Total Synthesis and Structure Revision of (Â±)-Clavilactone D Through

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Total Synthesis and Structure Revision of (±)-Clavilactone D Through Selective Cyclization of an #,#-Dicarbonyl Peroxide Leiyang Lv, Barry B Snider, and Zhiping Li J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2017 Downloaded from http://pubs.acs.org on May 5, 2017

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The Journal of Organic Chemistry

Total Synthesis and Structure Revision of (±)-Clavilactone D Through Selective Cyclization of an α,β-Dicarbonyl Peroxide Leiyang Lv, † Barry B. Snider‡ and Zhiping Li*† †

‡

Department of Chemistry, Renmin University of China, Beijing 100872, China

Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA *[email protected]

ABSTRACT: The structure of (±)-clavilactone D was revised and the synthesis was achieved in seven steps from a substituted benzaldehyde. The key step was the base-catalyzed cyclization of an α,β-carbonyl peroxide, which was obtained by an iron-catalyzed three-component reaction of a benzaldehyde, an alkene, and TBHP. NaBH4-mediated

reductive

lactonization

of

the

resulting

cis-dicarbonyl

epoxide

led

to

the

α,β-epoxy-γ-butyrolactone skeleton highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.

Clavilactones A-E, isolated from cultures of the Basidiomycetous fungus Clitocybe clavipes,1 are antifungal candidates and potent kinase inhibitors against Ret/ptc1and epidermal growth factor receptor (EGF-R) tyrosine kinases (see Figure 1).2 The clavilactones have novel structures with a ten-membered carbocycle fused to an α,β-epoxy-γ-butyrolactones and a benzoquinone or hydroquinone (Figure 1). The intriguing structures of the clavilactones and their significant biological properties have attracted the interest of chemists and the groups of

ACS Paragon Plus Environment


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Barrett,3 Takao,4 Yoshimitsu,5 and Li6 have achieved the synthesis of clavilactones A and B (1 and 2). Our synthetic strategy was based on the efficient and stereoselective construction of α,β-epoxy-γ-butyrolactone skeleton.6 Unfortunately, we found that neither the spectroscopic data of synthetic 5, the originally proposed structure of clavilactone D, nor its regioisomer 6 matched exactly with those of the natural product.6 However, at that time, we didn’t determine the correct structure of clavilactone D. In the original isolation report it was suggested that m/z 302 was M+ from CIMS (CH4). This seems to be incorrect because chemical ionization with methane leads to MH+, not M+, so the hydroxyquinone should show an MH+ at 303. In the CIMS spectrum of clavilactone E an MH+ is observed as expected. MH+ for an amino quinone would be 302. Comprehensive analysis of the mass spectral and NMR spectroscopic data suggested that an amino group (-NH2) instead of a hydroxy group (-OH) was likely attached to the benzoquinone skeleton of clavilactone D (7 or 8). We report here the synthesis of aminobenzoquione 8 and that both the mass spectral and NMR data of 8 are fully consistent with those of natural isolated clavilactone D. During the preparation of our manuscript, Takao and colleagues reported the total syntheses of both 7 and 8 and concluded that 8 was the correct structure of clavilactone D.7


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Figure 1. Structures of clavilactones. Herein, we disclose our total synthesis of the revised structure of (±)-clavilactone D (8) through the base-catalyzed cyclization of β-carbonyl peroxide 12 that selectively constructs highly functionalized epoxide 13, which can be reduced to the α,β-epoxy-γ-butyrolactone moiety of the clavilactones. Organic peroxides are receiving considerable attention in both biochemistry and synthetic chemistry and are used in the pharmaceutical industry.8-12 For example, the antimalarial drug artemisinin contains a bridged O-O bond, which plays a key role in its antimalarial activity.13 Recently, we developed an iron-catalyzed three-component strategy for the synthesis of a variety of β-carbonyl peroxides,14 which were transformed into cis-dicarbonyl epoxides efficiently and selectively by amine and/or lithium salt catalysis.15,16 Based on these results, our retrosynthetic analysis of the revised structure of clavilactone D (8) is shown in Scheme 1. The ten-membered carbocycle of 8 can be constructed by RCM of diene 15, which might be prepared by the sequences of cross-coupling reaction of bromoarene 14, which can be prepared by reductive lactonization of epoxide 13. We rationalized that epoxide 13 can be constructed from



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α-ester-β-keto peroxide 12, which can be prepared by our three-component iron-catalyzed strategy from benzaldehyde 11, diene 9, and t-butyl hydroperoxide (TBHP, 10). Scheme 1. Retrosynthetic analysis for the revised structure of clavilactone D

The synthesis started with the preparation of the required aldehyde 11 (Scheme 2). Nitration of 166 proceeded regiospecifically to give the nitro aldehyde 17 as a single isomer whose structure was unambiguously confirmed by X-ray diffraction (see Figure S1 in Supporting Information). Unfortunately, 17 failed to react with 1,5-diene 9 and TBHP 10 to give the expected acylation-peroxidation product. We speculated that the strongly electron-withdrawing nitro group might decrease the stability of the corresponding acyl radical,17 which is an intermediate in the iron-catalyzed acylation-peroxidation reaction. Accordingly, the N,N-dibenzylamino aldehyde was synthesized, but it also failed to undergo the iron-catalyzed acylation-peroxidation reaction, probably due to the coordination of the electron-rich amine to the iron catalyst. Therefore acetyl and trifluoroacetyl protected amino aldehydes 18 and 19 were prepared by reduction of the nitro group with iron powder and acylation. Although


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trifluoroacetylamino aldehyde 19 smoothly underwent the iron-catalyzed acylation-peroxidation reaction and following epoxidation, the reductive lactonization failed. Fortunately, the N-acetylamino aldehyde 18 was suitable. Scheme 2. Preparation of aldehydes

Reagents and conditions: (a) conc. HNO3, CH2Cl2, RT, 1.5 h, 97%; (b) Fe powder, EtOH/HOAc/H2O, reflux, 15 min; (c) AcCl, Pyr, CH2Cl2, RT, 3 h, 95% (two steps); (d) Trifluoroacetic anhydride, Et3N, CH2Cl2, -20 oC, 0.5 h, 51% (two steps). The three-component reaction of diene 9,18 TBHP

(10), and aldehyde 18 using FeCl2 as the catalyst proceeded

smoothly to give the desired β-carbonyl peroxide 12 in 72% yield (Scheme 3). Subsequently, pyrrolidine-catalyzed epoxidation delivered a 10:1 mixture of cis- and trans-13 in 94% yield. Interestingly, trans-13 was obtained as the major isomer when DBU was used as the catalyst. We rationalized that the stereoselectivity of the DBU-catalyzed cyclization is mainly controlled by the steric hindrance. To our delight, we obtained an 11:1 mixture the cis- and trans-13 in 95% yield by DBU/LiBr-cocatalyzed epoxidation.16 We presume that lithium ion coordinates with the two carbonyl groups of 12 to generate a key cyclic intermediate thereby enhancing both the efficiency and diastereoselectivity of the epoxidation as compared to that with only DBU (see Figure 2). Scheme 3. Selective synthesis of cis-epoxide 13



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Figure 2. DBU/LiBr-cocatalyzed diastereoselective epoxidation. NaBH4-mediated reductive lactonization of cis-dicarbonyl epoxide 13 gave α,β-epoxy-γ-butyrolactone 14 highly stereoselectively in 95% yield (Scheme 4). Stille coupling of 14 with tributyl(methallyl)stannane gave 15 (88%), which underwent ring closing metathesis (RCM) to form the ten-membered carbocycle 20 (82%). Oxidative demethylation of 20 by CAN delivered the N-acetylamino benzoquinone 21 (78%), which was hydrolyzed with sulfuric acid in MeOH/THF19 to afford the revised structure of (±)-clavilactone D (8). Gratifyingly, the 1H NMR and 13C NMR spectral data of synthetic 8 are in complete agreement with those of isolated natural clavilactone D20 and Takao’s synthetic clavilactone D.7 The stereochemistry of 8 was further confirmed by the comparison of NMR spectral data between 8 and methoxy analog clavilactone D derivative 22 (Figure 3).6


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Figure 3. Compound 22 and its X-ray structure. Scheme 4. Total synthesis of revised (+) clavilactone D

Reagents and conditions: (a) NaBH4, EtOH, 0 oC, 0.5 h, 95%; (b) tributyl(methallyl)stannane, [Pd(PPh3)4], CsF, MeCN, 100 oC, 6 h, 88%; (c) [Cl2(Cy3P)(sIMes)Ru=CHPh] (20 mol%), tetrafluorobenzoquinone (40 mol %), toluene (1 mM), 80 oC, 6 h, 82%; (d) CAN, MeCN/H2O (3:1), 0 oC, 10 min, 78%; (e) conc. H2SO4, MeOH/THF (3:1), RT, 24 h, 96%. In summary, the total synthesis of the revised structure of (+) clavilactone D was achieved in 10 steps from aldehyde 16 in 32.3% overall yield. The key step is the base-catalyzed cyclization of β-carbonyl peroxide 12 to give cis-13, which is obtained by the ferrous chloride-catalyzed three-component reaction of aldehyde 18, alkene 9, and TBHP 10. NaBH4-mediated reductive lactonization of cis-dicarbonyl epoxide cis-13 leads to



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α,β-epoxy-γ-butyrolactone 14 highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.

Experimental Section General Information. 1H NMR spectra were recorded on 400 MHz spectrometer and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quartet; m, multiplet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were obtained at 100 MHz and referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3, 29.8 ppm in (CD3)2CO). CDCl3 was used as the NMR solvent. Flash column chromatography was performed over silica gel 200-300. Melting points are uncorrected. All reagents were weighed and handled in air at room temperature. All reagents were purchased from commercial source and used without further purification. The HRMS measurements were recorded on a quadrupole analyzer using an ESI source in the positive mode. Synthesis of 17: To a stirred solution of 16 (7.35 g, 50.0 mmol) in CH2Cl2 (200 mL), concentrated nitric acid (60%, 25.4 mL, 400 mmol) was added dropwise to maintain the temperature below 20 oC. After being stirred at room temperature for 1.5 h, the mixture was diluted with H2O (1000 mL) and extracted with CH2Cl2 (200 mL × 3). The extracts were dried and concentrated under reduced pressure. The combined organic phase was washed sequentially with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 17 (14.0 g, 97%) as yellow solid. The product 17 was pure enough and used in the next step without further purification. mp 147.5-148.7 °C. Rf = 0.5 (ethyl acetate/petroleum ether = 1:10); IR (neat): νmax 3084， 2978， 2949， 2897， 1711， 1564， 1522， 1460， 1425，1393， 1362， 1310， 1238， 1078， 991， 937， 870， 779 cm-1; 1H NMR (600 MHz, CDCl3) δ 10.31 (s, 1H), 7.53 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 189.1, 152.5, 147.7, 143.4, 132.4, 119.7, 110.3, 65.6, 57.3; HRMS (ESI) calcd for


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C9H8BrNNaO5 [M + Na+], 311.9478; found: 311.9472. Synthesis of N-acetylamino benzaldehyde 18: To a rapidly stirred solution of 17 (8.7 g, 30.0 mmol) in the mixed solvent EtOH (100 mL)/H2O (30 mL)/HOAc (5.0 mL), Fe power (13.4 g, 240 mmol) was added. After being heated at reflux for 15 min, the mixture was allowed to cool at room temperature. Then ethyl acetate (300 mL) was added, and the mixture was filtered through a Buchner funnel, and the residue was washed with ethyl acetate (50 mL × 8). The combined organic phase was washed sequentially with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude amine, which was used in the next step without further purification. To a stirred solution of crude amine in CH2Cl2 (100 mL) at 0 oC, pyridine (10.4 mL, 90 mmol) and acetyl chloride (2.6 mL, 36 mmol) were added dropwise. After the resulting mixture was stirred at room temperature for 3 h, the mixture was diluted with dilute HCl (2M, 50 mL) and extracted with CH2Cl2 (100 mL × 3). The combined organic phase was washed sequentially with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.4) to give the desired N-acetylamino benzaldehyde 18 (8.6 g, 95%) as yellow solid. mp 129.8-131.2 °C. IR (neat): νmax 3321， 2982，2943， 1694， 1682， 1565， 1457， 1393， 1242， 1221， 1202， 1082， 993， 980 cm-1; 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.39 (s, 1H), 8.00 (br, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.9, 168.8, 152.5, 142.6, 132.4, 127.4, 108.0, 107.9, 63.3, 56.7, 24.8; HRMS (ESI) calcd for C11H13BrNO4 [M + H+], 302.0022; found: 302.0022. Synthesis of N-trifluoroacetylamino benzaldehyde 19: To a stirred solution of crude amine in CH2Cl2 (100 mL) at -20 oC, Et3N (6.3 mL, 45 mmol) and trifluoroacetic anhydride (5.0 mL, 45 mmol) were added dropwise under nitrogen atmosphere. After the resulting mixture was stirred at room temperature for 0.5 h, the mixture was diluted with dilute HCl (2M, 30 mL) and extracted with CH2Cl2 (100 mL × 3). The combined organic phase was



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washed sequentially with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.7) to give the desired N-trifluoroacetylamino benzaldehyde 19 (5.0 g, 51%) as pale yellow solid. mp 125.2-126.5 °C. IR (neat): νmax 3319, 3109, 3057, 2964, 2941, 2854, 1706, 1531, 1468, 1325, 1244, 1165, 1078, 993, 951, 826, 621 cm-1; 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.64 (br, 1H), 8.28 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H);

13C

NMR (100 MHz, CDCl3) δ 190.5, 154.9 (JC-F = 38.0 Hz), 152.9, 143.1, 129.8, 128.0, 115.4 (JC-F =

286.7 Hz), 111.2, 107.7, 63.9, 57.0; HRMS (ESI) calcd for C11H9BrF3NNaO4 [M + Na+], 377.9559; found: 377.9562.

Synthesis of Peroxide 12: To a mixture of 9 2 (280 mg, 2.0 mmol), 18 (3.02 g, 10.0 mmol) and FeCl2 (6.4 mg, 2.5 mmol %), freshly distilled MeCN (15.0 mL) was added under nitrogen at room temperature. Then tert-butyl hydroperoxide (10, 1.5 mL, 8.0 mmol, 5-6 M in decane) was dropped into the mixture. The mixture was stirred under 85 °C for 1 hour. After the resulting solution was cooled to room temperature, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.45) to give the peroxide 12 (763 mg, 72%) as a colourless oil. IR (neat): νmax 3342， 3115， 3078， 2978， 2947， 2860， 1746， 1717， 1701， 1601， 1582， 1506， 1462， 1399， 1364， 1354， 1244， 1200， 1169， 1086， 1069， 999， 912， 872， 858， 818， 737 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.76 (br, 1H), 5.89-5.79 (m, 1H), 5.05 (d, J = 17.4 Hz, 1H), 4.97 (d, J = 10.0 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.61 (d, J = 18.8 Hz, 1H), 3.38 (d, J = 18.8 Hz, 1H), 2.31-2.12 (m, 7H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 199.2, 171.4, 168.5, 152.7, 138.4, 137.9, 137.1, 131.8, 114.6, 104.3, 99.9, 83.4, 79.8, 63.4, 56.6, 51.8, 45.9, 31.1, 27.2, 26.3, 24.8; HRMS (ESI) calcd for C23H32BrNNaO8 [M + Na+], 552.1204; found: 552.1196.


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Synthesis of cis-13 and trans-13: Method A:To a stirred solution of 12 (265 mg, 0.5 mmol) in MeCN (5.0 mL) under nitrogen at 0 °C, pyrrolidine (12 μL,, 0.15 mmol) was added and the resulting mixture was stirred at the same temperature for 12 hour. Then the solvent was evaporated in vacuo. The diastereoselectivity was determined by 1H NMR analysis of the crude product. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:1, Rf = 0.4) to give the combined products cis-13 and trans-13 (214 mg, 94%, dr = 10:1) as pale yellow oils. Method B: To a stirred solution of 12 (265 mg, 0.5 mmol) in MeCN (5.0 mL) under nitrogen at 0 °C, DBU (23 μL, 0.15 mmol) was added and the resulting mixture was stirred at the same temperature for 0.5 hour. The rest of the procedure is similar to method A. This method gave the combined products cis-13 and trans-13 (195 mg, 86%, dr = 1:4). Method C: To a stirred solution of 12 (265 mg, 0.5 mmol) and LiBr (13 mg, 0.3 mmol) in MeCN (5.0 mL) under nitrogen at 0 °C, DBU (23 μL,, 0.15 mmol) was added after 10 min and the resulting mixture was stirred at the same temperature for 0.5 hour. The rest of the procedure is similar to method B. This method gave the combined products cis-13 and trans-13 (216 mg, 95%, dr = 11:1). cis-13: IR (neat): νmax 3358， 3315， 3076， 3005， 2976， 2949， 2856， 1740， 1698， 1597， 1582， 1564， 1462， 1447， 1397， 1341， 1244， 1204， 1150， 1084， 997， 917， 858， 733 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.76 (br, 1H), 5.83-5.73 (m, 1H), 5.05 (dq, J = 17.2, 1.5 Hz, 1H), 4.97 (dq, J = 10.2, 1.5 Hz, 1H), 3.97 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 2.40-2.14 (m, 6H), 1.78-1.71 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 194.9, 168.5, 167.1, 152.8, 139.8, 136.1, 133.9, 132.0, 115.8, 105.7, 101.1, 66.0, 63.8, 62.4, 56.7, 52.5, 32.7, 28.5, 24.8; HRMS (ESI) calcd for C19H22BrNNaO7 [M + Na+], 478.0472; found: 478.0462. trans-13: IR (neat): νmax 3356， 3116， 3078， 3001， 2976， 2945， 2855， 1740， 1699， 1599， 1582， 1506， 1462， 1448， 1397， 1340， 1244， 1220， 1204， 1155， 1084， 997， 916， 860， 723 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.66 (br, 1H), 5.91-5.77 (m, 1H), 5.08 (dd, J = 17.2, 1.5 Hz, 1H), 5.01 (dd, J = 10.2, 1.5 Hz, 1H), 4.16 (s, 1H), 3.91 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 2.36-2.22 (m, 6H), 1.88-1.79 (m, 1H);



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C NMR (100 MHz, CDCl3) δ 195.2, 168.7, 168.6, 153.1, 139.5, 137.0, 134.3, 132.2, 115.6, 105.7, 100.9, 64.3,

63.8, 62.5, 56.8, 53.0, 29.4, 26.0, 25.0; HRMS (ESI) calcd for C19H22BrNNaO7 [M + Na+], 478.0472; found: 478.0463.

Synthesis of lactone 14: To a stirred solution of cis-13 (296 mg, 0.65 mmol) in EtOH (5.0 mL) under nitrogen at 0 °C, NaBH4 (24.0 mg, 0.65 mmol) was added and the resulting mixture was stirred at the same temperature for 1 hour. Then the resulting mixture was quenched by saturated NH4Cl solution and extracted with EtOAc (10 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude products was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:1, Rf = 0.5) to give the desired lactone 14 (262 mg, 95%) as a colourless oil. IR (neat): νmax 3358, 3118, 3078， 3005， 2976， 2941， 2922， 2849， 1784， 1694， 1682， 1584， 1504， 1462， 1403， 1333， 1223， 1084， 1036， 995 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.58 (br, 1H), 6.10 (s, 1H), 5.87-5.79 (m, 1H), 5.07 (dq, J = 17.2, 1.5 Hz, 1H), 5.00 (dd, J = 10.2, 1.5 Hz, 1H), 3.93 (s, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 2.34-2.07 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 172.0, 168.5, 153.2, 142.3, 136.9, 132.1, 126.7, 115.5, 106.4, 105.8, 78.1, 62.7, 62.3, 61.0, 56.8, 27.5, 25.0, 24.0; HRMS (ESI) calcd for C18H20BrNNaO6 [M + Na+], 448.0366; found: 448.0357.

Synthesis of diene 15: To a mixture of 14 (178 mg, 0.42 mmol) and tributyl(2-methallyl)stannane (290 mg, 0.84 mmol) in freshly distilled MeCN (4.0 mL) was added dried cesium fluoride (141 mg, 0.92 mmol) and Pd(PPh3)4 (49 mg, 0.042 mmol) under nitrogen at room temperature. Then the mixture was heated at 100 oC for 6 hours. After the resulting mixture was cooled to room temperature, a small amount of silica was added. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:1, Rf = 0.5) to give the desired diene 15 (148 mg, 88%) as a pale yellow oil. IR (neat):


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νmax 3312， 3078， 2940， 2853， 1780， 1674， 1601， 1514， 1464， 1410， 1331， 1250， 1221， 1194， 1121， 1080， 1032， 974， 920， 893， 800， 735 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.49 (br, 1H), 5.86-5.76 (m, 1H), 5.51 (s, 1H), 5.05 (d, J = 17.2, 1H), 4.98 (d, J = 10.2, 1H), 4.78 (s, 1H), 4.30 (s, 1H), 3.79 (s, 3H), 3.75 (s, 1H), 3.60 (s, 3H), 3.53 (d, J = 17.2 Hz, 1H), 3.28 (d, J = 17.2 Hz, 1H), 2.32-2.01 (m, 7H), 1.77 (s, 3H);

13C

NMR (100 MHz, CDCl3) δ 172.2, 168.3, 154.2, 144.4, 142.3, 137.0, 130.7,

126.0, 122.9, 115.3, 111.0, 105.8, 76.2, 62.9, 62.0, 60.9, 56.2, 33.0, 27.4, 24.8, 24.1, 22.8; HRMS (ESI) calcd for C22H27NNaO6 [M + Na+], 424.1731; found: 424.1721.

Synthesis of 20: To the solution of 15 (126 mg, 0.3 mmol) in toluene (200.0 mL), Grubbs catalyst second generation (50 mg, 60 µmol) in toluene (50.0 mL) and tetrafluoro-p-benzoquinone (22 mg, 0.12 mmol) in toluene (50.0 mL) were added simultaneously via syringe pump over 6 hours at 80 ºC and nitrogen was bubbled through the reaction mixture during the course of the reaction. After the mixture cooled at room temperature, solvent was evaporated in vacuo and the crude mixture was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:1, Rf = 0.4) to give the desired product 20 (92 mg, 82%) as a blue oil. IR (neat): νmax 3343， 2940， 2880， 1778， 1694， 1682， 1601， 1510， 1462， 1456， 1408， 1348， 1337， 1244， 1227， 1120， 1148， 1099， 1013 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.81 (br, 1H), 5.99 (s, 1H), 5.22 (t, J = 7.8 Hz, 1H), 4.02 (s, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.65 (d, J = 15.8 Hz, 1H), 2.93 (d, J = 15.8 Hz, 1H), 2.69 (d, J = 13.8 Hz, 1H), 2.43 (q, J = 13.8 Hz, 1H), 2.22 (s, 3H), 2.17-2.11 (m, 1H), 1.47 (s, 3H), 1.25 (dt, J = 13.8, 2.6 Hz, 1H);

13C

NMR (100 MHz, CDCl3) δ 172.0, 168.6, 155.2, 141.8, 137.8, 130.7, 125.9,

123.6, 121.8, 105.1, 75.3, 63.2, 62.9, 61.5, 55.8, 27.0, 25.0, 24.9, 22.3, 21.2; HRMS (ESI) calcd for C20H23NNaO6 [M + Na+], 396.1418; found: 396.1415.



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Synthesis of quinone 21: To the solution of 20 (60 mg, 0.16 mmol) in MeCN (3.0 mL) at 0 ºC, CAN (219 mg, 0.4 mmol) in H2O (1.0 mL) was added. After 10 min, the reaction mixture was extracted with EtOAc (5 mL × 3). The combined organic layers were washed by brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude products was purified by flash column chromatography on silica gel (dichloromethane/methanol = 30:1, Rf = 0.3) to give the desired quinone 21 (43 mg, 78%) as a yellow solid. mp 183.2 °C (decomposition). IR (neat): νmax 3345， 1778， 1642， 1602， 1335， 1100 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.16 (br, 1H), 7.72 (s, 1H), 6.06 (s, 1H), 5.34 (t, J = 7.8 Hz, 1H), 3.98 (s, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.92 (d, J = 13.8 Hz, 1H), 2.71 (d, J = 13.0 Hz, 1H), 2.38 (q, J = 11.0 Hz, 1H), 2.27 (s, 3H), 2.25-2.21 (m, 1H), 1.49 (s, 3H), 1.32-1.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 185.9, 181.2, 171.0, 169.2, 151.1, 137.8, 134.8, 134.1, 124.0, 115.1, 71.5, 62.5, 60.5, 26.9, 24.9, 24.5, 22.9, 22.7. HRMS (ESI) calcd for C18H17NNaO6 [M + Na+], 366.0948; found: 366.0944.

Synthesis of the revised structure of (±)-clavilactone D 8: To a solution of 21 (30 mg, 0.087 mmol) in MeOH (3.0 mL)/THF (1.0 mL) at room temperature, conc. H2SO4 (175 μL, 3.2 mmol) was added. The resulting red mixture was stirred further for 24 hour. Then H2O was added and the reaction mixture was extracted with EtOAc (5.0 mL × 3). The combined organic layers were washed sequentially with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude products was purified by flash column chromatography on silica gel (dichloromethane/methanol = 30:1, Rf = 0.2) to give the desired clavilactone D (8) (25 mg, 96%) as a red solid. mp 165.2 °C (decomposition). IR (neat): νmax 3452， 1778， 1641， 1603， 1331， 1234， 1099， 617 cm-1; 1H NMR (400 MHz, (CD3)2CO) δ 6.56 (br, 2H), 5.99 (s, 1H), 5.90 (s, 1H), 5.39-5.38 (m, 1H), 4.42 (s, 1H), 3.65 (d, J = 14.0 Hz, 1H), 2.86 (d, J = 14.0 Hz, 1H), 2.63-2.61 (m, 1H), 2.38-2.36 (m, 1H), 2.28-2.24 (m, 1H), 1.57 (s, 3H), 1.37-1.35 (m, 1H); 13C NMR (100 MHz, (CD3)2CO) δ 184.2, 183.3, 172.6, 151.3, 148.9, 136.5, 134.5, 124.1, 101.8, 73.2, 63.6, 61.2, 27.3, 25.2, 23.3, 23.0. HRMS (ESI) calcd for C16H16NO5 [M + H+], 302.1023; found: 302.1022 and C16H15NNaO5 [M + Na+], 324.0842; found: 324.0842.


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AUTHOR INFORMATION

Corresponding Author *[email protected] ORCID Zhiping Li: 0000-0001-7987-279X Notes The authors declare no competing financial support.

ACKNOWLEDGMENT

Financial support from the National Science Foundation of China (21672259).

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

X-ray crystallographic data of compound 17 (CIF)

X-ray crystallographic data of compound 22 (CIF)

Copies of 1H and 13C NMR spectra for all new compounds (PDF)

REFERENCES (1) (a) Arnone, A.; Cardillo, R.; Meille, S. V.; Nasini, G.; Tolazzi, M. J. Chem. Soc. Perkin Trans. 1 1994, 2165. (b) Merlini, L.; Nasini, G.; Scaglioni, L.; Cassinelli, G.; Lanzi, C. Phytochemistry 2000, 53, 1039. (2) Cassinelli, G.; Lanzi, C.; Pensa, T.; Gambetta, R. A.; Nasini, G.; Cuccuru, G.; Cassinis, M.; Pratesi, G.; Polizzi,



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D.; Tortoreto, M.; Zunino, F. Biochem. Pharmacol. 2000, 59, 1539. (3) Larrosa, I.; Da Silva, M. I.; Gόmez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042. (4) (a) Takao, K.; Nanamiya, R.; Fukushima, Y.; Namba, A.; Yoshida, K.; Tadano, K. Org. Lett. 2013, 15, 5582. (b) Yasui, H.; Yamamoto, S.; Takao, K.; Tadano, K. Heterocycles 2006, 70, 135. (5) (a) Suizu, H.; Shigeoka, D.; Aoyama, H.; Yoshimitsu, T. Org. Lett. 2015, 17, 126. (b) Yoshimitsu, T.; Nojima, S.; Hashimoto, M.; Tsukamoto, K.; Tanaka, T. Synthesis 2009, 17, 2963. (6) Lv, L.; Shen, B.; Li, Z. Angew. Chem. Int. Ed. 2014, 53, 4164. (7) Takao, K.; Nemoto, R.; Mori, K.; Namba, A.; Yoshida, K.; Ogura, A. Chem. Eur. J. 2017, 23, 3828. (8) Cheng, J.-K.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 42. (9) Schweitzer-Chaput, B.; Demaerel, J.; Engler, H.; Klussmann, M. Angew. Chem. Int. Ed. 2014, 53, 8737. (10) Willand-Charnley, R.; Puffer, B. W.; Dussault, P. H. J. Am. Chem. Soc. 2014, 136, 5821. (11) (a) Jiang, J.; Liu, J.; Yang, L.; Shao, Y.; Cheng, J.; Bao, X.; Wan, X. Chem. Commun. 2015, 51, 14728. (b) Shi, E.; Liu, J.; Liu, C.; Shao, Y.; Wang, H.; Lv, Y.; Ji, M.; Bao, X.; Wan, X. J. Org. Chem. 2016, 81, 5878. (12) (a) Lu, S.; Qi, L.; Li, Z. Asian J. Org. Chem. 2017, 6, 313. (b) Zheng, X.; Lv, L.; Lu, S.; Wang, W.; Li, Z. Org. Lett. 2014, 16, 5156. (c) Zheng, X.; Lu, S.; Li, Z. Org. Lett. 2013, 15, 5432. (13) (a) Zhou, W. S.; Xu, X. X. Acc. Chem. Res. 1994, 27, 211. (b) Wu, Y. Acc. Chem. Res. 2002, 35, 255. (c) Graham, I. A.; Besser, K.; Blumer, S.; Branigan, C. A.; Czechowski, T.; Elias, L.; Guterman, I.; Harvey, D.; Isaac, P. G.; Khan, A. M.; Larson, T. R.; Li, Y.; Pawson, T.; Penfield, T.; Rae, A. M.; Rathbone, D. A.; Reid, S.; Ross, J.; Smallwood, M. F.; Segura, V.; Townsend, T.; Vyas, D.; Winzer, T.; Bowles, D. Science 2010, 327, 328. (14) (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am. Chem. Soc. 2011, 133, 10756. (b) Liu, K.; Li, Y.; Zheng, X.; Liu, W.; Li, Z. Tetrahedron 2012, 68, 10333. (c) Zong, Z.; Lu, S.; Wang, W.; Li, Z. Tetrahedron Lett. 2015, 56, 6719.


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(15) Liu, K.; Li, Y.; Liu, W.; Zheng, X.; Zong, Z.; Li, Z. Chem. Asian. J. 2013, 8, 359. (16) Zong, Z.; Bai, X.; Lu, S.; Li, Z. Tetrahedron Lett. 2016, 57, 3827. (17) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991. (18) Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61, 5743. (19) Behforouz, M.; Haddad, J.; Cai, W.; Gu, Z. J. Org. Chem. 1998, 63, 343. (20) We are grateful to Prof. L. Merlini and Dr. L.Scaglioni for providing the original spectra of natural isolated clavilactone D.


Total Synthesis and Structure Revision of (Â±)-Clavilactone D Through

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