{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:33:46Z","timestamp":1791804826008,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["CA197999"],"award-info":[{"award-number":["CA197999"]}]},{"name":"NIH","award":["CA260749"],"award-info":[{"award-number":["CA260749"]}]},{"name":"NIH","award":["CA276846"],"award-info":[{"award-number":["CA276846"]}]},{"name":"NIH","award":["GM121316"],"award-info":[{"award-number":["GM121316"]}]},{"name":"NIH","award":["CA036727"],"award-info":[{"award-number":["CA036727"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Isatin-derived spirocyclic cores are found in several biologically active molecules. Here, we report nucleophilic domino reactions for the synthesis of \u03b1-methylene-\u03b3-butyrolactone\/lactam containing spirocyclic oxindoles. The Zn-mediated one-step reaction accommodates a range of substrates and can be used to rapidly generate focused libraries of highly substituted spirocyclic compound.<\/jats:p>","DOI":"10.3390\/molecules29153612","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T17:08:34Z","timestamp":1722359314000},"page":"3612","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Domino Reactions Enable Zn-Mediated Direct Synthesis of Spiro-Fused 2-Oxindole-\u03b1-Methylene-\u03b3-Butyrolactones\/Lactams from Isatin Derivatives and 2-(Bromomethyl)acrylates"],"prefix":"10.3390","volume":"29","author":[{"given":"Prathap Reddy","family":"Mukthapuram","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 698198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-0203","authenticated-orcid":false,"given":"Amarnath","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 698198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1021\/cr950027e","article-title":"Domino Reactions in Organic Synthesis","volume":"96","author":"Tietze","year":"1996","journal-title":"Chem. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1021\/acscentsci.1c00075","article-title":"Natural Product Synthesis Enabled by Domino Processes Incorporating a 1,2-Rearrangement Step","volume":"7","author":"Delayre","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Fan, L., Zhu, X., Liu, X., He, F., Yang, G., Xu, C., and Yang, X. (2023). Recent Advances in the Synthesis of 3,n-Fused Tricyclic Indole Skeletons via Palladium-Catalyzed Domino Reactions. Molecules, 28.","DOI":"10.3390\/molecules28041647"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1002\/ejoc.200300050","article-title":"Construction of Spiro[pyrrolidine-3,3\u2032-oxindoles]\u2014Recent Applications to the Synthesis of Oxindole Alkaloids","volume":"2003","author":"Marti","year":"2003","journal-title":"Eur. J. Org. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/nature05569","article-title":"Total synthesis of marine natural products without using protecting groups","volume":"446","author":"Baran","year":"2007","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8748","DOI":"10.1002\/anie.200701342","article-title":"Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents","volume":"46","author":"Galliford","year":"2007","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17938","DOI":"10.1021\/ja806981k","article-title":"Enantiospecific Total Synthesis of the Hapalindoles, Fischerindoles, and Welwitindolinones via a Redox Economic Approach","volume":"130","author":"Richter","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1021\/ja076663z","article-title":"Evolution of a Synthetic Strategy:\u2009 Total Synthesis of (\u00b1)-Welwitindolinone A Isonitrile","volume":"130","author":"Reisman","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6104","DOI":"10.1021\/cr300135y","article-title":"Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks","volume":"112","author":"Singh","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9599","DOI":"10.1002\/chem.201301008","article-title":"Efficient Enantioselective Total Synthesis of (\u2212)-Horsfiline","volume":"19","author":"Hong","year":"2013","journal-title":"Chem. A Eur. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4909","DOI":"10.1002\/anie.201201736","article-title":"Biomimetic Total Synthesis of (+)-Gelsemine","volume":"51","author":"Zhou","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16720","DOI":"10.1021\/ja409013m","article-title":"Rapid Access to Spirocyclic Oxindole Alkaloids: Application of the Asymmetric Palladium-Catalyzed [3 + 2] Trimethylenemethane Cycloaddition","volume":"135","author":"Trost","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14184","DOI":"10.1021\/ja5074646","article-title":"Enantioselective total syntheses of citrinadins A and B. Stereochemical revision of their assigned structures","volume":"136","author":"Bian","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"128713","DOI":"10.1016\/j.bmcl.2022.128713","article-title":"Dimers of isatin derived \u03b1-methylene-\u03b3-butyrolactone as potent anti-cancer agents","volume":"65","author":"Rana","year":"2022","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kour, S., Rana, S., Kubica, S.P., Kizhake, S., Ahmad, M., Mu\u00f1oz-Trujillo, C., Klinkebiel, D., Singh, S., Mallareddy, J.R., and Chandra, S. (2022). Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101890"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1039\/D1CB00183C","article-title":"Stapling proteins in the RELA complex inhibits TNF\u03b1-induced nuclear translocation of RELA","volume":"3","author":"Kour","year":"2022","journal-title":"RSC Chem. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1111\/cbdd.13684","article-title":"Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK","volume":"96","author":"Rana","year":"2020","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1021\/acs.jmedchem.6b00400","article-title":"Isatin Derived Spirocyclic Analogues with \u03b1-Methylene-\u03b3-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study","volume":"59","author":"Rana","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1039\/C2OB27008K","article-title":"Face selective reduction of the exocyclic double bond in isatin derived spirocyclic lactones","volume":"11","author":"Rana","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1016\/S0960-894X(01)80742-3","article-title":"Preparation and biological evaluation of \u03b3-fluoromethyl-\u03b1-methylene-\u03b3-butyrolactone and \u03b3-butyrolactam","volume":"3","author":"Murata","year":"1993","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6629","DOI":"10.1021\/ja980513u","article-title":"Structure-Based Design of a New Class of Protein Kinase C Modulators","volume":"120","author":"Qiao","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1021\/jm048970a","article-title":"Novel synthesis, cytotoxic evaluation, and structure-activity relationship studies of a series of alpha-alkylidene-gamma-lactones and lactams","volume":"48","author":"Janecki","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9426","DOI":"10.1002\/anie.200903108","article-title":"The renaissance of alpha-methylene-gamma-butyrolactones: New synthetic approaches","volume":"48","author":"Kitson","year":"2009","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/tcr.200900013","article-title":"Alpha-methylene-gamma-butyrolactones: Versatile skin bioactive natural products","volume":"9","author":"Lepoittevin","year":"2009","journal-title":"Chem. Rec."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ejmech.2017.02.050","article-title":"Natural \u03b1-methylenelactam analogues: Design, synthesis and evaluation of \u03b1-alkenyl-\u03b3 and \u03b4-lactams as potential antifungal agents against Colletotrichum orbiculare","volume":"130","author":"Delong","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4393","DOI":"10.1016\/j.bmcl.2013.05.073","article-title":"New antifungal scaffold derived from a natural pharmacophore: Synthesis of \u03b1-methylene-\u03b3-butyrolactone derivatives and their antifungal activity against Colletotrichum lagenarium","volume":"23","author":"He","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14951","DOI":"10.1021\/acs.jmedchem.0c01464","article-title":"Synthesis of Guaianolide Analogues with a Tunable \u03b1-Methylene\u2212\u03b3-lactam Electrophile and Correlating Bioactivity with Thiol Reactivity","volume":"63","author":"Jackson","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6042","DOI":"10.1021\/jm049937r","article-title":"Quantitative Structure\u2212Activity Relationship of Sesquiterpene Lactones as Inhibitors of the Transcription Factor NF-\u03baB","volume":"47","author":"Siedle","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11204","DOI":"10.1021\/acs.joc.2c01530","article-title":"Thiol Reactivity of N-Aryl \u03b1-Methylene-\u03b3-lactams: Influence of the Guaianolide Structure","volume":"87","author":"Dempe","year":"2022","journal-title":"J. Org. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9391","DOI":"10.1021\/acs.joc.2c00694","article-title":"One-Pot Diastereoselective Synthesis of Pyrrolopiperazine-2,6-diones by a Ugi\/Nucleophilic Substitution\/N-Acylation Sequence","volume":"87","author":"Pertejo","year":"2022","journal-title":"J. Org. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11091","DOI":"10.1002\/chem.201403357","article-title":"Catalytic Enantioselective Amide Allylation of Isatins and Its Application in the Synthesis of 2-Oxindole Derivatives Spiro-Fused to the \u03b1-Methylene-\u03b3-Butyrolactone Functionality","volume":"20","author":"Takahashi","year":"2014","journal-title":"Chem.-Eur. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6182","DOI":"10.1021\/ol403014u","article-title":"Construction of Spiro-Fused 2-Oxindole\/\u03b1-Methylene- \u03b3-Butyrolactone Systems with Extremely High Enantioselectivity via Indium-Catalyzed Amide Allylation of N-Methyl Isatin","volume":"15","author":"Murata","year":"2013","journal-title":"Org. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1002\/ejoc.201800084","article-title":"Electrophilic Amide Allylation of 3-Heterosubstituted Oxindoles: A Route to Spirocyclic 2-Oxindoles Containing the \u03b1-Methylene-\u03b3-butyrolactam Structure","volume":"2018","author":"Sengoku","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6860","DOI":"10.1039\/C7CC03765A","article-title":"Metal-free formal carbon-halogen bond insertion: Facile syntheses of 3-halo 3,3\u2032-disubstituted oxindoles and spirooxindole-\u03b3-butyrolactones","volume":"53","author":"Zhou","year":"2017","journal-title":"Chem. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1002\/ejoc.201301684","article-title":"Enantioselective Synthesis of Spirooxindole \u03b1-exo-Methylene-\u03b3-butyrolactones from 3-OBoc-Oxindoles","volume":"2014","author":"Jayakumar","year":"2014","journal-title":"Eur. J. Org. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3986","DOI":"10.1016\/j.tetlet.2016.07.080","article-title":"Advances in the chemistry of organozinc reagents","volume":"57","author":"Dilman","year":"2016","journal-title":"Tetrahedron Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/jps.2600700117","article-title":"Synthesis and antibacterial and anticancer evaluations of alpha-methylene-gamma-butyrolactones","volume":"70","author":"Heindel","year":"1981","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8489","DOI":"10.1016\/S0040-4039(02)02088-9","article-title":"Synthesis of 3,4-disubstituted \u03b1-methylene-\u03b3-lactones via sonochemical Barbier-type reaction","volume":"43","author":"Lee","year":"2002","journal-title":"Tetrahedron Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/S0957-4166(97)00166-3","article-title":"Enantioselective Dreiding-Schmidt reactions: Asymmetric synthesis and analysis of \u03b1-methylene-\u03b3-butyrolactones","volume":"8","author":"Csuk","year":"1997","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.6023\/cjoc201801021","article-title":"Tin Powder-Promoted \u201cOne-Pot\u201d Synthesis of \u03b1-Methylene-\u03b3-butyrolactones","volume":"38","author":"Yang","year":"2018","journal-title":"Chin. J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/15\/3612\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:26:54Z","timestamp":1760110014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/15\/3612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["molecules29153612"],"URL":"https:\/\/doi.org\/10.3390\/molecules29153612","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,30]]}}}