Diastereoselective synthesis of dioxaadamantane skeletons from coumarin-fused bridged ketones via a triple Grignard addition and hydroalkoxylation sequence

Abstract

Highly functionalized adamantanes and heteroadamantanes are privileged structures present in pharmaceuticals and are also prevalent in bioactive natural products. However, efficient synthetic methods for these frameworks remain underdeveloped. Herein, we report a sequential protocol that constructs chromane-annulated dioxaadamantane skeletons through a triple Grignard addition to readily accessible coumarin-fused bridged ketones and a subsequent C–O bond-forming cyclization. This method features readily available starting materials, operational simplicity, efficient multiple bond formation and excellent diastereoselectivity. Furthermore, synthetic manipulations of the products including ring-closing metathesis and catalytic hydrogenation were performed to access more structurally sophisticated architectures.