Via conversion to Katritzky pyridinium salts, alkyl amines can now be used as alkyl radical precursors for a range of deaminative functionalization reactions. The key step of all of these methods is single-electron reduction of the pyridinium ring, which triggers C−N bond cleavage. However, little has been done to understand how the precise nature of the pyridinium influences these events. Using a combination of synthesis, computation, and electrochemistry, this study delineates the steric and electronic effects that substituents have on the canonical steps and the overall process. Depending on the approach taken, consideration of both the reduction and the subsequent radical dissociation may be necessary. Whereas the electronic effects on these steps work in opposition to each other, the steric effects are synergistic, with larger substituents favoring both steps. This understanding provides a framework for future design of pyridinium salts to match the mode of catalysis or activation.
A deaminative reductive coupling of amino acid pyridinium
salts
with aryl bromides has been developed to enable efficient synthesis
of noncanonical amino acids and diversification of peptides. This
method transforms natural, commercially available lysine, ornithine,
diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and
homologated derivatives with varying chain lengths. Attractive features
include ability to transverse scales, tolerance of pharma-relevant
(hetero)aryls and biorthogonal functional groups, and the applicability
beyond monomeric amino acids to short and macrocyclic peptide substrates.
The success of this work relied on high-throughput experimentation
to identify complementary reaction conditions that proved critical
for achieving the coupling of a broad scope of aryl bromides with
a range of amino acid and peptide substrates including macrocyclic
peptides.
A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid (DAB), and diaminopropanoic acid (DAP) to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include scalability, tolerance of pharma-relevant (hetero)aryls and functional groups, applicability to both monomeric amino acid and short peptide substrates, and compatibility with biorthogonal handles useful for chemical biology. Furthermore, these cross-couplings can be conducted in microscale and nanoscale and are amenable to solid-phase peptide synthesis platforms. The success of this work relied on an academic/industry collaboration and high-throughput experimentation to identify complementary conditions that proved critical for achieving broad scope of aryl bromides and pyridinium substrates.
A nickel-catalyzed deaminative cyanation
of Katritzky pyridinium
salts has been developed. When it is coupled with formation of the
pyridinium salt from primary amines, this method enables alkyl amines
to be converted to alkyl nitriles. A less toxic cyanide reagent, Zn(CN)2, is utilized, and diverse functional groups and heterocycles
are tolerated. The method also enables a one-carbon homologation of
alkyl amines via reduction of the nitrile products, in addition to
many other potential transformations of the versatile nitrile group.
An
electrochemical, nickel-catalyzed reductive coupling
of alkylpyridinium
salts and aryl halides is reported. High-throughput experimentation
(HTE) was employed for rapid reaction optimization and evaluation
of a broad scope of pharmaceutically relevant structurally diverse
aryl halides, including complex drug-like substrates. In addition,
the transformation is compatible with both primary and secondary alkylpyridinium
salts with distinct conditions. Mechanistic insights were critical
to enhance the efficiency of coupling using secondary alkylpyridinium
salts. Systematic comparisons of the electrochemical and non-electrochemical
methods revealed the complementary scope and efficiency of the two
approaches.
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