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Foldamer-templated catalysis of macrocycle formation

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Science  20 Dec 2019:
Vol. 366, Issue 6472, pp. 1528-1531
DOI: 10.1126/science.aax7344

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Macrocycles made easy

Macrocycles, which are molecules with large rings of 12 or more atoms, are challenging to produce by intramolecular cyclization because floppy ends tend to join up with another molecule rather than fold back on themselves. Girvin et al. identified a foldamer—a short, structured peptide—that can cyclize floppy, dialdehyde substrates through a templated aldol condensation (see the Perspective by Gutiérrez Collar and Gulder). Variation of the residues within the foldamer suggests that its helical structure helps position amine functional groups crucial for catalysis. The authors prepared molecules with a wide range of ring sizes and developed a synthesis for robustol, a macrocycle natural product with a 22-member ring.

Science, this issue p. 1528; see also p. 1454

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.

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