Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs
Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects....
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/87107 http://hdl.handle.net/10220/49866 |
| _version_ | 1826129092091576320 |
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| author | Liu, Yingguo Chen, Qiao Mou, Chengli Pan, Lutai Duan, Xiaoyong Chen, Xingkuan Chen, Hongzhong Zhao, Yanli Lu, Yunpeng Jin, Zhichao Chi, Robin Yonggui |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Liu, Yingguo Chen, Qiao Mou, Chengli Pan, Lutai Duan, Xiaoyong Chen, Xingkuan Chen, Hongzhong Zhao, Yanli Lu, Yunpeng Jin, Zhichao Chi, Robin Yonggui |
| author_sort | Liu, Yingguo |
| collection | NTU |
| description | Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules. |
| first_indexed | 2024-10-01T07:35:04Z |
| format | Journal Article |
| id | ntu-10356/87107 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:35:04Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/871072023-02-28T19:30:30Z Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs Liu, Yingguo Chen, Qiao Mou, Chengli Pan, Lutai Duan, Xiaoyong Chen, Xingkuan Chen, Hongzhong Zhao, Yanli Lu, Yunpeng Jin, Zhichao Chi, Robin Yonggui School of Physical and Mathematical Sciences Asymmetric Catalysis Drug Discovery and Development Science::Chemistry Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) Published version 2019-09-04T06:40:24Z 2019-12-06T16:35:20Z 2019-09-04T06:40:24Z 2019-12-06T16:35:20Z 2019 Journal Article Liu, Y., Chen, Q., Mou, C., Pan, L., Duan, X., Chen, X., . . . Chi, R. Y. (2019). Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs. Nature Communications, 10(1), 1675-. doi:10.1038/s41467-019-09445-x https://hdl.handle.net/10356/87107 http://hdl.handle.net/10220/49866 10.1038/s41467-019-09445-x en Nature Communications © 2019 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 8 p. application/pdf |
| spellingShingle | Asymmetric Catalysis Drug Discovery and Development Science::Chemistry Liu, Yingguo Chen, Qiao Mou, Chengli Pan, Lutai Duan, Xiaoyong Chen, Xingkuan Chen, Hongzhong Zhao, Yanli Lu, Yunpeng Jin, Zhichao Chi, Robin Yonggui Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title | Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title_full | Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title_fullStr | Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title_full_unstemmed | Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title_short | Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| title_sort | catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs |
| topic | Asymmetric Catalysis Drug Discovery and Development Science::Chemistry |
| url | https://hdl.handle.net/10356/87107 http://hdl.handle.net/10220/49866 |
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