Pd/SadPhos-Catalyzed Modular and Enantioselective Assembly of Triarylmethanes
Created on 02.06
Pd/SadPhos-Catalyzed Modular and Enantioselective Assembly of Triarylmethanes
– Research by Fudan University Zhang Junliang/Peking University Shenzhen Graduate School Academician Wu Yundong Team Published in JACS
1. Background and Significance
Chiral triarylmethanes possess unique three-dimensional structures with significant applications in biomedical sciences (e.g., drug design) and functional materials (e.g., chiral luminescent materials). However, their enantioselective synthesis has long faced challenges: conventional methods rely on steric or electronic differences between aryl rings to achieve chirality control, making it difficult to prepare para-substituted or unsubstituted heteroaromatic derivatives, often requiring directing groups. Developing a general and efficient asymmetric catalytic strategy has become an urgent need in this field.
2. Core Advantages of PC-Phos Ligand
PC-Phos, designed by Zhang Junliang’s team based on the wide bite angle of the achiral bisphosphine ligand Xantphos, is the first member of the Sadphos family derived from a privileged ligand scaffold. Its features include:
- Scaffold Innovation: Using a xanthene backbone with chiral sidechains to construct a stereocontrol environment;
- Broad Applicability: Since its first report in 2017, it has demonstrated high activity and stereoselectivity in asymmetric Pictet–Spengler cyclization, C–S/C–P coupling, Suzuki coupling, deromative kinetic resolution, palladacycle allylic cyclization, and tandem Heck/Tsuji–Trost reactions;
- Adaptive Coordination: Dynamically switches coordination modes (e.g., P,O-bidentate to P-monodentate) during catalysis, stabilizing key intermediates via Pd…H agostic interactions.
3. Innovations in This Work
3.1 Reaction Design
Using hydrazones, aryl halides, and aryl boronic esters as three-component substrates, a Pd/PC-Phos-catalyzed one-pot cascade coupling simultaneously forms two C–C bonds, enabling modular synthesis of chiral triarylmethanes.
3.2 Mechanistic Insights
- Preferred Pathway: DFT calculations indicate the three-component pathway dominates due to lower energy barriers compared to stepwise coupling;
- Rate-Determining Step: Transmetalation (energy barrier: 26.1 kcal/mol);
- Enantiodetermining Step: Carbene migration insertion; the agostic interaction and steric modulation by PC-Phos lead to high ee values (>92%).
3.3 Substrate Scope
- Aryl Diversity: Tolerates electron-donating groups (-OMe, -NMe₂), electron-withdrawing groups (-CF₃, -NO₂), heteroaryl groups (pyridyl, furyl), and alkenes/alkynes;
- Bioactive Molecule Derivatization: Successfully applied to gram-scale synthesis and late-stage modification of drug-like molecules.
4. Key Technical Highlights of Sadphos Ligands
- Dynamic Coordination Ability: Adaptive switching between coordination modes balances reactivity and stereocontrol;
- Breaking Traditional Limits: Differentiates structurally similar aryl rings without relying on electronic/steric biases;
- Byproduct Suppression: Effectively suppresses competitive two-component coupling pathways (e.g., hydrazone–aryl halide coupling);
- Anti-Racemization: Products maintain high enantiopurity (ee >90%) without epimerization.
5. Industrial Support
To promote methodology adoption, Anhui Cat-Lab offers a PC-Phos Kit containing 10 privileged ligand structures, along with custom synthesis services to support chiral catalysis research.
6. Publication Details
Title: Pd/SadPhos Enabled Modular and Enantioselective Assembly of Triarylmethanes
Authors: Shuai Zhu, Bo Xiao, Meihua Huang, Yi Wu, Tian-Yu Sun, Junfeng Yang, Yun-Dong Wu, Junliang Zhang
Journal: Journal of the American Chemical Society
DOI: 10.1021/jacs.5c14810