In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin.

New scaffolds for drug discovery, 6‐azaspiro[4.3]alkanes, have been synthesized in two steps from four‐membered‐ring ketones: cyclobutanone, thienone, N‐Boc‐azetidinone (Boc = tert‐butoxycarbonyl), etc. The key transformation was the reaction between electron‐deficient exocyclic alkenes and an in‐situ generated N‐benzylazomethine ylide.

What is the most significant result of this study?The developed procedure allows for the rapid milligram synthesis of novel 3D-shaped building blocks for drug discovery-spirocyclic pyrrolidines-in only two steps from the common cyclic ketones: cyclobutanone, N-Boc-4-piperidone, tetrahydro-4-pyranone, etc. The developed method is highly practical-the syntheses were performed in up to 100 gs cale with no expensive catalysts. Therefore, we do expect that medicinal chemists at pharmaceutical companies will prepare and use these building blocks, which will then become very popular in drug discovery. What prompted you to investigate this topic?The phrase "Escape the Flatland"w as recently introduced, and has already changed drug discovery.N ow,m edicinal chemists look more and more into the novel 3D-shaped alicyclic building blocks. In fact, over the past years we at Enamine Ltd,aworld-leading supplier of building blocks, has received many requests from the famous pharmaceutical companies on the synthesis of novel spirocyclic pyrrolidines. The known synthetic approaches to this class of compounds, however,i ncluded multistep procedures from rather exotic starting materials, thereby making the gram-scale preparation problematic. Therefore, we decided to develop at ruly practical method to novel spirocyclic pyrrolidines from available chemicals in two steps, so that everyone could easily synthesize themand we have achieved our dream! What was the inspiration for the cover design?The front page picture shows aconstellation on anovel fluorinated spirocyclic pyrrolidine. Every star symbolizes the corresponding atom within the molecule. We used this cover design because we were very much impressed by the high practical potential of the developed procedure:f rom every cyclic ketone, av ariety of spirocyclic pyrrolidines can be obtained. It seems that the diversity of spirocyclic compounds that can be prepared using our method is even larger than the number of stars in the sky! Invited for the cover of this issue is the group of Pavel K. Mykhailiuk at the Taras Shevchenko National University of Kyiv and Enamine Ltd. The image depicts spirocyclic pyrrolidine-a novel building block for drug discovery.R ead the full text of the article at