Rhodium-Catalyzed Hydrogenation Research Articles

Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Rhodium-Catalyzed ON-OFF Switchable Hydrogenation Using a Molecular Shuttle Based on a [2]Rotaxane with a Phosphine Ligand.

A novel pH-responsive molecular shuttle based on a [2]rotaxane with a phosphine ligand has been designed and synthesized. In the rhodium-catalyzed hydrogenation of α,β-dehydroamino acid esters and aryl enamides, ON/OFF-switchable catalysis was accomplished with high ON/OFF ratios by adjusting the movements of the rotaxane wheels located at the catalyst terminals with acid/base. Mechanistic studies using NMR spectroscopy and quasi in situ X-ray photoelectron spectroscopy revealed that RhIII -hydride species are possibly formed in a H2 atmosphere when the catalyst is in the OFF state. During the reaction, a heterolytic activation of dihydrogen occurs by the interlocked rotaxane dibenzylamine and RhI catalytic center acting as a frustrated Lewis pair. Subsequent homolytic splitting of dihydrogen with the newly formed RhI -hydride species generates RhIII -hydride species. These findings show that a substrate-selective hydrogenation can be achieved by using the OFF-state catalyst.

Enantioselective Rhodium-Catalyzed Hydrogenation of (Z)-N-Sulfonyl-α-dehydroamido Boronic Esters.

Highly enantioselective rhodium-catalyzed hydrogenation of (Z)-N-sulfonyl-α-dehydroamido boronic esters is realized for the first time using a JosiPhos-type ligand. This method has enabled convenient synthesis of a series of enantio-enriched N-sulfonyl-α-amido boronic esters in good yields and excellent enantioselectivities (up to 99% ee).

Rhodium-Catalyzed Hydrogenation of Enamides and α-or β-Dehydroamino Acids

Key words rhodium catalysis - hydrogenation - enamides - dehydroamino acids - acetamides - asymmetric catalysis

Diastereoselective Rhodium-Catalyzed Hydrogenation of 2-Oxindoles and 3,4-Dihydroquinolones.

The benzene ring of indolin-2-ones (2-oxindoles) and 3,4-dihydroquinol-2-ones was converted to a saturated cyclohexane ring by hydrogenation in the presence of the rhodium complex Cy(CAAC)Rh(cod)Cl. The stereoselectivity of the process was found to be high with respect to both external substituent R1 within the saturated part of the heterocyclic ring and substituent X on the benzene ring. Twenty-one hexahydroindolin-2(3H)-ones (70-99% yield, dr = 83/17 to >99/1) and twelve octahydro-2(1H)-quinolinones (87-96% yield, dr = 64/36 to >99/1) were obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward functional groups and the compatibility with existing stereogenic centers are key features of the hydrogenation protocol presented here.

Real-Time Detection of Intermediates in Rhodium-Catalyzed Hydrogenation of Alkynes and Alkenes by Dissolution DNP

The hydrogenation of alkynes and alkenes using Shrock–Osborn catalysts was followed in situ with dissolution dynamic nuclear polarization (dDNP) NMR. Natural abundance and 13C-labeled dimethyl acetylenedicarboxylate was hyperpolarized prior to hydrogenation using (1,4-bis{diphenylphosphino}butane)(2,5-norbornadiene) rhodium(I) perchlorate, [Rh(NBD)(DPPB)]ClO4. The increased signal-to-noise ratio of dDNP compared to conventional 13C NMR allowed real-time detection of substrates and products as well as the modeling of the hydrogenation kinetics. The build-up of an intermediate was observed during interruption in hydrogen flow, substantiating the current view of the reaction mechanism. Selective inversion of the carbonyl NMR signal of the substrate was applied to demonstrate unequivocally that the new peak appearing in the spectrum originates from a reaction intermediate. The scope of the dDNP method for following reaction dynamics in real time was further demonstrated by substrate competition experiments.

Rhodium-Catalyzed Hydrogenation–Desymmetrization of Cyclohexadienones

Rhodium-Catalyzed Hydrogenation–Desymmetrization of Cyclohexadienones

Rhodium-Catalyzed Hydrogenation of Enol Esters

Rhodium-Catalyzed Hydrogenation of Enol Esters

Rhodium-Catalyzed cis-Selective Hydrogenation of Fluoroarenes

Rhodium-Catalyzed cis-Selective Hydrogenation of Fluoroarenes

Enantioselective Rhodium-Catalyzed Hydro-genation of Tri- and Tetrasubstituted Olefins

Enantioselective Rhodium-Catalyzed Hydro-genation of Tri- and Tetrasubstituted Olefins

Rhodium-Catalyzed Hydrogenation of Tetrasubstituted Cyclic Enamides

Rhodium-Catalyzed Hydrogenation of Tetrasubstituted Cyclic Enamides

Asymmetric Rhodium-Catalyzed Hydrogenation Generating Benzodiazepines

Asymmetric Rhodium-Catalyzed Hydrogenation Generating Benzodiazepines

Mass transfer and convection effects in small-scale catalytic hydrogenation

The reaction rate of rhodium-catalyzed hydrogenation of alkynes was shown to be strongly influenced by the transfer of the hydrogen gas into the solution and stirring in the solution.

Synthesis of α-Amino Ketones by Rhodium-Catalyzed Hydrogenation

Synthesis of α-Amino Ketones by Rhodium-Catalyzed Hydrogenation

An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

A classical resolution of a racemic carboxylic acid through salt formation and an asymmetric hydrogenation of an α,β-unsaturated carboxylic acid were investigated in parallel to prepare an enantiomerically pure alkanoic acid used as a key intermediate in the synthesis of an antiplaque candidate drug. After an extensive screening of rhodium- and ruthenium-based catalysts, we developed a rhodium-catalyzed hydrogenation that gave the alkanoic acid with 90% ee, and after a subsequent crystallization with (R)-1-phenylethanamine, the ee was enriched to 97%. The chiral acid was then used in sequential Negishi and Suzuki couplings followed by basic hydrolysis of a nitrile to an amide to give the active pharmaceutical ingredient in 22% overall yield.

A DFT study of the role of water in the rhodium-catalyzed hydrogenation of acetone.

The positive effect of the addition of water to acetone hydrogenation by [RhH2(PR3)2S2]+ catalysts has been studied by DFT calculations. The studied energetic profiles reveal that the more favourable mechanistic path involves a hydride migration to the ketone followed by a reductive elimination that is assisted by two water molecules.

ChemInform Abstract: Pinene‐Derived Monodentate Phosphoramidites for Asymmetric Hydrogenation.

AbstractNewly synthesized phosphoramidite ligands are used in asymmetric catalysis.

ChemInform Abstract: Tandem Rhodium Catalysis: Exploiting Sulfoxides for Asymmetric Transition‐Metal Catalysis

AbstractReview: 29 refs.

Enantioseletive Rhodium-Catalyzed Hydrogenation of Enamides

Key words rhodium - bisdentate phosphine ligands - asymmetric hydrogenation

Enantioseletive Rhodium-Catalyzed Hydrogenation of Enamides

Enantioseletive Rhodium-Catalyzed Hydrogenation of Enamides