The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives
This article describes the synthesis of new chiral 3-(piperidin-3-yl)-1H-indole derivatives <b>(R)-10a-c</b> and <b>(S)-11a-c</b> from the corresponding diastereomers: (3R, 2R) and (3S, 2R)-2-[3-(1H-indol-3-yl)-1-piperidyl]-2-phenyl-acetamides <b>(3R, 2R)-4a, (3R, 2R)-6...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/517 |
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| author | Marek Król Grzegorz Ślifirski Jerzy Kleps Piotr Podsadni Ilona Materek Anna E. Kozioł Franciszek Herold |
| author_facet | Marek Król Grzegorz Ślifirski Jerzy Kleps Piotr Podsadni Ilona Materek Anna E. Kozioł Franciszek Herold |
| author_sort | Marek Król |
| collection | DOAJ |
| description | This article describes the synthesis of new chiral 3-(piperidin-3-yl)-1H-indole derivatives <b>(R)-10a-c</b> and <b>(S)-11a-c</b> from the corresponding diastereomers: (3R, 2R) and (3S, 2R)-2-[3-(1H-indol-3-yl)-1-piperidyl]-2-phenyl-acetamides <b>(3R, 2R)-4a, (3R, 2R)-6b, (3R, 2R)-8c</b> and <b>(3S, 2R)-5a, (3S, 2R)-7b, (3S, 2R)-9c</b>. Diastereomers were obtained by N-alkylation of derivatives of racemic 3-(piperidin-3-yl)-1H-indoles <b>1a-c</b> using (S)-2-(4-toluenesulfonyloxy)-phenylacetic amide <b>(S)–II</b>. The same method was applied to obtain (3R, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate <b>(3R, 2S)-2a</b> and (3S, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate <b>(3S, 2S)-3a</b> diastereomers by treating amine <b>1a</b> with (R)-2-(4-toluenesulfonyloxy)-phenylacetic acid methylester <b>(R)-I</b>. Systematic studies via single crystal X-ray crystallography were used to determine the molecular structure of the racemates <b>1a-c</b> and the absolute configuration of the enantiomers. The solid racemates <b>1b</b> and <b>1c</b> were “true racemates” crystallizing in a centrosymmetric space group, while <b>1a</b> formed a racemic conglomerate of homoenantiomeric crystals. The absolute configuration was determined for the enantiomeric pairs <b>(R)-10a/(S)-11a</b>, <b>(R)-10b/(S)-11b</b>, and <b>(R)-12c/(S)-13c</b>, as well as for <b>(3S,2S)-3a</b>. Spectra of <sup>1</sup>H, <sup>13</sup>CNMR, HPLC, and HRMS for diastereomers and enantiomers were consistent with the determined structures. |
| first_indexed | 2024-03-11T09:58:52Z |
| format | Article |
| id | doaj.art-5aae0087b5b745d4925ca85f61f85afd |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:58:52Z |
| publishDate | 2022-12-01 |
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| spelling | doaj.art-5aae0087b5b745d4925ca85f61f85afd2023-11-16T15:34:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124151710.3390/ijms24010517The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole DerivativesMarek Król0Grzegorz Ślifirski1Jerzy Kleps2Piotr Podsadni3Ilona Materek4Anna E. Kozioł5Franciszek Herold6Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandFaculty of Chemistry, Maria Curie-Skłodowska University, 3, M. Curie-Skłodowskiej Sq., 20-031 Lublin, PolandFaculty of Chemistry, Maria Curie-Skłodowska University, 3, M. Curie-Skłodowskiej Sq., 20-031 Lublin, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandThis article describes the synthesis of new chiral 3-(piperidin-3-yl)-1H-indole derivatives <b>(R)-10a-c</b> and <b>(S)-11a-c</b> from the corresponding diastereomers: (3R, 2R) and (3S, 2R)-2-[3-(1H-indol-3-yl)-1-piperidyl]-2-phenyl-acetamides <b>(3R, 2R)-4a, (3R, 2R)-6b, (3R, 2R)-8c</b> and <b>(3S, 2R)-5a, (3S, 2R)-7b, (3S, 2R)-9c</b>. Diastereomers were obtained by N-alkylation of derivatives of racemic 3-(piperidin-3-yl)-1H-indoles <b>1a-c</b> using (S)-2-(4-toluenesulfonyloxy)-phenylacetic amide <b>(S)–II</b>. The same method was applied to obtain (3R, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate <b>(3R, 2S)-2a</b> and (3S, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate <b>(3S, 2S)-3a</b> diastereomers by treating amine <b>1a</b> with (R)-2-(4-toluenesulfonyloxy)-phenylacetic acid methylester <b>(R)-I</b>. Systematic studies via single crystal X-ray crystallography were used to determine the molecular structure of the racemates <b>1a-c</b> and the absolute configuration of the enantiomers. The solid racemates <b>1b</b> and <b>1c</b> were “true racemates” crystallizing in a centrosymmetric space group, while <b>1a</b> formed a racemic conglomerate of homoenantiomeric crystals. The absolute configuration was determined for the enantiomeric pairs <b>(R)-10a/(S)-11a</b>, <b>(R)-10b/(S)-11b</b>, and <b>(R)-12c/(S)-13c</b>, as well as for <b>(3S,2S)-3a</b>. Spectra of <sup>1</sup>H, <sup>13</sup>CNMR, HPLC, and HRMS for diastereomers and enantiomers were consistent with the determined structures.https://www.mdpi.com/1422-0067/24/1/517serotonin analogspiperidin-3-yl-1H-indolesenantiomerschiral auxiliariesHPLC separationX-ray crystallography |
| spellingShingle | Marek Król Grzegorz Ślifirski Jerzy Kleps Piotr Podsadni Ilona Materek Anna E. Kozioł Franciszek Herold The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives International Journal of Molecular Sciences serotonin analogs piperidin-3-yl-1H-indoles enantiomers chiral auxiliaries HPLC separation X-ray crystallography |
| title | The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives |
| title_full | The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives |
| title_fullStr | The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives |
| title_full_unstemmed | The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives |
| title_short | The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives |
| title_sort | synthesis and absolute configuration of enantiomeric pure r and s 3 piperidin 3 yl 1h indole derivatives |
| topic | serotonin analogs piperidin-3-yl-1H-indoles enantiomers chiral auxiliaries HPLC separation X-ray crystallography |
| url | https://www.mdpi.com/1422-0067/24/1/517 |
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