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Methyl groups are ubiquitous in natural products and biologically active compounds, but methods for their selective transformation in such structures are limited. For example, terpenoids contain many methyl groups, due to their biosynthetic pathways, but few reactions of these groups in such structures have been reported. We demonstrate that the combination of methyl C-H silylation and oxidation proximal to native hydroxyl or carbonyl groups occurs in a range of terpenoids and show that the installed hydroxyl group serves as a toehold to enable substitution, elimination, or integration of the methyl carbon into the terpenoid skeleton by the cleavage of C-C bonds. In one case, substitution of the entire methyl group occurs by further oxidation and decarboxylative coupling. In a second, substitution of the methyl group with hydrogen occurs by photochemical hydrodecarboxylation or epimerization by retro-Claisen condensation. In a third, photocatalytic decarboxyolefination formally eliminates methane from the starting structure to generate a terminal olefin for further transformations. Finally, a Dowd-Beckwith-type rearrangement cleaves a nearby C-C bond and integrates the methyl group into a ring, forming derivatives with unusual and difficult-to-access expanded rings. This strategy to transform a methyl group into a synthon marks a distinct approach to restructuring the skeletons of complex architectures and adding functional groups relevant to medicinal chemistry., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

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.

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.

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.

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.

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(sp 3 )-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., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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, BF 3 ·Et 2 O) were ineffective in this glycosylation, but B(C 6 F 5 ) 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/CF 3 Ph) to provide flexible, effective access to the β-linked pentasaccharide.

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.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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 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.

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 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.