The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A ...central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.
Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemoselective and enantioselective methodologies have emerged from ...total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three‐dimensional molecular architectures.
1, 2, …︁ 3 dearomaticity: The conversion of planar, aromatic scaffolds (arenes, phenols, and heteroarenes) into three‐dimensional molecular architectures is a powerful strategy for the total synthesis of complex natural products. This Review highlights recent developments and outlines future perspectives and opportunities for catalytic, enantioselective dearomatization processes.
Total syntheses of the dimeric tetrahydroxanthone natural products secalonic acids A and D are described. Key steps involve kinetic resolution of the tetrahydroxanthone core structure using ...homobenzotetramisole catalysis and late‐stage copper(I)‐mediated homodimerization of complex aryl stannane monomers.
It takes two: Concise syntheses of the natural products secalonic acids A and D using copper(I)‐mediated dimerization of complex aryl stannane monomers to construct the requisite 2,2′‐biphenol linkage are reported. Highly efficient kinetic resolution of the monomeric tetrahydroxanthone core structures was achieved using homobenzotetramisole catalysis. DMA=N,N‐dimethyl acetamide, MOM=methoxymethyl.
New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and ...drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans. Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe's species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy.
We report a stereodivergent, asymmetric total synthesis of (−)‐clusianone in six steps from commercial materials. We implement a challenging cationic cyclization forging a bond between two sterically ...encumbered quaternary carbon atoms. Mechanistic studies point to the unique ability of formic acid to mediate the cyclization forming the clusianone framework.
Aim for selectivity: (−)‐Clusianone was produced by a stereodivergent asymmetric total synthesis in six steps from commercial materials. The synthesis utilizes a challenging formic acid‐mediated cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms.
Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the ...early structure diversity‐generating step in fungal meroterpenoid biosynthetic pathways: the multibond‐forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline‐sponge‐based X‐ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non‐canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.
Fungal meroterpenoid cyclases, a recently discovered family of membrane‐integrated terpene cyclases, have been exploited as tools for the synthesis of second generation meroterpenoid natural products. The results demonstrate a broad substrate tolerance leading to several new meroterpenoid scaffolds. DFT calculations provided insights into the mechanism of enzyme‐mediated polyene cyclizations.
Covering: 1972 to 2012
Polycyclic xanthone natural products are a family of polyketides which are characterized by highly oxygenated, angular hexacyclic frameworks. In the last decade, this novel ...class of molecules has attracted noticeable attention from the synthetic and biological communities due to emerging reports of their potential use as antitumour agents. The aim of this article is to highlight the most recent developments of this subset of the xanthone family by detailing the innate challenges of the construction of this class of natural products, new synthetic approaches, and pharmacological data.
Polycyclic xanthones have recently attracted significant attention due to their potential as antitumour agents. This
Highlight
summarizes key advancements in the construction of this class of natural products, new synthetic approaches, and pharmacological data.
An unprecedented caged 2H-benzo-dioxo-pentacycloundecane framework was serendipitously obtained in a single transformation via triple-dearomative photocycloaddition of chromone esters with furans. ...This caged structure was generated as part of an effort to access a tricyclic, oxygen-bridged intermediate enroute to the dihydroxanthone natural product nidulalin A. Reaction scope and limitations were thoroughly investigated, revealing the ability to access a multitude of synthetically challenging caged scaffolds in a two-step sequence. Photophysical studies provided key mechanistic insights on the process for formation of the novel caged scaffold.
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis ...and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nidulaxanthone A is a dimeric, dihydroxanthone natural product that was isolated in 2020 from Aspergillus sp. Structurally, the compound features an unprecedented heptacyclic 6/6/6/6/6/6/6 ring ...system which is unusual for natural xanthone dimers. Biosynthetically, nidulaxanthone A originates from the monomer nidulalin A via stereoselective Diels–Alder dimerization. To expedite the synthesis of nidulalin A and study the proposed dimerization, we developed methodology involving the use of allyl triflate for chromone ester activation, followed by vinylogous addition, to rapidly forge the nidulalin A scaffold in a four-step sequence which also features ketone desaturation using Bobbitt’s oxoammonium salt. An asymmetric synthesis of nidulalin A was achieved using acylative kinetic resolution (AKR) of chiral, racemic 2H-nidulalin A. Dimerization of enantioenriched nidulalin A to nidulaxanthone A was achieved using solvent-free, thermolytic conditions. Computational studies have been conducted to probe both the oxoammonium-mediated desaturation and (4 + 2) dimerization events.
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