Jie, Yang, Zhao, and Fu (ChemRxiv 2022; iScience 26:106344, 2023) introduced an 'adjustable' axially chiral [1,1'-biphenyl]-2,2'-diol (BIPOL) scaffold in which substituents at the 2,2'-positions select the ligand/catalyst type, substituents at the 3,3'- and 5,5'-positions tune steric and electronic properties, and substituents at the 6,6'-positions tune the dihedral angle, and showed on six benchmark asymmetric reactions that this substitution logic modulates reactivity, diastereoselectivity, and enantioselectivity. The open problem is to establish what deeper structure-property rules govern these substituent effects, how far the substitution logic generalizes to other ligand classes, and within what reaction scope the scaffold is optimal, so that ligand selection becomes predictive rather than empirical.

Background

Asymmetric catalysis produces one mirror-image form (enantiomer) of a chiral product preferentially; its efficiency is usually reported as percent enantiomeric excess (ee, the imbalance between the two enantiomers; a signed ee value records which enantiomer predominates) and, where new stereocenters or diastereomers arise, diastereoselectivity (dr). The outcome depends acutely on the chiral ligand or catalyst bound to the metal or acting as an organocatalyst. A dominant class of such ligands is built on axially chiral biaryl cores: molecules whose stereogenic element is a twisted aryl-aryl bond (atropisomerism), the standard examples being BINOL ([1,1'-binaphthyl]-2,2'-diol) and SPINOL (1,1'-spirobiindane-7,7'-diol). It is a long-recognized premise of the field that any ligand or catalyst has only a limited range of applications, because slight changes in the geometric, steric, and electronic properties of a chiral ligand or catalyst can cause dramatic variations in the reactivity of substrates and the enantioselectivity of products, so ligand development has remained largely empirical, case-by-case screening.

Against this background, Jie, Yang, Zhao, and Fu (Tsinghua University; ChemRxiv preprint 10.26434/chemrxiv-2022-mrz8m, posted October 2022, published in essentially identical form in iScience 26:106344, 2023) designed a new family of axially chiral [1,1'-biphenyl]-2,2'-diol cores they call BIPOL, meant to be 'adjustable' at three zones: varying the 2,2'-substituents interconverts ligand and catalyst types (the free biphenyldiol; phosphoramidite ligands, i.e., P(III) compounds with a chiral biaryl backbone widely used in asymmetric transition-metal catalysis; and chiral phosphoric acids, Brønsted-acid organocatalysts whose 3,3'-substituents form a chiral hydrogen-bonding pocket); varying the 3,3'- and 5,5'-substituents tunes steric and electronic properties; and varying the 6,6'-substituents tunes the dihedral angle (the twist about the aryl-aryl bond) together with steric and electronic effects. The scaffold was evaluated on six model reactions: titanium-mediated addition of diethylzinc to aldehydes; asymmetric alkynylation of aldehydes (addition of a metal acetylide to an aldehyde to give a chiral propargylic alcohol); two palladium-catalyzed asymmetric cycloadditions with BIPOL-based phosphoramidite ligands; and chiral-phosphoric-acid-catalyzed asymmetric synthesis of a SPINOL derivative and a [4+3] cyclization (a cycloaddition joining a four-atom and a three-atom pi-system to build a seven-membered ring). The results are qualitative but instructive: in the diethylzinc addition to benzaldehyde all tested ligands L1-L11 gave high yields with ee values from 80 to 93%, and — crucially — the best ligand was strongly substrate-dependent, e.g., 4-methoxybenzaldehyde gave only 50% ee with (S)-L2, whereas replacing (S)-L2 with (R)-L4 gave a higher enantioselectivity of the opposite sense, reported in the source as -91% ee (the source quotes signed ee values, so switching the ligand configuration reverses the preferred product enantiomer; compare (R)-BINOL at -90% ee in the alkynylation), and different aldehydes required different ligands for high ee. The paper concludes that substituent adjustment 'could make ligands and catalysts more efficient' and offers the design strategy as 'new and useful'; its only explicitly stated limitation is that the ligand and catalyst syntheses require many steps and that 'more concise synthetic pathways are required'.

What the paper does not provide is any quantitative structure-property relationship: no mechanistic account of why particular 3,3'/5,5'/6,6'-substituents improve a given reaction, no model predicting which ligand should be chosen for a new substrate, and no systematic comparison establishing where the BIPOL family outperforms the mature BINOL/SPINOL families. In the adjacent literature, computer-driven catalyst-design workflows combined with machine learning have demonstrated prediction of higher-selectivity catalysts for individual reaction classes (e.g., Zahrt et al., Science 2019), and density-functional-theory analyses of the origin of enantioselectivity exist for other catalyst systems, but no general predictive framework for chiral ligand/catalyst selection has been achieved.

Problem Statement

For the adjustable axially chiral biphenyl (BIPOL) ligand and catalyst family of Jie, Yang, Zhao, and Fu, establish the structure-property relationship between the substitution pattern — ligand/catalyst-type-setting 2,2'-substituents, steric/electronic 3,3'- and 5,5'-substituents, and dihedral-angle-setting 6,6'-substituents — and the reactivity, diastereoselectivity, and enantioselectivity observed across the reported reaction classes, such that: (a) the mechanistic origin of the documented substituent effects, including the strong substrate dependence of the optimal ligand choice (e.g., ligand switching required among substituted benzaldehydes in the diethylzinc addition), is explained; (b) selection of the BIPOL ligand or catalyst for a new substrate or reaction becomes predictive rather than empirical; and (c) the reaction scope in which this scaffold is advantageous relative to established axially chiral biaryl families such as BINOL and SPINOL, and the ligand classes to which the zone-based substitution logic extends, are delimited. These three parts are mutually dependent and must be established together. The concrete examples given (e.g., the ligand switching among substituted benzaldehydes in the diethylzinc addition) illustrate the required behaviour rather than bounding it.

References

  1. Jiyang Jie, Haijun Yang, Yufen Zhao, Hua Fu. 'Development of diverse adjustable axially chiral biphenyl ligands and catalysts.' iScience 26(4) (2023) 106344. DOI: 10.1016/j.isci.2023.106344. https://doi.org/10.1016/j.isci.2023.106344
  2. Jiyang Jie, Haijun Yang, Yufen Zhao, Hua Fu. 'Design, synthesis and evaluation in enantioselective catalysis of diverse adjustable axially chiral biphenyl ligands and catalysts.' ChemRxiv preprint, posted 2022-10-11. DOI: 10.26434/chemrxiv-2022-mrz8m. https://doi.org/10.26434/chemrxiv-2022-mrz8m
  3. Zhengyi Yi, Weixin Xiao, Jiyang Jie, Haijun Yang, Hua Fu. 'Ligand-Enabled Palladium-Catalyzed Asymmetric Synthesis of Cyclic Sulfamidate-Fused Imidazolidinones.' Organic Letters 27(24) (2025) 6330-6336. DOI: 10.1021/acs.orglett.5c01505. https://doi.org/10.1021/acs.orglett.5c01505
  4. Zhengyi Yi, Weixin Xiao, Yong Liu, Lunyu Ou, Hongyun Li, Haijun Yang, Hua Fu. 'Ligand-Enabled Palladium-Catalyzed Asymmetric Synthesis of Indole-Fused Chiral Eight-Membered N-Heterocycles via [4 + 4] Cycloaddition.' Organic Letters 27(45) (2025) 12651-12657. DOI: 10.1021/acs.orglett.5c04101. https://doi.org/10.1021/acs.orglett.5c04101
  5. Zhengyi Yi, Yong Liu, Weixin Xiao, Lunyu Ou, Hongyun Li, Haijun Yang, Hua Fu. 'Development of Axially Chiral Phosphoramidite Ligands and Their Application in Pd-Catalyzed Asymmetric Synthesis of Spiro-Pyrazolone-Pyrrolidinones via [2 + 3] Cycloaddition.' Organic Letters 28(4) (2026) 1399-1406. DOI: 10.1021/acs.orglett.5c05246. https://doi.org/10.1021/acs.orglett.5c05246
  6. Weixin Xiao, Yuming Li, Zhengyi Yi, Jiyang Jie, Wuxian Zhang, Hua Fu. 'Development of Diverse Ligands and Catalysts Derived from Axially Chiral Cyclic Biphenyldiols.' Chemistry - A European Journal 31(21) (2025) e202500274. DOI: 10.1002/chem.202500274. https://doi.org/10.1002/chem.202500274
  7. Xinliang Guo, Huan Chang, Ruizhe Chang, Kehong Duan, Huajie Zhu. 'Synthesis of 13-Membered Ring L-Bitryptophanes and Their Enantioselective Indole Friedel-Crafts Reactions.' Chirality 37(12) (2025) e70064. DOI: 10.1002/chir.70064. https://doi.org/10.1002/chir.70064
  8. Yu-Hao Qiao, Xiao-Heng Wang, Dong Xie, Xin-Ting He, Hao Qiu, Zhe-Rui Zhang, Pan-Pan Zhou, Zhaoyong Yang. 'Mechanism and origin of enantioselectivity for Diels-Alder reaction catalyzed by chiral phosphoric acids in synthesising 1-trifluoroacetamido cyclohex-1-ene.' Organic & Biomolecular Chemistry 23(46) (2025) 10561-10573. DOI: 10.1039/d5ob01404b. https://doi.org/10.1039/d5ob01404b
  9. Andrew F. Zahrt, Jeremy J. Henle, Brennan T. Rose, Yang Wang, William T. Darrow, Scott E. Denmark. 'Prediction of higher-selectivity catalysts by computer-driven workflow and machine learning.' Science 363(6424) (2019) eaau5631. DOI: 10.1126/science.aau5631. https://doi.org/10.1126/science.aau5631
  10. Sandeep Singh, P. Geetha, R. Ramajayam. 'Isolation, synthesis and medicinal chemistry of biphenyl analogs - A review.' Results in Chemistry 6 (2023) 101135. DOI: 10.1016/j.rechem.2023.101135. https://doi.org/10.1016/j.rechem.2023.101135