We are a Chemical Biology group that aims to address problems at the interface of chemistry and biochemistry, including the chemical synthesis and biosynthesis of bioactive peptides, protein functionalization and biological function of non-coding RNA in bacteria.
Macrocycles Are Great Cycles!
Biologically active macrocycles represent a remarkably diverse group of molecules and are emerging as an exciting area of medicinal chemistry. Macrocycles in drug discovery are defined as molecules containing at least one large ring composed of 12 or more atoms. Many natural products have a macrocyclic core, suggesting that an evolutionary advantage may be associated with the production of secondary metabolites based upon these scaffolds. Our group is particularly interested in macrocyclic peptides from both natural and synthetic sources. We are engaged in elucidating Nature’s strategy to utilize various enzymes to produce cyclic peptide natural products. The chemistry evolved by Nature further guides us to develop synthetic methods for peptide macrocyclization and diversification, which would lead to library of peptide/peptidomimetics for screening bioactive compounds.
Transition metal catalyzed C‐H activation have shown potential in the functionalization of peptides with expanded structural diversity. Herein, we report the development of late‐stage peptide macrocyclization methods via palladium‐catalyzed site‐selective C(sp 2 )‐H olefination of tryptophan residues at C‐2 and C‐4 positions. This strategy utilizes peptide backbone as endogenous directing groups and provide access to peptide macrocycles with unique Trp‐alkene crosslinks.
Peptide macrocycles are widely used in fields ranging from medicinal chemistry to materials science. Efficient chemical methods for the synthesis of cyclic peptides with novel three-dimensional structures are highly desired to facilitate the development of this unique class of compounds. However, the range of methods available for constructing peptide macrocycles is limited compared with that for small molecules. We recently developed new methods for synthesizing highly constrained cyclic peptides with C–C crosslinks through Pd-catalyzed C–H activation reactions. These methods use endogenous backbone amides as directing groups and, therefore, have the potential for use in late-stage functionalization of peptide natural products.
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