Stereoselective Synthesis of the ABC Ring System of Aspterpenacids

7 days ago - Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also ...
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Stereoselective Synthesis of the ABC Ring System of Aspterpenacids Shengling Xie,†,∥ Pan Ren,†,‡,∥ Jieping Hou,† Chengqing Ning,*,†,§ and Jing Xu*,† †

Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China ‡ School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang 150006, China § SUSTech Academy for Advanced Interdisciplinary Studies, Shenzhen, Guangdong 518055, China

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S Supporting Information *

ABSTRACT: Aspterpenacids A and B are sesterterpenoids that possess a unique and highly congested 5/3/7/6/5 fused ring system. These compounds also contain a sterically encumbered isopropyl trans-hydrindane motif and a cyclopropane motif bearing two quaternary centers, which make them remarkably challenging synthetic targets. Herein, we report the successful construction of the key highly substituted ABC ring system in a stereoselective manner.

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esterterpenoids are a small family of terpenes that commonly have complex chemical architectures and intriguing biological activities, such as anti-inflammatory, anticarcinogenic, and antimicrobial activities.1,2 Isopropyl trans-hydrindane sesterterpenoids are a major class of sesterterpenoids that contain isopropyl- or isopropenylsubstituted trans-hydrindane motifs as common features.3 Representative compounds include aspterpenacids,4 retigeranic acids,5 astellatol,6 and nitidasin7 (Figure 1). These isopropyl trans-hydrindane sesterterpenoids also commonly possess a

highly congested ring system containing various stereocenters, including several quaternary and/or tetrasubstituted carbon centers, that presents a significant synthetic challenge. Another obvious challenge is also presented by the well-known problematic trans-hydrindane motif3,8 of these unique sesterterpenoids. Unsurprisingly, the total synthesis of these sesterterpenoids have long attracted the attention of synthetic chemists.9 The pioneering synthesis of retigeranic acid A was achieved by the Corey,8 Paquette,10 Hudlicky,11 and Wender12 groups. In 2014, the Trauner group accomplished an impressive asymmetric synthesis of nitidasin.13 Recently, our group also achieved the first and enantiospecific synthesis of astellatol.14 Encouraged by these endeavors, we now report recent efforts toward the synthesis of the challenging ABC ring moiety of aspterpenacids. Aspterpenacids A and B were isolated from the mangrove endophytic fungus Aspergillus terreus H010 by Huang and She in 2016.4 These compounds possess a unique highly congested 5/3/7/6/5 fused ring system featuring a cyclopropane motif bearing two quaternary centers and a sterically encumbered isopropyl trans-hydrindane moiety. Our retrosynthetic analysis of these aspterpenacids is shown in Scheme 1. We envisaged that the challenging trans-hydrindane motif of aspterpenacids could be constructed from intermediate 1 via a metal-mediated cyclization reaction, such as the Pauson−Khand reaction or enyne cycloisomerization reaction, and directed hydrogenation, similar to chemistry established in our synthesis of astellatol.14 The installation of a methyl group at the C-7 position should deliver compound 1 from 2. The seven-

Figure 1. Isopropyl trans-hydrindane sesterterpenoids.

Received: September 1, 2018 Published: October 31, 2018

© 2018 American Chemical Society

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DOI: 10.1021/acs.joc.8b02263 J. Org. Chem. 2018, 83, 14152−14157

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The Journal of Organic Chemistry

compound 3. The presence of the terminal alkyne was thought to deactivate the catalysts. Therefore, the terminal alkyne in compound 7 was protected with a TMS group to afford compound 11 (Scheme 3). The

Scheme 1. Retrosynthetic Analysis of Aspterpenacids

Scheme 3. Synthetic Efforts toward Tetracyclic Compound 16

membered ring in 2 should be accessible from alkyne 3 via a gold-catalyzed Conia−ene reaction. Finally, sequential reduction/acylation/intramolecular cyclopropanation of 4 would furnish the congested skeleton of key compound 3. The C-7 methyl group is planned to be introduced at a rather late stage because early stage introduction would most likely produce the opposite stereochemistry in the cyclopropanation step, while the feasibility of the corresponding intermolecular cyclopropanation is also uncertain. Our synthetic attempts started from commercially available alkyne 6 (Scheme 2), which was converted into ketone 4 using Scheme 2. Synthetic Efforts toward Compound 3 secondary alcohol was also silylated in the reaction, but then deprotected during the acidic workup. Acylation of 11 furnished ketoester 12, which was subjected to the diazotransfer reaction under the same p-ABSA conditions to afford diazoketoester 13. Although most cyclopropanation conditions were unsuccessful, in the presence of Cu(TBSal)2 (10 mol %), compound 14 was isolated in 25% yield.16 Removal of the TMS group using TBAF smoothly furnished key compound 3, which contained the critical cyclopropane motif bearing two quaternary centers. An intramolecular gold-catalyzed Conia− ene reaction between the silyl enol ether and alkyne moieties of 1517 was expected to afford the desired seven-membered ring via a 7-exo-dig cyclization. However, all attempts to prepare desired product 16 under various conditions were unsuccessful. The theoretical calculation for reasoning the failed attempts is currently under investigation and will be reported in due course. These unsuccessful Conia−ene cyclization attempts forced us to reconsider our strategy (Scheme 4). From readily available diketone 17,18 an olefination and reduction sequence afforded compound 19 in the racemic form. Following the same transformations described earlier, 19 was acylated, diazolated, and subjected to Cu-catalyzed cyclopropanation conditions to successfully afford tricyclic compound 22. Methylenation under Eschenmoser’s conditions yielded diene 23. The initially attempted ring-closing metathesis (RCM) of substrate 23 was unsuccessful. However, after reducing ketone 23, the corresponding allylic alcohol smoothly underwent RCM to afford compound 24 as a mixture of two diastereomers. Subsequent Ley oxidation afforded key compound 2 bearing the desired aspterpenacid ABC ring system. In summary, we have developed a facile synthesis of the sterically encumbered ABC ring system of aspterpenacids, a

the procedure of Danishefsky et al.15 The 1,2-reduction of 4 afforded allylic alcohol 7. Initially, the attempted coupling of 7 and diazo ketoacid 8 was unsuccessful.16 Therefore, alcohol 7 was reacted with the diketene first to afford ketoester 10 in 84% yield. Treatment of 10 with 4-acetamidobenzenesulfonyl azide (p-ABSA) afforded the desired diazoketoester. Various intramolecular cyclopropanation conditions were tested on substrate 9. However, all metal catalysts tested under these conditions, including Rh2(OAc)4, Rh2(Ooct)4, Cu(acac)2, and Cu(TBSal)2, did not afford even trace amounts of desired 14153

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organic phase was dried over MgSO4, filtered, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 5:1) to afford compound 7 (4.97 g, 98%) as a colorless oil: TLC Rf = 0.3 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.60 (s, 1H), 4.65 (d, J = 7.3 Hz, 1H), 2.45−2.30 (m, 5H), 2.23 (dddd, J = 17.4, 15.3, 7.6, 4.8 Hz, 2H), 2.12 (s, 1H), 1.95 (s, 1H), 1.67 (ddt, J = 12.3, 7.9, 4.2 Hz, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 144.4, 128.5, 84.6, 78.6, 68.7, 34.0, 29.7, 27.3, 17.3 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C9H13O 137.0961, found 137.0960. Compound 10. To a solution of compound 7 (2.0 g, 14.7 mmol) in dry CH2Cl2 (120 mL) at room temperature was added DMAP (179.4 mg, 1.5 mmol), and the mixture was stirred for 5 min. Diketene (1.5 g, 17.6 mmol) was carefully added, and the resulting mixture was stirred for 8 h at room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc, 20:1) to afford compound 10 (2.7 g, 84%) as a yellow oil: TLC Rf = 0.60 (silica gel, petroleum ether/EtOAc = 8:1); 1H NMR (400 MHz, CDCl3) δ 5.81 (s, 1H), 5.77−5.67 (m, 1H), 3.45 (s, 2H), 2.51−2.42 (m, 1H), 2.41− 2.27 (m, 6H), 2.26 (s, 3H), 1.95 (s, 1H), 1.87−1.75 (m, 1H) ppm; 13 C{1H} NMR (100 MHz, CDCl3) δ 200.7, 167.3, 140.2, 132.1, 84.0, 82.4, 68.8, 50.5, 30.9, 30.4, 30.3, 27.4, 17.2 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C13H17O3221.1172, found 221.1169. Compound 9. To a solution of compound 10 (3.0 g, 13.6 mmol) and p-acetamidobenzensulfonyl azide (p-ABSA, 3.9 g, 16.3 mmol) in MeCN (150 mL) at 0 °C was added triethylamine (5.7 mL, 40.9 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure and the residue triturated with ether/hexanes (1:1, 200 mL). The mixture was then filtered, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 20:1) to give compound 9 (3.3 g, 98%) as a colorless oil: TLC Rf = 0.73 (silica gel, petroleum ether/EtOAc = 8:1); 1H NMR (400 MHz, CDCl3) δ 5.84 (s, 1H), 5.83−5.78 (m, 1H), 2.47 (s, 4H), 2.45−2.27 (m, 6H), 1.96 (t, J = 2.5 Hz, 1H), 1.91−1.82 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.3, 161.6, 139.9, 132.5, 83.8, 82.8, 68.9, 31.2, 30.3, 28.4, 27.5, 17.3 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C13H15N2O3 247.1077, found 247.1074. Compound 11. To a stirred solution of compound 7 (2.0 g, 14.7 mmol) in THF (150 mL) at −78 °C was added n-BuLi (2.4 M, 14.1 mL, 33.8 mmol) dropwise via cannula. The resulting reaction mixture was stirred for another 2 h at −78 °C. Chlorotrimethylsilane (TMSCl, 4.0 g, 36.7 mmol) was then added slowly via syringe. The reaction mixture was then warmed to 0 °C over 4 h, 2 N HCl (30 mL) was slowly added at 0 °C, and the mixture was stirred for an additional 30 min. The reaction mixture was extracted with Et2O (3 × 100 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo to afford compound 11 (2.66 g, 87%) as a colorless oil: TLC Rf = 0.58 (silica gel, petroleum ether/EtOAc = 10:1); 1H NMR (400 MHz, CDCl3) δ 5.61 (s, 1H), 4.69 (s, 1H), 2.47−2.34 (m, 5H), 2.34−2.25 (m, 1H), 2.24−2.15 (m, 1H), 1.78 (s, 1H), 1.74−1.65 (m, 1H), 0.13 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 144.7, 128.8, 107.6, 85.2, 78.7, 34.1, 29.8, 27.6, 19.2, 0.2 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C12H21OSi 209.1356, found 209.1353. Compound 12. To a solution of compound 11 (3 g, 14.4 mmol) in CH2Cl2 (150 mL) at room temperature was added DMAP (175.9 mg, 1.4 mmol), and the mixture was stirred for 5 min. Diketene (1.5 g, 17.3 mmol) was carefully added, and the resulting mixture was stirred for 8 h at room temperature and then concentrated. The residue was purified by column chromatography (petroleum ether/ EtOAc, 25:1) to afford compound 12 (3.3 g, 79%) as a yellow oil: TLC Rf = 0.64 (silica gel, petroleum ether/EtOAc = 10:1); 1H NMR (500 MHz, CDCl3) δ 5.78 (s, 1H), 5.75−5.67 (m, 1H), 3.44 (s, 2H), 2.45 (dddd, J = 15.6, 9.0, 4.5, 2.3 Hz, 1H), 2.41−2.22 (m, 9H), 1.82 (ddt, J = 10.5, 8.4, 3.9 Hz, 1H), 0.13 (s, 9H) ppm; 13C{1H} NMR (MHz, CDCl3) δ 200.8, 167.3, 140.3, 132.1, 106.8, 85.1, 82.5, 50.5, 31.0, 30.4, 30.3, 27.5, 18.8, 0.2 ppm; HRMS-ESI (m/z) [M − H]− calcd for C16H23O3Si291.1422, found 291.1425.

Scheme 4. Synthesis of the Aspterpenacid ABC Ring System

rare type of sesterterpenoid. Our strategy features an intramolecular cyclopropanation to form the B ring and an RCM reaction to form the C ring and paves the way for the total synthesis of aspterpenacids. Notably, accessing the asymmetric synthetic route should be feasible because the asymmetric reduction of compound 18 would be readily achieved via a Corey−Bakshi−Shibata reduction19 or asymmetric hydrogenation.20 Further efforts toward the total synthesis of aspterpenacids are currently underway in our laboratory and will be reported in due course.

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EXPERIMENTAL SECTION

General Information. Unless otherwise mentioned, all reactions were conducted under a nitrogen atmosphere and anhydrous conditions. Tetrahydrofuran (THF) was distilled from sodiumbenzophenone under an argon atmosphere. Dichloromethane (DCM) was distilled from calcium hydride. Reactions were monitored by thin-layer chromatography (TLC; GF254) using plates supplied by Yantai Chemicals (China) and visualized under UV or by staining with an ethanolic solution of phosphomolybdic acid, cerium sulfate, basic KMnO4 solution, or iodine. Flash column chromatography was performed using silica gel (particle size, 0.040−0.063 mm). NMR spectra were recorded on a Bruker AV400 or AV500 MHz instrument and calibrated using residual undeuterated chloroform in CDCl3 (δ H = 7.26 ppm, δ C = 77.0 ppm) as an internal reference. The following abbreviations were used to describe signal multiplicities: s, singlet; d, doublet; t, triplet; dt, double triplet; dq, double quartet; ddd, doublet of double doublet; ddt, doublet of double triplet; m, multiplet. High-resolution mass spectra (HRMS) were recorded on a Thermo Scientific Q Exactive Hybrid QuadrupoleOrbitrap mass spectrometer. Compound 7. To a solution of compound 4 (5.0 g, 37.3 mmol)15 in MeOH (100 mL) at 0 °C was added CeCl3·7H2O (18.0 g, 48.5 mmol), and the mixture was stirred for 5 min at 0 °C. NaBH4 (2.1 g, 55.9 mmol) was then added carefully, followed by stirring for 5 min at room temperature. Aqueous NH4Cl (30 mL) was then added, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was sequentially washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The combined 14154

DOI: 10.1021/acs.joc.8b02263 J. Org. Chem. 2018, 83, 14152−14157

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The Journal of Organic Chemistry Compound 13. To a solution of compound 12 (3.5 g, 12.0 mmol) and p-acetamidobenzensulfonyl azide (p-ABSA, 3.5 g, 14.4 mmol) in MeCN (150 mL) at 0 °C was added Et3N (7.0 mL, 35.9 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was then removed under reduced pressure and the residue triturated with ether/hexanes (1:1, 200 mL). The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 25:1) to afford compound 13 (3.74 g, 98%) as a colorless oil: TLC Rf = 0.74 (silica gel, petroleum ether/EtOAc = 10:1); 1H NMR (400 MHz, CDCl3) δ 5.83−5.76 (m, 2H), 2.46 (s, 4H), 2.43−2.35 (m, 3H), 2.35−2.24 (m, 3H), 1.89−1.80 (m, 1H), 0.12 (s, 9H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 190.4, 161.6, 140.0, 132.6, 106.5, 85.3, 82.9, 31.2, 30.3, 28.4, 27.7, 18.9, 0.2 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C16H23N2O3Si 319.1472, found 319.1470. Compound 14. A solution of Cu(TBSal)2 (39.4 mg, 0.094 mmol) in toluene (2.4 mL) was heated to 110 °C under an argon atmosphere. A warm solution of diazo compound 13 (200.0 mg, 0.628 mmol) in toluene (20 mL) was then added dropwise over 30 min, and the reaction was monitored by TLC (EtOAc/hexanes, 1:5). After 100 min, the reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was purified by flash chromatography (petroleum ether/EtOAc, 25:1) to afford compound 14 (45.6 mg, 25%) as a yellow oil: TLC Rf = 0.48 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (500 MHz, CDCl3) δ 4.98 (s, 1H), 2.88 (d, J = 6.3 Hz, 1H), 2.55 (s, 3H), 2.36−2.25 (m, 3H), 2.09−2.00 (m, 3H), 1.94 (ddd, J = 14.3, 8.0, 6.3 Hz, 1H), 1.84−1.76 (m, 1H), 0.15 (s, 9H) ppm; 13C{1H} NMR 125 MHz, CDCl3) δ 199.6, 172.7, 105.1, 86.7, 85.5, 60.0, 50.0, 43.3, 38.7, 30.6, 24.4, 24.3, 18.4, 0.0 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C16H23O3Si 291.1411, found 291.1406. Compound 3. To a solution of compound 14 (300 mg, 1.03 mmol) in THF (10 mL) and H 2 O (3 mL) were added tetrabutylammonium fluoride (TBAF) solution (1.3 mL, 1.0 M in THF) and AcOH (3 mL) at 0 °C. The reaction mixture was stirred for 8 h at 55 °C, quenched with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc, 15:1) to afford compound 3 (198.5 mg, 88%) as a colorless oil: TLC Rf = 0.42 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 4.97 (s, 1H), 2.87 (d, J = 6.4 Hz, 1H), 2.55 (s, 3H), 2.36−2.25 (m, 3H), 2.14−2.06 (m, 1H), 2.06−1.92 (m, 4H), 1.86−1.76 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 199.7, 172.6, 85.1, 82.5, 70.3, 59.8, 49.9, 43.4, 38.7, 30.6, 24.4, 23.9, 17.1 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C13H15O3 219.1016, found 219.1010. Compound 15. To a solution of compound 3 (300.0 mg, 1.4 mmol) and triethylamine (417.0 mg, 4.1 mmol) in CH2Cl2 (15 mL) at 0 °C was added TBSOTf (445.6 mg, 2.1 mmol), followed by stirring for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with cold sodium bicarbonate. The organic layer was dried over MgSO4 and concentrated, and the residue was washed with dry ether to remove the insoluble triethylammonium triflate salt. The combined ether solution was then concentrated and underwent chromatography on basic alumina (pH 9.0−9.5) using hexane as the eluent to afford compound 15 (402.2 mg, 88%) as a yellow oil: TLC Rf = 0.59 (silica gel, petroleum ether/EtOAc = 20:1); 1H NMR (400 MHz, CDCl3) δ 4.89 (s, 1H), 4.45 (d, J = 2.0 Hz, 1H), 4.39 (d, J = 1.8 Hz, 1H), 2.35 (td, J = 7.3, 2.7 Hz, 3H), 2.29−2.18 (m, 1H), 2.13 (dt, J = 13.2, 6.6 Hz, 1H), 2.06−1.94 (m, 3H), 1.80 (dt, J = 14.8, 7.6 Hz, 1H), 1.77−1.69 (m, 1H), 0.90 (s, 9H), 0.21 (d, J = 5.3 Hz, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 150.7, 95.0, 85.5, 83.3, 69.6, 52.2, 46.9, 39.7, 36.6, 26.7, 25.8, 23.9, 18.2, 16.8, −4.4, −5.0 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C19H29O3Si 333.1880, found 333.1871. Compound 18. To a solution of methyltriphenylphosphonium bromide (9.4 g, 26.2 mmol) in THF (100 mL) at −78 °C was added n-BuLi (2.4 M, 10.4 mL, 25.0 mmol) dropwise. The reaction was then warmed to 0 °C and stirred for 30 min. A solution of compound 17 (2 g, 13.1 mmol)18 in THF (10 mL) was then added dropwise via

syringe, and the mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL). The combined organic extracts were washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 15:1) to afford compound 18 (1.6 g, 80%) as a colorless oil: TLC Rf = 0.61 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.56 (tt, J = 4.8, 2.2 Hz, 2H), 2.43−2.35 (m, 2H), 2.36−2.28 (m, 2H), 2.20 (dd, J = 9.5, 5.6 Hz, 2H), 1.73 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 210.1, 157.7, 145.9, 145.0, 110.6, 35.7, 34.7, 26.6, 23.0, 22.5 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C10H15O 151.1117, found 151.1117. Compound 19. To a solution of compound 18 (3.0 g, 20.0 mmol) in MeOH (70 mL) at 0 °C was added CeCl3·7H2O (11.2 g, 30.0 mmol), and the mixture was stirred for 5 min. NaBH4 (1.0 g, 26 mmol) was then carefully added, followed by stirring for 5 min at room temperature. The resulting reaction mixture was quenched with aqueous NH4Cl (30 mL) and concentrated under reduced pressure. The resulting residue was diluted with H2O (100 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was sequentially washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, concentrated, and purified by column chromatography (petroleum ether/ EtOAc, 5:1) to afford compound 19 (3.0 g, 98%) as a colorless oil: TLC Rf = 0.4 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.56 (s, 1H), 4.71 (d, J = 6.7 Hz, 2H), 4.66 (s, 1H), 2.47−2.37 (m, 1H), 2.35−2.14 (m, 6H), 1.74 (s, 3H), 1.70 (ddd, J = 13.0, 8.8, 4.2 Hz, 1H), 1.42 (d, J = 6.1 Hz, 1H) ppm; 13 C{1H} NMR (100 MHz, CDCl3) δ 146.0, 145.9, 127.5, 110.1, 79.1, 36.0, 34.2, 29.8, 26.4, 22.6 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C10H17O153.1274, found 153.1271. Compound 20. To a solution of compound 19 (2 g, 13.1 mmol) in dry CH2Cl2 (100 mL) was added DMAP (0.16 g, 1.3 mmol), and the mixture was stirred for 5 min at room temperature. Diketene (1.2 g, 14.4 mmol) was carefully added, and the resulting reaction mixture was stirred for 8 h at room temperature and then concentrated. The resulting residue was purified by column chromatography (petroleum ether/EtOAc, 20:1) to afford compound 20 (2.6 g, 84%) as a colorless oil: TLC Rf = 0.54 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.73 (d, J = 6.8 Hz, 2H), 4.72 (s, 1H), 4.69 (s, 1H), 3.45 (s, 2H), 2.44 (dddd, J = 17.1, 8.8, 4.3, 2.1 Hz, 1H), 2.38−2.32 (m, 1H), 2.28−2.14 (m, 8H), 1.81 (ddt, J = 13.3, 7.7, 3.5 Hz, 1H), 1.72 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 200.7, 167.4, 145.4, 141.8, 130.9, 110.3, 82.7, 50.5, 35.8, 30.9, 30.3, 30.3, 26.4, 22.5 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C14H21O3 237.1485, found 237.1477. Compound 21. To a solution of compound 20 (2.5 g, 10.6 mmol) and p-acetamidobenzensulfonyl azide (p-ABSA, 3.1 g, 12.7 mmol) in MeCN (100 mL) at 0 °C was added Et3N (4.4 mL, 31.8 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was triturated with ether/hexanes (1:1, 200 mL). The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 20:1) to afford compound 21 (2.7 g, 98%) as a colorless oil: TLC Rf = 0.63 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 5.79 (d, J = 4.0 Hz, 1H), 5.75 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.48 (s, 3H), 2.47−2.36 (m, 2H), 2.34−2.26 (m, 1H), 2.26−2.12 (m, 4H), 1.90−1.80 (m, 1H), 1.72 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.4, 161.7, 145.2, 141.4, 131.3, 110.4, 83.1, 35.8, 31.2, 30.3, 28.4, 26.5, 22.5 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C14H19N2O3 263.1390, found 263.1382. Compound 22. To a hot solution (110 °C) of Cu(TBSal)2 (0.4 g, 0.95 mmol) in toluene (100 mL) was added a warm solution of diazo compound 21 (2.5 g, 9.5 mmol) in toluene (10 mL) dropwise over 30 min. The reaction was monitored by TLC (EtOAc/hexanes, 1:5). After 3 h, the reaction mixture was allowed to cool to ambient temperature, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 25:1) to afford compound 22 (0.6 g, 27%) 14155

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The Journal of Organic Chemistry

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as a colorless oil: TLC Rf = 0.38 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 4.79 (d, J = 1.6 Hz, 1H), 4.73 (s, 1H), 4.67 (s, 1H), 2.82 (d, J = 6.4 Hz, 1H), 2.52 (s, 3H), 2.32− 2.23 (m, 1H), 2.09 (dddd, J = 14.5, 10.3, 6.3, 1.5 Hz, 1H), 2.03−1.77 (m, 6H), 1.67 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 172.9, 144.0, 111.6, 84.9, 60.8, 49.9, 42.9, 38.6, 36.0, 30.4, 24.4, 23.4, 22.2 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C14H19O3 235.1329, found 235.1326. Compound 23. To a solution of compound 22 (200 mg, 0.85 mmol) and Et3N (0.35 mL, 2.6 mmol) in CH2Cl2 (50 mL) at 0 °C was added TMSOTf (0.31 mL, 1.7 mmol) slowly. The resulting reaction mixture was stirred for 2 h at room temperature and then diluted with water (50 mL), extracted with CH2Cl2 (3 × 25 mL), dried over MgSO4, and concentrated. The residue was dissolved in CH2Cl2 (50 mL), and Eschenmoser’s salt (393 mg, 2.1 mmol) was added at 0 °C. The resulting mixture was then stirred for 2 h at room temperature and then diluted with water (30 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with brine and dried with MgSO4. The solvent was evaporated to give a gray−green oil that was then dissolved in CH2Cl2 (50 mL). To this solution was added MeI (0.16 mL, 2.6 mmol), and the mixture was stirred for 5 min. DBU (0.39 mL, 2.6 mmol) was then added, and the reaction mixture was stirred for a further 1 h at room temperature. Aqueous NaHCO3 (30 mL) was then added, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic extract was washed with brine, dried with MgSO4, concentrated, and purified by column chromatography (petroleum ether/EtOAc, 15:1) to afford compound 23 (160 mg, 76%) as a colorless oil: TLC Rf = 0.41 (silica gel, petroleum ether/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 17.0, 10.4 Hz, 1H), 6.33 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.4, 1.8 Hz, 1H), 4.84 (d, J = 3.1 Hz, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 2.93 (d, J = 6.2 Hz, 1H), 2.36−2.26 (m, 1H), 2.15−1.77 (m, 7H), 1.67 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 172.9, 144.0, 133.2, 129.2, 111.7, 85.2, 61.2, 49.9, 42.8, 38.7, 36.1, 24.4, 23.7, 22.2 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C15H19O3 247.1329, found 247.1325. Compound 2. To a solution of compound 23 (100 mg, 0.41 mmol) in MeOH (15 mL) at 0 °C was added CeCl3·7H2O (227 mg, 0.61 mmol), and the reaction mixture was stirred for 5 min. NaBH4 (20 mg, 0.53 mmol) was then added, followed by stirring for 5 min at room temperature. The reaction mixture was then quenched with aqueous NH4Cl (10 mL) and concentrated. The resulting residue was diluted with H2O (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were sequentially washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered, and concentrated, and the resulting residue was used directly in the next step. A solution of the as-obtained alcohol (50 mg, 0.201 mmol) and Grubbs second generation catalyst (17 mg, 0.020 mmol, 10 mol %) in toluene (30 mL) was heated to 80 °C for 3 h. The reaction mixture was then concentrated and purified by column chromatography (petroleum ether/EtOAc, 10:1 → 2:1) to afford compound 24 (44 mg, 94%) as a colorless oil. To a suspension of compound 24 (40 mg, 0.18 mmol) in dry CH2Cl2 were added TPAP (6.5 mg, 0.018 mmol) and NMO (42.3 mg, 0.36 mmol). The mixture was vigorously stirred for 2 h and then filtered through a pad of Celite. The filtrate was concentrated and purified by flash chromatography (petroleum ether/EtOAc, 2:1 → 1:1) to afford ketone 2 (32 mg, 81%) as a colorless oil: TLC Rf = 0.3 (silica gel, petroleum ether/EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) δ 5.88 (s, 1H), 4.76 (d, J = 1.2 Hz, 1H), 2.74 (d, J = 6.5 Hz, 1H), 2.58−2.52 (m, 1H), 2.52−2.47 (m, 1H), 2.41−2.33 (m, 1H), 2.33−2.26 (m, 1H), 2.12 (ddd, J = 14.7, 6.1, 3.7 Hz, 1H), 2.09−2.03 (m, 1H), 2.00−1.93 (m, 1H), 1.90 (s, 3H), 1.89−1.82 (m, 1H) ppm; 13 C{1H} NMR (100 MHz, CDCl3) δ 189.9, 170.1, 154.5, 127.8, 85.2, 53.4, 49.3, 40.7, 39.0, 34.0, 28.1, 25.3, 24.7 ppm; HRMS-ESI (m/z) [M + H]+ calcd for C13H15O3 219.1016, found 219.1009.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02263. 1 H and 13C NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jing Xu: 0000-0002-5304-7350 Author Contributions ∥

S.X. and P.R. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21402082 and 21772082), SZDRC (Discipline Construction Program), SZSTI (JCYJ20170817110515599 and KQJSCX2017072815423320), and the Shenzhen Nobel Prize Scientists Laboratory Project (C17783101) is greatly appreciated.

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REFERENCES

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