Selective Triazenation Reaction (STaR) of Secondary Amines for Tagging Monomethyl Lysine Post-Translational Modifications.

Lysine monomethylation (Kme) is an impactful post-translational modification (PTM) responsible for regulating biological processes and implicated in diseases, thus there is great interest in identifying these methylation marks globally. However, the progress in this area has been challenging because the addition of a small methyl group on lysine leads to negligible change in the bulk, charge, and hydrophobicity. Herein, we report an empowering chemical technology selective triazenation reaction, which we term "STaR", of secondary amines using arene diazonium salts to achieve highly selective, rapid, and robust tagging of Kme peptides from a complex mixture under biocompatible conditions. Although the resulting triazene-linkage with Kme is stable, we highlight the efficient decoupling of the triazene-conjugate to afford unmodified starting components under mild conditions when desired. Our work establishes a unique chemoselective, traceless bioconjugation strategy for the selective enrichment of Kme PTMs.

Bioinspired Nitroalkylation for Selective Protein Modification and Peptide Stapling.

Nitroalkanes react specifically with aldehydes, providing rapid, stable, and chemoselective protein bioconjugation. These nitroalkylated proteins mimic key post-translational modifications (PTMs) of proteins and can be used to understand the role of these PTMs in cellular processes. Demonstrated here is the substrate scope of this bioconjugation by attaching a variety of tags, such as NMR tags, fluorescent tags, affinity tags, and alkyne tags, to proteins. The structure and enzymatic activity of modified proteins remain conserved after labeling. Notably, the nitroalkane group leads to easy characterization of proteins by mass spectrometry because of its distinct fingerprint pattern. Importantly, the nitro-alkylated peptides provide a new handle for site-selective fluorination of peptides, thus installing a specific probe to study peptide-protein interactions by 19 F NMR spectroscopy. Furthermore, nitroalkane reagents can be used for the late-stage diversification of peptides and for the synthesis of peptide staples.

Amide Bond Activation of Biological Molecules.

Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their ability to form resonating structures, thus, they are highly stable and adopt particular three-dimensional structures, which, in turn, are responsible for their functions. The main focus of this review article is to report the methodologies for the activation of the unactivated amide bonds present in biomolecules, which includes the enzymatic approach, metal complexes, and non-metal based methods. This article also discusses some of the applications of amide bond activation approaches in the sequencing of proteins and the synthesis of peptide acids, esters, amides, and thioesters.

B(C6F5)3 catalysed reduction of para-quinone methides and fuchsones to access unsymmetrical diaryl- and triarylmethanes: elaboration to beclobrate.

A mild and efficient method for the synthesis of unsymmetrical diaryl- and triarylmethanes through a B(C6F5)3 catalyzed reduction of para-quinone methides and fuchsones respectively, using the Hantzsch ester as a reducing source has been developed. Detailed mechanistic investigations revealed that the reaction actually proceeds through a Lewis acid-base pair complex derived from B(C6F5)3 and the Hantzsch ester.

Secondary amine selective Petasis (SASP) bioconjugation.

Selective modification of proteins enables synthesis of antibody-drug conjugates, cellular drug delivery and construction of new materials. Many groups have developed methods for selective N-terminal modification without affecting the side chain of lysine by judicious pH control. This is due to lower basicity of the N-terminus relative to lysine side chains. But none of the methods are capable of selective modification of secondary amines or N-terminal proline, which has similar basicity as lysine. Here, we report a secondary amine selective Petasis (SASP) reaction for selective bioconjugation at N-terminal proline. We exploited the ability of secondary amines to form highly electrophilic iminium ions with aldehydes, which rapidly reacted with nucleophilic organoboronates, resulting in robust labeling of N-terminal proline under biocompatible conditions. This is the first time the Petasis reaction has been utilized for selective modification of secondary amines on completely unprotected peptides and proteins under physiological conditions. Peptide screening results showed that the reaction is highly selective for N-terminal proline. There are no other chemical methods reported in literature that are selective for N-terminal proline in both peptides and proteins. This is a multicomponent reaction leading to the synthesis of doubly functionalized bioconjugates in one step that can be difficult to achieve using other methods. The key advantage of the SASP reaction includes its high chemoselective and stereoselective (>99% de) nature, and it affords dual labeled proteins in one pot. The broad utility of this bioconjugation is highlighted for a variety of peptides and proteins, including aldolase and creatine kinase.

A Cascade Synthesis of Hetero-arylated Triarylmethanes Through a Double 5-endo-dig Cyclization Sequence.

A sequential two-step method for the synthesis of hetero-arylated triarylmethanes through a Ag-catalyzed sequential double cyclization-nucleophilic addition cascade is described. This methodology basically involves an initial 5-endo-dig cyclization of o-alkynyl anilines to provide 2-substituted indole derivatives, which then react with 2-(2-enynyl)-pyridines to afford indolizine-containing unsymmetrical triarylmethanes through another 5-endo-dig cyclization.

N-heterocyclic carbene catalyzed highly chemoselective intermolecular crossed acyloin condensation of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal.

A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields.

Bis(amino)cyclopropenylidene-Catalyzed 1,6-Conjugate Addition of Aromatic Aldehydes to para-Quinone Methides: Expedient Access to α,α'-Diarylated Ketones.

A bis(amino)cyclopropenylidene-catalyzed direct method for the synthesis of α,α'-diarylated ketones from aromatic as well as heteroaromatic aldehydes has been developed. This unprecedented organocatalytic protocol offers access to a wide range of α,α'-diarylated ketones in moderate to excellent yields under mild conditions through umpolung of aldehydes followed by 1,6-conjugate addition with para-quinone methides.

Combining oxidative N-heterocyclic carbene catalysis with click chemistry: a facile one-pot approach to 1,2,3-triazole derivatives.

A combination of the oxidative N-heterocyclic carbene catalysis and click chemistry has been explored for the direct, one-pot synthesis of 1,2,3-triazole derivatives from aromatic aldehydes. This procedure was found to be very efficient and a variety of 1,2,3-triazole derivatives could be accessed through their corresponding propargyl esters in moderate-to-good yields under mild conditions.