and proposed a biosynthetic kinetic resolution process to produce enantiomeric rocaglamides and aglains. Herein, we report a biomimetic approach for the synthesis of enantiomerically enriched aglains and rocaglamides via kinetic resolution of a bridged ketone utilizing enantio­selective transfer hydrogenation. The methodology has been employed to synthesize and confirm the absolute stereochemistries of the pyrimidone rocaglamides (+)-aglaiastatin and (−)-aglaroxin C. Additionally, the enantiomers and racemate of each metabolite were assayed for inhibition of the heat-shock response, cytotoxicity, and translation inhibition

Attempted [2]Catenane Synthesis via a Quasi[1]catenane by a Templated Backfolding Strategy

A templated backfolding concept to construct a [2]catenane was attempted via a quasi[1]catenane showing an inverted spiro geometry. The template is covalently connected to the ketal-connected semi-perpendicular-arranged linear precursors and spatially directs the sterically congested backfolding macrocyclizations that are required to give a quasi[1]catenane. So far, we are unable to hydrolyze the cyclic ketal to liberate the [2]catenane

Remodeling Natural Products: Chemistry and Serine Hydrolase Activity of a Rocaglate-Derived β‑Lactone

Flavaglines are a class of natural products with potent insecticidal and anticancer activities. β-Lactones are a privileged structural motif found in both therapeutic agents and chemical probes. Herein, we report the synthesis, unexpected light-driven di-epimerization, and activity-based protein profiling of a novel rocaglate-derived β-lactone. In addition to <i>in vitro</i> inhibition of the serine hydrolases ABHD10 and ACOT1/2, the most potent β-lactone enantiomer was also found to inhibit these enzymes, as well as the serine peptidases CTSA and SCPEP1, in PC3 cells