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

Abstract

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, due 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.

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

“…14) of this study with the collection of 15 FDA-approved drugs containing pyrimidine moiety37 (Supplementary Fig. 15) and 71 bioactive natural products (Supplementary Table 6)38. The reference set of drugs containing pyrimidine moiety were narrowly dispersed in the region of rod-and disc-like shapes.…”

Principal Component Analysis as a Tool for Library Design: A Case Study Investigating Natural Products, Brand-Name Drugs, Natural Product-Like Libraries, and Drug-Like Libraries

“…However, despite these attractive features of macrocycles and medium rings, they remain severely underexploited in current drug and probe discovery efforts [12, 13], due to challenges associated with their synthesis. To address the underrepresentation of these compounds, we have sought to circumvent the inherent limitations of classical cyclization-based strategies for macrocycle and medium-ring synthesis by developing alternative ring-expansion approaches that are tolerant of a broad range of substitution patterns and functional groups.…”

“…We recently developed two such methods (Fig. 1) [12, 13], both of which can be employed on gram scale, provide products bearing handles for further diversification, and are transferable to parallel synthesis platforms.…”

“… 18 Several PC axes were inverted in this example to maintain resemblance to our previous PCA plots [12, 13] by adding the “ylim” and “xlim” axis limit options to the “biplot” command in “R”: R > biplot(b, choices = c(1, 2), col = c(“gray”, “red”), ylim = c(0.12, −0.12), xlim = c(−0.12, 0.12))This does not impact data interpretation because the signs of all PC axes are arbitrary. …”

Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings

“…The achievement of high efficiency remains a formidable challenge with conventional cyclization-based methods, mainly due to unfavourable enthalpic and entropic reasons. To address this, an alternative, more flexible strategy is the use of ring expansion reactions of bicyclic or polycyclic substrates to the desired medium-sized rings141516171819. For example, Harrowven has reported a ring expansion approach involving radical ipso -substitution triggered by sp 2 -radical intermediates generated from the dehalogenation of aryl or vinyl halides in the presence of toxic tin hydride reagents16.…”