Organocatalytic Cascade Reaction Research Articles

Stereodivergent Synthesis of All Stereoisomers of 2,3-Disubstituted δ-Lactam Derivatives via Organocatalytic Cascade Reactions and Base-Induced Epimerization.

A protocol was developed to achieve stereodivergent synthesis of stereoisomers of δ-lactam bearing vicinal chiral centers. Organocatalytic cascade reactions were employed to produce the target products as the kinetic products, which exhibited remarkable enantioselectivities. In the presence of DBU, the kinetic product underwent epimerization to form a thermodynamically more stable diastereomer without loss in enantioselectivity. By simply switching the chiral organocatalyst and its enantiomer, we can efficiently obtain four stereoisomers with high enantioselectivities.

Enantioselective synthesis of 8-membered lactone derivatives via organocatalytic cascade reactions

The challenging 8-membered lactone derivatives bearing two vicinal chiral stereocenters were synthesized via a cascade reaction mediated by the chiral squaramide.

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.

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

Cover Picture: From Three‐ to Six‐Membered Heterocycles Bearing a Quaternary Stereocenter: an Asymmetric Organocatalytic Approach (Chem. Rec. 5/2023)

The installation of quaternary stereocenters is one of the most challenging operations to accomplish in asymmetric synthesis. Organocatalytic cascade reactions leading to a variety of heterocyclic compounds, bearing a quaternary stereocenter, are illustrated on the Front Cover. See the Personal Account by A. Lattanzi (DOI:10.1002/tcr.202300066).

Recent advances in organocatalytic cascade reactions for enantioselective synthesis of chiral spirolactone skeletons

Chiral spirolactones, including spiropropyllactones, spirobutyrolactones, and spirovalerolactones, are important heterocyclic frameworks that attracted the attention of organic and medicinal chemists because these motifs constitute the core structure of several natural products and bioactive molecules. The absolute configuration and the substituents on the fully substituted spirocyclic stereocenter of the lactone can potentially enhance specificity for ligand-protein binding and enhance bioavailability, potency, and metabolic stability. So, intensive attention from chemists has been paid to the synthetic methods leading to such prominent structural motifs. The synthetic methods can be divided into two main classes. The first approach takes advantage of the presence of the existing lactone structure and focuses on its functionalization. The second approach is the lactone framework constructed from various precursors in a direct spirolactonization reaction. In this review, for convenience in reading, the recent advances in the synthesis of spirolactones are summarized and discussed according to the two major organocatalytic asymmetric synthetic routes: (i) using the lactone-related frameworks as building blocks; and (ii) direct spirolactonization reaction using various reagents. This review also describes both the mechanisms and related transformations, and gives some insights into challenging issues in this research field, which will enlighten the future development of this field.

Asymmetric Organocatalytic Syntheses of Bioactive Compounds.

The total syntheses of complex natural products have evolved to include new methodologies to save time, simplifying the form to achieve these natural compounds. In this review, we have described the asymmetric synthesis of different natural products and biologically active compounds of the last ten years until the current day. An asymmetric organocatalytic reaction is a key to generate stereoselectively the main structure with the required stereochemistry. Even more remarkable, the organocatalytic cascade reactions, which are carried out with high stereoselectivity, as well as a possible approximation of the organocatalysts activation with substrates are also described.

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.

Stereoselective Cyclopropanation of Boron Dipyrromethene (BODIPY) Derivatives by an Organocascade Reaction

AbstractThe synthesis of enantiopure chiral boron dipyrromethenes (BODIPYs) is of importance due the intrinsic properties of BODIPYs as fluorophores that could be used as probes for molecular sensing. The present study reports an asymmetric organocatalytic cascade reaction of meso‐chloromethyl BODIPY derivatives with α,β‐unsaturated aldehydes catalyzed by a chiral secondary amine. The corresponding BODIPY‐derived cyclopropanes were produced in isolated yields 66–98%, and with diastereomeric ratios 3/2–>20/1, and 92–99% ee for major diastereomer. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding optically pure compounds. In addition, a study explaining the reaction mechanism (DFT computations) and photophysical characterization of all enantioenriched products were accomplished.magnified image

Cover Feature: Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems (Eur. J. Org. Chem. 29/2021)

The Cover Feature shows three examples of cascade reactions leading to chiral halogenated cyclic molecules. The multiple reactions that take place in succession (cascade-like) once the reagents are mixed, provide a sustainable, atom-, step- and labor-efficient way to create chirality and molecular complexity. Easy-to-handle halogenating agents or synthetic building blocks and organocatalysts make this possible. The cascades of Buk Skradinski waterfall in the Krka National Park, Croatia illustrate the reaction pathways. More information can be found in the Minireview by A. M. Faisca Phillips and A. J. L. Pombeiro

Enantioselective Construction of Spirooxindole-Fused Cyclopentanes.

The present study reports an asymmetric organocatalytic cascade reaction of oxindole derivates with α,β-unsaturated aldehydes efficiently catalyzed by simple chiral secondary amine. Spirooxindole-fused cyclopentanes were produced in excellent isolated yields (up to 98%) with excellent enantiopurities (up to 99% ee) and moderate to high diastereoselectivities. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spiro compounds. In addition, a study showing the promising biological activity of selected enantioenriched products was accomplished.

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

AbstractChiral halogenated substances have many applications in pharmaceuticals, agrochemicals, and materials, such as polymers, liquid crystals and as intermediates in synthesis. The presence of a halogen atom in a molecule can have a large effect in its properties; for instance, halogens are used in drugs to improve lipophilicity, membrane permeability and absorption, and even the blood‐brain barrier permeability. As highlighted in this review, there are nowadays a range of highly selective, versatile halogenating reagents, electrophilic, nucleophilic or radical in nature, which operate under mild conditions, allowing late‐stage functionalization of complex molecules in cascade reactions. Recent developments in organocatalyst design revealed novel Cinchona alkaloids derivatives, chiral phosphoric acids, amines, phosphines and several bifunctional catalysts, mostly thiourea‐ or squaramide‐based, which introduced chirality, with high levels of enantio‐ and diastereoselection, in the formation of one or multiple chiral centers in a single synthetic operation, as shown. In this review we survey the literature published in this field from 2014 to 2020.

The Motifs from Isocytosine and Fused Isocytosine with Quinazoline: Organocatalytic Cascade Reaction of β‐Ketoamides

AbstractA method for the synthesis of isocytosine analogs from β‐ketoamides was investigated. Application of the method to β‐ketoamides including a 2‐cyanoaryl group leads to isocytosine fused quinazolines by the organocatalytic Cascade reaction. 20 examples of pyrimidone derivatives were synthesized in different patterns.

A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals

AbstractHerein, we report a general iminium ion‐based catalytic method for the enantioselective conjugate addition of carbon‐centered radicals to aliphatic and aromatic enals. The process uses an organic photoredox catalyst, which absorbs blue light to generate radicals from stable precursors, in combination with a chiral amine catalyst, which secures a consistently high level of stereoselectivity. The generality of this catalytic platform is demonstrated by the stereoselective interception of a wide variety of radicals, including non‐stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium‐ion‐based radical trap with an enamine‐mediated step, affording stereochemically dense chiral products in one‐step.

A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals.

Herein, we report a general iminium ion‐based catalytic method for the enantioselective conjugate addition of carbon‐centered radicals to aliphatic and aromatic enals. The process uses an organic photoredox catalyst, which absorbs blue light to generate radicals from stable precursors, in combination with a chiral amine catalyst, which secures a consistently high level of stereoselectivity. The generality of this catalytic platform is demonstrated by the stereoselective interception of a wide variety of radicals, including non‐stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium‐ion‐based radical trap with an enamine‐mediated step, affording stereochemically dense chiral products in one‐step.

Stereoselective synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactam through the organocatalytic cascade reaction of 3-((2,2,2-trifluoroethyl)amino)indolin-2-one.

Newly designed 3-((2,2,2-trifluoroethyl)amino)indolin-2-ones were used for the facile synthesis of chiral fluoroalkyl-containing 3,2'-spirooxindole γ-lactam products. The secondary amine-catalysed Michael/hemiaminalization cascade reaction of 3-((2,2,2-trifluoroethyl)amino)indolin-2-one with α,β-unsaturated aldehydes followed by oxidation can easily produce the desired products in high yields (up to 86%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to >95 : 5 dr).

Organocatalytic cascade reactions for multi-functionalized chiral cyclic ethers through vinylidene ortho-quinone methides.

An organocatalytic approach to installing various alcohols into the carbonyl of α,β-unsaturated ketones mediated by VQM intermediates was achieved, followed by dearomatization to provide the stereo-defined cyclic ethers via a cascade process. Along with the transformations, this strategy affords efficient access to the underexplored chiral cyclic ether chemospace.

Organocatalytic Cascade Reactions for the Diversification of Thiopyrano-Piperidone Fused Rings Utilizing Trienamine Activation.

An aminocatalytic privileged diversity-oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans-piperidone fused rings through a thia-Diels-Alder/nucleophilic ring-closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis-dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet-Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta- hexa- and heptacyclic fused ring derivatives in a one-pot process. This investigation opens new perspectives for the synthesis of a new class of complex and diverse thiopyrans that contribute to populate new relevant regions in the chemical space.

Organo‐Cascade Catalysis: Application of Merged Iminium‐Enamine Activation Technique and Related Cascade Reactivities

AbstractIminium‐enamine catalyzed chemical reactions provide a blueprint to carry out diverse organocatalyzed cascade reactions with high selectivity and efficiency and therefore, this class of reactions holds a great promise to offer important synthetic strategies to deliver valuable and useful natural products as well as biologically potent compounds with immense significance. The applications of enamine‐iminium (EN‐IM) catalysis in organocatalytic cascade reactions become a very useful strategy in organic synthesis. This review article aims to focus on an important overview about different strategies employed in the production of value added organic products. An effort has also been made to demonstrate the applications of merged Iminium‐enamine activation techniques in proceeding organo‐cascade reactions to illuminate the advantage of atom economy and step economy in the chemical reactions.

Organocatalytic Cascade Reaction of Aliphatic Enals and Benzoylnitromethane: Synthesis of Enantioenriched Tetrasubstituted Cyclohexene Carbaldehyde

A new example of the reactivity of enals with benzoylnitromethane was studied in a Michael-Michael-Aldol-Dehydration quadruple organocascade reaction. The reaction unexpectedly yielded a tetrasubstituted cyclohexene carbaldehyde with excellent enantiomeric excess when crotonaldehyde was used as the Michael-acceptor, whereas using (E)-Hex-2-enal as the Michael-acceptor formed a cyclic hemiacetal by steering the reaction into the intramolecular formation of the same intermediate via a Michael-Heterocyclization domino reaction.