Ligand design principles for perfecting stereoretention in Suzuki-Miyaura cross-coupling of unactivated CSP3 boronic acids

The strategy of building block-based, iterative synthesis has revolutionized the preparation of oligonucleotides and oligopeptides. However, small molecules possess greater structural diversity than these classes of macromolecules. The development of an iterative, building block-based synthetic strategy could nonetheless accelerate the discovery of new small molecule functions. A key challenge in building block assembly is finding reactions to forge carbon-carbon bonds between a range of structurally diverse building blocks. Iteration of metal-mediated cross-coupling reactions represents a promising direction, and such an approach has already been automated and used to make many different small molecules. Still, the lack of methods for Csp3 coupling dramatically limits the scope of building block-based synthesis. With the goal of developing a stereospecific cross-coupling reaction for unactivated secondary alkylboronic acids, it was critical to understand the competition between stereoretentive and stereoinvertive transmetalation mechanisms. Achieving perfect transfer of stereochemistry from building blocks to products required that one of these transmetalation pathways be completely mitigated. By systematically studying the effect of the phosphine ligand on the outcome of a model Csp3 cross-coupling reaction, we have elucidated ligand steric and electronic design principles for maximizing stereoretention. These ligand design principles are applicable across different reaction conditions and a broad substrate scope. Continued progress in stereocontrolled Csp3 couplings will accelerate the generalization of building block-based synthesis.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Lehmann, Jonathan W.

Contributors dc:contributor

• Burke, Martin D.
• Denmark, Scott E.
• Hergenrother, Paul J.
• Moore, Jeffrey S.

• Cross-coupling
• methodology
• Csp3 coupling
• stereospecific
• stereospecific coupling
• unactivated boronic acid
• stereoretentive transmetalation
• stereoinvertive transmetalation
• transmetalation
• beta-hydride elimination
• P(o-tol)3
• tri-ortho-tol phosphine

Statement dc:rights

• Copyright 2018 Jonathan W. Lehmann

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/102779

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/102779