Hailong Yan

Asymmetric synthesis of axially chiral biaryls with multiple stereogenic elements remains challenging. Herein, we report an enzymatic asymmetric aldol condensation via desymmetrization that constructs carbon-centered stereocenters and biaryl axes simultaneously. This biocatalytic strategy affords a range of atropisomers with high diastereo- and enantioselectivities (up to >99:1 er and >19:1 dr). The protocol operates at high substrate loadings under mild conditions and tolerates a range of substrates, giving products containing both axial and central chirality.

Catalytic asymmetric dearomative cycloaddition provides a powerful route to polycyclic chiral frameworks, yet the precise control of selectivity in such cycloadditions remains a formidable challenge. Herein we report a mechanism-guided strategy that harnesses the unique reactivity of vinylidene ortho -quinone methides as highly reactive and multifunctional synthons to realize such cycloaddition with diverse (hetero)polycyclic aromatics. Density functional theory calculations revealed that the distinctive charge distribution, orbital delocalization, and narrow frontier molecular orbital gap of the synthons underpin their multisite reactivity and predictable selectivity. Leveraging these features, we accomplished cycloadditions at challenging sites with excellent regio-, chemo-, and enantioselectivity, including the C6a–C13c site of dibenzo[ c , g ]carbazole, the C9–C10 site of anthracene, and the C5–C6/C5–C8 sites of quinoline. This work establishes an efficient and controllable pathway for the modular synthesis of chiral polycyclic scaffolds and expands the conceptual scope of vinylidene ortho -quinone methide chemistry.

The stereoselective construction of Z-configured olefins remains a fundamental challenge in synthetic chemistry, particularly when additional stereogenic elements with high enantioselectivity are simultaneously introduced. Furthermore, vicinal dihaloalkenes are privileged scaffolds in organic and medicinal chemistry, and the traditional protocol for preparing vicinal dihaloalkenes relies on a halonium intermediate-mediated pathway and typically yields E-configured adducts. Herein, we report the catalytic stereoselective synthesis of enantioenriched Z-vicinal dihaloalkene atropisomers in high yields (up to 95%) with excellent enantioselectivity (up to 99%) and a Z/E ratio of more than 20:1. This transformation was achieved through an allene-mediated organocatalyzed assembly of readily available N-Bromosuccinimide (NBS) and acyl halides as halogenation reagents.

We report herein an efficient approach for the enantioselective synthesis of inherently chiral calix[4]arenes (ICCs) via chiral phosphoric acid (CPA)‐catalyzed lower‐rim asymmetric functionalization. With vinylidene ortho ‐quinone methides (VQMs) as the key intermediates, a stepwise asymmetric halo‐cyclization strategy was applied to construct diverse inherently chiral calix[4]arenes bearing multiple C─C axially stereogenic elements with high enantio‐ and diastereoselectivities (up to 96% ee, all d.r. > 20:1). The obtained lower‐rim functionalized products underwent further photocatalytic transformations to access novel inherently chiral naphthofuran‐based calix[4]arene architectures. Further synthetic modifications and analysis of their photophysical/chiroptical properties demonstrated their potential in optoelectronic materials and related fields. Mechanistic studies reveal that the reaction proceeds via a stepwise process, with the stereoselectivity‐determining step occurring in the first VQMs‐mediated cyclization, and the second step constituting a chiral transfer process.

We report herein an efficient approach for the enantioselective synthesis of inherently chiral calix[4]arenes (ICCs) via chiral phosphoric acid (CPA)‐catalyzed lower‐rim asymmetric functionalization. With vinylidene ortho ‐quinone methides (VQMs) as the key intermediates, a stepwise asymmetric halo‐cyclization strategy was applied to construct diverse inherently chiral calix[4]arenes bearing multiple C─C axially stereogenic elements with high enantio‐ and diastereoselectivities (up to 96% ee, all d.r. > 20:1). The obtained lower‐rim functionalized products underwent further photocatalytic transformations to access novel inherently chiral naphthofuran‐based calix[4]arene architectures. Further synthetic modifications and analysis of their photophysical/chiroptical properties demonstrated their potential in optoelectronic materials and related fields. Mechanistic studies reveal that the reaction proceeds via a stepwise process, with the stereoselectivity‐determining step occurring in the first VQMs‐mediated cyclization, and the second step constituting a chiral transfer process.

Unnatural α- and γ-amino acids display a diverse range of biological activities and serve as crucial intermediates in pharmaceutical production. Specifically, the synthesis of such molecules has been highly sought after in both academia and industry. Nevertheless, their direct synthesis from simple bulk feedstocks has remained largely unexplored, and the switchable synthesis of α- and γ-amino acids through a shared intermediate has never been documented. We disclose herein a four-component reaction involving readily available bulk chemicals to facilitate the switchable synthesis of α- and γ-amino acids from a shared extended p-quinone methide through a tailored amination strategy. A diverse array of amines, including several unmodified drug molecules, along with various other nucleophiles, are readily utilized as suitable substrates in this reaction. We believe this work could inspire future intensive efforts toward the switchable synthesis of amino acids in a practical and efficient manner.

Here, an organocatalytic asymmetric [1,3]‐sigmatropic rearrangement process for aryl ether insertion through C─O bond cleavage and downstream transformation is reported, enabling the practical and atom‐economic synthesis of diverse valuable chiral benzofuran derivatives bearing a quaternary carbon stereocenter. The reaction shows a wide substrate scope, yielding moderate to good products with excellent enantioselectivity and diastereoselectivity (up to >99% ee and >99:1 d.r.). Initial biological activity tests suggest that the resulting enantioenriched benzofuran products hold potential as anticancer agents.

Helicene-shaped molecules are compelling chemical structures with unique twisted helical chirality and remarkable properties. Although progress occurs in the catalytic asymmetric synthesis of helicene (-like) molecules, the enantioselective synthesis of multiple helicenes, especially four or higher helicity, is still challenging and has yet to be achieved. Herein, we report an organocatalytic [4 + 2] cycloadditions to achieve double S-shaped quadruple helicene-like molecules with high enantioselectivity (up to 96% e.e.). The enantioselective synthesis of (P,P,P,P) and (M,M,M,M) configurational quadruple helical molecules can be achieved by modulating the structure of the catalyst. Density functional theory (DFT) calculations show that the reaction involves the formation of a duplex vinylidene ortho-quinone methide (VQM) intermediate and two successive cycloaddition reactions. Configurational stability studies elucidate the isomerization process between the isomers. In addition, the structural features and optical properties of the quadruple helicene-like molecules were investigated to explore their potential applications.