Total Synthesis of (+)-Pyrenolide D - The Journal of Organic Chemistry

Sep 14, 2018 - The spiro-γ-lactone derivative was then used in an efficient total synthesis of (+)-pyrenolide D. The developed chemistry paves the wa...
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Total Synthesis of (+)-Pyrenolide D Yuya Ogawa, Marina Kato, Ikuo Sasaki, and Hideyuki Sugimura* Department of Chemistry and Bioscience, Faculty of Science and Technology, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku, Sagamihara 252-5258, Japan

J. Org. Chem. 2018.83:12315-12319. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/05/18. For personal use only.

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ABSTRACT: An efficient approach to stereoselective construction of a spiro-γ-lactone core structure via BF3-promoted formal [3 + 2] annulation of aldehydo-aldose derivatives with γ-methylene-γ-butyrolactone has been developed. The spiro-γlactone derivative was then used in an efficient total synthesis of (+)-pyrenolide D. The developed chemistry paves the way for total synthesis of structurally diverse natural products containing spiro-lactone cores.

T

he phytogenic fungus Pyrenophora teres (Diedicke) Drechsler (IFO 7508) is the source of a number of fungal metabolites with broad spectrum biological activities. Three of these metabolites, pyrenolides A−C, have 10membered keto-lactone structures and exhibit potent growth inhibition and morphogenic activity toward fungi (Figure 1).1

Scheme 1. Synthetic Plan for (+)-Pyrenolide D

Figure 1. Structures of pyrenolides A−D.

A fourth metabolite, pyrenolide D (1), is structurally distinct from the other members of this family and has been isolated from the same fungus.2 It possesses a highly oxygenated tricyclic spiro-γ-lactone structure. Unlike the other pyrenolides, pyrenolide D is not active toward fungi but exhibits cytotoxic activity toward HL-60 cells. Because of its biological activity and interesting structural features, pyrenolide D has attracted interest in chemistry. Three total syntheses of the natural product have been achieved to date,3−5 and each method has used a carbohydratebased starting material as a chiral template.6 As part of our ongoing research on synthesis of natural products based on BF3-promoted formal [3 + 2] annulation of aldehydo-aldoses,7 we report herein an efficient and stereoselective total synthesis of (+)-pyrenolide D using L-arabinose as a chiral template. Our approach for the synthesis of (+)-1 is shown in Scheme 1. We envisaged that the spiro-γ-lactone core 4 could be directly constructed by BF3-promoted formal [3 + 2] annulation of aldehydo-aldoses, using a method previously established in our laboratory. The reaction of aldehyde 2 and γ-methylene-γ-butyrolacone 3 in the presence of BF3·OEt2 could be expected to produce the desirable spiro-γ-lactone 4. © 2018 American Chemical Society

To date, we have used 2,3-O-isopropylidene derivatives of aldehydo-aldoses for the formal [3 + 2] annulation. However, the spiro-acetal moiety of (+)-pyrenolide D is presumably acidsensitive and would not tolerate acidic conditions for removal of the isopropylidene group. In this study, we planned to use the 2,3-O-benzylidene derivative 2, from which the benzylidene group could be removed under neutral hydrogenolysis conditions, although we have not previously used 2,3-Obenzylidene derivatives for this [3 + 2] annulation. If the annulation reaction proceeds as expected to afford the desirable spiro-γ-lactone 4, removal of the TIPS group could be followed by mesylation of the resultant hydroxy group to afford compound 5. Removal of the benzylidene group in 5 could produce the tricyclic spiro-γ-lactone 6 via spontaneous cyclization. Finally, the total synthesis of (+)-1 could be accomplished by introducing the unsaturated bond of the γlactone. Received: August 3, 2018 Published: September 14, 2018 12315

DOI: 10.1021/acs.joc.8b02003 J. Org. Chem. 2018, 83, 12315−12319

Note

The Journal of Organic Chemistry Our approach began with the preparation of the desired aldehyde 2 from L-arabinose dipropyl dithioacetal 7 (Scheme 2). Conversion of L-arabinose derivative 7 into the 2,3-O-

Scheme 3. Synthesis of (+)-Pyrenolide D

Scheme 2. Preparation of Aldehyde 2

benzylidene derivative 8 was achieved using an analogous procedure to that reported for the preparation of the antipode, 2,3-O-benzylidene-D-arabinose dipropyl dithioacetal.8 To remove the terminal hydroxy group of compound 8, selective tosylation of the primary alcohol in diol 8 was accomplished by treatment with TsCl and Et3N in the presence of a catalytic amount of Bu2SnO9 in DCM to afford monotosylate 9 in 98% yield. Reductive detosylation10 of 9 with LiAlH4 in Et2O led to 5-deoxy derivative 10 in 72% yield. Next, the secondary alcohol was protected as the TIPS ether by treating alcohol 10 with TIPSCl in the presence of imidazole in DMF to afford 11 in 93% yield. Hydrolysis of the dithioacetal group in 11 proceeded smoothly by treatment with the I2−NaHCO3 system in acetone−H2O11 to produce the desired aldehyde 2 in quantitative yield. To construct the spiro-γ-lactone core, aldehyde 2 and γmethylene-γ-butyrolactone 3 were reacted in the presence of BF3·OEt2 in DCM at −78 °C for 5 h to generate the desired spiro-γ-lactone 4 in 74% yield as a single stereoisomer (Scheme 3). An attempt to determine the relative stereochemistry of the newly generated stereogenic centers at C4 and C6 (pyrenolide numbering) by direct spectroscopic analysis using NOESY experiments was inconclusive. Removal of the TIPS group in 4 was achieved by treatment with Bu4NF in THF to afford alcohol 12 in 76% yield. At this stage, the structure of 12 was unambiguously confirmed by X-ray crystallography. The desirable 4R and 6R configurations of the newly generated stereogenic centers were clearly seen in the ORTEP diagram (Figure 2). Next, alcohol 12 was converted into the corresponding mesylate 5 in 90% yield by treatment with MsCl in pyridine. Removal of the benzylidene group from 5 under catalytic hydrogenolysis conditions (H2, 10% Pd/C in AcOEt), followed by addition of imidazole as a base to induce an in situ ring-closing reaction, afforded dihydro-pyrenolide D (6)6d in 54% yield over two steps. Finally, to introduce the

Figure 2. ORTEP diagram of 12.

unsaturated bond into the lactone ring, a two-step process involving α-phenylselenation (LHMDS, PhSeCl in THF) followed by oxidative β-elimination (m-CPBA, NaHCO3 in DCM) without protection of the C8 hydroxy group produced (+)-pyrenolide D in 70% yield over two steps. No epimerization at the spirocyclic carbon was observed throughout this reaction sequence.12 The spectroscopic data (1H and 13C NMR)13 and a specific rotation of the synthetic (+)-pyrenolide D were in good agreement with the reported values ([α]D21 +77.7 (c 0.69, CHCl3), lit.:2 [α]D23 +79.5 (c 0. 9, CHCl3)). To explain the observed stereoselective formation of the spiro-γ-lactone in 4, we propose the following plausible mechanism (Scheme 4). Addition of γ-methylene-γ-butyr12316

DOI: 10.1021/acs.joc.8b02003 J. Org. Chem. 2018, 83, 12315−12319

Note

The Journal of Organic Chemistry

2,3-O-Benzylidene-5-O-tosyl-aldehydo-L-arabinose Dipropyl Dithioacetal (9). To a solution of diol 88 (313 mg, 0.84 mmol) in CH2Cl2 (8.4 mL) were added Bu2SnO (20 mg, 10 mol %), Et3N (0.3 mL, 3 mmol), and TsCl (194 mg, 1.0 mmol) at 0 °C. After the mixture was stirred at room temperature for 14 h, the reaction was quenched with saturated aqueous NH4Cl. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 4:1) to afford the title compound 9 (432 mg, 98%) as a yellow liquid and immediately used for the next step: [α]D21 −31.1 (c 1.00, CHCl3); IR (neat) 3509 (br), 3035, 2962, 2929, 2872, 1459, 1402, 1362, 1308, 1293 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.01 (t, J = 7.45 Hz, 6H), 1.62−1.68 (m, 4H), 2.44 (s, 3H), 2.61 (d, J = 5.7 Hz, 1H), 2.62−2.79 (m, 4H), 3.85−3.89 (m, 1H), 4.02 (d, J = 5.7 Hz, 1H), 4.14 (q, J = 5.7 Hz, 1H), 4.26−4.29 (m, 2H), 4.47 (t, J = 5.2 Hz, 1H), 6.05 (s, 1H), 7.32−7.37 (m, 7H), 7.79 (d, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.6, 21.7, 22.6, 32.9, 33.4, 54.1, 71.1, 71.4, 79.0, 82.6, 104.6, 127.0, 128.1, 128.3, 128.4, 129.5, 129.9, 130.0, 132.4, 136.9, 145.1 2,3-O-Benzylidene-5-deoxy-aldehydo-L-arabinose Dipropyl Dithioacetal (10). To a solution of tosylate 9 (200 mg, 0.38 mmol) in Et2O (20 mL) was added LiAlH4 (21.6 mg, 0.57 mmol) at 0 °C. After the mixture was stirred at 0 °C for 1 h, the reaction was quenched with saturated aqueous NaHCO3. The resulting mixture was filtered through a pad of Celite and washed thoroughly with Et2O. The organic layer was separated, and the aqueous layer was extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 4:1) to afford the title compound 10 (97 mg, 72%) as a yellow liquid: [α]D21 −14.7 (c 0.97, CHCl3); IR (neat) 3315 (br), 2962, 1460, 1460, 1408, 1377, 1336, 1312, 1290, 1221 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.02 (t, J = 7.5 Hz, 6H), 1.30 (d, J = 6.9 Hz, 3H), 1.62−1.71 (m, 4H), 2.06 (d, J = 4.6 Hz, 1H), 2.65−2.82 (m, 4H), 4.00 (d, J = 5.2 Hz, 2H), 4.24 (t, J = 5.2 Hz, 1H), 4.46 (t, J = 5.2 Hz, 1H), 6.13 (s, 1H), 7.38−7.39 (m, 3H), 7.47−7.49 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 13.6, 19.0, 22.7, 33.1, 33.5, 54.7, 68.2, 81.1, 84.01, 104.3, 126.6, 128.4, 129.5, 137.2; HRMS (ESI) m/z [M + Na]+ calcd for C18H28NaO3S2 379.1378; found 379.1372. 2,3-O-Benzylidene-5-deoxy-4-O-triisopropylsilyl-aldehydoL-arabinose Dipropyl Dithioacetal (11). To a solution of alcohol 10 (113 mg, 0.32 mmol) in DMF (3.2 mL) were added imidazole (129 mg, 1.92 mmol) and TIPSCl (0.09 mL, 0.48 mmol) at room temperature. After the mixture was stirred at 70 °C for 53 h, the reaction was quenched with saturated aqueous NH4Cl. The resulting mixture was poured into Et2O. The organic layer was separated, and the aqueous layer was extracted with Et2O. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 20:1) to afford the title compound 11 (151 mg, 93%) as a colorless liquid: [α]D21 −12.7 (c 0.89, CHCl3); IR (neat) 2854, 1459, 1375, 1294, 1215, 1069, 972, 958, 909, 883 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.96−1.03 (m, 6H), 1.03−1.09 (m, 21H), 1.32 (d, J = 6.3 Hz, 3H), 1.61−1.69 (m, 4H), 2.59−2.82 (m, 4H), 4.00 (d, J = 4.0 Hz, 1H), 4.07 (q, J = 6.3 Hz, 1H), 4.20 (t, J = 5.7 Hz, 1 H), 4.42 (dd, J = 4.6, 5.7 Hz, 1H), 6.10 (s, 1H), 7.33−7.37 (m, 3H), 7.46−7.48 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 12.8, 13.6 (×2), 18.1, 18.2, 20.4, 22.7, 22.8, 33.0, 33.4, 55.3, 70.2, 83.3, 84.9, 104.4, 126.7, 128.2, 129.2, 137.7; HRMS (ESI) m/z [M + Na]+ calcd for C27H48NaO3S2Si 535.2712; found 535.2706. 2,3-O-Benzylidene-5-deoxy-4-O-triisopropylsilyl-aldehydoL-arabinose (2). To a solution of dithioacetal 11 (1.47 g, 2.87 mmol) in acetone (14 mL) and H2O (0.3 mL) were added NaHCO3 (671 mg, 11.5 mmol) and I2 (1.47 g, 5.74 mmol) at 0 °C. After the mixture was stirred at room temperature for 15.5 h, NaHCO3 (168 mg, 2.87 mmol) and I2 (730 mg, 2.87 mmol) were further added. After the mixture was stirred for another 1 h, the reaction was quenched with

Scheme 4. Mechanism of the Stereoselective [3 + 2] Annulation

olactone 3 to the Re face of aldehyde 2 via the Felkin−Anh conformation produces the oxo-carbenium ion intermediate I, followed by attack of the neighboring acetal oxygen to the Si face to generate the oxonium ion intermediate II (the observed R configuration). An alternative approach of the acetal oxygen to the Re face of the oxo-carbenium ion I′ is not favored because of the unsuitable electrostatic repulsion of the negatively charged C6 oxygen and lone pair of the lactonering oxygen.14 The transacetalization of II via the intermediate III leads to the desired spiro-γ-lactone 4. In conclusion, we have demonstrated a practical and efficient approach for the total synthesis of (+)-pyrenolide D in 10 steps with a 12.6% overall yield starting from the known L-arabinose derivative 8. A key feature of the synthesis is stereoselective construction of the spiro-γ-lactone core by BF3-promoted formal [3 + 2] annulation of 2,3-O-benzylidene-aldehydo-Larabinose with γ-methylene-γ-butyrolactone. Further investigation of this chemistry to synthesize complex natural products is underway in our laboratory, and the results will be reported in due course.

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EXPERIMENTAL SECTION

All experiments were performed in well-dried glassware fitted with rubber septa under an argon atmosphere. Solvents and commercially available chemicals were purified by standard methods or used as purchased. Analytical TLC was performed on silica gel plates 60 F254 (Merck Co.). Flash column chromatography was performed on silica gel 60A (Kanto Co.). Melting points (Mp) were determined in open capillaries and are uncorrected. IR spectra were recorded on a JASCO FTIR-4100A spectrometer as thin film. NMR spectra were recorded on a JEOL JNM-ECX-500II spectrometer in CDCl3 with TMS as the internal standard. Optical rotations were measured on a JASCO P2200 polarimeter. High-resolution ESI and APCI mass spectra were recorded with an Orbitrap analyzer in positive or negative ion mode by using an Exactive mass spectrometer at Global Facility Center, Creative Research Institution (Hokkaido University). 12317

DOI: 10.1021/acs.joc.8b02003 J. Org. Chem. 2018, 83, 12315−12319

Note

The Journal of Organic Chemistry

cm−1; 1H NMR (500 MHz, CDCl3) δ 1.56 (s, 1H), 1.59 (d, J = 6.3 Hz, 3H), 2.40−2.49 (m, 2H), 2.55−2.68 (m, 2H), 2.75−2.84 (m, 2H), 3.02 (s, 1H), 4.03 (dd, J = 1.7, 8.6 Hz, 1H), 4.19 (t, J = 2.3 Hz, 1H), 4.62 (dd, J = 2.3, 5.2 Hz, 1H), 7.91−7.97 (m, 1H), 5.53 (s, 1H), 7.37−7.40 (m, 3H), 7.43−7.47 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 18.8, 28.9, 34.1, 38.2, 44.0, 73.4, 76.6, 76.9, 99.5, 115.7, 126.0, 128.4, 129.3, 137.0, 175.4; HRMS (ESI) m/z [M + Na]+ calcd for C18H22NaO8S 421.0933; found 421.0928. Dihydro-(+)-pyrenolide D (6).6d A solution of mesylate 5 (274 mg, 0.69 mmol) containing 10% Pd/C in AcOEt (16 mL) was stirred under H2 for 42 h. After addition of imidazole (220 mg, 3.28 mmol), stirring continued for 24 h. The reaction mixture was filtered through a pad of Celite and washed with AcOEt. The combined organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 1:1) to afford the title compound 6 (79 mg, 54%) as white solids: Mp 139−140 °C; [α]D21 +49.8 (c 0.11, CHCl3); IR (KBr) 3306 (br), 2984, 1766, 1340, 1285, 1190, 1062, 990, 903, 797 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.30 (d, J = 6.3 Hz, 3H), 1.71 (d, J = 6.3 Hz, 1H), 2.09 (dd, J = 4.0,14.9 Hz, 1H), 2.32−2.42 (m, 2H), 2.55 (dq, J = 2.9, 8.6 Hz, 1H), 2.71 (q, J = 7.5 Hz, 1H), 2.74−2.82 (m, 1H), 4.01− 4.07 (m, 2H), 4.62 (d, J = 6.3 Hz 1H), 5.02 (q, J = 4.01 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.8, 28.7, 31.1, 43.5, 75.4, 76.1, 80.0, 89.4, 116.5, 175.6; HRMS (APCI) m/z [M + H]+ calcd for C10H15O5 215.0919; found 215.0914. (2S,3a′R,5′R,6′S,6a′R)-6′-Hydroxy-5′-methyl-4-(phenylselanyl)hexahydro-3′H,5H-spiro[furan-2,2′-furo[3,2-b]furan]5-one. To a solution of dihydro-pyrenolide 6 (27.0 mg, 0.126 mmol) in THF (2.5 mL) was added LHMDS (0.25 mL, 0.26 mmol) at −78 °C. After stirring at −78 °C for 1 h, PhSeCl (29 mg, 0.16 mmol) was added to the reaction mixture at −78 °C. After the mixture was stirred at −78 °C for 20 h, the reaction was quenched with silica gel. The resulting mixture was filtered through a pad of Celite and washed with AcOEt. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 1:1) to afford the α-phenylselenide compound (40 mg, 86%) as a diastereomeric mixture (dr = 1.4:1) and immediately used for the next step: IR (neat) 3444 (br), 2946, 1759, 1577, 1476, 1438, 1274, 1111, 1052, 886 cm−1 Major Isomer. 1H NMR (500 MHz, CDCl3) δ 1.25 (d, J = 6.3 Hz, 3H), 1.90 (dd, J = 3.4, 14.9 Hz, 1H), 2.36−2.45 (m, 2H), 2.76 (dd, J = 9.2, 14.9 1H), 3.94−3.98 (m, 2H), 4.18 (t, J = 9.2 Hz, 1H), 4.57 (d, J = 4.6 Hz, 1H), 4.93 (q, J = 4.0 Hz, 1H), 7.31−7.34 (m, 3H), 7.62− 7.65 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 12.8, 23.0, 28.9, 36.9, 39.0, 43.5, 75.3, 76.0, 79.8, 89.5, 115.0, 128.8, 129.2, 129.5, 135.9, 174.5. Minor Isomer. 1H NMR (500 MHz, CDCl3) δ 1.29 (d, J = 6.3 Hz, 3H), 2.06 (dd, J = 3.4, 14.9 Hz, 1H), 2.53 (dd, J = 2.9, 14.9 Hz, 1H), 2.68 (q, J = 7.5 Hz, 1H), 2.89 (dd, J = 9.2, 14.9 Hz, 1H), 3.86 (dd, J = 2.9, 9.7 Hz, 1H), 4.01−4.06 (m, 2H), 4.20−4.25 (m, 1H), 4.65 (d, J = 5.15 Hz, 1H), 5.00 (q, J = 4.01 Hz, 1H), 7.35−7.39 (m, 3H), 7.70−7.72 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.0, 23.7, 30.3, 36.3, 39.3, 43.8, 75.4, 76.0, 79.7, 89.9, 115.2, 128.7, 128.8, 129.3, 134.9, 175.1. (+)-Pyrenolide D (1). To a solution of the selenide compound (52 mg, 0.14 mmol) in CH2Cl2 (2.8 mL) were added NaHCO3 (118 mg, 1.40 mmol) and m-CPBA (48 mg, 0.28 mmol) at −78 °C. After the mixture was stirred at room temperature for 1 h, the reaction was quenched with H2O. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 1:1) to afford pyrenolide D (1) (24 mg, 81%) as white solids: Mp 157−158 °C: [α]D21 +77.7 (c 0.69, CHCl3); IR (KBr) 3398 (br), 2930, 2857, 1728, 1428, 1113, 1080, 703 cm−1; 1H NMR (500 MHz, acetone-d6) δ 1.21 (d, J = 6.3 Hz, 3H), 2.37 (dd, J = 3.4, 14.9 Hz, 1H), 2.55 (dd, J = 7. 5, 14.9 Hz, 1H), 4.00 (dd, J = 2.9, 5.2 Hz, 1H), 4.11 (dq, J = 3.4, 6.3 Hz, 1H), 4.21 (d, J = 5.2 Hz, 1H), 4.68 (d, J = 4.6 Hz, 1H), 5.06 (ddd, J = 3.4, 4.0, 7.5 Hz, 1H), 6.22 (d, J = 5.7 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H);

saturated aqueous Na2S2O3. The mixture was extracted with AcOEt (3 × 30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 4:1) to afford the title compound 2 (1.09 g, quant.) as a yellow liquid and immediately used for the next step: [α]D21 +15.8 (c 1.16, CHCl3); IR (neat) 3455, 2868, 1737, 1462, 1380, 1311, 1292, 1221, 1164, 1069 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.03−1.10 (m, 21H), 1.30 (d, J = 6.3 Hz, 3H), 4.04 (t, J = 5.2 Hz, 1H), 4.17 (q, J = 5.7 Hz, 1H), 4.67 (dd, J = 1.2, 5.7 Hz, 1H), 5.92 (s, 1H), 7.35−7.41 (m, 3H), 7.47− 7.53 (m, 2H), 9.87 (d, J = 1.7 Hz, CHO); 13C NMR (125 MHz, CDCl3) δ 12.8, 18.2, 20.9, 68.9, 81.6, 82.3, 105.1, 126.8, 128.3, 129.7, 136.1, 200.8. (2R,2′R,4′R,4a′S,7a′R)-2′-Phenyl-4′-((S)-1-((triisopropylsilyl)oxy)ethyl)hexahydro-5H-spiro[furan-2,6′-furo[3,2-d][1,3]dioxin]-5-one (4). To a solution of aldehyde 2 (242 mg, 0.64 mmol) and γ-methylene-γ-butyrolactone (5) (79 mg, 0.80 mmol) in CH2Cl2 (25 mL) at −78 °C was added BF3·OEt2 (89.0 μL, 0.70 mmol) dropwise. After the mixture was stirred at −78 °C for 3.5 h, the reaction was quenched with Et3N (1 mL). The resulting mixture was warmed to room temperature and poured into saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ ethyl acetate = 4:1) to afford the title compound 4 (225 mg, 74%) as white solids: Mp 80−81 °C: [α]D21 +31.3 (c 0.99, CHCl3); IR (KBr) 2932, 1795, 1126, 756, 676, 643, 564, 513, 502, 494 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.05−1.11 (m, 21H), 1.34 (d, J = 5.4 Hz, 3H), 2.34−2.41 (m, 1H), 2.42 (d, J = 14.9 Hz, 1H), 2.49−2.58 (m, 2H), 2.70−2.80 (m, 2H), 3.69 (dd, J = 1.7, 8.6 Hz, 1H), 4.22−4.28 (m, 1H), 4.34 (t, J = 2.3 Hz, 1H), 4.56 (dd, J = 2.3, 4.6 Hz, 1H), 5.51 (s, 1H), 7.34−7.39 (m, 3H), 7.47 (dd, J = 1.7, 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 12.8, 18.1 (×2), 21.1, 29.2, 34.4, 44.2, 67.2, 74.4, 80.9, 99.3, 115.7, 126.0, 128.2, 128.9, 137.8, 175.8; HRMS (ESI) m/z [M + Na]+ calcd for C26H40NaO6Si 499.2492; found 499.2486. (2R,2′R,4′S,4a′S,7a′R)-4′-((S)-1-Hydroxyethyl)-2′-phenylhexahydro-5H-spiro[furan-2,6′-furo[3,2-d][1,3]dioxin]-5-one (12). To a solution of spiro-γ-lactone 4 (110 mg, 0.23 mmol) in THF (2.3 mL) was added Bu4NF (1 M in THF, 0.46 mL, 0.46 mmol) at 0 °C. After the mixture was stirred at room temperature for 5 h, the reaction was quenched with saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 1:1) to afford the title compound 12 (56 mg, 76%) as white solids: Mp 149− 150 °C; [α]D21 +51.1 (c 0.98, CHCl3); IR (KBr) 3464 (br), 2978, 2922, 2871, 1750, 1639, 1455, 1400, 1343, 1297 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.35 (d, J = 6.3 Hz, 3H), 2.11 (s, 1H, −OH), 2.40− 2.46 (m, 2H), 2.55−2.61 (m, 2H), 2.74−2.84 (m, 2H), 3.80 (dd, J = 1.7, 8.3 Hz, 1H), 4.07−4.14 (m, 2H), 4.31 (t, J = 2.3 Hz, 1H), 4.59 (dd, J = 2.3, 5.2 Hz, 1H), 5.51 (s, 1H), 7.34−7.40 (m, 3H), 7.47− 7.49 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 19.8, 29.0, 34.4, 44.1, 66.9, 74.6, 79.8, 99.3, 115.9, 126.1, 128.3, 129.1, 137.6, 175.7; HRMS (ESI) m/z [M + Na]+ calcd for C17H20NaO6 343.1158; found 343.1152. (S)-1-((2R,2′R,4′R,4a′S,7a′R)-5-Oxo-2′-phenylhexahydro-3Hspiro[furan-2,6′-furo[3,2-d][1,3]dioxin]-4′-yl)ethylmethanesulfonate (5). To a solution of alcohol 12 (72.7 mg, 0.227 mmol) in pyridine (2.3 mL) was added MsCl (35 μL, 0.45 mmol) at 0 °C. After the mixture was stirred at room temperature for 3 h, the reaction was quenched with saturated aqueous CuSO4 (10 mL) and diluted with CH2Cl2 (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 2:1) to afford the title compound 5 (81.0 mg, 90%) as white solids: Mp 81−82 °C; [α]D21 +42.4 (c 1.02, CHCl3); IR (KBr) 1787, 1409, 1360, 1175, 1092, 1046, 930, 757, 702, 655 12318

DOI: 10.1021/acs.joc.8b02003 J. Org. Chem. 2018, 83, 12315−12319

Note

The Journal of Organic Chemistry C NMR (125 MHz, acetone-d6) δ 13.5, 42.9, 76.6, 76.8, 81.2, 92.3, 116.0, 124.4, 153.2, 170.3; HRMS (APCI) m/z [M + H]+ calcd for C10H13O5 213.0763; found 213.0758. 13

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[3 + 2] Annulation: Total Synthesis of Plakortone L. Org. Lett. 2014, 16, 3384−3387. (c) Hotoda, K.; Ohnuma, A.; Kusakabe, K.; Tanaka, A.; Sasaki, I.; Sugimura, H. Stereoselective Synthesis of the (−)-Dysiherbaine Furopyran Core via BF3-Promoted Formal [3 + 2] Annulation of aldehydo-Aldoses with Allylsilanes. Tetrahedron Lett. 2016, 57, 5359−5362. (8) Kuszmann, J.; Gács-Baitz, E. O-Benzylidene Derivatives of DArabinose Diethyl and Dipropyl Dithioacetal. Aust. J. Chem. 1996, 49, 273−280. (9) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R. Dibutyltin Oxide Catalyzed Selective Sulfonylation of α-Cheletable Primary Alcohols. Org. Lett. 1999, 1, 447−450. (10) Zinner, H.; Wessely, K.; Kristen, H. Derivate der Zuckermercaptale, XVII. Die partielle Veresterung von D-Arabinosemercaptalen mit Sulfonsäurechloriden und eine einfache Synthese der 5-Desoxy-D-arabinose. Chem. Ber. 1959, 92, 1618. (11) (a) Driguez, P.-A.; Barrere, B.; Quash, G.; Doutheau, A. Synthesis of Transion-state Analogues as Potential Inhibitors of Sialidase from Influenza Virus. Carbohydr. Res. 1994, 262, 297−310. (b) Ohlsson, J.; Magnusson, G. A Short and Practical Route to 3-OBenzoyl Azidosphingosine. Carbohydr. Res. 2001, 331, 91−94. (12) The results of NOESY experiments of compounds 6 and 1 are given in the Supporting Information. (13) Comparison of 1H and 13C NMR data for the synthetic product 1 with those of the natural pyrenolide D is given in the Supporting Information. (14) Alternate diagrams are given in the Supporting Information.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02003. Figure of mechanism for ring-closing step, 1H and 13C NMR spectra of all compounds, comparison table of synthetic and natural NMR data, NOESY spectra of 6 and 1, and X-ray data for compound 12 (PDF) Crystallographic data for 12 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hideyuki Sugimura: 0000-0001-9689-8094 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Professor Yoshitaka Yamaguchi (Yokohama National University) for the X-ray crystallographic analysis and Ms. Miho Yamada (Instrumental Analysis Division, Global Facility Center, Creative Research Institution, Hokkaido University) for the HRMS measurements. This work was partially supported by Aoyama Gakuin University-Supported Program “Promotion for Ongoing Research Program”.

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REFERENCES

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DOI: 10.1021/acs.joc.8b02003 J. Org. Chem. 2018, 83, 12315−12319