HTE-Guided Cyclization Strategies for Oxacycle Synthesis

Polycyclic ethers constitute a family of compounds of great interest due to their structural complexity and
broad range of biological activities, including antibiotic, antifungal1, and anticarcinogenic2 properties.
However, their synthesis remains challenging because of the entropic and enthalpic barriers associated with
cyclization processes.3,4 In this work, we present our progress towards the construction of a chemical library
of natural product-like cyclic ethers using monoterpene-derived epoxides as building blocks for cyclization. A
series of epoxides was synthesized from geraniol and evaluated under palladium-catalyzed Tsuji–Trost
cyclization conditions using a High-Throughput Experimentation5 (HTE) approach. Using micro-scale, and
parallel screening, a diverse set of catalysts, ligands, and aditives were tested. The difficulties encountered
in the oxycyclization step using the Tsuji–Trost methodology prompted us to synthesize the corresponding
oxacycles through an already reported bromonium-mediated approach, thereby enabling the identification of
several oxacyclic targets of interest.