Total Synthesis of Kanamienamide and Clarification of Biological

Oct 30, 2017 - The total synthesis of kanamienamide, an enamide with an enol ether and an 11-membered macrolactone of marine origin, was achieved. The...
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Total Synthesis of Kanamienamide and Clarification of Biological Activity Daisuke Ojima, Arihiro Iwasaki, and Kiyotake Suenaga* Department of Chemistry, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan S Supporting Information *

ABSTRACT: The total synthesis of kanamienamide, an enamide with an enol ether and an 11-membered macrolactone of marine origin, was achieved. The synthesis features the construction of an enamide adjacent to an enol ether by Buchwald amidation and an 11-membered ring by Mitsunobu lactonization. In addition, on the basis of the biological assay of synthetic 1, we clarified that kanamienamide (1) was not an apoptosis-like cell death inducer, as reported in the isolation paper, and revealed its real biological activity as a necrosis-like cell death inducer.

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INTRODUCTION In 2016, kanamienamide (1), an enamide with an enol ether and an 11-membered macrolactone, was isolated from the marine cyanobacterium Moorea bouillonii collected at the shore of Kanami, Kagoshima, Japan (Figure 1).1 Kanamienamide (1)

Scheme 1. Retrosynthetic Analysis of Kanamienamide

Figure 1. Structure of kanamienamide (1).

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showed growth-inhibitory activity and induced apoptosis-like cell death in HeLa cells. This apoptosis-like cell death was not inhibited by the caspase inhibitor Z-VAD-FMK at a high concentration of 1. However, little is known about its bioactivity, including its mode of action, target biomolecules, and structure−activity relationship. Kanamienamide (1) is the first discovered natural product that contains an N-Me-enamide group adjacent to an enol ether moiety. Its bioactivity and novel structure motivated synthetic chemists to initiate the synthesis of 1, and recently, total synthesis of kanamienamide (1) has been achieved by He’s group.2 Herein, we also report the total synthesis of kanamienamide (1). Our retrosynthetic analysis is shown in Scheme 1. The NMe-enamide adjacent to the enol ether of kanamienamide (1) was planned to be constructed by Buchwald amidation of vinyl iodide 2. Vinyl iodide 2 could be synthesized by Mitsunobu lactonization of hydroxy carboxylic acid 3, which could be derived from known phosphonate 4,3 known alcohol 5,4 and TFA·N-Me-L-Leu-OMe (6) using several reactions including the Horner−Wadsworth−Emmons reaction. © 2017 American Chemical Society

RESULTS AND DISCUSSION Our synthesis was started from known alcohol 5, which was synthesized from (S)-Roche ester in four steps by a stereoselective crotylboration reaction developed by Roush (Scheme 2).4 Alcohol 5 was converted into the corresponding tosylate, which was reduced with LAH to give olefin 7. Oxidative cleavage of the olefin, followed by the Horner− Wadsworth−Emmons reaction with known phosphonate 43 afforded enone 9. A reagent-controlled 1,2-reduction of enone 9 with (S)-Me-CBS catalyst provided an inseparable mixture of diastereomeric alcohols 10 and epi-10 (12:1 dr).5 The undesired diastereomer derived from epi-10 could be separated at a later stage in the synthesis, i.e., after Mitsunobu lactonization of hydroxy carboxylic acid 3. The stereochemistry of the hydroxy group in 10 was determined by a modified Mosher method6 (see Figure S1). Reduction of the double Received: September 11, 2017 Published: October 30, 2017 12503

DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

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The Journal of Organic Chemistry Scheme 2. Synthesis of Vinyl Iodide 2

Table 1. Construction of the Enamide9

bond by in situ-generated diimide from p-toluenesulfonyl hydrazide7 followed by protection of the hydroxy group afforded TBS ether 11. Removal of the benzyl protecting group by catalytic hydrogenolysis using Raney nickel gave rise to alcohol 12. Aldehyde 13 generated by Swern oxidation of 12 was converted to vinyl iodide 14 by the Wittig−Stork−Zhao olefination reaction using known phosphonium salts.8 Removal of the PMB protecting group followed by Swern oxidation and Pinnick oxidation gave carboxylic acid 15. Having completed the synthesis of the fatty acid moiety, we then initiated the construction of the 11-membered macrolactone. The construction began with coupling between 15 and amine 6 to give amide 16. Removal of the TBS protecting group followed by saponification gave hydroxy carboxylic acid 3. Subsequent Mitsunobu lactonization gave rise to vinyl iodide 2. Although we have tried macrolactamization to construct the 11-membered ring, the desired product was obtained only in low yield as a mixture with its dimer (see Scheme S1 and Table S1). Next, to construct the enamide moiety, we explored the reaction conditions for Buchwald amidation13 by using vinyl iodide 17 as a model substrate (Table 1). At first, we tried direct conversion to the N-Me-enamide adjacent to the enol ether (entry 1); however, no desired product was obtained, and the enol ether moiety was decomposed under this condition. Next, we examined β-keto amide 19 without an unstable enol ether, and only α,β-unsaturated amide 22 was obtained by side reactions, such as undesired C−C bond formation, depropionylation, and olefin isomerization (entry 2). To prevent C− C bond formation, we used β-hydroxy amide 20 as an amide

a

CuI, K3PO4, trans-1,2-diaminocyclohexane, 1,4-dioxane 100−110 °C.13 bCuI, Cs2CO3, N,N′-dimethylethylenediamine (DMEDA), DMF, 60 °C.14,15

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DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

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The Journal of Organic Chemistry

spectra were recorded on a 400 MHz NMR spectrometer. Chemical shifts are reported as δ values in parts per million relative to the residual solvent signal (CHCl3, δ = 7.26 ppm; C6HD5, δ = 7.16 ppm for 1H), and coupling constants are in hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. 13C NMR spectra were recorded on a 100 MHz NMR spectrometer using CDCl3 and C6D6 as a solvent. Chemical shifts are reported as δ values in parts per million from the solvent signal (CDCl3, δ = 77.2 ppm; C6HD5, δ = 128.1 ppm). IR spectra were recorded on an FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded by electrospray ionization (ESI) using time-of-flight (TOF). Reactions were monitored by thin-layer chromatography (TLC), and TLC plates were visualized either by both UV detection and phosphomolybdic acid solution. Silica Gel 60N (Irregular, 63-212 μm) was used for column chromatography unless otherwise noted. Organic solvents for moisture-sensitive reactions were distilled from the following drying agents: THF (Na-benzophenone ketyl), diethyl ether (Na-benzophenone ketyl), benzene (Na), toluene (Na), and CH2Cl2 (P2O5). Anhydrous DMF was used as obtained from commercial supplies. All moisture-sensitive reactions were performed under an atmosphere of nitrogen, and the starting materials were azeotropically dried with benzene before use. Experimental Procedure. 1-((((2R,4R)-2,4-Dimethylhex-5-en-1yl)oxy)methyl)-4-methoxybenzene 7. To a stirred solution of known alcohol 54 (703 mg, 2.66 mmol) in THF (10 mL) at −78 °C was added nBuLi (2.6 M in hexane) (1.30 mL, 3.38 mmol) dropwise. The solution was stirred at −78 °C for 30 min; then, p-toluenesulfonyl chloride (667.3 mg, 3.50 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was diluted with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with brine (70 mL), dried (Na2SO4), and concentrated to give the crude tosylate as a pale yellow oil. To a solution of the resulting tosylate in THF (12 mL) cooled at 0 °C was added LAH (1.0 M in THF) (7.0 mL, 7.0 mmol) dropwise. The reaction mixture was heated to reflux for 1.5 h. After being cooled to room temperature, the reaction was quenched with saturated aqueous Na/K tartrate (70 mL), and the mixture was stirred overnight and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with saturated aqueous NaHCO3 (80 mL) and brine (80 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (45 g, hexane-EtOAc 100:1,50:1) to give olefin 7 (499 mg, 76%) as a colorless oil: [α]D23 −10.6 (c 0.992, CHCl3); IR (neat, cm−1) 2957, 2848, 1639, 1613, 1248, 1093, 910; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.70 (ddd, J = 7.3, 10.3, 17.1 Hz, 1H), 4.94 (d, J = 17.1 Hz, 1H), 4.89 (d, J = 10.3 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 3.81 (s, 3H), 3.32 (dd, J = 5.4, 9.3 Hz, 1H), 3.19 (dd, J = 7.3, 9.3 Hz, 1H), 2.20 (m, 1H), 1.82 (m, 1H), 1.32 (ddd, J = 6.1, 7.3, 13.7 Hz, 1H), 1.12 (td, J = 7.3, 13.7 Hz, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 145.3, 131.0, 129.2 (2C), 113.8, (2C), 112.3, 75.7, 72.7, 55.4, 40.8, 35.3, 31.1, 20.1, 17.7; HRMS (ESI) m/z 249.1854 calcd for C16H25O2 [M + H]+ 249.1855. (2R,4R)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentanal 8. To a stirred solution of olefin 7 (499 mg, 2.01 mmol) in tBuOH/THF/H2O (5:2:1) (8 mL) were added 4-methylmorpholine N-oxide (363 mg, 3.10 mmol) and OsO4 (30 mM in THF) (2.0 mL, 0.060 mmol). After stirring for 5 h, to the mixture was added pH 7 phosphate buffered solution (10 mL) and NaIO4 (2.13 g, 9.96 mmol). After stirring for 1.5 h, the mixture was diluted with water (70 mL) and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with brine (80 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (41 g, hexane-EtOAc 20:1, 10:1) to give aldehyde 8 (439 mg, 88%) as a colorless oil: [α]D23 −6.39 (c 0.974, CHCl3); IR (neat, cm−1) 2960, 2854, 1723, 1613, 1248, 1091; 1H NMR (400 MHz, CDCl3) δ 9.60 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.41 (s, 2H), 3.81 (s, 3H), 3.29 (dd, J = 6.4, 9.3 Hz, 1H), 3.26 (dd, J = 6.4, 9.3 Hz, 1H), 2.43 (m, 1H), 1.85 (m, 1H), 1.55 (ddd, J = 5.9, 8.8, 13.7 Hz, 1H), 1.44

source. However, the desired product was obtained only in low yield. Finally, we expected that a primary amide would be much more reactive than a secondary amide and tried to use primary amide 21 for this reaction. As a result, this coupling reaction proceeded smoothly, and the desired enamide was obtained in excellent yield. On the basis of the results of the model experiments described above, we selected primary amide 21 for Buchwald amidation to construct the enamide moiety and obtained desired enamide 23 in good yield (Scheme 3). N-Methylation Scheme 3. Synthesis of Kanamienamide

of the enamide group in 23 was effected by the use of methyl iodide,15 and total synthesis of kanamienamide (1) was achieved. The spectroscopic data (1H and 13C NMR, HRMS, and optical rotation) for synthetic kanamienamide were fully consistent with those of the natural product (see Table S2−S4). In addition, we also examined the possibility of epimerization of synthetic 1 based on the comparison of HPLC retention time and NOESY spectrum, and as a result, we excluded it (see Figures S2 and S3). To verify the reported biological activity of kanamienamide (1),1 we evaluated the growth inhibitory activity of synthetic 1 against HeLa cells. It has been reported that natural 1 shows the growth inhibitory activity against HeLa cells with an IC50 value of 2.5 μM, whereas our synthetic 1 showed much weaker activity against HeLa cells (IC50 32 μM) than that of natural 1 (see Table S5). In addition, the cell death induced by synthetic 1 was necrosis-like based on observation of morphology of the cell, although natural 1 induced apoptosis-like cell death. Regarding this discrepancy between synthetic 1 and natural 1, we suspect that natural 1 might contain a trace of impurity, which induced apoptosis-like cell death (see Figure S4).

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CONCLUSIONS In conclusion, we have achieved the total synthesis of kanamienamide (1) from (S)-Roche ester via a longest linear sequence of 23 steps; the overall yield over the longest linear sequence is 6.4%. In addition, on the basis of the biological assay of synthetic 1, we clarified that kanamienamide (1) was not the bioactive component reported in the isolation paper and revealed its real biological activity as a necrosis-like cell death inducer.1

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EXPERIMENTAL SECTION

General Information. Chemicals and solvents were of the best grade available and were used as received from commercial sources. Optical rotations were measured with a digital polarimeter. 1H NMR 12505

DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

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The Journal of Organic Chemistry (ddd, J = 5.4, 8.3, 13.7 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.5, 159.2, 130.7, 129.3 (2C), 113.9 (2C), 75.5, 72.8, 55.4, 44.1, 34.5, 31.1, 17.0, 13.5; HRMS (ESI) m/z 273.1463 calcd for C15H22O3Na [M + Na]+ 273.1467. (8R,10R,E)-1-(Benzyloxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundec-6-en-5-one 9. To a stirred solution of β-keto phosphate (4)3 (1.52 g, 4.84 mmol) in THF/H2O (20:1) (25 mL) was added Ba(OH)2·8H2O (1.39 g, 4.41 mmol). The reaction mixture was stirred vigorously at room temperature for 1 h; then, a solution of aldehyde 8 (1.08 g, 4.33 mmol) in THF/H2O (20:1) (9 mL) was added. After stirring for 5.5 h, the mixture was diluted with saturated aqueous NH4Cl solution (70 mL) and extracted with EtOAc (3 × 40 mL). The combined extracts were washed with brine (80 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (40 g, hexane-EtOAc 8:1) to give enone 9 (1.63 g, 86%) as a colorless oil: [α]D23 −18.7 (c 0.994, CHCl3); IR (neat, cm−1) 2855, 1670, 1616, 1508, 1362, 1086; 1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 5H), 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.70 (dd, J = 7.8, 16.1 Hz, 1H), 6.02 (d, J = 16.1 Hz, 1H), 4.49 (s, 2H), 4.43 (d, J = 11.7 Hz, 1H), 4.40 (d, J = 11.7 Hz, 1H), 3.81 (s, 3H), 3.48 (t, J = 6.4 Hz, 2H), 3.27 (dd, J = 5.9, 8.8 Hz, 1H), 3.22 (dd, J = 6.4, 8.8 Hz, 1H), 2.55 (t, J = 6.8 Hz, 2H), 2.38 (m, 1H), 1.83−1.59 (m, 5H), 1.44 (m, 1H), 1.21 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.8, 159.2, 153.0, 138.7, 130.8, 129.2 (2C), 128.5 (2C), 128.4 (2C), 127.8, 127.6, 113.8 (2C), 75.4, 73.0, 72.8, 70.2, 55.4, 40.2, 40.0, 34.3, 31.2, 29.3, 21.1, 19.4, 17.5; HRMS (ESI) m/z 439.2841 calcd for C28H39O4 [M + H]+ 439.2848. (5R,8R,10R,E)-1-(Benzyloxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundec-6-en-5-ol 10. To a stirred solution of (S)-Me-CBS catalyst (766 mg, 2.76 mmol) in toluene (10 mL) cooled at 0 °C was added borane·SMe2 complex (0.24 mL, 2.53 mmol) followed by a solution of enone 9 (841 mg, 1.91 mmol) in toluene (10 mL) dropwise. After stirring for 30 min, the reaction mixture was quenched with MeOH, and the mixture was stirred at room temperature for 30 min and concentrated. The residual oil was purified by column chromatography on silica gel (41 g, hexane-EtOAc 6:1, 4:1) to give a mixture of diastereomeric allylic alcohols 10 and epi-10 (797 mg, 95%, 12:1 dr) as a colorless oil: [α]D23 −12.1 (c 1.01, CHCl3); IR (neat, cm−1) 3444, 2930, 2860, 1612, 1455, 1248, 1096; 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 7.25 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.51 (dd, J = 7.6, 15.6 Hz, 1H), 5.38 (dd, J = 7.3, 15.6 Hz, 1H), 4.49 (s, 2H), 4.42 (s, 2H), 4.03 (m, 1H), 3.80 (s, 3H), 3.47 (t, J = 6.4 Hz, 2H), 3.29 (dd, J = 5.4, 9.3 Hz, 1H), 3.19 (dd, J = 6.8, 9.3 Hz, 1H), 2.20 (m, 1H), 1.79 (m, 1H), 1.67−1.30 (m, 7H), 1.10 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 138.7, 138.4, 131.0 (2C) 129.2 (2C), 128.4 (2C), 127.8 (2C), 127.6, 113.8 (2C), 75.6, 73.2, 73.0, 72.7, 70.4, 55.4, 41.0, 37.2, 33.9, 31.2, 29.7, 22.4, 20.4, 17.7; HRMS (ESI) m/z 463.2830 calcd for C28H40O4Na [M + Na]+ 463.2824. (5R,8S,10R)-1-(Benzyloxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundecan-5-ol SI1 (see Figure S5). To a solution of allylic alcohol 10 (924 mg, 2.09 mmol) in dimethoxyethane (40 mL) was added ptoluenesulfonyl hydrazide (1.95 g, 10.5 mmol). The solution was warmed to 85 °C, and an aqueous solution of AcONa (11 mL, 1.0 M) was added dropwise. The solution was refluxed overnight, then diluted with water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with brine (150 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (37 g, hexane-EtOAc 4:1) to give alcohol SI1 (857 mg, 92%) as a colorless oil: [α]D23 +6.96 (c 1.02, CHCl3); IR (neat, cm−1) 2932, 2859, 1614, 1508, 1456, 1245; 1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 5H), 7.26 (d, J = 8,3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 4.50 (s, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.55 (m, 1H), 3.48 (t, J = 6.8 Hz, 2H), 3.26 (dd, J = 6.4, 9.3 Hz, 1H), 3.19 (dd, J = 6.8, 9.3 Hz, 1H), 1.86 (m, 1H), 1.65−1.56 (m, 5H), 1.54−1.35 (m, 5H), 1.27 (m, 1H), 1.18 (ddd, J = 4.9, 8.8, 13.7 Hz, 1H), 1.07 (ddd, J = 4.9, 9.3, 13.7 Hz, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 138.7,

131.0, 129.3 (2C), 128.5 (2C), 127.8 (2C), 127.7, 113.8 (2C), 76.5, 73.0, 72.7, 72.2, 70.4, 55.4, 41.4, 37.4, 35.0, 33.7, 31.0, 30.0, 29.9, 22.5, 19.5, 17.1; HRMS (ESI) m/z 443.3164 calcd for C28H43O4 [M + H]+ 443.3161. (((5R,8S,10R)-1-(Benzyloxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundecan-5-yl)oxy)(tert-butyl)dimethylsilane 11. To a stirred solution of alcohol SI1 (837 mg, 1.89 mmol) in DMF (4 mL) were added imidazole (387 mg, 5.68 mmol) and TBSCl (440 mg, 2.91 mmol) at room temperature. After stirring for 4 h, the mixture was diluted with EtOAc (50 mL), washed with water (30 mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (38 g, hexane-EtOAc 30:1, 10:1) to give silyl ether 11 (988 mg, 94%) as a colorless oil: [α]D23 +6.94 (c 0.995, CHCl3); IR (neat, cm−1) 2930, 2854, 1512, 1249, 1098; 1H NMR (400 MHz, CDCl3) δ 7.34−7.26 (m, 5H), 7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.50 (s, 2H), 4.44 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 3.80 (s, 3H), 3.60 (m, 1H), 3.47 (t, J = 6.4 Hz, 2H), 3.27 (dd, J = 5.9, 9.3 Hz, 1H), 3.18 (dd, J = 7.3, 9.3 Hz, 1H), 1.83 (m, 1H), 1.64− 1.52 (m, 2H), 1.48−1.29 (m, 7H), 1.26−1.12 (m, 2H), 1.05 (ddd, J = 4.9, 9.8, 14.2 Hz, 1H), 0.93−0.84 (m, 4H), 0.88 (s, 9H), 0.82 (d, J = 6.4 Hz, 3H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.1, 138.8, 131.0, 129.2 (2C), 128.5, (2C), 127.7 (2C), 127.6, 113.8 (2C), 76.6, 73.0, 72.7, 72.6, 70.6, 55.4, 41.2, 37.1, 34.6, 33.5, 31.0, 30.2, 30.1, 26.0 (3C), 22.2, 19.5, 18.3, 17.1, −4.3 (2C); HRMS (ESI) m/z 579.3853 calcd for C34H56O4SiNa [M + Na]+ 579.3846. (5R,8S,10R)-5-((tert-Butyldimethylsilyl)oxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundecan-1-ol 12. To a stirred suspension of Raney Ni (in EtOH, 6.6 g, prepared according to ref 16) in EtOH (10 mL) was added a solution of silyl ether 11 in EtOH (12 mL) under argon. The reaction mixture was degassed, charged with hydrogen 3 times, and stirred vigorously at room temperature. After stirring for 6 h under the hydrogen atmosphere, Raney Ni was filtered, and the filtrate was concentrated. The residual oil was purified by column chromatography on silica gel (37 g, hexane-EtOAc 5:1) to give alcohol 12 (919 mg, quant) as a colorless oil: [α]D23 +7.14 (c 1.02, CHCl3); IR (neat, cm−1) 3420, 2931, 2856, 1248, 1038; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 3.62 (m, 1H), 3.27 (dd, J = 5.9, 9.3 Hz, 1H), 3.18 (dd, J = 6.8, 9.3 Hz, 1H), 1.83 (m, 1H), 1.60−1.33 (m, 9H), 1.27−1.13 (m, 2H), 1.06 (ddd, J = 4.4, 9.3, 13.7 Hz, 1H), 0.92−0.87 (m, 13H), 0.83 (d, J = 6.8 Hz, 3H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.2, 131.0, 129.2 (2C), 113.8 (2C), 76.6, 72.7, 72.6, 63.1, 55.4, 41.3, 37.0, 34.6, 33.4, 33.1, 31.0, 30.2, 26.1 (3C), 21.6, 19.5, 18.3, 17.1, −4.2 (2C); HRMS (ESI) m/z 467 3560 calcd for C27H51O4Si [M + H]+ 467.3557. (5R,8S,10R)-5-((tert-Butyldimethylsilyl)oxy)-11-((4-methoxybenzyl)oxy)-8,10-dimethylundecanal 13. To a solution of oxalyl chloride (0.14 mL, 1.6 mmol) in CH2Cl2 (3 mL) was added DMSO (0.24 mL, 3.4 mmol) in CH2Cl2 (1 mL) dropwise at −78 °C. This mixture was stirred for 15 min; then, a solution of alcohol 12 (495 mg, 1.06 mmol) in CH2Cl2 (6 mL) was added dropwise. The reaction mixture was stirred at −78 °C for 30 min. DIPEA (0.94 mL, 5.4 mmol) was then added, and the mixture was allowed to warm to room temperature. After stirring for 1 h, the mixture was diluted with Et2O (40 mL) and washed with 1 M HCl (30 mL), saturated aqueous NaHCO3 (30 mL), and brine (30 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (39 g, hexane-EtOAc 11:1, 3:1) to give aldehyde 13 (403 mg, 82%) as a colorless oil: [α]D23 +11.2 (c 1.02, CHCl3); IR (neat, cm−1) 2929, 2855, 1726, 1249, 1090; 1H NMR (400 MHz, CDCl3) δ 9.76 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.44 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 3.81 (s, 3H), 3.63 (m, 1H), 3.27 (dd, J = 5.4, 8.8 Hz, 1H), 3.18 (dd, J = 6.8, 8.8 Hz, 1H), 2.42 (m, 2H), 1.83 (m, 1H), 1.70−1.52 (m, 3H), 1.48−1.39 (m, 5H), 1.26−1.12 (m, 2H), 1.05 (ddd, J = 4.9, 9.3, 14.2 Hz, 1H), 0.92−0.87 (m, 12H), 0.83 (d, J = 6.8 Hz, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 202.9, 159.2, 131.0, 129.2 (2C), 113.8 (2C), 76.5, 72.7, 72.3, 55.4, 44.2, 41.2, 36.5, 34.5, 33.4, 31.0, 30.2, 26.1 (3C), 19.5, 12506

DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

Article

The Journal of Organic Chemistry 18.3, 18.1, 17.0, −4.2, −4.3; HRMS (ESI) m/z 487.3228 calcd for C27H48O4SiNa [M + Na]+ 487.3220. tert-Butyl(((6R,9S,11R,Z)-1-iodo-12-((4-methoxybenzyl)oxy)-9,11dimethyldodec-1-en-6-yl)oxy)dimethylsilane 14. To a stirred solution of NaHMDS (1.0 M in THF) (2.6 mL, 2.6 mmol) in THF ( 1 7 m L ) w a s a d d e d a su sp e n si o n o f ( i o do m e t h y l ) triphenylphosphonium iodide (1.39 g, 2.62 mmol, prepared according to ref 8a) in HMPA (13 mL) at 0 °C. After 1 min, the mixture was cooled to −78 °C, and a solution of aldehyde 13 (696 mg, 1.49 mmol) in THF (9 mL) was added dropwise. After stirring at −78 °C for 40 min, the reaction mixture was stirred at room temperature. After stirring for 2 min, the mixture was diluted with saturated aqueous NH4Cl (150 mL) and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with brine (3 × 100 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (40 g, hexane-EtOAc 50:1) to give vinyl iodide 14 (570 mg, 65%) as a colorless oil: [α]D23 +5.74 (c 1.00, CHCl3); IR (neat, cm−1) 2952, 2928, 2855, 1461, 1247, 1094; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.20−6.13 (m, 1H), 6.19 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 3.81 (s, 3H), 3.61 (m, 1H), 3.27 (dd, J = 5.9, 9.3 Hz, 1H), 3.19 (dd, J = 6.8, 9.3 Hz, 1H), 2.16− 2.09 (m, 2H), 1.84 (m, 1H), 1.58−1.54 (m, 2H), 1.52−1.38 (m, 5H), 1.27−1.13 (m, 3H), 1.05 (ddd, J = 4.4, 9.3, 14.2 Hz, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.88 (s, 9 H), 0.83 (d, J = 6.4 Hz, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.1, 141.4, 131.0, 129.2 (2C), 113.8 (2C), 82.6, 76.6, 72.7, 72.4, 55.4, 41.2, 36.5, 35.0, 34.6, 33.5, 31.0, 30.2, 26.1 (3C), 23.9, 19.5, 18.3, 17.1, −4.2 (2C); HRMS (ESI) m/z 611.2379 calcd for C28H49IO3SiNa [M + Na]+ 611.2393. (2R,4S,7R,Z)-7-((tert-Butyldimethylsilyl)oxy)-12-iodo-2,4-dimethyldodec-11-en-1-ol SI2 (see Figure S5). To a solution of iodide 14 (549 mg, 0.932 mmol) in CH2Cl2 (3.7 mL) and pH 7.0 phosphate buffer (0.9 mL) was added DDQ (265 mg, 1.17 mmol), and the reaction mixture was stirred at room temperature for 20 min. The reaction was quenched with saturated aqueous NaHCO3 (40 mL), and the mixture was extracted with CH2Cl2 (3 × 30 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (36 g, hexane-Et2O 10:1, 5:1) to give alcohol SI2 (376 mg, 0.778 mmol) and the mixture of alcohol SI2 and anisaldehyde (47.9 mg), which was further purified by column chromatography on Silica Gel 60 (spherical, neutrality) (hexane-Et2O 5:1) to give alcohol SI2 (26.6 mg, 0.0551 mmol). Totally, this reaction provided 402 mg (89%) of alcohol SI2 as a colorless oil: [α]D23 +10.9 (c 0.995, CHCl3); IR (neat, cm−1) 2952, 2928, 2856, 1461, 1035; 1H NMR (400 MHz, CDCl3) δ 6.21−6.14 (m, 2H), 3.63 (m, 1H), 3.48 (dd, J = 5.9, 10.7 Hz, 1H), 3.41 (dd, J = 6.8, 10.7 Hz, 1H), 2.16−2.10 (m, 2H), 1.71 (m, 1H), 1.58−1.37 (m, 6H), 1.30−1.04 (m, 5H), 0.90−0.88 (m, 12H), 0.84 (d, J = 6.4 Hz, 3H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 141.4, 82.6, 72.4, 69.2, 40.7, 36.5, 34.9, 34.5, 33.4 (2C), 30.2, 26.1 (3C), 23.8, 19.5, 18.3, 16.5, −4.2 (2C); HRMS (ESI) m/z 469.1988 calcd for C20H42IO2Si [M + H]+ 469.1999. (2R,4S,7R,Z)-7-((tert-Butyldimethylsilyl)oxy)-12-iodo-2,4-dimethyldodec-11-enal SI3 (see Figure S5). To a solution of oxalyl chloride (0.10 mL, 1.2 mmol) in CH2Cl2 (1.0 mL) was added DMSO (0.20 mL, 2.8 mmol) in CH2Cl2 dropwise at −78 °C. This mixture was stirred for 15 min; then, a solution of alcohol SI2 (382 mg, 0.792 mmol) in CH2Cl2 (1.4 mL) was added dropwise. The reaction mixture was stirred at −78 °C for 30 min. DIPEA (0.90 mL, 5.2 mmol) was then added, and the mixture was allowed to warm to room temperature. After stirring for 2.5 h, the mixture was diluted with EtOAc (25 mL), washed with 1 M HCl (15 mL), saturated aqueous NaHCO3 (15 mL), and brine (15 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (16 g, hexane-EtOAc 20:1, 3:1) to give aldehyde SI3 (319 mg, 84%) as a colorless oil: [α]D23 −5.75 (c 1.01, CHCl3); IR (neat, cm−1) 2929, 2856, 2705, 1726, 1080; 1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 2.0 Hz, 1H), 6.21−6.13 (m, 2H), 3.63 (m, 1H), 2.42 (m, 1H), 2.18−2.11 (m, 2H), 1.56−1.34 (m, 9H), 1.30−1.21 (m, 2H), 1.07 (d, J = 6.8 Hz, 3H), 0.88−0.85 (m, 12H), 0.04 (s, 6H); 13C NMR

(100 MHz, CDCl3) δ 205.5, 141.3, 82.7, 72.2, 44.4, 37.7, 36.5, 34.9, 34.4, 32.9, 30.5, 26.1 (3C), 23.8, 19.4, 18.2, 13.5, −4.2 (2C); HRMS (ESI) m/z 467.1837 calcd for C20H40IO2Si [M + H]+ 467.1842. (2R,4S,7R,Z)-7-((tert-Butyldimethylsilyl)oxy)-12-iodo-2,4-dimethyldodec-11-enoic Acid 15. To a stirred solution of aldehyde SI3 (297 mg, 0.617 mmol) in tBuOH (3.6 mL) at room temperature were added 2-methyl-2-butene (3.6 mL), 1 M aqueous NaH2PO4 solution (1.2 mL), and 1 M aqueous NaClO2 solution (1.2 mL). After stirring for 1 h, the reaction mixture was diluted with saturated aqueous Na2SO3 (3 mL), stirred for 10 min, acidified with 1 M HCl (20 mL), and extracted with EtOAc (3 × 20 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (16 g, hexane-EtOAc-AcOH 300:20:1) to give carboxylic acid 15 (279 mg, 91%) as a colorless oil: [α]D23 −5.03 (c 1.01, CHCl3); IR (neat, cm−1) 2931, 2857, 1707, 1462, 1078; 1H NMR (400 MHz, CDCl3) δ 6.21− 6.13 (m, 2H), 3.63 (m, 1H), 2.54 (tq, J = 6.9, 7.3 Hz, 1H), 2.16−2.10 (m, 2H), 1.58−1.19 (m, 11H), 1.16 (d, J = 7.3 Hz, 3H), 0.88−0.86 (m, 12H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 183.4, 141.4, 82.6, 72.3, 40.9, 37.2, 36.5, 34.9, 34.3, 32.5, 30.8, 26.1 (3C), 23.8, 19.4, 18.3, 17.0, −4.2 (2C); HRMS (ESI) m/z 483.1795 calcd for C20H40IO3Si [M + H]+ 483.1791. Methyl N-((2R,4S,7R,Z)-7-((tert-Butyldimethylsilyl)oxy)-12-iodo2,4-dimethyldodec-11-enoyl)-N-methyl-L-leucinate 16. To a stirred solution of N-Me-L-Leu-OMe·TFA (6) (33 mg, ∼0.103 mmol, prepared from Boc-N-Me-L-Leu-OMe) and carboxylic acid 15 (34.9 mg, 70.2 μmol) in CH2Cl2 (0.2 mL) and DMF (0.04 mL) were added DIPEA (0.06 mL, 0.34 mmol) and HATU (31.7 mg, 83.4 μmol) at 0 °C. The reaction mixture was warmed to room temperature. After stirring for 20 h, the reaction mixture was diluted with EtOAc (20 mL), washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on Silica Gel 60 (spherical, neutrality) (8 g, hexane-EtOAc 7:1) to give amide 16 (41.3 mg, 94%) as a colorless oil: [α]D23 −18.9 (c 1.01, CHCl3); IR (neat, cm−1) 2953, 2857, 1743, 1650, 1201, 1079; 1H NMR (400 MHz, CDCl3) δ 6.21−6.13 (m, 2H), 5.37 (dd, J = 6.8, 9.3 Hz, 1H), 3.69 (s, 3H), 3.61 (m, 1H), 2.94 (s, 3H), 2.80 (m, 1H), 2.17−2.10 (m, 2H), 1.73−1.69 (m, 2H), 1.59 (m, 1H), 1.57−1.12 (m, 11H), 1.11 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.88− 0.86 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.8, 172.9, 141.3, 82.6, 72.4, 54.2, 52.2, 41.2, 37.5, 36.5, 34.9, 34.4, 33.8, 32.8, 31.4, 30.9, 26.1 (3C), 25.2, 23.8, 23.5, 21.4, 19.7, 18.3, 17.1, −4.2 (2C); HRMS (ESI) m/z 624.2963 calcd for C28H55INO4Si [M + H]+ 624.2945. Methyl N-((2R,4S,7R,Z)-7-Hydroxy-12-iodo-2,4-dimethyldodec11-enoyl)-N-methyl-L-leucinate SI4 (see Figure S5). To a stirred solution of amide 16 (118 mg, 0.190 mmol) in MeOH (1 mL) was added 0.8 M HCl in MeOH (2 mL) (prepared from concd HCl(aq) and MeOH) at 0 °C. After stirring for 1 h, the mixture was diluted with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (3 × 10 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (8 g, hexane-EtOAc 6:1, 5:1, 2:1) to give alcohol SI4 (96.7 mg, quant) as a colorless oil: [α]D23 −24.8 (c 1.02, CHCl3); IR (neat, cm−1) 3676, 2931, 2869, 1741, 1635, 1269, 1007; 1H NMR (400 MHz, CDCl3) δ 6.22−6.14 (m, 2H), 5.31 (dd, J = 7.8, 8.3 Hz, 1H), 3.69 (s, 3H), 3.58 (m, 1H), 2.96 (s, 3H), 2.82 (m, 1H), 2.21−2.13 (m, 2H), 1.72 (dd, J = 6.8, 8.3 Hz, 2H), 1.59−1.23 (m, 12H), 1.11 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.8, 172.9, 141.1, 82.8, 71.9, 54.5, 52.2, 41.2, 37.4, 37.0, 34.9, 34.7, 33.7, 32.9, 31.6, 30.6, 25.2, 24.2, 23.5, 21.4, 19.7, 17.2; HRMS (ESI) m/z 510.2083 calcd for C22H41INO4 [M + H]+ 510.2080. (3S,6R,8S,11S)-11-((Z)-5-Iodopent-4-en-1-yl)-3-isobutyl-4,6,8-trimethyl-1-oxa-4-azacycloundecane-2,5-dione 2. To a stirred solution of alcohol SI4 (75.4 mg, 0.148 mmol) in THF/H2O (10:7) (3.4 mL) was added LiOH·H2O (19.7 mg, 0.469 mmol) and stirred at room temperature for 1 h. The reaction mixture was acidified with 1 M aqueous HCl (20 mL) and extracted with EtOAc (3 × 10 mL). The 12507

DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

Article

The Journal of Organic Chemistry

colorless amorphous solid: IR (neat, cm−1) 3310, 2979, 1716, 1650; 1 H NMR (400 MHz, CDCl3) δ 7.02 (br m, 1H, NH)), 3.40 (s, 2H), 2.83 (d, J = 4.8 Hz, 3H), 2.56 (q, J = 7.3 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.7, 166.4, 48.5, 37.3, 26.3, 7.5; HRMS (ESI) m/z 130.0862 calcd for C6H12NO2 [M + H]+ 130.0868. 3-Hydroxy-N-methylpentanamide 20. To a stirred solution of methyl 3-oxopentanoate (1.29 g, 9.91 mmol) in MeOH (25 mL) cooled at 0 °C was added NaBH4 (425 mg, 11.2 mmol), and the reaction mixture was warmed to room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with 10% aqueous citric acid (70 mL) and extracted with EtOAc (3 × 40 mL) to give the crude alcohol. To the resulting alcohol was added a 40% MeNH2 solution in MeOH (25 mL) at room temperature. After stirring for 5.5 h, the reaction mixture was concentrated. The residual oil was purified by column chromatography on silica gel (40 g, chloroform-EtOAc-MeOH 10:10:1) to give amide 20 (1.12 g, 86%) as a colorless amorphous solid: IR (neat, cm−1) 3311, 2965, 2936, 2880, 1634; 1H NMR (400 MHz, CDCl3) δ 5.78 (br m, 1H, NH), 3.91 (m, 1H), 3.55 (br s, 1H, OH), 2.83 (d, J = 4.9 Hz, 3H), 2.36 (dd, J = 2.7, 15.3 Hz, 1H), 2.25 (dd, J = 9.2, 15.3 Hz, 1H), 1.58−1.44 (m, 2H), 0.96 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.4, 70.1, 42.0, 29.9, 26.2, 9.9; HRMS (ESI) m/z 154.0839 calcd for C6H13NO2Na [M + Na]+ 154.0844. (E)-3-Methoxypent-2-enamide 21. To a stirred solution of known enol ether SI610 (see Figure S5) (702 mg, 4.87 mmol) in THF/H2O (7:5) (60 mL) was added LiOH·H2O (657 mg, 15.6 mmol). The reaction mixture was refluxed for 10.5 h. Because the reaction was not completed, to the suspension was added MeOH (18 mL), which was refluxed overnight. Organic solvent was removed in vacuo, and the residual suspension was diluted with EtOAc (50 mL) and 1 M aqueous HCl (11 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine (40 mL), dried (Na2SO4), and concentrated to give the crude carboxylic acid (501 mg). To a stirred solution of the resulting carboxylic acid (501 mg) and NH4Cl (253 mg, 4.73 mmol) in DMF (7.6 mL) were added DIPEA (1.7 mL, 9.76 mmol), HOBt (518 mg, 3.83 mmol), and EDCI·HCl (1.19 g, 6.21 mmol). After stirring at room temperature for 11 h, the reaction mixture was diluted with saturated aqueous NaHCO3 (30 mL), and the water layer was saturated with NaCl and extracted with EtOAc (2 × 50 mL). The combined extracts were dried (Na2SO4) and concentrated. The residual oil was purified by column chromatography on Silica Gel 60 (spherical, neutrality) (16 g, chloroform-EtOAcMeOH 50:50:1, 20:20:1) to give the 1:1 mixture of amide 21 and DMF (655 mg, ∼67% in two steps) as a colorless oil. This mixture was used for the subsequent reaction with vinyl iodide 2 and 17: 1H NMR (400 MHz, CDCl3) δ 5.41−4.92 (br m, 2H, NH), 4.87 (s, 1H), 3.62 (s, 3H), 2.79 (q, J = 7.3 Hz, 2H), 1.10 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8, 169.4, 90.9, 55.2, 25.1, 12.0. General Procedure for Buchwald Amidation Using Amides 18− 20.13 To a mixture of iodide 17, K3PO4, and CuI were added amides 18−20 in 1,4-dioxane and trans-1,2-diaminocyclohexane at room temperature, and the reaction mixture was stirred at 100 °C. After the consumption of iodide 17, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated, and the residual oil was purified by PLC. (E)-8-((4-Methoxybenzyl)oxy)-N-methyloct-2-enamide 22. The general procedure was followed using iodide 17 (7.4 mg, 21 μmol), amide 18 (77.4 mg, 599 μmol) in 1,4-dioxane (1 mL), CuI (12.4 mg, 65.1 μmol), K3PO4 (96.2 mg, 453 μmol), and trans-1,2-diaminocyclohexane (0.01 mL, 83.2 μmol). Upon completion of the conversion of iodide 17, the crude product was purified by PLC (chloroformEtOAc 1:3) to give byproduct 22 (4.6 mg, 74%) as a colorless oil: IR (neat, cm−1) 3289, 2934, 2857, 1671, 1614, 1247, 1097; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 6.80 (td, J = 6.8, 15.6 Hz, 1H), 5.72 (d, J = 15.6 Hz, 1H), 5.52 (br m, 1H, NH), 4.42 (s, 2H), 3.80 (s, 3H), 3.42 (t, J = 6.8 Hz, 2H), 2.85 (d, J = 4.9 Hz, 3H), 2.16 (q, J = 6.8 Hz, 2H), 1.59 (m, 2H), 1.47− 1.33 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 166.9, 159.2, 144.5, 130.8, 129.4 (2C), 123.6, 113.9 (2C), 72.7, 70.0, 55.4, 32.0, 29.6, 28.1,

combined extracts were washed with brine (10 mL), dried (Na2SO4), and concentrated to give crude carboxylic acid 3. To a stirred solution of the crude hydroxy carboxylic acid 3 (77.5 mg) in toluene (74 mL) were added PPh3 (158 mg, 0.605 mmol) and DEAD (40% in toluene, 0.20 mL, 0.44 mmol) at 60 °C. After stirring at 60 °C for 4 h, the reaction mixture was concentrated, diluted with EtOAc (50 mL), washed with 0.05 M HCl (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (9 g, hexane-EtOAc 8:1) to give vinyl iodide 2 (50.1 mg, 71%) as a colorless oil: [α]D23 −44.3 (c 0.975, CHCl3); IR (neat, cm−1) 2955, 2868, 1725, 1651, 1255, 1092; 1H NMR (400 MHz, CDCl3) δ 6.23 (d, J = 7.3 Hz, 1H), 6.14 (td, J = 6.8, 7.3 Hz, 1H), 5.05 (m, 1H), 4.54 (dd, J = 7.8, 7.3 Hz, 1H), 2.88 (s, 3H), 2.82 (m, 1H), 2.14 (m, 2H), 1.93−1.73 (m, 4H), 1.64−1.52 (m, 3H), 1.44−1.36 (m, 2H), 1.19−0.92 (m, 5H), 1.10 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 5.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.0, 173.0, 140.6, 83.3, 77.1, 58.4, 43.3, 38.4, 35.0, 34.4, 34.3, 33.7, 31.5, 30.7, 29.0, 24.8, 23.8, 23.4, 22.4, 20.9, 18.7; HRMS (ESI) m/z 478.1822 calcd for C21H37INO3 [M + H]+ 478.1818. (Z)-1-(((6-Iodohex-5-en-1-yl)oxy)methyl)-4-methoxybenzene 17. To a stirred solution of NaHMDS (1.0 M in THF) (1.1 mL, 1.1 mmol) in THF (15 mL) was added a suspension of (iodomethyl)triphenylphosphonium iodide (590 mg, 1.11 mmol, prepared according to ref 8a) in HMPA (6.2 mL) at 0 °C. After 1 min, the mixture was cooled to −78 °C, and a solution of the known aldehyde SI517 (see Figure S5) (165 mg, 0.737 mmol) in THF (3 mL) was added dropwise. After stirring at −78 °C for 15 min, the reaction mixture was stirred at room temperature. After stirring for 2 min, the mixture was diluted with saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine (100 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (18 g, hexane-EtOAc 100:1, 50:1) to give vinyl iodide 17 (172 mg, 68%) as a colorless oil: IR (neat, cm−1) 2934, 2857, 1611, 1246, 1100, 1037; 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.21−6.13 (m, 1H), 6.19 (d, J = 8.4 Hz, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.46 (t, J = 6.3 Hz, 2H), 2.16 (m, 2H), 1.65 (m, 2H), 1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.2, 141.2, 130.8, 129.4 (2C), 113.9 (2C), 82.6, 72.7, 69.9, 55.4, 34.6, 29.3, 24.8; HRMS (ESI) m/z 347.0498 calcd for C14H20IO2 [M + H]+ 347.0508. (E)-3-Methoxy-N-methylpent-2-enamide 18. To known enol ether SI610 (see Figure S5) (38.0 mg, 0.263 mmol) were added a 40% MeNH2 solution in MeOH (1.2 mL, 12 mmol) and magnesium chloride (13.5 mg, 0.142 mmol) at room temperature. After stirring for 42.5 h, the reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 × 10 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on DIOL Silica Gel (8 g, hexane-EtOAc 16:1) to give amide 18 (19.5 mg, E/Z 10:1, 52%) as a colorless oil. Amide 18 was used for the subsequent Buchwald amidation without further purification: IR (neat, cm−1) 3370, 3298, 2977, 2946, 1653, 1606, 1173; 1H NMR (400 MHz, CDCl3) δ 8.50 (br m, 1H, NH), 4.48 (s, 1H), 3.62 (s, 3H), 2.91 (d, J = 5.4 Hz, 3H), 2.22 (q, J = 7.3 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 168.1, 79.7, 50.1, 29.3, 25.2, 12.0; HRMS (ESI) m/z 166.0840 calcd for C7H13NO2Na [M + Na]+ 166.0844. N-Methyl-3-oxopentanamide 19. To methyl 3-oxopentanoate (1.02 g, 7.72 mmol) were added a 40% MeNH2 solution in MeOH (10 mL, 98 mmol), THF (12 mL), and H2O (2 mL) at room temperature. After stirring for 22.5 h, the reaction mixture was concentrated to give the crude imine. To a stirred solution of the resulting imine in THF (24 mL) was added 1 M HCl (15 mL, 15 mmol) at room temperature. After stirring overnight, the reaction mixture was diluted with saturated aqueous NaHCO3 (80 mL) and extracted with EtOAc (3 × 40 mL) and CH2Cl2 (2 × 40 mL). The combined extracts were dried (Na2SO4) and concentrated. The residual oil was purified by column chromatography on silica gel (38 g, chloroform-MeOH 50:1) to give amide 19 (476 mg, 48%) as a 12508

DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

Article

The Journal of Organic Chemistry 26.4, 25.8; HRMS (ESI) m/z 292.1907 calcd for C17H26NO3 [M + H]+ 292.1912. (Z)-3-Hydroxy-N-(6-((4-methoxybenzyl)oxy)hex-1-en-1-yl)-Nmethylpentanamide SI7 (see Figure S5). The general procedure was followed using iodide 17 (9.0 mg, 25.9 μmol), amide 20 (69.5 mg, 529 μmol) in 1,4-dioxane (1 mL), CuI (10.9 mg, 57.2 μmol), K3PO4 (96.2 mg, 453 μmol), and trans-1,2-diaminocyclohexane (0.01 mL, 83.2 μmol). Upon completion of the conversion of iodide 17, the crude product was purified by PLC (chloroform-EtOAc 1:2) to give enamide SI7 (2.6 mg, 29%) as a colorless oil: IR (neat, cm−1) 3437, 2934, 2859, 1632, 1247, 1097, 1034; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.09 (td, J = 1.6, 8.1 Hz, 1H), 5.36 (td, J = 7.6, 8.1 Hz, 1H), 4.42 (s, 2H), 4.23 (d, J = 2.5 Hz, 1H, OH), 3.89 (m, 1H), 3.81 (s, 3H), 3.43 (t, J = 6.3 Hz, 2H), 3.01 (s, 3H), 2.47 (dd, J = 2.5, 16.6 Hz, 1H), 2.23 (dd, J = 9.7, 16.6 Hz, 1H), 2.04 (tdd, J = 7.4, 7.6, 1.6 Hz, 2H), 1.64−1.41 (m, 6H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.2, 159.3, 130.7, 130.3, 129.4 (2C), 128.9, 113.9 (2C), 77.4, 72.8, 69.7, 55.4, 39.8, 35.1, 29.6, 29.5, 26.6, 25.7, 10.1; HRMS (ESI) m/z 350.2318 calcd for C20H32NO4 [M + H]+ 350.2331. (E)-3-Methoxy-N-((Z)-6-((4-methoxybenzyl)oxy)hex-1-en-1-yl)pent-2-enamide SI8 (see Figure S5). To a mixture of amide 21 (30.6 mg, ∼115 μmol, 1:1 mixture with DMF), CuI (18.9 mg, 99.2 μmol), and Cs2CO3 (71.4 mg, 219 μmol) were added iodide 17 (10.1 mg, 29.1 μmol) in degassed DMF (0.8 mL) and N,N′-dimethylethylenediamine (0.02 mL, 190 μmol). The reaction mixture was heated at 60 °C, stirred for 2 h, and cooled to room temperature. To the reaction mixture was added silica gel (2 g), and the mixture was diluted with EtOAc and filtered through a pad of silica gel, which was washed with EtOAc. The filtrate and washings were concentrated, and the residual oil was purified by PLC (hexane-EtOAc 1:1) to give enamide SI8 (9.8 mg, 97%) as a colorless oil: IR (neat, cm−1) 3307, 2936, 2858, 1650, 1613,1247, 1196, 1165, 1099, 1036; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 10.3 Hz, 1H, NH), 6.87 (d, J = 8.5 Hz, 2H), 6.80 (dd, J = 10.3, 8.8 Hz, 1H), 4.80 (s, 1H), 4.66 (td, J = 7.6, 8.8 Hz, 1H), 4.56 (s, 2H), 3.80 (s, 3H), 3.57 (s, 3H), 3.48 (t, J = 6.1 Hz, 2H), 2.81 (q, J = 7.4 Hz, 2H), 2.06 (td, J = 6.5, 7.6 Hz, 2H), 1.63 (m, 2H), 1.50 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.3, 164.0, 159.3, 130.6, 129.3 (2C), 121.9, 113.9 (2C), 109.3, 91.7, 72.8, 70.4, 55.4, 53.3, 29.8, 26.8, 25.8, 25.5, 12.1; HRMS (ESI) m/z 348.2166 calcd for C20H30NO4 [M + H]+ 348.2174. (E)-N-((Z)-5-((3S,6R,8S,11S)-3-isobutyl-4,6,8-trimethyl-2,5-dioxo1-oxa-4-azacycloundecan-11-yl)pent-1-en-1-yl)-3-methoxypent-2enamide 23. To a mixture of amide 21 (24.7 mg, ca. 122 μmol, 1:1 mixture with DMF), CuI (20.1 mg, 105 μmol), and Cs2CO3 (113 mg, 347 μmol) were added vinyl iodide 2 (32.6 mg, 68.3 μmol) in degassed DMF (1.2 mL) and N,N′-dimethylethylenediamine (0.02 mL, 190 μmol). The reaction mixture was heated at 60 °C, stirred for 2 h, and cooled to room temperature. To the reaction mixture was added silica gel (2 g), and the mixture was diluted with EtOAc and filtered through a pad of silica gel, which was washed with EtOAc. The filtrate and washings were washed with water (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated. The residual oil was purified by column chromatography on silica gel (8 g, hexane-EtOAc 2:1) to give enamide 23 (29.7 mg, 91%) as a colorless oil: [α]D23 −103 (c 1.01, CHCl3); IR (neat, cm−1) 3309, 2958, 2869, 1727, 1651, 1620, 1461, 1259, 1163, 1099; 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 11.7 Hz, 1H, NH), 6.80 (br m, 1H), 5.13 (m, 1H), 5.01 (s, 1H), 4.62 (m, 1H), 4.52 (dd, J = 6.3, 9.3 Hz, 1H), 3.66 (s, 3H), 2.86 (s, 3H), 2.90−2.74 (m, 3H), 2.16 (m, 1H), 1.93−1.74 (m, 3H), 1.68−1.51 (m, 3H), 1.46−1.23 (m, 2H), 1.19−1.05 (m, 4H), 1.12 (t, J = 7.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.02−0.82 (m, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.0, 176.3, 173.8, 164.2, 122.1, 108.4, 91.9, 76.7, 58.5, 55.4, 43.3, 38.3, 35.2, 34.4, 33.7, 32.0, 30.6, 28.9, 25.4, 25.3, 25.1, 24.7, 23.4, 22.3, 20.7, 18.7, 12.1; HRMS (ESI) m/z 479.3481 calcd for C27H47N2O5 [M + H]+ 479.3485. Kanamienamide (1). To a stirred solution of enamide 23 (13.0 mg, 27.1 μmol) and MeI (0.07 mL, 1.1 mmol) in DMF (0.8 mL) cooled at 0 °C was added 60% NaH (8.2 mg, 205 μmol). After stirring at room

temperature for 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined extracts were washed with saturated aqueous sodium thiosulfate (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residual oil was purified by HPLC (Cosmosil AR-II (ϕ20 × 250 mm), MeOH/H2O 80:20, flow rate 5 mL/min, detection UV 215 nm) to give kanamienamide (1) (9.4 mg, tR = 46 min, 70%) as a colorless oil: [α]D23 −51 (c 0.63, CHCl3); IR (neat, cm−1) 2956, 2869, 1726, 1646, 1610, 1458, 1211; 1 H NMR (400 MHz, C6D6) δ 5.92 (br m, 1H), 5.20 (s, 1H), 4.96 (m, 1H), 4.88 (td, J = 7.3, 7.8 Hz, 1H), 4.39 (dd, J = 4.4, 11.2 Hz, 1H), 3.14 (s, 3H), 3.12 (q, J = 7.3 Hz, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.60 (m, 1H), 2.02 (m, 1H), 1.94−1.86 (m, 3H), 1.66 (ddd, J = 3.4, 11.2, 14.7 Hz, 1H), 1.53−1.30 (m, 4H), 1.32 (t, J = 7.3 Hz, 3H), 1.27−1.08 (m, 4H), 1.04 (d, J = 6.8 Hz, 3H), 0.99−0.94 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H), 0.81 (m, 1H), 0.76 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 177.9, 174.7, 172.7, 166.6, 131.0, 126.0, 91.4, 76.8, 58.4, 54.6, 43.6, 38.4, 35.4, 34.8, 34.5, 33.6, 31.8, 30.9, 28.7, 27.1, 26.0, 25.0, 24.7, 23.2, 22.5, 20.8, 19.0, 12.6; HRMS (ESI) m/z 493.3642 calcd for C28H49N2O5 [M + H]+ 493.3641. Cell Growth Analysis. HeLa cells were cultured at 37 °C with 5% CO2 in DMEM (Nissui, Japan) supplemented with 10% heatinactivated FBS, 100 units/mL penicillin, 100 μg/mL of streptomycin, 0.25 μg/mL of amphotericin, 300 μg/mL of L-glutamine, and 2.25 mg/ mL of NaHCO3. HeLa cells were seeded at 4 × 103 cells/well in 96well plates (Iwaki, Japan) and cultured overnight. Various concentrations (5, 10, 25, and 50 μM) of compounds were then added, and the cells were incubated for 72 h. Cell proliferation was measured by MTT assay.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02288. Spectroscopic data and 1H and 13C NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Arihiro Iwasaki: 0000-0002-3775-5066 Kiyotake Suenaga: 0000-0001-5343-5890 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number 16H03285. We thank the Kaneka Corporation for their gift of (S)-Roche ester.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510

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DOI: 10.1021/acs.joc.7b02288 J. Org. Chem. 2017, 82, 12503−12510