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Synlett 2012; 23(15): 2183-2188
DOI: 10.1055/s-0032-1317020
DOI: 10.1055/s-0032-1317020
letter
Diversity-Oriented Approach to Macrocyclic Cyclophane Derivatives via Ring-Closing Metathesis[ 1 ]
Weitere Informationen
Publikationsverlauf
Received: 04. Mai 2012
Accepted after revision: 10. Juli 2012
Publikationsdatum:
31. August 2012 (online)
![](https://www.thieme-connect.de/media/synlett/201215/lookinside/thumbnails/10.1055-s-0032-1317020-1.jpg)
Dedicated to Professor Mariappan Periasamy on the occasion of his 60th birthday.
Abstract
A short synthetic approach to the macrocyclic framework of longithorone C is described via ring-closing metathesis using the Grubbs 2nd generation catalyst.
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References and Notes
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- 17 We have determined the E/Z ratio of RCM products 16–19 (Figure 2), based on 1H NMR spectral data. In most of the cases, we observed E-configured compounds as the major product; this assumption was based on our earlier experience on cyclophane derivatives. See reference 11i.
- 18 Alkene Derivatives of Malonate Ester; General Procedure: To a suspension of NaH (3 equiv) in THF was added 3 (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Bromide 5c (1.1 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction mixture was quenched with H2O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 4%) to afford 6c (67%) as a liquid. 1H NMR (400 MHz, CDCl3): δ = 1.18–1.22 (m, 6 H), 1.35–1.40 (m, 2 H), 1.81–1.90 (m, 2 H), 2.01–2.05 (m, 2 H), 3.26 (t, J = 7.2 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 4 H), 4.88–4.97 (m, 2 H), 5.66–5.70 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.90, 26.38, 28.02, 33.14, 51.69, 61.05, 114.83, 137.77, 169.23. IR (neat): 2929, 2859, 1741, 1640, 1464, 1368, 1183 cm–1. HRMS (Q-Tof): m/z [M + Na] calcd for C12H20O4Na: 251.1259; found: 251.1265. Alkylation of Ethyl Acetoacetate; General Procedure: In a 100 mL round-bottomed flask equipped with a nitrogen gas inlet, ethyl acetoacetate 4 (1 equiv) was added dropwise at r.t. to K2CO3 (4 equiv) in acetonitrile and the mixture was stirred for 1 h. Bromide 5c (1.1 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under a nitrogen atmosphere. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad and extracted with diethyl ether. The organic layer was washed with brine and dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 4%) to afford alkylated ethyl acetoacetate derivative 8c (68%) as a liquid. 1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 3 H), 1.32–1.44 (m, 2 H), 1.80–1.92 (m, 2 H), 2.00–2.10 (m, 2 H), 2.22 (s, 3 H), 3.41 (t, J = 7.4 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.94–5.04 (m, 2 H), 5.72–5.82 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 14.16, 26.64, 27.62, 28.82, 33.41, 59.77, 61.37, 115.13, 137.96, 169.88, 203.24. IR (neat): 2991, 2934, 1742, 1716, 1641, 1448, 1360, 1216 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C11H19O3: 199.1334; found: 199.1334. General Procedure for 10c: To a suspension of NaH (3 equiv) in THF was added alkylated malonate ester 6c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Dibromide 1 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 8%) to afford bis-alkene malonate derivative 10c (65%) as a white solid material. Mp 60–65 °C. 1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 12 H), 1.34–1.41 (m, 4 H), 1.70–1.74 (m, 4 H), 1.99 (q, J = 7.1 Hz, 4 H), 3.24 (s, 4 H), 3.64 (s, 6 H), 4.08–4.23 (m, 8 H), 4.89–5.00 (m, 4 H), 5.70–5.81 (m, 2 H), 6.52 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.21, 23.87, 31.73, 31.97, 34.18, 55.68, 58.72, 61.13, 114.04, 114.76, 124.20, 138.52, 151.87, 171.76. IR (neat): 3054, 2989, 1729, 1641, 1422, 1266 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C34H51O10: 619.3482; found: 619.3499. General Procedure for 11c: To a suspension of NaH (3 equiv) in THF was added alkylated malonate ester 6c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. p-Xylylene dibromide 2 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction was quenched with H2O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 8%) to afford bis-alkene malonate ester derivative 11c (62%) as a white solid material. Mp 60–65 °C. 1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 12 H), 1.34–1.40 (m, 4 H), 1.73–1.77 (m, 4 H), 2.04 (q, J = 7.2 Hz, 4 H), 3.19 (s, 4 H), 4.10–4.22 (m, 8 H), 4.97–5.03 (m, 4 H), 5.78–5.80 (m, 2 H), 6.95 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ = 14.22, 23.72, 31.54, 33.90, 37.87, 58.90, 61.33, 115.16, 129.92, 134.97, 138.21, 171.45. IR (neat): 3054, 2989, 1729, 1641, 1422, 1266 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C32H47O8: 559.3271; found: 559.3286. General Procedure for 12c: In a 100 mL round-bottomed flask equipped with a nitrogen gas inlet, K2CO3 (4 equiv) in acetonitrile was added to alkylated ethyl acetoacetate 8c (1 equiv) dropwise at r.t. and stirred for 1 h. Dibromo compound 1 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad and extracted with diethyl ether. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 6%) to afford the alkylated ethyl acetoacetate derivative 12c (72%) as a solid. Mp 60–65 °C. 1H NMR (400 MHz, CDCl3): δ = 1.23–1.25 (m, 6 H), 1.29–1.37 (m, 4 H), 1.64–1.76 (m, 4 H), 2.03 (q, J = 7.0 Hz, 4 H), 2.11 (s, 6 H), 3.06–3.31 (m, 4 H), 3.62 (s, 6 H), 4.09–4.26 (m, 4 H), 4.91–5.01 (m, 4 H), 5.69–5.80 (m, 2 H), 6.50 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.20, 23.76, 27.15, 31.30, 31.66, 34.22, 55.53, 61.32, 64.32, 114.29, 115.05, 124.30, 138.28, 151.66, 172.61, 205.10. IR (neat): 2979, 2911, 1739, 1717, 1531, 1212 cm–1. HRMS (Q-Tof): m/z [M + Na] calcd for C32H46O8Na: 581.3090; found: 581.3105. General procedure for 13c: To a suspension of NaH (3 equiv) in THF was added alkylated ethyl acetoacetate 8c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Dibromide 1 (0.5equiv) was added to the reaction mixture, which was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction was quenched with H2O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 10%) to afford bis-alkylated derivative 13c (66%) as a white solid. Mp 60–65 °C. 1H NMR (400 MHz, CDCl3): δ = 1.12–1.15 (m, 6 H), 1.33–1.45 (m, 4 H), 1.45–1.54 (m, 2 H), 1.59–1.70 (m, 2 H), 2.00–2.07 (m, 4 H), 2.65–2.75 (m, 2 H), 2.75–2.85 (m, 4 H), 3.74 (s, 6 H), 4.00–4.08 (m, 4 H), 4.90–5.00 (m, 4 H), 5.71–5.82 (m, 2 H), 6.59 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.43, 26.71, 32.01, 33.48, 33.75, 45.83, 56.11, 60.15, 113.64, 114.74, 126.60, 138.70, 151.36, 176.23. IR (neat): 2931, 2860, 1726, 1506, 1211 cm–1. HRMS (Q-Tof): m/z calcd: for C28H43O6 [M + H]: 475.3060; found 475.3060. General Procedure for 14c and 15c: To a degassed solution of bis-alkylated derivative 10c or 11c in anhydrous toluene (5 mL) was added Grubbs 2nd generation catalyst (5 mol%) at r.t., and reaction mixture was heated at reflux overnight. At the conclusion of the reaction (TLC monitoring), the crude reaction mixture was filtered through a Celite pad (washed with CH2Cl2) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 5%) to afford cyclophane derivatives 14c and 15c. Compound 14c: Yield: 78%. 1H NMR (400 MHz, CDCl3): δ = 1.01–1.14 (m, 4 H), 1.23–1.30 (m, 12 H), 1.44 (td, J = 13.4, 4.4 Hz, 2 H), 1.59 (td, J = 13.4, 4.4 Hz, 2 H), 1.76–1.77 (m, 2 H), 1.92–1.95 (m, 2 H), 3.13 (s, 1 H), 3.17 (s, 1 H), 3.62 (s, 1 H), 3.66 (s, 1 H), 3.67 (s, 6 H), 4.14–4.30 (m, 8 H), 5.06 (t, J = 3.9 Hz, 2 H), 6.63 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.26, 23.50, 31.27, 32.43, 33.27, 55.78, 57.63, 61.13, 114.36, 124.43, 130.34, 151.71, 172.40. IR (neat): 2931, 2860, 1730, 1510, 1212 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C32H47O10: 591.3169; found: 591.3160. Compound 15c: Yield: 80%. 1H NMR (400 MHz, CDCl3): δ = 1.10 (m, 4 H), 1.28 (m, 12 H), 1.46–1.48 (m, 4 H), 1.83–1.88 (m, 4 H), 3.30 (s, 4 H), 4.25 (m, 8 H), 5.07–5.09 (m, 2 H), 7.02 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ = 14.27, 23.49, 31.53, 32.49, 39.06, 58.15, 61.50, 129.75, 130.53, 135.36, 172.06. IR (neat): 2982, 2940, 1732, 1446, 1266 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C30H43O8: 531.2958; found: 531.2957. General Procedure for 18: In a 100 mL round-bottomed flask was charged flash chromatographic-grade silica gel (6 g). A solution of CAN (5 mol%) in water (2.5 mL) was added dropwise until a free-flowing yellow solid was obtained. CH2Cl2 (25 mL) was added and the bis-alkylated derivative 13c dissolved in CH2Cl2 (2 mL) was added dropwise. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad (washed with CH2Cl2) and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 5%) to afford bis-alkylated quinone derivative 18 (67%) as a liquid. 1H NMR (400 MHz, CDCl3): δ = 1.19–1.22 (m, 6 H), 1.37–1.45 (m, 4 H), 1.49–1.56 (m, 2 H), 1.63–1.70 (m, 2 H), 2.06 (q, J = 7.0 Hz, 4 H), 2.59–2.65 (m, 6 H), 4.07–4.12 (m, 4 H), 4.94–5.02 (m, 4 H), 5.71–5.81 (m, 2 H), 6.54 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.42, 26.40, 31.75, 32.22, 33.52, 44.24, 60.67, 115.10, 133.89, 138.24, 146.68, 174.78, 187.40. IR (neat): 2931, 2858, 1728, 1464, 1266 cm–1. HRMS (Q-Tof): m/z [M + H] calcd for C26H37O6: 445.2590; found: 445.2601.