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Introduction and Characteristics

Yong-Bin Wang, Shao-Hua Xiang, and Bin Tan

Department of Chemistry, Southern University of Science and Technology, No. 1088, Xueyuan Rd., Nanshan District, Shenzhen, 518055, China

1.1 Introduction and Classification

If a rigid object or the spatial arrangement of points including atoms is nonsuperposable on its mirror image, such an object possesses no symmetry elements of the second kind and the geometric property displayed is denoted as chirality (IUPAC). Chirality is widely represented in nature and plays crucial roles in life-sustaining processes. In living systems, chiral homogeneity of monomer units (such as a-amino acid and nucleoside) is found to induce more rapid polymerization and longer chain length of biopolymers (proteins, DNA, or RNA). Thus, the biomacromolecules assembled from the homochiral monomeric building blocks exhibit homochirality, which is considered the sine qua non for molecule-based life. As such, virtually all chiral biomolecules including small monomers and biopolymers in living organisms are enantiomerically pure to engender biological homochirality. This affects the differential interactions between biomacromolecules with a pair of enantiomers [1]. For this reason, pharmaceuticals development is progressively gravitating toward deriving single isomers instead of racemates [2, 3]. In the domain of material science, chiral homogeneity is critical for the properties of materials [4, 5]. Taken together, asymmetric synthesis toward molecular targets with high stereochemical purities has been a central research theme in many organic chemistry-oriented research laboratories.

Early investigations of asymmetric chemistry have centered on central chirality, which refers to stereoisomerism that arises from asymmetric spatial arrangement of a set of ligands attached to an atom (Cabcd, Nabcd+, and P(X)abc). With the progression of chemical science, additional types of stereoisomerisms began to garner increasing attention. Stereoisomers that feature axial chirality, helical chirality, and planar chirality assume different topological structures, but unlike those projecting central chirality, they exist as enantiomers in the absence of stereogenic center. Axial chirality refers to stereoisomerism resulting from nonplanar arrangement of four groups in pairs about a chirality axis (IUPAC). In diverse conformational topologies, atropisomers [6], chiral allenes [7], spiranes [8], and spiro chiral molecules [9] fulfill the definition of axial chirality. Among these axially chiral structures, atropisomers are unique in that the chirality is derived from restricted rotation about a single bond (chiral axis) and racemization proceeds simply through the rotation of this axis rather than the breaking and forming of chemical bond [6, 10] (Figure 1.1).

• Central Chirality: Stereoisomerism resulting from the asymmetric spatial arrangement of a set of ligands attached to an atom (Cabcd, Nabcd+, and P(X)abc).
• Helical Chirality: Stereoisomerism resulting from the arrangement of atoms in molecules along screw rotation.
• Planar Chirality: Stereoisomerism resulting from the arrangement of out-of-plane groups with respect to a plane (chirality plane)
• Axial Chirality: Stereoisomerism resulting from the nonplanar arrangement of four groups in pairs about a chirality axis.
• Atropisomerism: Subclass of axial chirality; stereoisomerism resulting from the restricted rotation about a single bond.

When Christie and Kenner made the seminal discovery of atropisomerism in 1922, the importance of axial chirality has been largely overlooked until 1980. Noyori and coworkers developed and illustrated the superiority of axially chiral 1,1-biphenyl-derived 2,2´-bis(di-phenylphosphino)-1,1´-binaphthyl (BINAP) as a chiral ligand for asymmetric metal-catalyzed reaction [11]. This work spurred the development of several excellent ligands derived from axially chiral 1,1-biphenyl and related spiro frameworks [9]. 1,1´-Bi-2-naphthol (BINOL), as one representative axially chiral reagent, finds utility as a ligand in metal catalysis and also asymmetric organocatalysis [12]. The formative works of Akiyama and Terada revealed the valuable potential of axially chiral BINOL-derived phosphoric acids as robust hydrogen-bonding catalysts in asymmetric Mannich reactions [13, 14]. Their discovery spawned intense research into organocatalysis and chiral Brønsted acid catalysis, from where the application of axially chiral skeletons in asymmetric catalysis vastly expanded. It is especially noteworthy that existing axially chiral catalysts, by empowering new stereoselective reaction manifolds, could in turn expedite the discovery of novel and more efficient axially chiral ligands/organocatalysts. Given many factors often govern the activity and stereoselectivity of catalysts/ligands, axially chiral architectures present high structural adaptability to meet requirements of different catalytic reactions through convenient adjustment of their dihedral angles and substituents. To date, diverse types of axially chiral ligands and organocatalysts with highly enabling performance have been developed and constitute the most extensively used class of ligands in asymmetric catalysis [10, 15, 16] (Figure 1.2).

Figure 1.1 Various forms of chiralities and axial chiralities.

In addition to atropostable analogs, conformationally more labile tropos ligands, characterized by high interconversion rate between enantiomers that could preclude isolation of single enantiomers, can be evolved toward integration in asymmetric catalysis. Herein, chiral activator preferentially induces redistribution of the atropisomeric composition of these ligands to single atropisomer through coordination to transition metal, even with the use of catalytic amount per tropos ligands [17]. This section will be discussed in Chapter 11 (Figure 1.3).

Figure 1.2 Representative organocatalysts and ligands containing axial chirality.

Figure 1.3 Tropos ligands.

Chiral biaryl or heterobiaryl axis is innate in many naturally occurring compounds where axial chirality could and often present in conjunction with other stereogenic elements. Therefore, natural products possessing axial stereogenicity could exhibit high structural diversity, from structurally sophisticated heptapeptide vancomycin to simple biaryls. The iconic antibiotic, vancomycin, contains numerous stereocenters, two chiral planes, and a rotationally hindered biaryl axis. The configurationally locked axis rigidifies the three-dimensional framework thus enhances its efficient binding with the bacterial target, resulting in remarkable bioactivities. Naturally occurring atropisomers are generally isolated in enantiopure or racemic form [18]. Although modern bioassays have revealed the huge biological activity differences elicited by two atropochiral antipodes, several marketed drugs bearing stable chiral axes are used in racemic form. Efforts dedicated in interrogating activity differences between enantiomeric atropisomers through structure-activity relationship (SAR) studies have resulted in highly active and selective axially chiral candidates [19, 20]. The promising biological activities of enantiopure atropisomers render research into biological enantioselectivity of axially chiral compounds high desirable (Figure 1.4).

Determining absolute configuration and enantiomeric purity of chiral compounds is one important if not mandatory procedure in the preparations of chiral compounds as well as in the research of biological enantioselectivity. Axially chiral skeletons have served well in this capacity, where they have been successfully applied in several characterization techniques based on chiral recognition. For example, the BINOL-derived chiral stationary phases for high-performance liquid chromatography (HPLC) aptly resolve a wide range of racemates containing amino group in diverse mobile-phase modes [21]. The fluorescent probe equipped with atropisomeric biphenyl skeleton can determine the enantiomeric excess (ee) of chiral hydroxycarboxylic acids and N-protected amino acids through fluorescent enhancement. The exquisite chiral recognition ability also enables real-time ee detection of asymmetric catalytic reaction, an application that is highly serviceable in optimization studies and one that is hardly achieved with conventional chiral HPLC [22, 23]. On top of chiral recognition, atropisomers are employed as chiral dopants of cholesteric liquid crystals since 40?years ago, a utility fostered by their ultrawide helical twisting power (up to 757?µm-1) [24]. Amalgamation of this property with cholesteric liquid crystals provide valuable stimulus-responsive optical device [25] (Figure 1.5).

In summary, axial chirality is ubiquitously encountered and increasingly exploited in organic synthesis, asymmetric catalysis, research of medicinal chemistry, and functional materials [10, 18,26-28]. This supplies steady demand to stimulate development of novel axially chiral scaffolds as well as preparations of the privileged ones in higher efficiency. Chiral...