PhotoBioSH2 – Photo-biocatalytic decarboxylative bimolecular homolytic substitution

The purpose of this project called PhotoBioSH2 is to develop new-to-nature enzymatic cross-coupling reactions (CCRs) driven by light, with broad substrate tolerance operating under mild conditions.

The ultimate objective is to enable enzymatic, co-enzyme free bimolecular homolytic substitutions; one type of CCR referred to as SH2.CCRs are a cornerstone in chemistry to join different fragments together, which mainly relies on transition metals, organic solvents and harsh conditions.

PhotoBioSH2 will develop terpene synthase enzymes into general carbon-carbon (C-C) and carbon-heteroatom -bond-forming photobiocatalysts, achieved by metal replacement and the power of LEDs.

We will implement radical mechanisms in enzymes involving single-electron transfer (SET), allowing even for construction of congested quaternary carbon centers.

Combining enzymes and LEDs, radicals will be generated from carboxylated substrates, followed by interception of these reactive intermediates by nucleophiles to finalize the CCR in the active site.

Efficiency and stereoselectivity of photoenzymatic CCRs will be improved by enzyme design and engineering guided by mechanistic understanding. In this way, photobiocatalytic, decarboxylative cross-nucleophile couplings can be achieved (year 1-3).

The more challenging SH2 transformations will be realized in year 4 by a double-decarboxylation mechanism in the active site. The outcome will be a complete green solution for mild, atom efficient chemical synthesis.