Development of deaminative nickel-catalyzed cross-couplings
Date
2023
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
This dissertation is focused on developing methods to form new C(sp3)–C(sp2) bonds through the activation of C–N bonds. In addition to method development, a thorough mechanistic study was performed to understand the C–N bond activation of alkylpyridinium salts. ☐ In Chapter 1, an overview of C–N bond activation is discussed. Alkyl amines are a privileged class of starting materials due to the ubiquity, ease of purification through acid/base extraction, and ability to be protected, carried through a synthesis, and revealed for a late-stage functionalization. However, until recently, deaminative transformations were rare. Our group has led a renaissance of the 2,4,6-triphenyl alkylpyridinium salt or Katritzky salt, as an effective activating group for unactivated primary alkyl amines. Since our discovery of these alkylpyridinium salts as efficient electrophiles in nickel-catalyzed cross-couplings, many methods have been developed, enabling the conversion of primary amines into countless other functional groups and transforming the conventional logic applied to alkyl amines in synthesis. ☐ Chapter 2 describes a cross-electrophile deaminative arylation of amino-acid derived alkylpyridinium salts to prepare non-canonical amino acids. Non-canonical amino acids are critical for the invention of the novel peptide therapeutics, which is an exponential growing field due to the unique ability of peptides to bind proteins previously thought to be undruggable. Peptide therapeutics can provide substantial improvements in selectivity and potency, while decreasing the risk of toxicity due to their metabolism to form amino acids. In collaboration with researchers at Merck & Co., Inc., I have developed a cross-electrophile coupling of pyrdinium derivatives of lysine and other amino acids bearing an amino side chain to synthesize both non-canonical aryl alanine monomers and their homologs, as well as functionalize peptides in solution and on solid support. The success of this reaction relied on multiparameter high-throughput optimization to identify multiple sets of conditions to facilitate broad functional group tolerance of both aryl bromides and amino acids and peptides. This method will benefit medicinal chemists performing structure-activity relationship studies for the development of peptide therapeutics by enabling late-stage functionalization of peptide substrates of various levels of complexity. ☐ In Chapter 3, a computational and electrochemical study of the deamination process of alkylpyridinium salts is described. Deaminative methods of alkylpyridinium salts have seen broad and rapid development since our initial report demonstrating their use as electrophiles in nickel-catalyzed cross-couplings. This has precipitated substantial discussion in the literature about how to facilitate these deaminative couplings. We performed a comprehensive study to understand the critical factors for deamination, which relied on collaboration with Prof. Marisa Kozlowski at the University of Pennsylvania and Prof. Joel Rosenthal at the University of Delaware. Together, we were able to provide a deeper understanding about both the single-electron reduction and C–N bond cleavage steps. We found that the single-electron reduction event is promoted by both electronic and steric nature of the pyridinium salt, while the C–N bond cleavage step is driven almost exclusively by steric effects. This study has elucidated the nuances of the deamination process and will enable the manipulation of the pyridinium activating group to overcome current limitations.
Description
Keywords
Cross-couplings, Deaminative arylation, Alkylpyridinium salts, Amino acids, C-N bonds