Multifunctional reagents with orthogonally reactive nodes are capable of engaging multiple reaction partners in a chemoselective manner, allowing for the rational design of novel reactions. (N-isocyanimino)triphenylphosphorane (Pinc) is a trifunctional reagent with two nucleophilic nodes and one electrophilic node (Fig. A). Our group has previously utilized Pinc to generate 1,3,4-oxadiazole-containing macrocycles, which have showcased the ability of heterocycles to increase the conformational stability of peptidic macrocycles. However, the cyclization of short linear inserts, such as tripeptides, was not feasible and represented a limitation of this method. In a serendipitous discovery, we observed the ability of proximal imidazole N’s to intercept the Pinc-mediated macrocyclization (Fig. B) allowing us to expand on the scope of the rerouted cyclization. Based on the choice of N-heterocyclic trap and its relative position with respect to the tethered amine, a wide range of novel cyclic systems ranging from 6- to 22- membered rings containing a bis-heterocyclic graft have been generated (Fig C). The high tolerance of a wide range of ring sizes in this cyclization methodology and its ability to cyclize highly strained medium-sized rings showcases a significant improvement over the previously reported system. Furthermore, its application to small molecules showcases the wide range of azole nucleophiles that is tolerated by this system. The presence of the heteroatom rich biaryl system in a peptidic macrocycle renders it a potent control element capable of establishing multiple hydrogen bonds.

Condensation-driven assembly of bis(heteroaryl) motifs using a linchpin reagent

2019 Fall National Meeting

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