New Building Blocks For Drug Discovery Are Getting Closer: Gem-difluorocyclopropane-derived Amines

Modern drug discovery relies heavily on the ability of chemists to produce good starting points for producing high-quality lead compounds. Several concepts were established in the last two decades to aim synthetic organic chemistry onto the proper areas of chemical space, in particular, the so-called lead-oriented approach which describes paradigm shift towards low-molecular-weight, relatively hydrophilic, conformationally restricted, sp3-enriched structures.

On the other hand, introducing fluorine into organic molecules is another well-recognized approach to improving the compound success rate in drug discovery and development; in fact, over 20% of marketed drugs contain fluorine. Gem-difluorocyclopropane moiety is an example of a structural framework which combines the above-mentioned ideas, and this fragment has already proven its utility for medicinal chemistry.



A general approach to the synthesis of gem-difluorocyclopropanes relies on the reaction of alkenes with difluorocarbene source. Although this chemical reaction is known for more than 50 years, it represented merely academic interest until recently, and gem-difluorocyclopropane building blocks were rarely utilized in drug discovery programs due to their limited synthetic and commercial availability. In particular, the most important class of building blocks which are used in many MedChem reactions – amines – was virtually unknown for gem-difluorocyclopropane series in the literature to date.

The group of Ukrainian scientists developed an approach to the synthesis of these compounds which relies on the use of the known difluorocarbene source for the alkene difluorocyclopropanation– a combination of readily available, non-toxic Ruppert–Prakash reagent (CF3SiMe3) and sodium iodide (NaI), discovered by Prakash, Olah, and co-workers. Pavel Nosik, Oleksandr Grygorenko, Dmitriy Volochnyuk, Sergey Ryabukhin and their colleagues found that the amino group is not compatible with the difluorocyclopropanation cyclopropanation; however, its protection as a tert-butoxycarbonyl (Boc) changes the situation.

Thus original protocol by Prakash, Olah, and co-workers is applicable to Boc-protected secondary amines bearing 1,1-disubstituted, tri- or tetrasubstituted double bonds, and the corresponding products including spirocyclic compounds were obtained on a gram scale in good to excellent yields. With mono- and 1,2-disubstituted double bonds, however, the method did not work as planned. A more detailed study showed that relatively fast decomposition of the Ruppert–Prakash reagent occurs in the reaction system, so it does not have enough time to react with less reactive substrates.


An elegant still simple solution to the problem is slow introducing of the reagent into the reaction mixture; this modification of the original method allowed for the effective difluorocyclopropanation of even above-mentioned low-reactive Boc derivatives. The extended procedure allowed for the preparation of monocyclic and fused gem-difluorocyclopropanes, as well as compounds with isolated rings.

Although the method works well, the results obtained by the Ukrainian team have raised many questions which need further addressing. First of all, the relative reactivity of the substrates is not completely understood. The authors postulate non-synchronous transition state for the difluorocyclopropanation step, which explains the data obtained, but this mechanistic hypothesis requires further clarification, possibly using quantum mechanics calculations. Applicability of the procedure to other functionalized substrates is also not clear and would be interesting. Finally, further scale-up of the method should be checked for possible industrial applications.

This study, Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety, was recently published in Advanced Synthesis & Catalysis.



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