Olefin metathesis for chemical biology

Abstract

Chemical biology relies on effective synthetic chemistry for building molecules to probe and modulate biological function. Olefin metathesis in organic solvents is a valuable addition to this armamentarium, and developments during the previous decade are enabling metathesis in aqueous solvents for the manipulation of biomolecules. Functional group-tolerant ruthenium metathesis catalysts modified with charged moieties or hydrophilic polymers are soluble and active in water, enabling ring-opening metathesis polymerization, cross metathesis, and ring-closing metathesis. Alternatively, conventional hydrophobic ruthenium complexes catalyze a similar array of metathesis reactions in mixtures of water and organic solvents. This strategy has enabled cross metathesis on the surface of a protein. Continuing developments in catalyst design and methodology will popularize the bioorthogonal reactivity of metathesis.

Figure 1

Conventional ruthenium catalysts for olefin metathesis.

Figure 2

Olefin metathesis reactions and their application to chemical biology. (a) Ring-opening metathesis polymerization can produce highly-functionalized and well-defined macromolecules, such as this carbohydrate-displaying polymer [10]. (b) Cross metathesis links two alkene fragments to create increasingly complex molecules, including this proline–glycine dipeptide mimic [15,16]. (c) Ring-closing metathesis is an effective reaction for producing cyclic molecules with constrained conformations, such as this oxytocin hormone mimic [20].

Figure 3

Ruthenium catalysts for aqueous olefin metathesis.

Figure 4

Olefin cross metathesis for site-specific protein modification at allyl sulfide substituents [49]. The allyl group is appended to Cys156 of the S156C variant of subtilisin Bacillus lentus. The protein structure is based on the atomic coordinates in PDB entry 1st3.