Advances in bioconjugation and native protein modification are appearing at a blistering pace, making it increasingly time consuming for practitioners to identify the best chemical method for modifying a specific amino acid residue in a complex setting. The purpose of this perspective is to provide an informative, graphically rich manual highlighting significant advances in the field over the past decade. This guide will help triage candidate methods for peptide alteration and will serve as a starting point for those seeking to solve long-standing challenges.
C–N
cross-coupling is one of the most valuable and widespread
transformations in organic synthesis. Largely dominated by Pd- and
Cu-based catalytic systems, it has proven to be a staple transformation
for those in both academia and industry. The current study presents
the development and mechanistic understanding of an electrochemically
driven, Ni-catalyzed method for achieving this reaction of high strategic
importance. Through a series of electrochemical, computational, kinetic,
and empirical experiments, the key mechanistic features of this reaction
have been unraveled, leading to a second generation set of conditions
that is applicable to a broad range of aryl halides and amine nucleophiles
including complex examples on oligopeptides, medicinally relevant
heterocycles, natural products, and sugars. Full disclosure of the
current limitations and procedures for both batch and flow scale-ups
(100 g) are also described.
Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.
A thermodynamic approach to peptide
macrocyclization inspired by
the cyclization of non-ribosomal peptide aldehydes is presented. The
method provides access to structurally diverse macrocycles by exploiting
the reactivity of transient macrocyclic peptide imines toward inter-
and intramolecular nucleophiles. Reactions are performed in aqueous
media, in the absence of side chain protecting groups, and are tolerant
of all proteinogenic functional groups. Macrocyclic products bearing
non-native and rigidifying structural motifs, isotopic labels, and
a variety of bioorthogonal handles are prepared, along with analogues
of four distinct natural products. Structural interrogation of the
linear and macrocyclic peptides using variable-temperature NMR and
circular dichroism suggests that preorganization of linear substrates
is not a prerequisite for macrocyclization.
The modern constraints of drug discovery demand a rigorous validation process of all new reactions prior to widespread implementation. To this end, sulfinates (now marketed as Diversinates) have seen alacritous adoption by the medicinal chemistry community, as evidenced by the recent outpour of both patent and primary reports. Featuring more than 50 examples, this review seeks to highlight those particularly compelling cases published in the past 5 years, with an eye toward the identification of robust and predictable trends in reactivity.
This
Communication reports the first general method for rapid,
chemoselective, and modular functionalization of serine residues in
native polypeptides, which uses a reagent platform based on the P(V)
oxidation state. This redox-economical approach can be used to append
nearly any kind of cargo onto serine, generating a stable, benign,
and hydrophilic phosphorothioate linkage. The method tolerates all
other known nucleophilic functional groups of naturally occurring
proteinogenic amino acids. A variety of applications can be envisaged
by this expansion of the toolbox of site-selective bioconjugation
methods.
A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickelmediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol was demonstrated by its use in an industrial carbon-14 radiolabeling setting.
Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.
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