Stereoselective Synthesis of 1,4,5-Tri-cis-guaiane Sesquiterpene: FirstTotal Synthesis of (−)-Dendroside C AglyconJaehoon Sim,†,‡ Hyunkyung Park,† Juhee Lim,‡ Inah Yoon,† Changjin Lim,† Hongchan An,†

Hwayoung Yun,§ Hyun Jin Choi,‡ and Young-Ger Suh*,†,‡

†College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea‡College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi-do 13488, Republic of Korea§College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea

*S Supporting Information

ABSTRACT: The first total synthesis of (−)-dendroside C aglycon, consisting of a 1,4,5-tri-cis-guaiane skeleton, from a versatilehydroazulene intermediate has been accomplished. The key features of the syntheses include the stereoselective preparation ofthe unusual cis-hydroazulene core via a sequence of a unique Dieckmann condensation of the bicyclic lactone system, which wasconcisely prepared by the tandem conjugate addition and intramolecular allylic alkylation of a butenolide precursor, and con-struction of the characteristic tricyclic skeleton by a carbene-mediated cyclopropanation.

Recently, the target-oriented synthesis of complex naturalproducts has been remarkably advanced via the discovery of

useful catalytic reactions, the development of efficient bond for-mations, and innovative synthetic planning by eminent organicchemists.1 Despite these improvements, extensive syntheses ofarchitecturally complex natural products, which co-occur inbiological pathways, are still not easily achievable on a substantialscale. Thus, the syntheses of structurally or biologically uniquenatural products from a pluripotent synthetic intermediate havedrawn much attention from organic and medicinal chemists.2

Guaianes belong to a family of naturally occurring sesquiter-penes that have recently received considerable attention owing totheir unique skeletal features and broad range of biologicalactivities.3 They are characterized by a 5,7-fused hydroazuleneframework which usually contains abundant stereogenic cen-ters. Although the syntheses of numerous biologically relevantguaianes, such as arglabin,4 englerin A,5 cladantholide,6 andchinesiolide B,7 have been achieved through enormous efforts, aunified synthetic strategy toward their congeners has not beenwell established. In particular, synthetic studies toward the 1,4,5-tri-cis-guaiane skeleton have been limited partly due to the highlycongested core structure. In pursuit of a synthetic strategy forstructurally constrained guaianes possessing potential biologicalactivities, we herein report the first stereoselective total synthesisof dendroside C,8 which consists of an unusual 5/7/3 cis-fusedtricyclic system, contiguous seven stereogenic centers, and aunique cyclopropane unit. (Figure 1)

Our synthetic strategy for alloaromadendrane-type guaianesesquiterpene is depicted in Scheme 1. We envisioned that thetargeted dendroside C aglycon (2) could be accessed by the final

Received: November 29, 2017Published: January 16, 2018

Figure 1. Representative guaianes and alloaromadendrane-type guaianesesquiterpenes.

Letter

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intermolecular cyclopropanations of the bicyclic intermediate 3,which possesses the requisite carbon skeleton and functionalitiesfor the diverse guaiane natural products. The key intermediate 3could be obtained through a chemo- and diastereoselective dihy-droxylation of hydroazulene 4. The highly formidable 1,4,5-tri-cis-hydroazulene structure could be prepared via an intramolec-ular C-acyl transfer of bicyclic lactone 5. We anticipated that atandem conjugate addition/intramolecular allylic alkylation ofbutenolide 6 would stereoselectively produce the pivotal cyclo-pentane core 5 of the hydroazulene system as well as threeadjacent stereogenic centers. Butenolide 6 could be efficientlyprepared by the convergent assembly of readily available pheny-lsulfonyl acetate 7, epoxide 8, and olefin 9.Our synthesis commenced with the convergent synthesis of

butenolide 6, as shown in Scheme 2. The convergent assembly of

three components, as our first task to prepare lactone 11 with atrisubstituted olefin, was essential for our unique strategy. Weemployed Robinson’s CM protocol recently reported for thesynthesis of a sterically demanding olefin unit.9 Cross metathesisof the germinal dimethyl olefin 10 and the sterically hinderedolefin 910 provided intermediate 11 as a mixture of E and Zisomers in a viable chemical yield. The gem-dimethyl olefin 10was readily prepared by the nucleophilic epoxide opening of(R)-811 with an anion of sulfone 7 followed by spontaneous tran-sesterification. Finally, a sequence of selenylation/selenoxideelimination of 11 furnished butenolide 6.We next focused on the stereoselective and concise prepara-

tion of the cyclopentane core of the guaiane skeleton. (Table 1)Inspired by a tandem conjugate addition/alkylation12 based onour intramolecular allylic alkylation protocol,13 we envisaged thatenolate 6a resulting from the conjugate addition of an organ-ocuprate to butenolide 6 could be involved in the Pd(0)-assistedintramolecular allylic alkylation. Ultimately, the C4-stereochemistry

would control the newly generated three contiguous stereo-genic centers of bicyclic lactone 5. The initial attempt for theCu-catalytic conjugate addition with organozinc, organoalumi-num, and a Grignard reagent gave a complex mixture with nodesired product (entries 1−3). The in situ generated lithiumdimethylcuprate in diethyl ether underwent conjugate additionbut did not undergo intramolecular allylic alkylation (entry 4).However, the facile intramolecular allylic alkylation of enolate 6aproceeded in THF to afford the desired bicyclic lactone 5 withnearly complete stereocontrol (dr = 30:1, entry 5) in 82% yield.The high diastereoselectivity is likely due to the preference of thePd−π-allyl complex with a less steric interaction.13,14

The hydroazulene cores of the guaiane natural products aregenerally constructed via cycloisomerization5c,15 or RCM4−7,16

after allylation of cyclopentanecarbaldehyde. However, the highlycongested 1,4,5-tri-cis-guaiane systems are not accessible by thesesynthetic methods. As shown in Scheme 3, we investigated theintramolecular O to C-acyl transfer reactions of 5 to efficientlyconstruct tri-cis-fused guaiane sesquiterpenes after appropriatemanipulation of the terminal alkoxy moiety.The Barbier-type reaction of alkyl halide 12a mediated by

magnesium, zinc, and samarium diiodide17 gave a simply pro-tonated product. The Dieckmann condensation of ester 12bprovided the desired hydroazulene system 4a. However, thethermodynamically favored trans-hydroazulene was consistentlyobtained due to facile epimerization at C5 during the thermaldecarboxylation of the hydroazulene product.18 In this connec-tion, the benzenesulfonyl group turned out crucial for oursuccessful transformation. Reductive desulfonylation with SmI2at −78 °C of the Dieckmann condensation product 4 afteralcohol protection provided the cis-hydroazulene intermediate13 without epimerization at C5. The sulfone precursor 12 was

Scheme 1. Retrosynthetic Analysis for the Synthesis ofDendroside C Aglycon

Scheme 2. Convergent Synthesis of Butenolide 6

Table 1. Tandem Conjugate Addition/Intramolecular AllylicAlkylation

entry reagentsa (equiv) solvent result

1 Me2Zn (1.0), CuOTf (0.1),Pd(PPh3)4 (0.05)

tolueneb complex mixture

2 MeMgBr (1.0), CuOTf (0.1),Pd(PPh3)4 (0.05)

tolueneb complex mixture

3 AlMe3 (1.0), CuOTf (0.1), Pd(PPh3)4(0.05)

tolueneb complex mixture

4 MeLi (2.0), CuCN (1.0), Pd(PPh3)4(0.05)

Et2O 1,4-additionproductc

5 MeLi (2.0), CuCN (1.0) Pd(PPh3)4(0.05)

THF 82% (dr = 30:1)d

aAfter complete addition of the organometallic reagents at −78 °C,the palladium catalyst was added and the reaction mixture was slowlywarmed to 70 °C. bSimilar results were obtained with different sol-vents. cOnly a single diastereomer was observed. The poor solubility ofthe Pd catalyst in Et2O might hinder the allylic alkylation. dDiaster-eomers produced by the tandem conjugate addition/intramolecularallylic alkylation were separated by flash column chromatography.

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easily acquired from 5 via a sequence of desulfonylation, TBS-deprotection, mesylation, and benzenesulfonylation. The struc-ture of 4, including stereochemistries, was confirmed by X-raycrystallographic analysis of silylenol ether 16 and a NOE study ofdesulfonylated hydroazulene 13. To avoid facile epimerization atC5, ketone 13 was readily converted to enol phosphonate 14.Phosphate 14 underwent a chemo and diastereoselective dihy-droxylation in the presence of OsO4 to give diol 15 as a single iso-mer. Finally, acetonide protection of diol 15 followed by dephos-phorylation provided the versatile intermediate 3 (Scheme 3).With the key intermediate 3 in hand, we turned our attention

to the construction of tricyclic skeleton bearing a unique hydro-xymethyl cyclopropane unit (Scheme 4). To elaborate the hydo-xymethyl cyclopropane possessing a quaternary carbon center,we conducted a Rh-catalyzed intermolecular cyclopropanationof 3 with ethyl 2-diazopropanoate.19 Following extensive inves-tigation, we finally obtained cyclopropane 17 using a tripheny-lacetate (TPA) ligand with a high steric effect at −40 °C in 61%yield (BRSM 97%) and with excellent diastereocontrol (>30:1)of all three stereogenic centers. The observed high diaster-eoselectivity could be rationalized by a concerted asynchronousmechanism20 in favor of transition state 17b compared to transi-tion state 17a by less steric interaction between the hydroazulenemoiety and the rhodium carbenoid (Scheme 5). To the best ofour knowledge, our cyclopropanation is the first syntheticapplication of catalytic and diastereoselective cyclopropanationusing alkyl diazoacetate.Deprotection of TBS-ether and Barton−McCombie deoxy-

genation of the resulting alcohol 18 successfully afforded esterintermediate 19. However, final removal of the acetonide pro-tecting group failed despite numerous attempts, as ester 19 andthe corresponding alcohol resulting from DIBAL-H reduction of

19 were consistently degraded under standard deprotectionconditions, such as use of HCl, AcOH, TFA, BCl3, and TsOH.After intensive examination of the reaction conditions withvarious mild Lewis acids, (−)-dendroside C aglycon (2) wasfinally obtained by assistance of a lanthanum nitrate catalyst inCH3CN.

21 Spectral data of synthesized 2 was all identical withthe reported data of natural (−)-dendroside C aglycon (2).8

In summary, we accomplished the first total synthesis of thestructurally unique alloaromadendrane-type guaiane sesquiter-pene (−)-dendroside C aglycon from the versatile hydroazuleneintermediate. Facile construction of the challenging 1,4,5-tri-cis-hydroazulene core using an effective Dieckmann condensation isnoteworthy. In addition, the tandem stereoselective conjugateaddition and intramolecular allylic alkylation of butenolide effi-ciently provided the cyclopentane core with the desired ste-reochemistries. Elaboration of the characteristic 5/7/3 tricyclicbackbone was completed by a late-stage carbene-mediated cyclo-propanation with high diastereocontrol. Our versatile syntheticstrategy is anticipated to be widely utilized for a variety of guaianesesquiterpenes. Further studies toward collective syntheses ofguaiane sesquiterpenes and evaluation of biological activities arecurrently underway in our laboratory.

Scheme 3. Synthesis of the Key Intermediate 3 Scheme 4. Completion of the Dendroside C AglyconSynthesis

Scheme 5. Diastereoselective Rh-CatalyzedCyclopropanation of 3

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■ ASSOCIATED CONTENT*S Supporting Information

The Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.orglett.7b03701.

Experimental details and procedures, compound charac-terization data, and 1H and 13C NMR spectra for all newcompounds (PDF)

Accession Codes

CCDC 1562116 contains the supplementary crystallographicdata for this paper. These data can be obtained free of chargevia www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The CambridgeCrystallographic Data Centre, 12 Union Road, CambridgeCB2 1EZ, UK; fax: +44 1223 336033.

■ AUTHOR INFORMATIONCorresponding Author

*E-mail: ygsuh@snu.ac.kr, ygsuh@cha.ac.kr.ORCID

Hongchan An: 0000-0001-6689-9571Hwayoung Yun: 0000-0003-1414-6169Young-Ger Suh: 0000-0003-1799-8607Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis work was supported by the Global Frontier Project grant(NRF-2015M3A6A4065798) of the National Research Founda-tion funded by the Ministry of Science and ICT of Korea and bythe GRRC program of Gyeonggi province (GRRC-CHA2017-B02).

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