The invention of selective, biologically-compatible, bond-forming methodology to synthesize complex molecular & multi-molecular biological structures.

Since the early 2000s, we have been developing a new mode of chemical synthesis applied to biology that cannot rely upon established strategies in more traditional chemistry (e.g. protecting groups, organic solvents, extremes of pH or temperature). It has demanded the development of unprecedented chemical synthetic methodology under aqueous, mild conditions and its precise application in a manner that is benign with respect to biological processes. The intrinsic chemistry of biomolecules is dominated by the presence of nucleophiles. Through the development of novel regio-, chemo- and stereo-selective processes that instead rely on a) electrophilic, b) metal-mediated, c) radical, d) photochemical, e) pericyclic, f) enzymatic reactions, we have demonstrated leading examples of C-C, C=C, C-S, C-N, C-F C-O, C-P, S-S, S-Se & C-H/D bond-forming reactions. We have discovered & demonstrated >20 unique examples of protein reactions, including the first multi-reaction-site-selective protein reactions.[pub 85] These reactions, site-selective methods and the associated ‘tag-and-modify’ strategy[pub 165] are now increasingly adopted.

The development of metal-mediated chemistry in biology, for example, is allowing abiotic metals to be used to selectively probe & control biology. We have found methods that have allowed the first examples, for example, of biological, Ru-controlled bond formation (C=C (olefin) metathesis)[pub 100]) and Pd-catalyzed C-C formation (Suzuki)[pub 129] reactions.

The use of compatible ‘soft electrophiles’ in proteins has allowed the chemical recapitulation of many of the important natural post-translational modifications. For example, the development of ‘SeS-Cys’ and ‘Dha’ as selectively-reactive unnatural amino acids has enabled the first examples of direct, site-selective, chemical protein glycosylation,[pub 48][pub 51][pub 85][pub 97] lipidation,[pub 97] sulfation,[pub 85] ane phosphorylation[pub 98][pub 197]. The extension of these reactions to act as well-tolerated processes in cells and animals has provided a form of molecular manipulation ('in vivo chemistry’) that has the potential for direct organismal reprogramming, interrogation and intervention.[pub 172]