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Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization
Accepted Manuscript Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization Miyu Furuta, Kengo Hanaya, Takeshi Sugai, Mitsuru Shoji PII:
S0040-4020(17)30247-8
DOI:
10.1016/j.tet.2017.03.021
Reference:
TET 28527
To appear in:
Tetrahedron
Received Date: 30 January 2017 Revised Date:
6 March 2017
Accepted Date: 7 March 2017
Please cite this article as: Furuta M, Hanaya K, Sugai T, Shoji M, Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization
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Miyu Furuta, Kengo Hanaya, Takeshi Sugai, Mitsuru Shoji* 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University
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Tetrahedron journal homepage: www.elsevier.com
Miyu Furuta, Kengo Hanaya, Takeshi Sugai, and Mitsuru Shoji∗
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Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Limonoids are characterized by a polycyclic structure and show a wide variety of bioactivities. In particular, mesendanin L, 12-hydroxyamoorastatone, and meliatoosenin F have unique structures containing a trans-A/B/C and cis-C/D-fused tetracyclic skeleton. We synthesized the core structure of these limonoids via Mn(OAc)3 and Cu(OAc)2-mediated radical domino cyclization of an acyclic tetraene precursor having a terminal β-keto ester. To the best of our knowledge, this is the first example of the radical-mediated construction of a 6/6/6/5-membered tetracyclic skeleton.
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Keywords: Limonoid Tetracyclic core Domino cyclization Radical cyclization Stereoselective
1. Introduction
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Limonoids, which belong to the class of phytochemicals, are widely distributed in citrus fruits and in other plants of the Rutaceae and Meliaceae families. These compounds are known to show diverse bioactivities.1 For example, mesendanin L (1, Fig. 1) was isolated from the bark of Melia azedarach and found to exhibit cytotoxicity against the human cell line HL-60.2 12Hydroxyamoorastatone (2) was isolated from the seeds of the Eastern Himalayan plant Aphanamixis grandifolia Bl and showed cytotoxicity against the human tumor cell lines A-549 and SK-
Fig. 1. Structures of mesendanin L (1), 12-hydroxyamoorastatone (2), and meliatoosenin F (3).
2009 Elsevier Ltd. All rights reserved.
MEL-2.3 Meliatoosenin F (3) was isolated from the fruits of Melia toosendan4 and its bioactivity is unknown. As compounds 1− 3 have oxygen substituents on the C ring and a rare transA/B/C and cis-C/D-fused tetracyclic structure, development of their synthetic methodology is significant.
The unique polycyclic skeletons of terpenoids and steroids have attracted the attention of the synthetic chemistry community. Corey and Behenna prepared the tetracyclic moiety of a protolimonoid via the Lewis acid-mediated polycyclization of epoxypolyene.5 MacMillan and Rendler reported the imidazolidinone-catalyzed enantioselective radical polycyclization of polyene possessing a terminal formyl group.6 While these research groups elegantly constructed the polycyclic skeleton, there were no oxygen substituents on the C ring, as shown for limonoids 1–3. Recently, our group achieved the stereoselective preparation of cis-decalin7a and pseudoenantiomers for the ABC-ring moiety of steroids7b by modifying Zoretic’s polycyclization conditions.8 We herein constructed a trans,trans,cis-fused tetracyclic skeleton with an oxygen substituent on the C ring via manganese(III) and copper(II)-mediated radical domino cyclization. We envisaged that tetracyclic β-keto ester 4 could be constructed from tetraene 6 via Mn(III)/Cu(II)-mediated radical domino cyclization (Scheme 1). An electrophilic carbon radical tends to react with an electron-rich alkene to form a carboncarbon bond and thus becomes nucleophilic. For this reason, cyclization precursor 6 was designed such that it had alternate
——— ∗ Corresponding author. Tel. & fax: +3-5400-2695; e-mail: [email protected]
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Scheme 1. Retrosynthesis of trans,trans,cis-tetracyclic skeleton.
butyldimethylsilyl (TBS) group was removed under acidic conditions to produce another propargyl alcohol 14. Regioselective hydroalumination11 of 14, followed by iodination, furnished vinyl iodide 15. Reprotection of the allylic alcohol of 15 as TBS ether and conversion of the iodine atom into a benzyloxymethyl group by treatment with sec-butyl lithium and benzyloxymethyl (BOM) chloride afforded benzyl ether 16, which possessed an oxygen functional group at the C18 position.
2. Results and discussion
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electron-donating and electron-withdrawing groups on the alkene moiety for effective carbon-carbon bond formation between the electrophilic radical and the electron-rich alkene, or between the nucleophilic radical and the electron-deficient alkene. Transition state 5b shows 1,3-diaxial repulsion between the C11-benzyloxy and C13-benzyloxy groups; hence, we expected the domino cyclization to proceed via intermediate 5a. The cyclization precursor 6 would be prepared by the Horner–Wadsworth– Emmons reaction between cyanophosphonate 88 and αbenzyloxyaldehyde 9, followed by alkylation with methyl 2chloroacetoacetate (7) and cross metathesis with methyl acrylate (10). The alkoxy group on C18-position in 9 would be helpful to prepare the various analogs of the limonoids for structure-activity relationship studies.
Removal of the triisopropylsilyl (TIPS) group on 18 generated primary alcohol 20 (Scheme 3). Oxidation of 20 with Dess– Martin periodinane and Horner–Wadsworth–Emmons reaction of the resulting aldehyde with cyanophosphonate 88 afforded α,β-
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The synthesis of 6 was commenced from a known epoxide (±)-119 derived from commercially available glycidol (Scheme 2). Treatment of 11 with lithium acetylide derived from propargyl alcohol10 afforded secondary alcohol 13. The hydroxyl group of 13 was protected as a benzyl ether and the tert-
Then, the TBS group on 16 was removed, and the resulting hydroxy group was substituted with a bromine atom via mesylate to afford allylic bromide 17. Alkylation of 17 with allylmagnesium bromide in the presence of copper iodide gave the desired 1,5-diene 18. The undesired conjugated diene 19 was also formed via elimination of both the bromine atom and the benzyloxy group, but this reaction could be suppressed by the addition of HMPA.
Scheme 2. Synthesis of 1,5-diene 18.
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Fig. 2. Stereostructure of tetracyclic β-keto esters 25.
Scheme 3. Preparation of cyclization precursor 6.
3. Conclusion
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In conclusion, we synthesized for the first time a tetracyclic βketo ester, the core structure of limonoids. The key step in our strategy is the radical domino cyclization of a functionalized acyclic tetraene. The proposed methodology would be useful for the preparation of various trans-A/B/C and cis-C/D-fused tetracyclic keto esters. Deprotection-oxidation at C11 and functionalization at C17 should provide various limonoid analogs for structure-activity relationship studies.
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unsaturated nitrile 21 as a single isomer. Removal of the tetrahydropyranyl (THP) group on tetraene 21, followed by mesylation with methanesulfonic anhydride and substitution with bromide, afforded a primary allylic bromide. Alkylation of the bromide with a dianion derived from methyl 2-chloroacetoacetate (7)7b afforded β-keto ester 22. Subsequently, cross metathesis of the terminal alkene with methyl acrylate (10) furnished 6, which possessed an α,β-unsaturated ester and the desired geometry in the double bonds.
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and 4.00 ppm (ddd, J = 4.0, 9.6, 9.6 Hz, axial), respectively.7b Along with the NOESY signals between H9 and H11, the 1H NMR signal of the 11-position for compound 25 appearing at 3.84 ppm (ddd, J = 2.9, 2.9, 2.9 Hz) indicated that the proton at 11-position located in equatorial position.
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With the cyclization precursor in hand, we focused our attention on the radical domino cyclization (Scheme 4). Treatment of α,β-unsaturated ester 6 with manganese(III) and copper(II) acetates in ethanol7b gave only trace amounts of the imperfect tricyclic β-keto ester 24. The failure of the fourth cyclization could be attributed the steric hindrance of the methoxycarbonyl group at C18. Therefore, carbon-carbon bond formation between the radical on C13 and the electron-deficient carbon on C17 would be suppressed. For this reason, we expected to achieve the fourth cyclization using β-keto ester 22, which possess a terminal alkene. Radical domino cyclization of 22 gave many kinds of cyclized products, and only 25 was isolated as the tetracyclic β-keto ester, along with tricyclic β-keto ester 26 as the major byproduct. NOESY analysis revealed the stereochemistry of 25 to be trans-A/B/C and cis-C/D-fused, as shown in Fig. 2. We have prepared the two tricyclic compounds via the radical domino cyclization and the 1H NMR signals of the 11-position of the two diastereomers were 4.05 (brs, equatorial)
Scheme 4. Radical domino cyclization of acyclic tetraenes.
4. Experimental section
4.1. General methods Merck silica gel 60 F254 thin-layer plates (1.05744, 0.5 mm thickness) was used for preparative thin-layer chromatography. Merck silica gel 60 F254 thin-layer plates (1.05715) was used for thin-layer chromatography. Silica gel 60 (spherical and neutral; 63-210 µm, 37560-79) from Kanto Chemical Co. was used for column chromatography.
IR spectra were measured as thin films for oils on a JEOL FTIR SPX60 spectrometer. 1H NMR spectra were measured at 400 MHz on a VARIAN 400-MR spectrometer 500 MHz on a VARIAN 500-MR spectrometer or 600 MHz on a JEOL JNMECP 600 spectrometer and 13C NMR spectra were measured at 100 MHz on a VARIAN 400-MR or at 125 MHz on a VARIAN 500-MR or at 150 MHz on a JEOL JNM-ECP 600 spectrometer. High resolution mass spectra were recorded on a JEOL JMST100LP Accu TOF spectrometer. IR spectra were measured as thin films for oil or ATR for solid. 1H and 13C NMR spectra were measured in CDCl3 at 400 and 100 MHz, respectively. HRMS analyses were recorded on a FAB-MS mass spectrometer. Column chromatography was performed on silica gel. 4.2. (2R*)-6-(tert-Butyldimethylsilyl)oxy-1[(triisopropylsilyl)oxy]hex-4-yn-2-ol (13) To a solution of alkyne 1210 (2.22 g, 13.0 mmol) in dry THF (25 mL) was added n-butyl lithium (8.35 mL, 13.0 mmol, 1.56 M in hexane) and the mixture was stirred for 30 min at 0 °C under argon atmosphere. To the mixture was added boron trifluoride diether complex (1.64 mL, 13.0 mmol) and a solution of epoxide (±)-119 (2.00 g, 8.69 mmol) in dry THF (15 mL) at –78 °C. The mixture was stirred for 15 min at that temperature. The reaction was quenched with saturated NaHCO3 aq. and the organic materials were extracted with AcOEt three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by
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mmol) at –78 °C and stirred for 20 h at room temperature. The silica gel column chromatography with hexane-AcOEt (98:2– MANUSCRIPT ACCEPTED reaction was quenched with Na2S2O3 aq. and the organic 89:11) to afford 13 (3.34 g, 96%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 0.08 (s, 6H), 0.88 (s, 9H), 1.02–1.11 (m, materials were extracted with AcOEt twice. Aqueous layer was 3H), 1.06 (d, J = 6.1 Hz, 18H), 2.40 (brs, 1H), 2.43–2.46 (m, added 2 M HCl aq. and the organic materials were extracted with 2H), 3.64–3.68 (m, 1H), 3.76–3.80 (m, 2H), 4.27 (t, J = 2.2 Hz, AcOEt twice. The combined organic layers were washed with 2H); 13C NMR (CDCl3, 125 MHz) δ –5.2 (2C), 11.8 (3C), 17.9 brine, dried over anhydrous Na2SO4 and concentrated in vacuo. (6C), 18.3, 23.4, 25.8 (3C), 51.9, 65.9, 70.3, 80.8, 81.0; IR νmax The residue was purified by silica gel column chromatography 3410, 2943, 2897, 2806, 2719, 2362, 2339, 1464, 1383, 1367, with hexane-AcOEt (50:1–10:1) to afford 15 (1.14 g, 82%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.01–1.11 (m, 3H), 1252, 1138, 1119, 1078, 1014, 997, 970, 939, 835 cm–1; HRMS (ESI): calcd for C21H44O3Si2Na: [M+Na]+: 423.2727; found: 1.05 (d, J = 5.1 Hz, 18H), 1.63 (brs, 1H), 2.69 (dd, J = 7.6, 14.4 423.2719. Hz, 1H), 2.80 (dd, J = 3.3, 14.4 Hz, 1H), 3.66–3.70 (m, 1H), 3.77-3.80 (m, 2H), 4.14 (d, J = 5.8 Hz, 2H), 4.58 (d, J = 11.7 Hz, 4.3. (5R*)-5-Benzyloxy-6-[(triisopropylsilyl)oxy]hex-2-ynol (14) 1H), 4.68 (d, J = 11.7 Hz, 1H), 5.92 (t, J = 5.8 Hz, 1H), 7.25– 7.33 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 11.9 (3C), 18.0 To a suspension of sodium hydride (60% in mineral oil, 367 (6C), 47.8, 64.8, 67.3, 72.8, 78.5, 105.8, 127.6, 127.9 (2C), 128.3 mg, 9.18 mmol) in dry DMF (10 mL) was added 13 (3.34 g, 8.34 (2C), 136.3, 138.6; IR νmax 3377, 3032, 2941, 2891, 2863, 2364, mmol) in dry DMF (20 mL) and benzyl bromide (990 µL, 8.34 2321, 1647, 1497, 1462, 1423, 1381, 1348, 1365, 1252, 1207, mmol) at 0 °C under argon atmosphere. The mixture was stirred 1117, 1092, 1068, 1012, 997, 918, 881 cm–1; HRMS (ESI): calcd for 2 h at that temperature. The reaction was quenched with 2 M for C22H37IO3SiNa: [M+Na]+: 527.1454; found: 527.1467. NaOH aq. and the organic materials were extracted with Et2O three times. The combined organic layers were washed with 4.5. (Z)-(5R*)-5-Benzyloxy-3-(benzyloxy)methyl-1-(tertsaturated NH4Cl aq. and brine. The solution was dried over butyldimethylsilyl)oxy-6-[(triisopropylsilyl)oxy]hex-2-ene (16) anhydrous Na2SO4, and concentrated in vacuo. The residue was To a solution of 15 (859 mg, 1.69 mmol) in dry DMF (6 mL) purified by silica gel column chromatography with hexanewas added imidazole (177 mg, 2.60 mmol) and TBSCl (288 mg, AcOEt (98:2–90:10) to afford corresponding benzyl ether 27 2.20 mmol) at 0 °C under argon atmosphere. The mixture was (3.31 g, 81%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 0.09 stirred for 20 h at room temperature. The reaction was quenched (s, 6H), 0.88 (s, 9H), 1.01–1.09 (m, 3H), 1.04 (d, J = 4.9 Hz, with H2O and the organic materials were extracted with Et2O 18H), 2.46 (tdd, J = 2.2, 5.6, 16.8 Hz, 1H), 2.55 (tdd, J = 2.2, 5.6, three times. The combined organic layers were washed with brine 16.8 Hz, 1H), 3.58–3.63 (m, 1H), 3.77 (d, J = 5.6 Hz, 2H), 4.28 twice, dried over anhydrous Na2SO4, and concentrated in vacuo. (t, J = 2.2 Hz, 2H), 4.66 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 11.7 The residue was purified by silica gel column chromatography Hz, 1H), 7.23–7.26 (m, 1H), 7.29–7.33 (m, 2H), 7.35 (d, J = 6.8 with hexane-AcOEt (1:0–50:1) to afford corresponding TBS Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ –5.2 (2C), 11.9 (3C), ether 28 (1.02 g, 97%) as a colorless oil. 1H NMR (CDCl3, 500 17.87, 17.90, 18.0 (4C), 18.3, 21.6, 25.8, 25.9 (2C), 52.0, 64.9, MHz) δ 0.07 (s, 6H), 0.89 (s, 9H), 1.01–1.11 (m, 3H), 1.05 (d, J 72.1, 78.3, 80.0, 81.9, 127.5, 127.8 (2C), 128.3 (2C), 138.6; IR = 5.4 Hz, 18H), 2.68 (dd, J = 6.9, 14.4 Hz, 1H), 2.79 (brd, J = νmax 2929, 2941, 2895, 2864, 2721, 2368, 1734, 1461, 1363, 14.4 Hz, 1H), 3.65–3.70 (m, 1H), 3.74–3.80 (m, 2H), 4.19 (d, J = 1252, 1140, 1076, 1028, 999, 918, 881, 835 cm–1; HRMS (ESI): 4.9 Hz, 2H), 4.60 (d, J = 11.7 Hz, 1H), 4.66 (d, J = 11.7 Hz, 1H), calcd for C28H50O3Si2Na: [M+Na]+: 513.3196; found: 513.3207. 5.89 (t, J = 4.9 Hz, 1H), 7.23–7.35 (m, 5H); 13C NMR (CDCl3, To a solution of corresponding benzyl ether 27 (2.76 g, 5.62 125 MHz) δ –5.2 (2C), 11.9 (3C), 18.0 (6C), 18.3, 25.9 (3C), mmol) in MeOH (12 mL) and THF (2 mL) was added pyridinium 47.6, 64.8, 68.5, 72.7, 78.6, 102.5, 127.5, 127.9 (2C), 128.3 (2C), p-toluenesulfonate (147 mg, 0.585 mmol) and the mixture was 137.3, 138.7; IR νmax 3030, 2941, 2927, 2864, 2717, 2360, 2343, stirred for 12 h at room temperature. The reaction mixture was 1647, 1462, 1388, 1360, 1348, 1252, 1205, 1099, 1065, 1005, concentrated and added saturated NaHCO3 aq. The organic 881 cm–1; HRMS (ESI): calcd for C28H51IO3Si2Na: [M+Na]+: materials were extracted with AcOEt three times. The combined 641.2319; found: 641.2333. organic layers were washed with brine, dried over anhydrous To a solution of corresponding TBS ether 28 (79.2 mg, 0.128 Na2SO4, and concentrated in vacuo. The residue was purified by mmol) in dry Et2O (0.9 mL) was added sBuLi (246 µL, 0.256 silica gel column chromatography with hexane-AcOEt (96:4– mmol, 1.04 M in cyclohexane, n-hexane), and the mixture was 72:28) to afford 14 (2.12 g, 94%) as a colorless oil. 1H NMR stirred for 10 min at –78 °C under argon atmosphere. To the (CDCl3, 500 MHz) δ 1.01–1.11 (m, 3H), 1.04 (d, J = 4.9 Hz, mixture was added benzyl chloromethyl ether (31.6 µL, 0.230 18H), 1.75 (brs, 1H), 2.48 (tdd, J = 2.2 5.6, 16.8 Hz, 1H), 2.56 mmol) and Et2O (0.1 mL) at that temperature. The solution was (tdd, J = 1.9, 5.6, 16.8 Hz, 1H), 3.59–3.63 (m, 1H), 3.77 (dd, J = warmed to 0 °C and stirred for 1 h. The reaction was quenched 5.6, 10.3 Hz, 1H), 3.78 (dd, J = 5.6, 10.3 Hz, 1H), 4.20 (brs, 2H), with Et3N and H2O, and the organic materials were extracted 4.67 (s, 2H), 7.26 (t, J = 7.8, 1H), 7.32 (dd, J = 7.1, 7.8 Hz, 2H), with AcOEt three times. The combined organic layers were 7.35 (d, J = 7.1 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 11.9 washed with brine, dried over anhydrous Na2SO4, and (3C), 17.7, 17.9 (5C), 21.6, 51.3, 64.6, 72.0, 78.0, 79.8, 83.0, concentrated in vacuo. The residue was purified by silica gel 127.6, 127.8 (2C), 128.3 (2C), 138.4; IR νmax 3388, 3032, 2940, column chromatography with hexane-AcOEt (1:0–50:1) to afford 2922, 2864, 2362, 2341, 2225, 1497, 1456, 1423, 1383, 1352, 16 (59.1 mg, 75%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) 1313, 1252, 1209, 1107, 1066, 1012, 918, 881 cm–1; HRMS + δ 0.02 (s, 6H), 0.87 (s, 9H), 1.01–1.07 (m, 3H), 1.04 (d, J = 5.4 (ESI): calcd for C22H36O3SiNa: [M+Na] : 399.2354; found: Hz, 18H), 2.28 (dd, J = 7.1, 13.9 Hz, 1H), 2.43 (dd, J = 4.6, 13.9 399.2331. Hz, 1H), 3.63 (dddd, J = 4.6, 4.6, 5.8, 7.1 Hz, 1H), 3.66 (dd, J = 4.4. (Z)-(5R*)-5-Benzyloxy-3-iodo-6-[(triisopropylsilyl)oxy]hex4.6, 10.0 Hz, 1H), 3.74 (dd, J = 5.8, 10.0 Hz, 1H), 3.91 (d, J = 2-enol (15) 11.5 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 4.18 (d, J = 6.1 Hz, 2H), 4.39 (d, J = 11.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.55 (d, J = To a solution of 14 (1.03 g, 2.74 mmol) in dry Et2O (15 mL) 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 5.61 (t, J = 6.3 Hz, 1H), was added Red-Al® (1.04 mL, 3.56 mmol, 65% in toluene 7.22–7.32 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ –5.2 (2C), solution) at 0 °C and the mixture was stirred for 3 h at room 11.9 (3C), 18.0 (6C), 18.3, 25.9 (3C), 37.5, 60.0, 66.0, 67.6, 72.0, temperature. To the mixture was added iodine (904 mg, 3.56
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initiated, a solution of allyl bromide (390 µL, 4.50 mmol) in dry 72.2, 78.9, 127.3, 127.5, 127.7 (2C), 127.8 ACCEPTED (2C), 128.2 (2C), MANUSCRIPT Et2O (4.5 mL) was added dropwise. To a copper(I) iodide (31.4 128.3 (2C), 131.6, 134.1, 138.3, 139.0; IR νmax 3031, 2941, 2927, 2864, 2719, 2362, 2343, 1497, 1462, 1383, 1360, 1311, 1252, mg, 0.165 mmol) were added a solution of 17 (93.6 mg, 0.165 1205, 1068, 1027, 1007, 881 cm–1; HRMS (ESI): calcd for mmol) in HMPA (800 µL) and dry THF (800 µL). The solution C36H60O4Si2Na: [M+Na]+: 635.3928; found: 635.3946. was added the above allyl magnesium bromide (2.14 mL, 1.07 mmol, ca. 1.0 M in Et2O) and the mixture was stirred for 1 h at 0 4.6. (Z)-(5R*)-5-Benzyloxy-3-(benzyloxy)methyl-1-bromo-6°C under argon atmosphere. The reaction was quenched with [(triisopropylsilyl)oxy]hex-2-ene (17) saturated NH4Cl aq. and the organic materials were extracted with AcOEt three times. The organic layers were washed with To a solution of 16 (1.15 g, 1.88 mmol) in MeOH (6.0 mL) H2O and brine, dried over anhydrous Na2SO4, and concentrated and THF (1.0 mL) was added pyridinium p-toluenesulfonate in vacuo. The residue was purified by silica gel column (47.2 mg, 0.188 mmol) and the mixture was stirred for 11 h at chromatography with hexane-AcOEt (1:0–50:1) to afford 18 room temperature. The reaction mixture was concentrated and (53.5 mg, 61%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ added saturated NaHCO3 aq. The organic materials were 1.01–1.09 (m, 3H), 1.05 (d, J = 4.9 Hz, 18H), 2.05–2.15 (m, 4H), extracted with AcOEt three times. The combined organic layers 2.28 (dd, J = 7.3, 14.0 Hz, 1H), 2.42 (dd, J = 5.2, 14.0 Hz, 1H), were washed with brine, dried over anhydrous Na2SO4, and 3.63 (dddd, J = 4.7, 5.2, 6.1, 7.3 Hz, 1H), 3.68 (dd, J = 4.7, 10.3 concentrated in vacuo. The residue was purified by silica gel Hz, 1H), 3.73 (dd, J = 6.1, 10.3 Hz, 1H), 3.93 (d, J = 11.5 Hz, column chromatography with hexane-AcOEt (50:1–3:1) to afford 1H), 3.99 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.43 (d, corresponding alcohol 29 (854.5 mg, 91%) as a colorless oil. 1H J = 12.0 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.67 (d, J = 11.8 Hz, NMR (CDCl3, 500 MHz) δ 1.02–1.17 (m, 3H), 1.05 (d, J = 5.2 1H), 4.94 (tdd, J = 1.5, 1.5, 10.3 Hz, 1H), 4.99 (tdd, J = 1.5, 1.5, Hz, 18H), 1.84 (brs, 1H), 2.28 (dd, J = 7.8, 14.0 Hz, 1H), 2.45 16.6 Hz, 1H), 5.48 (t, J = 7.0 Hz, 1H), 5.78 (tdd, J = 5.4, 10.3, (dd, J = 4.4, 14.0 Hz, 1H), 3.60 (dddd, J = 4.4, 5.1, 5.7, 7.8 Hz, 16.6 Hz, 1H), 7.23–7.32 (m, 10H); 13C NMR (CDCl3, 125 MHz) 1H), 3.66 (dd, J = 5.1, 10.3 Hz, 1H), 3.76 (dd, J = 5.7, 10.3 Hz, δ 11.9 (3C), 18.0 (6C), 27.2, 33.9, 37.6, 66.2, 67.4, 72.0, 72.2, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.98 (d, J = 11.5 Hz, 1H), 4.09 (d, 78.9, 114.8, 127.3, 127.5, 127.69 (2C), 127.72 (2C), 128.1 (2C), J = 6.8 Hz, 2H), 4.43 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 128.3 (2C), 131.4, 133.2, 138.2, 138.5, 139.2; IR νmax 3064, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 5.73 (t, 3030, 2941, 2922, 2864, 2154, 1639, 1497, 1454, 1385, 1356, J = 7.1 Hz, 1H), 7.24–7.34 (m, 10H); 13C NMR (CDCl3, 125 1311, 1248, 1205, 1092, 1066, 1028, 1012, 995, 910, 881 cm–1; MHz) δ 11.9 (3C), 18.0 (6C), 38.3, 58.7, 65.8, 68.0, 72.3, 72.5, HRMS (ESI): calcd for C33H50O3SiNa: [M+Na]+: 545.3427; 78.8, 127.4, 127.7, 127.79 (2C), 127.82 (2C), 128.2 (2C), 128.4 found: 545.3412. (2C), 130.7, 137.1, 137.8, 138.9; IR νmax 3413, 3030, 2941, 2922, 2889, 2864, 2362, 2328, 1736, 1716, 1497, 1454, 1380, 1363, 4.8. (Z)-(2R*)-2-Benzyloxy-4-[(benzyloxy)methyl]nona-4,81311, 1246, 1205, 1090, 1068, 1026, 1012, 997, 916, 881 cm–1; dienol (20) HRMS (ESI): calcd for C30H46O4SiNa: [M+Na]+: 521.3063; To a solution of 18 (11.9 mg, 0.023 mmol) in THF (0.5 mL) found: 521.3066. was added TBAF (27 µL, 0.027 mmol, 1.0 M in THF), and the To a solution of corresponding alcohol 29 (524 mg, 1.05 mixture was stirred for 4 h at room temperature. The reaction was mmol) and triethylamine (249 µL, 1.79 mmol) in dry CH2Cl2 (5.0 quenched with saturated NH4Cl aq., and the organic materials mL) was added methanesulfonic anhydride (256 mg, 1.47 mmol), were extracted with AcOEt three times. The combined organic and the mixture was stirred for 10 min at 0 °C under argon layers were washed with brine, dried over anhydrous Na2SO4, atmosphere. To the mixture was added lithium bromide (456 mg, and concentrated in vacuo. The residue was purified by silica gel 5.25 mmol) in THF (1.0 mL) and stirred for 6 h at room column chromatography with hexane-AcOEt (30:1–3:1) to afford temperature. The reaction was quenched with saturated NH4Cl 20 (6.3 mg, 75%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ aq. and the organic materials were extracted with AcOEt three 2.03 (brs, 1H), 2.06–2.14 (m, 4H), 2.28 (dd, J = 4.0, 13.7 Hz, times. The organic layers were washed with brine, dried over 1H), 2.51 (dd, J = 5.2, 13.7 Hz, 1H), 3.51 (dd, J = 7.1, 12.4 Hz, anhydrous Na2SO4, and concentrated in vacuo. The residue was 1H), 3.63–3.68 (m, 2H), 4.00 (s, 2H), 4.46 (s, 2H), 4.49 (d, J = purified by silica gel column chromatography with hexane11.7 Hz, 1H), 4.60 (d, J = 11.7 Hz, 1H), 4.95 (tdd, J = 1.5, 1.5, 1 AcOEt (1:0–20:1) to afford 17 (554 mg, 94%) as a yellow oil. H 10.3 Hz, 1H), 5.00 (tdd, J = 1.5, 1.5, 16.9 Hz, 1H), 5.47 (t, J = NMR (CDCl3, 500 MHz) δ 1.01–1.10 (m, 3H), 1.05 (d, J = 5.3 7.1 Hz, 1H), 5.77 (tdd, J = 6.4, 10.3, 16.9 Hz, 1H), 7.25–7.35 (m, Hz, 18H), 2.29 (dd, J = 7.4, 13.7 Hz, 1H), 2.50 (dd, J = 3.9, 13.7 10H); 13C NMR (CDCl3, 150 MHz) δ 27.1, 33.7, 36.6, 64.0, 67.4, Hz, 1H), 3.60–3.66 (m, 2H), 3.75 (dd, J = 5.1, 9.5 Hz, 1H), 4.00 71.4, 72.2, 78.4, 115.0, 127.6 (2C), 127.71 (3C), 127.74 (2C), (d, J = 8.6 Hz, 2H), 4.01 (d, J = 12.0 Hz, 1H), 4.05 (d, J = 12.0 128.4 (3C), 131.9, 132.5, 137.9, 138.2, 138.5; IR νmax 3446, Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 3064, 3032, 2922, 2860, 2051, 1965, 1722, 1639, 1604, 1497, 4.54 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 5.79 (t, J = 1454, 1354, 1311, 1252, 1205, 1085, 1068, 1028, 910, 818 cm–1; 13 8.6 Hz, 1H), 7.22–7.34 (m, 10H); C NMR (CDCl3, 125 MHz) δ HRMS (ESI): calcd for C24H30O3Na: [M+Na]+: 389.2093; found: 11.9 (3C), 18.0 (6C), 27.7, 37.7, 65.8, 66.9, 72.3, 72.5, 78.6, 389.2104. 126.8, 127.4, 127.7, 127.7 (2C), 127.9 (2C), 128.2 (2C), 128.4 4.9. (2Z,6Z)-(4R*)-4-Benzyloxy-6-(benzyloxy)methyl-2-[(E)-4(2C), 138.0, 138.8, 139.7; IR νmax 3064, 3030, 2941, 2864, 2162, methyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]pent-3-en-1-yl]undeca2011, 1873, 1807, 1734, 1655, 1497, 1454, 1381, 1365, 1309, 2,6,10-trienenitrile (21) 1255, 1203, 1092, 1066, 1026, 1014, 995, 918, 881 cm–1; HRMS (ESI): calcd for C30H45BrO3SiNa: [M+Na]+: 583.2219; found: To a solution of 20 (42.7 mg, 0.117 mmol) in CH2Cl2 (1.0 583.2200. mL) was added NaHCO3 (43.3 mg, 0.515 mmol) and Dess4.7. (Z)-(8R*)-8-Benzyloxy-6-(benzyloxy)methyl-9Martin periodinane (71.1 mg, 0.164 mmol) at 0 °C, and the [(triisopropylsilyl)oxy]nona-1,5-diene (18) mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated NaHCO3 aq. and Na2S2O3 aq., and the To magnesium turnings (156 mg, 6.43 mmol) were added a organic materials were extracted with AcOEt twice. The solution of allyl bromide (43.3 µL, 0.500 mmol) in dry Et2O (0.5 combined organic layers were washed with brine, dried over mL) dropwise under argon atmosphere. After the reaction had anhydrous Na2SO4, and concentrated in vacuo. The resulting
6
Tetrahedron
AC C
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SC
RI PT
in THF (0.1 mL) at 0 °C under argon atmosphere and the mixture crude aldehyde was used for the next reaction without further MANUSCRIPT ACCEPTED was stirred for 8 h at room temperature. The reaction was purification. quenched with saturated NH4Cl aq. and the organic materials To a solution of cyanophosphonate ester 8 (76.5 mg, 0.213 were extracted with AcOEt three times. The organic layer was mmol) in dry toluene (200 µL) was added KHMDS (426 µL, washed with brine, dried over anhydrous Na2SO4, and 0.213 mmol, 0.5 M in toluene) and the mixture was stirred for 15 concentrated in vacuo. The residue was purified by silica gel min at 0 °C under argon atmosphere. To the mixture was added column chromatography with hexane-AcOEt (1:0–10:1) to afford the above crude aldehyde in toluene (800 µL) and stirred for 0.5 corresponding bromide 31 (34.4 mg, 91%) as a yellow oil. 1H h at –78 °C. The reaction was quenched with saturated NH4Cl aq. NMR (CDCl3, 500 MHz) δ 1.77 (s, 3H), 2.04–2.14 (m, 4H), and the organic materials were extracted with AcOEt three times. 2.22–2.28 (m, 4H), 2.29 (dd, J = 6.6, 13.7 Hz, 1H), 2.56 (dd, J = The combined organic layers were washed with brine, dried over 6.8, 13.7 Hz, 1H), 3.90 (s, 2H), 3.98 (d, J = 11.7 Hz, 1H), 3.99 anhydrous Na2SO4, and concentrated in vacuo. The residue was (d, J = 11.7 Hz, 1H), 4.38 (ddd, J = 6.6, 6.8, 9.0 Hz, 1H), 4.39 (d, purified by silica gel column chromatography with hexaneJ = 12.0 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.94 AcOEt (10:1–1:2) to afford 21 (47.6 mg, 71%, as a single (tdd, J = 1.5, 1.5, 10.3 Hz, 1H), 4.98 (tdd, J = 1.5, 1.5, 16.7 Hz, 1 isomer) as a yellow oil. H NMR (CDCl3, 500 MHz) δ 1.47–1.58 1H), 5.41 (t, J = 6.6 Hz, 1H), 5.48 (brs, 1H), 5.76 (tdd, J = 6.4, (m, 4H), 1.66 (s, 3H), 1.57–1.71 (m, 1H), 1.77–1.83 (m, 1H), 10.3, 16.7 Hz, 1H), 6.01 (d, J = 9.0 Hz, 1H), 7.24–7.32 (m, 10H); 2.03–2.13 (m, 4H), 2.22–2.27 (m, 4H), 2.28 (dd, J = 6.6, 12.7 Hz, 13 C NMR (CDCl3, 125 MHz) δ 14.9, 26.6, 27.2, 33.69, 33.73, 1H), 2.56 (dd, J = 6.8, 12.7 Hz, 1H), 3.47 (ddd, J = 4.0, 5.2, 11.2 40.4, 40.7, 67.3, 71.3, 72.2, 77.0, 114.9, 116.0, 116.8, 127.5, Hz, 1H), 3.81 (d, J = 12.0 Hz, 1H), 3.84 (dd, J = 2.7, 7.8, 11.2 127.72, 127.76 (2C), 127.78 (2C), 128.0, 128.33 (2C), 128.34 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.99 (d, J = 11.5 Hz, 1H), (2C), 131.7, 132.3, 134.2, 137.9, 138.0, 138.4, 148.0; IR νmax 4.07 (d, J = 12.0 Hz, 1H), 4.38 (td, J = 3.7, 9.0 Hz, 1H), 4.42 (d, 3064, 3030, 2922, 2858, 2214, 1722, 1701, 1639, 1497, 1452, J = 11.8 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.8 Hz, 1H), 4.56 1437, 1367, 1263, 1205, 1088, 1068, 1028, 999, 910 cm–1; (dd, J = 4.2, 4.2 Hz, 1H), 4.93 (tdd, J = 1.3, 1.3, 10.3 Hz, 1H), HRMS (ESI): calcd for C32H38BrNO2Na: [M+Na]+: 570.1984; 4.97 (tdd, J = 1.3, 1.3, 16.9 Hz, 1H), 5.35 (brs, 1H), 5.40 (t, J = found: 570.1987. 6.9 Hz, 1H), 5.75 (tdd, J = 6.4, 10.3, 16.9 Hz, 1H), 6.00 (d, J = 9.0 Hz, 1H), 7.24–7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ To a suspension of sodium hydride (60% in mineral oil, 36.1 mg, 0.903 mmol) in dry THF (500 µL) was added a solution of 14.2, 19.5, 25.4, 26.2, 27.2, 30.6, 33.7, 34.2, 40.4, 62.2, 67.3, 71.26, 71.29, 72.2, 72.42, 72.44, 97.7, 114.9, 116.5, 116.9, 124.4, methyl 2-chloroacetoacetate (108 µL, 0.900 mmol) in THF (300 µL) at 0 °C and the mixture was stirred for 15 min at room 127.5, 127.70, 127.76 (2C), 127.81, 127.82, 128.3 (4C), 131.7, temperature under argon atmosphere. To the mixture was added 132.3, 134.2, 137.96, 137.99, 138.4; IR νmax 3064, 3030, 2939, 2922, 2854, 2366, 2214, 1736, 1641, 1497, 1454, 1358, 1321, n-butyl lithium (577 µL, 0.900 mmol, 1.56 M in hexane) at 0 °C 1261, 1201, 1182, 1155, 1117, 1068, 1020, 978, 943, 906, 868 and stirred for 10 min at room temperature. Subsequently, a cm–1; HRMS (ESI): calcd for C37H47NO4Na: [M+Na]+: 592.3403; solution of corresponding bromide 31 (98.7 mg, 0.180 mmol) in found: 592.3393. THF (1.2 mL) was added at 0 °C and the mixture was stirred for 20 min at that temperature. The reaction was quenched with 4.10. Methyl (6E,10Z,14Z)-(2R*,12S*)-12-benzyloxy-14saturated NH4Cl aq. and the organic materials were extracted (benzyloxy)methyl-2-chloro-10-cyano-6-methyl-3-oxononadecawith AcOEt three times. The combined organic layers were 6,10,14,18-tetraenoate (22) washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel To a solution of 21 (47.6 mg, 0.084 mmol) in MeOH (1.0 mL) column chromatography with hexane-AcOEt (50:1–10:1) to was added pyridinium p-toluenesulfonate (4.2 mg, 0.017 mmol) afford a 6.0:1 mixture of 22 and its enol tautomer (111 mg, 76%) and the mixture was stirred for 21 h at 40 °C. The reaction as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.61 (s, 3H), 2.03– mixture was concentrated and added saturated NaHCO3 aq. The 2.11 (m, 4H), 2.18–2.22 (m, 4H), 2.25–2.30 (m, 3H), 2.54–2.60 organic materials were extracted with AcOEt three times. The (m, 1H), 2.73–2.80 (m, 2H), 3.80 (s, 3H), 3.97 (d, J = 12.0 Hz, combined organic layers were washed with brine, dried over 1H), 3.99 (d, J = 12.0 Hz, 1H), 4.38 (brdd, J = 6.6, 9.0 Hz, 1H), anhydrous Na2SO4, and concentrated in vacuo. The residue was 4.39 (d, J = 11.5 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.5 Hz, 1H), purified by silica gel column chromatography with hexane4.74 (s, 1H), 4.94 (brdd, J = 1.5, 10.0 Hz, 1H), 4.98 (brdd, J = AcOEt (10:1–3:1) to afford corresponding alcohol 30 (37.7 mg, 1.5, 16.6 Hz, 1H), 5.08 (brs, 1H), 5.41 (t, J = 7.3 Hz, 1H), 5.75 92%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.41 (brs, (tdd, J = 6.1, 10.0, 16.6 Hz, 1H), 6.00 (d, J = 9.0 Hz, 1H), 7.24– 1H), 1.66 (s, 3H), 2.04–2.13 (m, 4H), 2.24–2.28 (m, 4H), 2.28 7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 14.0, 16.2, 23.1, (dd, J = 6.6, 13.7 Hz, 1H), 2.57 (dd, J = 5.6, 13.7 Hz, 1H), 3.95 26.5, 27.2, 33.0, 33.7, 34.3, 37.5, 40.4, 67.3, 71.3, 72.2, 114.9, (s, 2H), 2.98 (d, J = 2.2 Hz, 2H), 4.38 (ddd, J = 5.6, 6.6, 9.3 Hz, 116.5, 116.6, 117.0, 123.0, 127.5, 127.72 (2C), 127.76 (3C), 1H), 4.39 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.67 (d, J = 11.5 Hz, 127.79 (2C), 128.3 (3C), 131.7, 132.2, 135.1, 137.9, 138.4, 1H), 4.94 (tdd, J = 1.7, 1.7, 10.2 Hz, 1H), 4.97 (tdd, J = 1.7, 1.7, 147.6, 165.5, 198.3; IR νmax 3064, 3032, 2956, 2908, 2864, 2216, 16.8 Hz, 1H), 5.32 (brs, 1H), 5.42 (t, J = 6.8 Hz, 1H), 5.75 (tdd, J 2033, 1728, 1641, 1606, 1497, 1452, 1439, 1360, 1257, 1201, = 6.3, 10.2, 16.8 Hz, 1H), 6.00 (d, J = 9.3 Hz, 1H), 7.24–7.32 (m, 13 1167, 1090, 1066, 1028, 1001, 912, 818 cm–1; HRMS (ESI): 10H); C NMR (CDCl3, 125 MHz) δ 13.8, 26.0, 27.2, 33.7, 34.2, calcd for C37H44ClNO5Na: [M+Na]+: 640.2806; found: 640.2836. 40.3, 67.3, 68.4, 71.3, 72.2, 77.0, 114.9, 116.5, 117.0, 122.7, 127.6, 127.73, 127.77 (2C), 127.79 (2C), 128.3 (2C), 128.4 (2C), 4.11. Dimethyl (2E,6Z,10Z,14E)-(9R*,19S*)-9-benzyloxy-7131.63, 132.3, 137.0, 137.95, 137.98, 138.3, 147.8; IR νmax 3444, benzyloxy)methyl-19-chloro-11-cyano-15-methyl-18-oxoicosa3066, 3032, 2917, 2858, 2216, 1641, 1497, 1454, 1365, 1259, 2,6,10,14-tetraenedioate (6) 1205, 1086, 1065, 1026, 1007, 910 cm–1; HRMS (ESI): calcd for C32H39NO3Na: [M+Na]+: 508.2828; found: 508.2822. To a solution of 22 (18.8 mg, 0.030 mmol) in dry CH2Cl2 (100 µL) was added methyl acrylate (40.3 µl, 0.450 mmol) and a To a solution of corresponding alcohol 30 (33.6 mg, 0.069 solution of 2nd generation Grubbs catalyst (3.0 mg, 3.53 µmol) in mmol) and triethylamine (23.1 µL, 0.166 mmol) in dry CH2Cl2 dry CH2Cl2 (400 µL), and the mixture was stirred for 11 h at (0.5 mL) was added methanesulfonic anhydride (24.1 mg, 0.138 room temperature under argon atmosphere. The reaction mixture mmol) and a solution of lithium bromide (30.0 mg, 0.345 mmol)
7
References 1. 2.
Roy, A.; Saraf, S. Biol. Pharm. Bull. 2006, 29, 191–201. Yuan, C. M.; Zhang, Y.; Tang, G. H.; Li, Y.; He, H. P.; Li, S. F.; Hou, L.; Li, X. Y.; Di, Y. T.; Li, S. L.; Hua, H. M.; Hao, X. J. Planta Med. 2013, 79, 163–168. 3. Polonsky, J.; Varon, Z.; Arnoux, B.; Pettit, G. R.; Schmid, J. M.; Ochi, M.; Kotsuki, H. Experientia, 1979, 35, 987–989. 4. Zhang, Y.; Tang, C. P.; Ke, C. Q.; Li, X. Q.; Xie, H.; Ye, Y. Phytochemistry, 2012, 73, 106–113. 5. Behenna, D. C.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 6720– 6721. 6. Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027–5029. 7. (a) Suzuki, E.; Ueda, M.; Ohba, S.; Sugai, T.; Shoji, M. Tetrahedron Lett. 2013, 54, 1589–1952. (b) Furuta, M.; Hanaya, K.; Sugai, T.; Shoji, M. Tetrahedron Lett. 2014, 55, 3189–3191. 8. Zoretic, P. A.; Zhang, Y.; Ribeiro, A. A. Tetrahedron Lett. 1996, 37, 1751–1754. 9. Tirado, R.; Prieto, J. A. J. Org. Chem. 1993, 58, 5666–5673. 10. Takemura, A.; Fujiwara, K.; Shimawaki, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2005, 61, 7392–7419. 11. Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003, 68, 5274–5285.
AC C
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To 22 (18.3 mg, 0.030 mmol) was added a suspension of manganese(III) acetate dihydrate (18.9 mg, 0.072 mmol) and copper(II) acetate monohydrate (7.2 mg, 0.036 mmol) in degassed ethanol (500 µL) and the mixture was stirred for 3 h at room temperature under argon atmosphere. The reaction mixture was diluted with H2O and the organic materials were extracted with AcOEt twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography with hexane-AcOEt (20:1–5:1) to afford 25 (2.1 mg, 11%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.16– 1.20 (m, 1H), 1.24 (s, 3H), 1.24–1.32 (m, 1H), 1.57–1.62 (m, 2H), 1.72–1.77 (m, 2H), 1.79–1.83 (m, 1H), 1.93–1.99 (m, 2H), 2.06–2.10 (m, 1H), 2.30–2.38 (m, 2H), 2.40–2.47 (m, 2H), 2.53– 2.62 (m, 2H), 2.91 (ddd, J = 5.8, 14.9, 14.9 Hz, 1H), 3.30 (d, J = 8.8 Hz, 1H), 3.34 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.84 (ddd, J = 2.9, 2.9, 2.9 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 4.30 (d, J = 12.2 Hz, 1H), 4.38 (d, J = 12.4 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.87 (s, 1H), 5.00 (s, 1H), 7.15–7.33 (m, 10H); 13C NMR (CDCl3, 150 MHz) δ 12.9, 21.5, 26.0, 29.7, 32.2, 36.4, 38.8, 39.3, 39.7, 40.2, 47.5, 52.9, 53.6, 58.2, 59.2, 69.9, 73.0, 74.3, 76.7, 77.5, 105.8, 127.4 (2C), 127.5 (2C), 127.7, 128.2 (2C), 128.3, 128.4 (2C), 128.4, 137.8, 138.4, 156.8, 168.2, 198.1; IR νmax 2922, 2854, 2360, 2343, 1733, 1454, 1363, 1257, 1223, 1173, 1099,
Supplementary data related to this article can be found at online version.
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1028, 806, 742 cm–1; HRMS (ESI): calcd for C37H42ClNO5Na: was diluted with AcOEt. After filtration through a pad of silica MANUSCRIPT ACCEPTED gel, the filtrate was concentrated in vacuo. The residue was [M+Na]+: 638.2649; found: 638.2642. purified by silica gel column chromatography with hexaneAcOEt (20:1–3:1) to afford a 3.0:1 mixture of 6 and its enol Acknowledgments tautomer (11.9 mg, 59%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.61 (s, 3H), 2.15–2.22 (m, 8H), 2.25–2.30 (m, 3H), This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of 2.52–2.59 (m, 2H), 2.75–2.79 (m, 1H), 3.69 (s, 3H), 3.80 (s, 3H), 3.94 (d, J = 11.4 Hz, 1H), 3.97 (d, J = 11.4 Hz, 1H), 4.34–4.41 Education, Culture, Sports, Science and Technology, Japan. We (m, 1H), 4.38 d, J = 11.7 Hz, 1H), 4.42 (s, 2H), 4.47 (d, J = 11.7 also thank the Japan Society for the Promotion of Sciences for the JSPS Fellowship for Young Scientists (M.F.). We would like Hz, 1H), 4.75 (s, 1H), 5.07 (brs, 1H), 5.38 (t, J = 7.3 Hz, 1H), 5.79 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 9.0 Hz, 1H), 6.90 (td, J = to thank Editage (www.editage.jp) for English language editing. 6.3, 15.6 Hz, 1H), 7.24–7.31 (m, 10H); HRMS (ESI): calcd for C39H46ClNO7Na: [M+Na]+: 698.2861; found: 698.2859. Appendix A. Supplementary data
S0040-4020(17)30247-8
DOI:
10.1016/j.tet.2017.03.021
Reference:
TET 28527
To appear in:
Tetrahedron
Received Date: 30 January 2017 Revised Date:
6 March 2017
Accepted Date: 7 March 2017
Please cite this article as: Furuta M, Hanaya K, Sugai T, Shoji M, Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization
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Miyu Furuta, Kengo Hanaya, Takeshi Sugai, Mitsuru Shoji* 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University
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Tetrahedron journal homepage: www.elsevier.com
Miyu Furuta, Kengo Hanaya, Takeshi Sugai, and Mitsuru Shoji∗
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Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Limonoids are characterized by a polycyclic structure and show a wide variety of bioactivities. In particular, mesendanin L, 12-hydroxyamoorastatone, and meliatoosenin F have unique structures containing a trans-A/B/C and cis-C/D-fused tetracyclic skeleton. We synthesized the core structure of these limonoids via Mn(OAc)3 and Cu(OAc)2-mediated radical domino cyclization of an acyclic tetraene precursor having a terminal β-keto ester. To the best of our knowledge, this is the first example of the radical-mediated construction of a 6/6/6/5-membered tetracyclic skeleton.
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Keywords: Limonoid Tetracyclic core Domino cyclization Radical cyclization Stereoselective
1. Introduction
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Limonoids, which belong to the class of phytochemicals, are widely distributed in citrus fruits and in other plants of the Rutaceae and Meliaceae families. These compounds are known to show diverse bioactivities.1 For example, mesendanin L (1, Fig. 1) was isolated from the bark of Melia azedarach and found to exhibit cytotoxicity against the human cell line HL-60.2 12Hydroxyamoorastatone (2) was isolated from the seeds of the Eastern Himalayan plant Aphanamixis grandifolia Bl and showed cytotoxicity against the human tumor cell lines A-549 and SK-
Fig. 1. Structures of mesendanin L (1), 12-hydroxyamoorastatone (2), and meliatoosenin F (3).
2009 Elsevier Ltd. All rights reserved.
MEL-2.3 Meliatoosenin F (3) was isolated from the fruits of Melia toosendan4 and its bioactivity is unknown. As compounds 1− 3 have oxygen substituents on the C ring and a rare transA/B/C and cis-C/D-fused tetracyclic structure, development of their synthetic methodology is significant.
The unique polycyclic skeletons of terpenoids and steroids have attracted the attention of the synthetic chemistry community. Corey and Behenna prepared the tetracyclic moiety of a protolimonoid via the Lewis acid-mediated polycyclization of epoxypolyene.5 MacMillan and Rendler reported the imidazolidinone-catalyzed enantioselective radical polycyclization of polyene possessing a terminal formyl group.6 While these research groups elegantly constructed the polycyclic skeleton, there were no oxygen substituents on the C ring, as shown for limonoids 1–3. Recently, our group achieved the stereoselective preparation of cis-decalin7a and pseudoenantiomers for the ABC-ring moiety of steroids7b by modifying Zoretic’s polycyclization conditions.8 We herein constructed a trans,trans,cis-fused tetracyclic skeleton with an oxygen substituent on the C ring via manganese(III) and copper(II)-mediated radical domino cyclization. We envisaged that tetracyclic β-keto ester 4 could be constructed from tetraene 6 via Mn(III)/Cu(II)-mediated radical domino cyclization (Scheme 1). An electrophilic carbon radical tends to react with an electron-rich alkene to form a carboncarbon bond and thus becomes nucleophilic. For this reason, cyclization precursor 6 was designed such that it had alternate
——— ∗ Corresponding author. Tel. & fax: +3-5400-2695; e-mail: [email protected]
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Scheme 1. Retrosynthesis of trans,trans,cis-tetracyclic skeleton.
butyldimethylsilyl (TBS) group was removed under acidic conditions to produce another propargyl alcohol 14. Regioselective hydroalumination11 of 14, followed by iodination, furnished vinyl iodide 15. Reprotection of the allylic alcohol of 15 as TBS ether and conversion of the iodine atom into a benzyloxymethyl group by treatment with sec-butyl lithium and benzyloxymethyl (BOM) chloride afforded benzyl ether 16, which possessed an oxygen functional group at the C18 position.
2. Results and discussion
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electron-donating and electron-withdrawing groups on the alkene moiety for effective carbon-carbon bond formation between the electrophilic radical and the electron-rich alkene, or between the nucleophilic radical and the electron-deficient alkene. Transition state 5b shows 1,3-diaxial repulsion between the C11-benzyloxy and C13-benzyloxy groups; hence, we expected the domino cyclization to proceed via intermediate 5a. The cyclization precursor 6 would be prepared by the Horner–Wadsworth– Emmons reaction between cyanophosphonate 88 and αbenzyloxyaldehyde 9, followed by alkylation with methyl 2chloroacetoacetate (7) and cross metathesis with methyl acrylate (10). The alkoxy group on C18-position in 9 would be helpful to prepare the various analogs of the limonoids for structure-activity relationship studies.
Removal of the triisopropylsilyl (TIPS) group on 18 generated primary alcohol 20 (Scheme 3). Oxidation of 20 with Dess– Martin periodinane and Horner–Wadsworth–Emmons reaction of the resulting aldehyde with cyanophosphonate 88 afforded α,β-
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The synthesis of 6 was commenced from a known epoxide (±)-119 derived from commercially available glycidol (Scheme 2). Treatment of 11 with lithium acetylide derived from propargyl alcohol10 afforded secondary alcohol 13. The hydroxyl group of 13 was protected as a benzyl ether and the tert-
Then, the TBS group on 16 was removed, and the resulting hydroxy group was substituted with a bromine atom via mesylate to afford allylic bromide 17. Alkylation of 17 with allylmagnesium bromide in the presence of copper iodide gave the desired 1,5-diene 18. The undesired conjugated diene 19 was also formed via elimination of both the bromine atom and the benzyloxy group, but this reaction could be suppressed by the addition of HMPA.
Scheme 2. Synthesis of 1,5-diene 18.
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Fig. 2. Stereostructure of tetracyclic β-keto esters 25.
Scheme 3. Preparation of cyclization precursor 6.
3. Conclusion
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In conclusion, we synthesized for the first time a tetracyclic βketo ester, the core structure of limonoids. The key step in our strategy is the radical domino cyclization of a functionalized acyclic tetraene. The proposed methodology would be useful for the preparation of various trans-A/B/C and cis-C/D-fused tetracyclic keto esters. Deprotection-oxidation at C11 and functionalization at C17 should provide various limonoid analogs for structure-activity relationship studies.
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unsaturated nitrile 21 as a single isomer. Removal of the tetrahydropyranyl (THP) group on tetraene 21, followed by mesylation with methanesulfonic anhydride and substitution with bromide, afforded a primary allylic bromide. Alkylation of the bromide with a dianion derived from methyl 2-chloroacetoacetate (7)7b afforded β-keto ester 22. Subsequently, cross metathesis of the terminal alkene with methyl acrylate (10) furnished 6, which possessed an α,β-unsaturated ester and the desired geometry in the double bonds.
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and 4.00 ppm (ddd, J = 4.0, 9.6, 9.6 Hz, axial), respectively.7b Along with the NOESY signals between H9 and H11, the 1H NMR signal of the 11-position for compound 25 appearing at 3.84 ppm (ddd, J = 2.9, 2.9, 2.9 Hz) indicated that the proton at 11-position located in equatorial position.
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With the cyclization precursor in hand, we focused our attention on the radical domino cyclization (Scheme 4). Treatment of α,β-unsaturated ester 6 with manganese(III) and copper(II) acetates in ethanol7b gave only trace amounts of the imperfect tricyclic β-keto ester 24. The failure of the fourth cyclization could be attributed the steric hindrance of the methoxycarbonyl group at C18. Therefore, carbon-carbon bond formation between the radical on C13 and the electron-deficient carbon on C17 would be suppressed. For this reason, we expected to achieve the fourth cyclization using β-keto ester 22, which possess a terminal alkene. Radical domino cyclization of 22 gave many kinds of cyclized products, and only 25 was isolated as the tetracyclic β-keto ester, along with tricyclic β-keto ester 26 as the major byproduct. NOESY analysis revealed the stereochemistry of 25 to be trans-A/B/C and cis-C/D-fused, as shown in Fig. 2. We have prepared the two tricyclic compounds via the radical domino cyclization and the 1H NMR signals of the 11-position of the two diastereomers were 4.05 (brs, equatorial)
Scheme 4. Radical domino cyclization of acyclic tetraenes.
4. Experimental section
4.1. General methods Merck silica gel 60 F254 thin-layer plates (1.05744, 0.5 mm thickness) was used for preparative thin-layer chromatography. Merck silica gel 60 F254 thin-layer plates (1.05715) was used for thin-layer chromatography. Silica gel 60 (spherical and neutral; 63-210 µm, 37560-79) from Kanto Chemical Co. was used for column chromatography.
IR spectra were measured as thin films for oils on a JEOL FTIR SPX60 spectrometer. 1H NMR spectra were measured at 400 MHz on a VARIAN 400-MR spectrometer 500 MHz on a VARIAN 500-MR spectrometer or 600 MHz on a JEOL JNMECP 600 spectrometer and 13C NMR spectra were measured at 100 MHz on a VARIAN 400-MR or at 125 MHz on a VARIAN 500-MR or at 150 MHz on a JEOL JNM-ECP 600 spectrometer. High resolution mass spectra were recorded on a JEOL JMST100LP Accu TOF spectrometer. IR spectra were measured as thin films for oil or ATR for solid. 1H and 13C NMR spectra were measured in CDCl3 at 400 and 100 MHz, respectively. HRMS analyses were recorded on a FAB-MS mass spectrometer. Column chromatography was performed on silica gel. 4.2. (2R*)-6-(tert-Butyldimethylsilyl)oxy-1[(triisopropylsilyl)oxy]hex-4-yn-2-ol (13) To a solution of alkyne 1210 (2.22 g, 13.0 mmol) in dry THF (25 mL) was added n-butyl lithium (8.35 mL, 13.0 mmol, 1.56 M in hexane) and the mixture was stirred for 30 min at 0 °C under argon atmosphere. To the mixture was added boron trifluoride diether complex (1.64 mL, 13.0 mmol) and a solution of epoxide (±)-119 (2.00 g, 8.69 mmol) in dry THF (15 mL) at –78 °C. The mixture was stirred for 15 min at that temperature. The reaction was quenched with saturated NaHCO3 aq. and the organic materials were extracted with AcOEt three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by
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mmol) at –78 °C and stirred for 20 h at room temperature. The silica gel column chromatography with hexane-AcOEt (98:2– MANUSCRIPT ACCEPTED reaction was quenched with Na2S2O3 aq. and the organic 89:11) to afford 13 (3.34 g, 96%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 0.08 (s, 6H), 0.88 (s, 9H), 1.02–1.11 (m, materials were extracted with AcOEt twice. Aqueous layer was 3H), 1.06 (d, J = 6.1 Hz, 18H), 2.40 (brs, 1H), 2.43–2.46 (m, added 2 M HCl aq. and the organic materials were extracted with 2H), 3.64–3.68 (m, 1H), 3.76–3.80 (m, 2H), 4.27 (t, J = 2.2 Hz, AcOEt twice. The combined organic layers were washed with 2H); 13C NMR (CDCl3, 125 MHz) δ –5.2 (2C), 11.8 (3C), 17.9 brine, dried over anhydrous Na2SO4 and concentrated in vacuo. (6C), 18.3, 23.4, 25.8 (3C), 51.9, 65.9, 70.3, 80.8, 81.0; IR νmax The residue was purified by silica gel column chromatography 3410, 2943, 2897, 2806, 2719, 2362, 2339, 1464, 1383, 1367, with hexane-AcOEt (50:1–10:1) to afford 15 (1.14 g, 82%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.01–1.11 (m, 3H), 1252, 1138, 1119, 1078, 1014, 997, 970, 939, 835 cm–1; HRMS (ESI): calcd for C21H44O3Si2Na: [M+Na]+: 423.2727; found: 1.05 (d, J = 5.1 Hz, 18H), 1.63 (brs, 1H), 2.69 (dd, J = 7.6, 14.4 423.2719. Hz, 1H), 2.80 (dd, J = 3.3, 14.4 Hz, 1H), 3.66–3.70 (m, 1H), 3.77-3.80 (m, 2H), 4.14 (d, J = 5.8 Hz, 2H), 4.58 (d, J = 11.7 Hz, 4.3. (5R*)-5-Benzyloxy-6-[(triisopropylsilyl)oxy]hex-2-ynol (14) 1H), 4.68 (d, J = 11.7 Hz, 1H), 5.92 (t, J = 5.8 Hz, 1H), 7.25– 7.33 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 11.9 (3C), 18.0 To a suspension of sodium hydride (60% in mineral oil, 367 (6C), 47.8, 64.8, 67.3, 72.8, 78.5, 105.8, 127.6, 127.9 (2C), 128.3 mg, 9.18 mmol) in dry DMF (10 mL) was added 13 (3.34 g, 8.34 (2C), 136.3, 138.6; IR νmax 3377, 3032, 2941, 2891, 2863, 2364, mmol) in dry DMF (20 mL) and benzyl bromide (990 µL, 8.34 2321, 1647, 1497, 1462, 1423, 1381, 1348, 1365, 1252, 1207, mmol) at 0 °C under argon atmosphere. The mixture was stirred 1117, 1092, 1068, 1012, 997, 918, 881 cm–1; HRMS (ESI): calcd for 2 h at that temperature. The reaction was quenched with 2 M for C22H37IO3SiNa: [M+Na]+: 527.1454; found: 527.1467. NaOH aq. and the organic materials were extracted with Et2O three times. The combined organic layers were washed with 4.5. (Z)-(5R*)-5-Benzyloxy-3-(benzyloxy)methyl-1-(tertsaturated NH4Cl aq. and brine. The solution was dried over butyldimethylsilyl)oxy-6-[(triisopropylsilyl)oxy]hex-2-ene (16) anhydrous Na2SO4, and concentrated in vacuo. The residue was To a solution of 15 (859 mg, 1.69 mmol) in dry DMF (6 mL) purified by silica gel column chromatography with hexanewas added imidazole (177 mg, 2.60 mmol) and TBSCl (288 mg, AcOEt (98:2–90:10) to afford corresponding benzyl ether 27 2.20 mmol) at 0 °C under argon atmosphere. The mixture was (3.31 g, 81%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 0.09 stirred for 20 h at room temperature. The reaction was quenched (s, 6H), 0.88 (s, 9H), 1.01–1.09 (m, 3H), 1.04 (d, J = 4.9 Hz, with H2O and the organic materials were extracted with Et2O 18H), 2.46 (tdd, J = 2.2, 5.6, 16.8 Hz, 1H), 2.55 (tdd, J = 2.2, 5.6, three times. The combined organic layers were washed with brine 16.8 Hz, 1H), 3.58–3.63 (m, 1H), 3.77 (d, J = 5.6 Hz, 2H), 4.28 twice, dried over anhydrous Na2SO4, and concentrated in vacuo. (t, J = 2.2 Hz, 2H), 4.66 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 11.7 The residue was purified by silica gel column chromatography Hz, 1H), 7.23–7.26 (m, 1H), 7.29–7.33 (m, 2H), 7.35 (d, J = 6.8 with hexane-AcOEt (1:0–50:1) to afford corresponding TBS Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ –5.2 (2C), 11.9 (3C), ether 28 (1.02 g, 97%) as a colorless oil. 1H NMR (CDCl3, 500 17.87, 17.90, 18.0 (4C), 18.3, 21.6, 25.8, 25.9 (2C), 52.0, 64.9, MHz) δ 0.07 (s, 6H), 0.89 (s, 9H), 1.01–1.11 (m, 3H), 1.05 (d, J 72.1, 78.3, 80.0, 81.9, 127.5, 127.8 (2C), 128.3 (2C), 138.6; IR = 5.4 Hz, 18H), 2.68 (dd, J = 6.9, 14.4 Hz, 1H), 2.79 (brd, J = νmax 2929, 2941, 2895, 2864, 2721, 2368, 1734, 1461, 1363, 14.4 Hz, 1H), 3.65–3.70 (m, 1H), 3.74–3.80 (m, 2H), 4.19 (d, J = 1252, 1140, 1076, 1028, 999, 918, 881, 835 cm–1; HRMS (ESI): 4.9 Hz, 2H), 4.60 (d, J = 11.7 Hz, 1H), 4.66 (d, J = 11.7 Hz, 1H), calcd for C28H50O3Si2Na: [M+Na]+: 513.3196; found: 513.3207. 5.89 (t, J = 4.9 Hz, 1H), 7.23–7.35 (m, 5H); 13C NMR (CDCl3, To a solution of corresponding benzyl ether 27 (2.76 g, 5.62 125 MHz) δ –5.2 (2C), 11.9 (3C), 18.0 (6C), 18.3, 25.9 (3C), mmol) in MeOH (12 mL) and THF (2 mL) was added pyridinium 47.6, 64.8, 68.5, 72.7, 78.6, 102.5, 127.5, 127.9 (2C), 128.3 (2C), p-toluenesulfonate (147 mg, 0.585 mmol) and the mixture was 137.3, 138.7; IR νmax 3030, 2941, 2927, 2864, 2717, 2360, 2343, stirred for 12 h at room temperature. The reaction mixture was 1647, 1462, 1388, 1360, 1348, 1252, 1205, 1099, 1065, 1005, concentrated and added saturated NaHCO3 aq. The organic 881 cm–1; HRMS (ESI): calcd for C28H51IO3Si2Na: [M+Na]+: materials were extracted with AcOEt three times. The combined 641.2319; found: 641.2333. organic layers were washed with brine, dried over anhydrous To a solution of corresponding TBS ether 28 (79.2 mg, 0.128 Na2SO4, and concentrated in vacuo. The residue was purified by mmol) in dry Et2O (0.9 mL) was added sBuLi (246 µL, 0.256 silica gel column chromatography with hexane-AcOEt (96:4– mmol, 1.04 M in cyclohexane, n-hexane), and the mixture was 72:28) to afford 14 (2.12 g, 94%) as a colorless oil. 1H NMR stirred for 10 min at –78 °C under argon atmosphere. To the (CDCl3, 500 MHz) δ 1.01–1.11 (m, 3H), 1.04 (d, J = 4.9 Hz, mixture was added benzyl chloromethyl ether (31.6 µL, 0.230 18H), 1.75 (brs, 1H), 2.48 (tdd, J = 2.2 5.6, 16.8 Hz, 1H), 2.56 mmol) and Et2O (0.1 mL) at that temperature. The solution was (tdd, J = 1.9, 5.6, 16.8 Hz, 1H), 3.59–3.63 (m, 1H), 3.77 (dd, J = warmed to 0 °C and stirred for 1 h. The reaction was quenched 5.6, 10.3 Hz, 1H), 3.78 (dd, J = 5.6, 10.3 Hz, 1H), 4.20 (brs, 2H), with Et3N and H2O, and the organic materials were extracted 4.67 (s, 2H), 7.26 (t, J = 7.8, 1H), 7.32 (dd, J = 7.1, 7.8 Hz, 2H), with AcOEt three times. The combined organic layers were 7.35 (d, J = 7.1 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 11.9 washed with brine, dried over anhydrous Na2SO4, and (3C), 17.7, 17.9 (5C), 21.6, 51.3, 64.6, 72.0, 78.0, 79.8, 83.0, concentrated in vacuo. The residue was purified by silica gel 127.6, 127.8 (2C), 128.3 (2C), 138.4; IR νmax 3388, 3032, 2940, column chromatography with hexane-AcOEt (1:0–50:1) to afford 2922, 2864, 2362, 2341, 2225, 1497, 1456, 1423, 1383, 1352, 16 (59.1 mg, 75%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) 1313, 1252, 1209, 1107, 1066, 1012, 918, 881 cm–1; HRMS + δ 0.02 (s, 6H), 0.87 (s, 9H), 1.01–1.07 (m, 3H), 1.04 (d, J = 5.4 (ESI): calcd for C22H36O3SiNa: [M+Na] : 399.2354; found: Hz, 18H), 2.28 (dd, J = 7.1, 13.9 Hz, 1H), 2.43 (dd, J = 4.6, 13.9 399.2331. Hz, 1H), 3.63 (dddd, J = 4.6, 4.6, 5.8, 7.1 Hz, 1H), 3.66 (dd, J = 4.4. (Z)-(5R*)-5-Benzyloxy-3-iodo-6-[(triisopropylsilyl)oxy]hex4.6, 10.0 Hz, 1H), 3.74 (dd, J = 5.8, 10.0 Hz, 1H), 3.91 (d, J = 2-enol (15) 11.5 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 4.18 (d, J = 6.1 Hz, 2H), 4.39 (d, J = 11.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.55 (d, J = To a solution of 14 (1.03 g, 2.74 mmol) in dry Et2O (15 mL) 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 5.61 (t, J = 6.3 Hz, 1H), was added Red-Al® (1.04 mL, 3.56 mmol, 65% in toluene 7.22–7.32 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ –5.2 (2C), solution) at 0 °C and the mixture was stirred for 3 h at room 11.9 (3C), 18.0 (6C), 18.3, 25.9 (3C), 37.5, 60.0, 66.0, 67.6, 72.0, temperature. To the mixture was added iodine (904 mg, 3.56
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initiated, a solution of allyl bromide (390 µL, 4.50 mmol) in dry 72.2, 78.9, 127.3, 127.5, 127.7 (2C), 127.8 ACCEPTED (2C), 128.2 (2C), MANUSCRIPT Et2O (4.5 mL) was added dropwise. To a copper(I) iodide (31.4 128.3 (2C), 131.6, 134.1, 138.3, 139.0; IR νmax 3031, 2941, 2927, 2864, 2719, 2362, 2343, 1497, 1462, 1383, 1360, 1311, 1252, mg, 0.165 mmol) were added a solution of 17 (93.6 mg, 0.165 1205, 1068, 1027, 1007, 881 cm–1; HRMS (ESI): calcd for mmol) in HMPA (800 µL) and dry THF (800 µL). The solution C36H60O4Si2Na: [M+Na]+: 635.3928; found: 635.3946. was added the above allyl magnesium bromide (2.14 mL, 1.07 mmol, ca. 1.0 M in Et2O) and the mixture was stirred for 1 h at 0 4.6. (Z)-(5R*)-5-Benzyloxy-3-(benzyloxy)methyl-1-bromo-6°C under argon atmosphere. The reaction was quenched with [(triisopropylsilyl)oxy]hex-2-ene (17) saturated NH4Cl aq. and the organic materials were extracted with AcOEt three times. The organic layers were washed with To a solution of 16 (1.15 g, 1.88 mmol) in MeOH (6.0 mL) H2O and brine, dried over anhydrous Na2SO4, and concentrated and THF (1.0 mL) was added pyridinium p-toluenesulfonate in vacuo. The residue was purified by silica gel column (47.2 mg, 0.188 mmol) and the mixture was stirred for 11 h at chromatography with hexane-AcOEt (1:0–50:1) to afford 18 room temperature. The reaction mixture was concentrated and (53.5 mg, 61%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ added saturated NaHCO3 aq. The organic materials were 1.01–1.09 (m, 3H), 1.05 (d, J = 4.9 Hz, 18H), 2.05–2.15 (m, 4H), extracted with AcOEt three times. The combined organic layers 2.28 (dd, J = 7.3, 14.0 Hz, 1H), 2.42 (dd, J = 5.2, 14.0 Hz, 1H), were washed with brine, dried over anhydrous Na2SO4, and 3.63 (dddd, J = 4.7, 5.2, 6.1, 7.3 Hz, 1H), 3.68 (dd, J = 4.7, 10.3 concentrated in vacuo. The residue was purified by silica gel Hz, 1H), 3.73 (dd, J = 6.1, 10.3 Hz, 1H), 3.93 (d, J = 11.5 Hz, column chromatography with hexane-AcOEt (50:1–3:1) to afford 1H), 3.99 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 4.43 (d, corresponding alcohol 29 (854.5 mg, 91%) as a colorless oil. 1H J = 12.0 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.67 (d, J = 11.8 Hz, NMR (CDCl3, 500 MHz) δ 1.02–1.17 (m, 3H), 1.05 (d, J = 5.2 1H), 4.94 (tdd, J = 1.5, 1.5, 10.3 Hz, 1H), 4.99 (tdd, J = 1.5, 1.5, Hz, 18H), 1.84 (brs, 1H), 2.28 (dd, J = 7.8, 14.0 Hz, 1H), 2.45 16.6 Hz, 1H), 5.48 (t, J = 7.0 Hz, 1H), 5.78 (tdd, J = 5.4, 10.3, (dd, J = 4.4, 14.0 Hz, 1H), 3.60 (dddd, J = 4.4, 5.1, 5.7, 7.8 Hz, 16.6 Hz, 1H), 7.23–7.32 (m, 10H); 13C NMR (CDCl3, 125 MHz) 1H), 3.66 (dd, J = 5.1, 10.3 Hz, 1H), 3.76 (dd, J = 5.7, 10.3 Hz, δ 11.9 (3C), 18.0 (6C), 27.2, 33.9, 37.6, 66.2, 67.4, 72.0, 72.2, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.98 (d, J = 11.5 Hz, 1H), 4.09 (d, 78.9, 114.8, 127.3, 127.5, 127.69 (2C), 127.72 (2C), 128.1 (2C), J = 6.8 Hz, 2H), 4.43 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 128.3 (2C), 131.4, 133.2, 138.2, 138.5, 139.2; IR νmax 3064, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 5.73 (t, 3030, 2941, 2922, 2864, 2154, 1639, 1497, 1454, 1385, 1356, J = 7.1 Hz, 1H), 7.24–7.34 (m, 10H); 13C NMR (CDCl3, 125 1311, 1248, 1205, 1092, 1066, 1028, 1012, 995, 910, 881 cm–1; MHz) δ 11.9 (3C), 18.0 (6C), 38.3, 58.7, 65.8, 68.0, 72.3, 72.5, HRMS (ESI): calcd for C33H50O3SiNa: [M+Na]+: 545.3427; 78.8, 127.4, 127.7, 127.79 (2C), 127.82 (2C), 128.2 (2C), 128.4 found: 545.3412. (2C), 130.7, 137.1, 137.8, 138.9; IR νmax 3413, 3030, 2941, 2922, 2889, 2864, 2362, 2328, 1736, 1716, 1497, 1454, 1380, 1363, 4.8. (Z)-(2R*)-2-Benzyloxy-4-[(benzyloxy)methyl]nona-4,81311, 1246, 1205, 1090, 1068, 1026, 1012, 997, 916, 881 cm–1; dienol (20) HRMS (ESI): calcd for C30H46O4SiNa: [M+Na]+: 521.3063; To a solution of 18 (11.9 mg, 0.023 mmol) in THF (0.5 mL) found: 521.3066. was added TBAF (27 µL, 0.027 mmol, 1.0 M in THF), and the To a solution of corresponding alcohol 29 (524 mg, 1.05 mixture was stirred for 4 h at room temperature. The reaction was mmol) and triethylamine (249 µL, 1.79 mmol) in dry CH2Cl2 (5.0 quenched with saturated NH4Cl aq., and the organic materials mL) was added methanesulfonic anhydride (256 mg, 1.47 mmol), were extracted with AcOEt three times. The combined organic and the mixture was stirred for 10 min at 0 °C under argon layers were washed with brine, dried over anhydrous Na2SO4, atmosphere. To the mixture was added lithium bromide (456 mg, and concentrated in vacuo. The residue was purified by silica gel 5.25 mmol) in THF (1.0 mL) and stirred for 6 h at room column chromatography with hexane-AcOEt (30:1–3:1) to afford temperature. The reaction was quenched with saturated NH4Cl 20 (6.3 mg, 75%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ aq. and the organic materials were extracted with AcOEt three 2.03 (brs, 1H), 2.06–2.14 (m, 4H), 2.28 (dd, J = 4.0, 13.7 Hz, times. The organic layers were washed with brine, dried over 1H), 2.51 (dd, J = 5.2, 13.7 Hz, 1H), 3.51 (dd, J = 7.1, 12.4 Hz, anhydrous Na2SO4, and concentrated in vacuo. The residue was 1H), 3.63–3.68 (m, 2H), 4.00 (s, 2H), 4.46 (s, 2H), 4.49 (d, J = purified by silica gel column chromatography with hexane11.7 Hz, 1H), 4.60 (d, J = 11.7 Hz, 1H), 4.95 (tdd, J = 1.5, 1.5, 1 AcOEt (1:0–20:1) to afford 17 (554 mg, 94%) as a yellow oil. H 10.3 Hz, 1H), 5.00 (tdd, J = 1.5, 1.5, 16.9 Hz, 1H), 5.47 (t, J = NMR (CDCl3, 500 MHz) δ 1.01–1.10 (m, 3H), 1.05 (d, J = 5.3 7.1 Hz, 1H), 5.77 (tdd, J = 6.4, 10.3, 16.9 Hz, 1H), 7.25–7.35 (m, Hz, 18H), 2.29 (dd, J = 7.4, 13.7 Hz, 1H), 2.50 (dd, J = 3.9, 13.7 10H); 13C NMR (CDCl3, 150 MHz) δ 27.1, 33.7, 36.6, 64.0, 67.4, Hz, 1H), 3.60–3.66 (m, 2H), 3.75 (dd, J = 5.1, 9.5 Hz, 1H), 4.00 71.4, 72.2, 78.4, 115.0, 127.6 (2C), 127.71 (3C), 127.74 (2C), (d, J = 8.6 Hz, 2H), 4.01 (d, J = 12.0 Hz, 1H), 4.05 (d, J = 12.0 128.4 (3C), 131.9, 132.5, 137.9, 138.2, 138.5; IR νmax 3446, Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 3064, 3032, 2922, 2860, 2051, 1965, 1722, 1639, 1604, 1497, 4.54 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 5.79 (t, J = 1454, 1354, 1311, 1252, 1205, 1085, 1068, 1028, 910, 818 cm–1; 13 8.6 Hz, 1H), 7.22–7.34 (m, 10H); C NMR (CDCl3, 125 MHz) δ HRMS (ESI): calcd for C24H30O3Na: [M+Na]+: 389.2093; found: 11.9 (3C), 18.0 (6C), 27.7, 37.7, 65.8, 66.9, 72.3, 72.5, 78.6, 389.2104. 126.8, 127.4, 127.7, 127.7 (2C), 127.9 (2C), 128.2 (2C), 128.4 4.9. (2Z,6Z)-(4R*)-4-Benzyloxy-6-(benzyloxy)methyl-2-[(E)-4(2C), 138.0, 138.8, 139.7; IR νmax 3064, 3030, 2941, 2864, 2162, methyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]pent-3-en-1-yl]undeca2011, 1873, 1807, 1734, 1655, 1497, 1454, 1381, 1365, 1309, 2,6,10-trienenitrile (21) 1255, 1203, 1092, 1066, 1026, 1014, 995, 918, 881 cm–1; HRMS (ESI): calcd for C30H45BrO3SiNa: [M+Na]+: 583.2219; found: To a solution of 20 (42.7 mg, 0.117 mmol) in CH2Cl2 (1.0 583.2200. mL) was added NaHCO3 (43.3 mg, 0.515 mmol) and Dess4.7. (Z)-(8R*)-8-Benzyloxy-6-(benzyloxy)methyl-9Martin periodinane (71.1 mg, 0.164 mmol) at 0 °C, and the [(triisopropylsilyl)oxy]nona-1,5-diene (18) mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated NaHCO3 aq. and Na2S2O3 aq., and the To magnesium turnings (156 mg, 6.43 mmol) were added a organic materials were extracted with AcOEt twice. The solution of allyl bromide (43.3 µL, 0.500 mmol) in dry Et2O (0.5 combined organic layers were washed with brine, dried over mL) dropwise under argon atmosphere. After the reaction had anhydrous Na2SO4, and concentrated in vacuo. The resulting
6
Tetrahedron
AC C
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SC
RI PT
in THF (0.1 mL) at 0 °C under argon atmosphere and the mixture crude aldehyde was used for the next reaction without further MANUSCRIPT ACCEPTED was stirred for 8 h at room temperature. The reaction was purification. quenched with saturated NH4Cl aq. and the organic materials To a solution of cyanophosphonate ester 8 (76.5 mg, 0.213 were extracted with AcOEt three times. The organic layer was mmol) in dry toluene (200 µL) was added KHMDS (426 µL, washed with brine, dried over anhydrous Na2SO4, and 0.213 mmol, 0.5 M in toluene) and the mixture was stirred for 15 concentrated in vacuo. The residue was purified by silica gel min at 0 °C under argon atmosphere. To the mixture was added column chromatography with hexane-AcOEt (1:0–10:1) to afford the above crude aldehyde in toluene (800 µL) and stirred for 0.5 corresponding bromide 31 (34.4 mg, 91%) as a yellow oil. 1H h at –78 °C. The reaction was quenched with saturated NH4Cl aq. NMR (CDCl3, 500 MHz) δ 1.77 (s, 3H), 2.04–2.14 (m, 4H), and the organic materials were extracted with AcOEt three times. 2.22–2.28 (m, 4H), 2.29 (dd, J = 6.6, 13.7 Hz, 1H), 2.56 (dd, J = The combined organic layers were washed with brine, dried over 6.8, 13.7 Hz, 1H), 3.90 (s, 2H), 3.98 (d, J = 11.7 Hz, 1H), 3.99 anhydrous Na2SO4, and concentrated in vacuo. The residue was (d, J = 11.7 Hz, 1H), 4.38 (ddd, J = 6.6, 6.8, 9.0 Hz, 1H), 4.39 (d, purified by silica gel column chromatography with hexaneJ = 12.0 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.94 AcOEt (10:1–1:2) to afford 21 (47.6 mg, 71%, as a single (tdd, J = 1.5, 1.5, 10.3 Hz, 1H), 4.98 (tdd, J = 1.5, 1.5, 16.7 Hz, 1 isomer) as a yellow oil. H NMR (CDCl3, 500 MHz) δ 1.47–1.58 1H), 5.41 (t, J = 6.6 Hz, 1H), 5.48 (brs, 1H), 5.76 (tdd, J = 6.4, (m, 4H), 1.66 (s, 3H), 1.57–1.71 (m, 1H), 1.77–1.83 (m, 1H), 10.3, 16.7 Hz, 1H), 6.01 (d, J = 9.0 Hz, 1H), 7.24–7.32 (m, 10H); 2.03–2.13 (m, 4H), 2.22–2.27 (m, 4H), 2.28 (dd, J = 6.6, 12.7 Hz, 13 C NMR (CDCl3, 125 MHz) δ 14.9, 26.6, 27.2, 33.69, 33.73, 1H), 2.56 (dd, J = 6.8, 12.7 Hz, 1H), 3.47 (ddd, J = 4.0, 5.2, 11.2 40.4, 40.7, 67.3, 71.3, 72.2, 77.0, 114.9, 116.0, 116.8, 127.5, Hz, 1H), 3.81 (d, J = 12.0 Hz, 1H), 3.84 (dd, J = 2.7, 7.8, 11.2 127.72, 127.76 (2C), 127.78 (2C), 128.0, 128.33 (2C), 128.34 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 3.99 (d, J = 11.5 Hz, 1H), (2C), 131.7, 132.3, 134.2, 137.9, 138.0, 138.4, 148.0; IR νmax 4.07 (d, J = 12.0 Hz, 1H), 4.38 (td, J = 3.7, 9.0 Hz, 1H), 4.42 (d, 3064, 3030, 2922, 2858, 2214, 1722, 1701, 1639, 1497, 1452, J = 11.8 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.8 Hz, 1H), 4.56 1437, 1367, 1263, 1205, 1088, 1068, 1028, 999, 910 cm–1; (dd, J = 4.2, 4.2 Hz, 1H), 4.93 (tdd, J = 1.3, 1.3, 10.3 Hz, 1H), HRMS (ESI): calcd for C32H38BrNO2Na: [M+Na]+: 570.1984; 4.97 (tdd, J = 1.3, 1.3, 16.9 Hz, 1H), 5.35 (brs, 1H), 5.40 (t, J = found: 570.1987. 6.9 Hz, 1H), 5.75 (tdd, J = 6.4, 10.3, 16.9 Hz, 1H), 6.00 (d, J = 9.0 Hz, 1H), 7.24–7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ To a suspension of sodium hydride (60% in mineral oil, 36.1 mg, 0.903 mmol) in dry THF (500 µL) was added a solution of 14.2, 19.5, 25.4, 26.2, 27.2, 30.6, 33.7, 34.2, 40.4, 62.2, 67.3, 71.26, 71.29, 72.2, 72.42, 72.44, 97.7, 114.9, 116.5, 116.9, 124.4, methyl 2-chloroacetoacetate (108 µL, 0.900 mmol) in THF (300 µL) at 0 °C and the mixture was stirred for 15 min at room 127.5, 127.70, 127.76 (2C), 127.81, 127.82, 128.3 (4C), 131.7, temperature under argon atmosphere. To the mixture was added 132.3, 134.2, 137.96, 137.99, 138.4; IR νmax 3064, 3030, 2939, 2922, 2854, 2366, 2214, 1736, 1641, 1497, 1454, 1358, 1321, n-butyl lithium (577 µL, 0.900 mmol, 1.56 M in hexane) at 0 °C 1261, 1201, 1182, 1155, 1117, 1068, 1020, 978, 943, 906, 868 and stirred for 10 min at room temperature. Subsequently, a cm–1; HRMS (ESI): calcd for C37H47NO4Na: [M+Na]+: 592.3403; solution of corresponding bromide 31 (98.7 mg, 0.180 mmol) in found: 592.3393. THF (1.2 mL) was added at 0 °C and the mixture was stirred for 20 min at that temperature. The reaction was quenched with 4.10. Methyl (6E,10Z,14Z)-(2R*,12S*)-12-benzyloxy-14saturated NH4Cl aq. and the organic materials were extracted (benzyloxy)methyl-2-chloro-10-cyano-6-methyl-3-oxononadecawith AcOEt three times. The combined organic layers were 6,10,14,18-tetraenoate (22) washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel To a solution of 21 (47.6 mg, 0.084 mmol) in MeOH (1.0 mL) column chromatography with hexane-AcOEt (50:1–10:1) to was added pyridinium p-toluenesulfonate (4.2 mg, 0.017 mmol) afford a 6.0:1 mixture of 22 and its enol tautomer (111 mg, 76%) and the mixture was stirred for 21 h at 40 °C. The reaction as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.61 (s, 3H), 2.03– mixture was concentrated and added saturated NaHCO3 aq. The 2.11 (m, 4H), 2.18–2.22 (m, 4H), 2.25–2.30 (m, 3H), 2.54–2.60 organic materials were extracted with AcOEt three times. The (m, 1H), 2.73–2.80 (m, 2H), 3.80 (s, 3H), 3.97 (d, J = 12.0 Hz, combined organic layers were washed with brine, dried over 1H), 3.99 (d, J = 12.0 Hz, 1H), 4.38 (brdd, J = 6.6, 9.0 Hz, 1H), anhydrous Na2SO4, and concentrated in vacuo. The residue was 4.39 (d, J = 11.5 Hz, 1H), 4.43 (s, 2H), 4.47 (d, J = 11.5 Hz, 1H), purified by silica gel column chromatography with hexane4.74 (s, 1H), 4.94 (brdd, J = 1.5, 10.0 Hz, 1H), 4.98 (brdd, J = AcOEt (10:1–3:1) to afford corresponding alcohol 30 (37.7 mg, 1.5, 16.6 Hz, 1H), 5.08 (brs, 1H), 5.41 (t, J = 7.3 Hz, 1H), 5.75 92%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.41 (brs, (tdd, J = 6.1, 10.0, 16.6 Hz, 1H), 6.00 (d, J = 9.0 Hz, 1H), 7.24– 1H), 1.66 (s, 3H), 2.04–2.13 (m, 4H), 2.24–2.28 (m, 4H), 2.28 7.31 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 14.0, 16.2, 23.1, (dd, J = 6.6, 13.7 Hz, 1H), 2.57 (dd, J = 5.6, 13.7 Hz, 1H), 3.95 26.5, 27.2, 33.0, 33.7, 34.3, 37.5, 40.4, 67.3, 71.3, 72.2, 114.9, (s, 2H), 2.98 (d, J = 2.2 Hz, 2H), 4.38 (ddd, J = 5.6, 6.6, 9.3 Hz, 116.5, 116.6, 117.0, 123.0, 127.5, 127.72 (2C), 127.76 (3C), 1H), 4.39 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.67 (d, J = 11.5 Hz, 127.79 (2C), 128.3 (3C), 131.7, 132.2, 135.1, 137.9, 138.4, 1H), 4.94 (tdd, J = 1.7, 1.7, 10.2 Hz, 1H), 4.97 (tdd, J = 1.7, 1.7, 147.6, 165.5, 198.3; IR νmax 3064, 3032, 2956, 2908, 2864, 2216, 16.8 Hz, 1H), 5.32 (brs, 1H), 5.42 (t, J = 6.8 Hz, 1H), 5.75 (tdd, J 2033, 1728, 1641, 1606, 1497, 1452, 1439, 1360, 1257, 1201, = 6.3, 10.2, 16.8 Hz, 1H), 6.00 (d, J = 9.3 Hz, 1H), 7.24–7.32 (m, 13 1167, 1090, 1066, 1028, 1001, 912, 818 cm–1; HRMS (ESI): 10H); C NMR (CDCl3, 125 MHz) δ 13.8, 26.0, 27.2, 33.7, 34.2, calcd for C37H44ClNO5Na: [M+Na]+: 640.2806; found: 640.2836. 40.3, 67.3, 68.4, 71.3, 72.2, 77.0, 114.9, 116.5, 117.0, 122.7, 127.6, 127.73, 127.77 (2C), 127.79 (2C), 128.3 (2C), 128.4 (2C), 4.11. Dimethyl (2E,6Z,10Z,14E)-(9R*,19S*)-9-benzyloxy-7131.63, 132.3, 137.0, 137.95, 137.98, 138.3, 147.8; IR νmax 3444, benzyloxy)methyl-19-chloro-11-cyano-15-methyl-18-oxoicosa3066, 3032, 2917, 2858, 2216, 1641, 1497, 1454, 1365, 1259, 2,6,10,14-tetraenedioate (6) 1205, 1086, 1065, 1026, 1007, 910 cm–1; HRMS (ESI): calcd for C32H39NO3Na: [M+Na]+: 508.2828; found: 508.2822. To a solution of 22 (18.8 mg, 0.030 mmol) in dry CH2Cl2 (100 µL) was added methyl acrylate (40.3 µl, 0.450 mmol) and a To a solution of corresponding alcohol 30 (33.6 mg, 0.069 solution of 2nd generation Grubbs catalyst (3.0 mg, 3.53 µmol) in mmol) and triethylamine (23.1 µL, 0.166 mmol) in dry CH2Cl2 dry CH2Cl2 (400 µL), and the mixture was stirred for 11 h at (0.5 mL) was added methanesulfonic anhydride (24.1 mg, 0.138 room temperature under argon atmosphere. The reaction mixture mmol) and a solution of lithium bromide (30.0 mg, 0.345 mmol)
7
References 1. 2.
Roy, A.; Saraf, S. Biol. Pharm. Bull. 2006, 29, 191–201. Yuan, C. M.; Zhang, Y.; Tang, G. H.; Li, Y.; He, H. P.; Li, S. F.; Hou, L.; Li, X. Y.; Di, Y. T.; Li, S. L.; Hua, H. M.; Hao, X. J. Planta Med. 2013, 79, 163–168. 3. Polonsky, J.; Varon, Z.; Arnoux, B.; Pettit, G. R.; Schmid, J. M.; Ochi, M.; Kotsuki, H. Experientia, 1979, 35, 987–989. 4. Zhang, Y.; Tang, C. P.; Ke, C. Q.; Li, X. Q.; Xie, H.; Ye, Y. Phytochemistry, 2012, 73, 106–113. 5. Behenna, D. C.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 6720– 6721. 6. Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027–5029. 7. (a) Suzuki, E.; Ueda, M.; Ohba, S.; Sugai, T.; Shoji, M. Tetrahedron Lett. 2013, 54, 1589–1952. (b) Furuta, M.; Hanaya, K.; Sugai, T.; Shoji, M. Tetrahedron Lett. 2014, 55, 3189–3191. 8. Zoretic, P. A.; Zhang, Y.; Ribeiro, A. A. Tetrahedron Lett. 1996, 37, 1751–1754. 9. Tirado, R.; Prieto, J. A. J. Org. Chem. 1993, 58, 5666–5673. 10. Takemura, A.; Fujiwara, K.; Shimawaki, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2005, 61, 7392–7419. 11. Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem. 2003, 68, 5274–5285.
AC C
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To 22 (18.3 mg, 0.030 mmol) was added a suspension of manganese(III) acetate dihydrate (18.9 mg, 0.072 mmol) and copper(II) acetate monohydrate (7.2 mg, 0.036 mmol) in degassed ethanol (500 µL) and the mixture was stirred for 3 h at room temperature under argon atmosphere. The reaction mixture was diluted with H2O and the organic materials were extracted with AcOEt twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography with hexane-AcOEt (20:1–5:1) to afford 25 (2.1 mg, 11%) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 1.16– 1.20 (m, 1H), 1.24 (s, 3H), 1.24–1.32 (m, 1H), 1.57–1.62 (m, 2H), 1.72–1.77 (m, 2H), 1.79–1.83 (m, 1H), 1.93–1.99 (m, 2H), 2.06–2.10 (m, 1H), 2.30–2.38 (m, 2H), 2.40–2.47 (m, 2H), 2.53– 2.62 (m, 2H), 2.91 (ddd, J = 5.8, 14.9, 14.9 Hz, 1H), 3.30 (d, J = 8.8 Hz, 1H), 3.34 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.84 (ddd, J = 2.9, 2.9, 2.9 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 4.30 (d, J = 12.2 Hz, 1H), 4.38 (d, J = 12.4 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.87 (s, 1H), 5.00 (s, 1H), 7.15–7.33 (m, 10H); 13C NMR (CDCl3, 150 MHz) δ 12.9, 21.5, 26.0, 29.7, 32.2, 36.4, 38.8, 39.3, 39.7, 40.2, 47.5, 52.9, 53.6, 58.2, 59.2, 69.9, 73.0, 74.3, 76.7, 77.5, 105.8, 127.4 (2C), 127.5 (2C), 127.7, 128.2 (2C), 128.3, 128.4 (2C), 128.4, 137.8, 138.4, 156.8, 168.2, 198.1; IR νmax 2922, 2854, 2360, 2343, 1733, 1454, 1363, 1257, 1223, 1173, 1099,
Supplementary data related to this article can be found at online version.
SC
4.12. d,l-11β,18-dibenzyloxy-4-carbomethoxy-4-chloro-8βcyano-17-methylene-5α,13α-androst-3-one (25)
RI PT
1028, 806, 742 cm–1; HRMS (ESI): calcd for C37H42ClNO5Na: was diluted with AcOEt. After filtration through a pad of silica MANUSCRIPT ACCEPTED gel, the filtrate was concentrated in vacuo. The residue was [M+Na]+: 638.2649; found: 638.2642. purified by silica gel column chromatography with hexaneAcOEt (20:1–3:1) to afford a 3.0:1 mixture of 6 and its enol Acknowledgments tautomer (11.9 mg, 59%) as a yellow oil. 1H NMR (CDCl3, 500 MHz) δ 1.61 (s, 3H), 2.15–2.22 (m, 8H), 2.25–2.30 (m, 3H), This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of 2.52–2.59 (m, 2H), 2.75–2.79 (m, 1H), 3.69 (s, 3H), 3.80 (s, 3H), 3.94 (d, J = 11.4 Hz, 1H), 3.97 (d, J = 11.4 Hz, 1H), 4.34–4.41 Education, Culture, Sports, Science and Technology, Japan. We (m, 1H), 4.38 d, J = 11.7 Hz, 1H), 4.42 (s, 2H), 4.47 (d, J = 11.7 also thank the Japan Society for the Promotion of Sciences for the JSPS Fellowship for Young Scientists (M.F.). We would like Hz, 1H), 4.75 (s, 1H), 5.07 (brs, 1H), 5.38 (t, J = 7.3 Hz, 1H), 5.79 (d, J = 15.6 Hz, 1H), 5.99 (d, J = 9.0 Hz, 1H), 6.90 (td, J = to thank Editage (www.editage.jp) for English language editing. 6.3, 15.6 Hz, 1H), 7.24–7.31 (m, 10H); HRMS (ESI): calcd for C39H46ClNO7Na: [M+Na]+: 698.2861; found: 698.2859. Appendix A. Supplementary data