Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion

戒指(化学) 多样性(政治) 化学 立体化学 有机化学 政治学 法学
作者
Renato A. Bauer,Todd A. Wenderski,Derek S. Tan
出处
期刊:Nature Chemical Biology [Nature Portfolio]
卷期号:9 (1): 21-29 被引量:155
标识
DOI:10.1038/nchembio.1130
摘要

Medium-sized ring structures can provide unique entry points into natural product–like chemical space but are synthetically challenging to access. A biologically inspired method eases these challenges, employing a dearomatization-rearomatization sequence to form a diverse library of rings from tailored bicyclic compounds. Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.
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