Versatile Transformations Research Articles

Enantioselective Borylative Functionalization of Internal Alkenes: A Platform for Constructing Vicinal Stereocenters†

Comprehensive SummaryVicinal stereogenic centers are ubiquitous structural scaffolds in both natural products and synthetic compounds, yet their enantioselective construction remains a significant challenge in organic synthesis. Organoboron compounds are of paramount importance in synthetic chemistry due to their ability to undergo facile transformations, yielding diverse essential chemical bonds such as carbon‐carbon, carbon‐oxygen, carbon‐nitrogen, and carbon‐halogen bonds. Transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes offer a promising strategy for the enantioselective installation of two adjacent chiral centers across carbon‐carbon bonds. By leveraging the versatile transformations of the newly introduced boryl unit, this approach holds great potential for expanding the structural diversity of vicinal stereogenic scaffolds. In this concise review, we aim to highlight recent advancements in transition‐metal‐catalyzed asymmetric borylative functionalizations of internal alkenes, underscore their utility as a versatile approach for constructing vicinal stereogenic centers, and discuss unsolved challenges and future directions in this field. Key Scientists

Synthesis of N-Aryl-4-trifluoromethylthiazol-2-amines via Insertion/Annulation of Trifluoromethylimidoyl Sulfoxonium Ylides with Sodium Thiocyanate.

An efficient p-TsOH-mediated insertion of sodium thiocyanate into trifluoromethylimidoyl sulfoxonium ylides has been reported, affording annulated N-aryl-4-trifluoromethylthiazol-2-amines in 42-84% yields in a one-pot manner. This protocol encompasses a variety of trifluoromethylimidoyl sulfoxonium ylides with thiocyanate serving as the source of the "S-C═N" moiety of the thiazole ring. The versatile transformations of the resulting pharmacologically important N-aryl-4-trifluoromethylthiazol-2-amines were also demonstrated.

Synthesis of Benzopyrone-Fused Hydrobenzo[c,d]indoles via Cascade Annulation of p-Quinamines and 3-Formylchromones.

A 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed cascade annulation reaction between p-quinamines and 3-formylchromones was developed, affording a series of benzopyrone-fused hydrobenzo[c,d]indoles in moderate to high yields with excellent diastereoselectivity. This cascade reaction is efficient since two new rings as well as one C-N, one C═C, and two C-C bonds are created in a single step. The scale-up synthesis and versatile transformations of the products further demonstrated the practicality and utility of this approach.

Enantioselective Rh‐Catalyzed Hydroboration of Dialkyl Ketone‐Derived Silyl Enol Ethers

AbstractA Rh‐catalyzed asymmetric hydroboration of dialkyl ketone‐derived silyl enol ethers with HBpin has been developed using a commercially available catalyst and ligand ([RhCl (cod)]2 and MeO‐BIBOP). A variety of silyl enol ethers undergo this asymmetric transformation, providing the corresponding products with high enantioselectivity (up to 97 : 3 % er). In addition, the utility of this protocol is demonstrated by the versatile transformation of chiral borylether products to a range of valuable derivatives.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides

Despite recent advancements in catalytic synthesis of axial chirality, reports on non‐biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho‐aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Synthesis of β-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes.

An unprecedented trimethylsilyl trifluoromethanesulfonate (TMSOTf)-promoted selective double insertion of isocyanides into aldehydes was developed, providing an efficient protocol for synthetically challenging β-carbonyl α-iminoamides. The given approach is applicable for a diverse selection of readily accessible aldehydes, along with isocyanides serving as essential precursors for "amide" and "imine" scaffolds. The versatile transformations of the given products were demonstrated, and the pivotal intermediates for the plausible mechanism were identified.

Copper-Catalyzed Remote Regio- and Enantioselective Yne-Allylic Substitution of Coumarins.

Chiral coumarins and their derivatives are prominent bioactive structural units present in a wide range of natural products and pharmaceutical candidates. Therefore, the development of straightforward and efficient methodologies for the synthesis of readily functionalized chiral coumarins is of significant interest. Herein we report an enantioselective copper-catalyzed yne-allylic substitution of coumarins, resulting in a highly regioselective synthesis of diverse new classes of chiral coumarin derivatives with high efficiency and excellent functional group tolerance. Subsequent versatile transformations further demonstrate the substantial synthetic potential of this strategy in the field of biochemical research.

Palladium/Xu‐Phos Catalyzed Enantioselective Intramolecular Heck Reaction of Unactivated Alkenes

Comprehensive SummaryA highly enantioselective palladium‐catalyzed intramolecular Heck reaction of unactivated alkenes is developed, which provides a powerful route to access a broad range of chiral 3,3‐disubstituted‐2,3‐dihydrobenzofurans bearing all‐carbon quaternary stereocenter of interest in pharmaceutical research. Its salient features include high yield, excellent chemo‐ and enantioselectivity, mild conditions, a broad substrate scope as well as versatile transformations of the product.

Cobalt/Photoredox Cooperative Catalysis‐Enabled Cycloaddition Reactions of 1,6‐Diynes and Related Compounds

AbstractCobalt catalysts have recently gained considerable attention as alternatives to catalysts based on precious transition metals such as Rh and Ir. Recently, Co/photoredox cooperative catalysis has emerged as a powerful tool that enables versatile transformations, including cycloaddition reactions of unsaturated compounds. In particular, 1,6‐diyne derivatives are fascinating substrates for these reactions because the corresponding exocyclic 1,3‐diene products can be further transformed into sp3‐rich carbocycles and heterocycles via functionalization of the diene moiety. The dual catalytic system can facilitate not only the cycloaddition based on the activation of the π‐bond only, such as alkyne cyclotrimerization, but also the cycloaddition involving σ‐bond activation. This Concept highlights the recent advances in Co/photoredox cooperative‐catalysis‐enabled cycloaddition reactions, focusing on the reactions of 1,6‐diyne substrates, which are difficult to perform when well‐defined cationic CoI catalysis is employed.

Diastereocontrolled Construction of Spiroindolenines via Hexafluoroisopropanol-Promoted Dearomative Epoxide-Indole Cyclization.

Herein, we report the discovery of the ipso-selective, dearomatizing spirocyclization of indole-tethered epoxides as a fundamentally new approach for constructing spiroindolenines equipped with three contiguous stereogenic centers under complete diastereocontrol (dr >99:1) and in high yields. Promoted by hexafluoroisopropanol, the protocol features a broad substrate scope, easy scale-up, and versatile transformations of the synthesized spiroindolenines.

Palladium-Catalyzed Dual C-H Carbonylation of Diarylamines Leading to Diversified Acridones under CO-Free Conditions.

A Pd-catalyzed dual C-H carbonylation of commercially available diarylamines using Co2(CO)8 as a safe CO source has been developed. This methodology provides a facile approach for the synthesis of diversified acridones in moderate to good yields. The protocol features good functional group compatibility, operational safety, easy scale-up, and versatile transformations.

Recent advancement in the synthesis of isothiocyanates.

Isothiocyanates exhibit various biological characteristics, including antimicrobial, anti-inflammatory, and anticancer properties. Their significance extends to synthetic chemistry, where they serve as valuable platforms for versatile transformations. Consequently, they have attracted the attention of biologists and chemists. This review summarizes recent advancements in the synthesis of isothiocyanates. Access to a variety of starting materials is important to prepare isothiocyanates with diverse structures. This review categorizes synthetic methods into three types based on the starting materials and functional groups: (i) type A, derived from primary amines; (ii) type B, derived from other nitrogen functional groups; and (iii) type C, derived from non-nitrogen groups. Recent trends in synthetic methods have revealed the prevalence of type-A reactions derived from primary amines. However, type B reactions have rarely been reported. Notably, over the past four years, there has been a notable increase in type C reactions, indicating a growing interest in non-nitrogen-derived isothiocyanates. Overall, this review not only outlines the advancements in the synthesis of isothiocyanates but also highlights trends in the methodology.

Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center

AbstractThe skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Herein, we report a general strategy for the dearomative one‐carbon insertion of azoles using fluoroalkyl N‐triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring‐expanded heterocycles in excellent yields with good functional‐group compatibility. The broad generality of this methodology in the late‐stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated.

Mechanistic study on the side arm effect in a palladium/Xu-Phos-catalyzed enantioselective alkoxyalkenylation of γ-hydroxyalkenes

Recently, the asymmetric bifunctionalization of alkenes has received much attention. However, the development of enantioselective alkoxyalkenylation has posed a considerable challenge and has lagged largely behind. Herein, we report a new palladium-catalyzed enantioselective alkoxyalkenylation reaction, using a range of primary, secondary, and tertiary γ-hydroxy-alkenes with alkenyl halides. By employing newly identified Xu-Phos (Xu8 and Xu9) with a suitable side-arm adjacent to the PCy2 motif, a series of allyl-substituted tetrahydrofurans were obtained in good yields with up to 95% ee. Besides (E)-alkenyl halides, (Z)-alkenyl halide was also examined and provided the corresponding (Z)-product as a single diastereomer, supporting a stereospecific oxidative addition and reductive elimination step. Moreover, deuterium labeling and VCD experiments were employed to determine a cis-oxypalladation mechanism. DFT calculations helped us gain deeper insight into the side-arm effect on the chiral ligand. Finally, the practicability of this method is further demonstrated through a gram-scale synthesis and versatile transformations of the products.

A Knowledge Graph Framework for Dementia Research Data

Dementia disease research encompasses diverse data modalities, including advanced imaging, deep phenotyping, and multi-omics analysis. However, integrating these disparate data sources has historically posed a significant challenge, obstructing the unification and comprehensive analysis of collected information. In recent years, knowledge graphs have emerged as a powerful tool to address such integration issues by enabling the consolidation of heterogeneous data sources into a structured, interconnected network of knowledge. In this context, we introduce DemKG, an open-source framework designed to facilitate the construction of a knowledge graph integrating dementia research data, comprising three core components: a KG-builder that integrates diverse domain ontologies and data annotations, an extensions ontology providing necessary terms tailored for dementia research, and a versatile transformation module for incorporating study data. In contrast with other current solutions, our framework provides a stable foundation by leveraging established ontologies and community standards and simplifies study data integration while delivering solid ontology design patterns, broadening its usability. Furthermore, the modular approach of its components enhances flexibility and scalability. We showcase how DemKG might aid and improve multi-modal data investigations through a series of proof-of-concept scenarios focused on relevant Alzheimer’s disease biomarkers.

Palladium-Catalyzed Carbonylative Dearomatization of Indoles to Achieve Carbonyl-Containing Spirocyclic Indolenines Bearing an All-Carbon Quaternary Center.

A Pd-catalyzed carbonylative dearomatization via an acyl Pd complex has been developed. Diversified carbonyl-containing spirocyclic indolenines with an all-carbon quaternary center were constructed in an efficient and straightforward way with good to excellent yields. The protocol features a simple catalytic system, operational simplicity, a broad substrate scope, easy scale-up, and versatile transformations. In addition, the asymmetric reaction was initially explored with moderate enantioselectivity.

Diastereoselective Formal 1,3-Dipolar Cycloaddition of Trifluoroethyl Amine-Derived Ketimines Enables the Desymmetrization of Cyclopentenediones.

In this research, a metal-free diastereoselective formal 1,3-dipolar cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and cyclopentene-1,3-diones which can efficiently lead to the desymmetrization of cyclopentene-1,3-diones is developed. With the developed protocol, a series of tetracyclic spirooxindoles containing pyrrolidine and cyclopentane subunits can be smoothly obtained with good results (up to 99% yield and 91:9 dr). Furthermore, the methodology can be extended to trifluoromethyl-substituted iminomalonate, and the corresponding formal [3+2] cycloaddition reaction affords bicyclic heterocycles containing fused pyrrolidine and cyclopentane moieties in moderate yields with >20:1 dr. The synthetic potential of the methodology is demonstrated by the scale-up experiment and by versatile transformations of the products.

Synthesis of Multisubstituted Allenes by Palladium-Catalyzed Carboetherification of β,γ-Unsaturated Ketoximes with Propargylic Acetates.

A highly efficient Pd-catalyzed carboetherification reaction of β,γ-unsaturated ketoximes with propargylic acetates is demonstrated. This method provides a practical protocol for accessing the incorporation of an allene moiety into 3,5-disubstituted and 3,5,5-trisubstituted isoxazolines. The salient features of this transformation include a broad substrate scope, good functional group tolerance, an easy scale-up, versatile transformations, and applications in the late-stage modification of drugs.

Cu‐Catalyzed Asymmetric Kinetic Boron Conjugate Addition of γ‐Substituted α,β‐Unsaturated γ‐Lactams

AbstractChiral α,β‐unsaturated γ‐lactams bearing simple γ‐ substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ‐substituted α,β‐unsaturated γ‐lactams via a Cu‐catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral β‐hydroxy‐γ‐lactams with β,γ‐stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ‐alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N‐protected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin‐sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well‐known mechanism involving Cu−B species in Cu‐catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid CuI‐catalyzed mechanism is the likely pathway in the catalytic reaction.