CONCISE AND PRACTICAL AVENUES TO 5,5-SPIRO-α-PROLINES

Scaffold hopping and three-dimensionality are one of dominating notions in contemporary drug discovery process. Following these concepts is a verified and generally robust avenue to improve the biological activity of a lead against a protein target, selectivity issues as well as ADMET properties. Unfortunately, the freedom of medicinal chemists to replace molecular fragments responsible for the properties is restricted due to unrevealed areas of chemical space existing for even simple building blocks. This paper contributes to the support of drug discovery workflow and describes concise and practical synthetic approaches toward multigram preparation of value-added conformationally constrained 5-spirocyclic α-prolines from readily accessible starting materials. Direct carboxylation of 2-spiropyrrolidines was found to be a novel and promising approach to achieve the purpose and is the most fruitful for substrates with no acidic centers within a part spiro linked to pyrrolidine core. The method allows for quick and one-step preparation of the target chemicals in good yields. For substrates inapplicable to the straightforward method, an alternative synthetic avenue was designed. This 4-steps protocol deals with common for laboratory practice transformations and is comparable in its efficiency with the carboxylation method. The paper concludes a series of our works on the elaboration of efficient methods for the construction of spiro proline frameworks.