‘Elegant’ catalysts that tell left from right scoop chemistry Nobel
Benjamin List and David MacMillan share the award for developing cheap, environmentally friendly organic catalysts.
Benjamin List and David MacMillan share the award for developing cheap, environmentally friendly organic catalysts.
A long-standing problem in chemistry has been to find catalysts that allow molecules to distinguish between the two faces of reaction intermediates called carbocations. A way around the problem has been found. See Letter p.245
The field of organocatalysis has grown rapidly in the past decade to become, along with metal catalysis and biocatalysis, a third pillar of asymmetric catalysis. Here, progress in the use of organocatalytic cascade reactions for total synthesis is reviewed. The elegance and efficiency of such cascades mean that they have emerged as a powerful tool in synthetic organic chemistry.
An organocatalytic cascade reaction allows the rapid construction of (+)-ricciocarpin A, which exhibits potent molluscicidal activity against the water snails Biomphalaria glabrata. The concise synthesis also allowed the synthesis of five analogues, one of which was shown to have significantly improved biological activity.
The domination of metals in catalysis is under threat as organic catalysts gain ground. The latest example may expand chemical reactivity beyond the achievements of traditional metal complexes.
Organocatalysis has become a major pillar of (asymmetric) catalysis. Here, the authors discuss recent trends in organocatalytic activation modes for challenging stereoselective transformations and the emerging integration with other fields, such as photoredox catalysis and electrosynthesis.
A concise new synthesis of the most complex of the prostaglandins—diverse hormone-like chemical messengers—should make existing prostaglandin-based drugs cheaper and also facilitate other related syntheses.
Cross-coupling reactions are widely used for creating new carbon–carbon bonds in chemical syntheses. Using the cross-coupling concept, Wang and colleagues present an organocatalytic strategy for the direct and stereoselective α-arylation of enals that occurs under mild conditions.
A versatile and rapid metallaphotoredox catalytic method of making 3H- and 11C-labelled tracer compounds for use in positron emission tomography (PET) is reported.
In 1949, Winstein and Trifan proposed that the 2-norbornyl cation adopts a bridged, non-classical structure. Now, the generation of an asymmetric environment around the three-centre two-electron bond of such an ion has been reported, enabling highly enantioselective catalytic addition reactions to a simple, non-functionalized non-classical cation.
A one-step, three-component radical coupling of [1.1.1]propellane by a photoredox reaction mediated by a copper catalyst produces drug-like bicyclopentanes.
Investigation of a reaction scope usually starts with the optimization for a model substrate. Here, the authors apply a time-efficient multi-substrate screening approach to identify a general organocatalyst for the Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes.
Chiral tertiary aldols are encountered in a variety of biologically relevant molecules. Making these valuable compounds directly from unbiased ketones has proven to be extremely challenging. Now it has been shown that sub-ppm levels of in situ generated silylium-based organic Lewis acid catalysts can give quantitative product formation in very high enantiopurity through a Mukaiyama aldol reaction.
Using a triple catalytic approach, a selective sp3 C–H alkylation is demonstrated that is applicable in late-stage functionalization of pharmaceutical compounds.
The catalytic asymmetric α-alkylation of aldehydes has historically been a significant challenge within organic synthesis. Now, this elusive transformation has been achieved through the merger of organocatalysis, photoredox catalysis and hydrogen-atom transfer catalysis to enable the coupling of simple olefins and aldehydes.
Asymmetric cyanosilyation is a powerful method to convert carbonyls to chiral, configurationally stable cyanohydrins. Here, the authors report a catalyst capable of carrying out this reaction on large scales with extremely low catalyst loading, and also identify and explain a dormant period in the cycle.
The biochemical process of spin-centre shift is used to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors; this represents the first broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis.
Photoredox and organic catalysis are combined to achieve broadly effective direct arylation of allylic carbon–hydrogen bonds under mild conditions; this carbon–carbon bond forming reaction readily accommodates a wide range of alkene and electron-deficient arene coupling partners.
A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts.
Organocatalysts are useful in a wide range of useful transformations, including a carbon–carbon bond forming process known as the Mannich reaction. But these reactions always failed when the simplest possible substrate, acetaldehyde, was used. This paper has now filled this gap in the market by devising effective organocatalytic conditions for Mannich reactions with acetaldehyde, greatly expanding the chemical 'toolkit' of organic chemists.
After two decades of steady growing, symbiotic merger of organocatalysis with emerging electrochemical and photochemical tools are envisioned as hot topics in the coming decade. Here, these trends are discussed in parallel to the implementation of artificial intelligence-based technologies, which anticipate a paradigm shift in catalyst design.
Transition metal catalysis is well established as an enabling tool in synthetic organic chemistry. Photoredox catalysis has recently emerged as a method to effect reactions that occur through single-electron-transfer pathways. Here we review the combination of the two to show how this provides access to highly reactive oxidation states of transition metals and distinct activation modes that further enable the synthetic chemist.
The application of organocatalysis in biology is still in its infancy. In this Review, we evaluate organocatalytic reactions in terms of their applicability in biological settings, including new technologies in chemical biology and biomedicine.
Although it is a fundamental property of many small molecules, chirality is not widely exploited in materials applications as its benefits are not widely recognized — indeed, the need for stereoselective synthesis may be seen as a disadvantage. In this Review, we highlight recent research in which chirality has had an enabling impact in technological applications.
This Review discusses recent developments in the combination of organocatalysis and photochemistry for the activation of molecules, which has enabled previously inaccessible reaction pathways and influenced many fields of chemical research.
The past decade has seen unprecedented growth in the development of chemical methods that proceed by mechanisms involving radical intermediates, but controlling absolute stereochemistry has been a longstanding challenge in this area. This Review Article examines how attractive non-covalent interactions between a chiral catalyst and the substrate can exert enantiocontrol in radical reactions.
Asymmetric transamination of
Asymmetric activation of amide bonds remains a challenge due to the high stability of amide linkages. Here, the authors show an organocatalytic asymmetric C-N bond cleavage of N-sulfonyl biaryl lactams under mild conditions, to access axially chiral biaryl amino acids.
Natural products often contain complex N-fused polycyclic structures with multiple substituents and stereocentres. Here, the authors developed a bifunctional organocatalyst that is instrumental in obtaining such structures and applied it to the total synthesis of naucleofficine I and II in 6 steps.
Indole-fused polycyclic alkaloids are present in numerous bioactive natural products. Here an enantioselective N-heterocyclic carbene-catalysed Friedel–Crafts alkylation/annulation cascade using acyl azolium salts as the electrophile provides access to these products with high stereoselectivity.
Benzylic functionalisation of unactivated toluenes remains a challenge in asymmetric catalysis. Here a chiral Brønsted base catalyses the enantioselective C(sp3)-H functionalization of unactivated alkylarenes, enabling carbon-carbon bond formation at benzylic positions of toluene derivatives.
The use of activating and directing groups can dramatically alter the course of a reaction. Now, it has been shown that an azo group can effectively perform as both in chiral phosphoric-acid catalysed formal nucleophilic aromatic substitution of azobenzene derivatives with indoles, affording axially chiral arylindoles with excellent enantioselectivities.
Direct coupling of aliphatic C–H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis.
Axially chiral biaryls have proven to have a wide variety of uses—perhaps most importantly as ligands in asymmetric catalysis—but their synthesis remains challenging. Here, Bin Tan and colleagues report a redox-neutral aryl–aryl coupling, providing a direct route to N,N and N,O axially chiral biaryls in high yields and enantioselectivities.
There are very few methods for the organocatalytic aziridination of unactivated olefins. Here the authors report a simple ketone catalyst for the transfer of nitrogen to isolated carbon–carbon double bonds, with good substrate scope and in high yields.
The organocatalysed addition of aldehydes to nitroolefins is an extremely well-studied reaction that almost exclusively provides the syn-configured products. Here a general method to reverse the diastereoselectivity is reported, whereby a tripeptide catalyst consistently provides the anti product with high selectivity.
Enantioselective synthesis of atropisomeric biaryls is highly desirable due to the utility of these compounds as ligands and catalysts. Now, an organocatalytic polyketide cyclization is shown to convert poly-β-carbonyl compounds into binaphthalene derivatives in good enantioselectivities.
Stereochemical control in the asymmetric dihalogenation of alkenes and alkynes is challenging. Now, an organocatalytic method is developed, whereby installing a urea-directing moiety on these substrates enables their stereo- and regioselective homo- and hetero-dihalogenation.
Use of aryl halides as coupling precursors typically occurs through transition metal catalysis and/or photoredox chemistry, which requires some combination of light, metals, and oxidants or reductants. Here, the authors show a method to generate aryl radicals from halides using only an NHC organocatalyst.
Glycomimetics are structural mimics of carbohydrates that can replicate their biological activity but have improved drug-like properties. Here, using proline-catalysed α-halogenation/aldol cascades, carbohydrate building blocks are readily assembled and then diversified into glycomimetics including imino- and carbasugars.
Domino asymmetric electrophilic halocyclization is useful for the synthesis of polycyclic pharmaceutical compounds, but remains limited to the generation of fused rings. Now, the scope is extended to complex spirocycle products by a catalytic protocol involving an electron-rich thiourea catalyst.
Deuterated molecules are important both as labelled probes and as targets in their own right. Here the authors report a very simple and general deuteration of aldehydes, by the use of an N-heterocyclic carbene catalyst in the presence of D2O.
Axially chiral allenes that are normally present in natural products, bioactive molecules, organocatalysts, and functional materials are usually produced from propargylic derivatives. Here, the authors show direct use of propargylic alcohols for catalytic asymmetric allene synthesis.
The formation of chiral centres adjacent to carbonyl groups is a highly challenging task in asymmetric catalysis. Here, the authors report the asymmetric diakylation of carbonyls via an intramolceular α-cyclopropanation procedure.
Axially chiral compounds play an important role in areas such as asymmetric catalysis. Here, the authors report an organocatalytic asymmetric tyrosine click-like reaction, giving access to enantio enriched urazoles with restricted rotation around an N-C bond.