Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids

Immel, Jacob R.; Chilamari, Maheshwerreddy; Bloom, Steven

doi:10.1039/d1sc02562g

Cited by 47 publications

(27 citation statements)

References 126 publications

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“…(Note: Lumidox II allows for up to 96 photoredox reactions to be completed in parallel and is an optimal platform for smallscale reaction optimization and performance.) 32 A photograph of the setup is shown in Figure 1A. The small peptide angiotensin II (seq: H 2 N-DRVYIHPF-CO 2 H) and the Michael acceptor 3-methylene-2-norbornanone (herein termed NB for short) were used to screen experimental conditions for efficient conversion (reaction scheme shown in Figure 1B).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Photoredox-Catalyzed Decarboxylative C-Terminal Differentiation for Bulk- and Single-Molecule Proteomics

et al. 2021

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Methods for the selective labeling of biogenic functional groups on peptides are being developed and used in the workflow of both current and emerging proteomics technologies, such as single-molecule fluorosequencing. To achieve successful labeling with any one method requires that the peptide fragments contain the functional group for which labeling chemistry is designed. In practice, only two functional groups are present in every peptide fragment regardless of the protein cleavage site, namely, an N-terminal amine and a C-terminal carboxylic acid. Developing a global-labeling technology, therefore, requires one to specifically target the N-and/or C-terminus of peptides. In this work, we showcase the first successful application of photocatalyzed C-terminal decarboxylative alkylation for peptide mass spectrometry and singlemolecule protein sequencing that can be broadly applied to any proteome. We demonstrate that peptides in complex mixtures generated from enzymatic digests from bovine serum albumin, as well as protein mixtures from yeast and human cell extracts, can be site-specifically labeled at their C-terminal residue with a Michael acceptor. Using two distinct analytical approaches, we characterize C-terminal labeling efficiencies of greater than 50% across complete proteomes and document the proclivity of various C-terminal amino-acid residues for decarboxylative labeling, showing histidine and tryptophan to be the most disfavored. Finally, we combine Cterminal decarboxylative labeling with an orthogonal carboxylic acid-labeling technology in tandem to establish a new platform for fluorosequencing.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Photoredox-Catalyzed Decarboxylative C-Terminal Differentiation for Bulk- and Single-Molecule Proteomics

et al. 2021

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“…Unfortunately, primary boronic esters were not suitable substrates for radical generation and only the starting material was recovered. 37 When subjecting benzyl boronic acid (19) to the optimal conditions, the product could only be isolated in 20% yield, and the concomitant formation of unidentified side products was observed. Tertiary boronic esters reacted smoothly, but in moderate yield, under the reported conditions (17)(18); in addition to the adamantyl moiety mentioned before, a tert-butyl group was also coupled.…”

Section: Scope and Limitations Of The Reactionmentioning

confidence: 99%

“…Overall, the unattainable oxidation potential of these species has hindered their utilization as suitable radical precursors. Only recently, expedient strategies have been devised for this purpose [17][18][19][20] , including our previous work on free boronic acid activation under photo-flow conditions, which relied on the mediation of amide based solvents to form alkyl radicals (Figure 1B). 18 The application of these strategies is nevertheless mostly limited to redox-neutral additions on activated alkenes and a few related reactions.…”

Section: Introductionmentioning

confidence: 99%

“…18 The application of these strategies is nevertheless mostly limited to redox-neutral additions on activated alkenes and a few related reactions. [18][19][20][21][22][23] On the other hand, the Minisci reaction of boronic acids and derivatives is still largely dependent on stoichiometric use of oxidants ranging from K2S2O8, 12 O2, 15,16 and benziodoxole, 14 with the latter following an oxidative quenching pathway.…”

Section: Introductionmentioning

confidence: 99%

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Merging dual photoredox/cobalt catalysis and boronic acid (derivatives) activation for the Minisci reaction

Pillitteri

Ranjan

Ojeda-Carralero

et al. 2022

Preprint

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The merger of open-shell and closed-shell organometallic chemistry steps has enabled multiple effective cross-coupling pathways. Here we report a visible-light promoted photoredox-cobalt catalyzed Minisci reaction of N-heteroarenes under mild and sustainable conditions, employing various boronic acids and derivatives as alkyl radical precursors. This study demonstrates the prominent ability of the Co co-catalyst to promote the oxidation step of the photocatalytic cycle following a reductive quenching pathway, thus avoiding the use of stoichiometric (inorganic) oxidants. This feature enables the straightforward application of photo-flow conditions, particularly attractive for an easy scale-up and to enhance the efficiency of the reaction (throughput: 0.78 mmol/h in flow vs 0.02 mmol/h in batch) Furthermore, the process is predominantly selective towards the C2-alkylation of quinolines, and a mechanistic rationale has been provided with both experimental and DFT calculation support. The developed protocol demonstrates broad applicability for the alkylation of different N-heteroarenes under suitable homogeneous conditions for a flow-compatible Minisci reaction.

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“…The C−C linkage of c NPs could be made via a fragment‐based approach, combining a C‐centered nucleobase radical with a dehydroalanine (Dha) side chain, derived from a single cysteine residue, in a peptide. This type of approach has been successfully used by our lab (with boronic acids) and others to incorporate unnatural amino acids and non‐ribosomal side chains into peptides and proteins through photoredox catalysis [13, 14] . Unfortunately, borono ‐nucleobases are unstable [15] and, therefore, have low commercial availability and challenging syntheses.…”

Section: Introductionmentioning

confidence: 99%

carba‐Nucleopeptides (cNPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis

Immel

Bloom

2022

Angewandte Chemie

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Exchanging the ribose backbone of an oligonucleotide for a peptide can enhance its physiologic stability and nucleic acid binding affinity. Ordinarily, the eneamino nitrogen atom of a nucleobase is fused to the side chain of a polypeptide through a new CÀ N bond. The discovery of CÀ C linked nucleobases in the human transcriptome reveals new opportunities for engineering nucleopeptides that replace the traditional CÀ N bond with a non-classical CÀ C bond, liberating a captive nitrogen atom and promoting new hydrogen bonding and π-stacking interactions. We report the first late-stage synthesis of CÀ C linked carba-nucleopeptides (cNPs) using aqueous Rhodamine B photoredox catalysis. We prepare brand-new cNPs in batch, in parallel, and in flow using three long-wavelength photochemical setups. We detail the mechanism of our reaction by experimental and computational studies and highlight the essential role of diisopropylethylamine as a bifurcated twoelectron reductant.

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Combining flavin photocatalysis with parallel synthesis: a general platform to optimize peptides with non-proteinogenic amino acids

Abstract: Most peptide drugs contain non-proteinogenic amino acids (NPAAs), born out through extensive structure-activity relationship (SAR) studies using solid-phase peptide synthesis (SPPS). Synthetically laborious and expensive to manufacture, NPAAs also can...

Cited by 47 publications

References 126 publications

Photoredox-Catalyzed Decarboxylative C-Terminal Differentiation for Bulk- and Single-Molecule Proteomics

Photoredox-Catalyzed Decarboxylative C-Terminal Differentiation for Bulk- and Single-Molecule Proteomics

Merging dual photoredox/cobalt catalysis and boronic acid (derivatives) activation for the Minisci reaction

carba‐Nucleopeptides (cNPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis

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