Inherently Chiral Macrocycles: Catalytic Asymmetric Synthesis and Properties

ConspectusMolecular chirality defines the non-superimposability of three-dimensional molecules onto their mirror images. Due to the often drastically distinct biological effects exhibited by enantiomers, the synthesis of enantiopure small organic molecules remains a topic of persistent research interest. Molecular chirality is commonly divided into point, axial, planar, and helical types based on stereogenic elements. In contrast, inherently chiral molecules form a unique category that lacks these conventional chiral elements. Their chirality results from curvature introduced into a planar structure without a perpendicular symmetry plane in two dimensions. A prominent example of this category is inherently chiral macrocycles (ICMs), which possess chirality solely due to their macrocyclic, nonplanar structure. Conversely, ring-opening of an ICM yields an achiral linear molecule. It is noteworthy that while the synthesis and application of conventional chiral molecules have reached a high degree of sophistication, the chemistry of ICMs remains largely unexplored, primarily due to the significant challenges in obtaining them in highly enantioenriched forms. Resolution of racemic samples using analytical HPLC with columns coated with a chiral stationary phase is the most frequently used method to obtain small amounts of enantiomers.Since the beginning of my independent research career in 2018, driven by my long-standing interest in molecular chirality, our group has engaged in the chemistry of inherently chiral macrocyclic compounds, a research field largely neglected and underexplored by mainstream scientists. From the viewpoint of the structure and the diversity of molecular chirality, it is fascinating to generate a chiral molecular space consisting of almost limitless macrocyclic entities that do not rely on chiral building blocks. Beyond their conceivable applications as conventional chiral compounds, ICMs hold significant potential to offer unique advantages and open new opportunities in areas such as molecular recognition, asymmetric catalysis, and functional materials. Over the past six years, to address the limited availability of highly enantiopure ICMs, we have successfully developed three primary strategies: (1) de novo synthesis of ICMs from linear precursors; (2) desymmetrization of symmetric macrocycles; and (3) dynamic kinetic resolution (DKR) of racemic macrocycles, which enables efficient construction of enantiomerically enriched ICMs. With inherently chiral compounds in hand, we are free to systematically study their structure and properties. We have demonstrated that ICMs provide an extraordinary platform for the fabrication of chiroptical materials and chiral catalysts in supramolecular catalysis. In this Account, we summarize our efforts in exploring the chemistry of ICMs, with a focus on the catalytic enantioselective synthesis, their structural characteristics, the assignment of the absolute configuration, and their unique chiroptical properties and potential applications in supramolecular catalysis. We hope the advancement of synthetic methodology can open doors to the rational design and precise construction of novel ICMs. The easy availability of enantioenriched ICMs could then inspire scientists to explore their applications in chemistry, materials, and life sciences.