Rhodium-Catalyzed Annulation of Vinylated Tyrosines with Internal Alkynes to Access Oxepine-Mounted Unnatural Tyrosines and Its Peptide Late Stage Functionalization

Abstract

A Rh(III)-catalyzed [5+2] annulation of vinyl tyrosines with symmetrical and unsymmetrical internal alkynes was achieved, furnishing a series of oxepine-mounted tyrosine-based unnatural amino acids. In addition, the chemical applicability of the developed strategy was exemplified by stapling amino acid/peptide-appended alkynes with vinyl tyrosines and late stage functionalization of tyrosine-containing dipeptides and tripeptide with internal alkynes. P roteins perform differentiated functions such as metabolic reaction catalysis, DNA replication, stimulus response, and transportation of molecules in living organisms. 1 Though genetic code expansion of natural amino acids results in the synthesis of most proteins, yet co-translational amalgamation of a few unnatural amino acids (UAAs) into proteins offers unprecedented site-specific protein manipulation ability in living systems. 2 The incorporation of UAAs into a protein of interest (POI) thus provides access to modified natural biologics that could be used in applied areas such as proteomics, diagnostics, asymmetric syntheses, and drug delivery. 3 In addition, unnatural amino acids and their resulting peptides are found to be stable toward proteolytic enzymes, populating exclusive conformational space with distinct bioactivities. 4 Accordingly, focused efforts have been devoted in the recent past to synthesize designer UAAs via α-C(sp 3 )−H, β-C(sp 3 )− H, γ-C(sp 3 )−H, δ-C(sp 3 )−H, and C(sp 2 )−H bond functionalization under metal-catalyzed conditions to furnish UAAs. 5 Interestingly, the crucial importance of tyrosine in protein sequences and the presence of a phenolic functionality have provided an appealing tunable site for selective functionalization and assembling heterocyclic architectures with the aid of appropriate coupling partners. 6 Under this domain, a few C(sp 2 )−H bond functionalization strategies at the C-2 and/or C-3 position(s) on the aryl moiety in tyrosine and tyrosinecontaining peptides, including alkenylation, 7 acylation, 8 iodination, 9 arylation, 10 and recently disclosed acyloxylation, 11 have been successfully achieved via C−H activation (Scheme 1a). However, efficient strategies involving mounting a

On the Topic of Substrate Scope

“…An additional table of all other unreactive substrates attempted (eight examples) is listed in the Supporting Information in Scheme S1. Further examples published at Organic Letters within the past month, where the scope has largely been selected to provide the most information with fewer examples, typically illustrate 26–29 substrate combinations. − …”

Recent developments in the cleavage, functionalization, and conjugation of proteins and peptides at tyrosine residues

“…oxepine dipeptides and tripeptides. 51 The benzo[b]oxepine heterocyclic is found in several natural products and has constituted an important scaffold for the development of bioactive compounds, hence synthesizing peptides containing the oxepine heterocyclic system is highly desired. Peptide 44 was rst prepared via well-established liquid-phase peptide synthesis protocols.…”

“…The incorporation of modied amino acid residues into a peptide or protein is of interest as it provides access to modied natural biologics that could be used in applied areas such as proteomics, diagnostics, asymmetric syntheses, and drug delivery. 51 3.1.1. Chemical functionalization/modication of Tyr.…”

“…Importantly, it is essential to provide examples of Tyr-containing peptide functionalization combined with further modifications, such as the recent study by Kharat et al , who demonstrated a Rh-catalyzed annulation of ortho -vinylated Tyr with alkynes, resulting in functionalized oxepine dipeptides and tripeptides. 51 The benzo[ b ]oxepine heterocyclic is found in several natural products and has constituted an important scaffold for the development of bioactive compounds, hence synthesizing peptides containing the oxepine heterocyclic system is highly desired. Peptide 44 was first prepared via well-established liquid-phase peptide synthesis protocols.…”

Indole-Fused Benzoxepine Synthesis via Visible-Light-Driven Aerobic Dehydrogenative [5 + 2] Annulation

“…However, to the best of our knowledge, there are no reported examples of [5 + 2] annulations for constructing oxepine scaffolds from alkenes. Only a small amount of research has documented [5 + 2] annulation of alkynes or allenes with 2-vinylphenols to provide benzoxepines …”