Synthesis of Functionalized Medium-Sized trans-Cycloalkenes by 4π Electrocyclic Ring Opening/Alkylation Sequence

Significance 

Cycloalkenes are generally alkene hydrocarbons containing closed rings of carbon atoms with no aromatic characters. In particular, medium-sized trans-cycloalkenes have attracted significant research attention owing to their unique structural view and potential synthetic utilities. The properties of trans-cycloalkenes can be generally determined based on the number of rings forming its members. For example, those with rings smaller than seven-membered rings with highly distorted trans double bonds are not isolable under ambient conditions while on the other hand, those with eight or nine-membered rings are isolable even with distorted trans bonds. This is attributed to the fact that the distorted double bonds of trans-cycloalkenes exhibit much higher reactivity as compared to the typical double bond and thus have a significant influence on their transformations.

Despite their wide range of potential applications, efficient preparation methods for medium-sized trans-cycloalkenes have not been fully explored due to the difficulty in the formation of the distorted trans-double bonds based on enthalpy and entropy approaches. In a recently published literature, a method for preparing medium-sized ring fused indolines from cis-fused cyclobutenes based on thermal 4π electrocyclic reaction where the key features could be effectively controlled was reported. Inspired by these results, researchers have identified this approach as a promising method for the synthesis of medium-sized cycloalkenes.

Recently, Kyoto University researchers: Tomohiro Ito and Masaki Tsutsumi, Professor Ken-ichi Yamada, Dr. Hiroshi Takikawa, Dr. Yousuke Yamaoka and Professor Kiyosei Takasu developed a novel synthetic method for medium-sized trans-cycloalkenes based on domino 4π electrocyclic ring-opening/ desilylative alkylation sequence. The process fundamentally entailed four simple steps: enol silyl ether formation, [2+2] cycloaddition, and conjugate addition. To illustrate the feasibility of this novel approach, its application in the chirality-transfer reaction was investigated by utilizing the planar chirality of the trans-cycloalkenes. Their research work is currently published in the journal, Angewandte Chemie International Edition.

Based on the results, the research team reported that 4π electrocyclic ring-opening proceeded in a stereospecific manner enabling the construction of the trans double bonds. A relatively low hygroscopic reagent was utilized without purification. The reaction produces a relatively high yield with low reproducibility without treatment. However, high reproducibility was obtained when azeotropic treatment was applied. It was worth noting that some 4π electrocyclic reactions required high activation energy due to transannular steric repulsion of the methyl group during inward rotation. The synthesis of optically active trans-cycloalkenes by chirality transfer strategy was successfully achieved thanks to the atropoisomeric planar chirality of the medium-sized trans-cycloalkenes owing to their rigid ring structure. Further transformations of the functionalized trans-cycloalkenes were demonstrated at ambient conditions.

In summary, Kyoto University scientists developed a novel entry to medium-sized trans-cycloalkenes based on several functional groups. The synthetic utilities of functionalized trans-cycloalkenes were demonstrated. Based on the research findings, Professor Kiyosei Takasu, the corresponding author in a statement to Advances in Engineering, highlighted that their study provided useful insights that will pave way for more advance research and development in cycloalkenes.

Synthesis of Functionalized Medium-Sized trans-Cycloalkenes by 4π Electrocyclic Ring Opening/Alkylation Sequence - Advances in Engineering

About the author

Kiyosei Takasu was born in 1970 in Kyoto, Japan. He received his Bachelor and PhD degrees in 1993 and 1998, respectively, from Kyoto University under the direction of Professor Kaoru Fuji. During his PhD course, he spent one year in Professor Duy H. Hua’s group at Kansas State University as a visiting researcher (1996-1997). In 1998, he started his academic career as an assistant Professor in the group of Professor Masataka Ihara at Tohoku University, and then was promoted to Lecturer in 2005. After working with Professor Hidetoshi Tokuyama from 2006 to 2007 at the same university, he returned to the Graduate School of Pharmaceutical Sciences, Kyoto University as an associate Professor (Prof. Yoshiji Takemoto’s group) in 2007. He was appointed as the Full Professor at the same university in 2011. His research focuses on finding new synthetic methodologies to build strained and/or complex molecules from simple materials. He is also interested in natural product synthesis, bioorganic chemistry, molecular chirality and material chemistry.

Reference

Ito, T., Tsutsumi, M., Yamada, K., Takikawa, H., Yamaoka, Y., & Takasu, K. (2019). Synthesis of Functionalized Medium-Sized trans-Cycloalkenes by 4π Electrocyclic Ring Opening/Alkylation Sequence. Angewandte Chemie International Edition, 58(34), 11836-11840.

Go To Angewandte Chemie International Edition

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