Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-Enynes

A cooperative Cu/Pd-catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl₂(dppf) complexes as catalysts, the 1,4-arylboration of 1,3-enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2-substituted 1,3-enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate-limiting step of this transformation.     

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd‐Catalyzed 1,4‐Arylboration of 1,3‐Enynes

A cooperative Cu/Pd‐catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl₂(dppf) complexes as catalysts, the 1,4‐arylboration of 1,3‐enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2‐substituted 1,3‐enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate‐limiting step of this transformation.     

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.

A mild reaction protocol for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis has been developed, which led to efficient synthesis of α-allenyl sulfones or 1,3-dienyl sulfones.     

Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis

We disclose herein the first example of merging photoredox catalysis and copper catalysis for radical 1,4-carbocyanations of 1,3-enynes. Alkyl N-hydroxyphthalimide esters are utilized as radical precursors, and the reported mild and redox-neutral protocol has broad substrate scope and remarkable functional group tolerance. This strategy allows for the synthesis of diverse multi-substituted allenes with high chemo- and regio-selectivities, also permitting late stage allenylation of natural products and drug molecules.

An efficient synthesis of multi-substituted allenes by metallaphotoredox-catalyzed decarboxylative 1,4-carbocyanation of 1,3-enynes is described.     

Chiral Lewis acid-bonded picolinaldehyde enables enantiodivergent carbonyl catalysis in the Mannich/condensation reaction of glycine ester

A new strategy of asymmetric carbonyl catalysis via a chiral Lewis acid-bonded aldehyde has been developed for the direct Mannich/condensation cascade reaction of glycine ester with aromatic aldimines. The co-catalytic system of 2-picolinaldehyde and chiral Yb^III-N,N′-dioxides was identified to be efficient under mild conditions, providing a series of trisubstituted imidazolidines in moderate to good yields with high diastereo- and enantioselectivities. Enantiodivergent synthesis was achieved via changing the sub-structures of the chiral ligands. The reaction could be carried out in a three-component version involving glycine ester, aldehydes, and anilines with equally good results. Based on control experiments, the X-ray crystal structure study and theoretical calculations, a possible dual-activation mechanism and stereo-control modes were provided to elucidate carbonyl catalysis and enantiodivergence.

The catalytic asymmetric Mannich/condensation of glycine ester with aldimines was achieved by merging chiral N,N′-dioxide/Yb^III complex Lewis acid catalysis/carbonyl catalysis under mild condition.     

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

A chiral cobalt(ii) complex catalyzed enantioselective aza-Piancatelli rearrangement/Diels–Alder cascade reaction

A chiral N,N′-dioxide/cobalt(ii) complex catalyzed highly diastereoselective and enantioselective tandem aza-Piancatelli rearrangement/intramolecular Diels–Alder reaction has been disclosed. Various valuable hexahydro-2a,5-epoxycyclopenta[cd]isoindoles bearing six contiguous stereocenters have been obtained in good yields with excellent diastereo- and enantio-selectivities from a wide range of both readily available 2-furylcarbinols and N-(furan-2-ylmethyl)anilines.

An asymmetric aza-Piancatelli rearrangement/Diels–Alder cascade reaction between 2-furylcarbinols and N-(furan-2-ylmethyl)anilines was realized by using a chiral N,N′-dioxide/cobalt(ii) complex catalyst.     

Rh(I)-catalyzed asymmetric addition of arylboronic acids to NH isatins

The transition metal-catalyzed asymmetric variant of the title reaction is normally limited to N-protected isatins. However, Rh(I)/chiral sulfoxide phosphine complexes were found to catalyze the enantioselective addition of arylboronic acids to NH isatins under mild conditions. A variety of chiral 3-aryl-3-hydroxyl-2-oxindoles were obtained with high yields and with good to excellent enantioselectivities (85–92% ee).     

Palladium/Xu-Phos-catalyzed asymmetric carboamination towards isoxazolidines and pyrrolidines

An efficient palladium-catalyzed enantioselective carboamination reaction of N-Boc-O-homoallyl-hydroxylamines and N-Boc-pent-4-enylamines with aryl or alkenyl bromides was developed, delivering various substituted isoxazolidines and pyrrolidines in good yields with up to 97% ee. The reaction features mild conditions, general substrate scope and scalability. The obtained products can be transformed into chiral 1,3-aminoalcohol derivatives without erosion of chirality. The newly identified Xu-Phos ligand bearing an ortho-OⁱPr group is responsible for the good yield and high enantioselectivity.

The new chiral ligand (S,Rs)-Xu4 with ortho-OⁱPr showed good performance in the asymmetric carboamination reaction of N-Boc-O-homoallyl-hydroxylamines and N-Boc-pent-4-enylamines with aryl or alkenyl bromides.     

Enantioselective aerobic oxidative cross-dehydrogenative coupling of glycine derivatives with ketones and aldehydes via cooperative photoredox catalysis and organocatalysis

The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and simple ketones or aldehydes, which provides an efficient approach for the rapid synthesis of enantiopure unnatural α-alkyl α-amino acid derivatives in good yield with excellent diastereo- (up to >99 : 1) and enantioselectivities (up to 97% ee). This process includes the direct photoinduced oxidation of glycine derivatives to an imine intermediate, followed by the asymmetric Mannich-type reaction with an enamine intermediate generated in situ from a ketone or aldehyde and a chiral secondary amine organocatalyst. This mild method allows the direct formation of a C–C bond with simultaneous installation of two new stereocenters without wasteful removal of functional groups.

A visible-light-induced enantioselective aerobic oxidative cross-dehydrogenative coupling between glycine derivatives and simple ketones or aldehydes is achieved.     

H-bond donor-directed switching of diastereoselectivity in the Michael addition of α-azido ketones to nitroolefins

The development of catalyst-controlled stereodivergent asymmetric catalysis is important for providing facile access to all stereoisomers of chiral products with multiple stereocenters from the same starting materials. Despite progress, new design strategies for diastereodivergent asymmetric catalysis are still highly desirable. Here we report the potency of H-bond donors as the governing factor to tune diastereoselectivity in a highly diastereoselective switchable enantioselective Michael addition of α-azido ketones to nitroolefins. While a newly developed bifunctional tertiary amine, phosphoramide, preferentially afforded syn-adducts, an analogous squaramide catalyst selectively gave anti-adducts. The resulting multifunctional tertiary azides can be converted to spiro-pyrrolidines with four continuous stereocenters in a one-pot operation. Mechanistic studies cast light on the control of diastereoselectivity by H-bond donors. While the squaramide-catalyzed reaction proceeded with a transition state with both squaramide N–H bonds binding to an enolate intermediate, an unprecedented model was proposed for the phosphoramide-mediated reaction wherein an amide N–H bond and an alkylammonium ion formed in situ interact with nitroolefins, with the enolate stabilized by nonclassical C–H⋯O hydrogen-bonding interactions.

We report the successful reversal of the diastereoselectivity in an unprecedented Michael addition of α-azido ketones to nitroolefins catalyzed by bifunctional tertiary amines, simply by varying the H-bond donor from phosphoramide to squaramide.     

Cooperative copper-squaramide catalysis for the enantioselective N–H insertion reaction with sulfoxonium ylides

The first examples of a highly efficient and enantioselective carbene-mediated insertion reaction, from a sulfur ylide, are described. By way of a catalytic asymmetric insertion reaction into N–H bonds from carbonyl sulfoxonium ylides and anilines, using a copper-bifunctional squaramide cooperative catalysis approach, thirty-seven α-arylglycine esters were synthesized in enantiomeric ratios up to 92 : 8 (99 : 1 after a single recrystallization) and reaction yields ranging between 49–96%. Furthermore, the protocol benefits from quick reaction times and is conducted in a straightforward manner.

The first examples of a highly efficient and enantioselective carbene-mediated insertion reaction, from a sulfur ylide, are described.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Palladium-catalyzed asymmetric hydrosilylation of 1,3-dienes

Advances in the palladium-catalyzed asymmetric hydrosilylation of 1,3-dienes are presented according to substrate types and chiral monophosphine ligands. Chiral monodentate phosphine ligands with a binaphthyl moiety have been proven to be the most efficient ligands for cyclic 1,3-dienes, and planar chiral ferrocenylmonophosphine ligands with two ferrocenyl moieties for linear 1,3-dienes. The ferrocenylmonophosphine ligands have expanded the substrate scope to 1,3-enynes in the asymmetric hydrosilylation. Palladium-catalyzed asymmetric hydrosilylation of 1,3-dienes and 1,3-enynes leads to the stereoselective synthesis of allylsilanes and allenylsilanes, respectively.     

Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides

An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.

A Ni-catalyzed enantioselective reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. A MLR model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.     

Nickel-catalyzed enantioselective vinylation of aryl 2-azaallyl anions

A unique enantioselective nickel-catalyzed vinylation of 2-azaallyl anions is advanced for the first time. This method affords diverse vinyl aryl methyl amines with high enantioselectivities, which are frequently occurring scaffolds in natural products and medications. This C–H functionalization method can also be extended to the synthesis of enantioenriched 1,3-diamine derivatives by employing suitably elaborated vinyl bromides. Key to the success of this process is the identification of a Ni/chiraphos catalyst system and a less reducing 2-azaallyl anion, all of which favor an anionic vinylation route over a background radical reaction. A telescoped gram scale synthesis and a product derivatization study confirmed the scalability and synthetic potential of this method.

A unique enantioselective Ni-catalyzed vinylation of 2-azaallyl anions is advanced. This method affords vinyl aryl methyl amine or 1,3-diamine derivatives with high enantioselectivities, which are frequently occurring scaffolds in medications.     

Enantioselective transition metal catalysis directed by chiral cations

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis. Thus far, three strategies have been revealed: ligand scaffolds incorporated on chiral cations, chiral cations paired with transition metal ‘ate’-type complexes, and ligand scaffolds incorporated on achiral anions. Chiral cation ion-pair catalysis has been successfully applied to alkylation, cycloaddition, dihydroxylation, oxohydroxylation, sulfoxidation, epoxidation and C–H borylation. This development represents an effective approach to promote the cooperation between chiral cations and transition metals, increasing the versatility and capability of both these forms of catalysts. In this review, we present current examples of the three strategies and suggest possible inclusions for the future.

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis.     

Catalytic asymmetric addition of thiols to silyl glyoxylates for synthesis of multi-hetero-atom substituted carbon stereocenters

A chiral Lewis acid-catalyzed enantioselective addition of thiols to silyl glyoxylates was developed. The reaction proceeds well with a broad range of thiols and acylsilanes, affording the target tertiary chiral α-silyl–α-sulfydryl alcohols with multi-hetero-atom carbon stereocenters in excellent yields (up to 99%) and enantioselectivities (up to 98% ee). A series of control experiments were conducted to elucidate the reaction mechanism.

Enantioselective addition of thiols to silyl glyoxylates for construction of a multi-hetero-atom substituted carbon stereocenter was described.     

Enantioselective synthesis of highly oxygenated acyclic quaternary center-containing building blocks via palladium-catalyzed decarboxylative allylic alkylation of cyclic siloxyketones

The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported. The reaction proceeds smoothly to provide products bearing a quaternary stereocenter in excellent yields (up to 91% yield) with high levels of enantioselectivity (up to 94% ee). We further utilized the unique reactivity of the siloxy functionality to access chiral, highly oxygenated acyclic quaternary building blocks. In addition, we subsequently demonstrated the utility of these compounds through the synthesis of a lactone bearing vicinal quaternary-trisubstituted stereocenters.

The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported.