Phellilane L, Sesquiterpene Metabolite of Phellinus linteus: Isolation

Nov 1, 2017 - ABSTRACT: A new cyclopropane-containing sesquiterpe- noid, phellilane L (1), was isolated from the medicinal mushroom Phellinus linteus ...
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Phellilane L, Sesquiterpene Metabolite of Phellinus linteus: Isolation, Structure Elucidation, and Asymmetric Total Synthesis Koichiro Ota,† Ikuma Yamazaki,† Takahiro Saigoku,† Mei Fukui,† Tomoki Miyata,† Kazuo Kamaike,† Tatsuya Shirahata,‡ Fumi Mizuno,‡ Yoshihisa Asada,‡ Masao Hirotani,‡ Chieko Ino,‡ Takafumi Yoshikawa,‡ Yoshinori Kobayashi,‡ and Hiroaki Miyaoka*,† †

School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan

‡

S Supporting Information *

ABSTRACT: A new cyclopropane-containing sesquiterpenoid, phellilane L (1), was isolated from the medicinal mushroom Phellinus linteus (“Meshimakobu” in Japanese), a member of the Hymenochaetaceae family and a well-known fungus that is widely used in East Asia. The planar structure of 1 was determined on the basis of spectroscopic analysis. The authors achieved the first total synthesis of 1. Our protecting group-free synthesis features a highly stereoselective one-pot synthesis involving an intermolecular alkylation/cyclization/ lactonization strategy for construction of the key cyclopropane-γ-lactone intermediate. Additionally, our synthesis determined the absolute configuration of phellilane L (1).

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INTRODUCTION In recent years, numerous selective carbon−carbon bond formations have been developed for the generation of complex molecular frameworks.1−5 In particular, alkyl aryl sulfone has frequently been employed in the synthesis of natural products containing multisubstituted cycloalkanes.6−9 The α-sulfonyl carbanion generated by an appropriate base readily forms a carbon−carbon bond with an alkyl halide, aldehyde, ester, acyl halide, or epoxide. We previously reported on the one-pot stereoselective construction of cyclopropane-γ-lactone using methyl phenylsulfonylacetate and disubstituted epoxide possessing a leaving group (Figure 1) and accomplished the total synthesis of the marine eicosanoid hybridalactone.10 The onepot protocol comprised a sequence of intermolecular alkylation/cyclization/lactonization steps, where in particular the α-sulfonyl carbanion generated from methyl phenylsulfonylacetate reacted with di- or trisubstituted epoxyiodide I to afford epoxysulfone II, and then the corresponding αsulfonyl carbanions IIIa and IIIb were regenerated by excess base. Under the reaction conditions, α-sulfonyl carbanions IIIa and IIIb could exist in equilibrium with alkoxides IVa and IVb, cyclizing a cyclopropane. Subsequent lactonization accompanied by MeOH elimination from alkoxide IVa, possessing a spatially closed alkoxide anion and methoxycarbonyl groups, would yield cyclopropane-γ-lactone V. Additionally, cyclopropane-γ-lactone V was subjected to single-electron-transfer (SET) reductive desulfonylation followed by the reductive cleavage of lactone to yield ciscyclopropane VII (Figure 2). Meanwhile, cyclopropane-γ© 2017 American Chemical Society

Figure 1. One-pot synthesis of the cyclopropane-γ-lactone derivative from epoxide possessing a leaving group with methyl phenylsulfonylacetate.

lactone V can be cleaved with an aluminum hydride reagent to generate diol VIII, which in turn is reduced by SET desulfonylation to trans-cyclopropane IX. Two methodologies for the reduction of V could be selected as required. Natural products often possess a trans-cyclopropane IX moiety as the common partial structure (Figure 3). Rumphellolide F (a potent antimicrobial, marine sesquiterpeReceived: August 30, 2017 Published: November 1, 2017 12377

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

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The Journal of Organic Chemistry

Figure 4. Planar structure of phellilane L (1).

by reversed-phase preparative HPLC afforded a new sesquiterpenoid, namely phellilane L (1). Phellilane L (1) showed antibacterial activity against periodontal pathogens Porphyromonas gingivalis with a MIC of 278 μg/mL. Phellilane L (1), [α]28 D −117 (c 0.10, MeOH), was afforded as a colorless solid. The IR spectrum displayed absorptions at 3379 cm−1 (−OH group). The 13C NMR, 1H NMR, and DEPT spectra in MeOH-d4 (Table 1) showed signals indicating

Figure 2. Complementary synthesis of cis-/trans-cyclopropane derivatives.

Table 1. 13C and 1H NMR Spectroscopic Data for Phellilane L (1) 13 a

Hb

1

C

Figure 3. Reported structure of natural products possessing a common partial structure IX.

noid),11 chabrolol C (a rare C17-trinorditerpenoid),12 and halicholactone (a lipoxygenase inhibitor, marine oxylipin)13 are just some examples that have been reported. We supposed that these natural products could be successfully synthesized using the aforementioned one-pot procedure. In this paper, we report on the isolation, structure elucidation, and asymmetric protecting group-free total synthesis of the new sesquiterpene metabolite from Phellinus linteus, phellilane L (1).

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RESULTS AND DISCUSSION The medicinal mushroom Phellinus linteus (P. linteus, “Meshimakobu” in Japanese), a member of the Hymenochaetaceae family, is a well-known fungus that is widely used in East Asia such as China and Korea, and various pharmacological effects have been demonstrated following its use in the treatment of several ailments including tumors, diabetes, inflammation, and obesity.14 Experimental demonstrations of the antitumor,15 immunomodulatory,16 anti-inflammatory,17 and antioxidant18 activities of P. linteus have also been reported. Moreover, in the course of isolation studies using P. linteus, a large number of bioactive compounds have been found including polysaccharides, flavones, triterpenes, and phenols.19−22 Hence, chemical studies pertaining to P. linteus are strongly related to and impact the field of medical research. In the course of fractionation studies of cultured mycelia of P. linteus,23 a unique sesquiterpenoid, phellilane L (1), possessing a trans-cyclopropane ring was isolated (Figure 4). Cultured mycelia of P. linteus were extracted sequentially with methanol at room temperature. The concentrated methanolic extract was diluted with distilled water and partitioned with CHCl3 and ethyl acetate. Each fraction was dried in vacuo. The CHCl3 extract was chromatographed on silica gel and separated into fractions 1−10. Further purification

a

position

δC [ppm]

type

1

25.0

CH2

2 3 4 5

32.1 134.7 122.0 28.1

CH2 C CH CH2

6 7 8 9

46.1 72.9 24.0 4.4

CH C CH CH2

10 11 12 13 14 15

25.8 69.8 29.1 29.7 24.2 23.6

CH C CH3 CH3 CH3 CH3

δH [ppm] (J in Hz) 2.02, m 1.31, m 1.97 (2H), m 5.38, 2.15, 1.87, 1.54,

dd (1.0, 3.0) m m dddd (2.0, 5.0, 12.0, 12.0)

0.92, 0.50, 0.43, 0.94,

ddd ddd ddd ddd

1.18, 1.22, 1.12, 1.63,

s s s s

(6.0, (4.5, (4.5, (6.0,

6.0, 8.5) 6.0,8.5) 6.0,8.5) 6.0, 8.5)

100 MHz in MeOH-d4. b400 MHz in MeOH-d4.

the presence of four methyls, four sp3 methylenes, three sp3 methines, two sp3 nonprotonated carbons, one sp2 methine, and one olefinic quaternary carbon. The aforementioned spectroscopic data suggested that phellilane L (1) is a bicyclic sesquiterpenoid possessing one cyclopropane moiety [δH 0.94 (1H, ddd, J = 6.0, 6.0, 8.5 Hz), δH 0.92 (1H, ddd, J = 6.0, 6.0, 8.5 Hz), δH 0.50 (1H, ddd, J = 4.5, 6.0, 8.5 Hz), δH 0.43 (1H, ddd, J = 4.5, 6.0, 8.5 Hz), δC 25.8 (CH), δC 24.0 (CH), δC 4.4 (CH2)] and one methylcyclohexene ring moiety [δH 5.38 (1H, dd, J = 1.0, 3.0 Hz), δH 2.15 (1H, m), δH 2.02 (1H, m), δH 1.97 (2H, m), δH 1.87 (1H, m), δH 1.63 (3H, s), δH 1.54 (1H, dddd, J = 2.0, 5.0, 12.0, 12.0 Hz), δH 1.31 (1H, m), δC 134.7 (C), δC 122.0 (CH), δC 46.1 (CH), δC 32.1 (CH2), δC 28.1 (CH2), δC 25.0 (CH2), δC 23.6 (CH3)]. COSY cross-peaks indicated sequences of C-1 to C-2, C-1 to C-6, C-4 to C-5, C-5 to C-6, C-8 to C-9, C-8 to C-10, and C-9 to C-10 (Figure 5). The planar structure of phellilane L (1) was determined on the basis of the following correlations in the HMBC spectrum: H-13/C10, C-11, C-12; H-14/C-6, C-7, C-8; H-15/C-2, C-3, C-4. On the basis of the above data, the gross structure was determined as 2-(2-(1-hydroxy-1-(4-methylcyclohex-3-en-1-yl)ethyl)cyclopropyl)propan-2-ol. 12378

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

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The Journal of Organic Chemistry

Scheme 1. Synthetic Plan of Phellilane L Congener 1a

Figure 5. Key 1H−1H COSY and HMBC of phellilane L (1).

Due to the limited amount of available material, a single crystal for X-ray diffraction analysis could not be obtained. In an effort to estimate the stereochemistry of phellilane L (1), the solvent utilized for 1H NMR measurements was changed from MeOH-d4 to pyridine-d5 for the resolution improvement of cyclopropane moiety-derived peaks in the 1H NMR spectrum and subsequent examination of the cross-peaks in the ROESY spectrum. Correlations between H-8 (δ 1.39)/H-9a (δ 0.92) and H-9b (δ 1.01)/H-10 (δ 1.47) indicated a trans-geometry of the cyclopropane ring at the C8−C10 position. However, it was impossible to assign the relative configuration between C6, C7, and C8/C10. Thus, the absolute configuration of phellilane L (1) was expected to be 1a−d or the enantiomers (Figure 6).

Scheme 2. Synthesis of Epoxyiodide 3a

a

Reagents and conditions: (a) TBHP, L-(+)-DIPT, Ti(OiPr)4, 4 Å molecular sieves, CH2Cl2, −20 °C, 90% (5:1 dr); (b) TsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt; (c) NaI, NaHCO3, acetone, rt, 99% (2 steps).

diastereoselectivity was unsatisfactory in this step, we anticipated that the diastereomeric purity may be improved by recrystallization in a later step since the cyclopropane-γlactone derivative empirically retained high crystallinity, and we then embarked on the introduction of a leaving group. To epoxyalcohol 5 was added a p-toluenesulfonyl group to generate tosylate 6, and the leaving group was then exchanged under neutral conditions (NaI, NaHCO3) to generate epoxyiodide 3 in a 99% yield over two steps. When a one-pot synthesis involving intermolecular alkylation/cyclization/lactonization of epoxyiodide 3 was initially attempted with methyl phenylsulfonylacetate and K2CO3 in dry DMF at room temperature, the desired cyclopropane-γ-lactone 4 was produced in a moderate yield (75%, 5:1 dr). In this case, the diastereomeric ratio of 4 remarkably reflected the diastereomeric purity of epoxyiodide 3, although long reaction times (7 days) to achieve reaction completion were required. As before, carboxylic acid was formed due to the extended reaction time, undoubtedly contributing to the moderate yield. Following extensive optimization by careful tuning of the reaction temperature, it was found that the key one-pot procedure could be improved by performing the reaction in DMF at 60 °C for 12 h, providing cyclopropane-γ-lactone 4 in an excellent yield (91%, 5:1 dr) (Scheme 3). Following recrystallization, cyclopropane-γ-lactone 4 could be predictably obtained as a single diastereomeric isomer. This dramatic acceleration can be accounted for by consideration of the mechanisms outlined in Figure 1. The removal of MeOH by vaporization induced a shift of the equilibrium toward formation of the lactone. Following reduction of 4 with lithium aluminum hydride, the resulting diol 7 was converted to transcyclopropane 8 through SET reduction with Mg in MeOH26 in an 84% yield. Oxidation of primary alcohol 8 with 2-

Figure 6. Chemical structures of phellilane L congeners 1a−d.

In an effort to fully and unambiguously characterize phellilane L (1), we performed an asymmetric total synthesis of various congeners possessing trans-cyclopropane. The stereoselective formation of the trans-cyclopropane moiety is important in the synthetic strategy. Cyclopropane-γ-lactone V is easily converted into trans-cyclopropane IX via sequential hydride reduction/SET desulfonylation (Figure 2). We therefore designed a one-pot synthesis involving intermolecular alkylation/cyclization/lactonization steps as a key protecting group-free strategy in this synthesis. The synthetic strategy of phellilane L congener 1a is shown in Scheme 1. It was envisioned that epoxyiodide 3 could be prepared from known optically active allylic alcohol 2.24 The key intermediate, cyclopropane-γ-lactone 4, would be established utilizing our one-pot methodology from epoxyiodide 3. We anticipated that 1a would be obtained from cyclopropane-γ-lactone 4 by sequential lactone cleavage, SET reductive desulfonylation, and introduction of a gem-dimethyl group at C11. The synthesis of phellilane L congener 1a commenced with the conversion of (S)-limonene into allylic alcohol 224 (Scheme 2). Primary allylic alcohol 2 was subjected to Katsuki−Sharpless epoxidation25 with L-(+)-diisopropyl tartrate (DIPT) at −20 °C to generate α-epoxide 5 in a 90% yield as an inseparable diastereomeric mixture in a ratio of 5:1. Although the 12379

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

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The Journal of Organic Chemistry Scheme 3. Synthesis of Phellilane L Congener 1aa

Table 2. Comparison of the 13C and 1H NMR (MeOH-d4) Spectroscopic Data for Natural Phellilane L (1) and Synthetic 1a 13

natural phellilane L

synthetic 1a

position

δ [ppm]

δ [ppm]

1

25.0

25.5

−0.5

2 3 4 5

32.1 134.7 122.0 28.1

32.2 134.6 122.1 27.8

−0.1 0.1 −0.1 0.3

6 7 8 9

46.1 72.9 24.0 4.4

46.6 72.9 23.3 4.6

−0.5 0.0 0.7 −0.2

10 11 12 13 14 15

25.8 69.8 29.1 29.7 24.2 23.6

25.7 69.8 29.1 29.7 25.0 23.6

0.1 0.0 0.0 0.0 −0.8 0.0

a

Reagents and conditions: (a) methyl phenylsulfonylacetate, K2CO3, DMF, 60 °C, 91% (5:1 dr); (b) recrystallization, 75%; (c) LiAlH4, THF, 0 °C to rt, quant; (d) Mg, MeOH, 50 °C, 84%; (e) IBX, DMSO/THF, rt; (f) NaClO2, NaH2PO4, 2-methylbut-2-ene, tBuOH/ H2O, rt; (g) TMSCHN2, Et2O/MeOH, 0 °C; (h) MeLi, THF, −78 °C, 78% (4 steps).

iodoxybenzoic acid (IBX)27,28 provided the aldehyde. Further oxidation of the aldehyde under Pinnick conditions29 employing sodium chlorite, NaH2 PO4, and 2-methylbut-2-ene furnished the carboxylic acid, which was readily converted into methyl ester 9 by employing TMS-diazomethane. Treatment with MeLi then led to the desired tertiary alcohol 1a in a 78% yield over four steps. The relative configuration of synthetic 1a was confirmed by single-crystal X-ray diffraction (Figure 7).

1

C

a

Δδ [ppm]a

H

natural phellilane L

synthetic 1a

δ [ppm]

δ [ppm]

δ [ppm]a

2.02 1.31 1.97

1.98 1.34 1.98

0.04 −0.03 −0.01

5.38 2.15 1.87 1.54

5.39 2.12 1.94 1.59

−0.01 0.03 −0.07 −0.05

0.92 0.50 0.43 0.94

0.98 0.52 0.43 0.93

−0.06 −0.02 0.00 0.01

1.18 1.22 1.12 1.63

1.18 1.21 1.12 1.63

0.00 0.01 0.00 0.00

Δδ [ppm] = natural phellilane L [ppm] − synthetic la [ppm].

its enantiomer 1b (Figure 6). Thus, we tried to obtain the congener 1b, which was prepared from the same allylic alcohol 2. Given the versatility of our developed one-pot methodology, compound 1b with the opposite configuration at C7, C8 and C10 was readily prepared from allylic alcohol 2 (Scheme 4). In Scheme 4. Total Synthesis of Phellilane L (1b)a

Figure 7. ORTEP drawing of 1a.

Unfortunately, the NMR analysis of our synthetic congener 1a, and in particular the 13C NMR spectrum, showed marked discrepancies when compared to the spectrum of natural phellilane L (1), and the greatest differences involved signals around the C6−C7 bond (Table 2). The 13C NMR signals associated with C1, C6, and C14 were shifted slightly downfield (>0.5 ppm) in comparison to those of natural phellilane L (1). The methylene protons of C5 of natural phellilane L (1) gave signals at δ 2.15 and δ 1.87, while signals from the corresponding protons in 1a were observed at δ 2.12 and δ 1.94. Furthermore, the methine proton of C8 of natural phellilane L (1) gave a signal at δ 0.92, while the signal from the corresponding proton in 1a was observed at δ 0.98. In contrast, the signals assigned for the gem-dimethyl group at C11−C13 were very similar between natural phellilane L (1) and 1a. Given the aforementioned results, we inferred that the actual structure of phellilane L (1) might comprise the C6-epi-1a or

a

Reagents and conditions: (a) TBHP, D-(−)-DIPT, Ti(OiPr)4, 4 Å molecular sieves, CH2Cl2, −20 °C, 97% (4:1 dr); (b) TsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt; (c) NaI, NaHCO3, acetone, rt, 99% (2 steps); (d) methyl phenylsulfonylacetate, K2CO3, DMF, 60 °C, 97% (4:1 dr); (e) recrystallization, 77%; (f) LiAlH4, THF, 0 °C to rt, 98%; (g) Mg, MeOH, 50 °C, 90%; (h) IBX, DMSO/THF, rt; (i) NaClO2, NaH2PO4, 2-methylbut-2-ene, tBuOH/H2O, rt; (j) TMSCHN2, Et2O/ MeOH, 0 °C; (k) MeLi, THF, −78 °C, 91% (4 steps).

a similar manner, primary allylic alcohol 2 was converted to βepoxyalcohol 10 using Katsuki−Sharpless asymmetric epoxidation in a workable diastereomeric ratio (4:1). Following conversion of the resulting β-epoxyalcohol 10 into epoxyiodide 11, we performed our one-pot synthesis involving intermolecular alkylation/cyclization/lactonization to generate cyclopropane-γ-lactone 12. Cyclopropane-γ-lactone 12 was then 12380

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

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body of P. linteus, a small piece of the stipe was inoculated onto a potato dextrose agar (PDA) medium [39 g, distilled water (DW) = 1 L]. The developing colonies of the new hyphae (from the stipe) were transferred to malt agar in Petri dishes. The pure mycelia were subcultured for 2 weeks and grown in a 500 mL Erlenmeyer flask in 125 mL of medium containing 10 g of sucrose, 30 g of malt extract, and 5 g of yeast extract in 1 L of DW. Each flask was seeded with 5 of the 10 mm plugs cut from the PDA culture. Extraction Procedure and Separation of the CHCl3 and EtOAc Extracts of the Mycelia. After 5 weeks of culture (100 flasks) (25 °C, dark, 63 rpm), the mycelia (990.55 g, fraction wt) were harvested with a nylon cloth, homogenized with MeOH in a Waring blender and allowed to stand for 1 week at room temperature. The homogenate was filtered, and the residue was re-extracted with the same solvent. The filtrates were combined, and the organic solvent was removed under reduced pressure. The concentrated methanolic extract was then diluted with water and partitioned with CHCl3 and EtOAc as follows: the residue was first extracted with CHCl3 (×2 in a total of 2 L), dried in vacuo, and evaporated to dryness to afford the CHCl3 extract (CHCl3, 20.99 g). The CHCl3 extract (20.99 g) was first subjected to silica gel chromatography eluted with a toluene/EtOAc (19:1) mixture to afford fractions 1−10. Purification of fraction 9 (339.3 mg) was achieved by preparative HPLC (column, μBONDASPHERE 5 μ C18−100 Å (5 μm, 19 Φ × 150 mm); solvent, 80% MeOH; flow rate, 6.0 mL/min) to afford fractions 9−3. Further purification of fractions 9−3 was achieved by preparative HPLC (column, Senshu Pak PEGASIL Silica 120−5 (5 μm, 20 Φ × 150 mm); solvent, CHCl3/MeOH = 19:1; flow rate: 6.0 mL/min) to afford phellilane L (1) (8.6 mg). Phellilane L (1): colorless solid; [α]28 D −117 (c 0.10, MeOH); IR (KBr) νmax 3379, 2979, 2920 cm−1; 13C and 1H NMR data (Table 1); HRMS (FAB-pos, m-nitrobenzylalcohol matrix) m/z [M + Na]+ calcd for C15H26O2Na 261.1830, found 261.1830. Antimicrobial Assay (Broth Dilution Assay). Porphyromonas gingivalis ATCC 33277, provided by the Meikai University School of Dentistry (Japan), was used as a test bacterium. The broth macrodilution assay of phellilane L (1) against P. gingivalis was carried out in GAM broth with test tubes under anaerobic conditions. Each tube contained 1 × 105 CFU mL−1 (CFU, colony forming units). Triclosan and hinokitiol were used as a positive control. All of the tubes were incubated at 37 °C for 3 days. Minimum inhibitory concentrations (MICs) were determined as the lowest concentration of each compound showing no growth. Phellilane L (1) showed antibacterial activity against P. gingivalis with an MIC of 278 μg/mL, weaker than that of a positive control (triclosan 3.13 μg/mL and hinokitiol 25.0 μg/mL). ((2S,3S)-3-Methyl-3-((S)-4-methylcyclohex-3-en-1-yl)oxiran-2-yl)methanol (5). To a cold (−20 °C) suspension of 4 Å molecular sieves (1.79 g) in CH2Cl2 (15.0 mL) were added L-(+)-DIPT (303 mg, 1.29 mmol), Ti(OiPr)4 (0.318 mL, 1.08 mmol), and TBHP (5.55 M solution in CH2Cl2, 5.82 mL, 32.3 mmol). After stirring the mixture for 30 min at the same temperature, a solution of allylic alcohol 2 (1.79 g, 10.8 mmol) in CH2Cl2 (200 mL) was added over 12 h. After stirring the mixture at −20 °C for 2 h, NaOH (30% solution in brine, 0.736 mL) was added. The mixture was diluted with Et2O, warmed to room temperature, and stirred for 30 min. MgSO4 (736 mg) and Celite (92.0 mg) were then added, and after stirring for 15 min, the mixture was passed through a pad of Celite and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 2:1) to give epoxyalcohol 5 (1.77 g, 90% yield, 5:1 dr) as a colorless oil. Major isomer: Rf 0.20 (hexane/EtOAc = 2:1); IR (neat) νmax 3435, 2924, 1641, 1440, 1386, 1230 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.36 (1H, m), 3.82 (1H, dd, J = 4.2, 12.1 Hz), 3.69 (1H, dd, J = 6.7, 12.1 Hz), 2.99 (1H, dd, J = 4.2, 6.7 Hz), 2.22 (1H, brs), 2.05 (1H, m), 2.01−1.81 (3H, m), 1.74 (1H, m), 1.62 (3H, s), 1.45 (1H, m), 1.28 (1H, m), 1.23 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 133.9 (C), 119.9 (CH), 63.8 (C), 61.8 (CH), 61.4 (CH2), 41.4 (CH), 30.2 (CH2), 27.0 (CH2), 24.7 (CH2), 23.3 (CH3), 14.4 (CH3); MS (ESI-TOF) m/z 205 [M + Na]+ (100); HRMS (ESITOF) m/z [M + Na]+ calcd for C11H18O2Na 205.1204, found

converted to 1b by following the established synthetic route. The relative configurations at C6, C7, C8, and C10 of 1b were confirmed by single-crystal X-ray diffraction (Figure 8). The 1H

Figure 8. ORTEP drawing of phellilane L (1b).

and 13C NMR spectra of 1b are identical to those of natural phellilane L (1), thereby unambiguously establishing the relative configuration of phellilane L (1). The optical rotation of 1b, [α]25 D −117 (c 0.47, MeOH), is in agreement with that of the natural product, [α]28 D −117 (c 0.10, MeOH), indicating that the absolute configuration is as shown.

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CONCLUSION In conclusion, we report on the isolation, structure elucidation, and first asymmetric, protecting group-free total synthesis of the sesquiterpenoid phellilane L (1b), featuring a highly stereoselective one-pot synthesis involving intermolecular alkylation/cyclization/lactonization on epoxyiodide 11 to construct the key cyclopropane-γ-lactone intermediate 12. Additionally, our synthesis determined the absolute configuration of phellilane L (1) as 6S, 7R, 8R, and 10R, respectively.

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EXPERIMENTAL SECTION

General Experimental Procedures. Melting points (mp) were measured using the Yanaco melting point apparatus MP-S3 and were uncorrected. Optical rotations were measured with a JASCO DIP1000 digital polarimeter and a JASCO P-1030 polarimeter. IR spectra were recorded with a JASCO DFT/IR 460 infrared and a JASCO FTIR/620 spectrometer. Single-crystal X-ray diffraction was recorded using a MacScience Co., Ltd. DIP 2020 Image Plate. 1H and 13C NMR spectra were recorded on a Varian XL-400 and a Bruker Biospin AVANCE III HD 400 Nanobay (400 MHz for 1H, 100 MHz for 13C), and the reported chemical shifts (δ) in parts per million (ppm) were relative to the internal CHCl3 (7.26 ppm for 1H and 77.0 ppm for 13C) and the internal MeOH (3.31, 4.84 ppm for 1H and 49.0 ppm for 13 C); the coupling constant (J) values were measured in hertz. The coupling patterns are denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Positive ion HR-FAB-MS measurements were recorded on JMS-700 MS stations with a quadrupole doublet. EI-MS data were measured on a JEOL JMSAX505 with an ion trap. HR-ESI-MS spectra were obtained using a Micromass LCT spectrometer with a time-of-flight (TOF) analyzer. Elemental analysis data were obtained using an Elementar Vario EL. HPLC analysis was carried out using a Shimadzu SPD-10AV UV−vis detector and a Waters HPLC-pump (Waters 515, UV; 254 nm) with a μ-BONDASPHERE 5 μ C18−100 Å column (5 μm, 19 Φ × 150 mm). Precoated silica gel plates with a fluorescent indicator (Merck 60 F254) were used for analytical and preparative thin-layer chromatography (TLC). Flash column chromatography was performed using Kanto Chemical silica gel 60N (spherical, natural) 40−50 μm. All reagents (Aldrich, Kanto, TCI, and Wako) and solvents were of commercial quality and were used as received. Culture Conditions for P. linteus Mycelium. A fruit body of Phellinus linteus was collected in Japan. Species identification was morphologically carried out. After sterilizing the cultivated fruiting 12381

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

Article

The Journal of Organic Chemistry

(1H, m), 7.60−7.56 (2H, m), 5.39 (1H, m), 4.26 (1H, d, J = 13.4 Hz), 3.99 (1H, d, J = 13.4 Hz), 2.15 (1H, m), 2.11 (1H, dd, J = 8.2, 10.2 Hz), 2.02 (1H, m), 2.00 (1H, m), 1.98−1.88 (2H, m), 1.66 (3H, s), 1.63−1.61 (2H, m), 1.40−1.30 (2H, m), 1.17 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 138.1 (C), 134.0 (C), 133.7 (CH), 129.1 (CH) × 2, 128.6 (CH) × 2, 120.1 (CH), 71.9 (C), 59.1 (CH2), 46.4 (C), 46.0 (CH), 31.2 (CH), 30.7 (CH2), 26.5 (CH2), 26.0 (CH3), 23.7 (CH2), 23.2 (CH3), 13.5 (CH2); MS (ESI-TOF) m/z 373 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26O4SNa 373.1450, found 373.1451. Anal. Calcd for C19H26O4S: C, 65.11; H, 7.48. Found: C, 64.94; H, 7.30. (S)-1-((1S,2S)-2-(Hydroxymethyl)cyclopropyl)-1-((S)-4-methylcyclohex-3-en-1-yl)ethan-1-ol (8). To a stirred solution of cis-cyclopropane 7 (1.04 g, 2.97 mmol) in MeOH (149 mL) was added Mg (7.43 g, 306 mmol) at 50 °C. After stirring for 20 min, the reaction mixture was cooled to room temperature, diluted with Et2O, washed with a 10% aqueous citric acid solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/ EtOAc = 1:1) to give trans-cyclopropane 8 (525 mg, 84% yield) as a white needle-like crystalline solid: Rf 0.15 (hexane/EtOAc = 1:1); white needles (CHCl3/hexane); mp 93−94 °C; [α]25 D −46.7 (c 1.02, CHCl3); IR (KBr) νmax 3305, 2953, 2925, 2886, 1023 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.39 (1H, m), 3.50 (1H, dt, J = 6.7, 11.0 Hz), 3.47 (1H, dt, J = 7.1, 11.0 Hz), 2.13−1.87 (5H, m), 1.64 (3H, s), 1.61 (1H, m), 1.34 (1H, dt, J = 6.0, 12.3 Hz), 1.11 (3H, s), 1.02 (1H, m), 0.92 (1H, m), 0.69 (1H, m), 0.34 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 134.0 (C), 120.6 (CH), 72.1 (C), 66.7 (CH2), 45.2 (CH), 30.9 (CH2), 26.7 (CH2), 24.7 (CH), 24.5 (CH3), 24.0 (CH2), 23.3 (CH3), 16.8 (CH), 6.2 (CH2); MS (ESI-TOF) m/z 233 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H22O2Na 233.1517, found 233.1514. Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C, 74.28; H, 10.65. 2-((1S,2S)-2-((S)-1-Hydroxy-1-((S)-4-methylcyclohex-3-en-1-yl)ethyl)cyclopropyl)propan-2-ol (1a). To a solution of IBX (699 mg, 2.50 mmol) in DMSO (5.00 mL) was added a solution of transcyclopropane 8 (210 mg, 0.998 mmol) in THF (5.00 mL). After stirring the mixture for 2.5 h at room temperature, H2O was added. After diluting with Et2O, the mixture was filtered through Celite, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude aldehyde, which was used for the next step without further purification. To a stirred solution of the crude aldehyde in tBuOH (9.98 mL) were added 2-methylbut-2-ene (2.11 mL, 20.0 mmol), NaH2PO4 (455 mg, 3.79 mmol), and the solution of NaClO2 (361 mg, 3.99 mmol) in H2O (3.33 mL) at room temperature. After stirring for 40 min, the reaction mixture was diluted with Et2O, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude carboxylic acid, which was used for the next step without further purification. To a stirred solution of the crude carboxylic acid in Et2O/MeOH (1:1, 20.0 mL) was added TMSCHN2 (2.00 M solution in Et2O, 1.25 mL, 2.50 mmol) at 0 °C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The residue was passed through a pad of silica gel (hexane/EtOAc = 4:1) and then concentrated in vacuo to give a crude methyl ester 9. To a stirred solution of the crude methyl ester 9 in THF (9.98 mL) was added MeLi (1.12 M solution in Et2O, 4.46 mL, 4.99 mmol) at −78 °C. After stirring for 10 min, the reaction mixture was diluted with Et2O, washed with a saturated aqueous NaHCO3 solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 2:1) to give tertiary alcohol 1a (186 mg, 78% yield for 4 steps) as a white needle-like crystalline solid: Rf 0.10 (hexane/EtOAc = 4:1); white needles (hexane/Et2O); mp 120−121 °C; [α]25 D −9.1 (c 0.75, MeOH); IR (KBr) νmax 3363, 2979, 2832, 1159 cm−1; 1H NMR (MeOH-d4, 400 MHz) δ 5.39 (1H, m), 2.12 (1H, m), 2.08−1.98 (2H, m), 1.98 (1H, m), 1.94 (1H, m), 1.63 (3H, s), 1.59 (1H, m), 1.34 (1H, m), 1.21 (3H, s), 1.18 (3H, s), 1.12 (3H, s), 0.98 (1H, m), 0.93 (1H, m), 0.52 (1H, ddd, J = 4.6, 6.2, 6.8 Hz), 0.43 (1H,

205.1212. Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.29; H, 9.82. (2S,3R)-3-(Iodomethyl)-2-methyl-2-((S)-4-methylcyclohex-3-en-1yl)oxirane (3). To a stirred solution of epoxyalcohol 5 (1.54 g, 8.45 mmol) in CH2Cl2 (84.5 mL) were added Et3N (10.6 mL, 76.1 mmol), DMAP (103 mg, 0.845 mmol), and TsCl (3.22 g, 16.9 mmol) at 0 °C. The mixture was then allowed to warm to room temperature. After stirring for 45 min, the reaction mixture was diluted with Et2O, washed with a saturated aqueous NaHCO3 solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude epoxytosylate 6, which was used for the next step without further purification. To a stirred solution of the crude epoxytosylate 6 in acetone (84.5 mL) were added NaHCO3 (1.06 g, 12.7 mmol) and NaI (6.33 g, 42.3 mmol) at room temperature. The resulting mixture was then heated to 40 °C. After stirring for 12 h, the reaction mixture was diluted with Et2O, filtered through silica gel, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 20:1) to give epoxyiodide 3 (2.44 g, 99% yield for 2 steps, 5:1 dr) as a colorless oil. Major isomer: Rf 0.30 (hexane/EtOAc = 20:1); IR (neat) νmax 2963, 2922, 1439, 1070 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.38 (1H, m), 3.40 (1H, dd, J = 5.4, 9.7 Hz), 3.12 (1H, dd, J = 5.4, 9.0 Hz), 2.98 (1H, dd, J = 9.0, 9.7 Hz), 2.10 (1H, m), 2.04−1.90 (3H, m), 1.79 (1H, m), 1.64 (3H, s), 1.46 (1H, m), 1.30 (1H, m), 1.23 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 133.9 (C), 119.8 (CH), 66.2 (C), 61.4 (CH), 41.5 (CH), 30.2 (CH2), 27.0 (CH2), 24.8 (CH2), 23.4 (CH3), 13.3 (CH3), 2.5 (CH2); MS (ESITOF) m/z 293 [M + H]+ (100); HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H18IO 293.0402, found 293.0408. Anal. Calcd for C11H17IO: C, 45.22; H, 5.87. Found: C, 45.48; H, 6.07. (1S,4S,5R)-4-Methyl-4-((S)-4-methylcyclohex-3-en-1-yl)-1-(phenylsulfonyl)-3-oxabicyclo[3.1.0]hexan-2-one (4). To a stirred solution of epoxyiodide 3 (5.65 g, 19.3 mmol) and methyl phenylsulfonylacetate (16.6 g, 77.4 mmol) in DMF (193 mL) was added K2CO3 (26.7 g, 193 mmol) at room temperature. The resulting mixture was then heated to 60 °C. After stirring for 12 h, the reaction mixture was diluted with Et2O, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (CHCl3/ hexane = 4:1) to give cyclopropane-γ-lactone 4 (6.10 g, 91% yield, 5:1 dr). The resulting diastereomeric mixture of 4 was recrystallized from CHCl3/hexane to give pure cyclopropane-γ-lactone 4 (5.01 g, 75% yield) as a white needle-like crystalline solid: Rf 0.80 (hexane/EtOAc = 1:1); white needles (CHCl3/hexane); mp 122−123 °C; [α]25 D +94.5 (c 1.12, CHCl3); IR (KBr) νmax 2923, 2840, 1756, 1447, 1325 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.07−8.04 (2H, m), 7.69 (1H, m), 7.60− 7.57 (2H, m), 5.36 (1H, m), 2.93 (1H, dd, J = 5.6, 8.5 Hz), 2.11 (1H, dd, J = 5.6, 8.5 Hz), 2.01−1.92 (4H, m), 1.77 (1H, m), 1.67 (1H, m), 1.63 (3H, s), 1.60 (1H, t, J = 5.6 Hz), 1.33 (1H, dt, J = 6.4, 12.2 Hz), 1.27 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 166.9 (C), 138.2 (C), 134.3 (CH), 133.5 (C), 129.18 (CH) × 2, 129.15 (CH) × 2, 119.7 (CH), 86.2 (C), 47.6 (C), 40.2 (CH), 35.6 (CH), 30.3 (CH2), 26.1 (CH2), 24.5 (CH2), 23.2 (CH3), 22.6 (CH3), 17.8 (CH2); MS (ESITOF) m/z 369 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H22O4SNa 369.1137, found 369.1137. Anal. Calcd for C19H22O4S: C, 65.87; H, 6.40. Found: C, 65.83; H, 6.51. (S)-1-((1R,2S)-2-(Hydroxymethyl)-2-(phenylsulfonyl)cyclopropyl)1-((S)-4-methylcyclohex-3-en-1-yl)ethan-1-ol (7). To a stirred solution of cyclopropane-γ-lactone 4 (3.95 g, 11.4 mmol) in THF (114 mL) was added LiAlH4 (1.08 g, 28.5 mmol) at 0 °C. The resulting mixture was warmed to room temperature. After stirring the mixture for 1 h, Na2SO4·10H2O (4.33 g) was added slowly, and the mixture was diluted with Et2O. After stirring the mixture for 12 h, MgSO4 (1.08 g) was added. After stirring for 30 min, the resulting mixture was passed through a pad of Na2SO4 and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 3:2) to give cis-cyclopropane 7 (3.99 g, quantitative yield) as a colorless oil: Rf 0.25 (hexane/EtOAc = 1:1); [α]25 D −9.4 (c 1.21, CHCl3); IR (neat) νmax 3500, 2924, 1446, 1288, 1140 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.90−7.88 (2H, m), 7.67 12382

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

Article

The Journal of Organic Chemistry ddd, J = 4.6, 6.6, 8.0 Hz); 13C NMR (MeOH-d4, 100 MHz) δ 134.6 (C), 122.1 (CH), 72.9 (C), 69.8 (C), 46.6 (CH), 32.2 (CH2), 29.7 (CH3), 29.1 (CH3), 27.8 (CH2), 25.7 (CH), 25.5 (CH2), 25.0 (CH3), 23.6 (CH3), 23.3 (CH), 4.6 (CH2); MS (ESI-TOF) m/z 261 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H26O2Na 261.1831, found 261.1834. Anal. Calcd for C15H26O2: C, 75.58; H, 10.99. Found: C, 75.45; H, 10.81. ((2R,3R)-3-Methyl-3-((S)-4-methylcyclohex-3-en-1-yl)oxiran-2-yl)methanol (10). To a cold (−20 °C) suspension of 4 Å molecular sieves (2.11 g) in CH2Cl2 (20.0 mL) were added D-(−)-DIPT (357 mg, 1.52 mmol), Ti(OiPr)4 (0.375 mL, 1.27 mmol), and TBHP (6.06 M solution in CH2Cl2, 6.28 mL, 38.1 mmol). After stirring the mixture for 30 min at the same temperature, a solution of allylic alcohol 2 (2.11 g, 12.7 mmol) in CH2Cl2 (234 mL) was added over 12 h. After stirring the mixture at −20 °C for 2 h, NaOH (30% solution in brine, 0.868 mL) was added. The mixture was diluted with Et2O, warmed to room temperature, and stirred for 30 min. MgSO4 (868 mg) and Celite (109 mg) were then added, and after stirring for 15 min, the mixture was passed through a pad of Celite and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 2:1) to give epoxyalcohol 10 (2.24 g, 97% yield, 4:1 dr) as a colorless oil. Major isomer: Rf 0.20 (hexane/EtOAc = 2:1); IR (neat) νmax 3424, 2925, 1439, 1386, 1030 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.35 (1H, m), 3.83 (1H, dd, J = 4.2, 12.0 Hz), 3.71 (1H, dd, J = 6.6, 12.0 Hz), 2.98 (1H, dd, J = 4.3, 6.6 Hz), 2.12−1.92 (3H, m), 1.90−1.81 (2H, m), 1.69 (1H, brs), 1.64 (3H, s), 1.50−1.35 (2H, m), 1.24 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 134.1 (C), 119.6 (CH), 63.5 (C), 62.5 (CH), 61.3 (CH2), 41.9 (CH), 29.9 (CH2), 27.3 (CH2), 24.5 (CH2), 23.4 (CH3), 13.7 (CH3); MS (ESI-TOF) m/z 205 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C11H18O2Na 205.1204, found 205.1203. Anal. Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.22; H, 9.86. (2R,3S)-3-(Iodomethyl)-2-methyl-2-((S)-4-methylcyclohex-3-en-1yl)oxirane (11). To a stirred solution of epoxyalcohol 10 (756 mg, 4.15 mmol) in CH2Cl2 (41.5 mL) were added Et3N (5.21 mL, 37.4 mmol), DMAP (50.7 mg, 0.415 mmol), and TsCl (1.58 g, 8.30 mmol) at 0 °C. The mixture was then allowed to warm to room temperature. After stirring for 45 min, the reaction mixture was diluted with Et2O, washed with a saturated aqueous NaHCO3 solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude epoxytosylate, which was used for the next step without further purification. To a stirred solution of the crude epoxytosylate in acetone (41.5 mL) were added NaHCO3 (523 mg, 6.23 mmol) and NaI (3.11 g, 20.8 mmol) at room temperature. The resulting mixture was then heated to 40 °C. After stirring for 12 h, the reaction mixture was diluted with Et2O, filtered through silica gel, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 20:1) to give epoxyiodide 11 (1.20 g, 99% yield for 2 steps, 4:1 dr) as a colorless oil. Major isomer: Rf 0.30 (hexane/ EtOAc = 20:1); IR (neat) νmax 2963, 2921, 1439, 1386, 1173 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.36 (1H, m), 3.39 (1H, dd, J = 5.4, 9.6 Hz), 3.10 (1H, dd, J = 5.4, 9.1 Hz), 2.97 (1H, dd, J = 9.1, 9.6 Hz), 2.04−1.94 (3H, m), 1.90−1.76 (2H, m), 1.64 (3H, s), 1.52−1.35 (2H, m), 1.25 (1H, brs), 1.22 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 134.1 (C), 119.7 (CH), 66.0 (C), 62.0 (CH), 41.9 (CH), 29.9 (CH2), 27.3 (CH2), 24.5 (CH2), 23.5 (CH3), 12.6 (CH3), 2.4 (CH2); MS (ESI-TOF) m/z 293 [M + H]+ (100); HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H18IO 293.0402, found 293.0403. Anal. Calcd for C11H17IO: C, 45.22; H, 5.87. Found: C, 45.01; H, 5.93. (1R,4R,5S)-4-Methyl-4-((S)-4-methylcyclohex-3-en-1-yl)-1-(phenylsulfonyl)-3-oxabicyclo[3.1.0]hexan-2-one (12). To a stirred solution of epoxyiodide 11 (3.02 g, 10.3 mmol) and methyl phenylsulfonylacetate (8.85 g, 41.3 mmol) in DMF (103 mL) was added K2CO3 (14.3 g, 103 mmol) at room temperature. The resulting mixture was then heated to 60 °C. After stirring for 12 h, the reaction mixture was diluted with Et2O, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (CHCl3/ hexane = 4:1) to give cyclopropane-γ-lactone 12 (3.46 g, 97% yield,

4:1 dr). Resulting diastereomeric mixture of 12 was recrystallized from CHCl3/hexane to give pure cyclopropane-γ-lactone 12 (2.75 g, 77% yield) as a white needle-like crystalline solid: Rf 0.80 (hexane/EtOAc = 1:1); white needles (CHCl3/hexane); mp 190−191 °C; [α]25 D −127 (c 1.41, CHCl3); IR (KBr) νmax 2958, 2829, 1758, 1447, 1325 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.07−8.05 (2H, m), 7.70 (1H, m), 7.61− 7.58 (2H, m), 5.35 (1H, m), 2.84 (1H, dd, J = 5.6, 8.6 Hz), 2.09 (1H, dd, J = 5.6, 8.6 Hz), 2.08 (1H, m), 2.00−1.93 (2H, m), 1.84−1.74 (2H, m), 1.64 (3H, s), 1.61 (1H, m), 1.58 (1H, t, J = 5.6 Hz), 1.35 (1H, m), 1.27 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 166.8 (C), 138.2 (C), 134.8 (C), 134.3 (CH), 129.14 (CH) × 2, 129.08 (CH) × 2, 118.7 (CH), 86.0 (C), 47.7 (C), 39.9 (CH), 35.4 (CH), 30.0 (CH2), 26.5 (CH2), 23.7 (CH2), 23.3 (CH3), 21.7 (CH3), 17.4 (CH2); MS (ESI-TOF) m/z 369 [M + Na]+ (100); HRMS (ESITOF) m/z [M + Na]+ calcd for C19H22O4SNa 369.1137, found 369.1136. Anal. Calcd for C19H22O4S: C, 65.87; H, 6.40. Found: C, 65.72; H, 6.47. (R)-1-((1S,2R)-2-(Hydroxymethyl)-2-(phenylsulfonyl)cyclopropyl)1-((S)-4-methylcyclohex-3-en-1-yl)ethan-1-ol (13). To a stirred solution of cyclopropane-γ-lactone 12 (390 mg, 1.13 mmol) in THF (11.3 mL) was added LiAlH4 (107 mg, 2.83 mmol) at 0 °C. The resulting mixture was warmed to room temperature. After stirring the mixture for 1 h, Na2SO4·10H2O (428 mg) was slowly added, and the mixture was diluted with Et2O. After stirring the mixture for 12 h, MgSO4 (107 mg) was added. After stirring for 30 min, the resulting mixture was passed through a pad of Na2SO4 and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 3:2) to give cis-cyclopropane 13 (389 mg, 98% yield) as a colorless oil: Rf 0.25 (hexane/EtOAc = 1:1); [α]25 D −85.7 (c 1.09, CHCl3); IR (neat) νmax 3501, 2963, 2921, 1446, 1288, 1140 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.90−7.88 (2H, m), 7.68 (1H, m), 7.60−7.56 (2H, m), 5.39 (1H, m), 4.28 (1H, dd, J = 5.3, 13.6 Hz), 3.95 (1H, dd, J = 7.8, 13.6 Hz), 3.09 (1H, dd, J = 5.4, 7.9 Hz), 2.17 (1H, m), 2.11 (1H, dd, J = 8.2, 10.3 Hz), 2.08−1.87 (6H, m), 1.66 (3H, s), 1.62 (1H, dd, J = 5.3, 10.4 Hz), 1.40−1.25 (2H, m), 1.19 (3H, s); 13C NMR (CDCl3, 100 MHz) δ 138.0 (C), 133.9 (C), 133.6 (CH), 129.0 (CH) × 2, 128.5 (CH) × 2, 120.0 (CH), 71.8 (C), 59.0 (CH2), 46.6 (C), 45.3 (CH), 31.8 (CH), 30.6 (CH2), 26.3 (CH2), 25.0 (CH3), 23.4 (CH2), 23.1 (CH3), 13.3 (CH2); MS (ESI-TOF) m/ z 373 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26O4SNa 373.1450, found 373.1455. Anal. Calcd for C19H26O4S: C, 65.11; H, 7.48. Found: C, 65.02; H, 7.55. (R)-1-((1R,2R)-2-(Hydroxymethyl)cyclopropyl)-1-((S)-4-methylcyclohex-3-en-1-yl)ethan-1-ol (14). To a stirred solution of ciscyclopropane 13 (337 mg, 0.962 mmol) in MeOH (48.1 mL) was added Mg (2.41 g, 99.1 mmol) at 50 °C. After stirring for 20 min, the reaction mixture was cooled to room temperature, diluted with Et2O, washed with a 10% aqueous citric acid solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/ EtOAc = 1:1) to give trans-cyclopropane 14 (182 mg, 90% yield) as a white needle-like crystalline solid: Rf 0.15 (hexane/EtOAc = 1:1); white needles (CHCl3/hexane); mp 116−117 °C; [α]25 D −109 (c 0.74, CHCl3); IR (KBr) νmax 3339, 2857, 1443, 1018 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.39 (1H, m), 3.54 (1H, dt, J = 11.2, 6.1 Hz), 3.46 (1H, ddd, J = 5.0, 6.8, 11.2 Hz), 2.15 (1H, m), 2.05−1.82 (4H, m), 1.65 (3H, s), 1.65−1.52 (2H, m), 1.37−1.23 (2H, m), 1.13 (1H, m), 1.10 (3H, s), 0.81 (1H, dt, J = 8.7, 5.3 Hz), 0.68 (1H, dt, J = 8.4, 4.9 Hz), 0.36 (1H, dt, J = 8.7, 4.9 Hz); 13C NMR (CDCl3, 100 MHz) δ 134.1 (C), 120.5 (CH), 72.2 (C), 66.7 (CH2), 45.1 (CH), 30.9 (CH2), 26.9 (CH2), 25.5 (CH), 23.8 (CH2), 23.4 (CH3), 23.3 (CH3), 16.9 (CH), 6.0 (CH2); MS (ESI-TOF) m/z 233 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H22O2Na 233.1517, found 233.1515. Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C, 74.03; H, 10.42. 2-((1R,2R)-2-((R)-1-Hydroxy-1-((S)-4-methylcyclohex-3-en-1-yl)ethyl)cyclopropyl)propan-2-ol (1b). To a solution of IBX (104 mg, 0.371 mmol) in DMSO (0.745 mL) was added a solution of transcyclopropane 14 (31.3 mg, 0.149 mmol) in THF (0.745 mL). After stirring the mixture for 2.5 h at room temperature, H2O was added. 12383

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

Article

The Journal of Organic Chemistry After diluting with Et2O, the mixture was filtered through Celite, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude aldehyde, which was used for the next step without further purification. To a stirred solution of the crude aldehyde in tBuOH (1.50 mL) were added 2-methylbut-2-ene (0.316 mL, 2.98 mmol), NaH2PO4 (67.9 mg, 0.566 mmol), and the solution of NaClO2 (53.9 mg, 0.596 mmol) in H2O (0.500 mL) at room temperature. After stirring for 40 min, the reaction mixture was diluted with Et2O, washed with H2O and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give a crude carboxylic acid, which was used for the next step without further purification. To a stirred solution of the crude carboxylic acid in Et2O/MeOH (1:1, 3.00 mL) was added TMSCHN2 (2.00 M solution in Et2O, 0.186 mL, 0.372 mmol) at 0 °C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The residue was passed through a pad of silica gel (hexane/EtOAc = 4:1) and then concentrated in vacuo to give a crude methyl ester. To a stirred solution of the crude methyl ester in THF (1.50 mL) was added MeLi (1.12 M solution in Et2O, 0.666 mL, 0.746 mmol) at −78 °C. After stirring for 10 min, the reaction mixture was diluted with Et2O, washed with a saturated aqueous NaHCO3 solution, H2O, and brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 2:1) to give phellilane L (1b) (32.4 mg, 91% yield for 4 steps) as a white needle-like crystalline solid: Rf 0.10 (hexane/EtOAc = 4:1); white needles (hexane/Et2O); mp 115−116 °C; [α]25 D −117 (c 0.47, MeOH); IR (KBr) νmax 3381, 2978, 2946, 1449, 1362, 1158 cm−1; 1H NMR (MeOH-d4, 400 MHz) δ 5.38 (1H, m), 4.56 (1H, brs), 2.15 (1H, m), 2.07−1.95 (3H, m), 1.90 (1H, m), 1.63 (3H, s), 1.54 (1H, ddt, J = 1.8, 4.9, 12.0 Hz), 1.32 (1H, m), 1.29 (1H, brs), 1.21 (3H, s), 1.18 (3H, s), 1.11 (3H, s), 0.94 (1H, dt, J = 8.5, 6.0 Hz), 0.92 (1H, dt, J = 8.5, 6.0 Hz), 0.50 (1H, ddd, J = 4.4, 6.0, 8.5 Hz), 0.43 (1H, ddd, J = 4.4, 6.0, 8.5 Hz); 1H NMR (CDCl3, 400 MHz) δ 5.39 (1H, m), 2.15 (1H, m), 2.05−1.85 (4H, m), 1.65 (3H, s), 1.62−1.52 (2H, m), 1.25 (3H, s), 1.21 (3H, s), 1.14 (3H, s), 1.03 (1H, brs), 0.97 (1H, dt, J = 8.8, 5.5 Hz), 0.92 (1H, dt, J = 8.8, 5.5 Hz), 0.88 (1H, brs), 0.51 (1H, ddd, J = 4.7, 5.7, 8.8 Hz), 0.45 (1H, ddd, J = 4.7, 5.7, 8.8 Hz); 13C NMR (MeOH-d4, 100 MHz) δ 134.7 (C), 122.0 (CH), 72.9 (C), 69.8 (C), 46.1 (CH), 32.1 (CH2), 29.7 (CH3), 29.1 (CH3), 28.1 (CH2), 25.8 (CH), 25.0 (CH2), 24.1 (CH3), 24.0 (CH), 23.6 (CH3), 4.4 (CH2); 13C NMR (CDCl3, 100 MHz) δ 134.0 (C), 120.6 (CH), 71.9 (C), 69.3 (C), 44.9 (CH), 30.9 (CH2), 29.5 (CH3), 28.9 (CH3), 26.9 (CH2), 25.0 (CH), 24.5 (CH3), 23.8 (CH2), 23.3 (CH3), 23.2 (CH), 4.2 (CH2); MS (ESI-TOF) m/z 261 [M + Na]+ (100); HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H26O2Na 261.1831, found 261.1826. Anal. Calcd for C15H26O2: C, 75.58; H, 10.99. Found: C, 75.74; H, 10.90.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Dr. Noritada Kobayashi from the Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, for his support with measurements of antimicrobial activity. We appreciate the contributions made by Ms. N. Sato and Dr. K. Nagai with the various instrumental analyses at Kitasato University.

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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.7b02141. 1

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REFERENCES

H and 13C NMR spectra of natural phellilane L (1), all new compounds, and synthetic phellilane L (1b) (PDF) Crystal data for compound 1a (CIF) Crystal data for compound 1b (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +81-42-676-3080. Fax: +81-42-676-3073. ORCID

Tatsuya Shirahata: 0000-0002-8812-4555 Hiroaki Miyaoka: 0000-0003-2486-0403 12384

DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385

Article

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DOI: 10.1021/acs.joc.7b02141 J. Org. Chem. 2017, 82, 12377−12385