Natural Product-like Combinatorial Libraries Based on Privileged Structures. 1. General Principles and Solid-Phase Synthesis of Benzopyrans

• Published in: Journal of the American Chemical Society 2000-10, Vol.122 (41), p.9939-9953
• Main Authors: Nicolaou, K. C, Pfefferkorn, J. A, Roecker, A. J, Cao, G.-Q, Barluenga, S, Mitchell, H. J
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja002033k

Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural 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 use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.