Our group has successfully developed PMC friendly approaches to the construction of gem-disubstituted cyclopropanes and 1-aryl-3-azabicyclo[3.1.0]hexanes. Both moeities are synthetically difficult to access. The need for pre-functionalized olefins and or diazo compounds poses a challenge for the rapid modification of the geminal substituents of a cyclopropyl ring. Furthermore, no known methods were available to directly modify the pendant aryl group of a 1-aryl-3-azabicyclo[3.1.0]hexane. After significant reaction optimization, we discovered an expedient and modular approach to the synthesis of 1-heteroaryl-3-azabicyclo[3.1.0]hexanes by Suzuki–Miyaura and Chan–Evans–Lam coupling reactions of tertiary trifluoroborate salts. Our cross-coupling protocols proved to be useful tools for SAR exploration by PMC. Application of these protocols in a number of libraries for a small molecule medicinal chemistry program lead to the discovery of a new lead compound that was &gt;15,000 fold more potent than the original hit in the series. We reasoned that the properties of our lead compound could be further improved by replacement of a diarylmethane motif with a gem-diarylcyclopropane analogue. Guided by our work on the cross-coupling of tertiary trifluoroborates, we developed a diastereoselective cross-coupling reaction of gem-bis(boryl)cyclopropanes. This reaction provides efficient access to tertiary cyclopropyl boronic esters which undergo facile derivatization or further cross-coupling to afford gem-disubstituted cyclopropanes. Products are formed in high yields from a broad range of functionalized aryl- and heteroaryl bromides.

Development of PMC friendly approaches to the construction of synthetically challenging cyclopropane motifs

2019 Fall National Meeting

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