Ru‐Catalyzed C−H Hydroxylation of Tyrosine‐Containing Di‐ and Tripeptides toward the Assembly of L‐DOPA Derivatives

Abstract

The development of catalytic tools for the late‐stage modification of amino acids within a peptide framework is a challenging task of capital importance. Herein, we report a Ru‐catalyzed C(sp2)−H hydroxylation of a collection of Tyr‐containing di‐ and tripeptides featuring the use of a carbamate as a removable directing group and PhI(OCOCF3)2 (PIFA) as oxidant. This air‐compatible tagging technique is reliable, scalable and provides access to L‐DOPA (L‐3,4‐dihydroxyphenylalanine) peptidomimetics in a racemization‐free fashion. Density Functional Theory calculations support a Ru(II)/Ru(IV) catalytic cycle.

Palladium‐Catalyzed Site‐Selective C(sp2)−H Acetoxylation of Tyrosine‐Containing Peptides

“…In this manner, L–DOPA ( 5 a ) and its peptidomimetics derivatives ( 5 b – c ) could be prepared in a reliable manner in up to 60 % yields (Scheme 3). Likewise, the selective cleavage of the appended oxygenated group could be performed upon treatment of 4 i with ammonium acetate to deliver hydroxylated tripeptide 6 in 58 % yield, thereby complementing our previously described Ru‐catalyzed hydroxylation protocol occurring upon weak chelation assistance with carbamates [12a] …”

Exploring Chemical Modifications of Aromatic Amino Acid Residues in Peptides

“…72 Along a similar vein, Correa et al have developed removable carbamate directed Ru-catalyzed C(sp 2 )-H hydroxylation to install -OH group in the tyrosine side chain of di-and tripeptides (Scheme 27). 73 Prior to this work, White group along with Osberger,…”

“…72 In a similar vein, Correa et al have developed a protocol for a removable carbamate-directed Ru-catalyzed C(sp 2 )–H hydroxylation to install an OH group on the tyrosine side chain of di- and tripeptides (Scheme 27 ). 73 Prior to this work, White’s group along with that of Osberger, Rogness and co-workers disclosed the C(sp 3 )–H hydroxylation of peptides and biomolecules under Fe catalysis. 74 Regardless of the position of Tyr in peptide scaffolds, a family of dipeptides and tripeptides was effectively hydroxylated on the phenol moiety to give products 103 .…”

Site-Selective C–H Amination of Phenol-Containing Biomolecules

“…Conversely, despite its prevalence in a myriad of medicinally relevant compounds, the modification of tyrosine (Tyr) has been comparatively overlooked. 4 The introduction of directing groups (DGs) into the oxygen atom of the phenol ring has enabled olefination, 5 hydroxylation, 6 acylation, 7 acetoxylation, 8 and acyloxylation 9 reactions at the ortho- C(sp 2 )–H bond. Although chelation assistance constitutes a common practice within the field and results in the assembly of unprecedented peptides, the cleavage of the required DG is often a low-yielding step, which deeply jeopardizes the practicality of the latter methods.…”