A simple method for synthesis of chiral α-amido aldehydes

Significance 

Aldehydes are interesting compounds in synthetic chemistry research because they can be converted to important functional groups. Specifically, chiral aldehydes have been utilized as key intermediates in several pharmaceuticals and the synthesis of many natural products. Therefore, several methodologies have been developed for the enantioselective synthesis of such compounds. However, most of these methods such as asymmetric hydrogenation has been mainly used in the hydrogenation of unsaturated carboxylic acids, esters, ketones and amides with limited success or evidence of unsaturated aldehydes which can be attributed to the difficulty in obtaining both high chemo- and enantioselectivity in a molecule containing both formyl and vinyl groups. Consequently, these methods do not satisfy the industrial requirements regarding cost, efficiency and environmental concerns. Therefore, alternative approaches are highly desirable.

Recently, a joint effort by Jian Zhang, Xincheng Zeng, Yuanhao Wang, Jia Jia, Dr. Zhenfeng Zhang, and led by distinguished Professor Wanbin Zhang from Shanghai Jiao Tong University in collaboration with Professor Ilya Gridnev at Tohuku University developed high chemo- and enantioselective hydrogenation of α-formyl enamides for the synthesis of chiral α-amino aldehydes. Inspired by their previous findings where they successfully used conjugated substates-based amido directing groups and electron-rich bisphosphine catalytic system to realize chemo- and enantioselectivity, the same strategy was hereby utilized to report the first chemo-selective asymmetric hydrogenation of α-amido-substituted α,β-unsaturated aldehydes. The research work is currently published in the journal, Angewandte Chemie.

Their results showed that high yields of the desired products: chiral α-amido aldehydes and ß-amido alcohols were obtained with excellent chemo- and enantioselectivities under different hydrogen pressures. β-Amido alcohols required relatively higher hydrogen pressure to be synthesized as compared to α-amido aldehydes. Besides, extremely high catalytic activities up to 20000 S/C were reported.

It was worth noting the possibility of conducting the reaction on a gram scale and applying it for further synthesis of numerous other useful chiral products. These products represent important structural units and intermediates with vast potential applications in areas of pharmaceuticals, synthesis of bioactive compounds and natural products. Additionally, the catalytic cycles were analyzed based on the density functional theory computations to reveal more useful insights on the R/S pathways. This enabled the authors to reasonably explain the enantioselectivity mechanism by revealing more specific features. Furthermore, the structure of the substrate and the reaction conditions were observed to influence the catalytic cycle in one way or the other. This justified the reason behind the slight discrepancies in the selectivity observed with some experiment examples.

In summary, the research team is the first to develop and report an efficient route for the synthesis of chiral α-amido aldehydes based on chemo- and enantioselective hydrogenation of α-formyl enamides. As such, the study has been selected by Advances in Engineering as a key scientific article and great contributor to the knowledge of synthesis of chiral aldehydes. Indeed Professor Wanbin Zhang, the lead author highlighted that their synthesis method is versatile and can be extended to synthesis other types of chiral compounds which will expand their application in various fields.

About the author

School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
[email protected]: +86-21-54743265
E-mail: [email protected]

Professor Wanbin Zhang received his BS and MS degrees from East China University of Science and Technology (ECUST) in 1985 and 1988 respectively. From 1993 to 1997, he undertook PhD studies at Osaka University under the supervision of Professor Isao Ikeda. He then worked as an assistant professor at Osaka University until 2001 and then as a research fellow at the Specialty Chemicals Research Centre of the Mitsubishi Chemical Corporation. Since 2003, he has worked as a professor in the School of Chemistry and Chemical Engineering at Shanghai Jiao Tong University (SJTU).

In 2013 he was promoted to the position of distinguished professor. Professor Zhang’s current research interests include organometallic chemistry, asymmetric catalysis, and pharmaceutical process chemistry.

Reference

Zhang, J., Jia, J., Zeng, X., Wang, Y., Zhang, Z., Gridnev, I., & Zhang, W. (2019). Chemo- and Enantioselective Hydrogenation of α-Formyl Enamides: An Efficient Access to Chiral α-Amido Aldehydes. Angewandte Chemie.

Go To Angewandte Chemie

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