Enyne Ring-rearrangement/Cross-metathesis Reactions of Cyclic Enones

Abstract

The use of efficient ring rearrangement metathesis reactions of cyclic enones involving cross-metathesis is reported. The resulting trienes from these reactions are substrates for intramolecular Diels-Alder cycloaddition reactions. Thus, the synthesis of highly stereoselective fused tricyclic products in four distinct steps is achieved.

ring-rearrangement - metathesis - Diels-Alder cycloaddition - enyne - enones

References

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8

In a 10 mL flask a solution of 11 (25 mg, 0.075 mmol) and catalyst 15 (6.4 mg, 10 mol%) in CH₂Cl₂ (0.05 molar) under N₂ was cooled with liquid nitrogen. To this cooled solution, 50 mL of CH₂CH₂ was added, which condensed rapidly and the sealed flask was stirred at 80 °C for 2 h. After the addition of an excess of ethyl vinyl ether the reaction mixture was stirred for an additional 60 h at 80 °C. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (hexane/MTBE 2:1) to yield 14.9 mg of 17b (55%) as a light yellow oil.

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10

The configuration of 18b was determinated by X-ray crystallography.

11

After following conversion in these reactions by ¹H NMR spectroscopy, it was found that 16a-19a decompose steadily to numerous unidentifiable products under the reaction conditions, in the case of the reaction of 10, 12 and 13, levels of 16a, 18a and 19a were typically in the range of 20-40% after 2 h, whereas 11 had undergone quantitative conversion at this time. In an attempt to enhance the yield, temperature ranges (between r.t. and 120 °C) were used as well as a Lewis acid (e.g. MeAlCl₂) that was added at the beginning of the reaction and after 2 h, but proved to be unsuccessful. It is noteworthy that 16b-19b are perfectly stable and show no signs of decomposition even after extended reaction times.

12a

The geometries of the reactants, products and transition states were optimised using the AM1 semi-empirical method as implemented in Gaussian 98.^12b Single point calculations were performed using these geometries with the resolution-of-identity method and the BP86 density functional, as implemented in Turbomol.^12c The TZV basis sets of Ahlrichs [12d] were used for all atoms with polarisation functions for the heavy atoms. It was found that the relative activation energy of 16a, 17a and 18a was 72 kJmol^-1, 47 kJmol^-1 and 61 kJmol^-1 respectively. This supports the argument that shorter chain lengths results in a less accessible transition state.

12b Frisch MJ. Trucks GW. Schlegel HB. Scuseria GE. Robb MA. Cheeseman JR. Zakrzewski VG. Montgomery JA. Stratmann RE. Burant JC. Dapprich S. Millam JM. Daniels AD. Kudin KN. Strain MC. Farkas O. Tomasi J. Barone V. Cossi M. Cammi R. Mennucci B. Pomelli C. Adamo C. Clifford S. Ochterski J. Petersson GA. Ayala PY. Cui Q. Morokuma K. Malick DK. Rabuck AD. Raghavachari K. Foresman JB. Cioslowski J. Ortiz JV. Baboul AG. Stefanov BB. Liu G. Liashenko A. Piskorz P. Komaromi I. Gomperts R. Martin RL. Fox DJ. Keith T. Al-Laham MA. Peng CY. Nanayakkara A. Gonzalez C. Challacombe M. Gill PMW. Johnson BG. Chen W. Wong MW. Andres JL. Head-Gordon M. Replogle ES. Pople JA. Gaussian 98 (Revision A.9)   Gaussian, Inc.; Pittsburgh PA: 1998. 

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13

In an attempt to improve stability, the possibility of employing reduced allyl alcohol analogues (protected as silylethers) was briefly investigated. While in the case of analogues of 11 these species proved stable and gave reasonable yields of RRM adduct (pre-cycloaddition) in accordance with ref. 4a, higher homologues were unreactive and offered no advantages over their oxidised counterparts 12 and 13.

14

To a solution of 11 (60.0 mg, 0.180 mmol) and 26 (56.1 mg, 0.540 mmol) in CH₂Cl₂ (0.05 molar) under N₂ was added catalyst 15 (15.2 mg, 10 mol%) and the reaction was stirred at 55 °C for 3 h. To this solution was added an excess of ethyl vinyl ether. After the solvent was removed, the residue was purified by flash column chromatography on silica gel (hexane/MTBE 10:1) to yield 86.0 mg of triene 29 (93%) as a light yellow oil. 29 (24 mg, 0.0467 mmol) was solved
in toluene (2 mL) and heated to 150 °C for 4 h in a sealed tube to yield after purifying by flash column chromato-graphy on silica gel (hexane/MTBE 4/1) 20.4 mg of 34 (85%) as a white waxy product.
¹H NMR (500 MHz, CDCl₃): δ (ppm) = 8.41-8.39 (d, J = 8.9 Hz, 2 H), 8.08-8.06 (d, J = 8.8 Hz, 2 H), 7.25-7.19 (m, 6 H), 7.06-7.00 (d, J = 6.9 Hz, 2 H), 6.99-6.98 (d, J = 7.2 Hz, 2 H), 6.10 (br, 1 H), 4.33-4.31 (dd, J = 13.4 Hz, J = 1.2 Hz, 1 H), 4.22-4.18 (ddd, J = 8.7 Hz, J = 6.4 Hz, J = 6.4 Hz, 1 H), 4.06-4.02 (ddd, J = 13.5 Hz, J = 1.8 Hz, J = 1.8 Hz, 1 H), 3.92-3.91 (dd, J = 2.9 Hz, J = 2.9 Hz, 1 H), 3.66 (br, 1 H), 2.75-2.73 (ddd, J = 8.7 Hz, J = 8.7 Hz, J = 0.5 Hz, 1 H), 2.58-2.57 (dd, J = 7.4 Hz, J = 3.2 Hz, 1 H), 2.46-2.40 (m, 1 H), 2.30-2.24 (m, 2 H), 2.10-2.06 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ (ppm) = 206.68 (C), 150.38 (C), 144.73 (C), 144.20 (C), 143.30 (C), 136.05 (C), 128.80 (CH ¥ 2), 128.75 (CH ¥ 2), 128.30 (CH ¥ 2), 127.90 (CH ¥ 2), 127.34 (CH ¥ 2), 126.81 (CH), 126.67 (CH), 124.96 (CH), 124.65 (CH ¥ 2), 58.72 (CH), 51.61 (CH₂), 49.84 (CH), 45.60 (CH), 44.44 (CH), 37.81 (CH), 35.63 (CH₂), 27.52 (CH₂). IR (ATR): ν (cm^-1) = 3103, 3060, 2926, 2867, 1713, 1529, 1349, 1168, 1091, 737. MS (EI, 100 °C): m/z (%) = 514 [M⁺], 355, 328, 182, 168, 141, 115, 91. HRMS calcd for C₂₉H₂₆N₂O₅S [M⁺]: 514.1562. Found: 514.1567.