Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation

Abstract

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.

Nickel-Catalyzed Electrochemical Reductive Cross-Electrophile Coupling of Alkylpyridinium Salts and Aryl Halides

“…To compare the scope and limitations against non-electrochemical conditions, 22 the set of aryl bromide substrates shown in Scheme 3 were also evaluated using previously reported non-electrochemical methods with Mn 0 powder or tetrakis(dimethylamino)ethylene (TDAE) as reductants. As illustrated in Scheme 4, use of Mn 0 as the reductant led to lower product LCAPs than obtained using electrochemistry for most substrates.…”

“…These reactions use stoichiometric amounts of metal powders as terminal reductants and enable the use of various alkyl and aryl electrophiles. Readily accessible and bench-stable electrophiles (organic halides, 8,13,23,24 redox-active esters, [25][26][27][28][29] alkylpyridinium salts, [20][21][22][30][31][32][33][34] etc.) have been successfully demonstrated in various Ni-catalyzed reductive cross-coupling reactions (Scheme 1A).…”

“…[Sn], [Zn], [MgX] etc.). For instance, the groups of Weix, [8][9][10][11] Reisman, [12][13][14] Gong 15,16 and others [17][18][19] together with our prior research [20][21][22] have demonstrated that nickel-catalyzed cross-electrophile couplings are an effective strategy for the construction of new C(sp 2 )-C(sp 3 ) bonds. These reactions use stoichiometric amounts of metal powders as terminal reductants and enable the use of various alkyl and aryl electrophiles.…”

Nickel-Catalyzed Electrochemical Reductive Cross-Electrophile Coupling of Alkylpyridinium Salts and Aryl Halides

“…[1][2][3][4][5][6][7] In particular, the direct coupling of two electrophiles represents an attractive strategy because it precludes the need to pre-form organometallic nucleophiles (R-M, in which M = [B], [Sn], [Zn], [MgX] etc.). For instance, the groups of Weix, [8][9][10][11] Reisman, [12][13][14] Gong 15,16 and others [17][18][19] together with our prior research [20][21][22] have demonstrated that nickel-catalyzed cross-electrophile couplings are an effective strategy for the construction of new C(sp 2 )-C(sp 3 ) bonds. These reactions use stoichiometric amounts of metal powders as terminal reductants and enable the use of various alkyl and aryl electrophiles.…”

“…These reactions use stoichiometric amounts of metal powders as terminal reductants and enable the use of various alkyl and aryl electrophiles. Readily accessible and bench-stable electrophiles (organic halides, 8,13,23,24 redox-active esters, [25][26][27][28][29] alkylpyridinium salts, [20][21][22][30][31][32][33][34] etc.) have been successfully demonstrated in various Ni-catalyzed reductive cross-coupling reactions (Scheme 1A).…”