Feb 06, 2019

Short-step synthesis of chiral compound using carbon-hydrogen bond double conversion

Keyword:RESEARCH

OBJECTIVE.

Associate Professor Keiji Mori of the Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology; Professor Takahiko Akiyama of the Department of Chemistry, Faculty of Science, Gakushuin University; and Professor Masahiro Yamanaka of the Department of Chemistry and Research Center for Smart Molecules, Rikkyo University developed a method for short-step synthesis of a polycyclic compound through sequential stereoselective conversion of carbon-hydrogen bonds, which are incredibly difficult to chemically react. These results could open the door to compounds with structures that previously could not be synthesized to provide an efficient supply of candidate compounds for new pharmaceuticals.

The results of this study were published in the May 9 online edition of the Journal of the American Chemical Society.
Article title: Chiral Magnesium Bisphosphate Catalyzed Asymmetric Double C(sp3)–H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process
URL:https://pubs.acs.org/doi/10.1021/jacs.8b02761

Present circumstances

With environmental issues posing a major problem for society, there is a great need to develop methods of synthesizing chemicals that produce fewer waste products. The direct conversion of carbon-hydrogen bonds has received attention as a means of meeting this social need. Because there is no need for a preliminary stage to exchange the hydrogen portion for a highly reactive functional group, there are fewer processes involved in the synthesis of desired compounds, which greatly reduces the amount of waste.

A variety of direct conversion methods have already been developed, but these have either required expensive and toxic transition metal catalysts or an oxidizing agent that then becomes a waste product. There have been only a few successful examples of sequential double carbon-hydrogen bond activation that were able to synthesize complex compounds such as drug candidate compounds in a short-step synthesis.

Study organization

This study was conducted by Associate Professor Keiji Mori of the Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology; Ryo Isogai M.S. and Professor Takahiko Akiyama of the Department of Chemistry, Faculty of Science, Gakushuin University; and Yuto Kamei M.S. and Professor Masahiro Yamanaka of the Department of Chemistry and Research Center for Smart Molecules, Rikkyo University. It was funded through scientific research grants for basic research (B)26288053, 17KT0011, and 17H03060, and the Inoue Foundation for Science.

Results

In this study, a method of sequentially converting carbon-hydrogen bonds that did not require transition metal catalysts or external oxidizing agents was used with the objective of developing methods of asymmetric synthesis for polycyclic compounds (selectively synthesizing only the desired stereostructure out of 2 compounds that are mirror images). To develop a new reaction, it was important to obtain a high level of reactivity and selectivity that could only produce the desired product. After investigating a variety of methods, it was discovered that sequential functionalization of carbon-hydrogen bonds adjacent to nitrogen atoms could be produced by using a wide variety of substrates involving two N-alkyl groups. This achieved the highly stereoselective synthesis of tricyclic nitrogen compounds that are difficult to synthesize with conventional methods. In addition, this reaction does not involve any toxic metallic elements and uses an environmentally friendly chiral acid as the catalyst.

Future prospects

Although the compound in the present study used a compound containing nitrogen atoms, these results could also be applied to synthesizing compounds with oxygen atoms or compounds containing only carbon atoms. This method could help provide an efficient supply of a variety of novel drug candidate compounds.

1) Chiral: Cannot be superpositioned on its mirror image.
2) Asymmetric synthesis: To selectively synthesize 1 side of an enantiomer.

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