Macrocyclization by Nickel‐Catalyzed, Ester‐Promoted, Epoxide–Alkyne Reductive Coupling: Total Synthesis of (−)‐Gloeosporone

Abstract

Macrocycles are found in important and diverse molecules such as naturally occurring peptides (e.g., cyclosporine), oligosaccharides (cyclodextrins), and polyketides (erythromycin) and synthetic compounds such as crown ethers and polyenes. The most common strategy to prepare macrocyclic lactones (macrolides) is by intramolecular C–O bond formation to provide the lactone functional group itself.[1] Though often successful and high yielding, this approach is also highly context-dependent and in some cases provides little to none of the desired macrocycle.[1] The development of methods for macrocyclization has thus received much attention.[2] Herein we report a new C–C bond forming strategy for macrocyclization, nickel-catalyzed epoxide alkyne reductive coupling,[3] and illustrate its use in the synthesis of the macrolide natural product (−)-gloeosporone (1).[4]

Recent Advances in the Total Synthesis of Natural Products Containing Eight-Membered Carbocycles (2009–2019)

“…As an important carbocyclization method, Ni-catalyzed reductive coupling has proven to be a useful tool in the preparation of carbocycles. − A representative intramolecular exo -selective Ni-catalyzed reductive coupling of ynals is shown in Scheme . In recent years, impressive alkyne–aldehyde reductive coupling reactions and their use in natural product synthesis have been reported by the groups of Montgomery , and Jamison. , …”