Furans as Versatile Synthons: Total Syntheses of Caribenol A andCaribenol BHong-Dong Hao and Dirk Trauner*

Department of Chemistry and Center for Integrated Protein Science, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse5-13, 81377 Munchen, Germany

*S Supporting Information

ABSTRACT: Two complex norditerpenoids, caribenols A and B, were accessed from a common building block. Our synthesisof caribenol A features the diastereoselective formation of the seven-membered ring through a Friedel−Crafts triflation and alate-stage oxidation of a furan ring. The first synthesis of caribenol B was achieved using an intramolecular organocatalyticα-arylation. An unusual intramolecular aldol addition was developed for the assembly of its cyclopentenone moiety, and thechallenging trans-diol moiety was installed through a selective nucleophilic addition to a hydroxy 1,2-diketone. Our overallsynthetic strategy, which also resulted in a second-generation synthesis of amphilectolide, confirms the usefulness of furans aspowerful nucleophiles and versatile synthons.

■ INTRODUCTIONFurans teeter on the edge of aromaticity and can behave bothas arenes and as very electron-rich dienes. As such, they canundergo a wide variety of chemical transformations, includingelectrophilic substitutions, metalations, cycloadditions, and oxida-tions (Scheme 1). If extended to furyl carbinols, their synthetic

power is increased even more, allowing for Piancatelli rearrange-ments and Achmatowicz reactions with subsequent cyclo-additions to access carbocyclic systems. Often associated witha significant increase in molecular complexity, these trans-formations have been extensively exploited in the total synthesisof complex target molecules.1

Many of the functional groups and ring systems accessiblefrom furans can be found in natural products isolated fromthe Caribbean sea plume Pseudopterogorgia. These includediterpenes and norditerpenes with novel carbon skeletons,2

such as aberrarone, caribenol A, and caribenol B (Figure 1)

that have shown biological activity against Mycobacteriumtuberculosis H37Rv and antiplasmodial activity.The caribenols A and B became attractive targets for the

synthetic community due to their intriguing biological activitiesas well as their unique skeletons.2i Caribenol A was shown topossess a caged structure and tricarbocyclic ring system withsix stereocenters. Its first synthesis by Yang and co-workers3a−c

was based on an intramolecular Diels−Alder reaction and alate-stage oxidation to install the hydroxy butenolide moiety.More recently, Luo and co-workers reported an approach tocaribenol A3d that hinges on a Cope rearrangement and a C−Hinsertion reaction.Some years ago, our group launched a program aimed at

a unified synthesis of the Pseudopterogorgia terpenoids. To thisend, we developed a scalable synthesis of furan building block 7

Received: January 8, 2017Published: February 20, 2017

Scheme 1. Furans and Furyl Carbinols as Powerful Synthons

Figure 1. Natural products isolated from Pseudopterogorgia elisabethae.

Article

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© 2017 American Chemical Society 4117 DOI: 10.1021/jacs.7b00234J. Am. Chem. Soc. 2017, 139, 4117−4122

from (−)-β-citronellol, which could be converted into twonatural products: sandresolide B and amphilectolide4

(Scheme 2). We now provide an account of our syntheses ofcaribenols A and B as well as a second-generation synthesisof amphilectolide. They are also based on furan 7 and requiredthe development and application of a new methodology thatexploits the special reactivity of furans.5

■ RESULTS AND DISCUSSIONOur initial synthetic strategies toward caribenol A focused onPauson−Khand reactions6 and gold-catalyzed cycloisomeriza-tions7 to forge the 5−7−6 ring system of the target molecule(Scheme 3). Although allene 8 underwent a clean allenic

Pauson−Khand reaction, the procedure suffered from lowyields and was difficult to scale up due to the instability of 8.Enyne 10, on the other hand, provided the unwanted 6−7−6isomer 11, which bears a quaternary carbon with the correctabsolute configuration. Extensive efforts to reverse the regio-selectivity of this Au-mediated process proved unsuccessful(for the details on the synthesis of 8 and 10, see the SupportingInformation).On the basis of these results and considering the high

nucleophilicity8 of the furan ring, we next explored ourFriedel−Crafts triflation9 for construction of the carbotricyclicframework. Our corresponding retrosynthetic analysis is shownin Scheme 4. It calls for the elaboration of cyclopentenone 13from furan building block 7. Following closure of the seven-membered ring, 12 would be converted into caribenol A viacross coupling and oxidation of the furan ring (Scheme 4).Toward cyclopentenone 13, furan 7 was first converted to

allylic alcohol 15 by Swern oxidation, Wittig olefination, andDIBAL-H reduction in excellent yield (Scheme 5). The terminalalkene 1610 was then made from 15 using Myers’ allylic

reductive transposition method.11 A subsequent cross-metathesisand transformation of the resulting methyl ester to an Evansoxazolidine afforded 18. Diastereoselective conjugate additionpromoted by TMSCl and HMPA12 then gave alkene 19, whichwas converted into 20 through alcoholysis13 and Weinrebamide14 formation. The requisite cyclopentenone 13 was thenconstructed through Grignard addition and a clean ring-closingmetathesis,15 which preserved the stereochemical integrity atC(3). The relative configuration of 13 was verified by X-raydiffraction (see Supporting Information).With enone 13 at hand, we proceeded to investigate the

closure of the seven-membered ring. A variety of Lewis andBrønsted acids failed to afford the desired tetracycle 12 inappreciable amounts (see Supporting Information for details).However, exposure of enone 13 to our Friedel−Crafts triflationconditions led to clean formation of the vinyl triflate 21 as asingle diastereomer.9 The hydrolysis of 21 to the correspondingcyclopentanone 12 was not trivial, but after screening severalconditions we found that TMSOK in THF16 smoothly achievedthis transformation. The structure of 12 was verified by X-raydiffraction (see Supporting Information).With the core structure of caribenol A in hand, the stage was

now set to add the missing methyl group and introduce thedouble bond in the correct position. Using standard conditions(KHMDS, Comins’ reagent), we again arrived at the undesiredisomer 21. Presumably, this was due to a directing effect of thefuran oxygen.Consequently, oxidation of the furan ring was first effected

using peracetic acid17 to provide butenolide 22, an intermediatein Yang’s synthesis of caribenol A.18 Using Barton’s protocol forvinyl iodide formation followed by Stille coupling, syntheticcaribenol A was obtained and found to be identical in all respectswith the natural product (see Supporting Information).We next turned our attention to caribenol B, which features a

fully substituted cyclopentenone ring containing a trans-1,2-diolmoiety. This is a rare structural motif in natural products19

due to its instability under either acidic or basic conditions. Weinitially attempted to access this challenging dihydroxycyclo-pentenone from a furan through the Piancatelli rearrangementor an Achmatowicz reaction20 with subsequent ring contraction(Scheme 6). Retrosynthetic analysis of acetal 23 identifiedfurfural 24 as a key intermediate. It could be traced back toaldehyde 25 and, via α-arylation, to aldehyde 26, which couldbe easily accessed from our previously used ester 14.Our synthesis commenced with hydrogenation and DIBAL-H

reduction of 14. The resulting aldehyde 26 was subjected to theradical cation cyclization21 catalyzed by 28, which, after in situreduction, afforded the stable primary alcohol 29, Scheme 7.The cyclization proved to be highly diastereoselective (dr 20:1)

Scheme 2. Previous Work toward Natural Products TotalSyntheses Using Furan Building Block 7

Scheme 3. Failed Attempts toward Caribenol A

Scheme 4. Revised Retrosynthetic Analysis of Caribenol A

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when the matched enantiomer22 of the catalyst was used. Theconfiguration of the newly formed stereocenter23 at C(3) wasconfirmed by transformation of 29 into amphilectolide. Thespectra of the natural product were identical in all respects tothose previously reported.2d,3d,4

With these results in mind, we proceeded to pursue caribenolB. Furan 29 was subjected to Vilsmeier−Haack conditions,in the course of which the primary alcohol was also formylated,to provide furfural 31, Scheme 8. Exposure to DIBAL-H,subsequent DMDO oxidation, and protection then yielded

Scheme 5. Total Synthesis of Caribenol Aa

aReagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, − 78 °C, then NEt3, −78 °C. (b) Methyl (triphenylphosphoranylidene)acetate, toluene,85 °C (86% over two steps). (c) DIBAL-H, CH2Cl2, −78 to 0 °C (92%). (d) Ph3P, DEAD, IPNBSH, THF, then HFIP, H2O. (e) Hoveyda−Grubbscatalyst second generation (7 mol %), methyl acrylate (20 equiv), CH2Cl2, rt (63% over two steps). (f) TMSOK, THF, 50 °C (94%). (g) Piv-Cl,NEt3, −78 to 0 °C (85%). (h) Isopropenylmagnesium bromide (4.5 equiv), CuCN (2.25 equiv), Et2O, then HMPA, −78 °C, then 18, TMSCl, THF,−78 °C (86%). (i) Sm(OTf)3, MeOH, 50 °C (88%). (j) HNMe(OMe)·HCl (10 equiv), Me2AlCl (10 equiv), 0 °C to rt (86%). (k) Vinylmagnesiumbromide (5 equiv), THF, 0 °C (94%). (l) Hoveyda−Grubbs catalyst second generation (10 mol %), toluene, reflux (77%). (m) 2,6-Di-tert-butylpyridine (2 equiv), Tf2O (3 equiv), CH3CN. (n) TMSOK, THF, 50 °C (53% over two steps). (o) CH3CO3H (2.2 equiv), NaOAc (2.3 equiv),CH2Cl2 (72%). (p) N2H4 (2 equiv), Et3N (3 equiv), EtOH, 50 °C, then I2 (2 equiv), TMG (3 equiv) (56%). (q) Me4Sn (2 equiv), AsPh3 (20 mol %),Pd(PPh3)4 (5 mol %), NMP, 60 °C (33%). IPNBSH = N-isopropylidene-N′-2-nitrobenzenesulfonyl hydrazine, HFIP = hexafluoroisopropanol, TMG =tetramethylguanidine, NMP = N-methyl-2-pyrrolidone.

Scheme 6. Retrosynthetic Analysis of Caribenol B Scheme 7. Organocatalytic α-Arylation and Second-Generation Synthesis of Amphilectolidea

aReagents and conditions: (a) Rh(PPh3)3Cl (10 mol %), H2 balloon,THF, 50 °C (98%). (b) DIBAL-H, CH2Cl2, −78 °C. (c) (2R,5R)-(+)-2-tert-Butyl-3-methyl-5-benzyl-4-imidazolidinone trifluoroaceticacid salt (40 mol %), CAN (2.2 equiv), H2O (2 equiv), DME,−20 °C, 18 h, then MeOH, NaBH4 (15 equiv) (66% over three steps).(d) CH3CO3H, NaOAc, CH2Cl2 (95%). (e) NaBH4, EtOH (82%).(f) TPAP (5 mol %), NMO, CH2Cl2 (60%). (g) n-BuLi, iso-propyltriphenylphosphonium iodide, THF (45%).

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dihydropyran 34 in excellent yield. Unfortunately, 34 couldnot be converted into cyclopentenone 35 via retro-6π-electrocylization and aldol closure despite literature precedence24

and extensive efforts from our side (see Supporting Informationfor details). Consequently, we modified our synthetic strategyto provide a better nucleophile for the aldol-type ring closure25

(for a detailed evolution of our synthetic strategy for caribenol B,see the Supporting Information).Our ultimately successful synthetic route toward caribenol B

is shown in Scheme 9. It commenced with oxidative cyclizationof aldehyde 26. The resulting unstable aldehyde 25 wasimmediately subjected to Julia−Kocienski olefination to installthe isobutenyl side chain in one pot.26 Installation of this side

chain at this stage by this method proved critical. Furan 37was then formylated, and the resulting aldehyde was homolo-gated by Van Leusen reaction27 to nitrile 38. Oxidation withDMDO28 presumably gave a cyanoketone 39, which underwentthe desired aldol cyclization to yield the tertiary alcohol 40.The diastereoselectivity of this addition is presumably governedby the adjacent isobutenyl group. The structure of 40 wasconfirmed by single-crystal X-ray diffraction (see SupportingInformation).29 Hydroxylation of 40 using DMDO affordedthe cyanohydrin 41, which was then treated with AgNO3 and2,6-lutidine30,31 to provide diketone 42 as the penultimateintermediate. To our delight, 42 underwent a diastereoselectiveGrignard addition,32 which afforded caribenol B as a singlediastereomer.In summary, we achieved an asymmetric synthesis of caribenol

A and the first total synthesis of caribenol B. Both of oursyntheses are highly stereoselective and protecting group free.33

The nucleophilicity of furans was critical to the success of ourprogram, as they were used in a Friedel−Crafts triflation and anintramolecular organocatalytic α-arylation. A novel strategy forthe conversion of furfurals into cyclopentenones and a mildmethod for the hydrolysis vinyl triflates were also developed.The scope of the gold-catalyzed cycloisomerization shown inScheme 3 is under active investigation in our laboratories, andresults will be reported in due course.

■ ASSOCIATED CONTENT

*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.7b00234.

(CIF)

(CIF)

Experimental procedures and data (PDF)

(CIF)

(CIF)

Scheme 8. Attempted Achmatowicz Reaction and RingContractiona

aReagents and conditions: (a) POCl3, DMF (70%). (b) DIBAL-H,CH2Cl2 (90%). (c) DMDO, CH2Cl2 (88%). (d) PPTS, MeOH(100%). (e) TBSCl, imidazole, CH2Cl2 (93%).

Scheme 9. Total Synthesis of Caribenol Ba

aReagents and conditions: (a) DIBAL (1.2 equiv), CH2Cl2, −78 °C. (b) (2R,5R)-(+)-2-tert-Butyl-3-methyl-5-benzyl-4-imidazolidinonetrifluoroacetic acid salt (40 mol %), CAN (2.2 equiv), H2O (2 equiv), DME, −20 °C, 18 h. (c) LiHMDS (12 equiv), 36 (12 equiv), −78 °C,1 h, then 0 °C (1 h), rt (30 min) (26% over three steps). (d) POCl3 (1.5 equiv), DMF (79%). (e) Tos-MIC (3 equiv), t-BuOK (4.5 equiv), THF,−50 °C, then MeOH, 65 °C (57%). (f) DMDO (1 equiv), K2CO3 (2 equiv), Na2SO4, CH2Cl2 (77%). (g) DMDO (2 equiv), K2CO3 (2 equiv),Na2SO4, O2 balloon, CH2Cl2 (54%). (h) AgNO3 (10 equiv), 2,6-lutidine (10 equiv), CH3CN. (i) MeMgBr (3 equiv), Et2O (45% over two steps).

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■ AUTHOR INFORMATIONCorresponding Author*E-mail: dirk.trauner@lmu.deORCIDDirk Trauner: 0000-0002-6782-6056NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe thank the Deutsche Forschungsgemeinschaft (SFB 749) forfinancial support. Dr. Peter Mayer is acknowledged for X-rayanalyses. We thank Felix Hartrampf, Giulio Volpin, Dr. Julius R.Reyes, and Dr. Bryan Matsuura (all LMU Munich) for helpfuldiscussions during the preparation of this manuscript and IrinaAlbrecht for early contribution to the project.

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Journal of the American Chemical Society Article

DOI: 10.1021/jacs.7b00234J. Am. Chem. Soc. 2017, 139, 4117−4122

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