University of Illinois Urbana-Champaign

Rhodium-catalyzed asymmetric synthesis of beta-branched amides and gamma-branched amines and hydroaminomethylation of alkenes via photoredox catalysis

Wu, Zhao

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WU-DISSERTATION-2018.pdf

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https://hdl.handle.net/2142/102894

Description

Title
Rhodium-catalyzed asymmetric synthesis of beta-branched amides and gamma-branched amines and hydroaminomethylation of alkenes via photoredox catalysis
Author(s)
Wu, Zhao
Issue Date
2018-09-12
Director of Research (if dissertation) or Advisor (if thesis)
Hull, Kami L.
Doctoral Committee Chair(s)
Hull, Kami L.
Committee Member(s)
  • Moore, Jeffrey S.
  • Zimmerman, Steven C.
  • Fout, Alison R.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2019-02-08T18:39:40Z
Keyword(s)
  • asymmetric isomerization
  • oxidative amidation
  • reductive amination
  • hydroaminomethylation
  • photoredox catalysis
Abstract
Nitrogen-containing organic molecules with adjacent stereocenters represent one of the most common motifs in modern pharmaceuticals and agrochemicals. Therefore, there have been tremendous efforts focusing on general, efficient, selective, and atom-economical syntheses of enantiopure amides and amines. However, the direct enantioselective synthesis of β-branched amides and γ-branched amines still requires multiple steps including asymmetric hydrogenation. As a result, these methods are very substrate dependent, meaning that a minor change on the stereocenter often requires re-examining of metal/ligand scaffolds. In this thesis, we will describe methods developed in our lab to address these challenges. We have first developed a tandem isomerization/oxidative amidation approach from allylic alcohols or aldehydes to synthesize β-branched amides using acetone or styrene as the hydrogen acceptor. The conditions are general, affording the products in good to excellent yields with a wide array of amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine intermediate and the hemiaminal, which can then undergo oxidation to the amide. The enantioselective isomerization/amidation was then achieved utilizing allylic amine as the precursor. After the known asymmetric isomerization, the chiral enamine intermediate, instead of being oxidized to the undesired byproduct, undergoes an exchange with exogenous amine nucleophile followed by oxidation to afford the chiral β-branched amide in one step. The enamine exchange allows for a rapid and modular synthesis of various amides, including challenging β-diaryl and β-cyclic. These kinds of substrates often require privileged ligands in asymmetric hydrogenation. We have further extended this method to synthesize amines with remote stereocenters in a reductive fashion. By intercepting the aforementioned chiral enamine intermediate with a highly chemoselective reduction, a general asymmetric route for the one-pot synthesis of chiral γ-branched amines was developed. This protocol is suitable for establishing various tertiary stereocenters, including those containing dialkyl, diaryl, cyclic, trifluoromethyl, difluoromethyl, and silyl substituents. To demonstrate the synthetic utility of this method, Terikalant and Tolterodine are synthesized using this method with high levels of enantioselectivity. Finally, an alternative method for γ-branched amine synthesis was realized through photoredox-catalyzed hydroaminomethylation of alkenes. The reaction conditions are very mild, and tolerate various functional groups, such as alkyl alkene, ester, ketone, lactone, indole, and tertiary amine, a great improvement compared to two-electron hydroaminomethylation. This reaction is also regiospecific: only linear amine products are formed regardless of the electronic property of alkene substrates. Three bioactive pheniramines are synthesized using this method on gram-scale with only 0.1% catalyst loading.
Graduation Semester
2018-12
Type of Resource
text
Permalink
http://hdl.handle.net/2142/102894
Copyright and License Information
Copyright 2018 Zhao Wu

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