Herein we report a new diversity-oriented synthetic pathway to skeletally diverse alkaloid-like compounds from simple, readily available starting materials. The synthetic strategy involves the generation and isolation of reactive, otherwise unstable dihydropyridines and dihydroisoquinolines on a solid support. A variety of reactions can be performed with the enamine double bond present in the isolated reactive intermediates, thus leading to skeletally diverse alkaloid-like products.
Small molecules used in chemical genetic screens can be synthesized with guidance from compounds known to have biological activity [2a] or with the desire to distribute the products in chemical descriptor space. In the latter case, it may be advantageous to maximize the representation of different functional groups and conformations in a screen, since in most cases the nature of the small-molecule-target interaction can not be foreseen. [2b,c] Whereas complex molecules with many distinct appendages can be synthesized efficiently by using complexity-generating reactions [3] and appending processes, there have been limited examples of synthetic pathways that yield products with a high degree of skeletal diversity. [5] Herein we report a three-step diversityoriented synthetic pathway (Figure ) based on reactive dihydroisoquinoline and dihydropyridine intermediates, which undergo a variety of transformations to generate skeletally diverse alkaloid-like compounds.
We anticipated that the enamine moiety contained in dihydropyridines and dihydroisoquinolines could be targeted selectively to undergo a variety of transformations known to