Top Organomet Chem (2020) 67: 153–190
https://doi.org/10.1007/3418_2020_47
# Springer Nature Switzerland AG 2020
Published online: 30 June 2020
Ligand Design for Asymmetric Catalysis:
Combining Mechanistic
and Chemoinformatics Approaches
Ruchuta Ardkhean, Stephen P. Fletcher, and Robert S. Paton
Contents
1 Introduction: Chirality in Life and Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2 Access to Enantioenriched Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3 Privileged Ligands: Phosphoramidites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
4 Approaches for Ligand Design in Asymmetric Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
4.1 Serendipitous Discovery and High-Throughput Screening (HTS) . . . . . . . . . . . . .. . . . . . 162
4.2 Mechanistically Driven Ligand Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5 Quantitative Structure-Selectivity Relationships (QSSRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
5.1 QSAR Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
5.2 Collecting Molecular Descriptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
5.3 Model Construction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
5.4 Predicting Enantioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
5.5 QSSR-Driven Ligand Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
5.6 Predicting Yield . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
5.7 Predicting Product Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Abstract A core element to the successful development of asymmetric catalytic
reactions is finding a suitable chiral catalyst or ligand. The discovery and optimization of chiral catalysts can be enormously challenging. Traditionally, chemists have
R. Ardkhean
Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science,
Chulabhorn Royal Academy, Bangkok, Thailand
S. P. Fletcher
Chemistry Research Laboratory, University of Oxford, Oxford, UK
R. S. Paton (*)
Chemistry Research Laboratory, University of Oxford, Oxford, UK
Department of Chemistry, Colorado State University, Fort Collins, CO, USA
e-mail: robert.paton@colostate.edu
https://doi.org/10.1007/3418_2020_47
# Springer Nature Switzerland AG 2020
Published online: 30 June 2020
Ligand Design for Asymmetric Catalysis:
Combining Mechanistic
and Chemoinformatics Approaches
Ruchuta Ardkhean, Stephen P. Fletcher, and Robert S. Paton
Contents
1 Introduction: Chirality in Life and Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2 Access to Enantioenriched Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3 Privileged Ligands: Phosphoramidites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
4 Approaches for Ligand Design in Asymmetric Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
4.1 Serendipitous Discovery and High-Throughput Screening (HTS) . . . . . . . . . . . . .. . . . . . 162
4.2 Mechanistically Driven Ligand Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5 Quantitative Structure-Selectivity Relationships (QSSRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
5.1 QSAR Best Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
5.2 Collecting Molecular Descriptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
5.3 Model Construction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
5.4 Predicting Enantioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
5.5 QSSR-Driven Ligand Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
5.6 Predicting Yield . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
5.7 Predicting Product Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Abstract A core element to the successful development of asymmetric catalytic
reactions is finding a suitable chiral catalyst or ligand. The discovery and optimization of chiral catalysts can be enormously challenging. Traditionally, chemists have
R. Ardkhean
Faculty of Medicine and Public Health, HRH Princess Chulabhorn College of Medical Science,
Chulabhorn Royal Academy, Bangkok, Thailand
S. P. Fletcher
Chemistry Research Laboratory, University of Oxford, Oxford, UK
R. S. Paton (*)
Chemistry Research Laboratory, University of Oxford, Oxford, UK
Department of Chemistry, Colorado State University, Fort Collins, CO, USA
e-mail: robert.paton@colostate.edu