{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T01:08:07Z","timestamp":1785892087567,"version":"3.56.0"},"reference-count":43,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T00:00:00Z","timestamp":1652745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemBioChem"],"published-print":{"date-parts":[[2022,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>LolO, a 2\u2010oxoglutarate\u2010dependent nonheme Fe oxygenase, catalyzes both the hydroxylation of 1\u2010<jats:italic>exo<\/jats:italic>\u2010acetamidopyrrolizidine (AcAP), a pathway intermediate in the biosynthesis of the loline alkaloids, and the cycloetherification of the resulting alcohol. We have prepared fluorinated AcAP analogues to aid in continued mechanistic investigation of the remarkable LolO\u2010catalyzed cycloetherification step. LolO was able to hydroxylate 6,6\u2010difluoro\u2010AcAP (prepared from <jats:italic>N<\/jats:italic>,<jats:italic>O<\/jats:italic>\u2010protected 4\u2010oxoproline) and then cycloetherify the resulting alcohol, forming a difluorinated analogue of <jats:italic>N<\/jats:italic>\u2010acetylnorloline and providing evidence for a cycloetherification mechanism involving a C(7) radical as opposed to a C(7) carbocation. By contrast, LolO was able to hydroxylate 7,7\u2010difluoro\u2010AcAP (prepared from 3\u2010oxoproline) but failed to cycloetherify it, forming (1<jats:italic>R<\/jats:italic>,2<jats:italic>R<\/jats:italic>,8<jats:italic>S<\/jats:italic>)\u20107,7\u2010difluoro\u20102\u2010hydroxy\u2010AcAP as the sole product. The divergent LolO\u2010catalyzed reactions of the difluorinated AcAP analogues provide insight into the LolO cycloetherification mechanism and indicate that the 7,7\u2010difluorinated compound, in particular, may be a useful tool to accumulate and characterize the iron intermediate that initiates the cycloetherification reaction.<\/jats:p>","DOI":"10.1002\/cbic.202200081","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T11:29:37Z","timestamp":1651145377000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis of 6,6\u2010 and 7,7\u2010Difluoro\u20101\u2010acetamidopyrrolizidines and Their Oxidation Catalyzed by the Nonheme Fe Oxygenase LolO"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-3289","authenticated-orcid":false,"given":"Nabin","family":"Panth","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Kentucky  Lexington Kentucky 40546-0312 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6391-8036","authenticated-orcid":false,"given":"Eliott S.","family":"Wenger","sequence":"additional","affiliation":[{"name":"Department of Chemistry The Pennsylvania State University  University Park Pennsylvania 16802 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-7053","authenticated-orcid":false,"given":"Carsten","family":"Krebs","sequence":"additional","affiliation":[{"name":"Department of Chemistry The Pennsylvania State University  University Park Pennsylvania 16802 USA"},{"name":"Department of Biochemistry and Molecular Biology The Pennsylvania State University  University Park Pennsylvania 16802 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0751-8585","authenticated-orcid":false,"suffix":"Jr.","given":"J. Martin","family":"Bollinger","sequence":"additional","affiliation":[{"name":"Department of Chemistry The Pennsylvania State University  University Park Pennsylvania 16802 USA"},{"name":"Department of Biochemistry and Molecular Biology The Pennsylvania State University  University Park Pennsylvania 16802 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8866-3754","authenticated-orcid":false,"given":"Robert B.","family":"Grossman","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Kentucky  Lexington Kentucky 40546-0312 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2007.01.010"},{"key":"e_1_2_10_2_1","unstructured":"\u00a0"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200400327"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200600066"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2013.11.015"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.8b00157"},{"key":"e_1_2_10_7_1","unstructured":"\u00a0"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fgb.2008.07.001"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0115590"},{"key":"e_1_2_10_10_1","unstructured":"\u00a0"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1104\/pp.84.1.144"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.05.042"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00479a023"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00222a034"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.9.4262"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1039\/np9971400309"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201900290"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201904053"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-5193(82)90320-4"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/10409230490440541"},{"key":"e_1_2_10_21_1","unstructured":"\u00a0"},{"key":"e_1_2_10_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar700066p"},{"key":"e_1_2_10_23_2","unstructured":"J.\u2005M. Bollinger W.-C. Chang M.\u2005L. Matthews R.\u2005J. Martinie A.\u2005K. Boal C. Krebs in2-Oxoglutarate-Dependent Oxygenases(Eds.: R.\u2005P. Hausinger C.\u2005J. Schofield) Royal Society of Chemistry London 2015."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b07374"},{"key":"e_1_2_10_25_1","unstructured":"\u00a0"},{"key":"e_1_2_10_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja972408a"},{"key":"e_1_2_10_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr9900275"},{"key":"e_1_2_10_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja004025"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/ed062p928"},{"key":"e_1_2_10_30_1","unstructured":"\u00a0"},{"key":"e_1_2_10_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909649106"},{"key":"e_1_2_10_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b01933"},{"key":"e_1_2_10_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b03567"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi602458m"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b06689"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2006.01.022"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/a701878i"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1039\/p19940002485"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol701845t"},{"key":"e_1_2_10_40_1","unstructured":"\u00a0"},{"key":"e_1_2_10_41_2","doi-asserted-by":"publisher","DOI":"10.1080\/00397918908050700"},{"key":"e_1_2_10_42_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-1996-5474"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(02)01835-X"}],"container-title":["ChemBioChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202200081","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbic.202200081","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbic.202200081","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T12:11:19Z","timestamp":1760271079000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cbic.202200081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,17]]},"references-count":43,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2022,7,5]]}},"alternative-id":["10.1002\/cbic.202200081"],"URL":"https:\/\/doi.org\/10.1002\/cbic.202200081","archive":["Portico"],"relation":{},"ISSN":["1439-4227","1439-7633"],"issn-type":[{"value":"1439-4227","type":"print"},{"value":"1439-7633","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,17]]},"assertion":[{"value":"2022-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202200081"}}