Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Abstract

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

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[232] Recent years have witnessedt he publication of numerouss ynthetic works on novel advanced buildingb locks for drug discovery,f ocusingm ainly on unusual bicyclic, spirocyclic, heteroaliphatic,o rh eteroaromatic compounds, especially those with fluorine atoms; selected examples are given in Figure 44. [233][234][235][236][237][238][239][240]…”

“…Among the bifunctional reagents, (monoprotected) amino acids and diamines are most popular . Recent years have witnessed the publication of numerous synthetic works on novel advanced building blocks for drug discovery, focusing mainly on unusual bicyclic, spirocyclic, heteroaliphatic, or heteroaromatic compounds, especially those with fluorine atoms; selected examples are given in Figure …”

Fluorene-Based Multicomponent Reactions

“…In recent years, there has been great interest in increasing the number of 3D-shaped alicyclic building blocks in drug discovery ('escape from Flatland'), and spiro compounds are of high importance. 63,64 For this reason, we were interested in combining the -acidity of isocyanide 1 with its isocyano functionality; we therefore subjected it to reaction with an aldehyde in a similar fashion to the van Leusen oxazole synthesis using tosylmethyl isocyanide (TosMIC). 65 To our delight, the reaction proceeded under mild conditions to give the required spirooxazolidines 12a-c in good to excellent yields after treatment with K 2 CO 3 at room temperature (Scheme 4).…”

Evaluation of antibiofilm properties of dehydroacetic acid (DHA) grafted spiro-oxindolopyrrolidines synthesized via multicomponent 1,3-dipolar cycloaddition reaction

“…Moreover, spirocyclic pyrrolidines are also key intermediates in the synthesis of many therapeutic drugs. For instance, spirocyclic pyrrolidine is an intermediate of the antibacterial drug sitafloxacin 39 .…”