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A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds a
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Hiroshi Kumagai , Mami Fujiwara , Masaki Kuse & Hirosato Takikawa a
Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan Published online: 23 Mar 2015.
Click for updates To cite this article: Hiroshi Kumagai, Mami Fujiwara, Masaki Kuse & Hirosato Takikawa (2015) A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds, Bioscience, Biotechnology, and Biochemistry, 79:8, 1240-1245, DOI: 10.1080/09168451.2015.1025036 To link to this article: http://dx.doi.org/10.1080/09168451.2015.1025036
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Bioscience, Biotechnology, and Biochemistry, 2015 Vol. 79, No. 8, 1240–1245
A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds Hiroshi Kumagai, Mami Fujiwara, Masaki Kuse and Hirosato Takikawa* Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan Received February 6, 2015; accepted February 24, 2015 http://dx.doi.org/10.1080/09168451.2015.1025036
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Solanacol, isolated from tobacco (Nicotiana tabacum L.), is a germination stimulant for seeds of root parasitic weeds. A concise synthesis of optically active solanacol has been achieved by employing enzymatic resolution as a key step. Key words:
solanacol; strigolactones; germination stimulant; enzymatic resolution
Witchweeds (Striga spp.) and broomrapes (Orobanche and Phelipanche spp.) are the two most devastating parasitic plants. They cause enormous loss of agricultural production in tropical and subtropical regions. Seeds of these parasitic weeds germinate only when stimulated by a chemical exuded from the roots of the host and some non-host plants.1) These chemicals include strigol,2,3) sorgolactone,4,5) orobanchol,6−8), alectrol,8−10) etc. which are collectively known as strigolactones.11) Strigolactones are also used as host recognition signals for arbuscular mycorrhizal fungi,12) and have been proposed as a new class of plant hormone that inhibit shoot branching.13,14) In 2007, Xie et al.15) reported the isolation and structure elucidation of solanacol from tobacco (Nicotiana tabacum L.), which is a known host for Phelipanche ramosa L. The proposed structure of solanacol (1) is unique because its A-ring is a substituted benzene, making solanacol the first natural strigolactone containing a benzene ring (Fig. 1). Inspired by the interesting biological profiles of strigolactones and the unique structure of solanacol, we initiated studies toward the synthesis of solanacol as a continuation of our synthetic studies on strigolactones.16) In 2009, we completed the first synthesis of 1, which proved the proposed structure to be incorrect.17) Reconsideration of the reported NMR data prompted us to propose a revised structure of solanacol as 2, with the exception of absolute configuration.17) In 2010, the first synthesis of optically active 2 was reported by Chen et al.18) This synthesis not only proved that the revised structure (2) was correct, but also provided the absolute configuration of solanacol as 3aR,4R,8bR,2′R. Here, we report our novel and facile synthesis of optically active solanacol (2). *Corresponding author. Email: [email protected] © 2015 Japan Society for Bioscience, Biotechnology, and Agrochemistry
Results and discussion Scheme 1 shows our synthetic plan. The target compound, solanacol (2), could be prepared from A via the usual method. For the synthesis of optically active A, we envisaged adopting enzymatic resolution because we had been successful in resolving A′ in the synthesis of optically active 4-HO-GR24.19) Tricyclic lactone A could be prepared by the hydroxylation of B, which could be synthesized from C. For the synthesis of bicyclic ketone C, we proposed a Nazarov cyclization as the key reaction, and chose 2,3-dimethylbenzaldehyde (D) as the starting material. Scheme 2 illustrates our synthesis of optically active 2. The starting material, 2,3-dimethylbenzaldehyde 3 (=D), was converted to an allylic alcohol 4 by treatment with a vinyl Grignard reagent (99%). Oxidation of 4 with activated MnO2 gave the corresponding enone 5 in moderate yield (up to 56%). Thus, there was a need to examine effective oxidizing agents. Although pyridinium dichromate and pyridinium chlorochromate were less effective than MnO2, oxidation with 2-iodoxybenzoic acid (IBX) was much more successful, affording 5 in 95% yield. Nazarov cyclization of 5 was performed by treatment with excess CF3SO3H to give 620,21) (92%). According to a conventional method,22) the resulting bicyclic ketone 6 was converted to carboxylic acid 7 (83% in 2 steps), which was then reduced with NaBH4 to give tricyclic lactone 823) (93%). Installation of a hydroxyl group at the C4 position was achieved by benzylic bromination with N-bromosuccinimide (NBS) and subsequent hydrolysis, affording desired hydroxylactone (±)-9 (60%) and its epimer (±)-9′ (21%). The structure of 9′ was assigned by 1H NMR analysis. The signal due to 4-H of 9′ (at δ 5.12) is a doublet (J = 7.5 Hz), whereas that of 9 (at δ 5.02) is a broad singlet. These data are similar to those reported for analogous compounds.7,17) This hydrolysis mainly proceeded in an SN1 manner because the radical bromination at the benzylic position afforded the β-bromide as a major product. This was supported by 1H NMR analysis of the crude bromide intermediates. The signal due to 4-H of the major bromide appears at δ 5.33 as a broad singlet.
Synthesis of optically active solanacol
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Fig. 1.
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Structures of strigolactones.
With the racemic key intermediate in hand, we then attempted to perform its enzymatic resolution. As mentioned previously, we had been successful in resolving a hydroxylactone with a similar structure.19) In that case, Chirazyme L-2 (Roche Diagnostics, Candida antherctica lipase B) was selected by screening hydrolytic enzymes. Enzymatic resolution of (±)-9 under the same conditions proceeded smoothly to give a mixture of (+)-9 and (−)-10, as expected. This mixture was cleanly separated by silica gel column chromatography to yield (+)-9 (47%) and (−)-10 (47%). Chiral HPLC analyses of (+)-9 and (−)-10 showed that they were optically pure. The obtained (−)-10 was then transesterified with K2CO3 in MeOH to afford (−)-9 (98%). The absolute configurations were determined by comparison with the reported specific rotation value.18) Finally, according to the reported procedure, (−)-9 was converted to (3aR,4R,8bR,2′S)-2 (2′-epi-solanacol) and (3aR,4R,8bR,2′R)-2 (solanacol),18) and (+)-9 was converted to (3aS,4S,8bS,2′R)-2 (ent-2′-epi-solanacol) and (3aS,4S,8bS,2′S)-2 (ent-solanacol). In conclusion, we accomplished a new and concise synthesis of solanacol by employing enzymatic resolution as a key step. A bioassay using our synthetic samples is now in preparation, which will allow the clarification of the structure–activity relationships
Scheme 1.
Synthetic plan for solanacol.
between stereoisomers of solanacol and seeds of root parasitic weeds.
Experimental General procedures. IR spectra were measured with a Thermo Scientific Nicolet iS5 spectrometer. 1H NMR spectra were recorded at 300 MHz with a Jeol JNM-AL300 spectrometer. TMS or the residual solvent peak in CDCl3 (at δH = 7.26) was used as the internal standard. 13C NMR spectra were recorded at 75 MHz with the Jeol JNM-AL300 spectrometer, the peak for CDCl3 (at δC = 77.0) being used as the internal standard. Optical rotations were taken with a HORIBA SEPA-300 polarimeter. Mass spectra were measured with a Jeol JMS-SX102A spectrometer or a Thermo Scientific LTQ Orbitrap Discovery instrument. 1-(2,3-Dimethylphenyl)prop-2-en-1-ol (4). To an ice cooled solution of 3 (5.00 g, 37.3 mmol) in THF (30 mL), vinylmagnesium bromide (1.0 M in THF; 43 mL, 43 mmol) was added under Ar. After stirring at 0 °C for 3 h, the reaction mixture was quenched with sat. NH4Cl aq. and extracted with Et2O. The organic layer was washed with water, sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 4 (5.99 g, 99%). IR (ATR): 3355 (O–H) cm−1. NMR δH (CDCl3): 2.24 (3H, s, CH3), 2.30 (3H, s, CH3), 2.81 (1H, br, OH), 5.18 (1H, d, J = 10.2 Hz, 3-H), 5.29 (1H, d, J = 17.1 Hz, 3-H), 5.41 (1H, d, J = 5.4 Hz, 1-H), 6.04 (1H, ddd, J = 17.1, 10.2, 5.4 Hz, 2-H), 7.07–7.14 (2H, m, Ar–H), 7.30 (1H, br d, J = 6.3 Hz, Ar–H). NMR δC (CDCl3): 14.6, 20.5, 72.1, 114.9, 123.7, 125.6, 129.2, 133.9, 136.9, 139.6, 140.3. HRESIMS m/z [M-OH]+: calcd. for C11H13,145.0012; found, 145.0011. 1-(2,3-Dimethylphenyl)prop-2-en-1-one (5). To a solution of IBX (10.7 g, 38.1 mmol) in DMSO (50 mL), a solution of 4 (4.12 g, 25.4 mmol) in DMSO (50 mL) was added. After stirring at room temperature for 1.5 h, the reaction mixture was diluted with water and filtered. The filtrate was extracted with EtOAc-hexane (ca. 1:1). The organic layer was washed with
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Scheme 2. Synthesis of solanacol. Notes: Reagents and conditions: (a) CH2=CHMgBr, THF (99%); (b) IBX, DMSO (95%); (c) CF3SO3H (92%); (d) NaH, CO(OMe)2, DMF then BrCH2CO2Et; (e) 6 M HCl, AcOH (83% in 2 steps); (f) NaBH4, EtOH then dil. HCl (93%); (g) NBS, AIBN, CCl4 then CaCO3 aq. (60% for 9; 21% for 9′); (h) Chirazyme L-2, CH2=CHOAc, toluene [47% for (+)-9, 47% for (−)-10]; (i) K2CO3, MeOH (98%); (j) t-BuOK, HCO2Et, THF then 4-bromo-2-methyl-2-buten-4-olide (27% for 2′-epi-solanacol, 26% for solanacol, 29% for ent-2′-epi-solanacol, and 28% for ent-solanacol).
water, sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 5 (3.87 g, 95%). This was immediately used for the next step. IR (ATR): 1660 (C=O) cm−1. NMR δH (CDCl3): 2.25 (3H, s, CH3), 2.31 (3H, s, CH3), 6.04 (1H, dd, J = 10.5, 1.2 Hz, 3-H), 6.08 (1H, dd, J = 17.4, 1.2 Hz, 3-H), 6.71 (1H, dd, J = 10.5, 17.4 Hz, 2-H), 7.10–7.30 (3H, m, Ar–H), NMR δC (CDCl3): 16.3, 19.9, 124.9, 125.4, 131.5, 131.6, 134.5, 137.1, 137.7, 138.7, 198.0.
6,7-Dimethylindan-1-one (6). A solution of 5 (535 mg, 3.34 mmol) in CF3SO3H (25 g) was stirred at room temperature for 3 days. The reaction mixture was diluted with ice water and extracted with CH2Cl2. The organic layer was washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 6 (492 mg, 92%) as yellow solid. This was recrystallized from hexane to afford pale yellow needles. Mp: 41 °C. IR (ATR): 1696 (C=O) cm−1. NMR δH (CDCl3): 2.30 (3H, s, 6-CH3), 2.59 (3H, s, 7-CH3), 2.61–2.68 (2H, m, 2-H2), 3.01 (2H, br t, J = 6.0 Hz, 3-H2), 7.17 (1H, d, J = 7.8 Hz, 5-H), 7.32 (1H, d, J = 7.8 Hz, 4-H). NMR δC (CDCl3): 13.5, 18.9, 24.6, 37.3, 123.4, 134.2, 135.7, 136.1, 137.2, 153.7, 208.4.
(6,7-Dimethyl-1-oxoindan-2-yl)acetic acid (7). To a mixture of NaH (55%; 113 mg, 2.60 mmol) and CO (OMe)2 (0.40 mL, 4.1 mmol) in DMF (2 mL), a solution of 6 (166 mg, 1.04 mmol) in DMF (5 mL) was added slowly at 70 °C under Ar. After stirring for 1 h, BrCH2CO2Et (0.20 mL, 1.8 mmol) was added, and the stirring was continued for 1 h at 70 °C. The reaction mixture was quenched with 1 M HCl and extracted with toluene. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give the diester. This was then dissolved into 6 M HCl (40 mL) and AcOH (40 mL), and the mixture was heated under reflux for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from EtOH to give 7 (187 mg, 83% in 2 steps). Mp: 182 °C. IR (ATR): 1699 (C=O), 1685 (C=O) cm−1. NMR δH (CDCl3): 2.31 (3H, s, 6-CH3), 2.61 (3H, s, 7-CH3), 2.60–2.67 (1H, m, 1′-H), 2.79 (1H, dd, J = 16.8, 4.5 Hz, 3-H), 2.94–3.07 (2H, m, 2- and 1′-H), 3.37 (1H, dd, J = 16.8, 7.8 Hz, 3-H), 7.17 (1H, d, J = 7.8 Hz, 5-H), 7.36 (1H, d, J = 7.8 Hz, 4-H). NMR δC (CDCl3): 13.7, 19.0, 32.0, 35.2, 44.1, 123.3, 133.3, 136.3, 136.5, 137.6, 151.6, 177.4, 208.0. HRESIMS m/z [M+H]+: calcd. for C13H15O3, 219.1016; found, 219.1017.
Synthesis of optically active solanacol *
*
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(3aS ,8bR )-7,8-Dimethyl-3,3a,4,8b-tetrahydroindeno [1,2-b]furan-2-one (8). To a solution of 7 (1.92 g, 8.79 mmol) in EtOH (40 mL), NaBH4 (0.87 g, 21 mmol) was added portionwise at 0 °C. After stirring overnight at room temperature, EtOH was removed under reduced pressure. The resulting mixture was diluted with 2-M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 8 (1.65 g, 93%). This was recrystallized from CH2Cl2 to afford pale yellow needles. Mp: 84 °C. IR (ATR): 1756 (C=O) cm−1. NMR δH (CDCl3): 2.27 (3H, s, 7-CH3), 2.33 (3H, s, 8CH3), 2.43 (1H, dd, J = 18.0, 4.8 Hz, 3-H), 2.84 (1H, br d, 4-H), 2.92 (1H, dd, J = 18.0, 9.6 Hz, 3-H), 3.21– 3.41 (2H, m), 5.96 (1H, d, J = 6.9 Hz, 8b-H), 6.99 (1H, d, J = 7.5 Hz, 5-H), 7.15 (1H, d, J = 7.5 Hz, 6-H). NMR δC (CDCl3): 15.4, 19.2, 35.7, 36.8, 37.9, 87.3, 122.0, 131.6, 134.9, 135.5, 137.5, 140.1, 177.0. (±)-(3aR*,4R*,8bR*)-4-Hydroxy-7,8-dimethyl-3,3a,4, 8b-tetrahydroindeno[1,2-b]furan-2-one [(±)-9]. To a solution of 8 (112 mg, 0.555 mmol) in CCl4 (20 mL), NBS (0.11 g, 0.61 mmol) and AIBN (9.0 mg, 56 μmol) were added. After stirring under reflux for 3 h, the reaction mixture was cooled and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the crude products, which was immediately dissolved into acetone–EtOH–H2O (1:1:1; 15 mL). To this solution was added CaCO3 (0.16 g, 1.6 mmol), and the stirring was continued overnight at room temperature. After removal of organic solvents under reduced pressure, the resulting mixture was diluted with 2-M HCl and extracted with EtOAc. The organic layer was washed brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give (±)-9 (72 mg, 60%) and (±)-9′ (25 mg, 21%). (±)-9: IR (ATR): 3400 (O–H), 1766 (C=O) cm−1. NMR δH (CDCl3): 2.28 (3H, s, 7-CH3), 2.31 (3H, s, 8-CH3), 2.43 (1H, dd, J = 18.3, 5.4 Hz, 3-H), 2.69 (1H, br s, OH), 2.89 (1H, dd, J = 18.3, 10.2 Hz, 3-H), 3.09–3.19 (1H, m, 3a-H), 5.02 (1H, br s, 4-H), 6.04 (1H, d, J = 6.9 Hz, 8b-H), 7.15 (1H, d, J = 7.8 Hz, 5-H), 7.22 (1H, d, J = 7.8 Hz, 6-CH). NMR δC (CDCl3): 15.5, 19.6, 33.3, 47.7, 80.6, 85.6, 122.1, 132.5, 135.5, 137.7, 138.8, 141.7, 176.5. (±)-9′: Mp: 102 °C (from EtOAc). NMR δH (CDCl3): 2.28 (3H, s, Ar-CH3), 2.31 (3H, s, Ar-CH3), 2.62 (1H, dd, J = 18.3, 10.5 Hz, 3-H), 2.93 (1H, dd, J = 18.3, 4.8 Hz, 3-H), 3.37 (1H, m, 3a-H), 5.12 (1H, d, J = 7.5 Hz, 4-H), 5.75 (1H, d, J = 7.2 Hz, 8b-H), 7.19 (1H, d, J = 8.1 Hz, Ar–H), 7.22 (1H, d, J = 8.1 Hz, Ar–H). NMR δC (CDCl3): 15.4, 19.5, 29.0, 42.9, 73.1, 84.5, 122.3, 132.3, 135.0, 137.1, 138.0, 142.3, 177.8. (+)-(3aS,4S,8bS)-4-Hydroxy-7,8-dimethyl-3,3a,4,8btetrahydroindeno[1,2-b]furan-2-one [(+)-9] and (−)(3aR,4R,8bR)-4-Hydroxy-7,8-dimethyl-3,3a,4,8b-tetrahydroindeno[1,2-b]furan-2-one [(−)-10]. To a solution of (±)-9 (98.1 mg, 0.449 mmol) in toluene
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(2 mL), Chirazyme L-2 (34.0 mg) and vinyl acetate (0.20 mL) were added. After stirring at room temperature for 3 days, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the residue, which was chromatographed on SiO2 to give (+)-9 (45.8 mg, 47%) and (−)-10 (54.9 mg, 47%). (+)-9: [α]D25 + 131 (c 1.02, CHCl3). HREIMS m/z [M]+: calcd. for C13H14O3, 218.0943; found, 218.0943. (−)-10: Mp: 151–153 °C. IR (ATR): 1773 (C=O), 1730 (C=O) cm−1. [α]D25 − 49.3 (c 1.03, CHCl3). NMR δH (CDCl3): 2.06 (3H, s, Ac), 2.30 (3H, s, Ar-CH3), 2.34 (3H, s, Ar-CH3), 2.63 (1H, dd, J = 18.6, 6.0 Hz, 3-H), 2.99 (1H, dd, J = 18.6, 10.8 Hz, 3-H), 3.23 (1H, m, 3a-H), 5.96 (1H, br s, 4-H), 6.09 (1H, d, J = 7.2 Hz, 8b-H), 7.17 (1H, d, J = 7.8 Hz, 6-H), 7.23 (1H, d, J = 7.8 Hz, 5-H). NMR δC (CDCl3): 15.4, 19.5, 21.0, 33.1, 45.1, 82.0, 85.2, 123.2, 132.4, 135.3, 137.5, 138.8, 139.2, 170.8, 176.0. HREIMS m/z [M]+: calcd. for C15H16O4, 260.1049; found, 260.1046. Determination of the enantiomeric purities of (+)-9 and (−)-10. The enantiomeric purities of (+)-9 and (−)-10 were estimated by HPLC analysis [column: Daicel Chiralcel® OD-H 250 mm X 4.6 mm; eluent: hexane/2-propanol = 5:1; flow rate 0.5 mL/min; detection: at 254 nm]: (+)-9: tR/min 30.1 [>99%, (+)-9], 28.5 [~0%, (−)-9]. The enantiomeric purity of (+)-9 was estimated to be >99% ee. (−)-10: tR/min 25.6 [>99%, (−)-10], 22.2 [~0%, (+)-10]. The enantiomeric purity of (−)-10 was estimated to be >99% ee. (−)-(3aS,4S,8bS)-7,8-Dimethyl-4-hydroxy-3,3a,4,8btetrahydroindeno[1,2-b]furan-2-one [(−)-9]. To a solution of (−)-10 (45.0 mg, 0.173 mmol) in MeOH (5 mL), K2CO3 (34 mg, 1.4 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with 2-M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give (−)-9 (37.2 mg, 0.170 mmol, 98%) as a colorless oil. However, after long storage in the refrigerator, we found that (−)-9 crystallized in colorless needles. Mp: 83 °C. [α]D27 − 148 (c 1.06, CHCl3). HREIMS m/z [M]+: calcd. for C13H14O3, 218.0943; found, 218.0939. It should be noted that we were not successful in crystallizing (+)-9.
2′-epi-Solanacol [(3aR,4R,8bR,2′S)-2] and solanacol [(3aR,4R,8bR,2′R)-2]. To a solution of (−)-9 (44.7 mg, 0.205 mmol) in THF (1 mL) were added t-BuOK (114 mg, 1.02 mmol) and HCO2Et (0.15 g, 2.0 mmol) at −78 °C under Ar. After removal of the cooling bath, it was stirred for 6 h. To this mixture, 4-bromo-2-methyl-2-buten-4-olide (56.6 mg, 0.320 mmol) was added at -78 °C. After stirring for 12 h with warming to room temperature, it was then quenched with 1-M HCl and extracted with EtOAc. The organic layer was washed with sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under
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reduced pressure. The residue was chromatographed on SiO2 to give 2′-epi-solanacol [(3aR,4R,8bR,2′S)-2] (less polar; 18.8 mg, 27%; Rf = 0.38, hexane: EtOAc = 1:2) and solanacol [(3aR,4R,8bR,2′R)-2] (more polar; 18.3 mg, 26%; Rf = 0.25, hexane: EtOAc = 1:2). 2′-epi-Solanacol: [α]D23 = −207 (c 0.42, CHCl3). NMR δH (CDCl3): 2.05 (3H, s, 4′-CH3), 2.30 (3H, s, 7-CH3), 2.36 (3H, s, 8-CH3), 3.81 (1H, ddd, J = 7.5, 2.7, and 1.8 Hz, 3a-H), 5.27 (1H, s, 4-H), 6.14 (1H, d, J = 7.5 Hz, 8b-H), 6.25 (1H, br s, 2′-H), 7.00 (1H, br s, 3′-H), 7.17 (1H, d, J = 7.8 Hz, 6-H), 7.24 (1H, d, J = 7.8 Hz, 5-H), 7.55 (1H, d, J = 2.4 Hz, 9-H). NMR δC (CDCl3): 10.8, 15.6, 19.6, 50.4, 80.0, 84.1, 100.4, 110.6, 122.3, 132.6, 135.4, 136.3, 138.0, 138.7, 140.9, 141.6, 151.4, 170.1, 170.9. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089. Solanacol: [α]D23 = −213 (c 0.36, CHCl3). NMR δH (CDCl3): 2.04 (3H, br s, 4′-CH3), 2.30 (3H, s, 7-CH3), 2.35 (3H, s, 8-CH3), 3.81 (1H, ddd, J = 7.5, 2.7, and 1.8 Hz, 3a-H), 5.24 (1H, s, 4-H), 6.14 (1H, d, J = 7.5 Hz, 8b-H), 6.23 (1H, t, J = 1.5 Hz, 2′-H), 6.99 (1H, t, J = 1.5 Hz, 3′-H), 7.16 (1H, d, J = 7.8 Hz, 6-H), 7.24 (1H, d, J = 7.8 Hz, 5-H), 7.55 (1H, d, J = 2.7 Hz, 9-H). NMR δC (CDCl3): 10.8, 15.6, 19.6, 50.3, 79.9, 84.1, 100.6, 110.5, 122.4, 132.7, 135.4, 136.1, 138.0, 138.7, 141.0, 141.6, 151.7, 170.2, 170.9. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089. ent-2′-epi-Solanacol [(3aS,4S,8bS,2′R)-2] and entsolanacol [(3aS,4S,8bS,2′S)-2]. In the same manner as described above, (+)-9 (45.4 mg, 0.208 mmol) was converted to ent-2′-epi-solanacol [(3aS,4S,8bS,2′R)-2] (less polar; 20.7 mg, 29%; Rf = 0.38, hexane: EtOAc = 1:2) and ent-solanacol [(3aS,4S,8bS,2′S)-2] (more polar; 19.7 mg, 28%; Rf = 0.25, hexane: EtOAc = 1:2). ent-2′-epi-Solanacol: [α]D23 = +201 (c 0.20, CHCl3). NMR data were identical to those of 2′-epi-solanacol. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1103. ent-Solanacol: [α]D23 = +227 (c 0.24, CHCl3). NMR data were identical to those of solanacol. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089.
Acknowledgments We thank Ms Chiaki Kawasaki (Kobe University) for her contribution to this work.
Disclosure statement No potential conflict of interest was reported by the authors.
Funding This research was financially supported by a Grant-in-Aid for Scientific Research from JSPS [No. 25450152] and JST/ JICA SATREPS.
References [1] Humphrey AJ, Galster AM, Beale MH. Strigolactones in chemical ecology: waste products or vital allelochemicals? Nat. Prod. Rep. 2006;23:592–614. [2] Cook CE, Whichard LP, Turner B, Wall ME, Egley GH. Germination of witchweed (Striga lutea Lour.): isolation and properties of a potent stimulant. Science. 1966;154:1189–1190. [3] Cook CE, Whichard LP, Wall ME, Egley GH, Coggon P, Luhan PA, McPhail AT. Germination stimulants. II. Structure of strigol, a potent seed germination stimulant for witchweed (Striga lutea Lour). J. Am. Chem. Soc. 1972;94:6198–6199. [4] Hauck C, Müller S, Schildknecht H. A germination stimulant for parasitic flowering plants from Sorghum bicolor, a genuine host plant. J. Plant Physiol. 1992;139:474–478. [5] Sugimoto Y, Wigchert SCM, Thuring JWJF, Zwanenburg B. Synthesis of all eight stereoisomers of the germination stimulant sorgolactone. J. Org. Chem. 1998;63:1259–1267. [6] Yokota T, Sakai H, Okuno K, Yoneyama K, Takeuchi Y. Alectrol and orobanchol, germination stimulants for Orobanche minor, from its host red clover. Phytochemistry. 1998;49:1967–1973. [7] Mori K, Matsui J, Yokota T, Sakai H, Bando M, Takeuchi Y. Structure and synthesis of orobanchol, the germination stimulant for Orobanche minor. Tetrahedron Lett. 1999;40:943–946. [8] Ueno K, Nomura S, Muranaka S, Mizutani M, Takikawa H, Sugimoto Y. Ent-2′-epi-orobanchol and its acetate, as germination stimulants for Striga gesnerioides seeds isolated from cowpea and red clover. J. Agric. Food. Chem. 2011;59:10485–10490. [9] Müller S, Hauck C, Schildknecht H. Germination stimulants produced by Vigna unguiculata Walp cv Saunders Upright. J. Plant Growth Regul. 1992;11:77–84. [10] Xie X, Yoneyama K, Kusumoto D, Yamada Y, Yokota T, Takeuchi Y, Yoneyama K. Isolation and identification of alectrol as (+)-orobanchyl acetate, a novel germination stimulant for root parasitic plants. Phytochemistry. 2008;69:427–431. [11] Butler, LG. Chemical communication between the parasitic weed Striga and its crop host, a new dimension in allelochemistry. In: Inderjit, Dakshini KMM, Einhellig, FA, editors. Allelopathy: organisms, processes, and applications. Washington, DC: American Chemical Society; 1995. pp. 158–168. [12] Akiyama K, Matsuzaki K, Hayashi H. Plant sesquiterpenes induce hyphal branching in arbuscular mycorrhizal fungi. Nature. 2005;435:824–827. [13] Gomez-Roldan V, Fermas S, Brewer PB, Puech-Pagès V, Dun EA, Pillot JP, Letisse F, Matusova R, Danoun S, Portais JC, Bouwmeester H, Bécard G, Beveridge CA, Rameau C, Rochange S. Strigolactone inhibition of shoot branching. Nature. 2008;455:189–194. [14] Umehara M, Hanada A, Yoshida S, Akiyama K, Arite T, TakedaKamiya N, Magome H, Kamiya U, Shirasu K, Yoneyama K, Kyozuka J, Yamaguchi S. Inhibition of shoot branching by new terpenoid plant hormones. Nature. 2008;455:195–200. [15] Xie X, Kusumoto D, Takeuchi Y, Yoneyama K, Yamada Y, Yoneyama K. 2′-epi-orobanchol and solanacol, two unique strigolactones, germination stimulants for root parasitic weeds, produced by tobacco. J. Agric. Food. Chem. 2007;55:8067–8072. [16] Kitahara S, Tashiro T, Sugimoto Y, Sasaki M, Takikawa H. First synthesis of (±)-sorgomol, the germination stimulant for root parasitic weeds isolated from Sorghum bicolor. Tetrahedron Lett. 2011;52:724–726. [17] Takikawa H, Jikumaru S, Sugimoto Y, Xie X, Yoneyama K, Sasaki M. Synthetic disproof of the structure proposed for solanacol, the germination stimulant for seeds of root parasitic weeds. Tetrahedron Lett. 2009;50:4549–4551. [18] Chen VX, Boyer FD, Rameau C, Retailleau P, Vors JP, Beau JM. Stereochemistry, total synthesis, and biological evaluation of the new plant hormone solanacol. Chem. Eur. J. 2010;16: 13941–13945. [19] Takikawa H, Imaishi H, Tanaka A, Jikumaru S, Fujiwara M, Sasaki M. Synthesis of optically active strigolactones: enzymatic resolution and asymmetric hydroxylation. Tetrahedron: Asymmetry. 2010;21:1166–1168.
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Bioscience, Biotechnology, and Biochemistry Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/tbbb20
A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds a
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Hiroshi Kumagai , Mami Fujiwara , Masaki Kuse & Hirosato Takikawa a
Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan Published online: 23 Mar 2015.
Click for updates To cite this article: Hiroshi Kumagai, Mami Fujiwara, Masaki Kuse & Hirosato Takikawa (2015) A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds, Bioscience, Biotechnology, and Biochemistry, 79:8, 1240-1245, DOI: 10.1080/09168451.2015.1025036 To link to this article: http://dx.doi.org/10.1080/09168451.2015.1025036
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Bioscience, Biotechnology, and Biochemistry, 2015 Vol. 79, No. 8, 1240–1245
A concise synthesis of optically active solanacol, the germination stimulant for seeds of root parasitic weeds Hiroshi Kumagai, Mami Fujiwara, Masaki Kuse and Hirosato Takikawa* Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Kobe, Japan Received February 6, 2015; accepted February 24, 2015 http://dx.doi.org/10.1080/09168451.2015.1025036
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Solanacol, isolated from tobacco (Nicotiana tabacum L.), is a germination stimulant for seeds of root parasitic weeds. A concise synthesis of optically active solanacol has been achieved by employing enzymatic resolution as a key step. Key words:
solanacol; strigolactones; germination stimulant; enzymatic resolution
Witchweeds (Striga spp.) and broomrapes (Orobanche and Phelipanche spp.) are the two most devastating parasitic plants. They cause enormous loss of agricultural production in tropical and subtropical regions. Seeds of these parasitic weeds germinate only when stimulated by a chemical exuded from the roots of the host and some non-host plants.1) These chemicals include strigol,2,3) sorgolactone,4,5) orobanchol,6−8), alectrol,8−10) etc. which are collectively known as strigolactones.11) Strigolactones are also used as host recognition signals for arbuscular mycorrhizal fungi,12) and have been proposed as a new class of plant hormone that inhibit shoot branching.13,14) In 2007, Xie et al.15) reported the isolation and structure elucidation of solanacol from tobacco (Nicotiana tabacum L.), which is a known host for Phelipanche ramosa L. The proposed structure of solanacol (1) is unique because its A-ring is a substituted benzene, making solanacol the first natural strigolactone containing a benzene ring (Fig. 1). Inspired by the interesting biological profiles of strigolactones and the unique structure of solanacol, we initiated studies toward the synthesis of solanacol as a continuation of our synthetic studies on strigolactones.16) In 2009, we completed the first synthesis of 1, which proved the proposed structure to be incorrect.17) Reconsideration of the reported NMR data prompted us to propose a revised structure of solanacol as 2, with the exception of absolute configuration.17) In 2010, the first synthesis of optically active 2 was reported by Chen et al.18) This synthesis not only proved that the revised structure (2) was correct, but also provided the absolute configuration of solanacol as 3aR,4R,8bR,2′R. Here, we report our novel and facile synthesis of optically active solanacol (2). *Corresponding author. Email: [email protected] © 2015 Japan Society for Bioscience, Biotechnology, and Agrochemistry
Results and discussion Scheme 1 shows our synthetic plan. The target compound, solanacol (2), could be prepared from A via the usual method. For the synthesis of optically active A, we envisaged adopting enzymatic resolution because we had been successful in resolving A′ in the synthesis of optically active 4-HO-GR24.19) Tricyclic lactone A could be prepared by the hydroxylation of B, which could be synthesized from C. For the synthesis of bicyclic ketone C, we proposed a Nazarov cyclization as the key reaction, and chose 2,3-dimethylbenzaldehyde (D) as the starting material. Scheme 2 illustrates our synthesis of optically active 2. The starting material, 2,3-dimethylbenzaldehyde 3 (=D), was converted to an allylic alcohol 4 by treatment with a vinyl Grignard reagent (99%). Oxidation of 4 with activated MnO2 gave the corresponding enone 5 in moderate yield (up to 56%). Thus, there was a need to examine effective oxidizing agents. Although pyridinium dichromate and pyridinium chlorochromate were less effective than MnO2, oxidation with 2-iodoxybenzoic acid (IBX) was much more successful, affording 5 in 95% yield. Nazarov cyclization of 5 was performed by treatment with excess CF3SO3H to give 620,21) (92%). According to a conventional method,22) the resulting bicyclic ketone 6 was converted to carboxylic acid 7 (83% in 2 steps), which was then reduced with NaBH4 to give tricyclic lactone 823) (93%). Installation of a hydroxyl group at the C4 position was achieved by benzylic bromination with N-bromosuccinimide (NBS) and subsequent hydrolysis, affording desired hydroxylactone (±)-9 (60%) and its epimer (±)-9′ (21%). The structure of 9′ was assigned by 1H NMR analysis. The signal due to 4-H of 9′ (at δ 5.12) is a doublet (J = 7.5 Hz), whereas that of 9 (at δ 5.02) is a broad singlet. These data are similar to those reported for analogous compounds.7,17) This hydrolysis mainly proceeded in an SN1 manner because the radical bromination at the benzylic position afforded the β-bromide as a major product. This was supported by 1H NMR analysis of the crude bromide intermediates. The signal due to 4-H of the major bromide appears at δ 5.33 as a broad singlet.
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Fig. 1.
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Structures of strigolactones.
With the racemic key intermediate in hand, we then attempted to perform its enzymatic resolution. As mentioned previously, we had been successful in resolving a hydroxylactone with a similar structure.19) In that case, Chirazyme L-2 (Roche Diagnostics, Candida antherctica lipase B) was selected by screening hydrolytic enzymes. Enzymatic resolution of (±)-9 under the same conditions proceeded smoothly to give a mixture of (+)-9 and (−)-10, as expected. This mixture was cleanly separated by silica gel column chromatography to yield (+)-9 (47%) and (−)-10 (47%). Chiral HPLC analyses of (+)-9 and (−)-10 showed that they were optically pure. The obtained (−)-10 was then transesterified with K2CO3 in MeOH to afford (−)-9 (98%). The absolute configurations were determined by comparison with the reported specific rotation value.18) Finally, according to the reported procedure, (−)-9 was converted to (3aR,4R,8bR,2′S)-2 (2′-epi-solanacol) and (3aR,4R,8bR,2′R)-2 (solanacol),18) and (+)-9 was converted to (3aS,4S,8bS,2′R)-2 (ent-2′-epi-solanacol) and (3aS,4S,8bS,2′S)-2 (ent-solanacol). In conclusion, we accomplished a new and concise synthesis of solanacol by employing enzymatic resolution as a key step. A bioassay using our synthetic samples is now in preparation, which will allow the clarification of the structure–activity relationships
Scheme 1.
Synthetic plan for solanacol.
between stereoisomers of solanacol and seeds of root parasitic weeds.
Experimental General procedures. IR spectra were measured with a Thermo Scientific Nicolet iS5 spectrometer. 1H NMR spectra were recorded at 300 MHz with a Jeol JNM-AL300 spectrometer. TMS or the residual solvent peak in CDCl3 (at δH = 7.26) was used as the internal standard. 13C NMR spectra were recorded at 75 MHz with the Jeol JNM-AL300 spectrometer, the peak for CDCl3 (at δC = 77.0) being used as the internal standard. Optical rotations were taken with a HORIBA SEPA-300 polarimeter. Mass spectra were measured with a Jeol JMS-SX102A spectrometer or a Thermo Scientific LTQ Orbitrap Discovery instrument. 1-(2,3-Dimethylphenyl)prop-2-en-1-ol (4). To an ice cooled solution of 3 (5.00 g, 37.3 mmol) in THF (30 mL), vinylmagnesium bromide (1.0 M in THF; 43 mL, 43 mmol) was added under Ar. After stirring at 0 °C for 3 h, the reaction mixture was quenched with sat. NH4Cl aq. and extracted with Et2O. The organic layer was washed with water, sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 4 (5.99 g, 99%). IR (ATR): 3355 (O–H) cm−1. NMR δH (CDCl3): 2.24 (3H, s, CH3), 2.30 (3H, s, CH3), 2.81 (1H, br, OH), 5.18 (1H, d, J = 10.2 Hz, 3-H), 5.29 (1H, d, J = 17.1 Hz, 3-H), 5.41 (1H, d, J = 5.4 Hz, 1-H), 6.04 (1H, ddd, J = 17.1, 10.2, 5.4 Hz, 2-H), 7.07–7.14 (2H, m, Ar–H), 7.30 (1H, br d, J = 6.3 Hz, Ar–H). NMR δC (CDCl3): 14.6, 20.5, 72.1, 114.9, 123.7, 125.6, 129.2, 133.9, 136.9, 139.6, 140.3. HRESIMS m/z [M-OH]+: calcd. for C11H13,145.0012; found, 145.0011. 1-(2,3-Dimethylphenyl)prop-2-en-1-one (5). To a solution of IBX (10.7 g, 38.1 mmol) in DMSO (50 mL), a solution of 4 (4.12 g, 25.4 mmol) in DMSO (50 mL) was added. After stirring at room temperature for 1.5 h, the reaction mixture was diluted with water and filtered. The filtrate was extracted with EtOAc-hexane (ca. 1:1). The organic layer was washed with
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Scheme 2. Synthesis of solanacol. Notes: Reagents and conditions: (a) CH2=CHMgBr, THF (99%); (b) IBX, DMSO (95%); (c) CF3SO3H (92%); (d) NaH, CO(OMe)2, DMF then BrCH2CO2Et; (e) 6 M HCl, AcOH (83% in 2 steps); (f) NaBH4, EtOH then dil. HCl (93%); (g) NBS, AIBN, CCl4 then CaCO3 aq. (60% for 9; 21% for 9′); (h) Chirazyme L-2, CH2=CHOAc, toluene [47% for (+)-9, 47% for (−)-10]; (i) K2CO3, MeOH (98%); (j) t-BuOK, HCO2Et, THF then 4-bromo-2-methyl-2-buten-4-olide (27% for 2′-epi-solanacol, 26% for solanacol, 29% for ent-2′-epi-solanacol, and 28% for ent-solanacol).
water, sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 5 (3.87 g, 95%). This was immediately used for the next step. IR (ATR): 1660 (C=O) cm−1. NMR δH (CDCl3): 2.25 (3H, s, CH3), 2.31 (3H, s, CH3), 6.04 (1H, dd, J = 10.5, 1.2 Hz, 3-H), 6.08 (1H, dd, J = 17.4, 1.2 Hz, 3-H), 6.71 (1H, dd, J = 10.5, 17.4 Hz, 2-H), 7.10–7.30 (3H, m, Ar–H), NMR δC (CDCl3): 16.3, 19.9, 124.9, 125.4, 131.5, 131.6, 134.5, 137.1, 137.7, 138.7, 198.0.
6,7-Dimethylindan-1-one (6). A solution of 5 (535 mg, 3.34 mmol) in CF3SO3H (25 g) was stirred at room temperature for 3 days. The reaction mixture was diluted with ice water and extracted with CH2Cl2. The organic layer was washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 6 (492 mg, 92%) as yellow solid. This was recrystallized from hexane to afford pale yellow needles. Mp: 41 °C. IR (ATR): 1696 (C=O) cm−1. NMR δH (CDCl3): 2.30 (3H, s, 6-CH3), 2.59 (3H, s, 7-CH3), 2.61–2.68 (2H, m, 2-H2), 3.01 (2H, br t, J = 6.0 Hz, 3-H2), 7.17 (1H, d, J = 7.8 Hz, 5-H), 7.32 (1H, d, J = 7.8 Hz, 4-H). NMR δC (CDCl3): 13.5, 18.9, 24.6, 37.3, 123.4, 134.2, 135.7, 136.1, 137.2, 153.7, 208.4.
(6,7-Dimethyl-1-oxoindan-2-yl)acetic acid (7). To a mixture of NaH (55%; 113 mg, 2.60 mmol) and CO (OMe)2 (0.40 mL, 4.1 mmol) in DMF (2 mL), a solution of 6 (166 mg, 1.04 mmol) in DMF (5 mL) was added slowly at 70 °C under Ar. After stirring for 1 h, BrCH2CO2Et (0.20 mL, 1.8 mmol) was added, and the stirring was continued for 1 h at 70 °C. The reaction mixture was quenched with 1 M HCl and extracted with toluene. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give the diester. This was then dissolved into 6 M HCl (40 mL) and AcOH (40 mL), and the mixture was heated under reflux for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from EtOH to give 7 (187 mg, 83% in 2 steps). Mp: 182 °C. IR (ATR): 1699 (C=O), 1685 (C=O) cm−1. NMR δH (CDCl3): 2.31 (3H, s, 6-CH3), 2.61 (3H, s, 7-CH3), 2.60–2.67 (1H, m, 1′-H), 2.79 (1H, dd, J = 16.8, 4.5 Hz, 3-H), 2.94–3.07 (2H, m, 2- and 1′-H), 3.37 (1H, dd, J = 16.8, 7.8 Hz, 3-H), 7.17 (1H, d, J = 7.8 Hz, 5-H), 7.36 (1H, d, J = 7.8 Hz, 4-H). NMR δC (CDCl3): 13.7, 19.0, 32.0, 35.2, 44.1, 123.3, 133.3, 136.3, 136.5, 137.6, 151.6, 177.4, 208.0. HRESIMS m/z [M+H]+: calcd. for C13H15O3, 219.1016; found, 219.1017.
Synthesis of optically active solanacol *
*
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(3aS ,8bR )-7,8-Dimethyl-3,3a,4,8b-tetrahydroindeno [1,2-b]furan-2-one (8). To a solution of 7 (1.92 g, 8.79 mmol) in EtOH (40 mL), NaBH4 (0.87 g, 21 mmol) was added portionwise at 0 °C. After stirring overnight at room temperature, EtOH was removed under reduced pressure. The resulting mixture was diluted with 2-M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give 8 (1.65 g, 93%). This was recrystallized from CH2Cl2 to afford pale yellow needles. Mp: 84 °C. IR (ATR): 1756 (C=O) cm−1. NMR δH (CDCl3): 2.27 (3H, s, 7-CH3), 2.33 (3H, s, 8CH3), 2.43 (1H, dd, J = 18.0, 4.8 Hz, 3-H), 2.84 (1H, br d, 4-H), 2.92 (1H, dd, J = 18.0, 9.6 Hz, 3-H), 3.21– 3.41 (2H, m), 5.96 (1H, d, J = 6.9 Hz, 8b-H), 6.99 (1H, d, J = 7.5 Hz, 5-H), 7.15 (1H, d, J = 7.5 Hz, 6-H). NMR δC (CDCl3): 15.4, 19.2, 35.7, 36.8, 37.9, 87.3, 122.0, 131.6, 134.9, 135.5, 137.5, 140.1, 177.0. (±)-(3aR*,4R*,8bR*)-4-Hydroxy-7,8-dimethyl-3,3a,4, 8b-tetrahydroindeno[1,2-b]furan-2-one [(±)-9]. To a solution of 8 (112 mg, 0.555 mmol) in CCl4 (20 mL), NBS (0.11 g, 0.61 mmol) and AIBN (9.0 mg, 56 μmol) were added. After stirring under reflux for 3 h, the reaction mixture was cooled and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the crude products, which was immediately dissolved into acetone–EtOH–H2O (1:1:1; 15 mL). To this solution was added CaCO3 (0.16 g, 1.6 mmol), and the stirring was continued overnight at room temperature. After removal of organic solvents under reduced pressure, the resulting mixture was diluted with 2-M HCl and extracted with EtOAc. The organic layer was washed brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give (±)-9 (72 mg, 60%) and (±)-9′ (25 mg, 21%). (±)-9: IR (ATR): 3400 (O–H), 1766 (C=O) cm−1. NMR δH (CDCl3): 2.28 (3H, s, 7-CH3), 2.31 (3H, s, 8-CH3), 2.43 (1H, dd, J = 18.3, 5.4 Hz, 3-H), 2.69 (1H, br s, OH), 2.89 (1H, dd, J = 18.3, 10.2 Hz, 3-H), 3.09–3.19 (1H, m, 3a-H), 5.02 (1H, br s, 4-H), 6.04 (1H, d, J = 6.9 Hz, 8b-H), 7.15 (1H, d, J = 7.8 Hz, 5-H), 7.22 (1H, d, J = 7.8 Hz, 6-CH). NMR δC (CDCl3): 15.5, 19.6, 33.3, 47.7, 80.6, 85.6, 122.1, 132.5, 135.5, 137.7, 138.8, 141.7, 176.5. (±)-9′: Mp: 102 °C (from EtOAc). NMR δH (CDCl3): 2.28 (3H, s, Ar-CH3), 2.31 (3H, s, Ar-CH3), 2.62 (1H, dd, J = 18.3, 10.5 Hz, 3-H), 2.93 (1H, dd, J = 18.3, 4.8 Hz, 3-H), 3.37 (1H, m, 3a-H), 5.12 (1H, d, J = 7.5 Hz, 4-H), 5.75 (1H, d, J = 7.2 Hz, 8b-H), 7.19 (1H, d, J = 8.1 Hz, Ar–H), 7.22 (1H, d, J = 8.1 Hz, Ar–H). NMR δC (CDCl3): 15.4, 19.5, 29.0, 42.9, 73.1, 84.5, 122.3, 132.3, 135.0, 137.1, 138.0, 142.3, 177.8. (+)-(3aS,4S,8bS)-4-Hydroxy-7,8-dimethyl-3,3a,4,8btetrahydroindeno[1,2-b]furan-2-one [(+)-9] and (−)(3aR,4R,8bR)-4-Hydroxy-7,8-dimethyl-3,3a,4,8b-tetrahydroindeno[1,2-b]furan-2-one [(−)-10]. To a solution of (±)-9 (98.1 mg, 0.449 mmol) in toluene
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(2 mL), Chirazyme L-2 (34.0 mg) and vinyl acetate (0.20 mL) were added. After stirring at room temperature for 3 days, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the residue, which was chromatographed on SiO2 to give (+)-9 (45.8 mg, 47%) and (−)-10 (54.9 mg, 47%). (+)-9: [α]D25 + 131 (c 1.02, CHCl3). HREIMS m/z [M]+: calcd. for C13H14O3, 218.0943; found, 218.0943. (−)-10: Mp: 151–153 °C. IR (ATR): 1773 (C=O), 1730 (C=O) cm−1. [α]D25 − 49.3 (c 1.03, CHCl3). NMR δH (CDCl3): 2.06 (3H, s, Ac), 2.30 (3H, s, Ar-CH3), 2.34 (3H, s, Ar-CH3), 2.63 (1H, dd, J = 18.6, 6.0 Hz, 3-H), 2.99 (1H, dd, J = 18.6, 10.8 Hz, 3-H), 3.23 (1H, m, 3a-H), 5.96 (1H, br s, 4-H), 6.09 (1H, d, J = 7.2 Hz, 8b-H), 7.17 (1H, d, J = 7.8 Hz, 6-H), 7.23 (1H, d, J = 7.8 Hz, 5-H). NMR δC (CDCl3): 15.4, 19.5, 21.0, 33.1, 45.1, 82.0, 85.2, 123.2, 132.4, 135.3, 137.5, 138.8, 139.2, 170.8, 176.0. HREIMS m/z [M]+: calcd. for C15H16O4, 260.1049; found, 260.1046. Determination of the enantiomeric purities of (+)-9 and (−)-10. The enantiomeric purities of (+)-9 and (−)-10 were estimated by HPLC analysis [column: Daicel Chiralcel® OD-H 250 mm X 4.6 mm; eluent: hexane/2-propanol = 5:1; flow rate 0.5 mL/min; detection: at 254 nm]: (+)-9: tR/min 30.1 [>99%, (+)-9], 28.5 [~0%, (−)-9]. The enantiomeric purity of (+)-9 was estimated to be >99% ee. (−)-10: tR/min 25.6 [>99%, (−)-10], 22.2 [~0%, (+)-10]. The enantiomeric purity of (−)-10 was estimated to be >99% ee. (−)-(3aS,4S,8bS)-7,8-Dimethyl-4-hydroxy-3,3a,4,8btetrahydroindeno[1,2-b]furan-2-one [(−)-9]. To a solution of (−)-10 (45.0 mg, 0.173 mmol) in MeOH (5 mL), K2CO3 (34 mg, 1.4 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with 2-M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was chromatographed on SiO2 to give (−)-9 (37.2 mg, 0.170 mmol, 98%) as a colorless oil. However, after long storage in the refrigerator, we found that (−)-9 crystallized in colorless needles. Mp: 83 °C. [α]D27 − 148 (c 1.06, CHCl3). HREIMS m/z [M]+: calcd. for C13H14O3, 218.0943; found, 218.0939. It should be noted that we were not successful in crystallizing (+)-9.
2′-epi-Solanacol [(3aR,4R,8bR,2′S)-2] and solanacol [(3aR,4R,8bR,2′R)-2]. To a solution of (−)-9 (44.7 mg, 0.205 mmol) in THF (1 mL) were added t-BuOK (114 mg, 1.02 mmol) and HCO2Et (0.15 g, 2.0 mmol) at −78 °C under Ar. After removal of the cooling bath, it was stirred for 6 h. To this mixture, 4-bromo-2-methyl-2-buten-4-olide (56.6 mg, 0.320 mmol) was added at -78 °C. After stirring for 12 h with warming to room temperature, it was then quenched with 1-M HCl and extracted with EtOAc. The organic layer was washed with sat. NaHCO3 aq. and brine, dried (MgSO4), and concentrated under
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reduced pressure. The residue was chromatographed on SiO2 to give 2′-epi-solanacol [(3aR,4R,8bR,2′S)-2] (less polar; 18.8 mg, 27%; Rf = 0.38, hexane: EtOAc = 1:2) and solanacol [(3aR,4R,8bR,2′R)-2] (more polar; 18.3 mg, 26%; Rf = 0.25, hexane: EtOAc = 1:2). 2′-epi-Solanacol: [α]D23 = −207 (c 0.42, CHCl3). NMR δH (CDCl3): 2.05 (3H, s, 4′-CH3), 2.30 (3H, s, 7-CH3), 2.36 (3H, s, 8-CH3), 3.81 (1H, ddd, J = 7.5, 2.7, and 1.8 Hz, 3a-H), 5.27 (1H, s, 4-H), 6.14 (1H, d, J = 7.5 Hz, 8b-H), 6.25 (1H, br s, 2′-H), 7.00 (1H, br s, 3′-H), 7.17 (1H, d, J = 7.8 Hz, 6-H), 7.24 (1H, d, J = 7.8 Hz, 5-H), 7.55 (1H, d, J = 2.4 Hz, 9-H). NMR δC (CDCl3): 10.8, 15.6, 19.6, 50.4, 80.0, 84.1, 100.4, 110.6, 122.3, 132.6, 135.4, 136.3, 138.0, 138.7, 140.9, 141.6, 151.4, 170.1, 170.9. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089. Solanacol: [α]D23 = −213 (c 0.36, CHCl3). NMR δH (CDCl3): 2.04 (3H, br s, 4′-CH3), 2.30 (3H, s, 7-CH3), 2.35 (3H, s, 8-CH3), 3.81 (1H, ddd, J = 7.5, 2.7, and 1.8 Hz, 3a-H), 5.24 (1H, s, 4-H), 6.14 (1H, d, J = 7.5 Hz, 8b-H), 6.23 (1H, t, J = 1.5 Hz, 2′-H), 6.99 (1H, t, J = 1.5 Hz, 3′-H), 7.16 (1H, d, J = 7.8 Hz, 6-H), 7.24 (1H, d, J = 7.8 Hz, 5-H), 7.55 (1H, d, J = 2.7 Hz, 9-H). NMR δC (CDCl3): 10.8, 15.6, 19.6, 50.3, 79.9, 84.1, 100.6, 110.5, 122.4, 132.7, 135.4, 136.1, 138.0, 138.7, 141.0, 141.6, 151.7, 170.2, 170.9. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089. ent-2′-epi-Solanacol [(3aS,4S,8bS,2′R)-2] and entsolanacol [(3aS,4S,8bS,2′S)-2]. In the same manner as described above, (+)-9 (45.4 mg, 0.208 mmol) was converted to ent-2′-epi-solanacol [(3aS,4S,8bS,2′R)-2] (less polar; 20.7 mg, 29%; Rf = 0.38, hexane: EtOAc = 1:2) and ent-solanacol [(3aS,4S,8bS,2′S)-2] (more polar; 19.7 mg, 28%; Rf = 0.25, hexane: EtOAc = 1:2). ent-2′-epi-Solanacol: [α]D23 = +201 (c 0.20, CHCl3). NMR data were identical to those of 2′-epi-solanacol. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1103. ent-Solanacol: [α]D23 = +227 (c 0.24, CHCl3). NMR data were identical to those of solanacol. HREIMS m/z [M]+: calcd. for C19H18O6, 342.1103; found, 342.1089.
Acknowledgments We thank Ms Chiaki Kawasaki (Kobe University) for her contribution to this work.
Disclosure statement No potential conflict of interest was reported by the authors.
Funding This research was financially supported by a Grant-in-Aid for Scientific Research from JSPS [No. 25450152] and JST/ JICA SATREPS.
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