New Breakthrough in the "Transformation" Technology of Pentane Skeleton Drugs: One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes
Preamble
Many drug molecules contain a benzene ring structure, but benzene rings can also cause some metabolic problems. In order to minimize this "side effect", scientists have explored a number of alternative structures to the benzene ring. Recently, a team of researchers at Emory University in the USA reported a new method to modify benzene-containing drug molecules into compounds containing a difluorobicyclo[1.1.1]pentane structure. The 2,2-difluorooxocyclo[1.1.1]pentane was rapidly prepared by generating 3-arylbicyclo[1.1.0]butane via a cyclopropanation reaction and reacting it with a difluorocarbonyl group in the same reaction flask. This method utilizes the modular synthetic properties of diazo compounds to obtain 2,2-difluorobicyclo[1.1.1]pentanes. This is unobtainable by previously reported methods and provides a new route for the synthesis of molecules with different ring systems and functions.
Scheme 1. Modular diazo starting materials provide rapid access to a range of different molecules
Modular synthesis strategies allow efficient synthesis of diverse compound libraries for drug discovery, materials science and other fields of research. By adjusting the structure of the diazo starting materials, the nature and structure of the synthesized products can be controlled, providing more options and customized synthesis methods, making the synthesis more flexible and controllable.
Scheme 2. One-pot synthesis of multiple carbon-based compounds
Researchers have successfully synthesized 2-arylbicyclo[1.1.0]butanes using intramolecular cyclopropanation reaction with α-allyl diazoacetate. Based on this study, the one-pot method for the synthesis of highly functionalized cyclobutanes was further explored, and the possibility of extending the intramolecular cyclopropanation reaction to that with difluorocarbonyls was suggested. By this method a variety of difluorobicyclo[1.1.1]pentanes were synthesized in one pot, thus avoiding the need to isolate intermediates. This study allows for the efficient synthesis of a wide range of carbonyl compounds and offers potential applications and directions for further research.
Scheme 3: Formation of methylenedifluorocyclobutenes 26 and 27
By modulating the reaction conditions, the researchers could control the stereochemical structure of the product and obtain a single conformation of the product. This laid the foundation for the next step of pharmacodynamic evaluation and drug development. More surprisingly, when the starting material was changed to 2-aryl-substituted bicyclo[1.1.0]butanes, the reaction generated another class of specific products, methylenedifluorocyclobutenes.
Scheme 4. Study of the reaction mechanism of difluorocarbons with bicyclo[1.1.0]butanes
The research team explored the insertion of difluorocarbons into 2-arylbicyclo[1.1.0]butanes, determining the structure of the unusual products generated and proposing a mechanism for their formation, although these compounds proved to be unstable.
Scheme 5. Ring expansion synthesis
Despite the modular design of the diazonium precursor, both products were obtained in very high yields, highlighting the stability of this chemistry.
Summarization
The one-pot synthesis of difluorobicyclo[1.1.1]pentanes via α-allyl azidoacetate is innovative in terms of the synthetic strategy, one-pot reaction, yield and applicability, and exhibits a wide range of substrate applicability and structural diversity of the products, which provides a brand new idea for the optimization of drugs. The researchers indicated that they will continue to expand this synthesis strategy and develop more new "drug transformation" technologies to support the development of innovative drugs. It is believed that this research method will lead to more amazing applications in the future.
Reference
Jack C. Sharland, Huw M. L. Davies. One-Pot synthesis of Difluorobicycl o[1.1.1] pentanes from α‑Allyldiazoacetates. Organic Letters 2023 25 (28), 5214-5219.
https://doi.org/10.1021/acs.orglett.3c01664
Aladdin：https://www.aladdinsci.com/