2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution,absolute configuration and hydrogen-bonding properties |
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| Affiliation: | 1. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6;2. Biofine International, 1650 Pandora Street, Vancouver, BC, Canada V5L 1L6;3. Department of Chemistry, The University of British Columbia, Vancouver, BC, Canada V6T 1Z1;1. Physics Department, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt;2. Spectroscopy Department, National Research Centre, Dokki, Cairo, Egypt;1. Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad 500049, India;2. Department of Chemistry, College of Engineering, JNTUH, Kukatpally, Hyderabad 500085, India;1. Institute of Science and Technology Research, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan;2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;3. Computational Science Department, Science and Technology Systems Division, Ryoka Systems Inc., Tokyo Skytree East Tower, 1-1-2, Oshiage, Sumida-ku, Tokyo 131-0045, Japan;1. Komsomolsk-on-Amur State Technical University, Lenin Ave. 27, Komsomolsk-on-Amur, 681013, Russia;2. A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences, Akad. Lavrentiev Ave. 3, Novosibirsk 630090, Russia;3. Novosibirsk State University, Pirogov Str. 2, Novosibirsk 630090, Russia;4. Institute of Chemistry, Far East Division, Russian Academy of Sciences, 100th years of Vladivostok Ave. 159, Vladivostok 690022, Russia;5. Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganov Str. 13, Minsk 220072, Belarus;1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;2. School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;3. Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, Taipei, Taiwan;4. Division of Cardiology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Executive Yuan, Taoyuan, Taiwan;5. Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan;6. Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan;7. Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;8. Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;9. Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan;1. Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan;2. Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan |
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| Abstract: | The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored. |
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