2016 Volume 64 Issue 7 Pages 772-777
Enantioselective total synthesis of the proposed structure of furan-containing polyketide was accomplished. The key features include a chemo- and enantioselective epoxidation of 1,4-cyclohexadiene by Shi asymmetric epoxidation, a regioselective epoxide ring opening, chemo- and diastereoselective dihydroxylation of the conjugated dienone derivative, and vinylation of the lactone accompanied by formation of the furan ring.
Fungi produce many kinds of metabolites such as terpenes, alkaloids, and polyketides, which are rich sources for new drug candidates.1–3) Fungal polyketides possess various biological activities and their attractive structures, such as macrolides, polyethers, and aromatic compounds, are classified as polyketides.4–6) In 1997, a novel polyketide 1, possessing inhibitory activity of intercellular adhesion molecule-1 (ICAM-1) expression, was isolated from Phialomyces macrosporus MCI3226.7) From this report, the structure of polyketide 1 was proposed, having a dihydroisobenzofuranone skeleton involving an aromatic furan ring as depicted in Fig. 1. Recently, a polyketide 2 exhibiting anti-proliferative activity against human non-small cell lung cancer A549 cells was isolated from Aspergillus nidulans, and named asperfuranone.8–11) Its structure also was proposed to contain a dihydroisobenzofuranone skeleton involving an aromatic furan ring as in polyketide 1. In the anti-proliferative activity of asperfuranone (2), the Fas/FasL apoptotic system plays an important role.9) To our knowledge, there have been no synthetic studies of these polyketides consisting of the dihydroisobenzofuranone skeleton and side chain to date. The structural features and biological activities of these two polyketides 1 and 2 attracted our attention, and synthetic studies of these dihydroisobenzofuranone polyketides based on a divergent synthetic methodology using a key intermediate were started. Very recently, we reported the total synthesis of the proposed structure of polyketide 1 in racemic form, and suggested that the proposed structure of natural polyketide from Phialomyces macrosporus required revision.12) This report describes the stereo- and enantioselective synthesis of the proposed structure of polyketide 1 using a key intermediate having a dihydroisobenzofuranone skeleton.
The synthetic strategy for this dihydroisobenzofuranone polyketide 1 is outlined in Chart 1. Target polyketide could be synthesized by the installation of the corresponding side chain to the Weinreb amide 3,13,14) which is the key intermediate, followed by several transformation steps. The Weinreb amide 3 would be derived from the vinyl furan derivative 4, produced by vinylation of bicyclic lactone 5, accompanied by furan ring formation. The functionalized bicyclic lactone 5 would be constructed from the allyl alcohol 6 in three steps involving protection of the secondary hydroxyl group of 6, chemo- and diastereoselective dihydroxylation, and protection of the resulting dihydroxyl groups. The allyl alcohol 6 would be derived from regioselective epoxide ring opening reaction of epoxide 7, which in turn would be obtained by the chemo- and enantioselective epoxidation of 8 by the Shi asymmetric epoxidation protocol.15–17) The bicyclic compound 8 can be easily prepared by the procedure in our previous report.12)
This synthetic project was started from the introduction of an asymmetric carbon to bicyclic lactone by Shi asymmetric epoxidation as shown in Chart 2. Chemo- and enantioselective epoxidation of 8 with Oxone® and Shi catalyst 9 prepared from D-fructose gave the epoxide 7, which was oxidized selectively at the C5–C6 carbon–carbon double bond in quantitative yield. Enantiomeric excess of the obtained epoxide 7 was measured by chiral HPLC methodology as 87%.18) After purified by recrystallization, enantiomerically pure 7 (99% enantiomeric excess (ee)) was obtained. Regioselective epoxide ring opening reaction of epoxide 7 was achieved after many trials. The use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base at low temperature (4°C) gave the best result to afford the desired secondary allyl alcohol 6 along with a trace amount of the tertiary allyl alcohol. The resulting secondary allyl alcohol 6 was immediately used in the next step, since it was an unstable compound. Protection of the resulting hydroxyl group with a tert-butyldimethylsilyl (TBS) group gave the desired conjugated dienone 10 in 80% yield for two steps. The absolute stereochemistry of the newly formed asymmetric carbon at C6 of 6 was confirmed by the modified Mosher’s method.19,20) Thus, the crude product of allyl alcohol 6 was transformed with (R)- and (S)-α-methoxy-α-trifluoromethylphenylacetyl (MTPA) chlorides to (S)- and (R)-MTPA esters 11 and 12, respectively. From 1H-NMR spectral analysis, the absolute configuration at the C6 asymmetric carbon was determined as R.
Having the desired compound 10 in hand, our aim in this project was the asymmetric synthesis of the key intermediate Weinreb amide 3 as shown in Chart 3. Transformation of 10 to the key compound 3 was carried out using the same protocol as in our previous report on the synthesis of the proposed structure of racemic polyketide 1.12) Diastereoselective dihydroxylation of 10 with osmium tetraoxide gave a mixture of the desired diol 13 and its diastereoisomer in a 10 : 1 ratio in 87% yield. Separation of these diastereomers was accomplished by protection of the resulting dihydroxyl group as an acetonide to afford the desired product 5 and its diastereoisomer 14 in 71 and 8% yields, respectively. Formation of the furan ring having a vinyl group was achieved by treatment of the desired lactone 5 with the vinyllithium species prepared from tetravinyltin and methyllithium to give the vinyl furan derivative 4 in 93% yield. Transformation of the vinyl group of 4 to the Weinreb amide group was carried out in three steps: oxidative cleavage of the vinyl group of 4, oxidative esterification21) of the resulting aldehyde 15, and amidation of the ester 16 with N,O-dimethylhydroxylamine hydrochloride and trimethylaluminum,22) to afford the Weinreb amide intermediate 3 in 71% yield over three steps.
With the key intermediate 3 synthesized, we focused our efforts on the synthesis of polyketide having the dihydroisobenzofuranone skeleton. Asymmetric synthesis of the proposed structure of polyketide 1, isolated from Phialomyces macrosporus, was carried out as shown in Chart 4. The synthetic route of polyketide 1 from the Weinreb amide 3 employed approximately the same procedure as in our previous report.12) Alkylation of the Weinreb amide 3 with n-propylmagnesium bromide gave 17 in 82% yield. Treatment of 17 with trifluoroacetic acid (TFA) in CH2Cl2–H2O for 6 h selectively cleaved the acetonide group to afford 18 in 72% yield. After Ley oxidation23,24) of the diol 18 to 19, treatment of the resulting ketone 19 with tetra-n-butylammonium fluoride (TBAF) provided the target compound 1 in 90% yield. Both 1H- and 13C-NMR spectral data were identical with those of the previously synthesized racemic 1.12)
In summary, enantioselective total synthesis of the proposed structure of polyketide 1, isolated from Phialomyces macrosporus, was achieved. The key features include a chemo- and enantioselective epoxidation of 1,4-cyclohexadiene by Shi asymmetric epoxidation, a regioselective epoxide ring opening, chemo- and diastereoselective dihydroxylation of the conjugated dienone derivative, and vinylation of the lactone accompanied by formation of a furan ring. This synthetic methodology will be useful for the synthesis of related polyketide asperfuranone (2) isolated from Aspergillus nidulans, which is currently underway in our laboratory.
All reactions involving air- and moisture-sensitive reagents were carried out using standard syringe-septumcap techniques. Unless otherwise noted, all solvents and reagents were obtained from commercial suppliers and used without further purification. Routine monitoring of reactions were carried out Merck silica gel 60 F254 TLC plates. Column chromatography was performed on Kanto Chemical Silica Gel 60N (spherical, neutral 60–230 µm) with the solvents indicated. Melting points were taken on a Yanako MP-S3 micro melting point apparatus and are uncorrected. 1H- and 13C-NMR spectra were measured with a Burker AV-300 (300 MHz) or a Burker DPX-400 (400 MHz) spectrometer. Chemical shifts were expressed in ppm using CHCl3 (7.26 ppm for 1H-NMR, 77.0 ppm for 13C-NMR) in CDCl3, CH3CN (1.94 ppm for 1H-NMR, 118.3 ppm for 13C-NMR) in CD3CN as internal standard. Infrared spectral measurements were carried out with a Perkin-Elmer Paragon 1000 FT-IR and only noteworthy absorptions were listed. HR-MS spectra was measured on a Micromass LCT spectrometer. X-ray crystallographic analysis was taken with Burker APEX2 Ultra TXS.
(1aR,6aS)-6a-Methyl-1a,2,6,6a-tetrahydrooxireno[2,3-f]isobenzofuran-3(5H)-one (7)To a stirred solution of 8 (500 mg, 3.33 mmol), tetra-n-butylammonium hydrosulfate (45.2 mg, 0.133 mmol) and ketone 9 (258 mg, 0.999 mmol) in CH3CN–DMM [formaldehyde dimethylacetal]–0.05 M sodium tetraborate in 0.4 mM disodium ethylenediaminetetraacetate (Na2EDTA) aqueous solution (1 : 2 : 2, 83 mL) were added dropwise simultaneously, a solution of Oxone® (2.83 g, 4.66 mmol) in 0.4 mM Na2EDTA aqueous solution (23 mL) and a solution of K2CO3 (2.67 g, 19.3 mmol) in 0.4 mM Na2EDTA aqueous solution (23 mL) by using the syringe pump (0.24 mL/min) at 0°C under Ar. After stirred for 2 h at 0°C, the reaction was quenched with H2O, and extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 1 : 1) to afford 7 (545 mg, 98, 87% ee) as white crystalls. Recrystallization from CHCl3–hexane gave the optically pure 7 (99% ee) as colorless needles. [α]D20+32.5 (c=1.0, CHCl3). mp: 90–93°C (CHCl3–hexane). IR (KBr) cm−1: 2982, 2925, 2908, 1766, 1758, 1755, 1746, 1692, 1445, 1433, 1413, 1352, 1342, 1276, 1202, 1151, 1087. 1H-NMR (400 MHz, CDCl3) δ: 1.48 (3H, d, J=2.8 Hz), 2.57–2.71 (2H, m), 2.75–2.92 (2H, m), 3.25–3.28 (1H, s), 4.57–4.73 (2H, m). 13C-NMR (100 MHz, CDCl3) δ: 21.9, 22.6, 29.5, 56.6, 57.9, 71.4, 121.8, 156.1, 173.3. High resolution (HR)-MS (electrospray ionization-time-of flight (ESI-TOF)) Calcd for C9H10O3Na [M+Na]+ 189.0528. Found 189.0526.
(R)-6-(tert-Butyldimethylsilyloxy)-5-methyl-6,7-dihydroisobenzofuran-1(3H)-one (10)To a stirred solution of 7 (420 mg, 2.53 mmol) in THF (25 mL) was added dropwise DBU (0.385 mL, 380 mg, 2.53 mmol) at 4°C, and the reaction mixture was stirred for 68 h at 4°C. The reaction mixture was quenched with H2O, and extracted with AcOEt. The combined organic layers was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was dissolved in N,N-dimethylformamide (DMF) (2.3 mL), and imidazole (413 mg, 6.07 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (458 mg, 3.04 mmol) were added in sequence to this reaction mixture at 0°C. After stirred for 1 h at 0°C, H2O was added to this reaction mixture at 0°C, and the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 1 : 1) to afford 10 (570 mg, 80% for 2 steps) as a colorless oil. [α]D20+141.5 (c=1.1, CHCl3). mp: 67–68°C (CHCl3–hexane). IR (KBr) cm−1: 2953, 2929, 2886, 2857, 1754, 1746, 1661, 1606, 1472, 1445, 1346, 1253, 1110, 1020, 1006. 1H-NMR (400 MHz, CDCl3) δ: 0.09 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 1.98 (3H, s), 2.47–2.57 (1H, m), 2.60–2.70 (1H, m), 4.45–4.51 (1H, m), 4.70–4.82 (2H, m), 5.94 (1H, s). 13C-NMR (100 MHz, CDCl3) δ: –4.9, –4.4, 18.0, 20.9, 25.7 (3C), 28.0, 69.6, 69.7, 114.5, 119.9, 150.1, 155.9, 173.4. HR-MS (ESI-TOF) Calcd for C15H24O3SiNa [M+Na]+ 303.1392. Found 303.1391.
(S)-[(R)-6-Methyl-3-oxo-1,3,4,5-tetrahydroisobenzofuran-5-yl]-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate (11)To a stirred solution of 6 (20.0 mg, 0.120 mmol) in CH2Cl2 (1.2 mL) was added pyridine (0.120 mL, 1.20 mmol) and 4-dimethylaminopyridine (1.47 mg, 12.0 µmol), and (R)-(–)-MTPA chloride (45.0 µL, 60.6 µg, 0.240 mmol) in 0°C. After stirred for 3 h at room temperature, the reaction was quenched with 1 M HCl aqueous solution, and extracted with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 3 : 1) to afford 11 (30.3 mg, 66%) as a colorless oil. [α]D20+137.6 (c=0.34, CHCl3). IR (neat) cm−1: 2948, 2850, 1755, 1610, 1450, 1351, 1270, 1250, 1169, 1122, 1013. 1H-NMR (400 MHz, CDCl3) δ: 1.86 (3H, s), 2.79–2.91 (2H, m), 3.49 (3H, s), 4.74–4.84 (2H, m), 5.78 (1H, dd, J=6.5, 6.5 Hz), 6.14 (1H, s), 7.31–7.61 (5H, m). 13C-NMR (100 MHz, CDCl3) δ: 20.8, 24.8, 55.4, 69.7, 71.7, 84.5 (q, J=27.9 Hz), 118.6, 119.4, 123.1 (q, J=289.0 Hz), 127.0 (2C), 128.5 (2C), 129.7, 131.8, 142.1, 155.4, 166.0, 172.4. HR-MS (ESI-TOF) Calcd for C19H17F3O5Na [M+Na]+ 405.0926. Found 405.0932.
(R)-[(R)-6-Methyl-3-oxo-1,3,4,5-tetrahydroisobenzofuran-5-yl]-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoate (12)To a stirred solution of 6 (20.0 mg, 0.120 mmol) in CH2Cl2 (1.2 mL) was added pyridine (0.120 mL, 1.20 mmol) and 4-dimethylaminopyridine (1.47 mg, 12.0 µmol), and (S)-(+)-MTPA chloride (45.0 µL, 60.6 µg, 0.240 mmol) in 0°C. After stirred for 3 h at room temperature, the reaction was quenched with 1 M HCl aqueous solution, and extracted with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 3 : 1) to afford 12 (21.1 mg, 46%) as a colorless oil. [α]D20+158.3 (c=0.04, CHCl3). IR (neat) cm−1: 2949, 2849, 1753, 1745, 1611, 1450, 1350, 1270, 1250, 1168, 1121, 1015. 1H-NMR (400 MHz, CDCl3) δ: 2.02 (3H, s), 2.70–2.88 (2H, m), 3.49 (3H, s), 4.76–4.79 (2H, m), 5.79 (1H, dd, J=7.3, 5.5 Hz), 6.19 (1H, s), 7.27–7.50 (5H, m). 13C-NMR (100 MHz, CDCl3) δ: 21.2, 24.6, 55.4, 69.7, 71.7, 84.7 (q, J=27.9 Hz), 118.6, 119.7, 123.1 (q, J=288.0 Hz), 127.1 (2C), 128.5 (2C), 129.8, 131.7, 141.7, 154.9, 166.0, 172.4. HR-MS (ESI-TOF) Calcd for C19H17F3O5Na [M+Na]+ 405.0926. Found 405.0933.
(4R,5R,6R)-6-(tert-Butyldimethylsilyloxy)-4,5-dihydroxy-5-methyl-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one (13)To a stirred solution of 10 (1.02 g, 3.63 mmol) and 4-methylmorpholine N-oxide (469 mg, 4.00 mmol) in acetone–H2O (4 : 1, 36 mL) was added dropwise osmium tetraoxide (4% in H2O, 0.462 mL, 0.0727 mmol) at 0°C, and the mixture was stirred for 1 h at 0°C. The reaction was quenched with sat. Na2S2O3 aqueous solution, and extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 1 : 1) to afford 13 and its diastereomer (0.996 g, 87%) as a separable mixture in ratio of 10 : 1 as wihte crystals. Recrystallization of the 13, obtained with difficulty, from CHCl3–hexane gave 13 as colorless needles.
Data for 13[α]D20–61.8 (c=1.0, CHCl3). mp: 142–144°C. IR (KBr) cm−1: 3433, 2952, 2929, 2886, 2857, 1738, 1732, 1682, 1470, 1462, 1350, 1257, 1219, 1077, 1020. 1H-NMR (400 MHz, CDCl3) δ: 0.05 (3H, s), 0.08 (3H, s), 0.82 (9H, s), 1.32 (3H, s), 2.15 (1H, br d, J=17.6 Hz), 2.62 (1H, br d, J=17.6 Hz), 2.79 (1H, s), 3.35 (1H, d, J=7.5 Hz), 3.99–4.02 (1H, m), 4.34 (1H, d, J=6.9 Hz), 4.79 (1H, br d, J=17.6 Hz), 4.93 (1H, br d, J=17.6 Hz). 13C-NMR (100 MHz, CDCl3) δ: –5.0, –4.4, 17.7, 21.5, 25.6 (3C), 26.9, 68.8, 71.0, 73.0, 73.4, 125.0, 160.0, 174.2. HR-MS (ESI-TOF) Calcd for C15H26O5SiNa [M+Na]+ 337.1447. Found 337.1448.
(3aR,4R,8bR)-4-(tert-Butyldimethylsilyloxy)-2,2,3a-trimethyl-4,5,8,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6(3aH)-one (5) and (3aS,4R,8bS)-4-(tert-Butyldimethylsilyloxy)-2,2,3a-trimethyl-4,5,8,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6(3aH)-one (14)To a stirred solution of the diastereomeric mixture of 13 (339 mg, 1.08 mmol) in CH2Cl2 (5 mL) were added 2,2-dimethoxypropane (1.32 mL, 1.12 g, 10.8 mmol) and p-toluenesulfonic acid monohydrate (20.5 mg, 0.108 mmol) at room temperature, and the mixture was stirred for 3 h at the same temperature. The reaction was quenched with sat. NaHCO3 aqueous solution, and extracted with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 7 : 1) to afford 5 (271 mg, 71%) as colorless needles, and 14 (28.8 mg, 8%) as colorless needles.
Data for 5[α]D20–15.9 (c=1.0, CHCl3). mp: 97–99°C (CHCl3–hexane). IR (KBr) cm−1: 2987, 2953, 2933, 2886, 2857, 1769, 1689, 1472, 1463, 1380, 1256, 1217, 1196, 1122, 1046, 1015. 1H-NMR (400 MHz, CDCl3) δ: 0.08 (3H, s), 0.10 (3H, s), 0.87 (9H, s), 1.35 (3H, s), 1.37 (3H, s), 1.45 (3H, s), 2.14–2.23 (1H, m), 2.53–2.62 (1H, m), 3.96 (1H, dd, J=7.6, 4.7 Hz), 4.47 (1H, s), 4.74–4.81 (1H, m), 4.93 (1H, ddd, J=17.3, 2.7, 2.7 Hz). 13C-NMR (100 MHz, CDCl3) δ: –4.73, –4.69, 17.9, 19.3, 25.7 (3C), 27.4, 27.6, 28.5, 70.7, 72.5, 75.7, 82.9, 110.8, 127.3, 155.7, 172.6. HR-MS (ESI-TOF) Calcd for C18H31O5Si [M+H]+ 355.1941. Found 355.1942.
Data for 14[α]D20–31.0 (c=1.0, CHCl3). mp: 124–126°C (CHCl3–hexane). IR (KBr) cm−1: 2955, 2932, 2887, 2857, 1765, 1686, 1473, 1463, 1380, 1370, 1258, 1236, 1138, 1105, 1073, 1039, 1020. 1H-NMR (400 MHz, CDCl3) δ: 0.11 (3H, s), 0.13 (3H, s), 0.93 (9H, s), 1.22 (3H, s), 1.48 (3H, s), 1.50 (3H, s), 2.47–2.53 (2H, m), 3.75 (1H, dd, J=8.1, 6.6 Hz), 4.51–4.54 (1H, br s), 4.69–4.76 (1H, m), 4.87–4.94 (1H, m). 13C-NMR (100 MHz, CDCl3) δ: –4.8, –4.3, 18.1, 23.4, 25.6, 25.8 (3C), 28.2, 29.0, 70.0, 73.6, 76.3, 82.9, 111.7, 126.5, 157.6, 172.5. HR-MS (ESI-TOF) Calcd for C18H30O5SiNa [M+Na]+ 377.1760. Found 377.1754.
tert-Butyldimethyl[(3aR,4R,8bR)-2,2,3a-trimethyl-6-vinyl-3a,4,5,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-4-yloxy]silane (4)To a stirred solution of 5 (1.24 g, 3.50 mmol) in Et2O (36 mL) was added dropwise a solution of vinyllithium in Et2O, prepared from tetravinyltin (0.236 mL, 294 mg, 1.29 mmol) and methyllithium (1.14 M in Et2O, 4.60 mL, 5.25 mmol) in Et2O (9.4 mL), at –78°C under Ar, and the mixture was stirred for 2 h at –78°C. The reaction was quenched with sat. NH4Cl aqueous solution, and extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 10 : 1) to afford 4 (1.19 g, 93%) as a colorless oil. [α]D20+15.1 (c=1.0, CHCl3). IR (neat) cm−1: 3101, 2984, 2953, 2931, 2886, 2856, 1647, 1540, 1472, 1462, 1378, 1255, 1215, 1200, 1180, 1121, 1099, 1039. 1H-NMR (300 MHz, CDCl3) δ: 0.07 (3H, s), 0.11 (3H, s), 0.89 (9H, s), 1.31 (3H, s), 1.43 (3H, s), 1.47 (3H, s), 2.35 (1H, dd, J=16.0, 9.7 Hz), 2.78 (1H, dd, J=16.0, 5.1 Hz), 4.02 (1H, dd, J=9.7, 5.1 Hz), 4.86 (1H, s), 5.15 (1H, d, J=11.4 Hz), 5.56 (1H, dd, J=17.5, 0.9 Hz), 6.45 (1H, dd, J=17.5, 11.4 Hz), 7.46 (1H, s). 13C-NMR (75 MHz, CDCl3) δ: –4.7, –4.5, 17.95, 18.00, 25.7 (3C), 27.2, 27.5, 28.7, 72.7, 74.3, 82.9, 109.1, 111.7, 117.1, 120.9, 123.4, 140.3, 147.4. HR-MS (ESI-TOF) Calcd for C20H32O4SiNa [M+Na]+ 387.1968. Found 387.1963.
(3aR,4R,8bR)-4-(tert-Butyldimethylsilyloxy)-2,2,3a-trimethyl-3a,4,5,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-carbaldehyde (15)To a stirred solution of 4 (479 mg, 1.31 mmol) and 2,6-lutidine (0.307 mL, 282 mg, 2.63 mmol) in 1,4-dioxane–H2O (4 : 1, 6.5 mL) were added dropwise osmium tetraoxide (4% in H2O, 0.250 mL, 0.0394 mmol) and sodium periodate (1.41 g, 6.57 mmol) at 0°C, and the mixture was stirred for 3 h at room temperature. The reaction was quenched with sat. Na2S2O3 aqueous solution, and the mixture was extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 10 : 1) to afford 15 (411 mg, 85%) as a colorless oil. [α]D20+20.0 (c=1.2, CHCl3). IR (neat) cm−1: 3142, 3113, 2986, 2952, 2932, 2885, 2855, 2824, 1686, 1681, 1607, 1537, 1472, 1462, 1421, 1371, 1253, 1236, 1216, 1200, 1178, 1126, 1096, 1048, 1029. 1H-NMR (300 MHz, CDCl3) δ: 0.07 (3H, s), 0.11 (3H, s), 0.84 (9H, s), 1.34 (3H, s), 1.38 (3H, s), 1.48 (3H, s), 2.77 (1H, dd, J=17.2, 7.9 Hz), 3.17 (1H, dd, J=17.2, 4.3 Hz), 4.07 (1H, dd, J=7.9, 4.3 Hz), 4.89 (1H, s), 7.71 (1H, s), 9.73 (1H, s). 13C-NMR (75 MHz, CDCl3) δ: –4.7 (2C), 17.9, 19.6, 25.6 (3C), 27.2, 27.6, 28.5, 72.3, 73.5, 82.5, 109.9, 123.5, 131.2, 146.1, 147.6, 178.2. HR-MS (ESI-TOF) Calcd for C19H30O5SiNa [M+Na]+ 389.1760. Found 389.1769.
(3aR,4R,8bR)-Methyl 4-(tert-butyldimethylsilyloxy)-2,2,3a-trimethyl-3a,4,5,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-carboxylate (16)To a stirred solution of 15 (1.35 g, 3.69 mmol) and potassium hydroxide (625 mg, 9.58 mmol) in MeOH (22 mL) was added dropwose a solution of iodine (1.22 g, 4.79 mmol) in MeOH (15 mL) at 0°C, and the mixture was stirred for 16 h at room temperature. The reaction was quenched with 1.0 M HCl aqueous solution, and extracted with AcOEt. The combined organic layers were washed with sat. Na2S2O3 aqueous solution and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 15 : 1) to afford 16 (1.36 g, 93%) as a colorless oil. [α]D20+14.5 (c=1.0, CHCl3). IR (neat) cm−1: 3126, 2986, 2953, 2930, 2886, 2856, 1736, 1715, 1619, 1549, 1472, 1462, 1440, 1408, 1378, 1372, 1325, 1256, 1200, 1122, 1099. 1H-NMR (400 MHz, CDCl3) δ: 0.06 (3H, s), 0.09 (3H, s), 0.84 (9H, s), 1.33–1.35 (6H, br s), 1.46 (3H, s), 2.72 (1H, dd, J=17.2, 8.4 Hz), 3.14 (1H, dd, J=17.2, 4.5 Hz), 3.88 (3H, s), 4.04 (1H, dd, J=8.4, 4.5 Hz), 4.86 (1H, s), 7.62 (1H, s). 13C-NMR (100 MHz, CDCl3) δ: –4.73, –4.66, 17.9, 19.3, 25.6 (3C), 27.5, 28.0, 28.5, 51.7, 72.4, 73.7, 82.5, 109.6, 122.5, 129.6, 138.9, 144.3, 159.4. HR-MS (ESI-TOF) Calcd for C20H32O6SiNa [M+H]+ 419.1866. Found 419.1881.
(3aR,4R,8bR)-4-(tert-Butyldimethylsilyloxy)-N-methoxy-N,2,2,3a-tetramethyl-3a,4,5,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-carboxamide (3)To a stirred solution of N,O-dimethylhydroxylamine hydrochloride (270 mg, 2.77 mmol) in CH2Cl2 (8 mL) was added dropwise trimethylaluminum (1.07 M in hexane, 2.59 mL, 2.77 mmol) at 0°C. To this mixture was added dropwise a solution of 16 (366 mg, 0.924 mmol) in CH2Cl2 (15 mL) at room temperature, and stirred for 40 h at room temperature. The reaction was quenched with sat. potassium sodium tartrate aqueous solution, and extracted with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 10 : 1) to afford 3 (354 mg, 90%) as a pale yellow oil. [α]D20+8.4 (c=1.0, CHCl3). IR (neat) cm−1: 3119, 2955, 2933, 2890, 2856, 1650, 1644, 1634, 1547, 1470, 1462, 1422, 1378, 1255, 1215, 1198, 1181, 1123, 1039. 1H-NMR (400 MHz, CDCl3) δ: 0.06 (3H, s), 0.09 (3H, s), 0.86 (9H, s), 1.33 (3H, s), 1.39 (3H, s), 1.47 (3H, s), 2.68 (1H, dd, J=17.4, 9.2 Hz), 3.21 (1H, dd, J=17.4, 4.7 Hz), 3.31 (3H, s), 3.79 (3H, s), 4.02 (1H, dd, J=9.2, 4.7 Hz), 4.87 (1H, s), 7.56 (1H, s). 13C-NMR (100 MHz, CDCl3) δ: –4.7, –4.6, 18.0, 18.5, 25.7 (3C), 27.4, 28.6, 28.8, 33.9, 62.0, 72.5, 73.9, 82.7, 109.4, 121.8, 129.5, 140.6, 142.4, 160.4. HR-MS (ESI-TOF) Calcd for C21H36NO6Si [M+H]+ 426.2312. Found 426.2317.
1-[(3aR,4R,8bR)-4-tert-Butyldimethylsilyloxy-2,2,3a-trimethyl-3a,4,5,8b-tetrahydro-[1,3]dioxolo[4,5-e]isobenzofuran-6-yl]butan-1-one (17)To a stirred solution of 3 (248 mg, 0.583 mmol) in THF (6 mL) was added n-propylmagnesium bromide (1.02 M in THF, 1.71 mL, 1.75 mmol) at 0°C under Ar. After stirred for 1 h at 0°C, the reaction was quenched with sat. NH4Cl aqueous solution, and extracted with AcOEt. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 10 : 1) to afford 17 (195 mg, 82%) as a colorless oil. [α]D18 +4.8 (c=0.10, CHCl3). IR (neat) cm−1: 3116, 2958, 2933, 2886, 2858, 1674, 1607, 1537, 1463, 1411, 1372, 1256. 1H-NMR (300 MHz, CDCl3) δ: 0.06 (3H, s), 0.10 (3H, s), 0.85 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.34 (3H, s), 1.37 (3H, s), 1.47 (3H, s), 1.72 (2H, qt, J=7.4, 7.4 Hz), 2.73 (1H, dd, J=17.6, 8.7 Hz), 2.79 (2H, td, J=7.4, 2.0 Hz), 3.22 (1H, dd, J=17.6, 4.7 Hz), 4.03 (1H, dd, J=8.7, 4.7 Hz), 4.87 (1H, s), 7.57 (1H, s); 13C-NMR (75 MHz, CDCl3) δ: –4.7, –4.6, 13.8, 17.3, 17.9, 19.0, 25.7 (3C), 27.5, 28.6 (2C), 40.8, 72.4, 73.8, 82.5, 109.6, 123.0, 128.3, 143.2, 147.5, 191.2. HR-MS (ESI-TOF) Calcd for C22H36O5SiNa [M+Na]+ 431.2230. Found 431.2222.
1-[(4R,5R,6R)-6-tert-(Butyldimethylsilyloxy)-4,5-dihydroxy-5-methyl-4,5,6,7-tetrahydroisobenzofuran-1-yl]butan-1-one (18)To a stirred solution of 17 (153 mg, 0.374 mmol) in CH2Cl2–H2O (4 : 1, 3.75 mL) was added dropwise TFA (0.75 mL) at 0°C, and the mixture was stirred for 6 h at room temperature. The reaction was quenched with 28% ammonia aqueous solution at 0°C, and extracted with with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 10 : 1) to afford 18 (99.7 mg, 72%) as a white powder. [α]D20–11.2 (c=0.44, CHCl3). mp 123–125°C. IR (KBr) cm−1: 3436, 3144, 2957, 2932, 2885, 2858, 1652, 1604, 1532, 1472, 1463, 1408, 1258, 1087. 1H-NMR (300 MHz, CDCl3) δ: 0.127 (3H, s), 0.133 (3H, s), 0.90 (9H, s), 0.98 (3H, t, J=7.4 Hz), 1.20 (3H, s), 1.72 (2H, qt, J=7.4, 7.4 Hz), 2.47 (1H, s), 2.71 (1H, dd, J=18.2, 8.1 Hz), 2.79 (2H, t, J=7.4 Hz), 2.84 (1H, d, J=3.2 Hz), 3.31 (1H, dd, J=18.2, 5.4 Hz), 4.21 (1H, dd, J=8.1, 5.4 Hz), 4.64 (1H, d, J=3.2 Hz), 7.56 (1H, s). 13C-NMR (75 MHz, CDCl3) δ: –4.9, –4.2, 13.9, 17.3, 17.9, 19.7, 25.7 (3C), 29.1, 40.7, 67.3, 71.3, 73.9, 126.0, 128.0, 143.1, 147.6, 191.2. HR-MS (ESI-TOF) Calcd for C19H33O5Si [M+H]+ 369.2097. Found 369.2089.
(5S,6R)-6-(tert-Butyldimethylsilyloxy)-1-butyryl-5-hydroxy-5-methyl-6,7-dihydroisobenzofuran-4(5H)-one (19)To a stirred suspension of 18 (50.6 mg, 0.137 mmol), 4-methylmorpholine N-oxide (48.3 mg, 0.412 mmol) and molecular sieves 4 Å (500 mg) in CH2Cl2 (7 mL) was added tetra-n-propylammonium perruthenate (TPAP, 4.83 mg, 0.0137 mmol), and the mixture was stirred for 2 h at room temperature. After the mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo. The resulted residue was purified by column chromatography (hexane–AcOEt, 15 : 1) to afford 19 (36.1 mg, 72%) as a white powder. [α]D20–39.0 (c=1.0, CHCl3). mp 87–89°C. IR (KBr) cm−1: 3478, 3136, 2930, 2856, 1694, 1682, 1668, 1592, 1531, 1470, 1463, 1403, 1372, 1293, 1257, 1191. 1H-NMR (400 MHz, CDCl3) δ: 0.09 (3H, s), 0.12 (3H, s), 0.90 (9H, s), 0.99 (3H, t, J=7.4 Hz), 1.31 (3H, s), 1.74 (2H, qt, J=7.4, 7.4 Hz), 2.79–2.84 (2H, m), 2.86 (1H, dd, J=18.0, 9.8 Hz), 3.19–3.28 (1H, br s), 3.46 (1H, dd, J=18.0, 5.4 Hz), 4.08 (1H, dd, J=9.8, 5.4 Hz), 8.06 (1H, s). 13C-NMR (100 MHz, CDCl3) δ: –4.9, –4.7, 13.8, 17.0, 18.1, 18.3, 25.7 (3C), 29.1, 41.0, 74.1, 78.5, 123.6, 128.5, 146.0, 148.4, 191.1, 195.8. HR-MS (ESI-TOF) Calcd for C19H31O5Si [M+H]+ 367.1941. Found 367.1940.
(5S,6R)-1-Butyryl-5,6-dihydroxy-5-methyl-6,7-dihydroisobenzofuran-4(5H)-one (Proposed 1)To a stirred solution of 19 (56.2 mg, 0.153 mmol) in THF (1.5 mL) was added dropwise TBAF (1.0 M in THF, 0.307 mL, 0.307 mmol) at 0°C, and the mixture was stirred for 1 h at 0°C. The reaction was quenched with H2O at 0°C, and extracted with with CHCl3. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by column chromatography (hexane–AcOEt, 5 : 1) to afford 1 (35.0 mg, 90%) as colorless needles. [α]D20–14.8 (c=0.50, MeOH). mp 84–87°C (AcOEt). IR (KBr) cm−1: 3398, 2965, 1700, 1669, 1636, 1591, 1560, 1527, 1508, 1458, 1405, 1961. 1H-NMR (400 MHz, CD3CN) δ: 0.94 (3H, t, J=7.4 Hz), 1.28 (3H, s), 1.61–1.70 (2H, m), 2.79 (2H, t, J=7.3 Hz), 2.86 (1H, dd, J=17.7, 8.2 Hz), 3.36 (1H, dd, J=17.7, 4.8 Hz), 3.45–3.53 (1H, br s), 3.80–3.88 (1H, br s), 4.04 (1H, dd, J=8.2, 4.8 Hz), 8.16 (1H, s). 13C-NMR (100 MHz, CD3CN) δ: 14.0, 17.6, 18.4, 28.2, 41.7, 74.1, 78.2, 124.9, 129.5, 147.6, 149.4, 191.5, 195.7. HR-MS (ESI-TOF) Calcd for C13H16O5Na [M+H]+ 275.0895. Found 275.0901.
This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
The authors declare no conflict of interest.
