{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:46:57Z","timestamp":1792140417746,"version":"4.4.0"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"23","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35-GM158168"],"award-info":[{"award-number":["R35-GM158168"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["RO1-GM144663"],"award-info":[{"award-number":["RO1-GM144663"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nonintuitive retrosynthetic disconnections can offer valuable insights for devising efficient synthetic routes to complex natural products. When such disconnections involve skeletal rearrangements, they often allow advanced intermediates to be traced back to much simpler building blocks. Guided by this paradigm and motivated by the aspiration to achieve the \u201cideal synthesis\u201d, we have undertaken multiple generations of development to accomplish a concise synthesis of the unique, propeller-shaped natural product hinckdentine A. At the core of our strategy is a novel dearomative indolic-Claisen rearrangement that efficiently transfers the chirality of a readily introduced alcohol to a newly formed, fully substituted chiral center. The resulting densely substituted tertiary amide intermediate was pivotal for progressing toward the final target. The route, however, was far from straightforward, and several pathways were explored, and numerous challenges were overcome before successfully advancing this intermediate to hinckdentine A. This comprehensive account details the evolution of our synthetic campaign, highlighting the unforeseen obstacles encountered and strategic maneuvers devised to surmount them en route to a concise synthesis of the natural product.<\/jats:p>","DOI":"10.1021\/acs.joc.5c02924","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T12:01:01Z","timestamp":1776340861000},"page":"7607-7631","source":"Crossref","is-referenced-by-count":1,"title":["Trials into Triumphs:\nThe Emergence of a Concise Total\nSynthesis of Hinckdentine A"],"prefix":"10.1021","volume":"91","author":[{"given":"Daler","family":"Baidilov","sequence":"first","affiliation":[{"name":"University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3446-4589","authenticated-orcid":true,"given":"Pavel K.","family":"Elkin","sequence":"additional","affiliation":[{"name":"University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4606-0239","authenticated-orcid":true,"given":"Viresh H.","family":"Rawal","sequence":"additional","affiliation":[{"name":"University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"2026101604062174100_cit1","doi-asserted-by":"publisher","first-page":"5561","DOI":"10.1016\/S0040-4039(00)96781-9","article-title":"Hinckdentine-a:\nA Novel Alkaloid from the Marine Bryozoan Hincksinoflustra Denticulata","volume":"28","author":"Blackman","year":"1987","journal-title":"Tetrahedron Lett."},{"key":"2026101604062174100_cit2a","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1039\/jr9560001319","article-title":"The Action\nof Acyl Cyanides on 2- and 1:2-Substituted Indoles","author":"Kiang","year":"1956","journal-title":"J. Chem. Soc."},{"key":"2026101604062174100_cit2b","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1002\/chin.199520201","article-title":"Chemistry of the\nIndolo[1,2-c]quinazolines","volume":"42","author":"Billimoria","year":"1996","journal-title":"Heterocycles"},{"key":"2026101604062174100_cit3","doi-asserted-by":"publisher","first-page":"152880","DOI":"10.1016\/j.tetlet.2021.152880","article-title":"Reinventing the Wheel for Enabling\nthe Synthesis of Hinckdentine A","volume":"67","author":"Ruan","year":"2021","journal-title":"Tetrahedron\nLett."},{"key":"2026101604062174100_cit4","first-page":"63","volume-title":"Alkaloids - A Treasury\nof Poisons and Medicines","author":"Funayama","year":"2015"},{"key":"2026101604062174100_cit5","doi-asserted-by":"publisher","first-page":"4240","DOI":"10.1021\/ja021380m","article-title":"Synthesis of 8-Desbromohinckdentine\nA","volume":"125","author":"Liu","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"2026101604062174100_cit6","doi-asserted-by":"publisher","first-page":"14831","DOI":"10.1021\/jacs.3c03611","article-title":"Rapid Access to\n2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement:\nConcise, Enantioselective Total Synthesis of (+)-Hinckdentine A","volume":"145","author":"Baidilov","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026101604062174100_cit7a","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1021\/ol802394n","article-title":"First Total Synthesis\nof Hinckdentine A","volume":"11","author":"Higuchi","year":"2009","journal-title":"Org. Lett."},{"key":"2026101604062174100_cit7b","doi-asserted-by":"publisher","first-page":"14578","DOI":"10.1021\/jacs.6b10237","article-title":"Enantioselective\nTotal Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization\nApproach","volume":"138","author":"Douki","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026101604062174100_cit7c","doi-asserted-by":"publisher","first-page":"5679","DOI":"10.1002\/anie.201800746","article-title":"Heteroannulation of\nArynes with \u03b1-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones\nand Application to the Enantioselective Total Synthesis of (+)-Hinckdentine\nA","volume":"57","author":"Torres-Ochoa","year":"2018","journal-title":"Angew. Chem. Int. Ed."},{"key":"2026101604062174100_cit7d","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1002\/cjoc.201800301","article-title":"Total Synthesis of Hinckdentine A","volume":"36","author":"Hou","year":"2018","journal-title":"Chin. J. Chem."},{"key":"2026101604062174100_cit7e","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1021\/acs.orglett.1c00323","article-title":"Total Synthesis\nof Hinckdentine A","volume":"23","author":"Jeon","year":"2021","journal-title":"Org. Lett."},{"key":"2026101604062174100_cit7f","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1021\/jacsau.2c00048","article-title":"Total Synthesis of (+)-Hinckdentine A: Harnessing Noncovalent\nInteractions for Organocatalytic Bromination","volume":"2","author":"Ruan","year":"2022","journal-title":"JACS Au"},{"key":"2026101604062174100_cit8","unstructured":"Elkin, P. K.\n          \n          Advances in\nPericyclic Reactions Ph.D. thesis Dissertation in\nChemical Sciences, University of Chicago, 2018."},{"key":"2026101604062174100_cit9","doi-asserted-by":"publisher","first-page":"6141","DOI":"10.1016\/S0040-4039(00)95036-6","article-title":"Thermolytic Removal\nof t-Butyloxycarbonyl\n(BOC) Protecting Group on Indoles and Pyrroles","volume":"26","author":"Rawal","year":"1985","journal-title":"Tetrahedron Lett."},{"key":"2026101604062174100_cit10a","doi-asserted-by":"publisher","first-page":"6983","DOI":"10.1021\/ja00413a045","article-title":"Substituent\nEffects on the Aliphatic Claisen Rearrangement. 1. Synthesis and Rearrangement\nof Cyano-Substituted Allyl Vinyl Ethers","volume":"103","author":"Burrows","year":"1981","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026101604062174100_cit10b","doi-asserted-by":"publisher","first-page":"6984","DOI":"10.1021\/ja00413a046","article-title":"Substituent Effects on the Aliphatic\nClaisen Rearrangement. 2. The Origins of the Rate Accelerations","volume":"103","author":"Burrows","year":"1981","journal-title":"J. Am. Chem. Soc."},{"key":"2026101604062174100_cit11","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1021\/acs.joc.0c02155","article-title":"Expeditious Approach to Indoloquinazolinones via Double Annulations\nof o-Aminoacetophenones and Isocyanates","volume":"86","author":"Ding","year":"2021","journal-title":"J.\nOrg. Chem."},{"key":"2026101604062174100_cit12a","doi-asserted-by":"publisher","first-page":"6777","DOI":"10.1021\/jo00101a043","article-title":"Chemistry\nof Indolo[1,2-c]quinazoline: An Approach to the Marine\nAlkaloid Hinckdentine\nA","volume":"59","author":"Billimoria","year":"1994","journal-title":"J. Org. Chem."},{"key":"2026101604062174100_cit12b","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1039\/C0CC03197F","article-title":"Synthesis\nof 6-trifluoromethylindolo[1,2-c]quinazolines and\nrelated heterocycles using N-(2-iodophenyl)trifluoroacetimidoyl\nchlorides as starting material via C-H bond functionalization","volume":"47","author":"Zhu","year":"2011","journal-title":"Chem. Commun."},{"key":"2026101604062174100_cit12c","doi-asserted-by":"publisher","first-page":"4675","DOI":"10.1016\/j.tetlet.2013.06.079","article-title":"Assembly of indolo[1,2-c]quinazolines\nusing ZnBr2-promoted domino hydroamination-cyclization","volume":"54","author":"Xu","year":"2013","journal-title":"Tetrahedron Lett."},{"key":"2026101604062174100_cit12d","doi-asserted-by":"publisher","first-page":"15636","DOI":"10.1039\/c3ra41644e","article-title":"General and efficient copper-catalyzed\naerobic oxidative synthesis of N-fused heterocycles\nusing amino acids as the nitrogen source","volume":"3","author":"Liu","year":"2013","journal-title":"RSC\nAdv."},{"key":"2026101604062174100_cit12e","doi-asserted-by":"publisher","first-page":"10955","DOI":"10.1021\/acs.joc.5b02076","article-title":"Regioselective Synthesis of Indolo[1,2-c]quinazolines\nand 11H-Indolo[3,2-c]quinolines\nvia Copper-Catalyzed Cascade Reactions of 2-(2-Bromoaryl)-1H-indoles with Aldehydes and Aqueous Ammonia","volume":"80","author":"Guo","year":"2015","journal-title":"J. Org. Chem."},{"key":"2026101604062174100_cit12f","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.3762\/bjoc.14.218","article-title":"Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed\nindole formation\/cyclization with N,N-dimethylformamide dimethyl acetal","volume":"14","author":"Arcadi","year":"2018","journal-title":"Beilstein\nJ. Org. Chem."},{"key":"2026101604062174100_cit12g","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/bkcs.11545","article-title":"Copper-Catalyzed\nC-N Coupling and Cyclization of 2-(2-Chlorophenyl)indole with Urea\nDerivatives","volume":"39","author":"Yoo","year":"2018","journal-title":"Bull. Korean Chem. Soc."},{"key":"2026101604062174100_cit13a","doi-asserted-by":"publisher","first-page":"11995","DOI":"10.1021\/ja002149g","article-title":"A Novel\nand Expeditious Reduction of Tertiary Amides to Aldehydes Using Cp2Zr(H)Cl","volume":"122","author":"White","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"2026101604062174100_cit13b","doi-asserted-by":"publisher","first-page":"3408","DOI":"10.1021\/ja066362+","article-title":"Mild and\nSelective Hydrozirconation of Amides to Aldehydes Using Cp2Zr(H)Cl: Scope and Mechanistic Insight","volume":"129","author":"Spletstoser","year":"2007","journal-title":"J.\nAm. Chem. Soc."},{"key":"2026101604062174100_cit14a","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1021\/ol403183a","article-title":"A Practical in situ\nGeneration of the Schwartz Reagent. Reduction of Tertiary Amides to\nAldehydes and Hydrozirconation","volume":"16","author":"Zhao","year":"2014","journal-title":"Org. Lett."},{"key":"2026101604062174100_cit14b","doi-asserted-by":"publisher","first-page":"6130","DOI":"10.1002\/anie.200601638","article-title":"Highly\nDiastereo- and Enantioselective Mukaiyama Aldol Reactions Catalyzed\nby Hydrogen Bonding","volume":"45","author":"McGilvra","year":"2006","journal-title":"Angew. Chem. Int. Ed."},{"key":"2026101604062174100_cit15","doi-asserted-by":"publisher","first-page":"8880","DOI":"10.1021\/acscatal.0c02377","article-title":"Catalytic Reductive Functionalization\nof Tertiary Amides using Vaska\u2019s Complex: Synthesis of Complex\nTertiary Amine Building Blocks and Natural Products","volume":"10","author":"Matheau-Raven","year":"2020","journal-title":"ACS Catal."},{"key":"2026101604062174100_cit16","doi-asserted-by":"publisher","first-page":"6837","DOI":"10.1021\/acs.chemrev.5b00400","article-title":"Use of Bromine\nand Bromo-Organic\nCompounds in Organic Synthesis","volume":"116","author":"Saikia","year":"2016","journal-title":"Chem. Rev."},{"key":"2026101604062174100_cit17","doi-asserted-by":"publisher","first-page":"7417","DOI":"10.1016\/S0040-4020(01)00712-8","article-title":"An Efficient\nBromination of Alkenes Using Cerium(IV)\nAmmonium Nitrate (CAN) and Potassium Bromide","volume":"57","author":"Nair","year":"2001","journal-title":"Tetrahedron"},{"key":"2026101604062174100_cit18","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1080\/00397911.2014.956367","article-title":"Rapid and\nTotal Bromination of Aromatic Compounds Using TsNBr2 Without\nAny Catalyst","volume":"45","author":"Saikia","year":"2015","journal-title":"Synth. Commun."},{"key":"2026101604062174100_cit19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/B978-0-08-052349-1.00218-3","article-title":"Reduction of\nC = N to CHNH by Metal Hydrides","volume-title":"Comprehensive\nOrganic Synthesis","author":"Hutchins","year":"1991"},{"key":"2026101604062174100_cit20","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1055\/s-1980-29174","article-title":"Reduction of Some Functional\nGroups with Titanium(IV) Chloride\/Sodium Borohydride","volume":"1980","author":"Kano","year":"1980","journal-title":"Synthesis"},{"key":"2026101604062174100_cit21","doi-asserted-by":"publisher","first-page":"2897","DOI":"10.1248\/cpb.26.2897","article-title":"A Convenient Method\nfor the Reduction of Oxime Ethers to the Corresponding Amines","volume":"26","author":"Umino","year":"1978","journal-title":"Chem. Pharm. Bull."},{"key":"2026101604062174100_cit22a","first-page":"387","article-title":"The Corey-Bakshi-Shibata\nReduction: Mechanistic and\nSynthetic Considerations - Bifunctional Lewis Base Catalysis with\nDual Activation","volume-title":"Lewis Base Catalysis in\nOrganic Synthesis","author":"Helal","year":"2006","edition":"1"},{"key":"2026101604062174100_cit22b","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1246\/bcsj.76.643","article-title":"Asymmetric\nSynthesis of the Main Pyridine Skeleton for a Macrobicyclic Antibiotic,\nCyclothiazomycin","volume":"76","author":"Endoh","year":"2003","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"2026101604062174100_cit23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1055\/s-1996-5331","article-title":"Asymmetric Borane Reduction of Prochiral\nKetones with\nOxazaborolidines Derived from \u03b1-Pinene","volume":"1996","author":"Masui","year":"1996","journal-title":"Synlett"}],"container-title":["The Journal of Organic Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.joc.5c02924","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/joceah\/article-pdf\/91\/23\/7607\/68881656\/acs.joc.5c02924.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/joceah\/article-pdf\/91\/23\/7607\/68881656\/acs.joc.5c02924.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:24:37Z","timestamp":1792139077000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/joceah\/article\/91\/23\/7607\/5186471\/Trials-into-Triumphs-The-Emergence-of-a-Concise"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2026,4,16]]},"published-print":{"date-parts":[[2026,6,12]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.joc.5c02924","relation":{},"ISSN":["0022-3263","1520-6904"],"issn-type":[{"value":"0022-3263","type":"print"},{"value":"1520-6904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}