Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters
In pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures...
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MDPI AG
2024-03-01
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| Series: | Crystals |
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| Online Access: | https://www.mdpi.com/2073-4352/14/3/256 |
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| author | Michael J. Campbell Daniel A. Decato Chun Li Matthew J. Weaver Nicholas R. Natale |
| author_facet | Michael J. Campbell Daniel A. Decato Chun Li Matthew J. Weaver Nicholas R. Natale |
| author_sort | Michael J. Campbell |
| collection | DOAJ |
| description | In pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures which we report herein. The C-9 nitrile oxide, after its reaction with bromine, was isolated, but when subjected to re-aromatization, it returned to the starting 10-bromo nitrile oxide <b>1</b>, which did provide an accurate crystal structure, with R = 0.018. The 10-halogenated 3-(9’-anthryl)-isoxazole esters were subjected to bromination and re-aromatization. Surprisingly, the yields obtained in the presence of the isoxazole were reasonably good (62–68% isolated yields), and the major diastereomers allowed for the characterization using Sc-xrd. The penta bromo product <b>2</b> showed a <i>trans</i>, <i>trans</i>, <i>cis</i> relationship for the four bromines on the A-ring of the anthracene, and we observed that for the unit cell, the atropisomers displayed a 1:1 ratio at the chiral axis between the isoxazole and anthrancene rings. Similarly, the 10-chloro <b>3</b> indicated a ratio of 1:1 at the chiral axis in the crystal structure. A base-induced re-aromatization afforded 3,10-dihalogenated analogues selectively in very good yields (X = Cl, 89%; X = Br 92%), of which the dibromo <b>4</b> was characterized using Sc-xrd. The improved yields of the unique diastereomeric bromination products suggested the consideration of a novel electrophilic aromatic substitution mechanism driven by the stereo-electronic environment, imposed by the isoxazole ester substituent. The promise of the application of this chemistry in the future development of AIM antitumor agents is suggested. |
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| language | English |
| last_indexed | 2024-04-24T18:24:21Z |
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| record_format | Article |
| series | Crystals |
| spelling | doaj.art-37917addf0fb4761a08ea47b67e1735b2024-03-27T13:32:30ZengMDPI AGCrystals2073-43522024-03-0114325610.3390/cryst14030256Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole EstersMichael J. Campbell0Daniel A. Decato1Chun Li2Matthew J. Weaver3Nicholas R. Natale4Medicinal Chemistry Graduate Program, University of Montana, Missoula, MT 59812, USAMedicinal Chemistry Graduate Program, University of Montana, Missoula, MT 59812, USADepartment of Chemistry, Ithaca College, 953 Danby Road, Ithaca, NY 14850, USAMedicinal Chemistry Graduate Program, University of Montana, Missoula, MT 59812, USAMedicinal Chemistry Graduate Program, University of Montana, Missoula, MT 59812, USAIn pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures which we report herein. The C-9 nitrile oxide, after its reaction with bromine, was isolated, but when subjected to re-aromatization, it returned to the starting 10-bromo nitrile oxide <b>1</b>, which did provide an accurate crystal structure, with R = 0.018. The 10-halogenated 3-(9’-anthryl)-isoxazole esters were subjected to bromination and re-aromatization. Surprisingly, the yields obtained in the presence of the isoxazole were reasonably good (62–68% isolated yields), and the major diastereomers allowed for the characterization using Sc-xrd. The penta bromo product <b>2</b> showed a <i>trans</i>, <i>trans</i>, <i>cis</i> relationship for the four bromines on the A-ring of the anthracene, and we observed that for the unit cell, the atropisomers displayed a 1:1 ratio at the chiral axis between the isoxazole and anthrancene rings. Similarly, the 10-chloro <b>3</b> indicated a ratio of 1:1 at the chiral axis in the crystal structure. A base-induced re-aromatization afforded 3,10-dihalogenated analogues selectively in very good yields (X = Cl, 89%; X = Br 92%), of which the dibromo <b>4</b> was characterized using Sc-xrd. The improved yields of the unique diastereomeric bromination products suggested the consideration of a novel electrophilic aromatic substitution mechanism driven by the stereo-electronic environment, imposed by the isoxazole ester substituent. The promise of the application of this chemistry in the future development of AIM antitumor agents is suggested.https://www.mdpi.com/2073-4352/14/3/256anthraceneatropisomerismaxial chiralitybrominationisoxazole |
| spellingShingle | Michael J. Campbell Daniel A. Decato Chun Li Matthew J. Weaver Nicholas R. Natale Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters Crystals anthracene atropisomerism axial chirality bromination isoxazole |
| title | Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters |
| title_full | Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters |
| title_fullStr | Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters |
| title_full_unstemmed | Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters |
| title_short | Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters |
| title_sort | synthesis and structure of unsymmetrical anthracenyl isoxazole antitumor agents via the diastereoselective bromination of 3 9 anthryl isoxazole esters |
| topic | anthracene atropisomerism axial chirality bromination isoxazole |
| url | https://www.mdpi.com/2073-4352/14/3/256 |
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