Modular Synthesis of Unnatural Peptides via Rh(III)-Catalyzed Diastereoselective Three-Component Carboamidation Reaction

Abstract

Herein we report a modular peptide ligation methodology that couples dioxazolones, arylboronic acids, and acrylamides to construct amide bonds in a diastereoselective manner under mild conditions, facilitated by Rh(III) catalysis. By converting the C-terminus of one peptide into a dioxazolone and the N-terminus of a second peptide into an acrylamide, the two pieces can be bridged by an arylboronic acid to construct unnatural phenylalanine, tyrosine, and tryptophan residues at the junction point with diastereoselectivity for their corresponding d-stereocenters. The reaction exhibits excellent functional group tolerance with a large substrate scope and is compatible with a wide array of protected amino acid residues that are utilized in Fmoc solid phase peptide synthesis. The methodology is applied to the synthesis of six diastereomeric proteasome inhibitor analogs, as well as the ligation of two 10-mer oligopeptides to construct a 21-mer polypeptide with an unnatural phenylalanine residue at the center.

Scheme 1.

Transition metal catalyzed methods of unnatural amino acid incorporation in peptides

Scheme 2.. Boronic acid scope

All yields and dr reported are isolated, with the crude dr in parentheses. All reactions conducted on 0.1 mmol scale. ^a0.033 mmol scale.

Scheme 3.. Dioxazolone scope (top) and acrylamide scope (bottom)

All yields and dr reported are isolated, with the crude dr in parentheses. ^a0.1 mmol scale. ^b0.033 mmol scale. ^c0.01 mmol scale. ^d0.6 M conc. ^e0.2 M conc. ^f0.1 M conc. ^g0.067 M conc. More dilute concentrations are to ensure full homogeneity of less soluble substrates.

Scheme 4.

Proposed catalytic cycle of three-component carboamidation reaction

Scheme 5.. Synthesis of proteasome inhibitor analogs

Crude dr of each reaction is in parentheses. All reactions conducted on 0.033 mmol scale.

Scheme 6.. Synthesis of 21-mer unnatural peptide

Reaction conducted on 0.01 mmol scale. Yield and diastereoselectivity is of the isolated compound.