Enantioselective Synthesis of Macrocyclic Planar Chiral Metacyclophanes via Desymmetrization
Created on 02.09
1. Research Background and Significance
Planar chiral cyclophanes, featuring unique three-dimensional cavity structures, are significant macrocyclic scaffolds in bioactive natural products, drug development, supramolecular chemistry, functional materials, and asymmetric catalysis. To date, the FDA has approved over 70 macrocyclic drugs, with at least one new approval annually. However, asymmetric synthesis efforts have predominantly focused on para-cyclophanes, while meta-cyclophanes—characterized by a smaller bond angle (120°), higher steric congestion, fewer reactive sites, and challenging substrate design—have long been overlooked. Recently, the collaborative teams of Prof. Xin Li (Nankai University) and Prof. Bin Wang (Tianjin Normal University) employed a chiral phosphoric acid catalyst to achieve the efficient synthesis of diverse planar chiral [n]metacyclophane quinoline derivatives via a desymmetrization strategy using a one-pot multicomponent Povarov/oxidative aromatization sequence.
2. Reaction Optimization and Conditions Screening
The team systematically evaluated catalyst structures, solvents, and additives to optimize enantioselectivity and yield. Key findings from the screening process include:
Optimal Conditions:
- Catalyst: 4k (2 mol%)
- Solvent System: DCM (Solvent 1) + THF (Solvent 2)
- Additive: 3Å molecular sieves
- Temperature: 0–25°C
- Yield: Up to 85%
- Enantioselectivity: Up to 97–99% ee
3. Substrate Scope and Versatility
The methodology demonstrates broad applicability across diverse meta-cyclophane substrates, tolerating electron-donating/withdrawing groups, heteroaryl motifs, and varying ring sizes:
4. Key Advantages of the Chiral Phosphoric Acid Catalyst
- High Enantioselectivity and Stereocontrol Achieves up to 99% ee for planar chiral metacyclophanes. Enantioselectivity can be reversed using the catalyst’s enantiomer.
- Low Loading and High Economical Efficiency Operates at only 2 mol% catalyst loading—significantly lower than existing methods. Proceeds at room temperature via a one-pot protocol, enhancing practicality.
- Broad Substrate Compatibility and Mechanistic Clarity Accommodates meta-cyclophanes with diverse substituents (e.g., halogens, ethers, heterocycles) and aldehydes. DFT calculations reveal π–π stacking interactions between the catalyst and substrates, stabilizing the favored transition state and guiding future catalyst design.
5. Industrial Support
To facilitate research, Anhui Kaitai Laibo offers a Chiral Phosphoric Acid/Phosphoramide Kit containing 7 privileged catalyst structures, along with custom synthesis services.
6. Publication Details
Title: Enantioselective Synthesis of Macrocyclic Planar Chiral Metacyclophanes via Desymmetrization
Authors: Ziyang Wang, Jiali Lin, Ying-Bo Shao, Bin Wang, Xin Li
Journal: ACS Catalysis
DOI: 10.1021/acscatal.5c05337