{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:12:05Z","timestamp":1780319525355,"version":"3.54.1"},"reference-count":91,"publisher":"Wiley","issue":"52","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100010278","name":"Kurata Memorial Hitachi Science and Technology Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010278","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2025,12,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Although conjugate addition to an \u03b1,\u03b2\u2010unsaturated carbonyl compound is a well\u2010established method in synthetic organic chemistry, controlling regioselectivity, olefin geometry, and positional isomerism in analogous 1,6\u2010addition chemistry, which provides a powerful approach for constructing molecular complexity, remains a key challenge. Herein, we report the iron\u2010catalyzed regio\u2010, stereo\u2010, and enantioselective 1,6\u2010additions of aliphatic Grignard reagents to \u03b1,\u03b2,\u03b3,\u03b4\u2010unsaturated carbonyl compounds. The incorporation of an\n                    <jats:italic>N<\/jats:italic>\n                    \u2010heterocyclic carbene (NHC) ligand effectively suppresses undesired \u03b2\u2010hydride elimination, thereby enabling the highly\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010selective installation of the aliphatic group. Remarkably, the use of a rigid tetracyclic chiral NHC ligand afforded the corresponding adducts with enantioselectivities of up to 99%. The developed reaction shows broad substrate scope, accommodating various aliphatic Grignard reagents and unsaturated carbonyl compounds, thereby providing direct access to optically active 1,6\u2010adducts bearing\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010configured olefins. Mechanistic investigations, including deuterium\u2010labeling experiments, support the involvement of magnesium enolates and an iron\u2013NHC catalytic cycle. The developed transformation provides a powerful strategy for the remote functionalization of extended conjugated carbonyl frameworks.\n                  <\/jats:p>","DOI":"10.1002\/anie.202518346","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T13:24:41Z","timestamp":1762435481000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Iron\/NHC\u2010Catalyzed Regio\u2010 and Stereoselective 1,6\u2010Additions of Aliphatic Grignard Reagents to \u03b1,\u03b2,\u03b3,\u03b4\u2010Unsaturated Carbonyl Compounds: Asymmetric Variants with Chiral NHCs"],"prefix":"10.1002","volume":"64","author":[{"given":"Kazuma","family":"Abe","sequence":"first","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoma","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumpei","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7500-5995","authenticated-orcid":false,"given":"Takeshi","family":"Hata","sequence":"additional","affiliation":[{"name":"Department of Life Science and Technology School of Life Science and Technology Institute of Science Tokyo  4259 Nagatsuta\u2010cho Midori\u2010ku Yokohama Kanagawa 226\u20108501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"e_1_2_5_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00013a002"},{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00013a002"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr068424k"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.11.60"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.12.116"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00692"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.16.24"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcat.2020.110814"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2QO01341J"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajoc.202400193"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1039\/b924486g"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100032\u20101316778"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.11.263"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.6b02769"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.8b04357"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja1034842"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1039\/C2CC16973H"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c05427"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.77.13"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol036309f"},{"key":"e_1_2_5_21_1","first-page":"585","author":"De la Herr\u00e1n G.","year":"2009","journal-title":"Synlett"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja309756k"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200703702"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetasy.2006.11.009"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200803735"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja910989n"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol1017382"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol200219m"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201300538"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201302649"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/cs501297s"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19063"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.8b01109"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201808392"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201812535"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201019293\u20109"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2CC00146B"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.202200900"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2004.11.131"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200801928"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol802170z"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol100022w"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201101273"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201100995"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201200410"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201201124"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.15227\/orgsyn.091.0307"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2018.12.043"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2023.154824"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.202400832"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.202401034"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300236r"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b01638"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.1c00212"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202006557"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c09486"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202017175"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c04773"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/cjoc.202300162"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c07473"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c11470"},{"key":"e_1_2_5_62_1","unstructured":"Thecis\u2010configuration of product2was confirmed by1H\u00a0NMR (J\u00a0=\u00a010.8\u00a0Hz) and NOE experiments as shown below."},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2sc21754f"},{"key":"e_1_2_5_64_1","first-page":"1733","volume":"12","author":"Agata R.","year":"2015","journal-title":"Synthesis"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6DT02995G"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC04750A"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.organomet.8b00466"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.20180333"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202102070"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200902237"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200902236"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.10.004"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.08.003"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.11.013"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13384"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.12.019"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4CS00441H"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201905924"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201905924"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1007\/s41061-019-0266-z"},{"key":"e_1_2_5_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201900859"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4CS01179A"},{"key":"e_1_2_5_83_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja062707c"},{"key":"e_1_2_5_84_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja066380r"},{"key":"e_1_2_5_85_1","unstructured":"The enantiomeric excess (ee) was determined by chiral\u2010phase HPLC analysis using a Daicel Chiralpak\u00aecolumn (see the Supporting Information for complete chromatographic conditions)."},{"key":"e_1_2_5_86_1","unstructured":"The absolute configuration of the chiral 1 6\u2010adduct was established by1H NMR analysis following ozonolysis and subsequent derivatization to the corresponding MTPA ester and was confirmed by comparison with an authentic sample (see the Supporting Information)."},{"key":"e_1_2_5_87_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202106742"},{"key":"e_1_2_5_88_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201914844"},{"key":"e_1_2_5_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201813578"},{"key":"e_1_2_5_90_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja075750o"},{"key":"e_1_2_5_91_1","unstructured":"The ee of derivatives of the chiral 1 6\u2010adduct was determined by chiral\u2010phase HPLC analysis or by ozonolysis followed by derivatization to the corresponding MTPA ester as described above. However the separation of (R)\u201035by chiral\u2010phase HPLC was insufficient to determine its ee (see the Supporting Information)."}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202518346","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202518346","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202518346","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:47:22Z","timestamp":1780318042000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202518346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":91,"journal-issue":{"issue":"52","published-print":{"date-parts":[[2025,12,22]]}},"alternative-id":["10.1002\/anie.202518346"],"URL":"https:\/\/doi.org\/10.1002\/anie.202518346","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]},"assertion":[{"value":"2025-08-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e18346"}}