Synthesis of medium-sized ring structured compounds

19 Dec 2018. NUS chemists have discovered new reaction pathways to synthesise medium-sized heterocyclic compounds for the development of therapeutic drug molecules.

Compounds containing medium-sized (8 to 12 membered) rings are not commonly used in the development of pharmaceutical drug compounds despite their significance in many bioactive natural products. This is associated with the lack of efficient methods to create these compounds using synthetic chemical means. Cycloaddition (combining two or more molecules to form cyclic organic compounds) is a chemical technique which is usually used for constructing compounds with ring structures from readily available building blocks. There are well-established methods for the synthesis of five-, six- and more recently seven-membered ring compounds using this technique. However, the synthesis of heterocycles larger than eight-membered rings remains challenging.

A research team led by Prof ZHAO Yu, from the Department of Chemistry, NUS has developed a series of palladium-catalysed reactions which can form nine- and ten-membered heterocycles through [5 + 4] and [6 + 4] cycloadditions. In these cycloaddition reactions, one compound provides a 4-atom unit, while the other cross partners provide either a 5- or 6-atom unit to prepare the nine- or ten-membered rings. These new reaction pathways make use of commercially available starting compounds and can produce heterocycles which are of a single type of stereoisomer. Stereoisomers are chemical compounds that have the same molecular formula and atom bonding sequence but differ in the orientation of their atoms in the three-dimensional space.

Prof Zhao said, “These structures represent new compounds with potential biological activities. There are many bioactive natural products that possess specific medium-sized rings, but their synthesis has been very difficult. We can now access this type of compounds with ease.”

“We are continuing to explore the development of other medium-sized ring structured compounds and the biological screening of these classes of compounds as potential anti-cancer therapeutics,” added Prof Zhao.

Figure shows the reaction scheme of chemical compounds with nine- and ten-membered ring formation. Chiraphos and SIPHOX are two commercially available compounds.

References

Wang YN; Yang LC; Rong ZQ; Liu TL; Liu R; Zhao Y*, “Pd-catalyzed enantioselective [6+4] cycloaddition of vinyl oxetanes with azadienes to access ten-membered heterocycles” ANGEWANDTE CHEMIE INTERNATIONAL EDITION Volume 57 Pages: 1596-1600 DOI:10.1002/anie.201711648 Published:2018.

Yang LC; Rong ZQ; Wang YN; Tan ZY; Wang M; Zhao Y*, “Construction of nine-membered heterocycles through palladium-catalyzed formal [5 + 4] cycloaddition” ANGEWANDTE CHEMIE INTERNATIONAL EDITION Volume 56 DOI: 10.1002/anie.201611474 Pages: 2927-2931 Published:2017.

Rong, ZQ; Yang LC; Liu S; Yu ; Wang YN; Tan ZY; Huang RZ; Lan Y;* Zhao Y*, “Nine-membered benzofuran-fused heterocycles: Enantioselective synthesis by Pd-catalysis and rearrangement via transannular bond formation” JOURNAL OF THE AMERICAN CHEMISTRY SOCIETY Volume 139, DOI: 10.1021/jacs.7b09161 Pages: 15304-15307 Published: 2017.