A shift in retrosynthetic paradigm

The current state-of-the-art synthesis for the formation of enantiomerically enriched all-carbon quaternary stereocenters in acyclic system relies on the formation of a single carbon-carbon bond per chemical step by asymmetric catalysis. These extraordinary sophisticated methods were logically classified among the most powerful and innovative ones. In this concept article, we are proposing a new retrosynthetic paradigm to solve differently such challenging problems. These new synthetic pathways lead to the diastereo- and enantiomerically pure formation of three new carbon-carbon bonds in acyclic system, in a one-pot reaction, including the formation of all-carbon quaternary stereocenters by using classical reagents and experimental conditions and from common starting materials.     

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C−C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C−C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C−C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.     

Asymmetric construction of all-carbon quaternary stereocenters in the total synthesis of natural products

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quaternary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.     

Catalytic enantioselective construction of all-carbon quaternary stereocenters: synthetic and mechanistic studies of the C-acylation of silyl ketene acetals

With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate).     

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

All-carbon quaternary stereocenters are ubiquitous in natural products and significant in drug molecules. However, construction of all-carbon stereocenters is a challenging project due to their congested chemical environment. And, when vicinal all-carbon quaternary stereocenters are present in one molecule, they will dramatically increase its synthetic challenge. A chiral titanium promoted enantioselective photoenolization/Diels–Alder (PEDA) reaction allows largely stereohindered tetra-substituted dienophiles to interact with highly active photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing vicinal all-carbon quaternary centers in excellent enantiomeric excess through one-step operation. This newly developed enantioselective PEDA reaction will inspire other advances in asymmetric excited-state reactions, and could be used in the total synthesis of structurally related complex natural products or drug-like molecules for drug discovery.

An enantioselective PEDA reaction was developed to enable stereohindered dienophiles to interact with transient photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing 2–3 vicinal all-carbon quaternary centers in good yield and excellent ee.     

Synthesis of Chiral Triarylmethanes Bearing All-Carbon Quaternary Stereocenters: Catalytic Asymmetric Oxidative Cross-Coupling of 2,2-Diarylacetonitriles and (Hetero)arenes

A direct and enantioselective oxidative cross-coupling of racemic 2,2-diarylacetonitriles with electron-rich (hetero)arenes has been described, which allows for efficient construction of triarylmethanes bearing all-carbon quaternary stereocenters with excellent chemo- and enantioselectivity. The reaction has an excellent functional group tolerance, and exhibits a broad scope with respect to both 2,2-diarylacetonitrile and (hetero)arene components. The rich chemistry of the cyano group allows for facile synthesis of other valuable chiral triarylmethanes bearing all-carbon quaternary centers that are otherwise difficult to access.     

Facile synthesis of enantioenriched Cγ-tetrasubstituted α-amino acid derivatives via an asymmetric nucleophilic addition/protonation cascade

An asymmetric nucleophilic addition/protonation reaction of 3-substituted oxindoles and ethyl 2-phthalimidoacrylate has been described. This strategy can give direct access to C(γ)-tetrasubstituted α-amino acid derivatives bearing 1,3-nonadjacent stereocenters with up to 98% yield, 94:6 dr, and >99% ee. Dual activation is proposed in the transition state, and the opposite enantiomers can be obtained simply by changing cinchonidine-derived catalyst to the cinchonine analogue.     

Dual-function cinchona alkaloid catalysis: catalytic asymmetric tandem conjugate addition-protonation for the direct creation of nonadjacent stereocenters

Catalytic tandem asymmetric reactions constitute a powerful strategy for the asymmetric construction of nonadjacent stereocenters in acyclic molecules directly from achiral precursors. In this Communication, we report a highly enantioselective and diastereoselective addition of trisubstituted carbon donors to 2-chloroacrylonitrile catalyzed by bifunctional cinchona alkaloid catalysts. This represents the first asymmetric tandem conjugate addition-protonation with efficient catalytic control of two nonadjacent stereocenters. As demonstrated in a concise and highly stereoselective formal total synthesis of (-)-manzacidin A, this asymmetric tandem reaction establishes a new and versatile catalytic approach for the enantioselective and diastereoselective creation of 1,3-tertiary-quaternary stereocenters.     

Enantioselective synthesis of decalin structures with all-carbon quaternary centers via one-pot sequential Cope/Rauhut–Currier reaction

The first example of a one-pot sequential Cope/Rauhut–Currier reaction is reported and used to make functionalized decalin structures with all-carbon quaternary stereocenters. The substrates for the new sequential reaction are generated through a six-step sequence including an enantioselective Birch reduction-allylation reaction which makes the overall process asymmetric.     

Asymmetric Catalytic [4+5] Annulation of ortho-Quinone Methides with Vinylethylene Carbonates and its Extension to Stereoselective Tandem Rearrangement

Palladium-catalyzed asymmetric [4+5] annulation of ortho-quinone methides (o-QMs) with substituted vinylethylene carbonates (VECs) is described for the first time, giving a novel enantioselective approach to chiral nine-membered benzoheterocycles. Based on this designed [4+5] annulation, an unprecedented silica gel-promoted tandem rearrangement reaction featuring a unique asymmetric aromatic Claisen rearrangement is explored at room temperature, offering a new method for asymmetric construction of all-carbon quaternary stereocenters embedded in chiral functionalized homoallylic alcohols.     

Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.     

Sterically Demanding Unsymmetrical Diaryl-λ3-iodanes for Electrophilic Pentafluorophenylation and an Approach to α-Pentafluorophenyl Carbonyl Compounds with an All-Carbon Stereocenter

A sterically demanding unsymmetrical pentafluorophenyl-triisopropylphenyl-λ³-iodane was developed as an effective reagent for the electrophilic pentafluorophenylation of various β-keto esters and a β-keto amide. 17 examples of α-pentafluorophenylated 1,3-dicarbonyl compounds 3 having a quaternary carbon center are provided. The resulting compounds were nicely transformed into chiral α-pentafluorophenyl ketones with an all-carbon stereogenic center in high yields and high enantioselectivities using asymmetric organocatalysis (up to 98 % ee) or asymmetric metal catalysis (up to 82 % ee).     

Copper(I)-catalyzed asymmetric desymmetrization: synthesis of five-membered-ring compounds containing all-carbon quaternary stereocenters

A highly stereoselective catalytic alkylation sequence for the synthesis of highly functionalized and versatile five-membered-ring compounds bearing all-carbon quaternary stereocenters was developed. Enantioselective desymmetrization of achiral cyclopentene-1,3-diones was thus executed by chiral Cu-phosphoramidite catalysts. A variety of complicated cyclopentane derivatives can be synthesized with excellent stereoselectivities using a low catalyst loading in a one-pot operation.     

Access to 1,3-Dinitriles by Enantioselective Auto-tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation

Enantioselective auto-tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one-pot conversion of a broad array of allylic alcohols into their corresponding 1,3-dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.     

Asymmetric Catalysis with CO2: The Direct α‐Allylation of Ketones

Quaternary stereocenters are found in numerous bioactive molecules. The Tsuji–Trost reaction has proven to be a powerful C?C bond forming process, and, at least in principle, should be well suited to access quaternary stereocenters via the α‐allylation of ketones. However, while indirect approaches are known, the direct, catalytic asymmetric α‐allylation of branched ketones has been elusive until today. By combining “enol catalysis” with the use of CO₂ as a formal catalyst for asymmetric catalysis, we have now developed a solution to this problem: we report a direct, highly enantioselective and highly atom‐economic Tsuji–Trost allylation of branched ketones with allylic alcohol. Our reaction delivers products bearing quaternary stereocenters with high enantioselectivity and water as the sole by‐product. We expect our methodology to be of utility in asymmetric catalysis and inspire the design of other highly atom‐economic transformations.     

Access to 1,3‐Dinitriles by Enantioselective Auto‐tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation

Enantioselective auto‐tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one‐pot conversion of a broad array of allylic alcohols into their corresponding 1,3‐dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.     

Axially chiral guanidine as highly active and enantioselective catalyst for electrophilic amination of unsymmetrically substituted 1,3-dicarbonyl compounds

A newly designed axially chiral guanidine is found to function as an effective platform for asymmetric induction at the alpha-carbon of unsymmetrically substituted 1,3-dicarbonyl compounds. Highly efficient and enantioselective electrophilic amination of various 1,3-dicarbonyl compounds with azodicarboxylate was successfully achieved using the present chiral guanidine catalyst, which provides efficient access to the construction of nitrogen-substituted quaternary stereocenters in an optically active form.     

Enantioselective construction of quaternary carbon centre catalysed by bifunctional organocatalyst

The bifunctional thiourea-tertiary amine derivatives of simple chiral diamines serve as highly enantioselective catalysts for the Michael addition of alpha-substituted cyanoacetates to vinyl sulfones, giving an efficient protocol for the construction of an all-carbon substituted quaternary stereocentre.     

Highly diastereo- and enantioselective tandem reaction toward functionalized pyrrolidines with multiple stereocenters

An efficient asymmetric tandem dual Michael reaction that constructs three contiguous stereocenters in acyclic open-chain systems with very high enantioselectivity and diastereoselectivity has been developed. This protocol provides a reliable and rapid approach for synthesis of chiral pyrrolidines with multiple stereocenters.     

Ruthenium(II)-Catalyzed Asymmetric Inert C−H Bond Activation Assisted by a Chiral Transient Directing Group

A ruthenium(II)-catalyzed asymmetric intramolecular hydroarylation assisted by a chiral transient directing group has been developed. A series of 2,3-dihydrobenzofurans bearing chiral all-carbon quaternary stereocenters have been prepared in remarkably high yields (up to 98 %) and enantioselectivities (up to >99 % ee). By this methodology, a novel asymmetric total synthesis of CB2 receptor agonist MDA7 has been successfully developed.