Modification of Proteins Using Olefin Metathesis

Abstract

Olefin metathesis has revolutionized synthetic approaches to carbon-carbon bond formation. With a rich history beginning in industrial settings through its advancement in academic laboratories leading to new and highly active metathesis catalysts, olefin metathesis has found use in the generation of complex natural products, the cyclization of bioactive materials, and in the polymerization of new and unique polymer architectures. Throughout this review, we will trace the deployment of olefin metathesis-based strategies for the modification of proteins, a process which has been facilitated by the extensive development of stable, isolable, and highly active transition-metal-based metathesis catalysts. We first begin by summarizing early works which detail peptide modification strategies that played a vital role in identifying stable metathesis catalysts. We then delve into protein modification using cross metathesis and finish with recent work on the generation of protein-polymer conjugates through ring-opening metathesis polymerization.

Figure 1.

(A) Abridged timeline of metathesis discoveries and some representative catalyst structures through the years. (B) Typically utilized metathesis reactions in the context of protein modification which include ring-closing metathesis (RCM), ring-opening metathesis polymerization (ROMP), and cross-metathesis (CM).

Figure 2.

(A) RCM of allylglycine substituted Balaram tetrapeptide in the presence of 2. (B) On-resin RCM of oligopeptide and subsequent liberation from solid support.

Figure 3.

(A) Relative reactivity of various modifications on protein substrates in CM processes as well as a few selected metathesis substrates used in protein CM studies. (B) General catalytic cycle for the modification of biomolecules through CM using 4.

Figure 4.

(A) Methods for the installation of chalcogenide allyl groups on proteins. Genetic incorporation of Ahc is expanded upon in Figure 5 (vide infra). (B) Side reactions observed on amino acid substrates when treated with MSH. See ref. for full experimental details.

Figure 5.

Incorporation of ahc into histone H3 was successful, whereas genetic incorporation of other unnatural amino acids (Ahs, Sac, and Seac) was unsuccessful. Reprinted with permission from J. Am. Chem. Soc., 2018, 140, 14599–14603. Copyright 2018 American Chemical Society.

Figure 6.

(A) Grafting-from lysozyme using ROMP in aqueous conditions using 7.(B) Grafting-to using polymers synthesized via ROMP using 6.

Figure 7.

Conjugation of rPEG polymer to Lys through reductive amination and subsequent depolymerization of the Lys-rPEG conjugate to produce the degraded Lys conjugate.

Figure 8.

Overview of new applications for metathesis in biological settings.