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Synlett 2003(7): 1058-1060
DOI: 10.1055/s-2003-39289
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Radical Cyclization Approach to Synthesis of Enantiopure Proline Derivatives

Claude Agami, Sébastien Comesse, Sébastien Guesné, Catherine Kadouri-Puchot*, Luc Martinon
Laboratoire de Synthèse Asymétrique (UMR 7611), Université P. et M. Curie, 4 place Jussieu, case courrier 47, 75005 Paris, France
e-Mail: kadouri@ccr.jussieu.fr;
Further Information

Publication History

Received 12 March 2003
Publication Date:
20 May 2003 (online)

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Αbstract

β-Amino alcohols possessing a vinylsilane functionality were transformed into bicyclic derivatives via a diastereoselective 5-exo-trig radical cyclization. Straightforward transformation led to enantiopure proline derivatives.

Key words

diastereoselective radical cyclization - β-amino alcohols - proline derivatives

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Typical Procedure: A solution of AIBN (0.44 mmol) and tris(trimethylsilyl)silane (4.43 mmol) in benzene (88 mL) was added dropwise over 2.5 h to a solution of compound 2 (4.43 mmol) in refluxing benzene (44 mL), under an argon atmosphere. This mixture was stirred at this temperature, the reaction was monitored by TLC, and after completion the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 95:5) to afford bicyclic compounds. Selected data for compound 7: mp = 96 °C, yield: 40%, [α]D 20 -28 (c 0.9, HCCl3). 1H NMR (250 MHz, CDCl3): 7.41-7.23 (m, 5 H, Ph), 4.22-4.10 (m, 2 H, CH2O), 3.77 (dd, J = 5.0 Hz and 9.2 Hz, 1 H, NCHPh), 3.63 (d, J = 6.5 Hz, 1 H, NCHCO), 3.01-2.55 (m, 2 H, NCHPr and CHCH2Si), 2.15-2.09 (m, 1 H, NCHCHHCH), 1.39-0.87 (m, 6 H, -CH 2CH 2-, CHHSiCH3 and NCHCHHCH), 0.70 (dd, J = 10.5 Hz and 14.2 Hz, 1 H, CHHSiMe3), 0.62 (t, J = 6.7 Hz, 3 H, CH3), 0.0 (s, 9 H, SiMe3). 13C NMR (62.5 MHz, CDCl3): 173.3 (CO), 139.9, 128.7, 128.0, 127.5 (Ph), 71.1 (CH2O), 68.0 (NCHCO), 66.9 (NCHPr), 62.1 (NCHPh), 39.8 (NCHCH2CH), 37.3 (CH2CH2CH3), 36.7 (CHCH2Si), 24.0 (CH2Si), 19.3 (CH2CH3), 14.2 (CH3), -0.7 (Si(Me3).

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Neither simple reduction products nor dimerization adduct were detected by 1H NMR on the crude mixture.

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Procedure for obtaining compound 9: A solution of tris(trimethylsilyl)silane (37 µL, 0.12 mmol) and triethylborane (1 M in hexane, 130 µL, 0.13 mmol) in benzene (1 mL) was added dropwise to a solution of compound 6 (50 mg, 0.10 mmol) in benzene (8 ml). The mixture was refluxed for 5h and evaporated under reduced pressure. Flash chromatography (Et2O/cyclohexane, 10:90) afforded compound 9 (15 mg, 40% yield)

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Typical Procedure: The bicyclic compound (0.16 mmol) was dissolved in aqueous methanol (20:1, MeOH:H2O, 3.2 mL). Trifluoroacetic acid (0.16 mmol, 1 equiv) and Pearlman’s catalyst (1 equiv by mass) were added to the mixture, which was degassed and was stirred under hydrogen for 3 days or 4 days. The suspension was then filtered under a pad of Celite®. After evaporation, amino acid 10 was purified by trituration with diethyl ether (yield: 80-90% according to the R substituent). Selected data for 10
(R = Pr): hygroscopic solid, yield: 90%, [α]D 20 +17 (c 0.5, MeOH). 1H NMR (250 MHz, CD3OD): 3.60-3.51 (m, 1 H, NCHPr), 3.44 (d, J = 8.5 Hz, 1 H, NCHCOOH)), 2.35-2.24 (m, 2 H, CHCH2TMS and NCHCHHCH), 1.78-1.67 (m 1 H, NCHCHHCH2), 1.61-1.53 (m, 1 H, NCHCHHCH2), 1.42-1.26 (m, 4 H, CH 2CH3 and NCHCHHCH and CHHSiMe3), 0.92 (t, J = 7.0 Hz, 3 H, CH3), 0.62 (dd, J = 12.5 Hz and 10.0 Hz, 1 H, CHHSiMe3), 0.00 (s, 9 H). 13C NMR (62.5 MHz, CD3OD): 174.9 (COOH), 70.4 (CHCOOH), 62.3 (CHPr), 42.6 (CHCH2SiMe3), 42.1 (NCHCH2CH), 36.7 (CH2CH2), 23.3 (CH2CH3), 21.8 (CH2SiMe3), 15.1 (CH3), 0.0 (SiMe3).