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Iterative Supervised Principal Component Analysis-Driven Ligand Design for Regioselective Ti-Catalyzed Pyrrole Synthesis

preprint
submitted on 12.05.2020 and posted on 13.05.2020 by Xin Yi See, Benjamin Reiner, Xuelan Wen, T. Alexander Wheeler, Channing Klein, Jason Goodpaster, Ian Tonks

Herein, we describe the use of iterative supervised principal component analysis (ISPCA) in de novo catalyst design. The regioselective synthesis of 2,5-dimethyl-1,3,4-triphenyl-1H- pyrrole (C) via Ti- catalyzed formal [2+2+1] cycloaddition of phenyl propyne and azobenzene was targeted as a proof of principle. The initial reaction conditions led to an unselective mixture of all possible pyrrole regioisomers. ISPCA was conducted on a training set of catalysts, and their performance was regressed against the scores from the top three principal components. Component loadings from this PCA space along with k-means clustering were used to inform the design of new test catalysts. The selectivity of a prospective test set was predicted in silico using the ISPCA model, and only optimal candidates were synthesized and tested experimentally. This data-driven predictive-modeling workflow was iterated, and after only three generations the catalytic selectivity was improved from 0.5 (statistical mixture of products) to over 11 (> 90% C) by incorporating 2,6-dimethyl- 4-(pyrrolidin-1-yl)pyridine as a ligand. The successful development of a highly selective catalyst without resorting to long, stochastic screening processes demonstrates the inherent power of ISPCA in de novo catalyst design and should motivate the general use of ISPCA in reaction development.

Funding

Ti-Catalyzed Nitrene Transfer Reactions

National Institute of General Medical Sciences

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Upgrade of a 500 MHz NMR Spectrometer for Applications in Biomedical Research

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MRI: Acquisition of a single-crystal diffractometer for the University of Minnesota

Directorate for Mathematical & Physical Sciences

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DE-AC02-05CH11231

Alfred P Sloan Foundation

History

Email Address of Submitting Author

itonks@umn.edu

Institution

University of Minnesota

Country

United States

ORCID For Submitting Author

0000-0001-8451-8875

Declaration of Conflict of Interest

No conflict of interest

Version Notes

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