{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T11:16:03Z","timestamp":1762686963619,"version":"build-2065373602"},"reference-count":30,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2024,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Enantiomerically pure 4\u2010hydroxymorphan\u20107\u2010ones were prepared in two steps from the natural product (<jats:italic>R<\/jats:italic>)\u2010carvone. At first, the isopropenyl moiety of (<jats:italic>R<\/jats:italic>)\u2010carvone was converted into the epoxide <jats:bold>7<\/jats:bold>. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the \u03b1,\u03b2\u2010unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans <jats:bold>8<\/jats:bold>\u2212<jats:bold>13<\/jats:bold> with different <jats:italic>N<\/jats:italic>\u2010substituents. Acylation or water elimination followed by hydrogenation led to esters <jats:bold>15<\/jats:bold> and <jats:bold>16<\/jats:bold> or the morphan <jats:bold>18<\/jats:bold> without a hydroxy moiety. The benzylidenemorphans <jats:bold>25a<\/jats:bold> and <jats:bold>26a<\/jats:bold> were prepared by condensation of the ketones <jats:bold>11a<\/jats:bold> and <jats:bold>12a<\/jats:bold> with benzaldehyde. Finally, the \u03b1\u2010methylene ketone of <jats:bold>11a<\/jats:bold> and <jats:bold>12a<\/jats:bold> was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan <jats:bold>19<\/jats:bold> and the quinolinomorphan <jats:bold>22<\/jats:bold> showed nanomolar \u03c3<jats:sub>1<\/jats:sub> receptor affinity (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=58\u2005nM and 20\u2005nM).<\/jats:p>","DOI":"10.1002\/cmdc.202400596","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T14:54:02Z","timestamp":1725548042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Two\u2010Step Synthesis of Enantiomerically Pure Morphans from (<i>R<\/i>)\u2010Carvone"],"prefix":"10.1002","volume":"19","author":[{"given":"Giuliana","family":"Costanzo","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 D-48149 M\u00fcnster Germany"},{"name":"Dipartimento di Scienze del Farmaco e della Salute University of Catania  Viale Andrea Doria 6 95125 Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Cosentino","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 D-48149 M\u00fcnster Germany"},{"name":"Dipartimento di Scienze del Farmaco e della Salute University of Catania  Viale Andrea Doria 6 95125 Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorella","family":"Pasquinucci","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco e della Salute University of Catania  Viale Andrea Doria 6 95125 Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Amata","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze del Farmaco e della Salute University of Catania  Viale Andrea Doria 6 95125 Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-5428","authenticated-orcid":false,"given":"Dirk","family":"Schepmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 D-48149 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-8417","authenticated-orcid":false,"given":"Bernhard","family":"W\u00fcnsch","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie Universit\u00e4t M\u00fcnster  Corrensstra\u00dfe 48 D-48149 M\u00fcnster Germany"},{"name":"GRK 2515 Chemical biology of ion channels (Chembion) Universit\u00e4t M\u00fcnster  Corrensstr. 48 D-48149 M\u00fcnster Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm061325e"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm980290i"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.114079"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00045a022"},{"key":"e_1_2_9_5_1","first-page":"313","volume":"62","author":"Crawford K. 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