Ligand Design for Asymmetric Catalysis: Combining Mechanistic and Chemoinformatics Approaches

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 approached this

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Ligand Design for Asymmetric Catalysis: Combining Mechanistic and Chemoinformatics Approaches Ruchuta Ardkhean, Stephen P. Fletcher, and Robert S. Paton

Contents 1 2 3 4

Introduction: Chirality in Life and Medicine Access to Enantioenriched Materials Privileged Ligands: Phosphoramidites Approaches for Ligand Design in Asymmetric Catalysis 4.1 Serendipitous Discovery and High-Throughput Screening (HTS) 4.2 Mechanistically Driven Ligand Discovery 5 Quantitative Structure-Selectivity Relationships (QSSRs) 5.1 QSAR Best Practices 5.2 Collecting Molecular Descriptors 5.3 Model Construction 5.4 Predicting Enantioselectivity 5.5 QSSR-Driven Ligand Optimization 5.6 Predicting Yield 5.7 Predicting Product Distribution 6 Summary References

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: [email protected]

R. Ardkhean et al.

approached this endeavour by screening existing ligands. The most promising structures are then modified based on mechanistic knowledge, chemical intuition and the results of screening experiments, with the aim of optimizing selectivity and yield. However, this empirical approach has begun to change: new methods to accelerate the experimental screening process have emerged together with computational and physical-organic approaches that provide a systematic, and hopefully faster, route to new catalysts. Practical and theoretical understanding of highthroughput screening and multi-parameter optimization are now requirements at the cutting edge of the field, in addition to synthetic and mechanistic expertise. In this chapter, we summarize the recent examples of combinatorial approaches taken to discover and develop asymmetric catalytic transformations. In particular, we highlight the use of quantitative models to predict reaction outcomes. A series of guidelines are presented to aid chemists in adopting these approaches, followed by illustrated examples of recent work in this area. Keywords Asymmetric catalysis · Chiral ligand design · Computational modelling · Enantiomeric excess · Quantitative structure-selectivity relationships (QSSR)

Abbreviations AARON AD AIC ANOVA ASO BINOL BINAP CAPT cat. CIP COD dba DCM DFT (DHQD)2PHAL DNA dr ee EPR er etc. FF GC-MS HPLC

An automated reaction optimizer for new (catalysts) Applicability domain Akaike information criterion Analysis of variance Average steric occupancy 1,10 -Bi-2-naphthol 2,20 -Bis(diphenylphosphino)-1,10 -binaphthyl Chiral anion phase transfer Catalytic Cahn-In