Foldamer-templated catalysis of macrocycle formation

Abstract

Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing. The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete. Here, we present a bioinspired strategy for macrocycle formation through carbon-carbon bond formation. The process relies on a catalytic oligomer containing α- and β-amino acid residues to template the ring-closing process. The α/β-peptide foldamer adopts a helical conformation that displays a catalytic primary amine-secondary amine diad in a specific three-dimensional arrangement. This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms. Utility is demonstrated in the synthesis of the natural product robustol.

Fig 1.. Macrocyclization Strategies.

(A) Prior approaches and foldamer approach to macrocyclization. (B) Divergent reactivity: foldamer vs. small molecule catalysis.

Fig 2.. Scope and structure-reactivity relationship.

(A) Foldamer-catalyzed macrocyclization: ring size variation. Isolated yields are reported for foldamer-catalyzed reactions; however, yields for the pyrrolidine/n-butylamine catalyst pair (“small molecule”) are estimated based on LC-MS data. Ts = p-toluenesulfonyl. (B) Identification of features critical for foldamer catalysis of macrocyclization. Details are included in supplementary material (fig. S8-S12).

Fig 3.. Applications of foldamer catalysis in total synthesis.

(A) Foldamer-catalyzed formation of the macrocyclic core of nostocyclyne A. Identity of product F2 was established via the crystal structure of the tosylhydrazone derivative (Ts = p-toluenesulfonyl). (B) Total synthesis of robustol. The key step, foldamer-catalyzed closure of the 22-membered ring, is highlighted. See supplementary materials for full reaction protocols and product characterization.