Organocatalytic intramolecular enantioselective, atropselective, and diastereoselective macrocyclization of quinone methylidenes with alcohols

A research team led by Associate Professor Changgui Zhao of Beijing Normal University reported the first intramolecular enantioselective, atropselective, and diastereoselective macrocyclization of quinone methylene (QM) with alcohols catalyzed by chiral phosphoric acid (CPA), successfully constructing planar chiral type III cyclophanes. This strategy, using 2-naphthol as a cofactor, significantly improved the reaction activity and stereoselectivity by generating the more reactive naphthoquinone methylene (NQM) intermediate. Thermodynamic studies demonstrated that the benzylic substituent significantly influences the conformational stability of the cyclophane: even when the ansa chain is extended by two carbon atoms, its planar chirality is maintained, indicating that the conformational stability of this type of cyclophane is controlled by both the macrocycle size and the position of the functional groups on the ansa chain. This study provides important insights into the relationship between the structure of cyclophanes and the mechanism of chirality. The article was published as an open access research article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background:
Cyclophanes are widely present in a variety of natural products and have shown important application potential in supramolecular chemistry, asymmetric catalysis and drug development. Structure-activity relationship studies have shown that the conformational stability of planar chiral cyclophanes has a significant impact on the activity of drug molecules. Restricting the rotation of the aromatic ring can enhance its interaction with biological targets, thereby improving its efficacy. Therefore, developing new strategies for the catalytic asymmetric synthesis of planar chiral cyclophanes and in-depth exploration of the relationship between their structure and conformational stability have become a hot topic in current research. Currently, the main strategies for stabilizing the conformation of cyclophanes include: (1) introducing large steric groups on the aromatic ring (type I); (2) shortening the length of the ansa bridge chain (type II); and (3) introducing chiral units in the ansa chain (type III). However, existing methods for synthesizing type III cyclophanes usually rely on pre-constructed linear precursors and require enantioselective macrocyclization reactions. At the same time, achieving efficient control of enantioselectivity, atropselectivity and diastereoselectivity still faces great challenges.

Zhao Changgui's research group at Beijing Normal University focuses on the study of planar chiral cyclophanes and has developed a variety of strategies for the catalytic asymmetric synthesis of planar chiral cyclophanes, including organocatalytic functional group structure modification, transition metal-catalyzed asymmetric C–H bond activation reactions of prochiral cyclophanes, and asymmetric macrocyclization reactions.

Highlights of this article:
Based on previous studies, the introduction of a remote all-carbon stereocenter within the ansa chain resulted in [15]-cyclophane exhibiting more stable planar chirality, while the similar [16]-cyclophane exhibited significant conformational instability (Figure 1B). Therefore, to further investigate the conformational stability of cyclophane, the authors hypothesized that the introduction of a large steric hindering group at the benzyl position might effectively increase the energy barrier for benzene ring rotation. Given the significant potential of QM intermediates in asymmetric construction of central chiral and axial chiral compounds, the authors proposed a strategy of intramolecular nucleophilic attack on QM intermediates by alcohols to achieve intramolecular macrocyclization of cyclophane. Among them, NQM intermediates, as a subclass of QM intermediates, have higher reactivity, lower decomposition rate, and greater steric hindrance, which may be beneficial for stereoselective control of the reaction. However, this strategy still faces the following challenges: (1) Currently, the asymmetric transformation of QM intermediates is mostly focused on the construction of central chiral and axial chiral molecules. The use of their asymmetric macrocyclization to synthesize planar chiral cyclophanes has not been explored and is uncertain; (2) The weak nucleophilicity of alcohols and the good leaving ability of alkoxy groups make the reaction potentially reversible and stereocontrol difficult; (3) Macrocyclization reactions are sensitive to substrate conformation, which may lead to variable and unpredictable reaction results; (4) Organic catalytic enantioselective, atropselective, and diastereoselective macrocyclization reactions are relatively rare, and effective control of diastereoselectivity remains challenging.

The authors first screened CPA catalyst types under highly diluted conditions (5 mM) using toluene as solvent and adding 3 Å molecular sieves (MS). They found that CPA C8 derived from H₈-BINOL with a large sterically hindered 3,3′-substituent performed best in terms of stereoselectivity and yield. Subsequent screening of solvents, additives and temperature did not yield better results. Thermal stability studies showed that the [15] cyclophane has stable planar chirality. It is worth noting that in the investigation of the auxiliary group, it was found that the QM precursor decomposed rapidly, resulting in a low reaction yield, and the enantioselectivity was significantly lower than that of the NQM precursor (2b–2f). This shows the important role of the naphthol auxiliary group in reaction efficiency and stereocontrol.

After obtaining the optimal conditions,the authors studied the substrate applicability of the reaction (Figure 3). First,substrates with methyl, bromine, phenyl, 3-thienyl and other substituents at the C3, C4, C6 or C7 positions of the naphthalene ring all showed good tolerance. In addition, when the substituent on the C2 hydroxyl group of the substrate benzene ring was changed from methyl to benzyl, 2-methylnaphthalene, 3,5-dimethylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 3-chlorobenzyl and 3,3-dimethylbutyl, the corresponding cyclophanes were obtained with excellent stereoselectivity. The authors furtherinvestigatedansa chains of differentlengths and types. The results showed that substrates with ansa chains of 12-17 atoms could obtain the target planar chiral cyclophanes with certain yields and good stereoselectivity. It is worth noting thatfurther extending theansachain length gave [18]-cyclophane 33 with low diastereoselectivity (2:1 dr), which may be due to the rapid epimerization of the planar chirality caused by the reduction of conformational stability. [16]Studieson the thermal stability of cyclophane 28 and [17] cyclophane 31 showed that no diastereoisomerization was observed in the ¹H NMR spectra of both. Compared with previous reports, this indicates that the introduction of a naphthyl group at the benzylic position can extendthe ansachainby two atoms while maintaining planar chirality.

Through a series of control experiments, the authors confirmed the reaction pathway and kinetic resolution mechanism involving the NQM intermediate and ruled out the S_N2 reaction pathway (Figure 4). The free naphthol hydroxyl group is crucial for the formation of the NQM intermediate, and the stereochemistry of the product is determined by the configuration of the chiral catalyst. Polymerization side reactions and decomposition of substrates with mismatched configurations and catalysts are the main reasons for the low reaction yield. Based on the experimental results, the authors then proposed a reasonable stereochemical model to explain how chiral catalysts control the face selectivity of nucleophilic attack through steric hindrance, thereby achieving high enantioselectivity and diastereoselectivity control.

In addition, the authors further explored the application potential of this cyclophane (Figure 5). Planar chiral cyclophane 2a can undergo a variety of derivatization reactions, such as propargylation, esterification with indomethacin, trifluoromethylsulfonylation, and subsequent Suzuki-Miyaura coupling reaction, to obtain a series of functionalized derivatives (36-39) in high yields and high enantioselectivity. Finally, the authors also successfully applied the cyclophane skeleton to the synthesis of a bifunctional thiourea catalyst (41), which exhibited moderate to good enantioselectivity (56-72% ee) in the Michael addition reaction, providing new ideas for the design of new chiral catalysts.

Summary and Outlook:
In summary, this study developed the first chiral Brønsted acid-catalyzed enantioselective, atropselective, and diastereoselective macrocyclization of methylene quinones with alcohols, providing a new, efficient, and highly selective pathway for the synthesis of type III planar chiral [n]-cyclophanes, achieving simultaneous stereoselective control of central and planar chirality . This work cleverly utilizes 2-naphthol as a cofactor to achieve efficient generation and stereocontrol of NQM intermediates. A systematic investigation reveals the key role of the benzylic substituent in stabilizing the macrocyclic conformation, enabling coordinated regulation of macrocyclic size and configurational stability, and deepening our understanding of the structure-activity relationship of this class of planar chiral molecules. Furthermore, the study confirms the promising application prospects of this class of compounds and their potential as novel chiral catalyst precursors. This article was published as a Research Article in CCS Chemistry. Associate Professor Changgui Zhao of Beijing Normal University is the corresponding author, and doctoral candidate Ting Yao is the first author.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.