The catalytic asymmetric polyene cyclization of homofarnesol to ambrox.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Asymmetric Catalytic Friedel-Crafts Reactions of Unactivated Arenes.

Since its discovery more than a century ago, the Friedel-Crafts reaction has manifested itself as a powerful method for the introduction of carbon substituents to arenes. Despite its potential generality, the scope of the reaction is intrinsically limited by the arene's nucleophilicity, which has previously restrained the applicability of asymmetric variants to activated substrates. To overcome this fundamental limitation, we report herein an asymmetric Friedel-Crafts reaction of unactivated, purely hydrocarbon arenes, alkoxybenzenes, and heteroarenes with N,O-acetals to give enantioenriched arylglycine esters. Highly regio- and stereoselective C-C bond formation was achieved using strong and confined Brønsted acid organocatalysts, enabling the first asymmetric catalytic Friedel-Crafts reaction of simple alkylbenzenes.

Direct Regioselective Dehydrogenation of α-Substituted Cyclic Ketones.

We disclose a highly regioselective, catalytic one-step dehydrogenation of α-substituted cyclic ketones in the presence of 2,3-dichlorobenzo-5,6-dicyano-1,4-benzoquinone (DDQ). The high regioselectivity originates from a phosphoric acid-catalyzed enolization, selectively affording the thermodynamically preferred enol, followed by the subsequent oxidation event. Our method provides reliable access to several α-aryl and α-alkyl substituted α,ß-unsaturated ketones.

Direct and Catalytic C-Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside.

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.

Bis-Cyclometalated Indazole and Benzimidazole Chiral-at-Iridium Complexes: Synthesis and Asymmetric Catalysis.

A new class of bis-cyclometalated iridium(III) catalysts containing two inert cyclometalated 6-tert-butyl-2-phenyl-2H-indazole bidentate ligands or two inert cyclometalated 5-tert-butyl-1-methyl-2-phenylbenzimidazoles is introduced. The coordination sphere is complemented by two labile acetonitriles, and a hexafluorophosphate ion serves as a counterion for the monocationic complexes. Single enantiomers of the chiral-at-iridium complexes (>99% er) are obtained through a chiral-auxiliary-mediated approach using a monofluorinated salicyloxazoline and are investigated as catalysts in the enantioselective conjugate addition of indole to an α,ß-unsaturated 2-acyl imidazole and an asymmetric Nazarov cyclization.

Dual copper- and photoredox-catalysed C(sp2)-C(sp3) coupling.

The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has recently emerged as a versatile means of developing new C-C bond forming reactions. In this work, dual copper and photoredox catalysis is exploited to effect C(sp2)-C(sp3) cross-couplings between aryl boronic acids and benzyl bromides.