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Synthetic Route Development for the Laboratory Preparation ofEupalinilide ETrevor C. Johnson,†,∥ Matthew R. Chin,‡,∥ and Dionicio Siegel*,§

†Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States‡Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States§Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, UnitedStates

*S Supporting Information

ABSTRACT: Following the discovery that the guaianolide naturalproduct eupalinilide E promotes the expansion of hematopoietic stemand progenitor cells; the development of a synthetic route to providelaboratory access to the natural product became a priority.Exploration of multiple synthetic routes yielded an approach thathas permitted a scalable synthesis of the natural product. Two routesthat failed to access eupalinilide E were triaged either as a result ofproviding an incorrect diastereomer or due to lack of syntheticefficiency. The successful strategy relied on late-stage allylicoxidations at two separate positions of the molecule, which significantly increased the breadth of reactions that could be usedto this point. Subsequent to C−H bond oxidation, adaptations of existing chemical transformations were required to permitchemoselective reduction and oxidation reactions. These transformations included a modified Luche reduction and a selectivehomoallylic alcohol epoxidation.

■ INTRODUCTIONA series of sesquiterpene lactones, including eupalinilide E (1)(Figure 1), were isolated in 2004 from Eupatorium lindleyanum,

a plant which has ethnopharmacological uses as an antibacterialand antihistamine.1 Eupalinilide E was unique among coisolatedcompounds, as it possessed selective antiproliferative activityagainst A549 cells (lung cancer harboring KRAS mutation)with an IC50 of 28 nM and no effects on P388 cells (leukemiacell line). Cytotoxic activity against A549 cells is notable, asKRAS mutations make cells significantly less susceptible tochemotherapeutic agents.2,3 As a consequence of this resistance,there is an urgent need to develop drugs for this form ofnonsmall cell lung cancer.4 Patients with cancers possessingKRAS mutations have reduced benefit from adjuvant chemo-therapy, are resistant to EGFR inhibitors, and experience lessclinical success from medication in comparison to other formsof cancer, all of which significantly contribute to a low

expectancy of survival for the patient.5 While it had been shownto possess selective cytotoxicity against a difficult cancer cellline, further evaluation of eupalinilide E did not occur beyondthe initial isolation until the discovery of its ability to controlstem cell fate.There has been a focused effort to discover compounds or

biologics that direct stem cell fate by controlling the cell’sability to undergo differentiation or expansion. Expansion isimportant, as the process increases the number of stem cells toprovide useful quantities of either transplantable cells or cellsthat can be transformed into desired cell types. A significantfocus has been to increase expansion of hematopoietic stem andprogenitor cells (HSPCs), which can transform into blood cells.Transplantable HSPCs are derived from human tissues, eithermobilized peripheral blood or cord blood. Cord blood isobtained from donated umbilical cords that are cryopreservedand stored in a cord blood bank.6 This source of HSPCs isparticularly useful in cases where patients do not have suitablehuman leukocyte antigen (HLA) matched donors.7,8 However,cord blood samples possess a relatively lower HSPC count,which can present an inadequate or reduced response.9

Notably, the number of HSPCs transplanted to the patientdirectly correlates with the successful treatment of autoimmunediseases and recovery from cancer therapy and, as a result ofthis and other factors, two units of cord blood are trans-ferred.10,11 This, as expected, puts increased demand on a

Received: February 2, 2017Published: April 25, 2017

Figure 1. Structure of eupalinilide E (1).

Article

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© 2017 American Chemical Society 4640 DOI: 10.1021/acs.joc.7b00266J. Org. Chem. 2017, 82, 4640−4653

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http://dx.doi.org/10.1021/acs.joc.7b00266

limited supply of donated human tissues. An ideal solution togenerate a limitless supply of HSPCs for transplantation wouldbe to produce the cells ex vivo, outside of the bodyin thelaboratory. While technologies for ex vivo culturing of HSPCshave been developed, a major impediment to culturing in anartificial environment has been rapid differentiation of theresulting cells. To date, the primary approach for expansion hasbeen the use of proteinaceous factors, which have had partialsuccess.12,13 Currently there are no FDA-approved methods forthe expansion of HSPCs; clinical trials are performed on thelaboratory HSPC cells produced. However, there are four smallmolecules that are currently undergoing or about to beginclinical trails for ex vivo expansion of HSPCs: StemRegenin-1(aka SR1 (2)),14,15 UM171 (3),16,17 nicotinamide (4),18,19 and16,16-dimethyl-PGE2 (5)20,21 (Figure 2). Given the impor-tance of developing large-scale, clinically applicable methods forthe production of HSPCs, additional agents functioningthrough novel mechanisms are needed, as related clinical trialshave failed in the past.22

As HSPC expansion is achieved ex vivo, one of the majorimpediments in the clinical development of natural products,pharmacokinetics, is avoided. This allows the diverse andprivileged chemical architectures of natural products to be useddirectly. Natural products that modulate the tailoring ofhistones have been found to be capable of expandingHSPCs.23−25 Schultz and co-workers screened Novartis’ naturalproduct collection in an effort to discover new chemicalscapable of promoting HSPC expansion. From a relatively smalllibrary of natural products of variable origin (∼700compounds), eupalinilide E was shown to markedly drive theexpansion of HSPCs and inhibit differentiation, leading to alarge increase in the number of HSPCs.26 This effect was

possible using either cord blood or human mobilized peripheralblood. Remarkably, this proliferative effect was demonstrated at600 nM, approximately 20-fold of the concentration usedpreviously to kill A549 lung cancer cells. In the first week oftreatment with eupalinilide E the percentage of CD34+ cellsincreased 50% and there was a 2-fold increase in the number ofTHY1+ cells (cells bearing CD34+ and THY+ immunophe-notypes on the surface of undifferentiated cells are identified asHSPCs). Prolonged incubation with the compound (18 days)led to a 4.5-fold increase in the number of cells. Finally, therewas a 45-fold increase in the number of cells after 45 days incomparison to controls using DMSO. The enrichment of bothCD34+ and THY1+ cells was achieved by eupalinilide E’sability to block differentiation and enhance HSPC expansion.The effects of eupalinilide E are reversible, and followingremoval of compound and transfer to fresh, compound-freemedia, the cells demonstrated the standard abilities to expandand differentiate. While the natural product was found toproduce these effects through a novel mode of action, thecharacterization of the target(s) of eupalinilide E was notpossible due to consumption of the eupalinilide E supply27 inthese studies. Similarly, the evaluation of the homing andengraftment abilities of the eupalinilide E expanded cells wasnot possible due to a lack of material.Developing a method for laboratory access to eupalinilide E

presented challenges as a result of the compound’s stereo-chemical complexity, a high degree of oxygenation, andmultiple electrophilic sites, including an α-methylene γ-butyrolactone and chlorohydrin. However, earlier guainolidenatural product syntheses that were successful provided insightinto how to approach the construction of eupalinilide E; inparticular syntheses starting from carvone appeared to provide

Figure 2. Structures of compounds in clinical trials for the ex vivo expansion of HSPCs: SR1 (2), UM171 (3), nicotinamide (4), and 16,16-dimethyl-PGE2 (5).

Figure 3. Syntheses of guainolide natural products starting from carvone (6) proceeding through a Favorskii rearrangement to generatecyclopentane (8).

The Journal of Organic Chemistry Article

DOI: 10.1021/acs.joc.7b00266J. Org. Chem. 2017, 82, 4640−4653

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functional handles for the synthesis. The elaboration of the keyintermediate cyclopentane (8)28 (Figure 3) utilized in thesyntheses of estafiatin (9),29 cladantholide (10),29 thapsigargin(11),30,31 8-epigrosheimin (12),32,33 and chinensiolide B (13)34

provided insight into how eupalinilide E, in large quantities,could be accessed through synthesis starting from carvone.35

■ RESULTS AND DISCUSSIONIn the search for an appropriately substituted cyclopentenestarting point, a report from Wallach (Nobel Prize inChemistry, 1910) in 189936 centered on the Favorskiirearrangement of tribromide 15 fit the requirements for thesynthesis of eupalinilide E (Scheme 1), providing the

appropriately modified cyclopentene 17 (Scheme 1). Wolinskyand co-workers subsequently found that tribromide 15,generated in two steps from carvone (6), underwent anefficient Favorskii rearrangement with isopropyl amine to yieldthe intermediate cyclic imidate 16.37 The intermediate imidatecould be directly hydrolyzed with aqueous acid to generate

lactone 17. This crystalline lactone 17 possesses the requiredcis configuration at the bicyclic junction and the requisitetrisubstituted olefin.Our synthetic efforts toward eupalinilide E began with the

hydrohalogentaion of (R)-carvone (6) using dry hydrobromicacid to furnish carvone monobromide (14) (Scheme 1).Bromination of the remaining trisubstituted olefin withbromine generated tribromide 15. This crude tribromide wascombined with isopropyl amine, forming bicyclic imidate 16.37

Direct hydrolysis of imidate 16 was facilitated by aqueous aceticacid, subsequently yielding lactone 17 (50% yield over foursteps, one silica gel purification) as a stable, crystalline solid(mp 33−35 °C). This short sequence has generated >300 g oflactone 17 during the course of these studies.Initially we sought to introduce oxygen into the cyclopentene

early in the synthetic sequence (Scheme 2). Mori and co-workers established the allylic oxidation of lactone 17 with anexcess of chromium trioxide and 3,5-dimethylpyrazole inmethylene chloride to provide enone 18 with a yield of16%.38 Optimization of oxidant, additive, and time increasedthe yield of 18 to 38% on a 60 g scale. The use of Florisil ratherthan silica gel during chromatography-based purificationincreased both the consistency and yield of this reaction.Selective 1,2-reduction of enone 18 using a Luche reductionproved highly diastereoselective, generating alcohol 19.39

Formation of an ether at the allylic alcohol was achieved withp-methoxybenzyl 2,2,2-trichloroacetimidate and catalytic cam-phorsulfonic acid to yield ether 20, conducted on a 16 g scale.40

Reduction of the lactone 20 using DIBAL yielded adiastereomeric mixture of lactols that when treated withvinylmagnesium bromide provided diol 22 in good yield andwith high diastereoselectivity (Scheme 2). Ether formation ofthe newly formed secondary alcohol was achieved at ambienttemperature using propargyl bromide, yielding diene-yne 23.An unoptimized elimination of the tertiary alcohol usingBurgess reagent selectively formed the required triene-yne 24.

Scheme 1. Synthesis of Lactone 17 Starting from Carvone(6)a

aReagents and conditions: (a): HBr, AcOH, 0 °C; (b) Br2, AcOH, 23°C; (c) i-PrNH2, Et2O, 23 °C; (d) 10% AcOH(aq), THF, 50 °C.

Scheme 2. Synthesis of Triene-yne 24 from Lactone 17a

aReagents and conditions: (a) CrO3, 3,5-dimethylpyrazole, CH2Cl2, 0 °C; (b) CeCl3·7H2O, NaBH4, MeOH, 0 °C; (c) 4-methoxybenzyl-2,2,2-trichloroacetimidate, (+)-camphorsulfonic acid, CH2Cl2, 23 °C; (d) DIBAL, CH2Cl2, −78 °C; (e) vinylmagnesium bromide, THF, 50 °C; (f)propargyl bromide, NaH, THF/DMSO, 23 °C; (g) Burgess reagent, THF, 23 °C.



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Triene-yne 24 provided a suitable substrate for palladium-catalyzed borylative enyne cyclizations that helped simplify thesynthetic approach (Scheme 3). Previously these conditionswere discovered to generate homoallylic boronates in goodyields and selectivities,41 as well as having the capacity to beinfluenced by directing group effects.42 Reaction of triene-yne24 with bis(pinacolato)diboron, palladium(II) acetate, andmethanol in toluene at 50 °C afforded the desired cyclic ether26 (formed after oxidation of the intermediate primaryboronate 25 with hydrogen peroxide and sodium hydroxide).The cyclization was highly diastereoselective and formed therequired trans configuration off of the furan of boronate 25.Oxidation under Swern conditions and immediate treatment ofthe resulting aldehyde 27 with diethylaluminum chlorideresulted in an ene cyclization to afford the 5,7,5-tricycle 28 asa white solid in 76% yield and excellent diastereoselectivity.This finding is in accord with related ene cyclization reactionsof guaianolide natural products.32 To induce crystallinity, thesecondary alcohol was made to react with 3,5-dinitrobenzylchloride to provide ester 29, which generated crystals suitablefor X-ray diffraction (Supporting Information). From thisstructure it was determined that the addition of vinyl-magnesium bromide into lactol 21 formed the incorrectdiastereomer (Scheme 2) which relayed subsequent stereo-chemistry generated in the synthesis (Scheme 3). Theformation of the diastereomer, can be rationalized by thechelation controlled addition of vinyl Grignard into the openform alkoxide of lactol 21. Although the stereocenter wasincorrect, the steps that followed achieved the proper relativeconfiguration.Two changes to the general approach were implemented:

delaying the C−H bond oxidation, previously using lactone 17,until later in the synthesis and installing the 1,1-disubstitutedolefin prior to the vinyl addition (Scheme 4). Reduction oflactone 17 with lithium aluminum hydride formed diol 30 inquantitative yield. Previously, the poor yields using Burgessreagent to eliminate the tertiary alcohol prompted thedevelopment of a different method for elimination to formolefin 32. Acetate pyrolysis, conducted in neat acetic anhydridein an oil bath heated to 150 °C, provided a mixture of thedesired olefin 32, the tetrasubstituted olefin 31, and diacetate of30. Initially the ratio of these three products varied as theconditions were modified. However, the addition of activated,crushed molecular sieves improved the consistency of this

reaction, after further optimization, yielding a 2/1 mixture of 32and 31, favoring the desired olefin 32, in 91% combined yieldwhen the reaction was conducted on a 40 g scale. Aldehyde 34was synthesized by lithium aluminum hydride cleavage of theprimary acetate to form alcohol 33 followed by oxidation withDess−Martin periodinane.In an optimized sequence aldehyde 34 in tetrahydrofuran

was added to a solution of vinyllithium, generated in situ fromtetravinyltin and n-butyllithium at −78 °C, to generate alkoxide35 (Scheme 5). To a solution of the alkoxide 35 was thenadded anhydrous HMPA followed by propargyl bromide. Thedesired triene-yne 36 was isolated in 81% yield on a 23 g scale.The alkyne was silylated with n-butyllithium and trimethylsilylchloride to attenuate the eventual reactivity of an α-methylene-γ-butyrolactone (vide infra). This modification had the addedbenefit that it doubled the previous yield for the borylativeenyne cyclization,41 and it was found this reaction could bereliably conducted on a 20 g scale. The structure of the cyclizedproduct 39 was confirmed by X-ray crystallographic diffraction(Supporting Information).Primary alcohol 39 was oxidized using Swern conditions, and

the crude aldehyde generated 40 on treatment withdiethylaluminum chloride, undergoing cyclization at −78 °C(Scheme 6). This allowed access to tricycle 41 in excellent yieldon a 12 g scale. The required tigloyl ester was installed withtiglic acid under Yamaguchi esterification conditions.43 Thisimproved route, accessing the correct diastereomer, enabled thesynthesis of over 55 g of carbocycle 42.

Scheme 3. Synthesis of Tricycle 29 from Triene-yne 24a

aReagents and conditions: (a) Pd(OAc)2, B2Pin2, MeOH, PhMe, 50 °C; (b) H2O2(aq), NaOH(aq), THF, 0 °C; (c) (COCl)2, DMSO, Et3N,CH2Cl2, −78 °C; (d) Et2AlCl, CH2Cl2, −78 °C; (e) 3,5-dinitrobenzoyl chloride, DMAP, Et3N, CH2Cl2, 23 °C.

Scheme 4. Synthesis of Aldehyde 34 from Lactone 17a

aReagents and conditions: (a) LiAlH4, Et2O, 0 °C; (b) Ac2O(neat),150 °C; (c) LiAlH4, Et2O, 0 °C; (d) Dess−Martin periodinane,NaHCO3, CH2Cl2, 23 °C.



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The carbocyle 42 underwent a double allylic oxidation ontreatment with chromium trioxide and 3,5-dimethylpyrazole toyield 43 in 30% on a 3 g scale (Table 1). Many other reagentsand conditions were investigated for this reaction, includingselenium dioxide, manganese(III) acetate, and other chromiumbased reagents such as PDC and Collins reagent. In general,these provided little to none of the desired product. Althoughearlier trials on a 500 mg scale gave a 46% yield, this could not

be replicated upon scale-up, as a result of poor scalability of thechemistry. Reduction of the enone carbonyl under Lucheconditions generated allylic alcohol 44 as a single diastereomerin 92% yield (Figure 4).In the absence of the vinyl trimethylsilyl group, significant

1,4-reduction of the α-methylene-γ-butyrolactone was observedunder Luche conditions. However, due to the reactivity of theα-methylene-γ-butyrolactone, problems arose when attemptingto remove the vinyl trimethylsilyl within 44. The use offluoride-based reagents such as tetrabutylammonium fluoride,pyridinium poly(hydrofluoride), cesium fluoride, and tetrabu-tylammonium difluorotriphenylsilicate resulted in nonproduc-tive reactions. Protic acids such as hydrochloric acid andtrilfuoroacetic acid induced extensive decomposition.Bachi and co-workers developed a strategy for the cleavage of

similar trimethylsilyl groups by the conjugate addition ofthiophenol into the α-methylene-γ-butyrolactone followed bythe addition of tetrabutylammonium fluoride.44 This sequenceformed the corresponding thioether and a small amount of there-formed α-methylene-γ-butyrolactone. The method wasimproved by the addition of excess methyl acrylate as aMichael acceptor trap to capture released thiophenol.This sequence was adapted for the desilylation of the vinyl

trimethylsilyl group of 44 (Scheme 7). Through this sequencethe desired “free” α-methylene-γ-butyrolactone 45 was isolatedin 53% yield. Purification complications associated with 45prompted the development of a more lengthy sequence. First

Scheme 5. Synthesis of Vinylsilane 39 from Aldehyde 34a

aReagents and conditions: (a) tetravinyltin, n-BuLi, THF, −78 °C, then 34, then HMPA, propargyl bromide, 23 °C; (b) TMSCl, n-BuLi, THF, −78°C; (c) Pd(OAc)2, B2Pin2, MeOH, PhMe, 50 °C; (d) H2O2(aq), NaOH(aq), THF, 0 °C.

Scheme 6. Synthesis of Tricycle 42 from Vinylsilane 39a

aReagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C; (b) Et2AlCl, CH2Cl2, −78 °C; (c) tiglic acid, DMAP, Et3N, 2,4,6-trichlorobenzoyl chloride, PhMe, 80 °C.

Table 1. Allylic Oxidation of Tricycle 42

oxidant additive solvent temp (°C) time (h) yield (%)

SeO2 n/a dioxane 80 2 decMn(OAc)3/TBHP O2, 3 Å MS EtOAc 70 24 decCrO3/H2SO4 n/a Me2CO 23 24 decPDC n/a DMF 50 24 <5CrO3·3,5-DMP n/a CH2Cl2 0 0.5 46 (500 mg scale)CrO3·3,5-DMP n/a CH2Cl2 0 0.5 30 (3 g scale)



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the addition of thiophenol proceeded well to form thioether 46,which underwent desilylation with tetrabutylammoniumfluoride to afford 47. Thio adduct 47 was oxidized, providingsulfone 48, which was eliminated with basic alumina to formthe desired α-methylene-γ-butyrolactone 45 in 50% overallyield from 44.This four-step sequence proved cumbersome and made

scale-up difficult; as a consequence silicon removal prior tooxidation was achieved by protodesilylation of 42 usingtrifluoroacetic acid, cleanly yielding triene 49 (Scheme 8).

Selective, double allylic C−H oxidation formed 50 in 36% yieldon a 1.6 g scale. Luche reduction of 50 was complicated bycompetitive reduction of the activated, exocyclic alkene of 50,leading to a mixture of the desired alcohol 45, 1,4-reduced α-methylene-γ-butyrolactone, and the over-reduced derivative of45. Attempts to use less reactive hydride sources including zinc

borohydride or sodium tris(hexafluoroisopropoxy)borohydridefailed to transform 50. It was observed that Luche reduction at−78 °C in methanol did not reduce 50 and it was only uponwarming that a reaction was observed. Garcia Ruano and co-workers utilized ytterbium(III) trifluoromethanesulfonate at−78 °C to promote 1,2-reduction of an enone, providing amodification to the Luche reduction.45 Slow addition of sodiumborohydride to a solution of stoichiometric ytterbium(III)trifluoromethanesulfonate and enone 50 at −78 °C formed thedesired allylic alcohol 45 in 75% isolated yield. It provedimportant to quench residual hydride at −78 °C by theaddition of an excess of acetaldehyde prior to removal of thecooling bath, minimizing the amount of over-reduced product.The final oxidative transformation to be achieved required

the diastereoseletive epoxidation of a homoallylic alcohol overan allylic alcohol with 45 (Table 2). Initial attempts using thedioxirane catalyst derived from fructose, developed by Shi,formed a small amount of desired epoxide 51 in 30% yield.46

Several other similar catalysts were examined but yieldedsimilar results. Hydroxyl-directed epoxidation reactions werealso examined. The use of tert-butyl hydroperoxide along withvanadyl acetylacetonate, molybdenum hexacarbonyl, or tita-nium isopropoxide produced a 50:50 mixture of 51 and theundesired epoxide 52 with minor doubly oxidized product 53.The addition of either (+)- or (−)-diethyl tartrate as ligandsinhibited the reaction. Takai and co-workers investigated theuse of less conventional aluminum complexes in theepoxidation of several different olefins.47 Initially, tert-butylhydroperoxide and trimethylaluminum in a solution ofmethylene chloride at ambient temperature afforded 51 and52 in the first favorable ratio of 80:20 (51:52). Furtheroptimization of this result led to the use of tert-butylhydroperoxide in combination with aluminum tri-sec-butoxideto increase the selectivity and provide 51 in 86% yield.Finally, opening of epoxide 51 with dry hydrochloric acid in a

lithium chloride saturated tetrahydrofuran solution cleanlyprovided eupalinilide E (1) as a white solid matching all

Figure 4. Selective conjugate reduction of 43 followed by an inability to remove silicon from vinylsilane 44.

Scheme 7. Multistep Removal of Trimethylsilyl Group from Silane 44a

aReagents and conditions: (a) NaH, PhSH, EtOH, 23 °C; (b) TBAF, THF, 23 °C; (c) NaIO4, MeOH/H2O, 23 °C; (d) basic alumina, CH2Cl2, 23°C.

Scheme 8. Improved Reaction Sequence Accessing α-Methylene-γ-butyrolactone 45a

aReagents and conditions: (a) TFA, CH2Cl2, 23 °C; (b) CrO3, 3,5-dimethylpyrazole, CH2Cl2, 0 °C; (c) Yb(OTf)3, NaBH4, MeOH/THF,− 78 °C (acetaldehyde quench).



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reported spectral data1 as well as independent 2D-NMRexperiments (Scheme 9). In the absence of added lithiumchloride the epoxide was opened by the proximal alcohol,forming furan 52.

■ CONCLUSIONThe chemistry and biology of eupalinilide E inspired thedevelopment of the first laboratory route to the natural product.With the evolution of multiple synthetic approaches a finalstrategy was developed that yielded eupalinilide E (>400 mg ina single batch), generating ample material for testing and probedevelopment. Preliminary route failure could be retrospectivelytraced to premature introduction of oxygen into syntheticintermediates. As a consequence, the successful strategyintroduced oxygen at a late stage through oxidation of activatedmethylene groups, providing carbonyls. This approachmaximized substrate compatibility with different reagents upto the late-stage oxidation. Following C−H bond oxidationtuning of chemical transformations, chemoselective reductionand oxidation were required and included a modified Luchereduction and a selective homoallylic alcohol epoxidation.

■ EXPERIMENTAL SECTIONMaterials and Methods: General Considerations. All reactions

were performed in flame-dried round-bottom flasks fitted with rubbersepta under a positive pressure of argon or nitrogen, unless otherwiseindicated. Air- and moisture-sensitive liquids and solutions weretransferred via syringe or cannula. Organic solutions were concen-trated by rotary evaporation at 20 Torr in a water bath heated to 40 °Cunless otherwise noted. Diethyl ether (Et2O), methylene chloride(CH2Cl2), tetrahydrofuran (THF), and toluene (PhMe) were purifiedusing a Pure-Solv MD-5 Solvent Purification System (InnovativeTechnology). Acetonitrile (MeCN), N,N-dimethylformamide (DMF),and methanol (MeOH) were purchased from Acros (99.8%,anhydrous), and ethanol (EtOH) was purchased from Pharmco-Aaper (200 proof, absolute). The molarity of n-butyllithium wasdetermined by titration against diphenylacetic acid. All other reagentswere used directly from the supplier without further purification unlessotherwise noted. Analytical thin-layer chromatography (TLC) wascarried out using 0.2 mm commercial silica gel plates (silica gel 60,F254, EMD chemical) and visualized using a UV lamp and/or aqueousceric ammonium molybdate (CAM), aqueous potassium permanga-nate (KMnO4) stain, or ethanolic vanillin. Infrared spectra wererecorded on a Nicolet 380 FTIR instrument using the neat thin filmtechnique. High-resolution mass spectra (HRMS) were recorded on aKaratos MS9 or Agilent Technologies 6530 Accurate-Mass Q-TOFLC/MS and are reported as m/z (relative intensity). Accurate massesare reported for the molecular ion [M + Na]+, [M + H]+, [M], or [M−H]−. Nuclear magnetic resonance spectra (1H NMR and 13C NMR)were recorded with a Varian Gemini (400 MHz, 1H at 400 MHz, 13Cat 100 MHz; 500 MHz, 1H at 500 MHz, 13C at 125 MHz; 600 MHz,1H at 600 MHz, 13C at 150 MHz). For CDCl3 solutions the chemicalshifts are reported as parts per million (ppm) referenced to residualprotium or carbon of the solvent: CHCl3, δ(H) 7.26 ppm; CDCl3,δ(D) 77.0 ppm. For (CD3)2SO solutions the chemical shifts arereported as parts per million (ppm) referenced to residual protium orcarbon of the solvents: (CD3)(CHD2)SO, δ(H) 2.50 ppm; (CD3)2SO,δ(C) 39.5 ppm. For CD3OD solutions the chemical shifts are reportedas parts per million (ppm) referenced to residual protium or carbon ofthe solvents: CHD2OD, δ(H) 3.31 ppm; CD3OD, δ(C) 49.0 ppm.Coupling constants are reported in hertz (Hz). Data for 1H NMRspectra are reported as follows: chemical shift (ppm, referenced toprotium; s = singlet, d = doublet, t = triplet, q = quartet, dd = doubletof doublets, td = triplet of doublets, ddd = doublet of doublet ofdoublets, ddq = doublet of doublet of quartets, bs = broad singlet, bd =broad doublet, m = multiplet, coupling constant (Hz), andintegration). Melting points were measured on a MEL-TEMP devicewithout corrections.

Table 2. Selective Epoxidation of α-Methylene-γ-butyrolactone 45 Generating Epoxide 51a

yield (%)

metal complex oxidant solvent temp (°C) 51 52 53

n/a mCPBA CH2Cl2 0 0 90 5n/a DMDO Me2CO −78 0 0 0VO(acac)2 TBHP CH2Cl2 0 45 50 5Mo(CO)6 TBHP CH2Cl2 0 45 50 5Ti(O-i-Pr)4 TBHP CH2Cl2 0 45 50 5Ti(O-i-Pr)4

b TBHP CH2Cl2 0 no reactionAlMe3 TBHP CH2Cl2 0 80 20 0Al(O-sec-Bu)3 TBHP CH2Cl2 0 95 5 0

aRatios were determined by integration of crude 1H NMR peaks. bWith (+)- or (−)-DET.

Scheme 9. Completion of the Synthesis of Eupalinilide E (1)from Epoxide 51



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(R)-5-(2-Bromopropan-2-yl)-2-methylcyclohex-2-en-1-one(14). To a stirred solution of 33% hydrobromic acid in acetic acid (219mL, 1.33 mmol, 2.0 equiv) at 0 °C was slowly added a solution of (R)-carvone (6) (104 mL, 666 mmol, 1.0 equiv) in acetic acid (100 mL)dropwise over 15 min. After 45 min, the reaction mixture was pouredover ice H2O (600 mL) and extracted with EtOAc (3 × 800 mL). Thecombined organic layers were washed with H2O (800 mL), saturatedaqueous NaHCO3 (800 mL), and brine (800 mL), dried over Na2SO4,and concentrated in vacuo to give the crude monobromide as anamber oil, which was used without purification: Rf = 0.36 (silica gel,10/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 6.0Hz, 1H), 2.75 (dq, J = 2.0, 16.0 Hz, 1H), 2.61−2.55 (m, 1H), 2.45−2.36 (m, 2H), 2.04 (m, 1H), 1.79 (s, 6H), 1.76 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 198.8, 144.1, 134.9, 69.9, 47.9, 40.9, 32.1, 31.9,28.8, 15.4; IR (film, cm−1) 2972, 2922, 1673, 1384; HRMS (ESI-TOF)m/z [M + H]+ calcd for C10H15OBr 231.0385, found 231.0381.(2R,3R,5S)-2,3-Dibromo-5-(2-bromopropan-2-yl)-2-methyl-

cyclohexan-1-one (15). To a stirred solution of crude monobromide14 (154 g, 666 mmol, 1.0 equiv) in AcOH (440 mL, 1.5 M) at 23 °Cin a water bath was added a solution of bromine (41 mL, 800 mmol,1.2 equiv) in AcOH (70 mL) dropwise over 1 h. After 1.5 h, thereaction mixture was poured over ice H2O (600 mL) and extractedwith Et2O (3 × 600 mL). The combined organic layers were washedwith H2O (600 mL), saturated aqueous NaHCO3 (5 × 600 mL), andbrine (600 mL), dried over Na2SO4, and concentrated in vacuo to givecrude tribromide 15 as an amber oil, which was used withoutpurification: Rf = 0.56 (silica gel, 10/1 hexanes/EtOAc); 1H NMR(400 MHz, CDCl3) δ 4.78 (t. J = 2.7 Hz, 1H), 3.26 (dd, J = 12.5, 15.3Hz, 1H), 2.89 (m, 1H), 2.63−2.57 (dq, J = 2.4, 15.3 Hz, 1H), 2.39−2.28 (m, 2H), 1.92 (s, 3H), 1.74 (s, 3H), 1.70 (s, 3H); 13C NMR (100MHz, CDCl3) δ 200.7, 69.6, 61.9, 58.7, 46.0, 38.2, 33.6, 32.6, 32.3,27.6; IR (film, cm−1) 1720, 1103; HRMS (ESI-TOF) m/z [M + H]+

calcd for C10H15OBr3 388.8751, found 388.8761.(3aR ,6aR)-3,3,6-Trimethyl-3,3a,4,6a-tetrahydro-1H-

cyclopenta[c]furan-1-one (17). To a stirred solution of crudetribromide 15 (260 g, 7.32 mol, 1.0 equiv) in Et2O (2.66 L, 0.25 M) at0 °C was slowly added isopropyl amine (630 mL, 7.32 mol, 11.0equiv) over 30 min. Upon complete addition, the reaction mixture waswarmed to 23 °C. After 12 h, the reaction mixture was cooled to 0 °Cbefore carefully adding 10% aqueous H2SO4 (600 mL). The aqueouslayer was separated, and the organic layer was extracted with 10%aqueous H2SO4 (3 × 600 mL). The combined aqueous layers werecooled to 0 °C with stirring before being brought to pH 8.0 with 10 NNaOH (600 mL). The neutralized solution was extracted with EtOAc(4 × 600 mL), washed with brine (600 mL), dried over Na2SO4, andconcentrated in vacuo to give crude imidate 16 as an amber oil, whichwas used without purification.A stirred solution of crude imidate 16 (138 g, 666 mol, 1.0 equiv) in

a 3/1 solution of THF/10% aqueous AcOH (1.33 L, 0.5 M) washeated to 50 °C. After 3 h, the reaction mixture was cooled to 23 °Cbefore pouring over ice and saturated aqueous NaHCO3 (1 L). Thereaction mixture was extracted with EtOAc (4 × 600 mL), washedwith brine (600 mL), dried over Na2SO4, and concentrated in vacuo togive an amber oil. The crude material was purified via silica gel columnchromatography (5/1 hexanes/EtOAc) followed by recrystallizationfrom hexanes to give pure bicycle 17 (55.3 g, 333 mmol, 50% over foursteps) as a white solid (mp 33−35 °C). Spectral data matched thosepreviously reported:38 Rf = 0.41 (silica gel, 5/1 hexanes/EtOAc); 1HNMR (400 MHz, CDCl3) δ 5.23 (bd, J = 2.0 Hz, 1H), 3.39 (d, J = 9.0Hz, 1H), 2.81, (q, J = 6.3 Hz, 1H), 2.30 (t, J = 2.0 Hz, 2H), 2.28 (t, J =2.0 Hz, 1H), 1.68 (s, 3H), 1.26 (s, 3H), 1.17 (s, 3H); 13C NMR (100MHz, CDCl3) δ 175.2, 135.5, 126.1, 85.2, 56.1, 47.9, 33.1, 30.2, 23.4,14.1; IR (film, cm−1) 1758, 1270, 1119; HRMS (ESI-TOF) m/z [M +Na]+ calcd for C10H14O2 189.08860, found 189.08940.(3aR,6aR)-3,3,6-Trimethyl-3a,6a-dihydro-1H-cyclopenta[c]-

furan-1,4(3H)-dione (18). To a stirred solution of 3,5-dimethylpyr-azole (521 g, 5.4 mol, 15 equiv) in CH2Cl2 (2.4 L, 0.15 M) at 0 °C wasadded solid CrO3 (541 g, 5.4 mol, 15 equiv) in five even portions over15 min. A solution of bicycle 17 (60 g, 361 mmol, 1.0 equiv) inCH2Cl2 (200 mL) was then added dropwise over 15 min. After it was

stirred for 5 h at 23 °C, the reaction mixture was diluted dropwise withdiethyl ether (800 mL) and filtered through a pad of Celite. The padof Celite was washed with EtOAc (3 × 500 mL), and the combinedorganics were concentrated in vacuo. The crude material was purifiedvia silica gel column chromatography (1/1 hexanes/EtOAc) twice togive pure enone 18 (24.8 g, 137 mmol, 38%) as an off-white solid (mp38−40 °C). Spectral data matched those previously reported:38 Rf =0.51 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ5.90 (s, 1H), 3.85 (d, J = 7.4 Hz, 1H), 2.95 (d, J = 7.4 Hz, 1H), 2.30(s, 3H), 1.51 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ205.3, 174.5, 172.5, 131.6, 84.6, 55.1, 52.9, 31.5, 24.6, 17.3; IR (film,cm−1) 1761, 1689, 1619, 1125; HRMS (ESI-TOF) m/z [M + H]+

calcd for C10H12O3 181.0865, found 181.0869.(3aS,4R,6aR)-4-Hydroxy-3,3,6-trimethyl-3,3a,4,6a-tetrahy-

dro-1H-cyclopenta[c]furan-1-one (19). To a stirred solution ofenone 18 (16 g, 89 mmol, 1.0 equiv) in MeOH (355 mL, 0.25 M) wasadded solid CeCl3·7H2O (66.2 g, 178 mmol, 2.0 equiv) in a singleportion at 0 °C. The clear reaction was stirred for 30 min at 0 °Cbefore solid NaBH4 (5.0 g, 133 mmol, 1.5 equiv) was added in threeequal portions over 15 min. The clear reaction mixture was stirredfurther for 1 h at 23 °C before the addition of saturated aqueousNH4Cl (200 mL). The aqueous mixture was extracted with Et2O (3 ×200 mL), and the combined organic layers were washed with brine (1× 100 mL), dried over Na2SO4, and concentrated in vacuo. The crudereaction mixture was purified via silica gel column chromatographyusing 1/1 hexanes/EtOAc to give the alcohol 19 (15.8 g, 87 mmol,98%) as a white solid (mp 107−110 °C): Rf = 0.55 (silica gel, 1/1hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.60 (s, 1H), 4.96(bs, 1H), 3.45 (d, J = 7.8 Hz, 1H), 2.88 (t, J = 7.8, 1H) 1.95 (s, 3H),1.66 (s, 3H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.4,140.0, 130.9, 86.2, 76.5, 54.9, 52.7, 31.2, 24.6, 15.0; IR (film, cm−1)3436, 1732, 1124; HRMS (ESI-TOF) m/z [M + H]+ calcd forC10H14O3 183.1021, found 183.1027.

(3aS,4R,6aR)-4-((4-Methoxybenzyl)oxy)-3,3,6-trimethyl-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-one (20). To astirred solution of alcohol 19 (15.8 g, 87 mmol, 1.0 equiv) in CH2Cl2(434 mL, 0.2 M) was added neat, freshly prepared1 4-methoxybenzyl-2,2,2-trichloroacetimidate (36.0 mL, 173 mmol, 2.0 equiv) and solid(+)-CSA (2.0 g, 8.67 mmol, 0.1 equiv) in single portions. The paleyellow homogeneous reaction was stirred at 23 °C for 18 h. Thereaction mixture was poured into pH 7.0 phosphate buffer (500 mL),and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL). Thecombined organic layers were washed with brine (1 × 100 mL), driedover Na2SO4, and concentrated in vacuo. The crude material waspurified via silica gel column chromatography (5/1 hexanes/EtOAc)to give the PMB alcohol 20 (22.8 g, 75 mmol, 87%) as a clear oil: Rf =0.29 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ7.25 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.63 (m, 1H), 4.72(m, 1H), 4.52 (q, J = 11.7 Hz, 2H), 3.81 (s, 3H), 3.38 (d, J = 7.0 Hz,1H), 3.07 (t, J = 7.0 Hz, 1H), 1.83 (s, 3H), 1.53 (s, 3H), 1.50 (s, 3H);13C NMR (100 MHz, CDCl3) δ 174.7, 159.2, 138.1, 130.2, 128.9,128.7, 113.8, 87.2, 83.1, 72.2, 55.2, 55.0, 51.2, 30.9, 26.2, 14.6; IR (film,cm−1) 2976, 2967, 2837, 1756; HRMS (ESI-TOF) m/z [M] calcd forC18H22O4 302.1518, found 302.1517.

(R ) -1- ( (1R ,4R ,5S ) -5- (2-Hydroxypropan-2-yl ) -4- ( (4-methoxybenzyl)oxy)-2-methylcyclopent-2-en-1-yl)prop-2-en-1-ol (22). To a stirred solution of PMB alcohol 20 (16 g, 52.9 mmol,1.0 equiv) in CH2Cl2 (265 mL, 0.2 M) at −78 °C was added a 1.0 Msolution of DIBAL-H in PhMe (79 mL, 79 mmol, 1.5 equiv) dropwiseover 5 min. The white heterogeneous reaction was stirred further at−78 °C for 1.5 h. H2O (30 mL) and 10% NaOH (30 mL) were addedin single portions, and the reaction mixture was warmed to 23 °C. Thecrude reaction mixture was filtered through a pad of Celite, and thepad of Celite was washed with CH2Cl2 (3 × 200 mL). The combinedorganics were concentrated in vacuo to give the lactol 21 as a yellowoil, which was used immediately without purification. To a stirredsolution of crude lactol 21 (16.0 g, 52.6 mmol, 1.0 equiv) in THF (526mL, 0.1 M) was added a 0.7 M solution of vinylmagnesium bromide inTHF (373 mL, 263 mmol, 5 equiv) dropwise via cannula over 30 min.The dark red homogeneous reaction mixture was stirred at 50 °C for



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1.5 h. The reaction mixtue was cooled to 0 °C before saturatedaqueous NH4Cl (500 mL) was added portionwise. The aqueousmixture was extracted with Et2O (3 × 200 mL), and the combinedorganic layers were washed with brine (1 × 100 mL), dried overNa2SO4, and concentrated in vacuo to give the alcohol 22 as a red oil,which was used directly without purification: Rf = 0.39 (silica gel, 3/1hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 6.7 Hz,2H), 6.88 (d, J = 6.7 Hz, 2H), 5.99 (m, 1H), 5.81 (m, 1H), 5.68 (d, J =3.1 Hz, 1H), 5.23 (d, J = 16.7 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 4.56(d, J = 11.0 Hz, 1H), 4.46−4.37 (m, 3H), 4.34 (d, J = 11.0, 1H), 3.81(s, 3H), 2.62 (q, J =5.9 Hz, 1H), 2.08 (t, J = 5.5 Hz, 1H), 1.84 (s, 3H),1.44 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2,153.1, 141.6, 130.7, 130.1, 126.4, 116.0, 114.5, 82.8, 76.9, 72.7, 70.4,57.7, 56.7, 55.6, 30.3, 27.9, 19.1; IR (film, cm−1) 3454.71, 2973.78,2909.44, 1612.34, 1514.76; HRMS (ESI-TOF) m/z [M + H]+ calcdfor C20H28O4 333.2066, found 333.2066.2-((1S,2R,5R)-5-((4-Methoxybenzyl)oxy)-3-methyl-2-((R)-1-

(prop-2-yn-1-yloxy)allyl)cyclopent-3-en-1-yl)propan-2-ol (23).To a stirred solution of crude alcohol 22 (17.5 g, 52.0 mmol, 1.0equiv) in a 10/1 solution of THF/DMSO (52.6 mL, 1.0 M) was added60% NaH (4.63 g, 116 mmol, 2.2 equiv) portionwise over 15 min. An80% solution of propargyl bromide in PhMe (11.7 mL, 105 mmol, 2.0equiv) was added, and the dark heterogeneous reaction mixture wasstirred at 23 °C for 18 h. H2O (100 mL) was added, and the reactionmixture was diluted with EtOAc (500 mL). The organic layer waswashed with H2O (3 × 100 mL) and brine (1 × 100 mL), dried overNa2SO4, and concentrated in vacuo. The crude material was purifiedvia silica gel column chromatography using 3/1 hexanes/EtOAc togive the alkyne 23 (6.24 g, 16.8 mmol, 32% over three steps) as ayellow oil: Rf = 0.31 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400MHz, CDCl3) δ 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H),5.74 (s, 1H), 5.68 (m, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.08 (d, J = 11.0Hz, 1H), 4.92 (d, J = 6.7 Hz, 1H), 4.48 (d, J = 11.0, 1H), 4.41 (d, J =5.9 Hz, 1H), 4.29 (d, J = 11.0 Hz, 1H), 4.17 (dd, J = 2.4, 15.6 Hz, 1H),4.06 (dd, J = 2.4, 15.6 Hz, 1H), 3.84 (s, 1H), 3.78 (s, 3H), 2.89 (d, J =7.0 Hz, 1H), 2.37 (t, J = 2.4 Hz, 1H), 2.15 (dd, J =2.3, 5.5 Hz 1H),1.85 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3)δ 159.0, 151.1, 135.0, 130.1, 129.2, 124.8, 116.7, 113.6, 82.4, 80.8, 78.8,73.4, 71.3, 69.3, 55.2, 55.0, 54.5, 53.7, 30.8, 28.0, 18.1; IR (film, cm−1)3367, 2982, 2950, 1761, 1689, 1619, 1390; HRMS (ESI-TOF) m/z[M + Na]+ calcd for C23H30O4 393.20360, found 393.20440.1-Methoxy-4-((((1R,4R,5R)-3-methyl-5-(prop-1-en-2-yl)-4-

((R)-1-(prop-2-yn-1-yloxy)allyl)cyclopent-2-en-1yl)oxy)-methyl)benzene (24). To a stirred solution of alcohol 23 (6.24 g,16.8 mmol, 1.0 equiv) in THF (168 mL, 0.1 M) at 23 °C was addedsolid, freshly prepared2 Burgess reagent (6.0 g, 25.3 mmol, 1.5 equiv)in a single portion. The pale yellow homogeneous reaction mixturewas stirred for 5 min before addition of pH 7 phosphate buffer (200mL). The aqueous mixture was extracted with Et2O (3 × 100 mL),and the combined organic layers were washed with brine (1 × 50 mL),dried over Na2SO4, and concentrated in vacuo. The crude material waspurified via silica gel column chromatography using 10/1 hexanes/EtOAc to give the triene 24 (2.19 g, 6.22 mmol, 37%) as a yellow oil:Rf = 0.5 (silica gel, 10/1 hexanes/EtOAc); 1H NMR (400 MHz,CDCl3) δ 7.25 (d, J =8.2 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 5.81 (m,1H), 5.58 (s, 1H), 5.30 (d, J = 9.8 Hz, 1H), 5.23 (s, 1H), 5.14 (d, J =2.7 Hz, 1H), 4.95 (s, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.48 (bs, 1H),4.38 (d, J = 11.4 Hz, 1H), 4.11 (dd, J = 2.2, 13.7 Hz, 1H), 3.89−3.79(m, 5H), 3.39 (t, J = 6.7 Hz, 1H), 2.78 (m, 1H), 2.37 (m, 1H), 1.81 (s,3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 143.2,141.8, 136.7, 131.0, 129.2, 129.1, 118.7, 115.6, 113.5, 82.5, 80.4, 80.1,73.4, 70.8, 55.2, 54.8, 53.6, 24.3, 17.5; IR (film, cm−1) 1514, 1248;HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H28O3 375.19310,found 375.19320.((2S,3S)-2-((1R,4R,5R)-4-((4-Methoxybenzyl)oxy)-2-methyl-5-

(prop-1-en-2-yl)cyclopent-2-en-1-yl)-4-methylenetetrahydro-furan-3-yl)methanol (26). To a stirred solution of triene 24 (1.36 g,3.86 mmol, 1.0 equiv) in PhMe (38.6 mL, 0.1 M) at 23 °C were addedsolid bis(pinacolato)diboron (1.08 g, 4.24 mmol, 1.1 equiv), solidpalladium(II) acetate (43 mg, 0.19 mmol, 0.05 equiv), and neat

MeOH (0.16 mL, 72.1 mmol, 1.0 equiv). The reaction mixture washeated to and stirred at 50 °C. After 4 h, the reaction mixture wascooled to 23 °C and concentrated in vacuo to give the boronate esteras an amber oil. To a stirred solution of the crude boronate ester inTHF (77.2 mL, 0.05 M) at 0 °C was carefully added 1 N NaOH (11.6mL, 11.6 mmol, 3.0 equiv) and 30% aqueous H2O2 (13.0 mL, 116mmol, 30 equiv) over 1 h. The reaction mixture was diluted with brine(100 mL), extracted with EtOAc (3 × 50 mL), dried over Na2SO4, andconcentrated in vacuo to give a yellow oil. The crude material waspurified via silica gel column chromatography (3/1 hexanes/EtOAc)to give pure alcohol 26 (500 mg, 1.35 mmol, 35% over two steps) as aclear oil: Rf = 0.34 (silica gel, 3/1 hexanes/EtOAc); 1H NMR (400MHz, CDCl3) δ 7.26 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H),5.74 (s, 1H), 5.29 (s, 1H), 4.97 (d, J = 10.4 Hz, 2H), 4.92 (s, 1H), 4.44(m, 3H), 4.28 (m, 2H), 4.18 (t, J = 4.8 Hz, 1H), 3.79 (s, 3H), 3.53 (m,2H), 3.09 (t, J = 6.4 Hz, 1H), 2.85 (m, 2H), 1.82 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 159.2, 150.2, 145.2, 143.0, 130.5, 129.6, 128.2,114.4, 113.8, 105.0, 82.4, 81.5, 70.7, 70.2, 64.2, 55.2, 53.2, 52.3, 48.1,23.8, 17.0; IR (film, cm−1) 3421, 2915, 2856, 1612.27, 1514, 1248;HRMS (ESI-TOF) m/z [M] calcd for C23H30O4 370.2144, found370.2139.

(2S,3R)-2-((1R,4R,5R)-4-((4-Methoxybenzyl)oxy)-2-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-4-methylenetetrahydro-furan-3-carbaldehyde (27). To a stirred solution of oxalyl chloride(64 μL, 0.73 mmol, 1.5 equiv) in CH2Cl2 (1.0 mL) at −78 °C wasslowly added a solution of dimethyl sulfoxide (172 μL, 2.43 mmol, 5equiv) in CH2Cl2 (1.0 mL). After 30 min, a solution of alcohol 26(180 mg, 0.49 mmol, 1.0 equiv) in CH2Cl2 (1.0 mL) was added in asingle portion. After 1.5 h, neat triethylamine (341 μL, 2.43 mmol, 5equiv) was added in a single portion and the reaction mixture waswarmed to 23 °C. The reaction mixture was then diluted with CH2Cl2(20 mL) and 0.1 N HCl (10 mL). The organic layer was separated,washed with 0.1 N HCl (2 × 10 mL) and 3.0 N LiCl (10 mL), driedover Na2SO4, and concentrated in vacuo to give crude aldehyde 27 asa clear oil, which was used immediately in the next reaction withoutpurification: Rf = 0.57 (silica gel, 3/1 hexanes/EtOAc); 1H NMR (400MHz, CDCl3) δ 9.30 (d, J = 3.1 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H),6.87 (d, J = 8.6 Hz, 2H), 5.75 (m, 1H), 5.17 (s, 1H), 5.09 (q, J = 2.3Hz, 1H), 4.98 (q, J = 2.4 Hz, 1H) 4.89 (s, 1H), 4.57 (dd, J = 4.3, 7.4Hz, 1H), 4.41−4.32 (m, 4H), 4.20 (m, 1H), 3.79 (s, 3H), 3.60 (m,1H), 3.04 (t, J = 6.3 Hz, 1H), 2.91 (m, 1H), 1.80 (s, 3H), 1.79 (s, 3H);13C NMR (100 MHz, CDCl3) δ 198.8, 159.9, 146.1, 145.3, 143.3,131.3, 130.2, 129.8, 115.5, 114.3, 108.6, 82.4, 80.1, 70.9, 70.6, 58.6,55.5, 53.1, 52.0, 24.1, 17.1; IR (film, cm−1) 2913, 2835, 1722, 1514,1248; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C23H28O4391.18800, found 391.18760.

(3aS,4S,6aR,7R,9aR,9bS)-7-((4-Methoxybenzyl)oxy)-9-meth-yl-3,6-dimethylene-2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno-[4,5-b]furan-4-ol (28). To a stirred solution of crude aldehyde 27(180 mg, 0.49 mmol, 1.0 equiv) in CH2Cl2 (4.8 mL, 0.1 M) at −78 °Cwas added a 1.0 M solution of diethylaluminum chloride in hexanes(244 μL, 0.24 mmol, 0.5 equiv) in a single portion. After 10 min, thereaction mixture was quenched with 10% aqueous NaOH (5 mL). Thereaction mixture was warmed to 23 °C and further diluted with brine(10 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 10mL). The combined organic layers were dried over Na2SO4 andconcentrated in vacuo to give a yellow oil. The crude material waspurified via silica gel column chromatography (1/1 hexanes/EtOAc)to give pure 5,7,5-tricycle 28 (137 mg, 0.37 mmol, 76% over twosteps) as a clear oil: Rf = 0.61 (silica gel, 1/1 hexanes/EtOAc); 1HNMR (600 MHz, CDCl3) δ 7.21 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7Hz, 2H), 5.57 (m, 1H), 5.13 (d, J = 2.3 Hz, 1H), 5.09 (q, J = 2.1 Hz,1H), 5.00 (q, J = 2.4 Hz, 1H), 4.96 (d, J = 2.3 Hz, 1H), 4.65 (m, 1H),4.57 (d, J = 10.8 Hz, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.32 (d, J = 10.8Hz, 1H), 4.18 (dq, J = 2.4, 13.2 Hz, 1H), 4.11 (m, 1H), 3.89 (dd, J =2.7, 10.6 Hz, 1H), 3.78 (s, 3H), 3.61 (t, J = 8.9 Hz, 1H), 3.21 (m, 1H),2.64 (dd, J = 2.2, 13.7 Hz, 1H), 2.57 (dd, J = 4.9, 13.7 Hz, 1H), 1.92(d, J = 7.1 Hz, 1H), 1.73 (s, 3H); 13C NMR (150 MHz, CDCl3) δ159.0, 149.8, 143.1, 142.2, 130.8, 130.4, 129.2, 120.3, 113.7, 104.2,84.0, 79.0, 72.2, 70.9, 64.1, 55.3, 50.8, 50.4, 50.4, 40.5, 16.9.



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2-((1R,2R)-2-(Hydroxymethyl)-3-methylcyclopent-3-en-1-yl)-propan-2-ol (30). To a stirred solution of bicycle 17 (32 g, 193mmol, 1.0 equiv) in Et2O (960 mL, 0.2 M) at 0 °C was slowly added a4.0 M solution of lithium aluminum hydride in Et2O (48 mL, 193mmol, 1.0 equiv) over 20 min. After 40 min, the reaction mixture wascarefully quenched with H2O (7.3 mL), 15% aqueous NaOH (7.3mL), and H2O (21.9 mL) at 0 °C. The reaction mixture was dried overNa2SO4, filtered through Celite, and concentrated in vacuo to givepure diol 30 (32.4 g, 191 mmol, 99%) as a white solid (mp 73−75°C): Rf = 0.23 (silica gel, 2/1 hexanes/EtOAc); 1H NMR (400 MHz,CDCl3) δ 5.43 (bs, 1H), 4.57 (bs, 1H), 4.36 (bs, 1H), 3.77 (d, J = 12Hz, 1H), 3.51 (dd, J = 11, 5.5 Hz, 1H), 2.5 (bd, J = 2.7 Hz, 1H), 2.31−2.23 (m, 2H), 2.09 (bd, J = 8.6 Hz, 1H), 1.65 (s, 1H), 1.33 (s, 1H),1.20 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 139.9, 125.8, 71.1, 60.1,53.6, 51.4, 32.2, 29.8, 29.4, 15.1; IR (film, cm−1) 3282, 1360, 1053,1004; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H18O2193.11930, found 193.11990.((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-

methyl Acetate (32). A stirred solution of diol 30 (40 g, 235 mmol,1.0 equiv), activated 4.0 Å molecular sieves (20 g, 50% by weight), andAc2O (160 mL, 1.5 M) was heated to 150 °C. After 16 h, the reactionmixture was cooled to 23 °C and passed through a short silica gel plug(10/1 hexanes/EtOAc) to give an inseparable 2/1 mixture of acetates32 and 31 (41.5 g, 214 mmol, 91%) as an amber oil. Data for [32]: Rf= 0.46 (silica gel, 10/1 hexanes/EtOAc); 1H NMR (400 MHz,CDCl3) δ 5.48 (bs, 1H), 4.86 (s, 1H), 4.80 (s, 1H), 4.07 (dd, J = 11,5.7 Hz, 1H), 3.83 (dd, J = 11, 5.7 Hz, 1H), 3.33 (bs, 1H), 2.88 (bs,1H), 2.43 (td, J = 11, 2.0 Hz, 1H), 2.16 (dd, J = 15, 7.7 Hz, 1H), 2.00(s, 3H), 1.79 (s, 3H), 1.75 (s, 3H), [87] 5.49 (bs, 1H), 4.25 (dd, J =11, 6.6 Hz, 1H),, 3.97 (dd, J = 11, 6.6 Hz, 1H), 2.93 (q, J = 8.7 Hz,1H), 2.88 (bs, 1H), 2.73 (q, J = 6.2 Hz, 1H), 2.03 (s, 3H), 1.77 (s,3H), 1.73 (s, 3H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ171.0, 170.9, 144.5, 140.4, 133.4, 126.2, 125.4, 124.9, 110.9, 110.9,66.2, 63.6, 63.6, 50.2, 49.6, 48.5, 36.3, 33.8, 23.1, 21.0, 20.9, 20.5, 16.0,15.9; IR (film, cm−1) 1741, 1379, 1252, 1038. Data for [31]: Rf = 0.30(silica gel, 10/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.47(bs, 1H), 4.44 (dd, J = 11, 5.5 Hz, 1H), 3.94 (dd, J = 11, 7.0 Hz, 1H),2.68 (q, J = 7.0 Hz, 1H), 2.40−2.30 (m, 2H), 2.15 (dd, J = 11, 5.5 Hz,1H), 2.01 (s, 3H), 1.95 (s, 3H), 1.76 (s, 3H), 1.65 (s, 3H), 1.50 (s,3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 170.2, 141.9, 125.8,125.8, 82.1, 64.6, 55.0, 47.7, 31.2, 25.5, 22.4, 21.1, 16.6; IR (film, cm−1)1732, 1367, 1228, 1023.((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-

methanol (33). To a stirred solution of acetates 32 and 31 (41.5 g,214 mmol, 1.0 equiv) in Et2O (1.1 L, 0.2 M) at 0 °C was slowly addeda 4.0 M solution of lithium aluminum hydride in Et2O (26.7 mL, 107mmol, 0.5 equiv) over 20 min. After 40 min, the reaction mixture wascarefully quenched with H2O (4.1 mL), 15% aqueous NaOH (4.1mL), and H2O (12.3 mL) at 0 °C. The reaction mixture was dried overNa2SO4, filtered through Celite, and concentrated in vacuo to give aclear oil. The crude material was purified via silica gel columnchromatography (50/1 to 20/1 hexanes/EtOAc) to give pure alcohol33 (15.9 g, 105 mmol, 49%) as a clear oil: Rf = 0.36 (silica gel, 5/1hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.51 (s, 1H), 4.94(s, 1H), 4.91 (s, 1H), 3.56 (dd, J = 9.4, 4.7, 2H), 2.96 (q, J = 8.6 Hz,1H), 2.63 (bs, 1H), 2.45 (dd, J = 12, 6.3 Hz, 1H), 2.17 (dd, J = 12, 6.3Hz, 1H), 1.83 (s, 3H), 1.73 (s, 3H), 1.59 (bs, 1H); 13C NMR (100MHz, CDCl3) δ 146.4, 139.5, 126.2, 110.8, 61.3, 52.6, 49.3, 34.3, 23.5,15.5; IR (film, cm−1) 3381, 1447, 1037, 888; HRMS (EC−CI) m/z[M] calcd for C10H16O 152.1201, found 152.1196.(1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent-2-ene-1-car-

baldehyde (34). To a stirred solution of alcohol 33 (26.2 g, 172mmol, 1.0 equiv) in CH2Cl2 (860 mL, 0.2 M) at 23 °C were addedsolid NaHCO3 (43.4 g, 517 mmol, 3 equiv), freshly prepared

3,4 Dess−Martin periodinane (110 g, 258 mmol, 1.5 equiv), and H2O (1 mL).After 45 min, the reaction mixture was diluted with saturated aqueousNaHCO3 (500 mL) and saturated Na2S2O4 and stirred for 10 min.The reaction mixture was extracted with CH2Cl2 (3 × 800 mL),washed with brine (800 mL), dried over Na2SO4, and concentrated invacuo to give an amber oil. The crude material was purified via silica

gel column chromatography (10/1 hexanes/EtOAc) to give purealdehyde 34 (22.5 g, 150 mmol, 87%) as a clear oil: Rf = 0.56 (silicagel, 5/1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 9.35 (d, J =5.5 Hz, 1H), 5.77 (bs, 1H), 4.90 (s, 1H), 4.87 (s, 1H), 3.22 (q, J = 9.1Hz, 1H), 3.17 (t, J = 6.3 Hz, 1H), 2.71 (t, J = 10 Hz, 1H), 2.43 (dd, J =16, 8.1 Hz, 1H), 1.75 (s, 3H), 1.67 (s, 3H); 13C NMR (150 MHz,CDCl3) δ 201.1, 143.2, 135.5, 130.0, 111.7, 63.4, 49.7, 34.6, 22.9, 15.6;IR (film, cm−1) 1720, 1446, 892. HRMS (APCI-TOFMS) m/z [M +H]+ calcd for C10H14O 151.1117, found 151.1119.

(4R,5R)-1-Methyl-4-(prop-1-en-2-yl)-5-((S)-1-(prop-2-yn-1-yloxy)allyl)cyclopent-1-ene (36). To a stirred solution oftetravinyltin (11 mL, 59.9 mmol, 0.4 equiv) in THF (600 mL) at−78 °C was added a 2.14 M solution of n-butyllithium in hexanes (91mL, 195 mmol, 1.3 equiv). The reaction mixture was warmed andstirred at 23 °C for 15 min before being cooled back down to −78 °C,and a solution of aldehyde 34 (22.5 g, 150 mmol, 1.0 equiv) in THF(150 mL) was added. After 15 min, freshly distilled neathexamethylphosphoramide (52 mL, 299 mmol, 2 equiv) was added.After an additional 10 min an 80% solution of propargyl bromide intoluene (83 mL, 749 mmol, 5 equiv) was added. Upon completeaddition the reaction mixture was warmed to 23 °C. After 3 h, thereaction mixture was diluted with saturated aqueous NH4Cl (50 mL),extracted with Et2O (3 × 50 mL), washed with 3.0 N LiCl (3 × 50mL), dried over Na2SO4, and concentrated in vacuo to give a yellowoil. The crude material was purified via silica gel columnchromatography (straight hexanes to 50/1 to 20/1 hexanes/EtOAc)to give pure enyne 36 (26.2 g, 121 mmol, 81%) as a clear oil: Rf = 0.50(silica gel, 2/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.86(ddd, J = 17, 11, 7.4 Hz, 1H), 5.56 (bs, 1H), 5.19 (d, J = 10 Hz, 1H),5.15 (d, J = 6.7 Hz, 1H), 4.90 (s, 2H), 4.10 (dd, J = 13, 2.4 Hz, 1H),3.93 (dd, J = 13, 2.4 Hz, 1H), 3.88 (dd, J = 8.6, 2.7 Hz, 1H), 2.88 (q, J= 8.2 Hz, 1H), 2.63 (bd, J = 7.8 Hz, 1H), 2.53 (ddq, J = 20, 9.4, 2.4Hz, 1H), 2.32 (t, J = 2.7 Hz, 1H), 2.12 (dd, J = 11, 7.4 Hz, 1H), 1.80(s, 3H), 1.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.3, 139.4,137.7, 127.4, 116.8, 111.7, 80.7, 80.4, 73.5, 55.7, 54.9, 51.1, 34.8, 23.5,17.8; IR (film, cm−1) 1384, 1074, 404; HRMS (EC-CI) m/z [M] calcdfor C15H20O 216.1514, found 216.1515.

Trimethyl(3-(((S)-1-((1R,5R)-2-methyl-5-(prop-1-en-2-yl)-cyclopent-2-en-1-yl)allyl)oxy)prop-1-yn-1-yl)silane (37). To astirred solution of enyne 36 (26.2 g, 121 mmol, 1.0 equiv) in THF(1.2 L, 0.1 M) at −78 °C was added a 2.14 M solution of n-butyllithium in hexanes (68 mL, 145 mmol, 1.2 equiv). After 20 min,freshly distilled neat trimethylsilyl chloride (31 mL, 242 mmol, 2equiv) was added. Upon complete addition the reaction mixture waswarmed to 23 °C. After 30 min, the reaction mixture was quenchedwith saturated aqueous NH4Cl (400 mL), extracted with Et2O (3 ×400 mL), washed with brine (400 mL), dried over Na2SO4, andconcentrated in vacuo to give pure TMS enyne 37 (35 g, 121 mmol,99%) as a clear oil: Rf = 0.44 (silica gel, 20/1 hexanes/EtOAc); 1HNMR (400 MHz, CDCl3) δ 5.85 (ddd, J = 17, 11, 7.4 Hz, 1H), 5.55(bs, 1H), 5.28 (d, J = 16 Hz, 1H), 5.14 (d, J = 9.0 Hz, 1H), 4.88 (s,2H), 4.11 (d, J = 16 Hz, 1H), 3.95 (d, J = 16 Hz, 1H), 3.94 (dd, J =7.8, 2.7 Hz, 1H), 2.87 (q, J = 7.8 Hz, 1H), 2.63 (bd, J = 6.7 Hz, 1H),2.50 (ddq, J = 20, 9.4, 2.4 Hz, 1H), 2.13 (dd, J = 7.8, 2.7 Hz, 1H), 1.81(s, 3H), 1.79 (s, 3H), 0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ145.1, 139.6, 137.6, 127.1, 116.8, 111.7, 102.3, 90.3, 80.2, 56.3, 54.8,50.9, 34.8, 23.3, 17.7, −0.3; IR (film, cm−1) 1384, 1251, 1076, 843,403; HRMS (EC−CI) m/z [M] calcd for C18H28OSi 288.1909, found288.1901.

((2R,3R,Z)-2-((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-4-((trimethylsilyl)methylene)tetrahydrofuran-3-yl)-methanol (39). To a stirred solution of TMS enyne 37 (20.8 g, 72.1mmol, 1.0 equiv) in PhMe (720 mL, 0.1 M) at 23 °C were added solidbis(pinacolato)diboron (20.1 g, 79 mmol, 1.1 equiv), palladium(II)acetate (809 mg, 3.60 mmol, 0.05 equiv), and MeOH (2.92 mL, 72.1mmol, 1.0 equiv). The reaction mixture was heated to 50 °C withstirring. After 15 h, the reaction mixture was cooled to 23 °C andconcentrated in vacuo to give the boronate ester as an amber oil. To astirred solution of crude boronate ester (30 g, 72.0 mmol, 1.0 equiv) inTHF (1.4 L, 0.05 M) at 0 °C were carefully added 3.33 N NaOH



4649


(64.9 mL, 216 mmol, 3 equiv) and 50% aqueous H2O2 (130 mL, 2.16mol, 30 equiv) over 1 h. The reaction mixture was diluted with brine(700 mL), extracted with EtOAc (3 × 500 mL), dried over Na2SO4,and concentrated in vacuo to give a yellow oil. The crude material waspurified via silica gel column chromatography (5/1 hexanes/EtOAc)to give pure alcohol 39 (13.7 g, 44.7 mmol, 62% over two steps) as awhite solid (mp 62−64 °C): Rf = 0.41 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.54 (bs, 1H), 5.50 (q, J =2.4 Hz, 1H), 4.88 (s, 1H), 4.85 (s, 1H), 4.38 (dd, J = 14, 2.4 Hz, 1H),4.23 (dt, J = 14, 2.4 Hz, 1H), 3.91 (t, J = 5.1 Hz, 1H), 3.65 (dt, J = 11,6.3 Hz, 1H), 3.60 (dt, J = 11, 6.3 Hz, 1H), 2.93 (q, J = 7.8 Hz, 1H),2.70−2.66 (bm, 2H), 2.45 (ddq, J = 15, 8.6, 2.4 Hz, 1H), 2.20 (dd, J =14, 7.8 Hz, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 1.63 (t, J = 5.9 Hz, 1H),0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.9, 145.9, 140.3,127.2, 119.9, 111.9, 81.2, 70.2, 64.0, 53.5, 51.8, 51.1, 34.7, 22.8, 17.8,−0.7; IR (film, cm−1) 3404, 1384, 401; HRMS (ESI-TOF) m/z [M +Na]+ calcd for C18H30O2Si 329.19070, found 329.19090.(2R,3S,Z)-2-((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent-2-

en-1-yl)-4-((trimethylsilyl)methylene)tetrahydrofuran-3-car-baldehyde (40). To a stirred solution of oxalyl chloride (5.23 mL,59.8 mmol, 1.5 equiv) in CH2Cl2 (250 mL) at −78 °C was slowlyadded a solution of dimethyl sulfoxide (14.2 mL, 199 mmol, 5 equiv)in CH2Cl2 (100 mL) over 10 min. After 30 min, a solution of alcohol39 (12.2 g, 39.9 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added. After2 h, neat triethylamine (28.0 mL, 199 mmol, 5 equiv) was added in asingle portion and the reaction mixture was warmed to 23 °C. Thereaction mixture was then diluted with 0.1 N HCl (200 mL). Theorganic layer was separated and washed with 0.1 N HCl (2 × 200 mL)and 3.0 N LiCl (400 mL), dried over Na2SO4, and concentrated invacuo to give crude aldehyde 40 (12.1 g, 39.9 mmol, yield taken aftersubsequent step) as a clear oil: Rf = 0.69 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 3.9 Hz, 1H), 5.55(s, 1H), 5.53 (bs, 1H), 4.85 (s, 2H), 4.41 (dd, J = 14, 2.4 Hz, 1H), 4.33(t, J = 6.3 Hz, 1H), 4.22 (dd, J = 14, 2.4 Hz, 1H) 3.40 (bt, J = 2.4, 1H),2.93 (q, J = 7.8 Hz, 1H), 2.71 (t, J = 6.3 Hz, 1H), 2.46 (dd, J = 15, 7.4Hz, 1H), 2.21 (dd, J = 15, 7.4 Hz, 1H), 1.82 (s, 3H), 1.73 (s, 3H), 0.08(s, 9H); 13C NMR (100 MHz, CDCl3) δ 196.6, 151.9, 144.9, 139.8,127.4, 124.0, 112.4, 78.7, 70.2, 63.7, 51.7, 50.6, 34.7, 22.9, 17.4, −0.9;IR (film, cm−1) 1722, 1249, 840; HRMS (ESI-TOF) m/z [M + Na]+

calcd for C18H28O2Si 327.17510, found 327.17530.(3aR ,4R ,6aR ,9aR ,9bR ,Z ) -9 -Methyl -6-methylene-3-

( ( tr imethyls i ly l )methylene)-2,3,3a ,4 ,5 ,6 ,6a ,7 ,9a,9b-decahydroazuleno[4,5-b]furan-4-ol (41). To a stirred solution ofcrude aldehyde 40 (12.1 g, 39.9 mmol, 1.0 equiv) in CH2Cl2 (400 mL,0.1 M) at −78 °C was added a 1.0 M solution of diethylaluminumchloride in hexanes (19.9 mL, 19.9 mmol, 0.5 equiv) in a singleportion. After 10 min, the reaction mixture was quenched with 10%aqueous NaOH (20 mL). The reaction mixture was warmed to 23 °Cand further diluted with brine (200 mL), and the aqueous layer wasextracted with CH2Cl2 (3 × 200 mL). The combined organic layerswere dried over Na2SO4 and concentrated in vacuo to give a yellow oil.The crude material was purified via silica gel column chromatography(5/1 hexanes/EtOAc) to give pure 5,7,5-tricycle 41 (12.1 g, 39.9mmol, 99% over two steps) as a white solid (mp 64−66 °C): Rf = 0.60(silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.47(s, 1H), 5.45 (d, J = 2.4 Hz, 1H), 4.97 (s, 1H), 4.88 (s, 1H), 4.48 (d, J= 14 Hz, 1H), 4.22 (dt, J = 8.2, 4.7 Hz, 1H), 4.09 (dt, J = 14, 2.4 Hz,1H), 3.73 (t, J = 9.8 Hz, 1H), 3.16 (q, J = 8.0 Hz, 1H), 2.63 (t, J = 9.0Hz, 1H), 2.54−2.40 (m, 5H), 1.96 (d, J = 4.7 Hz, 1H), 1.84 (s, 3H),0.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.6, 145.2, 142.3,125.1, 117.3, 115.0, 79.3, 71.1, 66.4, 57.0, 56.1, 49.1, 36.8, 17.3, −0.6;IR (film, cm−1) 3413, 1065, 838; HRMS (ESI-TOF) m/z [M + Na]+

calcd for C18H28O2Si 327.17510, found 327.17510.(3aR ,4R ,6aR ,9aR ,9bR ,Z ) -9 -Methyl -6-methylene-3-

( ( tr imethyls i ly l )methylene)-2,3,3a ,4 ,5 ,6 ,6a ,7 ,9a,9b-decahydroazuleno[4,5-b]furan-4-yl (E)-2-Methylbut-2-enoate(42). To a stirred solution of tiglic acid (13.8 g, 138 mmol, 2.0equiv) in PhMe (345 mL) at 23 °C was added neat triethylamine(38.4 mL, 276 mmol, 4.0 equiv) and neat 2,4,6-trichlorobenzoylchloride (23.7 mL, 152 mmol, 2.2 equiv). After 1 h, a solution of 5,7,5-

tricycle 41 (21.0 g, 69.0 mmol, 1.0 equiv) in PhMe (345 mL) and soliddimethylaminopyridine (21.9 g, 179 mmol, 2.6 equiv) were added.The reaction mixture was then heated to 80 °C. After 45 min, thereaction mixture was cooled to 23 °C, diluted with saturated aqueousNaHCO3, extracted with EtOAc (3 × 500 mL), dried over Na2SO4,and concentrated in vacuo to give an amber oil. The crude materialwas purified via silica gel column chromatography (20/1 hexanes/EtOAc) to give pure tigloyl ester 42 (24.0 g, 62.1 mmol, 90%) as aclear oil: Rf = 0.18 (silica gel, 20/1 hexanes/EtOAc); 1H NMR (400MHz, CDCl3) δ 6.75 (q, J = 6.7 Hz, 1H), 5.49 (s, 1H), 5.41 (q, J = 5.5Hz, 1H), 5.31 (s, 1H), 4.91 (s, 1H), 4.77 (s, 1H), 4.47 (d, J = 14 Hz,1H), 4.06 (d, J = 14 Hz, 1H), 3.89 (t, J = 9.4 Hz, 1H), 3.16 (q, J = 7.8Hz, 1H), 2.69 (d, J = 9.0 Hz, 1H), 2.68 (t, J = 9.0 Hz, 1H), 2.60 (dd, J= 14, 5.5 Hz, 1H), 2.47 (dd, J = 14, 5.1 Hz, 1H), 2.43 (d, J = 7.0 Hz,1H), 2.42 (d, J = 9.0 Hz, 1H), 1.86 (s, 3H), 1.76 (s, 3H), 1.75 (d, J =6.7 Hz, 3H), 0.0 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 167.5,156.6, 144.7, 142.1, 136.9, 128.6, 125.3, 117.3, 115.1, 80.5, 71.0, 69.8,56.3, 55.1, 48.7, 39.4, 37.0, 17.3, 14.3, 12.0, −0.7; IR (film, cm−1) 1713,1250, 1066, 805; HRMS (ESI-TOF) m/z [M + Na]+ calcd forC23H34O3Si 409.21710, found 409.21690.

(3aR,4R,6aR,9aR,9bR,Z)-9-Methyl-6-methylene-2,7-dioxo-3-( ( tr imethyls i ly l )methylene)-2 ,3 ,3a,4 ,5 ,6 ,6a,7,9a ,9b-decahydroazuleno[4,5-b]furan-4-yl (E)-2-Methylbut-2-enoate(43). To a stirred solution of CrO3 (20.7 g, 207 mmol, 20 equiv) inCH2Cl2 (100 mL, 0.05 M) at 0 °C was added solid 3,5-dimethylpyrazole (19.9 g, 207 mmol, 20 equiv) in a single portion.A solution of carbocycle 42 (4.0 g, 10.4 mmol, 1.0 equiv) in CH2Cl2(20 mL) was then added. After 45 min, the reaction mixture wasdirectly purified via Florasil column chromatography (2/1 hexanes/EtOAc) to give pure guaianolide 43 (1.29 g, 3.10 mmol, 30%) as aclear oil: Rf = 0.22 (silica gel, 2/1 hexanes/EtOAc); 1H NMR (400MHz, CDCl3) δ 6.70 (q, J = 7.0 Hz, 1H), 6.37 (d, J = 3.1 Hz, 1H),6.15 (s, 1H), 5.53 (td, J = 4.7, 2.7 Hz, 1H), 5.07 (s, 1H), 4.96 (s, 1H),4.54 (dd, J = 11, 9.0 Hz, 1H), 3.32 (d, J = 7.0 Hz, 1H), 3.20 (t, 9.8 Hz,1H), 3.18 (dt, J = 8.6, 2.7 Hz, 1H), 2.55 (bs, 2H), 2.36 (s, 3H), 1.75(d, J = 7.8 Hz, 3H), 1.74 (s, 3H), 0.15 (s, 9H); 13C NMR (125 MHz,CDCl3) δ 206.1, 177.9, 168.6, 166.9, 145.5, 138.9, 138.5, 138.1, 132.3,127.9, 120.4, 78.1, 67.1, 56.2, 53.4, 51.2, 41.1, 19.9, 14.3, 11.9, −1.0; IR(film, cm−1) 1765, 1707, 1249; HRMS (ESI-TOF) m/z [M + Na]+

calcd for C23H30O5Si 437.17550, found 437.17580.(3aR,4R,6aR,7R,9aR,9bR,Z)-7-Hydroxy-9-methyl-6-methyl-

e n e - 2 - o x o - 3 - ( ( t r i m e t h y l s i l y l ) m e t h y l e n e ) -2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno[4,5-b]furan-4-yl (E)-2-Methylbut-2-enoate (44). To a stirred solution of enone 43 (755mg, 1.82 mmol, 1.0 equiv) in MeOH (36 mL, 0.05 M) at 0 °C wasadded solid CeCl3·7H2O (1.36 g, 3.64 mmol, 2.0 equiv). After 20 min,solid NaBH4 (138 mg, 3.64 mmol, 2.0 equiv) was added in three evenportions. After 15 min, the reaction mixture was warmed to 23 °C anddiluted with 0.2 M aqueous pH 7.0 phosphate buffer. The organiclayer was separated, and the aqueous layer was extracted with EtOAc(3 × 20 mL). The combined organic layers were dried over Na2SO4and concentrated in vacuo to give pure allylic alcohol 44 (700 mg, 1.68mmol, 92%) as a clear oil: Rf = 0.24 (silica gel, 3/1 hexanes/EtOAc);1H NMR (400 MHz, CDCl3) δ 6.69 (q, J = 5.5 Hz, 1H), 6.24 (d, J =2.7 Hz, 1H), 5.71 (bs, 1H), 5.43 (td, J = 7.8, 3.9 Hz, 1H), 5.09 (s, 2H),4.71 (bt, J = 5.1 Hz, 1H), 4.65 (dd, J = 11, 9.0 Hz, 1H), 3.16 (dt, J =6.7, 2.7 Hz, 1H), 3.14 (d, J = 3.9 Hz, 1H), 2.88 (dd, J = 14, 7.4 Hz,1H), 2.71 (dd, J = 14, 7.4 Hz, 1H), 2.67 (t, J = 9.4 Hz, 1H), 1.99 (s,3H), 1.74 (d, J = 5.5 Hz, 3H), 1.73 (s, H), 0.13 (s, 9H); 13C NMR(125 MHz, CDCl3) δ 169.4, 167.2, 147.8, 144.5, 142.0, 139.9, 137.9,128.9, 128.0, 119.0, 80.8, 79.0, 68.5, 56.2, 52.6, 49.8, 38.7, 17.3, 14.3,11.9, −1.0; IR (film, cm−1) 3485, 1764, 1709, 1259, 1247; HRMS(ESI-TOF) m/z [M + Na]+ calcd for C23H32O5Si 439.19110, found439.19110.

(3aR,4R,6aR,7R,9aR,9bR)-7-Hydroxy-9-methyl-3,6-dimethy-lene-2-oxo-2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno[4,5-b]-furan-4-yl (E)-2-Methylbut-2-enoate (45). To a stirred solution ofvinylsilane 44 (267 mg, 0.641 mmol, 1.0 equiv) in EtOH (6.4 mL, 0.1M) at 23 °C was added neat thiophenol (2.88 mL, 28.2 mmol, 44equiv) and 60% NaH in mineral oil (103 mg, 2.56 mmol, 4.0 equiv).After 48 h, the reaction mixture was concentrated in vacuo and



4650


purified directly via silica gel column chromatography (straighthexanes to 2/1 hexanes/EtOAc) to give pure thiosilane 46 (238 mg,0.452 mmol, 71%) as a white foam. To a stirred solution of thiosilane46 (238 mg, 0.452 mmol, 1.0 equiv) in THF (4.5 mL, 0.1 M) at 23 °Cwas added a 1.0 M of tetrabutylammonium fluoride in THF (0.90 mL,1.38 mmol, 1.5 equiv). After 30 min, the reaction mixture was passedthrough a plug of silica gel (2/1 hexanes/EtOAc) to give the crudethio adduct 47 as an amber oil. To a stirred solution of the crude thioadduct 47 (205 mg, 0.452 mmol, 1.0 equiv) in MeOH (4.5 mL, 0.1 M)at 0 °C was added a solution of sodium periodate (145 mg, 0.678mmol, 1.5 equiv) in H2O (4.5 mL). After 15 h, the reaction mixturewas extracted with EtOAc (3 × 10 mL), dried over Na2SO4, andconcentrated in vacuo to give crude sulfone 48 as a white solid. Asolution of crude sulfone 48 (220 mg, 0.452 mmol, 1.0 equiv), basicalumina (440 mg, 200% by weight), and CH2Cl2 (4.5 mL, 0.1 M) wasstirred at 23 °C. After it was stirred for 12 h, the reaction mixture waspassed through a plug of Celite and concentrated to give a clear oil.The crude material was purified via silica gel column chromatography(2/1 hexanes/EtOAc) to give pure butyrolactone 45 (109 mg, 0.316mmol, 70% over three steps) as a clear oil: Rf = 0.54 (silica gel, 1/1hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.73 (q, J = 5.5 Hz,1H), 6.29 (d, J = 3.5 Hz, 1H), 5.73 (bs, 1H), 5.52 (dd, J = 11, 3.5 Hz,1H), 5.51 (d, J = 3.5 Hz, 1H), 5.12 (s, 1H), 5.11 (s, 1H), 4.73 (bs,1H), 4.66 (dd, J = 11, 8.6 Hz, 1H), 3.19 (dd, J = 12, 2.7 Hz, 1H), 3.17(d, J = 5.9 Hz, 1H), 2.85 (dd, J = 14, 6.7 Hz, 1H), 2.73 (dd, J = 14, 7.8Hz, 1H), 2.68 (t, J = 9.4 Hz, 1H), 1.99 (s, 3H), 1.76 (d, J = 5.9 Hz,3H), 1.75 (s, 3H), 1.70 (d, J = 5.1 Hz, 1H); 13C NMR (125 MHz,CDCl3) δ 169.6, 167.2, 147.3, 141.7, 138.3, 134.2, 129.2, 128.0, 122.4,119.2, 80.8, 78.8, 67.8, 56.1, 52.6, 47.8, 39.1, 17.3, 14.4, 12.0; IR (film,cm−1) 3413, 1384, 1137; HRMS (ESI-TOF) m/z [M + Na]+ calcd forC20H24O5 367.15160, found 367.15200.(3aR ,4R ,6aR ,9aR ,9bR ) -9 -Methyl -3 ,6-d imethylene-

2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno[4,5-b]furan-4-yl (E)-2-Methylbut-2-enoate (49). To a stirred solution of vinylsilane 42(2 g, 5.17 mmol, 1.0 equiv) in CH2Cl2 (52 mL, 0.1 M) was added neatTFA (3.96 mL, 51.7 mmol, 10 equiv) in a single portion at 23 °C.After 2 h, the reaction mixture was poured into saturated aqueousNaHCO3 (30 mL) and the aqueous layer was extracted with CH2Cl2(3 × 50 mL). The combined organic layers were washed withsaturated aqueous NaHCO3 (3 × 30 mL) and brine (1 × 30 mL),dried over Na2SO4, and concentrated in vacuo to give 49 as an amberoil (1.6 g, 5.09 mmol, 98%). The crude material was used directly inthe next reaction without purification: Rf = 0.61 (silica gel, 20/1hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 6.79 (q, J = 6.14 Hz,1H), 5.49 (s, 1H), 5.44 (m, 1H), 4.94 (m, 1H), 4.91 (s, 1H), 4.85 (m,1H), 4.75 (s, 1H), 4.40 (d, J = 13.04 Hz, 1H), 4.10 (dt, J = 2.2, 13.09Hz, 1H), 3.94 (t, J = 9.71 Hz, 1H), 3.15 (t, J = 7.70 Hz, 1H), 2.70 (m,2H), 2.64 (dd, J = 5.44, 13.68 Hz, 1H), 2.42 (m, 3H), 1.86 (s, 3H),1.77 (s, 3H), 1.75 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 167.4,148.5, 144.6, 141.9, 137.2, 128.6, 125.4, 115.1, 103.6, 81.0, 71.5, 69.4,56.3, 52.9, 48.4, 40.1, 37.1, 17.2, 14.3, 12.0; IR (film, cm−1) 2367,2078, 1640, 1401, 1114; HRMS (ESI-TOF) calcd for C20H26O3 [M +H]+ 315.1955, found 315.1954.(3aR,4R,6aR,9aR,9bR)-9-Methyl-3,6-dimethylene-2,7-dioxo-

2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno[4,5-b]furan-4-yl (E)-2-Methylbut-2-enoate (50). To a stirred solution of CrO3 (10.18 g,102 mmol, 20 equiv) in CH2Cl2 (30 mL) at 0 °C was added solid 3,5-dimethylpyrazole (9.78 g, 102 mmol, 20 equiv) in a single portion. Asolution of carbocycle 49 (1.6 g, 5.09 mmol, 1.0 equiv) in CH2Cl2 (20mL) was then added in a single portion. After 45 min, the reactionmixture was directly purified via Florasil column chromatography (1/1hexanes/EtOAc) to give a white solid. The white solid was dissolved inEtOAc (50 mL), washed with 1.0 M HCl (3 × 20 mL), dried overNa2SO4, and concentrated to give pure guaianolide 50 (630 mg, 1.84mmol, 36%) as a white foam: Rf = 0.38 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 6.67 (q, J = 6.97 Hz, 1H),6.26 (s, 1H), 6.10 (s, 1H), 5.56 (bs, 2H), 4.98 (s, 1H), 4.98 (s, 1H),4.48 (t, J = 9.72 Hz, 1H), 3.27 (d, J = 7.30 Hz, 1H), 3.15 (m, 2H), 2.53(m, 1H), 2.46 (m, 1H), 2.29 (s, 3H), 1.70 (s, 3H), 1.68 (s, 3H). 13CNMR (150 MHz, CDCl3) δ 205.9, 177.6, 168.7, 166.7, 138.5, 138.4,

133.6, 132.6, 127.8, 122.9, 120.4, 77.9, 66.3, 55.7, 53.3, 49.4, 41.8, 19.9,14.4, 11.9; IR (film, cm−1) 3438, 3154, 1769, 1704, 1650, 1619;HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H22O5 343.1540,found 343.1545.

(3aR,4R,6aR,7R,9aR,9bR)-7-Hydroxy-9-methyl-3,6-dimethy-lene-2-oxo-2,3,3a,4,5,6,6a,7,9a,9b-decahydroazuleno[4,5-b]-furan-4-yl (E)-2-Methylbut-2-enoate (45). To a stirred solution ofenone 50 (630 mg, 1.84 mmol, 1.0 equiv) in 3/1 MeOH/THF (18.4mL, 0.1 M) at −78 °C was added solid Yb(OTf)3 (1.25 g, 2.02 mmol,1.1 equiv). After 15 min, solid NaBH4 (84 mg, 2.21 mmol, 1.2 equiv)was added in three even portions every 30 min for 1.5 h. After themixture was stirred for an additional 10 min, neat acetaldehyde (1.0mL, 18.4 mmol, 10 equiv) was added in a single portion and thereaction mixture was stirred further for 15 min at −78 °C. EtOAc/H2O (1/1, 40 mL) was added, and the reaction mixture was warmedto 23 °C over 30 min. The reaction mixture was further diluted withbrine (20 mL), and the aqueous layer was extracted with EtOAc (3 ×20 mL). The combined organic extracts were washed with water (3 ×20 mL) and brine (1 × 20 mL), dried over Na2SO4, and concentratedin vacuo to give a brown oil. The crude material was purified via silicagel column chromatography (2/1 hexanes/EtOAc) to give pure allylicalcohol 45 (472 mg, 1.37 mmol, 75%) as a white foam: Rf = 0.54(silica gel, 2/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.73(q, J = 5.5 Hz, 1H), 6.29 (d, J = 3.5 Hz, 1H), 5.73 (bs, 1H), 5.52 (dd, J= 11, 3.5 Hz, 1H), 5.51 (d, J = 3.5 Hz, 1H), 5.12 (s, 1H), 5.11 (s, 1H),4.73 (bs, 1H), 4.66 (dd, J = 11, 8.6 Hz, 1H), 3.19 (dd, J = 12, 2.7 Hz,1H), 3.17 (d, J = 5.9 Hz, 1H), 2.85 (dd, J = 14, 6.7 Hz, 1H), 2.73 (dd,J = 14, 7.8 Hz, 1H), 2.68 (t, J = 9.4 Hz, 1H), 1.99 (s, 3H), 1.76 (d, J =5.9 Hz, 3H), 1.75 (s, 3H), 1.70 (d, J = 5.1 Hz, 1H); 13C NMR (125MHz, CDCl3) δ 169.6, 167.2, 147.3, 141.7, 138.3, 134.2, 129.2, 128.0,122.4, 119.2, 80.8, 78.8, 67.8, 56.1, 52.6, 47.8, 39.1, 17.3, 14.4, 12.0; IR(film, cm−1) 3413, 1384, 1137; HRMS (ESI-TOF) m/z [M + Na]+

calcd for C20H24O5 367.15160, found 367.15200.(3aR,4R,6R,6aS,7R,9aR,9bR)-7-Hydroxy-9-methyl-3-methyl-

ene-2-oxo-3,3a,4,5,6a,7,9a,9b-octahydro-2H-spiro[azuleno-[4,5-b]furan-6,2′-oxiran]-4-yl (E)-2-Methylbut-2-enoate (51).To a stirred solution of allylic alcohol 45 (472 mg, 1.37 mmol, 1.0equiv) in CH2Cl2 (13.7 mL, 0.1 M) was added a 1.0 M solution ofAl(O-s-Bu)3 in CH2Cl2 (2.1 mL, 2.1 mmol, 1.5 equiv, Aldrich catalog #558907) dropwise at 0 °C. The reaction mixture was stirred for 10 minbefore a 5.5−6.0 M solution of TBHP in decane (0.275 mL, 1.51mmol, 1.1 equiv) was added dropwise. The cooling bath was removed,and the reaction mixture was warmed to 23 °C over 30 min. Saturatedaqueous Na2S2O3 (10 mL) was added, and the mixture was stirred for15 min. The crude reaction mixture was further diluted with brine (20mL), and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).The combined organic layers were dried over Na2SO4 andconcentrated to give epoxide 51 as a clear oil. The crude materialwas used immediately in the next reaction without purification: Rf =0.54 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ6.70 (q, J = 6.4 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 5.71 (bs, 1H), 5.57(td, J = 8.6, 4.7 Hz, 1H), 5.55 (d, J = 2.8 Hz, 1H), 4.68 (bs, 1H), 4.67(t, J = 8.8 Hz, 1H), 3.56 (dd, J = 8.6, 4.7 Hz, 1H), 2.79 (q, J = 7.6 Hz,1H), 2.77 (t, J = 9.6 Hz, 1H), 2.61 (dd, J = 14, 7.6 Hz, 1H), 2.35 (d, J= 9.2 Hz, 1H), 2.25 (dd, J = 15, 8.4 Hz, 1H), 2.01 (s, 3H), 1.97 (d, J =7.2 Hz, 1H), 1.77 (s, 3H), 1.73 (s, 3H); 13C NMR (150 MHz, CDCl3)δ 169.6, 167.1, 148.9, 138.3, 133.9, 128.9, 127.9, 122.9, 81.0, 76.75,66.7, 56.3, 55.7, 55.4, 52.3, 47.8, 36.5, 17.4, 14.3, 12.0; IR (film, cm−1)3477, 1768, 1339, 1140, 1037; HRMS (ESI-TOF) m/z [M + Na]+

calcd for C20H24O6 383.14650, found 383.14680.Eupalinilide E (1). To a stirred solution of crude epoxide 51 (490

mg, 1.36 mmol, 1.0 equiv) in THF (13.6 mL, 0.1 M) at 23 °C wasadded solid lithium chloride (576 mg, 13.6 mmol, 10.0 equiv) in asingle portion. The mixture was sonicated for 5 min before addition ofa 1.25 M solution of hydrochloric acid in MeOH (3.26 mL, 4.08mmol, 3.0 equiv). After 5 min, the reaction mixture was diluted withbrine (40.0 mL), extracted with EtOAc (3 × 30 mL), dried overNa2SO4, and concentrated in vacuo to give a white solid. The crudematerial was purified via silica gel column chromatography (2/1hexanes/EtOAc) to give pure eupalinilide E (1) (466 mg, 1.17 mmol,



4651


86% over two steps) as a white solid (mp 72 °C dec): Rf = 0.63 (silicagel, 1/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.70 (q, J =5.5 Hz, 1H), 6.27 (d, J = 3.5 Hz, 1H), 5.75 (bs, 1H), 5.65 (td, J = 8.6,4.7 Hz, 1H), 5.45 (d, J = 3.5 Hz, 1H), 4.59 (bs, 1H), 4.58 (t, J = 8.6Hz, 1H), 3.94 (d, J = 11 Hz, 1H), 3.93 (bs, 1H), 3.67 (d, J = 11 Hz,1H), 2.77 (dd, J = 11, 7.4 Hz, 1H), 2.50−2.44 (m, 4H), 2.04 (s, 3H),1.74 (d, J = 5.3 Hz, 3H), 1.73 (s, 3H); 13C NMR (150 MHz, CDCl3) δ169.7, 167.2, 150.6, 138.1, 134.4, 128.6, 128.1, 122.1, 82.0, 75.1, 73.6,66.4, 55.2, 55.0, 52.2, 47.4, 36.4, 18.0, 14.4, 12.0; IR (film, cm−1) 3409,1654, 1384, 1129; HRMS (ESI-TOF) m/z [M + Na]+ calcd forC20H25ClO6 419.12320, found 419.12290.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.joc.7b00266.

NMR spectra and crystallographic data for newcompounds (PDF)Crystallographic data (CIF)Crystallographic data (CIF)

■ AUTHOR INFORMATIONCorresponding Author*E-mail for D.S.: [email protected] Siegel: 0000-0003-4674-9554Present Address∥Gilead Sciences, Inc., Foster City, CA 94404, USA.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe authors are grateful for the financial support of theCalifornia Institute for Regenerative Medicine (DISC1-08737)and the University of California, San Diego. We also thankSteve Sorey and Angela Spangenberg, at UT Austin, andBrendan Duggan, at UC San Diego, for assistance with NMRand Dr. Vincent Lynch, UT Austin, for assistance with X-raycrystallography.

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