Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo

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 culture

Suzuki-Miyaura diversification of amino acids and dipeptides in aqueous media

The authors gratefully acknowledge the IWT Flanders and Janssen Pharmaceutica for financial support of T.W. This work is supported by the Scientific Research Network (WOG) “Sustainable chemistry for the synthesis of fine chemicals” of the Research Foundation - Flanders (FWO).The Suzuki-Miyaura derivatisation of free amino acids, peptides and proteins is an attractive area with much potential utility for medicinal chemistry and chemical biology. Here we report the modification of unprotected and Boc-protected aromatic amino acids and dipeptides in aqueous media, enabling heteroarylation and vinylation. We systematically investigate the impact of the peptide backbone and adjacent amino acid residues upon the reaction. Our studies reveal that whilst asparagine and histidine hinder the reaction, by utilising dppf, a ferrocene-based bidentate phosphine ligand, cross-coupling of halophenylalanine or halotryptophan adjacent to such a residue could be enabled. Our studies reveal dppf to have good compatibility with all unprotected, proteinogenic amino acid side chains.PostprintPeer reviewe

Advances in Palladium-Catalyzed Cascade Cyclizations

The past decades in organic chemistry have witnessed significant improvements in synthetic efficiency as a result of considerable progress in cascade reactions, tandem reactions, and related one-pot processes. These methods are less time-consuming and produce less waste compared to the classical stepwise approach. However, cascade chemistry requires a more careful design and compatible reaction types for success. Palladium-catalyzed cross-coupling reactions, with their well understood multistep catalytic cycles, form a promising basis for the design of cascade reactions. Furthermore, they are compatible with a range of functional groups and can be combined with a range of secondary transformations. The resulting palladium-catalyzed cascade reactions have provided access to a plethora of complex small molecules of high medicinal relevance. This review provides an overview of the developments in palladium-catalyzed cascade reactions since 2011, classified according to the initiation, propagation, and termination steps comprising the palladium cascade reactions. This classification should assist the reader and may provide inspiration for the design of new cascade reactions. (Figure presented.)