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Synlett 2007(7): 1071-1074  
DOI: 10.1055/s-2007-973895
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Synthesis of Medium-Sized Carbocycles Using Alkoxy Radical Fragmentation as a Key Methodology

Tarun K. Pradhan, Alfred Hassner*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax: +972(3)7384053; e-Mail: hassna@mail.biu.ac.il;
Further Information

Publication History

Received 29 January 2007
Publication Date:
13 April 2007 (online)

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Abstract

Stereoselective and regioselective synthesis of functionalized seven- and eight-membered carbocyclic systems was achieved by the ring expansion-cleavage of readily prepared [3.2.1] and [3.3.1] bicyclic alcohols using alkoxy radical fragmentation at room temperature. Transannular migration in the cyclooctane ­system explain formation of unusual products.

Key words

carbocycles - bicyclic compounds - radical reaction - ­stereoselectivity - ring expansion

15

Synthesis of 4-Acetoxy-8-oxobicyclo[3.3.1]octane-1-carboxylic Acid Ethyl Ester(4a) - Analytical Data
endo-Isomer: 1H NMR (300 MHz, CDCl3): δ = 4.93 (ddd, J = 9, 6, 3 Hz, 1 H, CHO), 4.13 (q, J = 7 Hz, 2 H, CH2O), 2.65-2.62 (m, 1 H), 2.59-2.45 (m, 1 H), 2.07-1.82 (m, 9 H), 1.78-1.59 (m, 1 H), 1.19 (t, J = 7 Hz, 3 H, CH2CH 3). 13C NMR: δ = 208.9 (C=O), 170.8 (O-C=O), 169.6 (O-C=O), 74.2 (C4HO), 61.2 (OCH2), 56.8 (C1), 50.6 (C5H), 30.8, 26.8, 23.6, 21.0 (COCH3), 17.0, 14.1 (CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H18O5: 254.115; found: 254.123 (27) [M]+, 255.119 (45) [MH]+.
exo-Isomer: 1H NMR (300 MHz, CDCl3): δ = 5.15 (br s, 1 H, CHO), 4.19-4.15 (m, 2 H, CH2O), 2.61-2.42 (m, 3 H), 2.08-1.92 (m, 7 H), 1.78-1.61 (m, 2 H), 1.19 (t, J = 7 Hz, 3 H, CH2CH 3). 13C NMR: δ = 209.9 (C=O), 170.9 (O-C=O), 170.2 (O-C=O), 78.7 (C4HO), 61.3 (OCH2), 57.0 (C1), 48.6 (C5H), 33.8, 25.8, 23.3, 21.1 (COCH3), 19.2, 14.2 (CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H18O5: 254.115; found: 255.120 (33) [MH]+.

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Synthesis of 4-Acetoxy-8-hydroxybicyclo[3.2.1]octane-1-carboxylic Acid Ethyl Ester(1a) by NaBH 4 /EtOH Reduction of 4a - Analytical Data
exo-syn-Isomer of 1a: 1H NMR (300 MHz, CDCl3): δ = 4.90 (br s, 1 H, CHO), 4.22 (d, J = 4.5 Hz, 1 H, HOCH), 4.12 (q, J = 7.0 Hz, 2 H, CH2O), 2.98 (br s, 1 H, OH), 2.43-2.38 (m, 1 H), 2.22-2.11 (m, 1 H), 2.04-1.95 (m, 4 H), 1.90-1.58 (m, 5 H), 1.32-1.26 (m, 1 H), 1.20 (t, J = 7.0 Hz, 3 H, CH2CH 3). 13C NMR: δ = 176.7 (O-C=O), 170.5 (O-C=O), 75.8 (CHO), 70.1 (CHO), 60.7 (OCH2), 50.1 (C1), 42.3 (C5H), 29.1, 25.9, 23.6, 21.4 (COCH3), 19.2, 14.2 (CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H20O5: 256.131; found: 257.142 (11) [MH]+, 197.117 (34) [MH - HOAc]+, 196.110 (43) [M - HOAc]+, 150.070 (51) [M - HOAc - EtOH]+.

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ARF Reaction of exo - syn -Isomer of 1a
A solution of exo-syn-isomer of compound 1a (0.512 g, 20 mmol), diacetoxy iodobenzene (1.28 g, 40 mmol) and iodine (1.52 g, 60 mmol) in CH2Cl2 (60 mL) taking in a round-bottomed flask was irradiated under one 100 W tungsten filament lamp for 2 h at r.t. The mixture was washed with NaHSO3 solution (3 × 30 mL), brine (2 × 30 mL) and dried (Na2SO4). Solvent was removed under reduced pressure and the residue was chromatographed to obtain the colorless oily compound 5 as a mixture of diastereomers in an almost 1:1 ratio, and compound 6 [eluant: EtOAc-n-hexane (1:4)].
Compound 5 (diastereomeric mixture): 1H NMR (300 MHz, CDCl3): δ = 9.63 (d, J = 1.2 Hz, 1 H, CHO), 9.59 (d, J = 1.2 Hz, 1 H, CHO), 5.28-5.22 (m, 2 H, CHO), 4.28-4.19 (m, 4 H, CH2O), 2.80 (dd, J = 8.0, 15.0 Hz, 1 H), 2.66-2.56 (m, 3 H), 2.48-2.33 (m, 6 H), 2.04-1.97 (m, 5 H), 1.92-1.60 (m, 8 H), 1.47-1.32 (m, 1 H), 1.25-1.20 (m, 6 H). 13C NMR: δ = 200.7, 200.5 (CHO), 172.3 (O-C=O), 170.2 (O-C=O), 71.8, 71.2 (CHO), 62.3 (OCH2), 56.8, 56.3 (CHCHO), 44.7 (C-I), 42.1, 40.9, 37.1, 37.0, 30.4, 29.5, 23.0, 21.7, 21.2 (COCH3), 13.8. (CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H19IO5: 382.028; found: 383.033 (5) [MH]+, 355.013 (25) [MH - CO]+, 339.010 (40) [M - CH3CO]+.
Compound 6 (oil): 1H NMR (300 MHz, CDCl3): δ = 9.33 (s, 1 H, CHO), 6.85 (m, 1 H, CH=C), 4.28 (q, J = 7 Hz, 2 H, CH2O), 2.70-2.28 (m, 8 H), 1.30 (t, J = 7 Hz, 3 H, CH3). 13C NMR: δ = 193.4 (CHO), 172.4 (O-C=O), 154.2 (CH=), 146.0 (C=), 62.2 (OCH2), 48.3 (C-I), 39.5, 39.3, 27.6, 21.9, 13.8. (CH3). HRMS (CI, CH4): m/z (%) calcd for C11H15IO3: 322.007; found: 320.999 (23) [M - H]+, 194.076 (27) [M - HI]+, 193.068 (45) [M - H - HI]+.
Compound 7: 1H NMR (300 MHz, CDCl3): δ = 9.55 (br s, 1 H, CHO), 9.52 (br s, 1 H, CHO), 5.59-5.51 (m, 2 H, CHO), 4.28-4.16 (m, 4 H, CH2O), 2.94 (dd, J = 7, 15 Hz, 1 H), 2.75-2.09 (m, 10 H), 2.01-1.78 (m, 11 H), 1.74-1.45 (m, 2 H), 1.27-1.22 (m, 6 H). 13C NMR: δ = 200.1, 200.1 (CHO), 172.7, 172.3, 170.0, 169.9, 70.3, 70.2, 62.1, 62.1 (OCH2), 55.8, 55.5 (CHCHO), 46.0, 45.0 (C-I), 41.9, 40.9, 36.3, 36.3, 30.0, 29.0, 21.0, 20.9, 20.9, 19.3, 13.6, 13.6. (CH3CH2). HRMS (CI, CH4): m/z (%) calcd for C13H19IO5: 382.028; found: 382.029 (17) [M]+, 383.033 (23) [MH]+.

19

In the seven-membered-ring analogue 1a the C-3 hydrogen is less readily accessible for radical abstraction.

20

Compound 13: 1H NMR (300 MHz, CDCl3): δ = 9.39 (s, 1 H, CHO), 6.69 (dd, J = 2.1, 3.3 Hz, 1 H, CH=CH2), 4.20-4.10 (m, 2 H, CH2O), 2.68 (dt, J = 16.0, 5.0 Hz, 1 H), 2.54-2.46 (m, 1 H), 2.34-2.28 (m, 1 H), 2.18-2.07 (m, 1 H), 2.95-1.85 (m, 1 H), 1.66 (dd, J = 10.0, 4.0 Hz, 1 H), 1.40-1.21 (m, 6 H), 0.82 (dd, J = 4.0, 6.6 Hz, 1 H). 13C NMR: δ = 194.6 (CHO), 174.0 (O-C=O), 149.8 (CH=), 143.1 (C=), 60.9 (OCH2), 29.7 (C-I), 28.3, 25.4, 23.3, 22.7, 20.1, 14.2 (CH3). HRMS (CI, CH4): m/z (%) calcd for C12H17IO3: 336.022; found: 336.023 (24) [M]+, 337.025 (47) [MH]+.