1
Introduction

Mohamed S. H. Salem1,2 and Shinobu Takizawa1

1Osaka University, SANKEN, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan

2Suez Canal University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Ismailia, 4.5 KM Ring Road, 41522, Egypt

1.1 Molecular Chirality and Atropisomerism

1.1.1 Molecular Chirality

The exploration of stereochemistry has captivated the chemical community since Pasteur's groundbreaking revelation of molecular chirality in 1848 [1], followed by van 't Hoff and Le Bel's influential introduction of tetrahedral carbon in 1874 [2, 3]. The International Union of Pure and Applied Chemistry (IUPAC) defines chirality, derived from the Greek word ??í? (kheir) meaning hand, as the geometric property of a rigid object (or spatial arrangement of points or atoms) being nonsuperposable on its mirror image. Such an object lacks symmetry elements of the second kind, including a mirror plane, a center of inversion, or a rotation-reflection axis [4]. Chiral molecules typically possess at least one stereogenic element, giving rise to their chirality. The most prevalent type of stereogenic element is a stereogenic center or chirality center, which is an atom holding a set of ligands in a spatial arrangement which is not superposable on its mirror image (IUPAC) [5]. A chirality center is thus a generalized extension of the concept of the asymmetric carbon atom to the central atoms of any element, for example, nitrogen N or phosphorus P. There are other types of stereogenic elements that can give rise to chirality, including a stereogenic axis (axial chirality), a stereogenic plane (planar chirality), and a screw axis (helical chirality) (Figure 1.1) [5].

• Chirality axis: An axis around which a set of ligands is held so that it results in a spatial arrangement that is not superposable on its mirror image.
• Chirality plane: A planar unit connected to an adjacent part of the structure by a bond, which results in restricted torsion so that the plane cannot lie in a symmetry plane.
• Screw axis: An axis around which the atoms are held in a screw-shaped arrangement that is not superposable on its mirror image. While certain sources categorize helical chirality as a form of axial chirality, IUPAC does not acknowledge helicity as a subtype of axial chirality.

Figure 1.1 Different types of molecular chiralities and stereogenic elements.

Chirality is a ubiquitous phenomenon observed in various disciplines, mainly in the realms of biology, pharmaceuticals, organic chemistry, and materials science [6]. Biological homochirality of essential molecules such as L-amino acids in proteins and D-sugars in nucleic acids is vital for the proper functioning of living organisms [7]. The thing is reflected in the drug industry, as often only one enantiomer of a chiral drug exhibits therapeutic efficacy, leading to the development and production of single-enantiomer drugs to enhance their efficacy and minimize associated side effects [8]. Chirality extends its impact to materials science, where certain chiral molecules exhibit unique chiroptical features, such as circularly polarized luminescence (CPL) and circular dichroism (CD), facilitating the design of advanced materials and devices [9-12]. Chiral catalysts in organic chemistry have a key role in asymmetric synthesis, contributing to the selective production of enantioenriched chiral compounds, especially in the synthesis of pharmaceuticals and functionalized materials [13-16].

1.1.2 Axial Chirality and Atropisomerism

Earlier investigations primarily focused on central chirality, with the pioneering works of Pasteur, van't Hoff, and Lebel centered on chiral tetrahedral carbon with four distinct substituents [1-3]. However, a milestone was achieved a century ago in 1922 when George Christie and James Kenner first identified atropisomerism in a tetra-substituted biphenyl diacid 1 [17]. After this groundbreaking discovery, some efforts were exerted to explore this new type of chirality, but a quantum leap transpired with the advent of asymmetric catalysis. Ligands exhibiting axial chirality, such as derivatives of 1,1´-bi-2-naphthols (BINOLs), 2,2´-bis(di-phenylphosphino)-1,1´-binaphthyls (BINAPs), and 2,2´-diamino-1,1´-binaphthalenes (BINAMs) (refer to Chapters 7 and 8 for detailed insights), demonstrated superior efficacy in controlling asymmetric metal-based reactions, as elucidated by Ryoji Nyori [18]. The prevalence of axial-to-central chirality transfer became evident in the realm of asymmetric catalysis. Over the past two decades, these ligands have additionally proven their superiority in various organocatalysts, such as chiral phosphoric acid catalysts, independently developed by Akiyama and Terada (Figure 1.2). These advancements captivated researchers, prompting them to delve deeper into the study and exploration of axial chirality and atropisomerism [19, 20].

Figure 1.2 Atropisomerism in privileged chiral ligands and organocatalysts.

While some may mistakenly conflate axial chirality and atropisomerism concepts considering them synonymous, it is imperative to recognize that axial chirality encompasses broader forms. According to IUPAC, axial chirality is precisely defined as a stereoisomerism resulting from the nonplanar arrangement of four groups in pairs about a chirality axis [5]. In essence, these frameworks possess a chiral axis, imposing restrictions on the rotation of two pairs of groups. As per the IUPAC definition, this concept encompasses diverse families of organic molecules featuring noncoplanar arrangement of two pairs of substituents in the parent backbone. The most prominent class of axially chiral compounds falling under this definition is atropisomers, including biaryls, heterobiaryls, aryl alkenes, anilides, and diaryl ethers, whose axial chirality arises from the restricted rotation about single bonds [5]. Allenes, spiro compounds, spiranes, and alkylidene-cyclic compounds are other examples of axially chiral compounds, wherein their chirality comes from the perpendicular geometry of two pairs of substituents (Figure 1.3) [21].

Figure 1.3 The most prominent classes of axially chiral compounds.

The recent surge in literature addressing atropisomerism has significantly impacted the field, capturing attention with its exploration of naturally occurring molecules that exhibit this chirality element [22]. These molecules play a pivotal role in advancing various scientific domains, addressing not only physical organic issues related to structure and stability but also inspiring the development of innovative reaction concepts [23]. The design and synthesis of novel scaffolds showcasing atropisomerism contribute to the ongoing expansion of this interdisciplinary field, which seamlessly integrates chemistry, biology, and physics, finding applications in both medicinal chemistry and materials science [24-28]. Atropisomers, as a fundamental chirality element in nature, exhibit diverse biological activities and functions, rendering them indispensable in asymmetric catalysis. Numerous atropisomers serve as privileged chiral ligands, demonstrating their critical role in catalytic processes [29, 30]. However, despite their immense potential, challenges persist, exemplified by the varying biological activities observed in stable atropisomeric Food and Drug Administration (FDA)-approved drugs and experimental compounds. The phenomenon of rapidly interconverting atropisomerism adds complexity, as these compounds, while conventionally considered achiral, exhibit atroposelective binding to protein targets [31, 32].

Recognizing the need for a comprehensive resource addressing the opportunities and challenges in this field, we present this handbook, focusing on recent advances in atroposelective synthesis and their different applications. This book explores diverse atroposelective synthetic approaches, including cross-coupling reactions, ring-opening reactions, formation of aromatic rings, and desymmetrization via functional group transformation, utilizing different metal and organocatalysts [33, 34]. By showcasing the impact of these advances on asymmetric catalysis, the synthesis of natural products, functionalized materials, and drug industry, this book contributes to a deeper understanding of the current state of atropisomerism and highlights unresolved challenges. In alignment with the broader context, this book integrates and complements existing literature, particularly Axially Chiral Compounds: Asymmetric Synthesis and Applications by Bin Tan (WILEY-VCH GmbH, 2021) [35] and Atropisomerism and Axial Chirality by José M Lassaletta (World Scientific Publishing Europe Ltd, 2019) [36]. By collating and discussing recent advances, we aim to provide valuable insights for researchers working...