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Synlett 2004(11): 1917-1920  
DOI: 10.1055/s-2004-830859
LETTER
© Georg Thieme Verlag Stuttgart · New York

Studies toward Nitrogen-Containing Natural Products Using Radical Cyclizations of Chiral Vinylogous Amides

Martin Cordes*, Dagmar Franke
Chemisches Institut der Otto-von-Guericke-Universität, Universitätsplatz 2, 39106 Magdeburg, Germany
Fax: +49(391)6712223; e-Mail: Martin.Cordes@vst.uni-magdeburg.de;
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Publikationsverlauf

Received 17 May 2004
Publikationsdatum:
17. August 2004 (online)

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Abstract

The radical-promoted cyclization of various chiral vinyl­ogous amides to annulated azepines and to an azaspirocycle is presented. A relatively rare 7-endo cyclization process generated octahydrocyclopenta[b]azepines in fair yield and excellent stereoselectivity at the same time.

Key words

annulations - asymmetric induction - azepines - radical cyclization - spiro compounds

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All new compounds were fully characterized by 1H NMR, 13C NMR, MS, HRMS, IR and elemental analyses. The yields are based on isolated, purified (flash chromatography on silica gel) products. A print or word file of the characterization data for all new compounds in this paper can be obtained on request from MC.

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Crystallographic data of 6a, 6b, 8, 13 and 15 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 241704 (6a), 241705 (6b), 241706 (8), 241707 (13) and 241708 (15), respectively. Copies of these data may be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.

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Representative Procedure for the Preparation of the Cyclization Precursors: (1 S ,4 R )-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (3-oxo-cyclopent-1-enyl)-(4-phenylselenyl-butyl)-amide (12).
In a typical experiment, vinylogous amide 9 [6] (700 mg, 2.27 mmol) was dissolved in anhyd THF (15 mL) and cooled to -78 °C. This solution was treated with a solution of 1.6 M BuLi in hexane (1.56 mL, 2.50 mmol) and stirring was continued for 2 h at this temperature. Finally a solution of (1S)-(-)-camphanic chloride (786 mg, 3.63 mmol) in anhyd THF (5 mL) was added and the mixture was allowed to warm up to r.t. over a period of 15 h. The solvent was evaporated in vacuo and the residue was purified by subsequent flash chromatography on silica gel (Et2O) to yield the pure enaminone 12 (1.02 g, 92%) as a colorless oil; Rf (Et2O) = 0.37; [α]D 20 -193.6 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.96 (s, 3 H), 1.11 (s, 3 H), 1.19 (s, 3 H), 1.69-1.77 (m, 3 H), 1.84 (dd, J = 4.9 Hz, J = 10.2 Hz, 2 H), 1.94-2.04 (m, 2 H), 2.43 (dq, J = 4.2 Hz, J = 10.6 Hz, 2 H), 2.48 (qui, J = 6.3 Hz, 1 H), 2.72-2.76, 3.28-3.32 (m, 2 H), 2.89-2.95 (m, 2 H), 3.65-3.70, 3.77-3.81 (m, 2 H), 5.74 (s, 1 H), 7.24-7.28 (m, 3 H), 7.47-7.49 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 9.56 (q), 16.56 (q), 17.65 (q), 26.97 (t), 26.98 (t), 28.36 (t), 29.44 (t), 30.02 (t), 32.56 (t), 34.61 (t), 48.14 (t), 54.01 (s), 56.51 (s), 92.31 (s), 117.66 (d), 126.95 (d), 129.08 (d), 129.64 (s), 132.75 (d), 169.59 (s), 173.46 (s), 177.22 (s), 206.77 (s). MS (EI): m/z (%) = 489 (35)[M+], 487 (17) [M+], 332 (100), 304 (24), 222 (21), 152 (31), 83 (70), 55 (36). HRMS (EI): m/z calcd for C25H31NO4 78Se: 487.1426, found: 487.1426; C25H31NO4 80Se: 489.1418, found: 489.1420. IR (neat): ν = 2969, 2935, 1792, 1682, 1575, 1386, 1375, 1110, 1053 cm-1. Anal. Calcd for C25H31NO4Se: C, 61.47; H, 6.40; N, 2.87. Found: C, 61.31; H, 6.51; N, 2.66.

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Typical Procedure for the Cyclizations: (1 S ,4 R ,5a R ,8a S )-1-(4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carbonyl)-octahydro-cyclopenta[ b ]azepin-6-one (13).
The vinylogous amide 12 (2.54 g, 5.2 mmol) was dissolved in degassed anhyd toluene (210 mL) under an argon atmosphere and brought to a steady reflux. A solution of Bu3SnH (1.96 mL, 7.3 mmol) and ACN (889 mg, 3.6 mmol) in degassed anhyd toluene (50 mL) was added to the refluxing enaminone solution at a rate of 5 mL/h using a syringe pump. After the addition of the tin hydride solution was complete, the reaction mixture was cooled to r.t., and the solvent was removed under reduced pressure. The residue was purified by subsequent flash chromatography on silica gel (pentane-Et2O, 1:1, then Et2O) to give the pure octahydrocyclopenta[b]azepine 13 (763 mg, 44%) as a single stereoisomer as colorless crystals; mp 145.9 °C; Rf (Et2O) = 0.40; [α]D 20 -16.9 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.04 (s, 3 H), 1.12 (s, 3 H), 1.19 (s, 3 H), 1.27-1.31 (m, 2 H), 1.35 (q, J = 10.8 Hz, 1 H), 1.49 (dd, J = 9.2 Hz, J = 11.3 Hz, 1 H), 1.73 (dq, J = 4.1 Hz, J = 9.2 Hz, 1 H), 1.87-1.96 (m, 2 H), 1.99-2.03 (m, 1 H), 2.06-2.09 (m, 1 H), 2.23-2.28 (m, 1 H), 2.29 (d, J = 9.0 Hz, 1 H), 2.41-2.45 (m, 2 H), 2.52 (dd, J = 9.0 Hz, J = 19.5 Hz, 1 H), 2.71 (dq, J = 5.4 Hz, J = 12.4 Hz, 1 H), 3.16 (dd, J = 6.0 Hz, J = 9.9 Hz, 1 H), 4.17 (dq, J = 5.5 Hz, J = 13.7 Hz, 1 H), 4.55 (dd, J = 6.3 Hz, J = 9.5 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 9.62 (q), 16.76 (q), 17.68 (q), 25.37 (t), 27.20 (t), 27.33 (t), 29.31 (t), 31.44 (t), 32.26 (t), 36.24 (t), 44.32 (t), 53.70 (s), 54.13 (d), 55.29 (s), 62.50 (d), 92.56 (s), 167.34 (s), 178.60 (s), 213.09 (s). MS (EI): m/z (%) = 333 (56) [M+], 274 (90), 152 (100), 136 (57), 109 (31), 83 (55), 55 (38). HRMS (EI): m/z calcd for C19H27NO4: 333.1940; found: 333.1942. IR (neat): ν = 3456, 2957, 2935, 2849, 1786, 1747, 1732, 1626, 1427, 1101 cm-1. Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N, 4.20. Found: C, 68.40; H, 8.18; N, 4.28.