Vy M. Dong

Nickel‐Catalyzed Dehydrogenative Cross‐Coupling: Direct Transformation of Aldehydes into Esters and Amides

By exploring a new mode of nickel-catalyzed cross-coupling, a method to directly transform both aromatic and aliphatic aldehydes into either esters or amides has been developed. The success of this oxidative coupling depends on the appropriate choice of catalyst and organic oxidant, including the use of either α,α,α-trifluoroacetophenone or excess aldehyde. Mechanistic data that supports a catalytic cycle involving oxidative addition into the aldehyde C-H bond is also presented.

Rh-catalyzed C–C bond cleavage by transfer hydroformylation

Shifting hydroformylation into reverse The hydroformylation reaction is applied on large scale in the chemical industry to make aldehydes by adding hydrogen and carbon monoxide to olefins. The reverse process could also prove useful in modifying complex molecules for pharmaceutical research, but methods directed toward that end often strip off the CO without the hydrogen. Murphy et al. now show that a rhodium catalyst can achieve selective dehydroformylation of a diverse range of compounds under mild conditions (see the Perspective by Landis). The protocol relies on effective transfer of the CO and H2 equivalents to a sacrificial strained olefin added to the mix. Science, this issue p. 56; see also p. 29 A catalyst to selectively reverse a common chemical reaction offers versatile opportunities in molecular synthesis. [Also see Perspective by Landis] The dehydroformylation of aldehydes to generate olefins occurs during the biosynthesis of various sterols, including cholesterol in humans. Here, we implement a synthetic version that features the transfer of a formyl group and hydride from an aldehyde substrate to a strained olefin acceptor. A Rhodium (Xantphos)(benzoate) catalyst activates aldehyde carbon-hydrogen (C–H) bonds with high chemoselectivity to trigger carbon-carbon (C–C) bond cleavage and generate olefins at low loadings (0.3 to 2 mole percent) and temperatures (22° to 80°C). This mild protocol can be applied to various natural products and was used to achieve a three-step synthesis of (+)-yohimbenone. A study of the mechanism reveals that the benzoate counterion acts as a proton shuttle to enable transfer hydroformylation.

Substrate‐Directed Hydroacylation: Rhodium‐Catalyzed Coupling of Vinylphenols and Nonchelating Aldehydes

We report a protocol for the hydroacylation of vinylphenols with aryl, alkenyl, and alkyl aldehydes to form branched products with high selectivity. This cross-coupling yields α-aryl ketones that can be cyclized to benzofurans, and it enables access to eupomatenoid natural products in four steps or less from eugenol. Excellent reactivity and high levels of regioselectivity for the formation of the branched products were observed. We propose that aldehyde decarbonylation is avoided by the use of an anionic directing group on the alkene and a diphosphine ligand with a small bite angle.

Recognition and Site‐Selective Transformation of Monosaccharides by Using Copper(II) Catalysis

We demonstrate copper(II)-catalyzed acylation and tosylation of monosaccharides. Various carbohydrate derivatives, including glucopyranosides and ribofuranosides, are obtained in high yields and regioselectivities. Using this versatile strategy, the site of acylation can be switched by choice of ligand. Preliminary mechanistic studies support nucleophilic addition of a copper-sugar complex to the acyl chloride to be turnover limiting.

Transforming Olefins into γ,δ-Unsaturated Nitriles through Copper Catalysis

We have developed a strategy to transform olefins into homoallylic nitriles through a mechanism that combines copper catalysis with alkyl nitrile radicals. The radicals are easily generated from alkyl nitriles in the presence of the mild oxidant di-tert-butyl peroxide. This cross-dehydrogenative coupling between simple olefins and alkylnitriles bears advantages over the conventional use of halides and toxic cyanide reagents. With this method, we showcase the facile synthesis of a flavoring agent, a natural product, and a polymer precursor from simple olefins.

Enantioselective semireduction of allenes

Rh-hydride catalysis solves a synthetic challenge by affording the enantioselective reduction of allenes, thereby yielding access to motifs commonly used in medicinal chemistry. A designer Josiphos ligand promotes the generation of chiral benzylic isomers, when combined with a Hantzsch ester as the reductant. This semireduction proceeds chemoselectively in the presence of other functional groups, which are typically reduced using conventional hydrogenations. Isotopic labelling studies support a mechanism where the hydride is delivered to the branched position of a Rh-allyl intermediate.Reduction of allenes poses several challenges in terms of chemo-, regio- and enantio-selectivity. Here, the authors report a rhodium-Josiphos catalytic system that reduces a variety of aryl allenes to chiral benzylic compounds with excellent selectivity and functional group tolerance.

Hydrogenation catalyst generates cyclic peptide stereocentres in sequence

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst–substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.A simple amino acid can be recognized by a synthetic catalyst in a process that initiates the sequential reduction of cyclic dehydropeptides. An experimental and theoretical study provides evidence for a unique mechanism that involves unidirectional reduction to set four stereocentres around a macrocyclic ring.

Catalytic Hydrothiolation: Regio- and Enantioselective Coupling of Thiols and Dienes

We report a Rh-catalyzed hydrothiolation of 1,3-dienes, including petroleum feedstocks. Either secondary or tertiary allylic sulfides can be generated from the selective addition of a thiol to the more substituted double bond of a diene. The catalyst tolerates a wide range of functional groups, and the loading can be as low as 0.1 mol %.

Tandem Catalysis: Transforming Alcohols to Alkenes by Oxidative Dehydroxymethylation

We report a Rh-catalyst for accessing olefins from primary alcohols by a C-C bond cleavage that results in dehomologation. This functional group interconversion proceeds by an oxidation-dehydroformylation enabled by N, N-dimethylacrylamide as a sacrificial acceptor of hydrogen gas. Alcohols with diverse functionality and structure undergo oxidative dehydroxymethylation to access the corresponding olefins. Our catalyst protocol enables a two-step semisynthesis of (+)-yohimbenone and dehomologation of feedstock olefins.

Catalytic Alkyne Arylation Using Traceless Directing Groups

By using Pd0 /Mandyphos, we achieved a three-component aminoarylation of alkynes to generate enamines, which are then hydrolyzed to either α-arylphenones or α,α-diarylketones. This Pd-catalyzed method overcomes established known pathways to enable the use of amines as traceless directing groups for C-C bond formation.