Natural scaffolds-inspired synthesis of CF3-substituted macrolides enabled by Rh-catalyzed C-H alkylation macrocyclization

The development of innovative strategies and methods to provide natural product-like macrocycles not accessible by biosynthesis,but endowed with novel bioactivities and simplified structure,is highly de-sirable.Inspired by the key scaffolds of rapamycin and FR252921,herein,we report a Rh(Ⅲ)-catalyzed C-H alkylation macrocyclization,which enables access to CF3-substituted macrolides.DFT calculations reveal that the chemoselectivity between C-H alkylation and olefination macrocyclization was highly controllable.Moreover,the unique CF3-substituted macrolides showed potent anti-inflammation activi-ties against TNF-α,IL-6 and CCL2 mRNA expression.