Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans

Herein we report a novel strategy for the design and construction of natura l and natural product-like libraries based on the principle of privileged s tructures, a term originally introduced to describe structural motifs capab le of interacting with a variety of unrelated molecular targets. The identi fication of such privileged structures in natural products is discussed, an d subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugura l template for the construction of natural product-like Libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the us e of a new, polystyrene-based selenenyl bromide resin. Once the loading, el aboration, and cleavage of these benzopyrans was established, this new soli d-phase method was then thoroughly validated through the construction of si x focused combinatorial libraries designed around natural and designed mole cules of recent biological interest.