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Chemical Research in Chinese Universities ›› 2024, Vol. 40 ›› Issue (6): 1096-1105.doi: 10.1007/s40242-024-4011-y

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A Concise, Practical Chiral Resolution Approach of Racemic (E)-4,4-Dimethyl-1-(4-nitrophenyl) pent-1-en-3-ol to Its both Enantiomers via Strategy of Diastereomeric Ester Formation and Crystallization Using both N-Boc-D- and N-Boc-L-phenylglycines as Chiral Auxiliaries

JIANG Shanshan1,2, YUAN Jia1,2, QIN Yanlan2, LUO Ying2,4, JIN Zhengsheng2, ZHAO Guilong2,3, TI Huihui1   

  1. 1. School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China;
    2. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, P. R. China;
    3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China;
    4. School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
  • Received:2024-01-13 Online:2024-12-01 Published:2024-10-26
  • Contact: TI Huihui,tihuihui@gdpu.edu.cn;ZHAO Guilong,zhao_guilong@126.com E-mail:tihuihui@gdpu.edu.cn;zhao_guilong@126.com
  • Supported by:
    This work was supported by the Guangdong Basic and Applied Basic Research Foundation, China (Nos. 2021A1515010197, 2023A1515012259), the Zhongshan Municipal Natural Science Foundation, China (Nos. 200805173640573, 210730214049987, 221018194369472), the Project of the Creative Research Group of Zhongshan City, China (No. CXTD2022011) and Dazhou Applied Basic Research Foundation, China (No. 23YYJC0002).

Abstract: Chiral secondary alcohols are an important class of functionalities commonly seen in drugs and other bioactive compounds. In an ongoing drug discovery program in our laboratories, a nitro-bearing racemic allylic secondary alcohol (±)-1 was discovered as a promising drug candidate, and in the following preclinical studies, a concise, reliable, practical synthetic approach to its both enantiomers with high optical purities was greatly needed. In the present study, we developed a chiral resolution approach of (±)-1 to its both enantiomers, i. e., (+)-1 and (-)-1, via the strategy of diastereomeric ester formation and crystallization using both N-Boc-D- and N-Boc-L-phenylglycines as chiral auxiliaries. The absolute configurations of all the four key intermediates were unambiguously determined by single-crystal X-ray diffraction, providing a solid foundation for the stereochemistry of the present study. The two enantiomers were obtained in high optical purities. This approach is characterized by scalability and practicality and is envisaged to enable the chiral resolution of other racemic secondary alcohols, especially those with labile groups, such as NO2 and olefinic C=C bond.

Key words: Chiral resolution, Phenylglycine, Chiral auxiliary, Chiral secondary alcohol, Diastereomeric ester formation