Tandem Macrolactone Synthesis: Total Synthesis of (-)-Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy

Tetrahydropyran-containing macrolactones were synthesized by integrating Meyer-Schuster rearrangement, macrocyclic ring-closing metathesis, and transannular oxa-Michael addition under gold and ruthenium catalysis. Single-step access to a variety of 14- to 20-membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13-step synthesis of (-)-exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.

Automated summary

Tetrahydropyran-containing macrolactones were synthesized using gold and ruthenium catalysis through a three-step reaction sequence, demonstrating high synthetic efficiency and good diastereoselectivity. The synthesis of an anticancer marine macrolide showcased the potential application of this reaction sequence in the synthesis of natural products.