Stereoretentive Nucleophilic Substitution at the Tetrasubstituted Carbon of Galiellalactone
(2020) In Journal of Organic Chemistry 85(12). p.7704-7710- Abstract
The fungal metabolite galiellalactone (1) was, as its acetate 4, discovered to undergo a substitution reaction with cysteine derivatives. By studying the reaction mechanism and the intermediates formed, and in an effort to expand the chemical diversity of the galiellalactonoids, a mild and general method of preparing ether, thioether, and amine analogues of galiellalactone was developed. The reaction is a formal stereoretentive nucleophilic substitution at an oxygenated tertiary carbon. NMR analysis of the progressing reaction shows that it involves an initial allylic substitution to form a new Michael acceptor, followed by the addition of a second equivalent of the nucleophile to this and, finally, a retro Michael reaction. This... (More)
The fungal metabolite galiellalactone (1) was, as its acetate 4, discovered to undergo a substitution reaction with cysteine derivatives. By studying the reaction mechanism and the intermediates formed, and in an effort to expand the chemical diversity of the galiellalactonoids, a mild and general method of preparing ether, thioether, and amine analogues of galiellalactone was developed. The reaction is a formal stereoretentive nucleophilic substitution at an oxygenated tertiary carbon. NMR analysis of the progressing reaction shows that it involves an initial allylic substitution to form a new Michael acceptor, followed by the addition of a second equivalent of the nucleophile to this and, finally, a retro Michael reaction. This restores the original galiellalactone system with a double bond between C-2a and C-3, but with a new substituent at C-7b. As galiellalactone is a promising STAT3 inhibitor, this novel transformation facilitates the semisynthesis of a wide variety of new analogues for structure-activity relationship studies.
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- author
- Escobar, Zilma LU ; Nilsson, Jakob LU ; Gidlöf, Ritha LU ; Johansson, Martin and Sterner, Olov LU
- organization
- publishing date
- 2020
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Organic Chemistry
- volume
- 85
- issue
- 12
- pages
- 7 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85087819621
- pmid:32420737
- ISSN
- 0022-3263
- DOI
- 10.1021/acs.joc.0c00152
- language
- English
- LU publication?
- yes
- id
- 87d4dbb1-42f7-4311-8ec7-c03fedc62a67
- date added to LUP
- 2020-07-22 11:22:18
- date last changed
- 2024-06-12 18:12:45
@article{87d4dbb1-42f7-4311-8ec7-c03fedc62a67,
abstract = {{<p>The fungal metabolite galiellalactone (1) was, as its acetate 4, discovered to undergo a substitution reaction with cysteine derivatives. By studying the reaction mechanism and the intermediates formed, and in an effort to expand the chemical diversity of the galiellalactonoids, a mild and general method of preparing ether, thioether, and amine analogues of galiellalactone was developed. The reaction is a formal stereoretentive nucleophilic substitution at an oxygenated tertiary carbon. NMR analysis of the progressing reaction shows that it involves an initial allylic substitution to form a new Michael acceptor, followed by the addition of a second equivalent of the nucleophile to this and, finally, a retro Michael reaction. This restores the original galiellalactone system with a double bond between C-2a and C-3, but with a new substituent at C-7b. As galiellalactone is a promising STAT3 inhibitor, this novel transformation facilitates the semisynthesis of a wide variety of new analogues for structure-activity relationship studies. </p>}},
author = {{Escobar, Zilma and Nilsson, Jakob and Gidlöf, Ritha and Johansson, Martin and Sterner, Olov}},
issn = {{0022-3263}},
language = {{eng}},
number = {{12}},
pages = {{7704--7710}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of Organic Chemistry}},
title = {{Stereoretentive Nucleophilic Substitution at the Tetrasubstituted Carbon of Galiellalactone}},
url = {{http://dx.doi.org/10.1021/acs.joc.0c00152}},
doi = {{10.1021/acs.joc.0c00152}},
volume = {{85}},
year = {{2020}},
}