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Synthetic Route Development for the Laboratory Preparation of Eupalinilide E Trevor 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, United States ‡

S Supporting Information *

ABSTRACT: Following the discovery that the guaianolide natural product eupalinilide E promotes the expansion of hematopoietic stem and progenitor cells; the development of a synthetic route to provide laboratory access to the natural product became a priority. Exploration of multiple synthetic routes yielded an approach that has permitted a scalable synthesis of the natural product. Two routes that failed to access eupalinilide E were triaged either as a result of providing an incorrect diastereomer or due to lack of synthetic efficiency. The successful strategy relied on late-stage allylic oxidations at two separate positions of the molecule, which significantly increased the breadth of reactions that could be used to this point. Subsequent to C−H bond oxidation, adaptations of existing chemical transformations were required to permit chemoselective reduction and oxidation reactions. These transformations included a modified Luche reduction and a selective homoallylic alcohol epoxidation.

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expectancy of survival for the patient.5 While it had been shown to possess selective cytotoxicity against a difficult cancer cell line, further evaluation of eupalinilide E did not occur beyond the initial isolation until the discovery of its ability to control stem cell fate. There has been a focused effort to discover compounds or biologics that direct stem cell fate by controlling the cell’s ability to undergo differentiation or expansion. Expansion is important, as the process increases the number of stem cells to provide useful quantities of either transplantable cells or cells that can be transformed into desired cell types. A significant focus has been to increase expansion of hematopoietic stem and progenitor cells (HSPCs), which can transform into blood cells. Transplantable HSPCs are derived from human tissues, either mobilized peripheral blood or cord blood. Cord blood is obtained from donated umbilical cords that are cryopreserved and stored in a cord blood bank.6 This source of HSPCs is particularly useful in cases where patients do not have suitable human 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 patient directly correlates with the successful treatment of autoimmune diseases and recovery from cancer therapy and, as a result of this and other factors, two units of cord blood are transferred.10,11 This, as expected, puts increased demand on a

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

Figure 1. Structure of eupalinilide E (1).

a plant which has ethnopharmacological uses as an antibacterial and antihistamine.1 Eupalinilide E was unique among coisolated compounds, as it possessed selective antiproliferative activity against A549 cells (lung cancer harboring KRAS mutation) with an IC50 of 28 nM and no effects on P388 cells (leukemia cell line). Cytotoxic activity against A549 cells is notable, as KRAS mutations make cells significantly less susceptible to chemotherapeutic agents.2,3 As a consequence of this resistance, there is an urgent need to develop drugs for this form of nonsmall cell lung cancer.4 Patients with cancers possessing KRAS mutations have reduced benefit from adjuvant chemotherapy, are resistant to EGFR inhibitors, and experience less clinical success from medication in comparison to other forms of cancer, all of which significantly contribute to a low © XXXX American Chemical Society

Received: February 2, 2017

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DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

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Figure 2. Structures of compounds in clinical trials for the ex vivo expansion of HSPCs: SR1 (2), UM171 (3), nicotinamide (4), and 16,16-dimethylPGE2 (5).

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

possible using either cord blood or human mobilized peripheral blood. Remarkably, this proliferative effect was demonstrated at 600 nM, approximately 20-fold of the concentration used previously to kill A549 lung cancer cells. In the first week of treatment with eupalinilide E the percentage of CD34+ cells increased 50% and there was a 2-fold increase in the number of THY1+ cells (cells bearing CD34+ and THY+ immunophenotypes on the surface of undifferentiated cells are identified as HSPCs). Prolonged incubation with the compound (18 days) led to a 4.5-fold increase in the number of cells. Finally, there was a 45-fold increase in the number of cells after 45 days in comparison to controls using DMSO. The enrichment of both CD34+ and THY1+ cells was achieved by eupalinilide E’s ability to block differentiation and enhance HSPC expansion. The effects of eupalinilide E are reversible, and following removal of compound and transfer to fresh, compound-free media, the cells demonstrated the standard abilities to expand and differentiate. While the natural product was found to produce these effects through a novel mode of action, the characterization of the target(s) of eupalinilide E was not possible due to consumption of the eupalinilide E supply27 in these studies. Similarly, the evaluation of the homing and engraftment abilities of the eupalinilide E expanded cells was not 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 stereochemical complexity, a high degree of oxygenation, and multiple electrophilic sites, including an α-methylene γbutyrolactone and chlorohydrin. However, earlier guainolide natural product syntheses that were successful provided insight into how to approach the construction of eupalinilide E; in particular syntheses starting from carvone appeared to provide

limited supply of donated human tissues. An ideal solution to generate a limitless supply of HSPCs for transplantation would be to produce the cells ex vivo, outside of the bodyin the laboratory. While technologies for ex vivo culturing of HSPCs have been developed, a major impediment to culturing in an artificial environment has been rapid differentiation of the resulting cells. To date, the primary approach for expansion has been the use of proteinaceous factors, which have had partial success.12,13 Currently there are no FDA-approved methods for the expansion of HSPCs; clinical trials are performed on the laboratory HSPC cells produced. However, there are four small molecules that are currently undergoing or about to begin clinical trails for ex vivo expansion of HSPCs: StemRegenin-1 (aka SR1 (2)),14,15 UM171 (3),16,17 nicotinamide (4),18,19 and 16,16-dimethyl-PGE2 (5)20,21 (Figure 2). Given the importance of developing large-scale, clinically applicable methods for the production of HSPCs, additional agents functioning through novel mechanisms are needed, as related clinical trials have failed in the past.22 As HSPC expansion is achieved ex vivo, one of the major impediments in the clinical development of natural products, pharmacokinetics, is avoided. This allows the diverse and privileged chemical architectures of natural products to be used directly. Natural products that modulate the tailoring of histones have been found to be capable of expanding HSPCs.23−25 Schultz and co-workers screened Novartis’ natural product collection in an effort to discover new chemicals capable of promoting HSPC expansion. From a relatively small library of natural products of variable origin (∼700 compounds), eupalinilide E was shown to markedly drive the expansion of HSPCs and inhibit differentiation, leading to a large increase in the number of HSPCs.26 This effect was B

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

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lactone 17. This crystalline lactone 17 possesses the required cis configuration at the bicyclic junction and the requisite trisubstituted olefin. Our synthetic efforts toward eupalinilide E began with the hydrohalogentaion of (R)-carvone (6) using dry hydrobromic acid to furnish carvone monobromide (14) (Scheme 1). Bromination of the remaining trisubstituted olefin with bromine generated tribromide 15. This crude tribromide was combined with isopropyl amine, forming bicyclic imidate 16.37 Direct hydrolysis of imidate 16 was facilitated by aqueous acetic acid, subsequently yielding lactone 17 (50% yield over four steps, one silica gel purification) as a stable, crystalline solid (mp 33−35 °C). This short sequence has generated >300 g of lactone 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 coworkers established the allylic oxidation of lactone 17 with an excess of chromium trioxide and 3,5-dimethylpyrazole in methylene chloride to provide enone 18 with a yield of 16%.38 Optimization of oxidant, additive, and time increased the yield of 18 to 38% on a 60 g scale. The use of Florisil rather than silica gel during chromatography-based purification increased both the consistency and yield of this reaction. Selective 1,2-reduction of enone 18 using a Luche reduction proved highly diastereoselective, generating alcohol 19.39 Formation of an ether at the allylic alcohol was achieved with p-methoxybenzyl 2,2,2-trichloroacetimidate and catalytic camphorsulfonic acid to yield ether 20, conducted on a 16 g scale.40 Reduction of the lactone 20 using DIBAL yielded a diastereomeric mixture of lactols that when treated with vinylmagnesium bromide provided diol 22 in good yield and with high diastereoselectivity (Scheme 2). Ether formation of the newly formed secondary alcohol was achieved at ambient temperature using propargyl bromide, yielding diene-yne 23. An unoptimized elimination of the tertiary alcohol using Burgess reagent selectively formed the required triene-yne 24.

functional handles for the synthesis. The elaboration of the key intermediate cyclopentane (8)28 (Figure 3) utilized in the syntheses 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

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RESULTS AND DISCUSSION In the search for an appropriately substituted cyclopentene starting point, a report from Wallach (Nobel Prize in Chemistry, 1910) in 189936 centered on the Favorskii rearrangement of tribromide 15 fit the requirements for the synthesis of eupalinilide E (Scheme 1), providing the Scheme 1. Synthesis of Lactone 17 Starting from Carvone (6)a

Reagents 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.

a

appropriately modified cyclopentene 17 (Scheme 1). Wolinsky and co-workers subsequently found that tribromide 15, generated in two steps from carvone (6), underwent an efficient Favorskii rearrangement with isopropyl amine to yield the intermediate cyclic imidate 16.37 The intermediate imidate could be directly hydrolyzed with aqueous acid to generate Scheme 2. Synthesis of Triene-yne 24 from Lactone 17a

Reagents and conditions: (a) CrO3, 3,5-dimethylpyrazole, CH2Cl2, 0 °C; (b) CeCl3·7H2O, NaBH4, MeOH, 0 °C; (c) 4-methoxybenzyl-2,2,2trichloroacetimidate, (+)-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. a

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DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Synthesis of Tricycle 29 from Triene-yne 24a

Reagents 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.

a

Scheme 4. Synthesis of Aldehyde 34 from Lactone 17a

Triene-yne 24 provided a suitable substrate for palladiumcatalyzed borylative enyne cyclizations that helped simplify the synthetic approach (Scheme 3). Previously these conditions were discovered to generate homoallylic boronates in good yields and selectivities,41 as well as having the capacity to be influenced by directing group effects.42 Reaction of triene-yne 24 with bis(pinacolato)diboron, palladium(II) acetate, and methanol in toluene at 50 °C afforded the desired cyclic ether 26 (formed after oxidation of the intermediate primary boronate 25 with hydrogen peroxide and sodium hydroxide). The cyclization was highly diastereoselective and formed the required trans configuration off of the furan of boronate 25. Oxidation under Swern conditions and immediate treatment of the resulting aldehyde 27 with diethylaluminum chloride resulted in an ene cyclization to afford the 5,7,5-tricycle 28 as a white solid in 76% yield and excellent diastereoselectivity. This finding is in accord with related ene cyclization reactions of guaianolide natural products.32 To induce crystallinity, the secondary alcohol was made to react with 3,5-dinitrobenzyl chloride to provide ester 29, which generated crystals suitable for X-ray diffraction (Supporting Information). From this structure it was determined that the addition of vinylmagnesium bromide into lactol 21 formed the incorrect diastereomer (Scheme 2) which relayed subsequent stereochemistry generated in the synthesis (Scheme 3). The formation of the diastereomer, can be rationalized by the chelation controlled addition of vinyl Grignard into the open form alkoxide of lactol 21. Although the stereocenter was incorrect, the steps that followed achieved the proper relative configuration. 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-disubstituted olefin prior to the vinyl addition (Scheme 4). Reduction of lactone 17 with lithium aluminum hydride formed diol 30 in quantitative yield. Previously, the poor yields using Burgess reagent to eliminate the tertiary alcohol prompted the development of a different method for elimination to form olefin 32. Acetate pyrolysis, conducted in neat acetic anhydride in an oil bath heated to 150 °C, provided a mixture of the desired olefin 32, the tetrasubstituted olefin 31, and diacetate of 30. Initially the ratio of these three products varied as the conditions were modified. However, the addition of activated, crushed molecular sieves improved the consistency of this

Reagents 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. a

reaction, after further optimization, yielding a 2/1 mixture of 32 and 31, favoring the desired olefin 32, in 91% combined yield when the reaction was conducted on a 40 g scale. Aldehyde 34 was synthesized by lithium aluminum hydride cleavage of the primary acetate to form alcohol 33 followed by oxidation with Dess−Martin periodinane. In an optimized sequence aldehyde 34 in tetrahydrofuran was added to a solution of vinyllithium, generated in situ from tetravinyltin and n-butyllithium at −78 °C, to generate alkoxide 35 (Scheme 5). To a solution of the alkoxide 35 was then added anhydrous HMPA followed by propargyl bromide. The desired triene-yne 36 was isolated in 81% yield on a 23 g scale. The alkyne was silylated with n-butyllithium and trimethylsilyl chloride to attenuate the eventual reactivity of an α-methyleneγ-butyrolactone (vide infra). This modification had the added benefit that it doubled the previous yield for the borylative enyne cyclization,41 and it was found this reaction could be reliably conducted on a 20 g scale. The structure of the cyclized product 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 with diethylaluminum chloride, undergoing cyclization at −78 °C (Scheme 6). This allowed access to tricycle 41 in excellent yield on a 12 g scale. The required tigloyl ester was installed with tiglic acid under Yamaguchi esterification conditions.43 This improved route, accessing the correct diastereomer, enabled the synthesis of over 55 g of carbocycle 42. D

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 5. Synthesis of Vinylsilane 39 from Aldehyde 34a

Reagents 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.

a

Scheme 6. Synthesis of Tricycle 42 from Vinylsilane 39a

be replicated upon scale-up, as a result of poor scalability of the chemistry. Reduction of the enone carbonyl under Luche conditions generated allylic alcohol 44 as a single diastereomer in 92% yield (Figure 4). In the absence of the vinyl trimethylsilyl group, significant 1,4-reduction of the α-methylene-γ-butyrolactone was observed under Luche conditions. However, due to the reactivity of the α-methylene-γ-butyrolactone, problems arose when attempting to remove the vinyl trimethylsilyl within 44. The use of fluoride-based reagents such as tetrabutylammonium fluoride, pyridinium poly(hydrofluoride), cesium fluoride, and tetrabutylammonium difluorotriphenylsilicate resulted in nonproductive reactions. Protic acids such as hydrochloric acid and trilfuoroacetic acid induced extensive decomposition. Bachi and co-workers developed a strategy for the cleavage of similar trimethylsilyl groups by the conjugate addition of thiophenol into the α-methylene-γ-butyrolactone followed by the addition of tetrabutylammonium fluoride.44 This sequence formed the corresponding thioether and a small amount of the re-formed α-methylene-γ-butyrolactone. The method was improved by the addition of excess methyl acrylate as a Michael acceptor trap to capture released thiophenol. This sequence was adapted for the desilylation of the vinyl trimethylsilyl group of 44 (Scheme 7). Through this sequence the desired “free” α-methylene-γ-butyrolactone 45 was isolated in 53% yield. Purification complications associated with 45 prompted the development of a more lengthy sequence. First

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

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

oxidant

additive

solvent

temp (°C)

time (h)

yield (%)

SeO2 Mn(OAc)3/TBHP CrO3/H2SO4 PDC CrO3·3,5-DMP CrO3·3,5-DMP

n/a O2, 3 Å MS n/a n/a n/a n/a

dioxane EtOAc Me2CO DMF CH2Cl2 CH2Cl2

80 70 23 50 0 0

2 24 24 24 0.5 0.5

dec dec dec 400 mg in a single batch), generating ample material for testing and probe development. Preliminary route failure could be retrospectively traced to premature introduction of oxygen into synthetic intermediates. As a consequence, the successful strategy introduced oxygen at a late stage through oxidation of activated methylene groups, providing carbonyls. This approach maximized substrate compatibility with different reagents up to the late-stage oxidation. Following C−H bond oxidation tuning of chemical transformations, chemoselective reduction and oxidation were required and included a modified Luche reduction and a selective homoallylic alcohol epoxidation. G

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The Journal of Organic Chemistry

stirred for 5 h at 23 °C, the reaction mixture was diluted dropwise with diethyl ether (800 mL) and filtered through a pad of Celite. The pad of Celite was washed with EtOAc (3 × 500 mL), and the combined organics were concentrated in vacuo. The crude material was purified via silica gel column chromatography (1/1 hexanes/EtOAc) twice to give pure enone 18 (24.8 g, 137 mmol, 38%) as an off-white solid (mp 38−40 °C). Spectral data matched those previously reported:38 Rf = 0.51 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.90 (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) δ 205.3, 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-tetrahydro-1H-cyclopenta[c]furan-1-one (19). To a stirred solution of enone 18 (16 g, 89 mmol, 1.0 equiv) in MeOH (355 mL, 0.25 M) was added solid CeCl3·7H2O (66.2 g, 178 mmol, 2.0 equiv) in a single portion at 0 °C. The clear reaction was stirred for 30 min at 0 °C before solid NaBH4 (5.0 g, 133 mmol, 1.5 equiv) was added in three equal portions over 15 min. The clear reaction mixture was stirred further for 1 h at 23 °C before the addition of saturated aqueous NH4Cl (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 crude reaction mixture was purified via silica gel column chromatography using 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, 1/1 hexanes/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 for C10H14O3 183.1021, found 183.1027. (3aS,4R,6aR)-4-((4-Methoxybenzyl)oxy)-3,3,6-trimethyl3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-one (20). To a stirred 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-methoxybenzyl2,2,2-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 pale yellow homogeneous reaction was stirred at 23 °C for 18 h. The reaction mixture was poured into pH 7.0 phosphate buffer (500 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified 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) δ 7.25 (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); 13 C 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 for C18H22O4 302.1518, found 302.1517. ( R ) - 1 - ( (1 R , 4 R , 5 S ) - 5 - ( 2 - H y d ro x y p r o p a n - 2- yl )- 4- (( 4 methoxybenzyl)oxy)-2-methylcyclopent-2-en-1-yl)prop-2-en1-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 M solution of DIBAL-H in PhMe (79 mL, 79 mmol, 1.5 equiv) dropwise over 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 added in single portions, and the reaction mixture was warmed to 23 °C. The crude reaction mixture was filtered through a pad of Celite, and the pad of Celite was washed with CH2Cl2 (3 × 200 mL). The combined organics were concentrated in vacuo to give the lactol 21 as a yellow oil, which was used immediately without purification. To a stirred solution of crude lactol 21 (16.0 g, 52.6 mmol, 1.0 equiv) in THF (526 mL, 0.1 M) was added a 0.7 M solution of vinylmagnesium bromide in THF (373 mL, 263 mmol, 5 equiv) dropwise via cannula over 30 min. The dark red homogeneous reaction mixture was stirred at 50 °C for

(R)-5-(2-Bromopropan-2-yl)-2-methylcyclohex-2-en-1-one (14). To a stirred solution of 33% hydrobromic acid in acetic acid (219 mL, 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 poured over ice H2O (600 mL) and extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with H2O (800 mL), saturated aqueous NaHCO3 (800 mL), and brine (800 mL), dried over Na2SO4, and concentrated in vacuo to give the crude monobromide as an amber 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 = 6.0 Hz, 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-methylcyclohexan-1-one (15). To a stirred solution of crude monobromide 14 (154 g, 666 mmol, 1.0 equiv) in AcOH (440 mL, 1.5 M) at 23 °C in 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, the reaction mixture was poured over ice H2O (600 mL) and extracted with Et2O (3 × 600 mL). The combined organic layers were washed with H2O (600 mL), saturated aqueous NaHCO3 (5 × 600 mL), and brine (600 mL), dried over Na2SO4, and concentrated in vacuo to give crude tribromide 15 as an amber oil, which was used without purification: 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, 15.3 Hz, 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 (100 MHz, 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-1Hcyclopenta[c]furan-1-one (17). To a stirred solution of crude tribromide 15 (260 g, 7.32 mol, 1.0 equiv) in Et2O (2.66 L, 0.25 M) at 0 °C was slowly added isopropyl amine (630 mL, 7.32 mol, 11.0 equiv) over 30 min. Upon complete addition, the reaction mixture was warmed to 23 °C. After 12 h, the reaction mixture was cooled to 0 °C before carefully adding 10% aqueous H2SO4 (600 mL). The aqueous layer was separated, and the organic layer was extracted with 10% aqueous H2SO4 (3 × 600 mL). The combined aqueous layers were cooled to 0 °C with stirring before being brought to pH 8.0 with 10 N NaOH (600 mL). The neutralized solution was extracted with EtOAc (4 × 600 mL), washed with brine (600 mL), dried over Na2SO4, and concentrated in vacuo to give crude imidate 16 as an amber oil, which was 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) was heated to 50 °C. After 3 h, the reaction mixture was cooled to 23 °C before pouring over ice and saturated aqueous NaHCO3 (1 L). The reaction mixture was extracted with EtOAc (4 × 600 mL), washed with brine (600 mL), dried over Na2SO4, and concentrated in vacuo to give an amber oil. The crude material was purified via silica gel column chromatography (5/1 hexanes/EtOAc) followed by recrystallization from hexanes to give pure bicycle 17 (55.3 g, 333 mmol, 50% over four steps) as a white solid (mp 33−35 °C). Spectral data matched those previously reported:38 Rf = 0.41 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.23 (bd, J = 2.0 Hz, 1H), 3.39 (d, J = 9.0 Hz, 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 (100 MHz, 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-dimethylpyrazole (521 g, 5.4 mol, 15 equiv) in CH2Cl2 (2.4 L, 0.15 M) at 0 °C was added solid CrO3 (541 g, 5.4 mol, 15 equiv) in five even portions over 15 min. A solution of bicycle 17 (60 g, 361 mmol, 1.0 equiv) in CH2Cl2 (200 mL) was then added dropwise over 15 min. After it was H

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 1.5 h. The reaction mixtue was cooled to 0 °C before saturated aqueous NH4Cl (500 mL) was added portionwise. 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 to give the alcohol 22 as a red oil, which was used directly without purification: Rf = 0.39 (silica gel, 3/1 hexanes/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]+ calcd for 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, 1.0 equiv) in a 10/1 solution of THF/DMSO (52.6 mL, 1.0 M) was added 60% NaH (4.63 g, 116 mmol, 2.2 equiv) portionwise over 15 min. An 80% solution of propargyl bromide in PhMe (11.7 mL, 105 mmol, 2.0 equiv) was added, and the dark heterogeneous reaction mixture was stirred at 23 °C for 18 h. H2O (100 mL) was added, and the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with H2O (3 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified via silica gel column chromatography using 3/1 hexanes/EtOAc to give the alkyne 23 (6.24 g, 16.8 mmol, 32% over three steps) as a yellow oil: Rf = 0.31 (silica gel, 5/1 hexanes/EtOAc); 1H NMR (400 MHz, 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 = 11.0 Hz, 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 added solid, freshly prepared2 Burgess reagent (6.0 g, 25.3 mmol, 1.5 equiv) in a single portion. The pale yellow homogeneous reaction mixture was stirred for 5 min before addition of pH 7 phosphate buffer (200 mL). 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 was purified 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-methylenetetrahydrofuran-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 added solid bis(pinacolato)diboron (1.08 g, 4.24 mmol, 1.1 equiv), solid palladium(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 was heated to and stirred at 50 °C. After 4 h, the reaction mixture was cooled to 23 °C and concentrated in vacuo to give the boronate ester as an amber oil. To a stirred solution of the crude boronate ester in THF (77.2 mL, 0.05 M) at 0 °C was carefully added 1 N NaOH (11.6 mL, 11.6 mmol, 3.0 equiv) and 30% aqueous H2O2 (13.0 mL, 116 mmol, 30 equiv) over 1 h. The reaction mixture was diluted with brine (100 mL), extracted with EtOAc (3 × 50 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow oil. The crude material was purified via silica gel column chromatography (3/1 hexanes/EtOAc) to give pure alcohol 26 (500 mg, 1.35 mmol, 35% over two steps) as a clear oil: Rf = 0.34 (silica gel, 3/1 hexanes/EtOAc); 1H NMR (400 MHz, 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, found 370.2139. (2S,3R)-2-((1R,4R,5R)-4-((4-Methoxybenzyl)oxy)-2-methyl-5(prop-1-en-2-yl)cyclopent-2-en-1-yl)-4-methylenetetrahydrofuran-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 was slowly added a solution of dimethyl sulfoxide (172 μL, 2.43 mmol, 5 equiv) 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 a single portion. After 1.5 h, neat triethylamine (341 μL, 2.43 mmol, 5 equiv) was added in a single portion and the reaction mixture was warmed 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), dried over Na2SO4, and concentrated in vacuo to give crude aldehyde 27 as a clear oil, which was used immediately in the next reaction without purification: Rf = 0.57 (silica gel, 3/1 hexanes/EtOAc); 1H NMR (400 MHz, 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 = 2.3 Hz, 1H), 4.98 (q, J = 2.4 Hz, 1H) 4.89 (s, 1H), 4.57 (dd, J = 4.3, 7.4 Hz, 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); 13 C 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 C23H28O4 391.18800, found 391.18760. (3aS,4S,6aR,7R,9aR,9bS)-7-((4-Methoxybenzyl)oxy)-9-methyl-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 °C was 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, the reaction mixture was quenched with 10% aqueous NaOH (5 mL). The reaction mixture was warmed to 23 °C and further diluted with brine (10 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified via silica gel column chromatography (1/1 hexanes/EtOAc) to give pure 5,7,5-tricycle 28 (137 mg, 0.37 mmol, 76% over two steps) as a clear oil: Rf = 0.61 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 7.21 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 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 = 10.8 Hz, 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) δ 159.0, 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. I

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 2-((1R,2R)-2-(Hydroxymethyl)-3-methylcyclopent-3-en-1-yl)propan-2-ol (30). To a stirred solution of bicycle 17 (32 g, 193 mmol, 1.0 equiv) in Et2O (960 mL, 0.2 M) at 0 °C was slowly added a 4.0 M solution of lithium aluminum hydride in Et2O (48 mL, 193 mmol, 1.0 equiv) over 20 min. After 40 min, the reaction mixture was carefully quenched with H2O (7.3 mL), 15% aqueous NaOH (7.3 mL), and H2O (21.9 mL) at 0 °C. The reaction mixture was dried over Na2SO4, filtered through Celite, and concentrated in vacuo to give pure 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 = 12 Hz, 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 C10H18O2 193.11930, 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), and Ac2O (160 mL, 1.5 M) was heated to 150 °C. After 16 h, the reaction mixture 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 acetates 32 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) δ 171.0, 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 added a 4.0 M solution of lithium aluminum hydride in Et2O (26.7 mL, 107 mmol, 0.5 equiv) over 20 min. After 40 min, the reaction mixture was carefully quenched with H2O (4.1 mL), 15% aqueous NaOH (4.1 mL), and H2O (12.3 mL) at 0 °C. The reaction mixture was dried over Na2SO4, filtered through Celite, and concentrated in vacuo to give a clear oil. The crude material was purified via silica gel column chromatography (50/1 to 20/1 hexanes/EtOAc) to give pure alcohol 33 (15.9 g, 105 mmol, 49%) as a clear oil: Rf = 0.36 (silica gel, 5/1 hexanes/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, 6.3 Hz, 1H), 1.83 (s, 3H), 1.73 (s, 3H), 1.59 (bs, 1H); 13C NMR (100 MHz, 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-carbaldehyde (34). To a stirred solution of alcohol 33 (26.2 g, 172 mmol, 1.0 equiv) in CH2Cl2 (860 mL, 0.2 M) at 23 °C were added solid NaHCO3 (43.4 g, 517 mmol, 3 equiv), freshly prepared3,4 Dess− Martin periodinane (110 g, 258 mmol, 1.5 equiv), and H2O (1 mL). After 45 min, the reaction mixture was diluted with saturated aqueous NaHCO3 (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 in vacuo to give an amber oil. The crude material was purified via silica

gel column chromatography (10/1 hexanes/EtOAc) to give pure aldehyde 34 (22.5 g, 150 mmol, 87%) as a clear oil: Rf = 0.56 (silica gel, 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 = 9.1 Hz, 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-1yloxy)allyl)cyclopent-1-ene (36). To a stirred solution of tetravinyltin (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 (91 mL, 195 mmol, 1.3 equiv). The reaction mixture was warmed and stirred 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 neat hexamethylphosphoramide (52 mL, 299 mmol, 2 equiv) was added. After an additional 10 min an 80% solution of propargyl bromide in toluene (83 mL, 749 mmol, 5 equiv) was added. Upon complete addition the reaction mixture was warmed to 23 °C. After 3 h, the reaction mixture was diluted with saturated aqueous NH4Cl (50 mL), extracted with Et2O (3 × 50 mL), washed with 3.0 N LiCl (3 × 50 mL), dried over Na2SO4, and concentrated in vacuo to give a yellow oil. The crude material was purified via silica gel column chromatography (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, 2.4 Hz, 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] calcd for 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 a stirred 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 nbutyllithium in hexanes (68 mL, 145 mmol, 1.2 equiv). After 20 min, freshly distilled neat trimethylsilyl chloride (31 mL, 242 mmol, 2 equiv) was added. Upon complete addition the reaction mixture was warmed to 23 °C. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (400 mL), extracted with Et2O (3 × 400 mL), washed with brine (400 mL), dried over Na2SO4, and concentrated 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); 1H NMR (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) δ 145.1, 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, found 288.1901. ((2R,3R,Z)-2-((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)cyclopent2-en-1-yl)-4-((trimethylsilyl)methylene)tetrahydrofuran-3-yl)methanol (39). To a stirred solution of TMS enyne 37 (20.8 g, 72.1 mmol, 1.0 equiv) in PhMe (720 mL, 0.1 M) at 23 °C were added solid bis(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, 72.1 mmol, 1.0 equiv). The reaction mixture was heated to 50 °C with stirring. After 15 h, the reaction mixture was cooled to 23 °C and concentrated in vacuo to give the boronate ester as an amber oil. To a stirred solution of crude boronate ester (30 g, 72.0 mmol, 1.0 equiv) in THF (1.4 L, 0.05 M) at 0 °C were carefully added 3.33 N NaOH J

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry (64.9 mL, 216 mmol, 3 equiv) and 50% aqueous H2O2 (130 mL, 2.16 mol, 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 was purified 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 a white 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-2en-1-yl)-4-((trimethylsilyl)methylene)tetrahydrofuran-3-carbaldehyde (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 slowly added 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 alcohol 39 (12.2 g, 39.9 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added. After 2 h, neat triethylamine (28.0 mL, 199 mmol, 5 equiv) was added in a single portion and the reaction mixture was warmed to 23 °C. The reaction mixture was then diluted with 0.1 N HCl (200 mL). The organic 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 in vacuo to give crude aldehyde 40 (12.1 g, 39.9 mmol, yield taken after subsequent 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, 7.4 Hz, 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( ( t r i m e t h y l s i l y l ) m e t h y le n e ) - 2, 3, 3a ,4 ,5 ,6 , 6a ,7 ,9 a, 9b decahydroazuleno[4,5-b]furan-4-ol (41). To a stirred solution of crude 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 diethylaluminum chloride in hexanes (19.9 mL, 19.9 mmol, 0.5 equiv) in a single portion. After 10 min, the reaction mixture was quenched with 10% aqueous NaOH (20 mL). The reaction mixture was warmed to 23 °C and further diluted with brine (200 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were 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, 39.9 mmol, 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 = 9.0 Hz, 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( ( t r i m e t h y l s i l y l ) m e t h y le n e ) - 2, 3, 3a ,4 ,5 ,6 , 6a ,7 ,9 a, 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, 2.0 equiv) in PhMe (345 mL) at 23 °C was added neat triethylamine (38.4 mL, 276 mmol, 4.0 equiv) and neat 2,4,6-trichlorobenzoyl chloride (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 solid dimethylaminopyridine (21.9 g, 179 mmol, 2.6 equiv) were added. The reaction mixture was then heated to 80 °C. After 45 min, the reaction mixture was cooled to 23 °C, diluted with saturated aqueous NaHCO3, extracted with EtOAc (3 × 500 mL), dried over Na2SO4, and concentrated in vacuo to give an amber oil. The crude material was purified via silica gel column chromatography (20/1 hexanes/ EtOAc) to give pure tigloyl ester 42 (24.0 g, 62.1 mmol, 90%) as a clear oil: Rf = 0.18 (silica gel, 20/1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.75 (q, J = 6.7 Hz, 1H), 5.49 (s, 1H), 5.41 (q, J = 5.5 Hz, 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 = 7.8 Hz, 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 for C23H34O3Si 409.21710, found 409.21690. (3aR,4R,6aR,9aR,9bR,Z)-9-Methyl-6-methylene-2,7-dioxo-3( ( t r i m e t h y l s il y l ) m e th yl e n e )- 2 ,3 ,3 a, 4 ,5 ,6 ,6 a, 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) in CH2Cl2 (100 mL, 0.05 M) at 0 °C was added solid 3,5dimethylpyrazole (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 was directly purified via Florasil column chromatography (2/1 hexanes/ EtOAc) to give pure guaianolide 43 (1.29 g, 3.10 mmol, 30%) as a clear oil: Rf = 0.22 (silica gel, 2/1 hexanes/EtOAc); 1H NMR (400 MHz, 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-methylene-2-oxo-3-((trimethylsilyl)methylene)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 (755 mg, 1.82 mmol, 1.0 equiv) in MeOH (36 mL, 0.05 M) at 0 °C was added 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 even portions. After 15 min, the reaction mixture was warmed to 23 °C and diluted with 0.2 M aqueous pH 7.0 phosphate buffer. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give pure allylic alcohol 44 (700 mg, 1.68 mmol, 92%) as a clear oil: Rf = 0.24 (silica gel, 3/1 hexanes/EtOAc); 1 H 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, found 439.19110. (3aR,4R,6aR,7R,9aR,9bR)-7-Hydroxy-9-methyl-3,6-dimethylene-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 of vinylsilane 44 (267 mg, 0.641 mmol, 1.0 equiv) in EtOH (6.4 mL, 0.1 M) at 23 °C was added neat thiophenol (2.88 mL, 28.2 mmol, 44 equiv) 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 K

DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

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-dimethylene-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 of enone 50 (630 mg, 1.84 mmol, 1.0 equiv) in 3/1 MeOH/THF (18.4 mL, 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 the mixture was stirred for an additional 10 min, neat acetaldehyde (1.0 mL, 18.4 mmol, 10 equiv) was added in a single portion and the reaction mixture was stirred further for 15 min at −78 °C. EtOAc/ H2O (1/1, 40 mL) was added, and the reaction mixture was warmed to 23 °C over 30 min. The reaction mixture was further diluted with brine (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 concentrated in vacuo to give a brown oil. The crude material was purified via silica gel column chromatography (2/1 hexanes/EtOAc) to give pure allylic alcohol 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 (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 for C20H24O5 367.15160, found 367.15200. (3aR,4R,6R,6aS,7R,9aR,9bR)-7-Hydroxy-9-methyl-3-methylene-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, 1.0 equiv) in CH2Cl2 (13.7 mL, 0.1 M) was added a 1.0 M solution of Al(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 min before a 5.5−6.0 M solution of TBHP in decane (0.275 mL, 1.51 mmol, 1.1 equiv) was added dropwise. The cooling bath was removed, and the reaction mixture was warmed to 23 °C over 30 min. Saturated aqueous Na2S2O3 (10 mL) was added, and the mixture was stirred for 15 min. The crude reaction mixture was further diluted with brine (20 mL), and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated to give epoxide 51 as a clear oil. The crude material was used immediately in the next reaction without purification: Rf = 0.54 (silica gel, 1/1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3) δ 6.70 (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 was added solid lithium chloride (576 mg, 13.6 mmol, 10.0 equiv) in a single portion. The mixture was sonicated for 5 min before addition of a 1.25 M solution of hydrochloric acid in MeOH (3.26 mL, 4.08 mmol, 3.0 equiv). After 5 min, the reaction mixture was diluted with brine (40.0 mL), extracted with EtOAc (3 × 30 mL), dried over Na2SO4, and concentrated in vacuo to give a white solid. The crude material was purified via silica gel column chromatography (2/1 hexanes/EtOAc) to give pure eupalinilide E (1) (466 mg, 1.17 mmol,

purified directly via silica gel column chromatography (straight hexanes 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 thiosilane 46 (238 mg, 0.452 mmol, 1.0 equiv) in THF (4.5 mL, 0.1 M) at 23 °C was 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 passed through a plug of silica gel (2/1 hexanes/EtOAc) to give the crude thio adduct 47 as an amber oil. To a stirred solution of the crude thio adduct 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, 0.678 mmol, 1.5 equiv) in H2O (4.5 mL). After 15 h, the reaction mixture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4, and concentrated in vacuo to give crude sulfone 48 as a white solid. A solution of crude sulfone 48 (220 mg, 0.452 mmol, 1.0 equiv), basic alumina (440 mg, 200% by weight), and CH2Cl2 (4.5 mL, 0.1 M) was stirred at 23 °C. After it was stirred for 12 h, the reaction mixture was passed 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, 0.316 mmol, 70% over three steps) as a clear oil: Rf = 0.54 (silica gel, 1/1 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 (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 for C20H24O5 367.15160, found 367.15200. (3aR,4R,6aR,9aR,9bR)-9-Methyl-3,6-dimethylene2,3,3a,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 neat TFA (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 aqueous NaHCO3 (30 mL) and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (3 × 30 mL) and brine (1 × 30 mL), dried over Na2SO4, and concentrated in vacuo to give 49 as an amber oil (1.6 g, 5.09 mmol, 98%). The crude material was used directly in the next reaction without purification: Rf = 0.61 (silica gel, 20/1 hexanes/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, 13.09 Hz, 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-dioxo2,3,3a,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 3,5dimethylpyrazole (9.78 g, 102 mmol, 20 equiv) in a single portion. A solution of carbocycle 49 (1.6 g, 5.09 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was then added in a single portion. After 45 min, the reaction mixture was directly purified via Florasil column chromatography (1/1 hexanes/EtOAc) to give a white solid. The white solid was dissolved in EtOAc (50 mL), washed with 1.0 M HCl (3 × 20 mL), dried over Na2SO4, and concentrated to give pure guaianolide 50 (630 mg, 1.84 mmol, 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). 13C NMR (150 MHz, CDCl3) δ 205.9, 177.6, 168.7, 166.7, 138.5, 138.4, L

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The Journal of Organic Chemistry 86% over two steps) as a white solid (mp 72 °C dec): Rf = 0.63 (silica gel, 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 = 8.6 Hz, 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) δ 169.7, 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 for C20H25ClO6 419.12320, found 419.12290.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00266. NMR spectra and crystallographic data for new compounds (PDF) Crystallographic data (CIF) Crystallographic data (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail for D.S.: [email protected]. ORCID

Dionicio Siegel: 0000-0003-4674-9554 Present Address ∥

Gilead Sciences, Inc., Foster City, CA 94404, USA.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for the financial support of the California Institute for Regenerative Medicine (DISC1-08737) and the University of California, San Diego. We also thank Steve Sorey and Angela Spangenberg, at UT Austin, and Brendan Duggan, at UC San Diego, for assistance with NMR and Dr. Vincent Lynch, UT Austin, for assistance with X-ray crystallography.

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REFERENCES

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DOI: 10.1021/acs.joc.7b00266 J. Org. Chem. XXXX, XXX, XXX−XXX