Asymmetric Cascade Reaction Research Articles

Mass transfer-enhanced platform for heterogeneous dual organocatalysis to boost yield and diastereoselectivity in enantioselective Michael/benzoin cascade reaction

Mass transfer limitation and tedious anchoring of multiple expensive chiral organocatalysts are the key bottlenecks in heterogeneous asymmetric cascade/tandem reactions, leading to high-cost processes with low catalytic performances. In this paper, two chiral organocatalysts, including (S)-diphenylprolinoltrimethylsilyl ether (ProTMS) and N-heterocyclic carbenes (NHC), are simultaneously immobilized to hollow mesoporous polystyrene nanospheres (HMPNs) in one-pot via Friedel-Crafts alkylation to afford supported dual organocatalysts (ProTMS&NHC@HMPNs) at low cost. The catalyst possesses the spherical morphology with a hollow interior and a thin mesopore-abundant shell, providing suitable environments for reactants to quickly access to the catalytic sites of NHC and ProTMS. The side reactions caused by limited mass transfer are effectively suppressed, and superior yields (70–92 %) and diastereoselectivities (dr = 3:120:1) to homogeneous catalysis are achieved in heterogeneous Michael/benzoin cascade reaction. Overall, the mass transfer-enhanced platform for efficient heterogeneous dual organocatalysis is developed to boost yield and diastereoselectivity in asymmetric cascade reactions.

Asymmetric Three-Component Radical Cascade Reactions Enabled by Synergistic Photoredox/Brønsted Acid Catalysis: Access to α-Amino Acid Derivatives

Asymmetric Three-Component Radical Cascade Reactions Enabled by Synergistic Photoredox/Brønsted Acid Catalysis: Access to α-Amino Acid Derivatives

Pd-Catalyzed Asymmetric Allylic Substitution Cascade via Desymmetrization for the Construction of Chiral Polyheterocycles

Chiral polyheterocycles represent an important class of compounds because of their prevalence in bioactive natural products and chiral drugs. Pd-catalyzed allylic substitution is a powerful synthetic tool for forming C–C and C–X bonds (X = N, O, S, etc.). Naturally, asymmetric cascade reactions that utilize allylic substitution are undoubtedly efficient pathways to construct heterocycles. In this article, we reviewed the Pd-catalyzed asymmetric allylic substitution cascade via the desymmetrization of meso-diol diesters of cycloolefins, for the construction of chiral polyheterocycles and their derivatives.

Catalytically generated noncovalent ammonium dienolate: a versatile platform for the development of organocatalytic asymmetric cascade reactions

Catalytically generated noncovalent ammonium dienolate: a versatile platform for the development of organocatalytic asymmetric cascade reactions

Stereodivergent Construction of 1,5/1,7-Nonadjacent Tetrasubstituted Stereocenters Enabled by Pd/Cu-Cocatalyzed Asymmetric Heck Cascade Reaction.

The construction of chiral motifs containing nonadjacent stereocenters in an enantio- and diastereoselective manner has long been a challenging task in synthetic chemistry, especially with respect to their stereodivergent synthesis. Herein, we describe a protocol that enables the enantio- and diastereoselective construction of 1,5/1,7-nonadjacent tetrasubstituted stereocenters through a Pd/Cu-cocatalyzed Heck cascade reaction. Notably, a C=C bond relay strategy involving the shift of the π-allyl palladium intermediate was successfully applied in the asymmetric construction of 1,7-nonadjacent stereocenters. The current method allows for the efficient preparation of chiral molecules bearing two privileged scaffolds, oxindoles and non-natural α-amino acids, with good functional group tolerance. The full complement of the four stereoisomers of products bearing 1,5/1,7-nonadjacent stereocenters could be readily accessed by a simple combination of two chiral metal catalysts with different enantiomers.

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction.

Hindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.

Asymmetric construction of spirobenzofuran indolinones via a cascade reaction of 3-hydroxyoxindoles with coumarins

A series of enantioenriched spirobenzofuran indolinones were afforded via an asymmetric organocatalytic cascade reaction of 3-hydroxyoxindoles with coumarins. Meanwhile, the stereo-determining step of the reaction was disclosed.

Three-component modular synthesis of chiral 1,3-dioxoles via a Rh-catalyzed carbenic olefination cascade.

The advance of organic synthesis and the discovery of novel chemical transformations are often propelled by the rational programming of various bond-forming mechanisms and sequences that involve delicate reactive intermediates. In this study, we present an innovative Rh(ii)-catalyzed asymmetric three-component cascade reaction involving IIII/PV-hybrid ylides, aldehydes, and carboxylic acids for the synthesis of 1,3-dioxoles with moderate to good yields and high enantioselectivity. This method utilizes IIII/PV-hybrid ylides as carbene precursors to form α-PV-Rh-carbenes, which initiate the formation of carbonyl ylides, followed by stereoselective cyclization with carboxylate anions and an intramolecular Wittig olefination cascade, ultimately resulting in the modular assembly of chiral 1,3-dioxoles. By employing this strategy, we successfully coupled various aldehydes and carboxylic acids to give chiral non-benzofused 1,3-dioxole scaffolds, highlighting the potential for late-stage functionalization of biologically relevant molecules, versatile synthetic manipulation, and the production of poly-1,3-dioxole macromolecules.

Ir/Brønsted acid dual-catalyzed asymmetric synthesis of bisbenzannulated spiroketals and spiroaminals from isochroman ketals

An Ir/Brønsted acid dual-catalyzed asymmetric cascade reaction of 2-(1-hydroxyallyl)phenols with isochroman ketals was developed, affording antifungal spiroketals with high enantioselectivities.

Bifunctional Squaramide-Catalyzed Asymmetric Cascade Reaction of Benzothiazoles with 2-Nitroallylic Acetates or Nitroenynes.

We describe here an organocatalytic asymmetric cascade formal [3 + 3] cycloaddition of benzothiazoles with 2-nitroallylic acetates and nitroenynes. This dearomative methodology provided a facile and efficient strategy for the construction of a broad range of valuable benzothiazolopyridines bearing two adjacent stereogenic centers in moderate to good yields with good to excellent stereocontrol.

Efficient biosynthesis of (R)− 1-[3,5-bis(trifluoromethyl)phenyl]ethanamine with self-assembled dual-enzyme clusters

Purified SpyCatcher-ATA117 (5 µM) and SpyTag-ADH (5 µM) were covalently combined to form self-assembled dual-enzyme clusters (DENCs) at 4 °C for 3 h. The successful assembly of DENCs was verified using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and dynamic light scattering (DLS). DENCs improved the storage stability by 36.2% and pH stability by 11.2% compared with those of free double enzymes. 56.89 g/L (R)− 1-[3,5-bis(trifluoromethyl)phenyl]ethanamine (R-BPA) was synthesized using DENCs with high yield (99.9%) and high enantiomeric excess (99.9%) at 45 °C and pH 9 for 24 h. Moreover, DENCs retained more than 78% of the initial activity after being reused in the preparation of R-BPA for five cycles. Thus, DENCs were successfully formed, and efficient amination was achieved, providing a new biocatalyst for efficient biosynthesis of chiral amines via asymmetric transamination cascade reaction.

Bioinspired Total Syntheses of Secologanin-Related Natural Products: A Demonstration of the Power of Secologanin in the Flask

AbstractThe preparation of natural product libraries by total synthesis has become an extremely important and attractive research topic in organic chemistry. In higher plants, secologanin, which belongs to the monoterpene family, is the starting point for derivation into natural products with different skeletons and biological activities. This Account presents a practical total synthesis of secologanin using an asymmetric organocatalytic cascade reaction. In addition, a collective total synthesis of secologanin-related natural products, such as monoterpenoid indole alkaloids and hetero-oligomeric iridoid glycosides, is described from the synthesized secologanin and its derivatives. To date, we have successfully synthesized 39 secologanin-related natural products using bioinspired strategies with reference to biosynthesis, and in this Account, details of the synthetic strategies for 20 of them are presented. By combining these total syntheses into a single Account, we hope to provide a better view of how the pieces connect to one another and how each piece fits together into the overall body of work.1 Introduction2 A Practical Total Synthesis of Secologanin3 Total Syntheses of 5-Carboxystrictosidine and Related Indole Alkaloid Glycosides4 Total Syntheses of Strictosidine and Related Indole Alkaloid Glycosides5 Total Syntheses of β-Carboline-Type Monoterpenoid Indole Alkaloid Glycosides6 Total Syntheses of Non-Glycosylated Monoterpenoid Indole Alkaloids7 Total Syntheses of Hetero-Oligomeric Iridoid Glycosides8 Conclusion and Future Prospects

Zinc-Catalyzed Asymmetric Cascade Michael/Acyl Transfer Reaction between α-Hydroxy Aryl Ketones and Enynones.

We described herein a neoteric enantioselective cascade Michael/acyl transfer reaction of enynones and α-hydroxy aryl ketones catalyzed by dinuclear zinc cooperative catalysis. A series of structurally diverse chiral 1,5-dicarbonyl compounds were synthesized in good yields with excellent stereoselectivities. This strategy features broad substrate scope, high atom economy, as well as enynones as efficient electrophilic acyl transfer reagents in asymmetric cascade reactions for the first time.

Enantioselective Synthesis of Dispirooxindole Derivatives via Asymmetric Catalytic Cascade Reactions

AbstractA series of optically active 3,3′-pyrrolidinyl-dispirooxindole derivatives containing a CF3 moiety have been efficiently constructed through asymmetric catalytic cascade reactions catalyzed by cinchona-derived bifunctional squaramide catalyst, bearing four contiguous stereogenic centers, two of which are vicinal spiro-stereocenters. Additionally, a wide range of substituted products were achieved with moderate to high yields (up to 99% yield) and excellent stereoselectivities (up to >20:1 dr for all cases and up to 99% ee).

Simultaneous Dual Cu/Ir Catalysis: Stereodivergent Synthesis of Chiral β-Lactams with Adjacent Tertiary/Quaternary/Tertiary Stereocenters

A stereodivergent synthesis of chiral β-lactams with contiguous tertiary/quaternary/tertiary stereocenters has been achieved by a Cu/Ir-catalyzed three-component interrupted Kinugasa allylic alkylation reaction. The two catalysts independently exert high local stereocontrol, providing access to four of the eight possible stereoisomers in high yields with >99% ee. The features of this strategy are the asymmetric simultaneous dual metal-catalyzed cascade reactions with stereoselective coupling of highly transient organometallic intermediates.

1,2-Diamines as the Amine Sources in Amidation and Rhodium-Catalyzed Asymmetric Reductive Amination Cascade Reactions.

The sturdy chelation of 1,2-diamines and transition-metals would retard or even interrupt the routine catalytic cycles. In the amidation and asymmetric reductive amination (ARA) cascade reactions of diamines and ketoesters, we deployed sets of additives to ensure a smooth transformation catalyzed by the complexes of rhodium and versatile and highly modular phosphoramidite-phosphine ligands. The tunability of the ligands was fully exploited to accommodate various diamines and α-ketoesters for the efficient synthesis of chiral 3,4-dihydroquinoxalinones.

Regio- and enantioselective remote hydroarylation using a ligand-relay strategy.

The design of a single complicated chiral ligand to well-promote each step of an asymmetric cascade reaction is sometimes a formidable challenge in transition metal catalysis. In this work, a highly regio- and enantioselective Ni-catalysed migratory hydroarylation relay process has been achieved with the combination of two simple ligands, one which accomplishes chain-walking and the other causing asymmetric arylation. This formal asymmetric C(sp3)−H arylation provides direct access to a wide range of structurally diverse chiral 1,1-diarylalkanes, a structural unit found in a number of bioactive molecules. The value of this strategy was further demonstrated by the Ni-catalysed migratory asymmetric 1,3-arylboration.

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalytic Cascade Reactions under Curtin-Hammett Conditions.

Observations of nonlinear effects of catalyst enantiopurity on product enantiomeric excess in asymmetric catalysis are often used to infer that more than one catalyst species is involved in one or more reaction steps. We demonstrate here, however, that in the case of asymmetric catalytic cascade reactions, a nonlinear effect may be observed in the absence of any higher order catalyst species or any reaction step involving two catalyst species. We illustrate this concept with an example from a recent report of an organocatalytic enantioselective [10 + 2] stepwise cyclization reaction. The disruption of pre-equilibria (Curtin–Hammett equilibrium) in reversible steps occurring prior to the final irreversible product formation step can result in an alteration of the final product ee from what would be expected based on a linear relationship with the enantiopure catalyst. The treatment accounts for either positive or negative nonlinear effects in systems over a wide range of conditions including “major-minor” kinetics or the more conventional “lock-and-key” kinetics. The mechanistic scenario proposed here may apply generally to other cascade reaction systems exhibiting similar kinetic features and should be considered as a viable alternative model whenever a nonlinear effect is observed in a cascade sequence of reactions.

Solvent Dependency in Stereoselective δ‐Lactam Formation of Chiral α‐Fluoromalonate Derivatives: Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters

AbstractThe discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5‐aminofunctionalized‐2‐fluoromalonate ester derivatives, which gives access to highly functionalized δ‐lactams with a quaternary fluorine‐containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ‐lactam formation. The merging of this solvent‐dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine‐containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95‐>99% ee in one‐pot. It is also useful for application in total synthesis of fluorine‐containing pharmaceuticals.magnified image

Organocatalytic asymmetric synthesis of multifunctionalized α-carboline-spirooxindole hybrids that suppressed proliferation in colorectal cancer cells

An asymmetric organocatalytic cascade reaction has been reported for the rapid assembly of multifunctionalized α-carboline-spirooxindole hybrids, which suppressed proliferation in colorectal cancer cells.