Atropisomeric compounds are widely distributed in natural products and pharmaceuticals and serve as key scaffolds in asymmetric catalysis. Despite their remarkable structural diversity, current synthetic efforts have primarily focused on C–C biaryl atropisomers, while the synthesis of other classes of atropisomeric compounds has been much less explored. Biocatalysis offers precise control over the stereoselectivity of reactions, however, its application in the synthesis of atropisomeric compounds remains at an early stage. In this work, we report a versatile biocatalytic platform that integrates metalloenzyme-catalyzed reduction reactions to access a broad array of structurally diverse atropisomeric compounds, including C–N atropisomers, diaryl ethers, and styrene derivatives, with high yields and excellent enantioselectivities. Molecular dynamics simulations provided mechanistic insights into the origin of the high stereoselectivity, and this study expands the repertoire of metalloenzyme-catalyzed, new-to-nature transformations for the synthesis of valuable molecules.
Developing new reagents is one efficient strategy for expanding accessible chemical space. Recently, gem-diborylalkanes have emerged as a versatile class of boron-containing reagents with broad reactivity. However, most gem-diborylalkanes are achiral due to the pair of identical boryl groups, which restricts their utility in synthesis, especially for the production of enantioenriched products. To date, only a handful of chiral analogues have been reported, with constricted structural diversity and limited stereospecific transformations. Here, we report the design of a new class of chiral gem-diborylalkane (CDBA) reagents, featuring two boryl groups with chemically distinguishable reactivities, enabling highly selective and stepwise derivatizations. Their versatility is demonstrated through diverse downstream transformations, including the construction of boron stereogenic centers, the synthesis of boron-containing pharmaceuticals, and the preparation of key intermediates for small molecule drugs. These methods offer a powerful platform for the synthesis of enantioenriched alkylboron compounds and hold potential for enhancing synthetic capabilities in drug discovery and development.
Hong-Yi Tao, Zhong-Xing Huang, Hairong Lyu· Journal of the American Chem...· 0 citations
A stereoselective methodology for the synthesis of highly substituted spiropyrrolidines via synergistic catalysis was developed. The transformation is based on a cooperative catalytic system combining chiral phosphoric acid (CPA) catalysis with achiral palladium catalysis and proceeds through a formal [3+2] cycloaddition of activated vinylcyclopropanes with aldimines derived from imidazolones. Under the optimized reaction conditions, a broad range of spiropyrrolidines were obtained in good combined yields (up to 83%), with high diastereoselectivities (up to 1:12 dr) and enantioselectivities reaching 99% ee. The developed methodology tolerates various substitutions on both of the reaction partners. Furthermore, selected synthetic transformations demonstrated the utility of the obtained spiropyrrolidines for further derivatization while retaining the enantiomeric purity. This work highlights the potential of synergistic CPA/transition-metal catalysis for the efficient construction of structurally complex chiral spiropyrrolidine scaffolds.
Michael Franc, Ivana Císařová, J. Veselý· Journal of Organic Chemistry· 0 citations
The research of atropisomerism containing aza axes (such as C─N, N─N, C─O, and C─B) in synthetic chemistry has drawn considerable attention in the past few years, primarily due to its importance to natural products total synthesis, pharmaceuticals, and materials science. In contrast to the well-established field of C─C atropisomers, the catalytic asymmetric construction of aza-axial chirality was largely overlooked for a long time until the seminal reports by Taguchi and Curran in the early 2000s. This review mainly summarizes the progress in N-heterocyclic carbene-mediated atroposelective construction of aza-axial chiral atropisomers, covering strategies including kinetic resolution (KR), dynamic KR, desymmetrization, de novo annulation, and direct atroposelective N-acylation. Despite these achievements, the asymmetric synthesis of aza-axial chirality remains far less developed than that of C─C atropisomers, owing to the difficulty in controlling enantioselectivity. Exploration of efficient and novel methods for constructing aza-axial chiral molecules is highly desirable.
Xiao-Yong Duan, Dongyan Li, Zi-Tong Yao et al.· The chemical record· 0 citations
Benzimidazole represents one of the most extensively investigated nitrogen‐containing fused heterocyclic scaffolds owing to its unique structural features, synthetic versatility, and broad spectrum of biological and industrial applications. The presence of a benzene ring fused with an imidazole nucleus imparts remarkable physicochemical and pharmacological properties, making benzimidazole a privileged framework in medicinal chemistry, materials science, catalysis, and supramolecular chemistry. This review critically examines recent advances in the synthesis, reactivity, structure–activity relationships (SAR), and applications of benzimidazole derivatives. Various synthetic approaches, including classical condensation methods, transition‐metal‐catalyzed protocols, multicomponent reactions, microwave‐assisted synthesis, solvent‐free methodologies, and metal‐free organocatalytic routes, are comparatively evaluated with respect to efficiency, substrate scope, mechanistic features, scalability, and sustainability. Particular emphasis is placed on emerging catalytic strategies employing Earth‐abundant metals, recyclable catalysts, and carbon dioxide as a sustainable C1 feedstock. The review further analyzes the influence of N1, C2, and C5/C6 substitutions on biological activity, highlighting key SAR trends governing antimicrobial, anticancer, antiviral, anti‐inflammatory, antioxidant, antidiabetic, and neuroprotective properties. By integrating synthetic methodologies with biological and functional perspectives, this review provides a comprehensive and critical framework for understanding the current state of benzimidazole chemistry and identifies future directions for the development of sustainable and multifunctional benzimidazole‐based systems.
Pallavi V. Gaikwad, Sanjay G. Chavan, R. Pinjari· ChemistrySelect· 0 citations
During the last two decades, chemists have witnessed the explosive growth of organocatalysis, which provides a robust methodology for the preparation of numerous valuable compounds. The importance of organocatalysis in organic chemistry had been highlighted through the Nobel Prize in Chemistry 2021 was given to Prof. David W.C. MacMillan and Prof. Benjamin List for outstanding contributions to “the development of asymmetric organocatalysis”. Compared to the classical transition-metal catalysis and biocatalysis, organocatalysis has a number of unique properties, such as transition-metal-free, very good structural amenability, novel modes of activations, easy availability of a broad variety of naturally occurring small organic catalysts, including natural sources of chiral amino acids, Cinchona alkaloids, carbenes and others. Today, organocatalysis has been a powerful technology for organic synthesis. In addition to the applications in organic synthesis and catalysis, organocatalysis has also been used in the production of enantiomers, in fine chemistry, pharma, crop-protection, and fragrance chemistry. As one important type of organic catalyst, N-heterocyclic carbenes (NHCs) have broad applications in organic synthesis. Inspired by the natural coenzyme thiamine (vitamin B1) catalysis, chemists developed various NHCs and used them to catalyze a broad variety of transformations, including benzoin reaction, Stetter reaction, homoenolate transformations, redox reactions, cycloadditions, photoreactions and other reactions. On the other hand, aldol condensation reaction is one of the most important reactions for the construction of carbon-carbon bonds. Based on the unique Lewis basicity of NHCs, we and other groups realized efficient activation of different silylated nucleophiles and developed a variety of aldol-type reactions of carbonyl compounds. As a result, different functionalized alcohols and their derivatives were prepared through NHC catalysis.
This book can be used as a reference for scholars, graduate students, and researchers in the field of organic chemistry, fine chemistry and drug synthesis.
Metalloids bridge the properties of metals and nonmetals, creating unique opportunities in drug discovery. However, the potential of silicon- and germanium-containing scaffolds in organic synthesis and medicinal chemistry remain underexplored, largely owing to the lack of general stereocontrolled synthetic methods, particularly for value-added chiral α-silylamines and α-germylamines. Here, we report a robust nickel-catalyzed enantioselective decarboxylative cross-coupling of amino acid or peptide-derived redox-active esters with silylzinc and germylzinc reagents. The method exhibits a broad substrate scope and delivers excellent performance under mild conditions. Its efficacy is further demonstrated through the late-stage diversification of complex bioactive peptides, and both enantiomers can be accessed with high stereochemical fidelity. Mechanistic investigations delineate the origin of stereocontrol, while preliminary biological evaluations show promising activities, with Ge substitution in several cases surpassing Si and certain clinically marketed boron-containing drugs. Collectively, this work establishes an efficient and enantioselective route to chiral α-silylamines and α-germylamines, underscoring their potential to expand peptide chemical space and to enable the development of peptide-based therapeutics and diagnostics.
Qiang Tao, Yu-Juan Wang, Kai-Ge Lu et al.· Journal of the American Chem...· 0 citations
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