Phomoxanthone A Targets ATP Synthase.

Phomoxanthone A is a naturally occurring molecule and a powerful anti-cancer agent, although its mechanism of action is unknown. To facilitate the determination of its biological target(s), we used affinity-based labelling using a phomoxanthone A probe. Labelled proteins were pulled down, subjected to chemoproteomics analysis using LC-MS/MS and ATP synthase was identified as a likely target. Mitochondrial ATP synthase was validated in cultured cells lysates and in live intact cells. Our studies show sixty percent inhibition of ATP synthase by 260 µM phomoxanthone A.

Copper Bis(oxazoline)-Catalyzed Enantioselective Alkynylation of Benzopyrylium Ions.

The stereocontrolled construction of biologically relevant chromanones and tetrahydroxanthones has been achieved through the addition of alkynes to benzopyrylium trilfates under the influence of copper bis(oxazoline) catalysis. Excellent levels of enantiocontrol (63-98 % ee) are achieved in the addition of a variety of alkynes to an array of chromenones with a hydrogen in the 2-position. Promising levels of enantiocontrol (54-67 % ee) are achieved in the alkynylation of chromenones with esters in the 2-position, generating tertiary ether stereocenters resembling those frequently found in naturally occurring metabolites.

Enantioselective S-H Insertion Reactions of α-Carbonyl Sulfoxonium Ylides.

The first example of enantioselective S-H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S-H insertion reactions of aryl thiols and α-carbonyl sulfoxonium ylides.

Synthesis and Anticancer Activity of Structure Simplified Naturally-Inspired Dimeric Chromenone Derivatives.

Select dimeric chromenones exhibit low micromolar cyctotoxicity toward lymphoma and leukemia cell lines, L5178Y and HL60, respectively. The bioactive dimeric chromenones were identified from a focused library of structurally-simplified derivatives of naturally-occurring dimeric chromenones and tetrahydroxanthones that was prepared as part of this study. The simple dimeric chromenone scaffolds contain no stereogenic centers, are easily synthesized, and may be utilized as lead compounds in cancer research and drug discovery.

Enantioselective Catalyst Systems from Copper(II) Triflate and BINOL-Silanediol.

Silanediol and copper catalysis are merged, for the first time, to create an enhanced Lewis acid catalyst system for enantioselective heterocycle functionalization. The promise of this silanediol and copper catalyst combination is demonstrated in the enantioselective addition of indoles to alkylidene malonates to give rise to the desirable adducts in excellent yield and high enantiomeric excess. From these studies, 1,1'-bi-2-naphthol (BINOL)-based silanediols emerge as one-of-a-kind cocatalysts. Their potential role in the reaction pathway is also discussed.

Urea-induced acid amplification: a new approach for metal-free insertion chemistry.

The enhanced catalytic activity of difluoroboronate ureas proved to be essential as an acidity amplifier to promote metal-free O-H and S-H insertion reactions of α-aryldiazoacetates in high yield. This methodology was found to be generally applicable to a broad substrate scope and presents a conceptually new approach for organocatalytic diazo insertion reactions. Mechanistic investigations suggest that the reaction pathway involves a urea-induced protonation of the α-aryldiazoester.

Urea-catalyzed N-H insertion-arylation reactions of nitrodiazoesters.

The power of hydrogen-bond donor catalysis has been harnessed to elicit and control carbene-like reactivity from nitrodiazoesters. Specifically, select ureas have been identified as effective catalysts for N-H insertion and multicomponent coupling reactions of nitrodiazoesters, anilines, and aromatic nucleophiles, thereby preparing a variety of α-aryl glycines in high yield. Experimental and computational studies designed to probe the plausible reaction pathways suggest that difluoroboronate ureas are particularly well-suited to catalyze reactions of nitrodiazoesters with a range of anilines through a polar reaction pathway. Urea-facilitated loss of nitrite followed by addition of a nucleophile conceivably generates the observed aryl glycine products.

Nitrimines as reagents for metal-free formal C(sp(2) )-C(sp(2) ) cross-coupling reactions.

Nitrimines are employed as powerful reagents for metal-free formal C(sp(2) )-C(sp(2) ) cross-coupling reactions. The new chemical process is tolerant of a wide array of nitrimine and heterocyclic coupling partners giving rise to the corresponding di- or trisubstituted alkenes, typically in high yield and with high stereoselectivity. This method is ideal for the metal-free construction of heterocycle-containing drug targets, such as phenprocoumon.

Urea-catalyzed construction of oxazinanes.

Highly functionalized oxazinanes are efficiently prepared through urea-catalyzed formal [3 + 3] cycloaddition reactions of nitrones and nitrocyclopropane carboxylates. The reaction system is general with respect to both the nitrocyclopropane carboxylates and nitrones enabling the preparation of a large family of oxazinanes, typically in high yield. This method affords access to enantioenriched oxazinane products through chirality transfer from enantioenriched nitrocyclopropane carboxylates.

Arylation of diazoesters by a transient N-H insertion organocascade.

It takes two: A unique organocatalyzed cascade for the unsymmetric double arylation of α-nitrodiazoesters is described. This organocascade features the strategic use of carbene-activating anilines in conjunction with a urea catalyst, thus allowing for the synthesis of pharmaceutically attractive α-diarylesters through a transient NH insertion process.

Chiral silanediols in anion-binding catalysis.

A perfect pair: Silanediols are effective catalysts for the addition of silyl ketene acetals to N-acylisoquinolinium ions. Importantly, this is the first example of a silanediol plausibly participating in anion-binding catalysis, a relatively new direction in the field of hydrogen-bond-donor catalysis. The chiral, enantiopure C2 -symmetric silanediol 1 catalyzes enantioselective transformations.

Enantioselective Access to Tetrahydroxanthones via Copper-bis(oxazoline)-Catalyzed [4 + 2] Cycloaddition.

Highly enantioselective access to tetrahydroxanthone compounds was achieved through copper-bis(oxazoline)-catalyzed [4 + 2] cycloaddition of chrom-4-one dienophiles and Danishefsky's diene. Oxo-dihydroxanthone (enone) adducts, containing a quaternary stereocenter, are generated in up to 98% yield and 89% ee. Cycloadducts are utilized in the synthesis of tetrahydroxanthones, featuring a novel organotin-mediated quasi-Krapcho decarboxylation of ß-keto esters, with retention of stereochemistry. Tetrahydroxanthone is a versatile intermediate to a diverse array of biologically relevant, saturated xanthones.

Correction: Dearomatization of benzopyrylium triflates with sulfoxonium ylides.

Correction for 'Dearomatization of benzopyrylium triflates with sulfoxonium ylides' by Alexandria N. Leveille et al., Chem. Commun., 2022, 58, 12600-12603, https://doi.org/10.1039/D2CC02023H.

Highly Enantioselective Catalytic Alkynylation of Quinolones: Substrate Scope, Mechanistic Studies, and Applications in the Syntheses of Chiral N-Heterocyclic Alkaloids and Diamines.

The alkynylation of 4-siloxyquinolinium triflates has been achieved under the influence of copper bis(oxazoline) catalysis. The identification of the optimal bis(oxazoline) ligand was informed through a computational approach that enabled the dihydroquinoline products to be produced with up to 96% enantiomeric excess. The conversions of the dihydroquinoline products to biologically relevant and diverse targets are reported.

Urea activation of α-nitrodiazoesters: an organocatalytic approach to N-H insertion reactions.

The combination of a urea catalyst and an α-nitro-α-diazo ester gives rise to a reactive species able to undergo insertion into the N-H bonds of anilines. This new strategy to achieve N-H insertion reactivity is in contrast to typical metal-catalyzed conditions for the generation of carbenoids from α-diazocarbonyl compounds. This report includes the extension of the insertion reaction to a three-component coupling for the construction of α-amino-α-aryl esters in high yield.

Dearomatization of benzopyrylium triflates with sulfoxonium ylides.

Benzopyrylium triflates react with sulfoxonium ylides to give rise to cyclopropanated products in up to 90% yield as a single diastereomer. The cyclopropanated products can easily undergo acid-mediated ring-expansion to afford benzo[b]oxepines. Control over the absolute stereochemistry of the process is possible when the reaction is executed under the influence of a suitable anion-binding catalyst.

Enantioselective Dearomative Alkynylation of Chromanones: Opportunities and Obstacles.

A catalytic and highly enantioselective dearomative alkynylation of chromanones has been discovered that enables the construction of biologically relevant tertiary ether stereogenic centers. This methodology is robust, accommodating a variety of alkynes and chromanones. More than 40 substrates tested gave rise to >90% ee. Computational studies have indicated that the optimal indanyl ligand identified for most cases likely affords a network of supportive, non-covalent interactions that drive the enantioselective nature of the reaction.

Enantioselective Indole Insertion Reactions of α-Carbonyl Sulfoxonium Ylides.

The first example of organocatalytic enantioselective C-H insertion reactions of indoles and sulfoxonium ylides is reported. Under the influence of phosphoric acid catalysis, levels of enantiocontrol in the range of 20-93% ee and moderate yields (up to 50%) were achieved for 29 examples in formal C-H insertion reactions of free indoles and α-carbonyl sulfoxonium ylides. No nitrogen protection on the indole is necessary.

Robust, Enantioselective Construction of Challenging, Biologically Relevant Tertiary Ether Stereocenters.

A robust, catalytic enantioselective method to construct challenging, biologically relevant, tertiary ether stereocenters has been developed. The process capitalizes on readily accessible bis(oxazoline) ligands to control the facial selectivity of the addition of copper acetylides to benzopyrylium triflates, reactive species generated in situ. Up to 99% enantiomeric excesses are achieved with a broad substrate scope. Using density functional theory (DFT) calculations, the origin of the experimentally observed enantiocontrol was attributed to additional non-covalent interactions observed in the transition state leading to the major enantiomer, such as π-stacking. The resultant substrates have direct applications in the synthesis of naturally occurring bioactive chromanones and tetrahydroxanthones.