Cyclic ribosomally derived peptides possess diverse bioactivities and are currently of major interest in drug development. However, it can be chemically challenging to synthesize these molecules, hindering the diversification and testing of cyclic peptide leads. Enzymes used in vitro offer a solution to this; however peptide macrocyclization remains the bottleneck. PCY1, involved in the biosynthesis of plant orbitides, belongs to the class of prolyl oligopeptidases and natively displays substrate promiscuity. PCY1 is a promising candidate for in vitro utilization, but its substrates require an 11 to 16 residue C-terminal recognition tail. We have characterized PCY1 both kinetically and structurally with multiple substrate complexes revealing the molecular basis of recognition and catalysis. Using these insights, we have identified a three residue C-terminal extension that replaces the natural recognition tail permitting PCY1 to operate on synthetic substrates. We demonstrate that PCY1 can macrocyclize a variety of substrates with this short tail, including unnatural amino acids and nonamino acids, highlighting PCY1's potential in biocatalysis.

Axially chiral phenols are attractive targets in organic synthesis.T his motif is central to many natural products and widely used as precursors to,ordirectly,aschiral ligands and catalysts.D espite their utility few simple catalytic methods are available for their synthesis in high enantiopurity.Herein the atropselective acylation of ar ange of symmetric biaryl diols is investigated using isothiourea catalysis.S tudies on amodel biaryl diol substrate shows that the high product er observed in the process is ar esult of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with as econd chiroablative kinetic resolution. Extension of this process to ar ange of substrates, including achallenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples,u pt o9 8:2e r), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate.Computation has been used to understand the factors that lead to high enantiocontrol in this process,w ith maintenance of planarity to maximizea1,5-S···O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Axially chiral phenols are attractive targets in organic synthesis. This motif is central to many natural products and widely used as precursors to, or directly, as chiral ligands and catalysts. Despite their utility few simple catalytic methods are available for their synthesis in high enantiopurity. Herein the atropselective acylation of a range of symmetric biaryl diols is investigated using isothiourea catalysis. Studies on a model biaryl diol substrate shows that the high product er observed in the process is a result of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with a second chiroablative kinetic resolution. Extension of this process to a range of substrates, including a challenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples, up to 98:2 er), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate. Computation has been used to understand the factors that lead to high enantiocontrol in this process, with maintenance of planarity to maximize a 1,5‐S⋅⋅⋅O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Enantiomerically pure alcohols and amines are ubiquitous throughout Nature and are found within numerous biologically active compounds. This chapter provides a comprehensive overview of strategies for the nonenzymatic acylative kinetic resolution and desymmetrization of alcohols and amines, which have emerged as powerful methods for the preparation of a range of enantiomerically enriched alcohol and amine derivatives. The use of both stoichiometric chiral acylating agents and the use of small‐molecule catalysts for such processes is discussed. The chapter provides an overview of the variety of substrates that can be effectively resolved using the range of enantioselective acylation methods available. Key mechanistic considerations within each class of acylation and the origin of stereoselectivity are also discussed.

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