Total Synthesis of 3-epi-Juruenolide C

Abstract

In this study, the total synthesis of 3-epi-juruenolide C is achieved in 10 steps (longest linear sequence) starting from ethyl (2E,4S,5S)-4,5-dihydroxy-2-hexenoate. The synthetic highlights of our approach include one-pot regioselective bromination, intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel, and face-selective hydrogenation using a homogeneous Wilkinson’s catalyst.

Introduction

3-epi-Juruenolide C (1), which exhibits moderate antifungal activity against Cladosporium cladosporioides, was isolated from roots of Virola surinamensis collected from the Combú Island, near Belém in Pará State, Brazil¹⁾ (Fig. 1). The structure of 1 comprises a γ-lactone moiety bearing 2-[7-(1,3-benzodioxol-5-yl)heptyl], 3-hydroxy, and 4-methyl groups. The trans stereochemistry between C-2 and C-4 was determined using the nuclear Overhauser effect (NOE) experiment, and all the relative configurations were determined by comparison of ¹³C chemical shifts according to the literature observations.^2,3) Thus, the 4-methyl group (δ 14.7 ppm) was confirmed to be cis to the 3-hydroxy group. When the 4-methyl group is trans to the 3-hydroxy group, the methyl signal should appear at around δ 18 ppm. Contrastingly, the 2-alkyl group was confirmed to be trans to the 3-hydroxy group, since the signal of the C-1′ methylene appeared at lower field of δ 27.1 ppm than δ 23 ppm. The absolute stereochemistry was conclusively assigned as 2S, 3S, and 4S according to a comprehensive study including comparison with previously reported studies.^2–7) In 2001 and 2014, Clive and Ardlean, and Gharpure et al. have reported the total synthesis of a related natural product juruenolide C, respectively.^8,9) Herein, the first total synthesis of 1 is reported.

Fig. 1. Structure of 3-epi-Juruenolide C (1) and Determination of Relative Configuration

Our synthetic strategy for 1 was initiated using known chiral diol 2, which was derived from a commercially available ethyl sorbate via the Sharpless asymmetric dihydroxylation using 1 mol% of hydroquinine 1,4-phthalazinediyl diether ((DHQ)₂PHAL) as the chiral ligand^10–12) (Chart 1). The enantiomeric purity was estimated as 82% enantiomeric excess (ee) based on its specific optical rotation observed.^10–12) Next, the diol 2 was transformed to alkene 6 in the following 4 steps: (i) p-methoxybenzyl- (PMB-) protection of 2 using PMB imidate, (ii) diisobutylaluminium hydride (DIBAL-H) reduction of ethyl ester 3, (iii) mesylation of allyl alcohol 4, and (iv) LiAlH₄ reduction of mesylate 5.

Chart 1. Synthesis of 6

Next, we attempted to perform the cross metathesis of the internal akene 6 with terminal alkene 7, which was prepared using the Wittig reaction of the known aldehyde 8¹³⁾ with triphenylphosphonium methylide (Chart 2, method A) or using the Kumada coupling¹⁴⁾ of commercially available 1-bromo-3,4-(methylenedioxy)benzene (9) with 7-octenylmagnesium bromide (Chart 2, method B). With both the alkenes 6 and 7 in hand, the cross metathesis between 6 and 7 was performed under optimized conditions (6 : 7 = 1 : 1, 40°C in CH₂Cl₂)^15,16) in the presence of 10 mol% Hoveyda–Grubbs second generation catalyst affording desired (E)-alkene 10 in 65% yield with excellent selectivity along with recovered 6 (20%). Then, (E)-alkene 10 was transformed into a 3 : 1 mixture of (E)-vinyl bromide 11 and regioisomer 11′ (ca. 1 : 1 mixture of cis–trans isomers), utilizing one-pot bromination.^12,17–23) As it was difficult to separate a mixture of 11 and 11′, the deprotection of two PMB groups was performed under acidic conditions, affording diol 12 as a single product in 67% yield over 3 steps starting from 10. The intramolecular carbonylation of 12 using bis(triphenylphosphine)dicarbonylnickel under harsh conditions^24–28) afforded objective (E)-α,β′-conjugated γ-lactone 13 as the vinyl proton was observed at δ 6.95 ppm because of the deshielding effect in its ¹H-NMR spectrum.^12,29–34)

Chart 2. Preparation of 7 and Synthesis of 13

In the final stage, the metal-catalyzed face-selective hydrogenation of the trisubstituted olefin in 13 to obtain 1 was examined (Table 1). First, a palladium catalyst on carbon was used because the hydrogenation of various α,β′-conjugated γ-lactones preferably proceeded from the syn-side with the 3-hydroxy group regardless of the olefin geometry.^35–37) However, hydrogenation preferentially afforded undesired isomer 14 even under the completely selective conditions successfully reported by Ryu and colleagues (Entry 1).³⁷⁾ The use of the heterogeneous Pearlman’s catalyst was unsuccessful, predominantly affording undesired 14 (Entry 2). In fact, some studies have reported that hydrogenation of α,β′-conjugated γ-lactones bearing 3-hydroxy and 4-alkyl groups using a heterogeneous catalyst leads to the generation of γ-lactones with a predominant cis relation between the 2-alkyl and 3-hydroxy groups caused by the hydrogenation from the anti-side with the 3-hydroxy group.^34,38) These facts suggest that unexpected face-selective hydrogenation can proceed because of the steric hindrance of the 4-methyl group in 13, without the anticipated coordination of the 3-hydroxy group to the heterogeneous catalyst. Thus, the homogeneous Crabtree’s catalyst³⁹⁾ was subsequently used according to the report by Hong and Stoltz (Entry 3).⁴⁰⁾ As a result, desired γ-lactone 1 was clearly obtained as the main product, albeit the facial selectivity of only 3 : 2. In the anticipation of a stronger coordination effect with the 3-hydroxy group,⁴¹⁾ the Wilkinson’s catalyst was also examined as a typical homogeneous catalyst (Entries 4–6). The effect of the solvent on the Wilkinson’s catalyst was particularly remarkable for the facial selectivity,⁴²⁾ and eventually dichloromethane afforded the best selectivity of 5 : 1 (Entry 6). Finally, the diastereomixture of 1 and 14 was separated using preparative HPLC on a reversed-phase column, and spectroscopic data (¹H- and ¹³C-NMR, IR, and high resolution (HR)-MS) and specific rotation of 1 were identical to those reported by Kato and colleagues.¹⁾

Table 1. Face-Selective Hydrogenation of 13

Entry	Reagents	Solvent	Time (h)	Yield (1 + 14)	Selectivity (1 : 14)
1	Pd/C (10 mol%)	CH2Cl2	4	62	1 : 20
2	Pd(OH)2 (10 mol%)	CH2Cl2	4	76	1 : 19
3	[Ir(cod)(py)(PCy3)]PF6 (10 mol%)	CH2Cl2	19	70	3 : 2
4	Rh(PPh3)3Cl (10 mol%)	PhCH3	20	70	1 : 1
5	Rh(PPh3)3Cl (10 mol%)	EtOAc	19	70	2 : 3
6	Rh(PPh3)3Cl (10 mol%)	CH2Cl2	24	72	5 : 1

In conclusion, we achieved the total synthesis of 3-epi-juruenolide C (1) from the known chiral diol 2 for the first time. The synthetic highlights include one-pot regioselective bromination, intramolecular carbonylation, and face-selective hydrogenation.

Experimental

General Information

IR were recorded with a Horiba FT-710 model spectrophotometer. ¹H- and ¹³C-NMR spectral data were obtained with a Bruker Avance 600, a JEOL JNM-LA 500, or a JEOL JNM-AL 300 instruments. Chemical shifts are quoted in ppm using tetramethylsilane (TMS, δ = 0 ppm) as the reference for ¹H-NMR spectroscopy, and CDCl₃ (δ = 77.0 ppm) for ¹³C-NMR spectroscopy. Mass spectra were measured with a Bruker Daltonics microTOF or a Hitachi double focusing M-80B spectrometer. Optical rotations were recorded on a JASCO DIP-360 digital polarimeter. Column chromatography was carried out on silica gel (Kanto Chemical Co., Japan or Merck Co., Ltd., Germany). Preparative HPLC was performed using SSC-8200-25 RECYCLE SYSTEM (Senshu Scientific Co., Ltd., Japan), SSC-3325 degasser (Senshu Scientific Co., Ltd.), SSC-5410 UV/VIS Detector (Senshu Scientific Co., Ltd.), RefractoMax520 Refractive Index Detector (ERC), and JAIGEL-ODS column (20 × 250 mm, 15 µm, Japan Analytical Industry Co., Ltd., Japan).

(4S,5S,E)-4,5-Bis[(4-methoxybenzyl)oxy]hex-2-en-1-ol (4)

A mixture of 2 (296 mg, 1.70 mmol), PMBO(C=NH)CCl₃ (1.97 g, 6.97 mmol), and CSA (81.9 mg, 0.352 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 17 h. After the addition of H₂O (10 mL) at 0°C, the mixture was extracted with EtOAc (15 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 5 : 1) to afford 3 as an impure oil. To a solution of the crude product 3 in tetrahydrofuran (THF) (10 mL) was added DIBAL-H (1.02 M in hexane, 5.5 mL, 5.61 mmol) at −78°C. After being stirred for 6 h at the same temperature, the reaction was quenched by the slowly addition of Na₂SO₄·10H₂O (2.0 g). The reaction mixture was filtered through a pad of Celite^®, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 2 : 1 to 1 : 1) to afford 4 (418 mg, 1.12 mmol, 66% in 2 steps) as a colorless oil.

[α]_D²⁵ +12.5° (c = 1.00, CHCl₃) (82% ee); IR (neat) 3425, 2939, 1512, 1250 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ: 1.12 (d, J = 6.4 Hz, 3H), 1.88 (br s, 1H), 3.59 (qd, J = 6.4, 5.7 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.84 (m, 1H), 4.14 (m, 2H), 4.34 (d, J = 11.7 Hz, 1H), 4.49–4.56 (m, 3H), 5.66 (ddt, J = 15.7, 7.2, 1.3 Hz, 1H), 5.85 (dtd, J = 15.7, 5.5, 0.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H); ¹³C-NMR (125 MHz, CDCl₃) δ: 16.0 (CH₃), 55.2 (CH₃ × 2), 62.9 (CH₂), 70.3 (CH₂), 71.2 (CH₂), 76.4 (CH), 81.6 (CH), 113.61 (CH × 2), 113.62 (CH × 2), 128.3 (CH), 129.2 (CH × 2), 129.3 (CH × 2), 130.6 (C), 130.9 (C), 133.3 (CH), 158.99 (C), 159.01 (C); HR-MS-electrospray ionization (ESI): m/z [M + Na]⁺ Calcd for C₂₂H₂₈O₃Na: 395.1829. Found 395.1824.

(4S,5S,E)-4,5-Bis[(4-methoxybenzyl)oxy]hex-2-en-1-yl Methanesulfonate (5)

A mixture of 4 (347 mg, 0.932 mmol), Et₃N (0.21 mL, 1.40 mmol), and MsCl (0.11 mL, 1.03 mmol) in toluene (10 mL) was stirred at 0°C for 3 h. After the addition of H₂O (10 mL) at 0°C, the mixture was extracted with EtOAc (10 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 1 : 1) to afford 5 (411 mg, 0.913 mmol, 98%) as a colorless oil.

[α]²⁵ +12.0° (c = 1.00, CHCl₃) (82% ee); IR (neat) 2931, 2869, 2839, 1612, 1512, 1358 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 1.11 (d, J = 6.5 Hz, 3H), 2.98 (s, 3H), 3.61 (qd, J = 6.5, 5.2 Hz, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 3.90 (dd, J = 5.2, 5.2 Hz, 1H), 4.36 (d, J = 11.6 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 4.53 (d, J = 11.5 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.74 (d, J = 5.3 Hz, 2H), 5.84–5.91 (m, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H); ¹³C-NMR (125 MHz, CDCl₃) δ: 15.6 (CH₃), 38.1 (CH₃), 55.2 (CH₃ × 2), 69.8 (CH₂), 70.9 (CH₂), 71.1 (CH₂), 75.9 (CH), 80.5 (CH), 113.70 (CH × 2), 113.74 (CH × 2), 125.4 (CH), 129.29 (CH × 2), 129.31 (CH × 2), 130.2 (C), 130.6 (C), 134.9 (CH), 159.1 (C), 159.2 (C); HR-MS-ESI: m/z [M + Na]⁺ Calcd for C₂₃H₃₀O₇SNa: 473.1604. Found 473.1600.

(4S,5S,E)-4,5-Bis[(4-methoxybenzyl)oxy]hex-2-ene (6)

A mixture of 5 (411 mg, 0.913 mmol) and LiAlH₄ (70.9 mg, 2.28 mmol) in THF (10 mL) was stirred at room temperature for 3 h. The reaction was quenched by the slowly addition of Na₂SO₄·10H₂O (3.0 g) at 0°C. Then, the reaction mixture was filtered through a pad of Celite^®, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 2 : 1) to afford 6 (303 mg, 0.849 mmol, 93%) as a colorless oil.

[α]_D²⁵ +11.8° (c = 1.00, CHCl₃)(82% ee); IR (neat) 2931, 2823, 1635, 1589, 1512 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 1.10 (d, J = 6.4 Hz, 3H), 1.75 (dd, J = 6.5, 1.3 Hz, 3H), 3.55 (qd, J = 6.5, 6.0 Hz, 1H), 3.73 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 4.32 (d, J = 11.7 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 11.6 Hz, 2H), 5.42 (ddq, J = 15.4, 8.0, 1.3 Hz, 1H), 5.68 (dq, J = 15.4, 6.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H); ¹³C-NMR (125 MHz, CDCl₃) δ: 16.4 (CH₃), 18.0 (CH₃), 55.2 (CH₃ × 2), 69.9 (CH₂), 71.4 (CH₂), 76.8 (CH), 82.9 (CH), 113.66 (CH × 2), 113.69 (CH × 2), 128.5 (CH), 129.26 (CH × 2), 129.28 (CH × 2), 130.1 (CH), 131.1 (C), 131.3 (C), 159.0 (C), 159.1 (C); HR-MS-ESI: m/z [M + Na]⁺ Calcd for C₂₂H₂₈O₆Na: 379.1880. Found 379.1883.

5-(Oct-7-en-1-yl)benzo[d][1,3]dioxole (7)

Method A

To a suspension of MePPh₃I (1.82 g, 4.50 mmol) in THF (20 mL) was added nBuLi (1.60 M solution in hexane, 2.9 mL, 4.51 mmol) at 0°C for 0.5 h. A solution of 8 (664 mg, 2.84 mmol) in THF (5 mL) was added at 0°C and then, the mixture was stirred at room temperature for 2 h. After the addition of sat. NH₄Cl aq. (30 mL) at 0°C, the mixture was extracted with EtOAc (10 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 5 : 1) to afford 7 (587 mg, 2.53 mmol, 89%) as a colorless oil.

Method B

A suspension of Mg (30.6 mg, 1.26 mmol) and 8-bromo-1-octene (0.20 mL, 1.19 mmol) in THF (10 mL) was stirred at 50°C. After being stirred for 1 h, Mg solid was perfectly consumed. To a solution of 9 (0.11 mL, 1.00 mmol) and NiCl₂ (16.3 mg, 0.0300 mmol) in THF (5.0 mL) was added the prepared 7-octenylmagnesium bromide at 0°C and the mixture was stirred at room temperature for 1 h. After the addition of sat. NH₄Cl aq. (30 mL) at 0°C, the reaction mixture was extracted with EtOAc (10 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 5 : 1) to afford 7 (67.6 mg, 0.290 mmol, 29%) as a colorless oil.

IR (neat) 3070, 2924, 2854, 2360 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 1.26–1.61 (m, 8H), 2.03 (m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 4.93–4.99 (m, 2H), 5.81 (ddd, J = 17.2, 10.6, 6.6 Hz, 1H), 5.91 (s, 2H), 6.61 (dd, J = 7.8, 1.5 Hz, 1H), 6.67 (d, J = 1.5 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ: 28.8 (CH₂), 28.9 (CH₂), 29.0 (CH₂), 31.7 (CH₂), 33.7 (CH₂), 35.6 (CH₂), 100.6 (CH₂), 108.0 (CH), 108.8 (CH), 114.2 (CH₂), 121.0 (CH), 136.7 (C), 139.1 (CH), 145.4 (C), 147.4 (C); HR-MS-EI: m/z [M]⁺ Calcd for C₁₅H₂₀O₂: 232.1463. Found 232.1465.

5-{(9S,10S,E)-9,10-Bis[(4-methoxybenzyl)oxy]undec-7-en-1-yl}benzo[d][1,3]dioxole (10)

A mixture of 6 (89.8 mg, 0.252 mmol), 7 (58.6 mg, 0.252 mmol), and Hoveyda–Grubbs 2nd catalyst (20.2 mg, 0.0252 mmol) in CH₂Cl₂ (2.0 mL) was stirred at 40°C for 11 h. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane–acetone = 40 : 1) to afford 10 (89.6 mg, 0.164 mmol, 65%) as a pale-yellow oil and 6 (18.0 mg, 20%).

[α]_D²⁵ +13.6° (c = 0.50, CHCl₃) (82% ee); IR (neat) 2931, 2861, 2360, 1643 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ: 1.10 (d, J = 6.3 Hz, 3H), 1.25–1.60 (m, 8H), 2.07 (dt, J = 6.7, 6.7 Hz, 2H), 2.52 (t, J = 7.8 Hz, 2H), 3.55 (qd, J = 6.3, 6.0 Hz, 1H), 3.73 (m, 1H), 3.791 (s, 3H), 3.794 (s, 3H), 4.32 (d, J = 12.0 Hz, 1H), 4.54 (m, 3H), 5.39 (dd, J = 15.5, 8.0 Hz, 1H), 5.64 (dt, J = 15.5, 6.7 Hz, 1H), 5.91 (s, 2H), 6.61 (dd, J = 7.9, 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 7.25 (m, 4H); ¹³C-NMR (125 MHz, CDCl₃) δ: 16.5 (CH₃), 28.96 (CH₂), 28.98 (CH₂), 29.1 (CH₂), 31.7 (CH₂), 32.3 (CH₂), 35.6 (CH₂), 55.2 (CH₃ × 2), 69.7 (CH₂), 71.4 (CH₂), 76.8 (CH), 83.1 (CH), 100.7 (CH₂), 108.0 (CH), 108.8 (CH), 113.60 (CH × 2), 113.62 (CH × 2), 121.0 (CH), 127.1 (CH), 129.2 (CH × 4), 131.0 (C), 131.2 (C), 135.6 (CH), 136.7 (C), 145.4 (C), 147.4 (C), 158.9 (C × 2); HR-MS-ESI: m/z [M + Na]⁺ Calcd for C₃₄H₄₂O₆Na: 569.2874. Found 569.2874.

5-[(9R,10S,E)-8-Bromo-9,10-dihydroxyundec-7-en-1-yl]benzo[d][1,3]dioxole (12)

A mixture of 10 (406 mg, 0.742 mmol) and Pyr.-HBr₃ (>85%, 262 mg, 0.816 mmol) in pyridine (7.0 mL) was stirred at room temperature for 3 d. After confirming consumption of 10 by TLC, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.35 mL, 2.34 mmol) was added to the reaction mixture at 0°C and the reaction system was then stirred at 60°C for 8 h. After the addition of sat. NH₄Cl aq. (10 mL) at 0°C, the reaction mixture was extracted with EtOAc (10 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–acetone = 10 : 1) to afford a 3 : 1 mixture of (E)-vinyl bromide 11 and regioisomer 11′ (421 mg, 0.675 mmol, 91% in one-pot process) as a pale-yellow oil. A solution of the mixture (421 mg, 0.675 mmol) in EtOH (3.0 mL)–2 M HCl aq. (1.0 mL) was heated to reflux for 2 h. After the addition of sat. NaHCO₃ aq. (5.0 mL) at 0°C, the reaction mixture was extracted with EtOAc (5.0 mL × 3), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc = 3 : 1) to afford 12 (170 mg, 0.445 mmol, 67% from 10) as a colorless oil.

[α]_D²⁵ +20.6° (c = 0.73, CHCl₃) (82% ee); IR (neat) 3402, 2931, 2854, 1250 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ: 1.13 (d, J = 6.3 Hz, 3H), 1.25–1.60 (m, 8H), 2.11 (ddt, J = 14.8, 7.6, 7.6 Hz, 1H), 2.19 (ddt, J = 14.8, 7.6, 7.6 Hz, 1H), 2.52 (t, J = 7.8 Hz, 2H), 3.89 (dq, J = 8.2, 6.3 Hz, 1H), 4.11 (d, J = 8.2 Hz, 1H), 5.92 (s, 2H), 6.09 (dd, J = 7.6, 7.6 Hz, 1H), 6.61 (dd, J = 7.9, 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ: 18.1 (CH₃), 28.8 (CH₂), 28.9 (CH₂), 29.0 (CH₂), 29.9 (CH₂), 31.5 (CH₂), 35.6 (CH₂), 70.4 (CH), 74.4 (CH), 100.7 (CH₂), 108.0 (CH), 108.8 (CH), 121.0 (CH), 124.4 (C), 136.5 (C), 137.2 (CH), 145.4 (C), 147.4 (C); HR-MS-ESI: m/z [M + Na]⁺ Calcd for C₁₈H₂₅BrO₄Na: 407.0828. Found 407.0825.

(4S,5S,E)-3-[7-(Benzo[d][1,3]dioxol-5-yl)heptylidene]-4-hydroxy-5-methyldihydrofuran-2(3H)-one (13)

In a sealed tube, a mixture of 12 (60.6 mg, 0.157 mmol), Et₃N (65 µL, 0.471 mmol), and Ni(PPh₃)₂(CO)₂ (301 mg, 0.471 mmol) in THF (3.0 mL) was stirred at 80°C for 24 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (CHCl₃ to hexane–EtOAc = 2 : 1) to afford 13 (42.6 mg, 0.128 mmol, 82%) as a colorless oil.

[α]_D²⁵ −55.7° (c = 0.81, CHCl₃) (82% ee); IR (neat) 2923, 2854, 2391, 1727 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ: 1.25–1.62 (m, 8H), 1.45 (d, J = 6.6 Hz, 3H), 2.38 (m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 4.53 (qd, J = 6.6, 5.5 Hz, 1H), 4.80 (m, 1H), 5.92 (s, 2H), 6.61 (dd, J = 7.9, 1.8 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.95 (td, J = 7.9, 1.5 Hz, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ: 13.9 (CH₃), 28.3 (CH₂), 28.7 (CH₂), 29.1 (CH₂), 29.7 (CH₂), 31.4 (CH₂), 35.5 (CH₂), 67.7 (CH), 78.8 (CH), 100.7 (CH₂), 108.0 (CH), 108.8 (CH), 121.0 (CH), 130.5 (C), 136.4 (C), 145.4 (CH), 147.5 (C), 147.7 (C) 170.1 (C); HR-MS-ESI: m/z [M + H]⁺ Calcd for C₁₉H₂₅O₅: 333.1698. Found 333.1697.

3-epi-Juruenolide C (1) and 2,3-epi-Juruenolide C (14)

A mixture of 13 (9.80 mg, 0.0300 mmol) and Rh(PPh₃)₃Cl (2.80 mg, 0.00300 mmol) in CH₂Cl₂ (0.60 mL) was stirred at room temperature for 24 h under a hydrogen atmosphere. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane–EtOAc = 2 : 1) to afford a 5 : 1 mixture of 3-epi-juruenolide C (1) and its diastereomer 14 (7.1 mg, 0.0220 mmol, 72%) as a colorless oil. The mixture was further purified by preparative HPLC (MeOH, 10 mL/min, UV 254 nm) to afford 1 (5.5 mg, t_R = 10 min 54 s) and 14 (1.1 mg, t_R = 10 min 39 s).

1: [α]_D²⁵ −24.3° (c = 1.00, CHCl₃) (82% ee); IR (neat) 2923, 2854, 2391, 1727 cm⁻¹; ¹H-NMR (600 MHz, CDCl₃) δ: 1.25–1.34 (m, 7H), 1.41 (d, J = 6.7 Hz, 3H), 1.43–1.59 (m, 4H), 170 (m, 1H), 1.89 (br s, 1H), 2.50 (t, J = 7.5 Hz, 2H), 2.54 (m, 1H), 4.20 (dd, J = 4.2, 4.2 Hz, 1H), 4.63 (qd, J = 6.7, 4.2 Hz, 1H), 5.91 (s, 2H), 6.61 (dd, J = 7.9, 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H); ¹³C-NMR (75 MHz, CDCl₃) δ: 13.9 (CH₃), 27.2 (CH₂), 28.4 (CH₂), 28.9 (CH₂), 29.1 (CH₂), 29.2 (CH₂), 31.6 (CH₂), 35.6 (CH₂), 49.2 (CH), 74.0 (CH), 78.2 (CH), 100.7 (CH₂), 108.0 (CH), 108.8 (CH), 121.0 (C), 136.6 (C), 145.3 (CH), 147.4 (C), 177.7 (C); HR-MS-ESI: m/z [M + Na]⁺ Calcd for C₁₉H₂₆O₅Na: 357.1678. Found 357.0668.

14: [α]_D²⁵ −26.3° (c = 0.33, CHCl₃) (82% ee); IR (neat) 2923, 2854, 2391, 1727 cm⁻¹; ¹H-NMR (500 MHz, CDCl₃) δ: 1.24–1.46 (m, 7H), 1.43 (d, J = 6.6 Hz, 3H), 1.51–1.70 (m, 4H), 1.82 (m, 1H), 2.52 (t, J = 7.7 Hz, 2H), 2.57 (m, 1H), 4.30 (m, 1H), 4.44 (qd, J = 6.6, 3.1 Hz, 1H), 5.91 (s, 2H), 6.61 (dd, J = 7.9, 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H); ¹³C-NMR (125 MHz, CDCl₃) δ: 13.7 (CH₃), 23.3 (CH₂), 27.5 (CH₂), 29.0 (CH₂), 29.2 (CH₂), 29.3 (CH₂), 31.6 (CH₂), 35.6 (CH₂), 47.5 (CH), 71.2 (CH), 78.7 (CH), 100.7 (CH₂), 108.0 (CH), 108.8 (CH), 121.0 (C), 136.7 (C), 145.4 (CH), 147.4 (C), 177.4 (C); HR-MS-ESI: m/z [M + H]⁺ Calcd for C₁₉H₂₇O₅: 335.1853. Found 335.1855.

Acknowledgments

This work was partly supported by the Sasakawa Scientific Research Grant from the Japan Science Society, the Central Glass Co., Ltd. (Central Glass Co., Ltd. Award in Synthetic Organic Chemistry, Japan), Tokyo Ohka Foundation for The Promotion of Science and Technology, and JGC-S Scholarships Foundation. We thank Dr. Tadaaki Ohgiya (Laboratory Manager, Executive Officer, Medicinal Chemistry Dept., Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd.) for discussions. We also thank Dr. Yasuaki Koyama for purification of the products by preparative HPLC.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

• 1) Lopes N. P., Kato M. J., Yoshida M., Phytochemistry, 51, 29–33 (1999).
• 2) Chaves M. H., Roque N. F., Phytochemistry, 44, 523–528 (1997).
• 3) Chang S.-Y., Cheng M.-J., Peng C.-F., Chang H.-S., Chen I.-S., Chem. Biodivers., 5, 2690–2698 (2008).
• 4) Takeda K., Sakurawi K., Ishii H., Tetrahedron, 28, 3757–3766 (1972).
• 5) Vieira P. C., Yoshida M., Gottlieb O. R., Paulino Filho H. F., Nagem T. J., Braz Filho R., Phytochemistry, 22, 711–713 (1983).
• 6) Lopes N. P., Franca S. C., Pereira A. M. S., Maia J. G. S., Kato M. J., Cavalheiro A. J., Gottlieb O. R., Yoshida M., Phytochemistry, 35, 1469–1470 (1994).
• 7) Magri F. M. M., Kato M. J., Yoshida M., Phytochemistry, 43, 669–671 (1996).
• 8) Clive D. L., Ardelean E.-S., J. Org. Chem., 66, 4841–4844 (2001).
• 9) Gharpure S. J., Nanda L. N., Shukla M. K., Org. Lett., 16, 6424–6427 (2014).
• 10) Xu D., Crispino G. A., Sharpless K. B., J. Am. Chem. Soc., 114, 7570–7571 (1992).
• 11) Becker H., Soler M. A., Sharpless K. B., Tetrahedron, 51, 1345–1376 (1995).
• 12) Kutsumura N., Kiriseko A., Niwa K., Saito T., J. Org. Chem., 83, 11450–11457 (2018).
• 13) Rotherham L. W., Semple J. E., J. Org. Chem., 63, 6667–6672 (1998).
• 14) Tamao K., Sumitani K., Kiso Y., Zembayashi M., Fujioka A., Kodama S., Nakajima I., Minato A., Kumada M., Bull. Chem. Soc. Jpn., 49, 1958–1969 (1976).
• 15) Sa-ei K., Montgomery J., Tetrahedron, 65, 6707–6711 (2009).
• 16) Guasch J., Giménez-Nueno I., Funes-Ardoiz I., Bernús M., Matheu M. I., Maseras F., Castillón S., Díaz Y., Chem. Eur. J., 24, 4635–4642 (2018).
• 17) Kutsumura N., Niwa K., Saito T., Org. Lett., 12, 3316–3319 (2010).
• 18) Kutsumura N., Kiriseko A., Saito T., Tetrahedron Lett., 53, 3274–3276 (2012).
• 19) Kutsumura N., Matsubara Y., Niwa K., Ito A., Saito T., Eur. J. Org. Chem., 2013, 3337–3346 (2013).
• 20) Kutsumura N., Matsubara Y., Honjo T., Ohgiya T., Nishiyama S., Saito T., Tetrahedron, 71, 2382–2386 (2015).
• 21) Kutsumura N., Matsuo K., Saito T., Tetrahedron, 56, 2602–2604 (2015).
• 22) The less satisfactory selectivity of the desired 11 would be due to the electron-donating PMB-group of allylic alcohol, which decreased the regioselectivity of HBr-elimination of the intermediate vicinal dibromide, as mentioned in our previous papers. Kutsumura N., Iijima M., Toguchi S., Saito T., Chem. Lett., 40, 1231–1232 (2011).
• 23) Kutsumura N., Toguchi S., Iijima M., Tanaka O., Iwakura I., Saito T., Tetrahedron, 70, 8004–8009 (2014). In fact, the reaction of the relevant dibromide having an electron-withdrawing acetoxy group with DBU at 60°C afforded the desired vinyl bromide in a quantitative yield with perfect selectivity.¹²⁾
• 24) Semmelhack M. F., Brickner S. J., J. Org. Chem., 46, 1723–1726 (1981).
• 25) Uenishi J., Ohmi M., Heterocycles, 61, 365–376 (2003).
• 26) Ohgiya T., Nishiyama S., Heterocycles, 63, 2349–2354 (2004).
• 27) Yu C.-M., Youn J., Lee M.-K., Org. Lett., 7, 3733–3736 (2005).
• 28) Rauniyar V., Hall D. G., J. Org. Chem., 74, 4236–4241 (2009).
• 29) Juan C., Martinez V., Yoshida M., Gottlieb O. R., Phytochemistry, 20, 459–464 (1981).
• 30) Rollinson S. W., Amos R. A., Katzenellenbogen J. A., J. Am. Chem. Soc., 103, 4114–4125 (1981).
• 31) Tanaka H., Nakamura T., Ichino K., Ito K., Tanaka T., Phytochemistry, 29, 857–859 (1990).
• 32) Tanaka H., Takaya Y., Toyoda J., Yasuda T., Sato M., Murata J., Murata H., Kaburagi K., Iida O., Sugimura K., Sakai E., Phytochem. Lett., 11, 32–36 (2015).
• 33) Mailar K., Choi W. J., Carbohydr. Res., 432, 31–35 (2016).
• 34) Lee J., Mailar K., Yoo O.-K., Choi W. J., Keum Y.-S., Eur. J. Med. Chem., 150, 113–126 (2018).
• 35) Bernardi A., Beretta M. G., Colombo L., Gennari C., Poli G., Scolastico C., J. Org. Chem., 50, 4442–4447 (1985).
• 36) Chen M.-J., Lo C.-Y., Chin C.-C., Liu R.-S., J. Org. Chem., 65, 6362–6367 (2000).
• 37) Lee S. I., Jang J. H., Hwang G.-S., Ryu D. H., J. Org. Chem., 78, 770–775 (2013).
• 38) Tan D.-X., Xu Z.-J., Chen H.-J., Wu Y., You J., Eur. J. Org. Chem., 2016, 946–957 (2016).
• 39) Crabtree R. H., Davis M. W., J. Org. Chem., 51, 2655–2661 (1986).
• 40) Hong A. Y., Stoltz B. M., Angew. Chem. Int. Ed., 51, 9674–9678 (2012).
• 41) Thompson H. W., McPherson E., J. Am. Chem. Soc., 96, 6232–6233 (1974).
• 42) Jourdant A., González-Zamora E., Zhu J., J. Org. Chem., 67, 3163–3164 (2002).