The growing importance of axially chiral architectures in different scientific domains has unveiled shortcomings in terms of efficient synthetic access and skeletal variety. This account describes our strategies in answering these challenges within the organocatalytic context where the emergence of bifunctional catalysts such as chiral phosphoric acids (CPAs) has proven invaluable in controlling the sense of axial chirality. The wide occurrence of bi(hetero)aryl skeletons in privileged structures constitutes a strong motivation to devise more effective arylation methods. Our design revolves around modulating the intrinsic nucleophilicity of aromatic amines and alcohols. The first approach involves the design of an electron-withdrawing activating group which could associate with the catalyst for reactivity enhancement and selectivity control. The resonance of arenes offers the unique mechanistic possibility to select between activating sites. C2-Azo- and nitroso-substituted naphthalenes undergo atroposelective ortho C- or N-arylation with (hetero)aromatic nucleophiles. For monocyclic benzenes, programmable charge localization leads to regioselective activation by catalytic control alone or aided by substrate design. For instance, selective addition to nitroso nitrogen enables successive annulation initiated by the amine to yield axially chiral N-arylbenzimidazoles. In a biomimetic manner, a finely tuned catalyst could direct a para-selective nucleophilic approach in the atroposelective arylation of azobenzenes. The second strategy employs electrophilic arene precursors for arylation which occurs via rearomatization with central-to-axial chirality transfer. This enabled the arylation of (imino)quinones with indoles to access phenylindole atropisomers. By adapting this chemistry with an additional oxidation event to liberate the carbonyl functionalities, aryl-o-naphthoquinone and aryl-p-quinone atropisomers were attained. Along with the development of new arylation strategies, deriving new axially chiral structures has been another consistent theme of our research program. The atroposelective functionalization of alkynes provides broad entry to atropisomeric alkenes. The monofunctionalization of alkynes through the interception of an electrophilic vinylidene-quinone-methide (VQM) intermediate with 2-naphthols yielded the new EBINOL scaffolds. By designing an internal directing group, the atroposelective dihalogenation of alkynes was realized using abundant alkali halides despite their weak nucleophilicities and poor solubilities. The atroposelective N-alkylation of alkenes was pursued to prepare multifunctionalized alkene atropisomers that could be converted into 2-arylpyrroles with chirality transfer. The synthesis of B-aryl-1,2-azaborines containing a C–B chiral axis was accomplished where the CPA catalyst effects the desymmetrization and defines the configuration of the distal C–B bond. Inspired by the axially chiral scaffold of allenes, we leveraged the developed arene activation strategy to achieve para-addition and dearomatization of judiciously designed azobenzenes, which led to structurally novel cyclohexadienylidene-based hydrazones. To complement these structures, axially chiral cyclohexadienyl oxime ethers were also attained through CPA-catalyzed condensation between hydroxylamines and spiro[4.5]trienones.

中文翻译：

---

轴手性分子的有机催化对映选择性合成：策略和骨架的发展

轴向手性结构在不同科学领域的重要性日益增加，揭示了在有效合成途径和骨架多样性方面的缺点。该说明描述了我们在有机催化领域应对这些挑战的策略，在有机催化领域，双功能催化剂（如手性磷酸 (CPA)）的出现已被证明在控制轴向手性方面具有无可估量的价值。双（杂）芳基骨架在特殊结构中的广泛出现构成了设计更有效的芳基化方法的强大动力。我们的设计围绕调节芳香胺和醇的内在亲核性展开。第一种方法涉及设计吸电子活化基团，该基团可以与催化剂结合以提高反应性和选择性控制。芳烃的共振提供了在激活位点之间进行选择的独特机制可能性。C2-偶氮和亚硝基取代的萘经历阻转选择性与（杂）芳族亲核试剂的邻位 C - 或N - 芳基化。对于单环苯，可编程的电荷定位通过单独的催化控制或辅助底物设计导致区域选择性激活。例如，选择性地添加到亚硝基氮中可以使胺引发的连续环化产生轴向手性N -芳基苯并咪唑。以仿生方式，微调的催化剂可以引导对位-偶氮苯的阻转选择性芳基化中的选择性亲核方法。第二种策略采用亲电芳烃前体进行芳基化，芳基化通过中心到轴向手性转移的重芳构化发生。这使得 (亚氨基) 醌与吲哚的芳基化能够获得苯基吲哚阻转异构体。通过使用额外的氧化事件来调整这种化学反应以释放羰基官能团、芳基-邻-萘醌和芳基-对-获得醌阻转异构体。随着新芳基化策略的发展，推导新的轴向手性结构一直是我们研究计划的另一个一贯主题。炔烃的阻转选择性功能化为阻转异构烯烃提供了广泛的入口。通过用 2-萘酚拦截亲电亚乙烯基苯醌甲基化物 (VQM) 中间体，使炔烃单官能化，产生了新的 EBINOL 支架。通过设计内部导向基团，尽管碱金属卤化物亲核性弱且溶解度差，但仍可实现炔烃的阻转选择性二卤化。逆向选择性N对烯烃进行烷基化以制备多功能烯烃阻转异构体，这些异构体可以通过手性转移转化为 2-芳基吡咯。包含 C-B 手性轴的B -aryl-1,2-azaborines的合成是在 CPA 催化剂影响去对称化并定义远端 C-B 键的构型的情况下完成的。受丙二烯轴向手性支架的启发，我们利用开发的芳烃活化策略实现了精心设计的偶氮苯的对位加成和脱芳构化，从而产生了结构新颖的基于环己二烯叉的腙。为了补充这些结构，轴向手性环己二烯基肟醚还通过 CPA 催化的羟胺和螺[4.5]三烯酮之间的缩合获得。