Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living cultures.

Aqueous Sonogashira cross-coupling of unprotected bromotryptophan, tripeptides and a new to nature natural product (accessed through biosynthetic manipulation) is reported.

Microbial marine natural products hold significant potential for the discovery of new bioactive therapeutics such as antibiotics. Unfortunately, this discovery is hindered by the inability to culture the majority of microbes using traditional laboratory approaches. While many new methods have been developed to increase cultivability, a high‐throughput in situ incubation chamber capable of simultaneously isolating individual microbes while allowing cellular communication has not previously been reported. Development of such a device would expedite the discovery of new microbial taxa and, thus, facilitate access to their associated natural products. In this study, this concept is achieved by the development of a new device termed by the authors as the microbe domestication (MD) Pod. The MD Pod enables single‐cell cultivation by isolating marine bacterial cells in agarose microbeads produced using microfluidics, while allowing potential transmission of chemical signals between cells during in situ incubation in a chamber, or “Pod,” that is deployed in the environment. The design of the MD Pod was optimized to ensure the use of biocompatible materials, allow for simple assembly in a field setting, and maintain sterility throughout incubation. The encapsulation process was designed to ensure that the viability of marine sediment bacteria was not adversely impacted by the encapsulation process. The process was validated using representative bacteria isolated from temperate marine sediment samples: Marinomonas polaris, Psychrobacter aquimaris, and Bacillus licheniformis. The overall process appeared to promote metabolic activity of most representative species. Thus, microfluidic encapsulation of marine bacteria and subsequent in situ incubation in the MD Pod is expected to accelerate marine natural products discovery by increasing the cultivability of marine bacteria.

The blending of synthetic chemistry with biosynthetic processes provides a powerful approach to synthesis. Biosynthetic halogenation and synthetic cross‐coupling have great potential to be used together, for small molecule generation, access to natural product analogues and as a tool for chemical biology. However, to enable enhanced generality of this approach, further synthetic tools are needed. Though considerable research has been invested in the diversification of phenylalanine and tyrosine, functionalisation of tryptophans thorough cross‐coupling has been largely neglected. Tryptophan is a key residue in many biologically active natural products and peptides; in proteins it is key to fluorescence and dominates protein folding. To this end, we have explored the Heck cross‐coupling of halo‐indoles and halo‐tryptophans in water, showing broad reaction scope. We have demonstrated the ability to use this methodology in the functionalisation of a brominated antibiotic (bromo‐pacidamycin), as well as a marine sponge metabolite, barettin.