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Computational Studies Toward the Development of Virtual Screening Tools

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posted on 2022-06-28, 00:00 authored by Aaron Forbes

Asymmetric catalysis is fundamentally important in the creation of molecules that contain chiral centers, which is the case for many biologically active molecules. The process for choosing an appropriate chiral ligand and metal catalyst to confer high enantioselectivity for a desired stereospecific transformation is mainly accomplished through very expensive experimental screening. The expense can be dramatically reduced with the use of computational methods that can predict subsets of ligands that will induce high selectivity. To create computational tools that can aid in the accurate prediction of highly selective chiral catalysts, in-depth, atomistic knowledge of the reaction mechanism is necessary.

The Q2MM method has previously been used to generate a molecular mechanics force field that can predict experimental enantioselectivity for the rhodium-catalyzed asymmetric hydrogenation of enamide substrates. A limitation of the screening process is that it requires manual creation of the three dimensional structures for the screening process. A series of programs and scripts are implemented to rapidly generate three-dimensional libraries of ligand-catalyst-substrate combinations. This virtual screening technology dramatically reduces the setup time for screening implementation and makes it more accessible to a chemist that is less familiar with computational software.

The hydrogenation of acrylamide using chiral Rh(I) complexes is an attractive method for the enantioselective synthesis of highly functionalized intermediates. The mechanism of the reaction is not as well understood as that of the hydrogenation of the enamide substrates. The hydrogenation of acrylamide with simple Rh(I) bisphosphine complexes was studied at the B3LYP/LANL2TZ(f)/6-31++G** level of theory. The minimum energy reaction pathway was found to involve attack of the molecular hydrogen parallel to the C-Rh-P bond, followed by an isomerization at the stage of the dihydride complex to give an altered orientation of the hydride, which is the transferred to the beta carbon.

In examining modern ligands that induce high selectivity in hydrogenation reactions to use within TSFF for the prediction of selectivity, ferrocene based ligands show high promise and a necessary inclusion in virtual screens. The existing MM3* force field does not have parameters for ferrocene, so a ground state force field was created for ferrocene based ligands using the Q2MM method. The ground state force field is compatible with the enamide force field and is able to reproduce DFT structure and enthalpy data.

The ruthenium-catalyzed asymmetric hydrogenation of simple ketones is another well-studied reaction that is widely used in organic synthesis. A transition state force field for the hydrogenation of ketones using bisphosphine-RuCl2-diamine complexes has been created through the implementation of the Q2MM process. The completed force field was able to predict enantioselectivity in comparison to experimental selectivity from the literature with a MUE of 2.7 kJ/mol.

History

Date Modified

2022-08-06

Defense Date

2022-04-12

CIP Code

  • 40.0501

Research Director(s)

Paul Helquist

Committee Members

Olaf Wiest Brandon Ashfeld Seth Brown

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier

1338160200

Library Record

6263755

OCLC Number

1338160200

Program Name

  • Chemistry and Biochemistry

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