Asymmetric Cascade Reaction Research Articles

Recent Advances in Chiral Phosphoric Acid Catalyzed Asymmetric Reactions for the Synthesis of Enantiopure Indole Derivatives

Chiral indole derivatives are an intriguing class of heterocyclic compounds; their structural motifs are frequently found in natural products and synthetic compounds with significant bioactivity. Among many synthetic transformations leading to the production of enantiopure indole derivatives, chiral phosphoric acid catalyzed reactions are the most attractive methodologies, since these reactions can directly afford enantiomerically pure indole derivatives from readily accessible starting materials under mild conditions. In this review, the most recent achievements in this research area have been gathered and classified according to different reaction types for the synthesis of enantioenriched indole derivatives under the catalysis of chiral phosphoric acids. 1 Introduction 2 Chiral Phosphoric Acid Catalyzed Asymmetric Addition Reactions 2.1 1,2-Addition Reactions 2.2 1,4-Addition Reactions 3 Chiral Phosphoric Acid Catalyzed Asymmetric Cycloaddition Reactions 3.1 [3+2] Reactions 3.2 [4+2] Reactions 3.3 [3+3] Reactions 4 Chiral Phosphoric Acid Catalyzed Asymmetric Cascade Reactions 4.1 Cascade Reactions 4.2 Transition-Metal-Cocatalyzed Cascade Reactions 4.3 Other Organocatalyst-Cocatalyzed Cascade Reactions 5 Other Reactions Catalyzed by Chiral Phosphoric Acids 5.1 Aza-Claisen Rearrangement 5.2 Kinetic Resolution 5.3 Fischer Indolization 6 Conclusions and Perspective

Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules.

With the increasing concerns about chemical pollution and sustainability of resources, among the significant challenges facing synthetic chemists are the development and application of elegant and efficient methods that enable the concise synthesis of natural products, drugs, and related compounds in a step-, atom- and redox-economic manner. One of the most effective ways to reach this goal is to implement reaction cascades that allow multiple bond-forming events to occur in a single vessel. This Account documents our progress on the rational design and strategic application of asymmetric catalytic cascade reactions in constructing diverse scaffolds and synthesizing complex chiral molecules. Our research is aimed at developing robust cascade reactions for the systematic synthesis of a range of interesting molecules that contain structural motifs prevalent in natural products, pharmaceuticals, and biological probes. The strategies employed to achieve this goal can be classified into three categories: bifunctional base/Brønsted acid catalysis, covalent aminocatalysis/N-heterocyclic carbene catalysis, and asymmetric organocatalytic relay cascades. By the use of rationally designed substrates with properly reactive sites, chiral oxindole, chroman, tetrahydroquinoline, tetrahydrothiophene, and cyclohexane scaffolds were successfully assembled under bifunctional base/Brønsted acid catalysis from simple and readily available substances such as imines and nitroolefins. We found that some of these reactions are highly efficient since catalyst loadings as low as 1 mol % can promote the multistep sequences affording complex architectures with high stereoselectivities and yields. Furthermore, one of the bifunctional base/Brønsted acid-catalyzed cascade reactions for the synthesis of chiral cyclohexanes has been used as a key step in the construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of α-lycorane. Guided by the principles of covalent aminocatalysis and N-heterocyclic carbene catalysis, we synthesized chiral piperidine, indole, and cyclobutane derivatives. The synthesis of chiral cyclobutanes and pyrroloindolones showed unprecedented reactivity of substrates and catalysts. The development of the strategy of asymmetric organocatalytic relay cascades has provided a useful tool for the controlled synthesis of specific diastereomers in complex molecules. This Account gives a panoramic view and the logic of our research on the design, development, and applications of asymmetric catalytic cascade reactions that will potentially provide useful insights into exploring new reactions.

ChemInform Abstract: Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles.

AbstractA slight excess of 7‐vinylindole substrate reacts with isatin‐derived 3‐indolylmethanols in the presence of chiral phosphoric acid BNPA to produce the desired C‐7 functionalized structures combined with cyclopenta[b]indole/spirooxindole frameworks.

ChemInform Abstract: Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton.

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition–hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1–copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral β-nitro alcohol and α,β-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

ChemInform Abstract: Asymmetric Organocatalytic Cascade Reaction of Aldehydes with 2‐Amino‐β‐nitrostyrenes: Synthesis of Chiral Tetrahydroquinolines and Dihydroquinolines.

AbstractAn efficient organocatalyzed Michael addition/aza cyclization process is developed.

ChemInform Abstract: Diastereo‐ and Enantioselective Construction of a Bispirooxindole Scaffold Containing a Tetrahydro‐β‐carboline Moiety Through an Organocatalytic Asymmetric Cascade Reaction.

AbstractA three‐component cascade Michael/Pictet—Spengler reaction of isatins, isatin‐derived 3‐indolylmethanols, and 2‐aminomalonate in the presence of a BINOL‐phosphonic acid catalyst is developed to provide bisspirooxindoles with excellent diastereo‐ and enantioselectivities.

Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral β-nitro alcohol and α,β-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Three consecutive steps over the chirally modified Pt surface: asymmetric catalytic cascade reaction of 2-nitrophenylpyruvates

The influence of the reaction conditions on the asymmetric heterogeneous catalytic reaction of 2-nitrophenylpyruvates over Pt modified with cinchonidine showed that all three steps of the cascade occur on the metal surface.

ChemInform Abstract: Facile Synthesis of Chiral Spirooxindole‐Based Isotetronic Acids and 5‐1H‐Pyrrol‐2‐ones Through Cascade Reactions with Bifunctional Organocatalysts.

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole-based isotetronic acids and 5-1h-pyrrol-2-ones. the asymmetric 1,2-addition reactions of alpha-ketoesters to isatins and imines by using an acid-base bifunctional 6'-oh cinchona alkaloid catalyst, followed by cyclization and enolization of the resulting adducts, gave chiral spiroisotetronic acids and 5-1h-pyrrol-2-ones, respectively, in excellent optical purities (up to 98% ee). ft-ir analysis supported the existence of hydrogen-bonding interaction between the 6'-oh group of the cinchona catalyst and an isatin carbonyl group, an interaction that might be crucial for catalyst activity and stereocontrol.

Organocatalytic asymmetric cascade reactions of 7-vinylindoles: diastereo- and enantioselective synthesis of C7-functionalized indoles.

The first catalytic asymmetric cascade reaction of 7-vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin-derived 3-indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo- and enantioselective synthesis of C7-functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94->99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7-functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel-Crafts process, in which dual H-bonding activation of the two reactants plays a crucial role.

ChemInform Abstract: An Asymmetric Organocatalytic Quadruple Cascade to Tetraaryl‐Substituted 2‐Azabicyclo[3.3.0]octadienones.

AbstractThe new asymmetric cascade reaction of α‐ketoamides with α,β‐unsaturated aldehydes proceeds via a quadruple aza‐Michael/aldol condensation/vinylogous Michael/aldol condensation sequence.

A Site‐Isolated Organoruthenium‐/Organopalladium‐Bifunctionalized Periodic Mesoporous Organosilica Catalyzes Cascade Asymmetric Transfer Hydrogenation and Suzuki Cross‐Coupling

AbstractAn important challenge in asymmetric cascade reactions is solving the intrinsic incompatibility of two types of distinct organometallic complexes that participate in a one‐pot reaction. Herein, we develop an organoruthenium‐/organopalladium‐bifunctionalized periodic mesoporous organosilica and realize one‐pot cascade reactions of Ru‐catalyzed asymmetric transfer hydrogenation and Pd‐relay‐catalyzed cross‐coupling of haloacetophenones and arylboronic acids to various chiral biaryl alcohols, with quantitative conversions and up to 98 % enantioselectivity in an aqueous medium. This characteristics is attributed to the site‐isolated, uniformly distributed, well‐defined single‐site palladium and ruthenium active species. Furthermore, the heterogeneous catalyst is conveniently recovered and reused repeatedly for eight times without loss of its catalytic activity, showing particular attractiveness for practicing organic transformation.

Asymmetric organocatalytic cascade reaction of aldehydes with 2-amino-β-nitrostyrenes: synthesis of chiral tetrahydroquinolines and dihydroquinolines.

An organocatalytic enantioselective Michael addition/aza-cyclization cascade reaction of aldehydes with 2-amino-β-nitrostyrenes has been developed for the construction of fully substituted chiral tetrahydroquinolines. The reaction, promoted by diphenylprolinol TMS ether as an organocatalyst, generated the chiral tetrahydroquinolines in good to high yield with excellent diastereo- and enantioselectivities (up to >30:1 dr, >99% ee). The method also provided an alternative access to chiral 1,4-dihydroquinolines, which are difficult to synthesize by other methodologies.

Diastereo- and enantioselective construction of a bispirooxindole scaffold containing a tetrahydro-β-carboline moiety through an organocatalytic asymmetric cascade reaction.

The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet-Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all >95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-β-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.

Chiral Phase Transfer Catalysts for the Synthesis of Chiral N‐Heterocycles viaAsymmetric Cascade Reactions

The effectiveness of a series of chiral phase transfer catalysts in cascade reactions of active methylene compounds with 2‐cyanobenzaldehyde leading to chiral 3‐substituted isoindolinones and fused benzoindolizidinones has been investigated. High yields and moderate enantiomeric excesses (e.e.s) were achieved employing a chiral phase‐transfer catalyst derived from bifunctional urea–quinine. Moreover, an efficient process of heterochiral crystallization, performed on moderately enantioenriched compounds, led to an impressive increase of the enantiopurity up to 93% e.e.s.

ChemInform Abstract: Dual‐Organocatalyst‐Promoted Asymmetric Cascade Reaction: Highly Efficient Construction of Enantiopure Fully Substituted Tetrahydro‐1,2‐oxazines.

AbstractA four‐component asymmetric α‐aminoxylation/aza‐Michael/Mannich cascade reaction for the construction of fully substituted chiral tetrahydro‐1,2‐oxazine derivatives is accomplished with excellent diastereo‐ and enantioselectivities.

ChemInform Abstract: Metal‐Containing Carbonyl Ylides: Versatile Reactants in Catalytic Enantioselective Cascade Reactions

AbstractReview: 15 refs.

Asymmetric organocatalysis combined with metal catalysis: concept, proof of concept, and beyond.

Asymmetric catalysis has been considered to be the most intriguing means for building collections of functionalized optically active compounds. In particular, metal and organocatalysis have been well established to allow many fundamentally different reactions. Metal catalysis has enabled the participation of a much broader scope of chemical bonds in organic transformations than are allowed by organocatalysis, while organocatalysis permits a broader scope of functional groups to undergo a diverse range of enantioselective transformations, individually, simultaneously, or sequentially. Theoretically, the combination of organocatalysts and metal complexes could probably render new transformations through the simultaneous or sequential activation and reorganization of multiple chemical bonds if the superior features of both the catalysts are adopted. In 2001, both our research group and Takemoto's group separately described an asymmetric allylation of glycine imino esters with allyl acetate catalyzed by palladium complexes and chiral ammonium salts. In these cases, the oxidative addition of palladium complexes to allyl acetate formed the π-allylic fragments, while the chiral ammonium salts were actually responsible for controlling the stereoselectivity. These reactions in fact marked the beginning of asymmetric organo/metal combined catalysis. Since then, asymmetric organocatalysis combined with metal catalysis, including cooperative catalysis, relay catalysis, and sequential catalysis, has been a versatile concept for the creation of unknown organic transformations. Sequential catalysis describes a one-pot reaction involving two or more incompatible catalytic cycles. Alternatively, cooperative and relay catalyses require high compatibility of principally distinct catalysts and will be the focus of this Account. The catalysts in cooperative catalytic reactions must be able to simultaneously and individually activate both substrates to drive a bond-forming reaction, while relay catalysis is basically defined as a cascade process in which two or more sequential bond-forming transformations are independently catalyzed by distinct catalysts. In the past decade, we have discovered a variety of binary catalytic systems consisting of metals, including Rh(II), Pd(0), Au(I), and Mg(II), and chiral organocatalysts, including chiral phosphoric acids and quinine-based bifunctional molecules, for cooperative catalysis and relay catalysis, allowing the accomplishment of many unprecedented asymmetric transformations. In this Account, these achievements will be summarized, particularly focusing on the description of the concept and proof of the concept, to demonstrate the robustness of combined organo/metal catalysis in the creation of efficient enantioselective transformations. In addition, elegant studies from other laboratories using chiral phosphoric acid/Au(I) for the establishment of asymmetric cascade reactions involving the carbon-carbon triple bond functionality and typical combined organo/metal catalytic systems, very recently disclosed, will also be highlighted.

Facile synthesis of chiral spirooxindole-based isotetronic acids and 5-1H-pyrrol-2-ones through cascade reactions with bifunctional organocatalysts.

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole-based isotetronic acids and 5-1H-pyrrol-2-ones.The asymmetric 1,2-addition reactions of α-ketoesters to isatins and imines by using an acid-base bifunctional 6'-OH cinchona alkaloid catalyst, followed by cyclization and enolization of the resulting adducts, gave chiral spiroisotetronic acids and 5-1H-pyrrol-2-ones, respectively, in excellent optical purities (up to 98 % ee). FT-IR analysis supported the existence of hydrogen-bonding interaction between the 6'-OH group of the cinchona catalyst and an isatin carbonyl group, an interaction that might be crucial for catalyst activity and stereocontrol.

Asymmetric cascade reaction to allylic sulfonamides from allylic alcohols by palladium(II)/base-catalyzed rearrangement of allylic carbamates.

A regio- and enantioselective tandem reaction is reported capable of directly transforming readily accessible achiral allylic alcohols into chiral sulfonyl-protected allylic amines. The reaction is catalyzed by the cooperative action of a chiral ferrocene palladacycle and a tertiary amine base and combines high step-economy with operational simplicity (e.g. no need for inert-gas atmosphere or catalyst activation). Mechanistic studies support a Pd(II)-catalyzed [3,3] rearrangement of allylic carbamates--generated in situ from the allylic alcohol and an isocyanate--as the key step, which is followed by a decarboxylation.