Rhodium-Catalyzed Asymmetric Functionalization of Quinoxalinium Salts.

We report a rhodium-catalyzed asymmetric addition of aryl and alkenyl boronic acids to quinoxalinium salts that generates dihydroquinoxalines with high enantioselectivity. Functionalization of the reaction products, dihydroquinoxaline, allows the preparation of tetrahydroquinoxalines with various substitution patterns.

Catalyst-Controlled Enantioselective and Regiodivergent Addition of Aryl Boron Nucleophiles to N-Alkyl Nicotinate Salts.

Dihydropyridines are versatile building blocks for the synthesis of pyridines, tetrahydropyridines, and piperidines. Addition of nucleophiles to activated pyridinium salts allows synthesis of 1,2-, 1,4-, or 1,6-dihydropyridines; however, this process often leads to a mixture of constitutional isomers. Catalyst-controlled regioselective addition of nucleophiles to pyridiniums has the potential to solve this problem. Herein, we report that the regioselective addition of boron-based nucleophiles to pyridinium salts can be accomplished by the choice of a Rh catalyst.

Dearomatization of Heteroarenium Salts with ArBpin Reagents. Application to the Total Synthesis of a Nuphar Alkaloid.

Rhodium-catalyzed enantioselective addition of aryl and heteroaryl boron pinacol esters to pyridinium and quinolinium salts is developed for the synthesis of enantioenrichred dihydroheteroarenes. The methodology has enabled the synthesis of 2-heteroaryl-substituted dihydropyridines in high yield and ee, which provided efficient synthetic access to a nuphar alkaloid.

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

Synthesis of the hexacyclic triterpene core of the jujuboside saponins via tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction.

The jujubosides are saponin natural products reported to have immunoadjuvant, anticancer, antibacterial, antifungal, and antisweet activities. The triterpene component, jujubogenin contains a unique tricyclic ketal motif comprising the DEF ring system. Herein, we describe our efforts toward the total synthesis of jujubogenin, using a sterically-demanding intermolecular Diels-Alder reaction to assemble the C-ring and a tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction to form the DF-ring system. Acid-catalyzed cyclization of the resulting bicyclic enol ether then closes the E-ring to provide the hexacyclic core of jujubogenin.

Transition-Metal-Catalyzed Selective Functionalization of C(sp3 )-H Bonds in Natural Products.

Direct functionalization of natural products is important for studying the structure-activity and structure-property relationships of these molecules. Recent advances in the transition-metal-catalyzed functionalization of C(sp3 )-H bonds, the most abundant yet inert bonds in natural products, have allowed natural product derivatives to be created selectively. Strategies to achieve such transformation are reviewed.

Rapid assembly of the doubly-branched pentasaccharide domain of the immunoadjuvant jujuboside A via convergent B(C6F5)3-catalyzed glycosylation of sterically-hindered precursors.

A convergent synthesis of the complex, doubly-branched pentasaccharide domain of the natural-product immunoadjuvant jujuboside A is described. The key step is a sterically-hindered glycosylation reaction between a branched trisaccharide trichloroacetimidate glycosyl donor and a disaccharide glycosyl acceptor. Conventional Lewis acids (TMSOTf, BF3·Et2O) were ineffective in this glycosylation, but B(C6F5)3 catalyzed the reaction successfully. Inherent complete diastereoselectivity for the undesired α-anomer was overcome by rational optimization with a nitrile solvent system (1 : 5 t-BuCN/CF3Ph) to provide flexible, effective access to the ß-linked pentasaccharide.

Late Stage Azidation of Complex Molecules.

Selective functionalization of complex scaffolds is a promising approach to alter the pharmacological profiles of natural products and their derivatives. We report the site-selective azidation of benzylic and aliphatic C-H bonds in complex molecules catalyzed by the combination of Fe(OAc)2 and a PyBox ligand. The same system also catalyzes the trifluoromethyl azidation of olefins to form derivatives of natural products containing both fluorine atoms and azides. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Azides obtained by functionalization of C-H and C=C bonds were converted to the corresponding amines, amides, and triazoles, thus providing a wide variety of nitrogen-containing complex molecules.

Mild, Pd-catalyzed stannylation of radioiodination targets.

Trialkylstannanes are versatile precursors for chemical transformations, including radiolabeling with a variety of halogens, particularly iodine. In the present work a convenient, Pd-mediated stannylation method is presented that can be performed in an open flask. The method is selective for aryl iodides allowing selective stannylations in the presence of other halogen atoms. The reaction conditions are mild, making the method compatible with chemically sensitive bioactive compounds.

Preparation and X-ray crystal structure of 2-iodyl-N,N-dialkylaniline oxides: first entry into the heterocyclic system of benziodoxazole.

The oxidation of 2-iodo-N,N-dialkylanilines with an excess of dimethyldioxirane in acetone affords 2-iodyl-N,N-dialkylaniline oxides, structural features of which are in agreement with the new heterocyclic system of benziodoxazole.

Preparation and reactivity of polymer-supported 2-iodylphenol ethers, an efficient recyclable oxidizing system.

Preparation of new recyclable polymer-supported oxidizing reagents based on 2-iodylphenol ethers is described. The synthesis employs commercially available aminomethylated polystyrene or Merrifield resin and affords polymer-supported 2-iodylphenol ethers with loading up to 0.86 mmol/g with respect to IO2 groups. The new reagents effect clean and efficient conversion of a wide range of alcohols, including heteroatomic and unsaturated structures, to the corresponding carbonyl compounds. Recycling of the resins is possible with minimal loss of activity after several reoxidations.

RuCl3-catalyzed oxidation of iodoarenes with peracetic acid: new facile preparation of iodylarenes.

New facile methodology for the preparation of pentavalent iodine compounds using peracetic acid as an oxidant in the presence of catalytic amounts of ruthenium trichloride is described. The new procedure allows the preparation of several previously unknown iodylarenes bearing strongly electron-withdrawing CF3 groups in the aromatic ring.

2-iodylphenol ethers: preparation, X-ray crystal structure, and reactivity of new hypervalent iodine(V) oxidizing reagents.

2-Iodylphenol ethers were prepared by the dimethyldioxirane oxidation of the corresponding 2-iodophenol ethers and isolated as chemically stable, microcrystalline products. Single-crystal X-ray diffraction analysis of 1-iodyl-2-isopropoxybenzene 8c and 1-iodyl-2-butoxybenzene 8d revealed pseudopolymeric arrangements in the solid state formed by intermolecular interactions between IO2 groups of different molecules. 2-Iodylphenol ethers can selectively oxidize sulfides to sulfoxides and alcohols to the respective aldehydes or ketones.