The development of diastereoselective synthetic strategies that provide access to chemical space of skeletally diverse and privileged molecules is highly desirable in drug discovery. In this context, the identification of modular synthetic approaches that proceed with high chemo- and diastereoselectivity and incorporate substructures of biologically relevant compounds are critical to enable efficient library synthesis and SAR exploration. In this respect, privileged substructure diversity oriented synthesis (pDOS) of skeletally diverse small-molecule libraries is one of the most promising strategies used to yield high-value compound collections. Tandem reaction sequences that utilize readily available starting materials to rapidly access a large number of skeletally diverse molecules are particularly attractive. Indeed, many small molecules known to modulate the biological function of gene products have been discovered by screening DOS libraries. Following a build/couple/pair strategy we have established bidirectional approach to unprecedented benzoxazepines by employing a Pictet-Spengler/aza-Michael addition cascade and Schiff base/aza-Michael addition/reduction protocols, respectively. The corresponding β-carboline-fused benzoxazepines and peripherally substituted benzoxazepines are isolated in high diastereoselectivity, good to excellent yields and have, to the best of our knowledge, never been reported. The priliminaty anti-cancer and anti-iflammatory findings of these novel scaffold will be also discussed in this meeting.

Modular and diastereoselective bi-directional one-pot routes for the rapid access of constrained collections of b-carbolino-benzoxazepine scaffolds

255th National Meeting (2018)

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