{"paper_id":"47d0c0f6-3652-47e4-b132-2937e0785fef","body_text":"License and Terms: This document is copyright 2022 the Author(s); licensee Beilstein-Institut.\nThis is an open access work under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0). Please note that the reuse,\nredistribution and reproduction in particular requires that the author(s) and source are credited and that individual graphics may be subject to special legal provisions.\nThe license is subject to the Beilstein Archives terms and conditions: https://www.beilstein-archives.org/xiv/terms.\nThe definitive version of this work can be found at https://doi.org/10.3762/bxiv.2022.79.v1\nThis open access document is posted as a preprint in the Beilstein Archives at https://doi.org/10.3762/bxiv.2022.79.v1 and is\nconsidered to be an early communication for feedback before peer review. Before citing this document, please check if a final,\npeer-reviewed version has been published.\nThis document is not formatted, has not undergone copyediting or typesetting, and may contain errors, unsubstantiated scientific\nclaims or preliminary data.\nPreprint Title Synthetic study toward diterpenoid aberrarone\nAuthors Liang Shi, Zhiyu Gao, Yiqing Li, Yuanhao Dai, Yu Liu, Lili Shi and\nHong-Dong Hao\nPublication Date 28 Sep. 2022\nArticle Type Letter\nSupporting Information File 1 Supporting Information.pdf;  1.9 MB\nORCID® iDs Hong-Dong Hao - https://orcid.org/0000-0002-9236-3727\n\n1 \nSynthetic Study Toward Diterpenoid Aberrarone \nLiang Shi‡1, Zhiyu Gao‡1, Yiqing Li1, Yuanhao Dai1, Yu Liu1, Lili Shi*2 and Hong-Dong \nHao*1,2 \nAddress: 1Department Shaanxi Key Laboratory of Natural Products & Chemical \nBiology, C ollege of Chemistry & Pharmacy , Northwest A&F University , Yangling, \nShaanxi 712100, China  and 2State Key Laboratory of Chemical Oncogenomics, \nGuangdong Provincial Key Laboratory of Chemical Genomics, Peking University  \nShenzhen Graduate School, Shenzhen, Guangdong 518055, China  \n \nEmail: Hong-Dong Hao – hongdonghao@nwafu.edu.cn \n* Corresponding author \n‡ Equal contributors \nAbstract \nAn approach to aberrarone, an antimalarial diterpenoid natural product with \ntetracyclic skeleton was reported. Key to the stereoselective preparation of the [6-5-5] \ntricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-\ncarbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C-H \ninsertion. \nKeywords \ntotal synthesis; aberrarone; Pauson-Khand; gold; C-H insertion \n\n2 \nIntroduction \nMarine natural product s have found myriad use in  new drug development, \nexemplified by  ET-743 and eribulin.1 Back in  1990s, Rodriguez and co -workers \nisolated a rich array of terpenoid natural products from Caribbean sea whip, \nPseudopterogorgia elisabethae with unprecedented carbon skeleton, most of which \nshowed antitumor, antituberculosis and antimalarial activity. 2-6 Among these \nstructurally intriguing natural product s, aberrarone  (1), shows antimalarial activity \nagainst chloroquine -resistant strain of Plasmodium falciparum  (IC50 = 10 ug/mL) .7 \nStructurally, aberrarone  possess an unusual tetracyclic carbon skeleton yet-to-be \nfound in Pseudopterogorgia elisabethae species, although the related cyclohexane-\nangularly-fused triquinanes system have been found in waihoensene ( 3), \nconidiogenone (4), lycopodium alkaloids magellamine (5) and lycojaponicumin (6). Its \nseven stereogenic centers, including two all-carbon quaternary centers, together with \nthe non-enolizable cyclic -diketone moiety collectively render aberrarone as an \nattractive but challenging synthetic target.  Its congener elisabanolide ( 2) with a \nlactone in D ring shows their potential biosynthetic relationship. 2 These natural \nproducts have been popular synthetic targets mainly due to thei r intriguing structural \nfeatures. For example, several total synthes es of 3-6 have been reported. 8-28 \nPreviously, two synthetic studies of aberrarone were reported 29,30 and more recently, \nCarreira and co -workers reported31 the first total synthesis of aberrarone through an \nimpressive cascade reaction including gold-catalyzed Nazarov cyclization, \ncyclopropanation followed by intramolecular aldol reaction to forge the A, B and D \nrings. Impressed by the structural features and biological profiles, our grou p \nembarked a project on the total synthesis of this natural product. Herein we reported \nour stereoselective synthesis of its 6-5-5 tricyclic skeleton.   \n\n3 \n \nFigure 1: Selected represent natural product with [6-5-5] tricyclic skeleton \nOur retrosynthetic analysis is shown in Scheme 1. For the formation of D ring with \ntwo quaternary centers and 1,2 -dikeone moiety, Nazarov cyclization 32 of 7 was \nproposed for synthesizing this challenging moiety. The corresponding precursor \ncyclopentenone 8 would be afforded from alkynone 9 through the gold-catalyzed C-H \ninsertion.33 Alkynone 9 could be achieved through functional transformation from 10, \nwhich itself would be prepared through methylation and c onjugate addition from \nPauson-Khand adduct 11. This cyclopentenone could be readily accessed from 1,7-\nenyne 12 which can be obtained through reported procedure 34 from the commercially \navailable 5-hexenoicacid. \n \n \n \n \n \n \n \nScheme 1: Retro-synthetic analysis of aberrarone. \n\n\n4 \nResults and Discussion \nOur synthetic route commenced from the known compound 12 which are readily \naccessed from 5-Hexenoicacid through the reported procedure .34 In the mediation of \nCo2(CO)8, the 6 -5 bicyclic skeleton 35 was constructed with the right configuration at \nC6, and the explanation of this stereoselectivity is possible through the conformation \nof 14 that the OTBS group was in pseudo -equatorial position. Therefore, the PKR \nproceed to afford 11 containing -H at C 6. F rom this intermediate,  to our delight, \nstereoselective attachment of the requisite methyl group through the corresponding \nlithium enolate occurred from the convex face of the bicyclic ring system .36 After \nthese two continuous stereocenters were successfully installed, the expected \nchallenging all-carbon quaternary center at C1 was constructed utilizing Nagata \nreagent (Et 2AlCN). By using this strategy , the stereogenic center at C1 was \nsynthesized, along with  a smoothly attachment of the cyanate gr oup served for \nfurther functional group transformation to construct the C ring through C -H insertion. \nThe stereochemistry finding of this conjugate addition from the convex face of the 6-5 \nring system was further confirmed through X-ray crystallographic analysis. \nScheme 2: Synthetic study toward aberrarone. \n\n\n5 \nWith the key intermediate 10 in hand, we were in a position to test the planned two-\nstep transformation including palladium catalyzed reductive cross coupling with \nHCO2H followed by Pd/C catalyzed hydr ogenation. To our surprise, the \nhydrogenation turned out to be a difficult transformation due to the steric hinder ed \nenvironment of the trisubstituted double bond , mainly caused by the bulky OTBS \ngroup. However, direct subjection of compound 16 to hydrogenation 37 afforded \nreduction of both triflate and double bond.  The plausible pathway for this facile \ntransformation might proceed with first hydrogenation followed by the substitution of \nthe labile triflate ester  (for details, see Supporting Info rmation). Moving forward, \ncompound 17 was further converted into alkynone 9 through DIBAL-H reduction, \nnucleophilic addition and Dess-Martin oxidation. At this stage , t he pivotal C-H \ninsertion step was tried under the reported condition, 33 and cyclopentenone 8 was \nsuccessfully obtained. Further study with cross coupling or halogen -magnesium \nexchange shows this moiety is stable for functional group transformation. The \nattempt for constructing the D ring is currently undergoing. \nConclusion \nIn summary, w e have developed an approach to  assemble the tricyclic skeleton of \naberrarone through stereoselective methy lation, conjugate addition and gold-\ncatalyzed C-H insertion  from the readily accessed cyclopentenone . Further work to \naccess natural product  aberrarone from the key intermediate  cyclopentenone 8 is \ncurrently underway, and will be reported in due course. \n\n6 \nSupporting Information  \nThe crystallographic data of the compound s 10 (CCDC 2 204711) have been \ndeposited at the Cambridge Crystallographic Database Cente r \n(http://www.ccdc.cam.ac.uk) \nSupporting Information File 1: \nCharacterization data and 1H NMR, 13C NMR, and HRMS spectra of the \ncompounds.  \nFunding \nWe are grateful for financial support from Natural Science Foundation of China \n(Grant No. 21901211). \nReferences \n1. Altmann, K.-H. Chimia 2017, 71, 646-652. \n2. Rodríguez, A. D.; Gonzalez, E.; Huang, S. D. J. Org. Chem. 1998, 63, 7083-7091. \n3. Rodríguez, A. D.; Ramírez, C. Org. Lett. 2000, 2, 507-510. \n4. Rodríguez, A. D.; Ramírez, C.; Rodríguez, I. I.; Barn es, C. L. J. Org. Chem. 2000, \n65, 1390. \n5. Rodríguez, A. D.; Ramírez, C.; Shi, Y. P. J. Org. Chem. 2000, 65, 6682.  \n6. 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