Enantioselective Synthesis of Spirocyclic Pyrrolidine Derivatives

Keywords

organocatalysis - azetidines - oxetanes - bioisosteres - nitroolefins - conjugate addition - spirocycles

Significance

Both oxetanes and azetidines are attractive motifs within drug discovery owing to their ability to improve the solubility, metabolic stability and/or bioavailability of a compound. In addition, building these small heterocycles into a spirocyclic system provides the opportunity to not only increase the 3 D character of a specific molecule but also to provide a rigid framework to orient functional vectors to optimize their interactions with the biological target of interest. The current report describes the enantioselective, organocatalytic conjugate addition of a series of aldehydes to oxetane- and azetidine-containing nitro-olefins, with the subsequent products being elaborated further to provide several spirocyclic pyrrolidine derivatives.

Comment

Initial optimization experiments evaluated the use of a tripeptide catalyst for the reaction, however, limited solubility proved to be an issue, which led to further catalyst screening that showed the Hayashi–Jørgensen catalyst to be superior. Given the potential for aldehyde epimerization, the products were directly reduced to the corresponding alcohols. For the synthesis of the spirocyclic pyrrolidine derivatives, the γ-nitroaldehydes were subjected to zinc-mediated reductive cyclization followed by Cbz protection. In order to avoid racemization of the intermediate aldehyde, a three-step one-pot sequence was developed enabling it to be used crude.