Synlett 2006(5): 0689-0692  
DOI: 10.1055/s-2006-933116
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Radical Reactions: Formation of Chiral Quaternary Centers

Mukund P. Sibi*, Liwen He
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
Fax: +1(701)2311057; e-Mail: [email protected];
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Publikationsverlauf

Received 15 November 2005
Publikationsdatum:
09. März 2006 (online)

Abstract

A novel addition/trapping radical reaction to establish all-carbon chiral quaternary centers has been developed.

    References and Notes

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  • 2 Radicals in Organic Synthesis   Vol. 1 and 2:  Renaud P. Sibi MP. Wiley-VCH; Weinheim: 2001. 
  • 3 For a recent review see: Patil K. Sibi MP. In Quaternary Stereocenters - Challenges for Organic Synthesis   Christoffers J., Baro A., Wiley-VCH; Weinheim: 2005.  p.287-313  
  • 4a Sibi MP. Manyem S. Zimmerman J. Chem. Rev.  2003,  103:  3263 
  • 4b Sibi MP. Porter NA. Acc. Chem. Res.  1999,  33:  163 
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  • Also see:
  • 6c Yang D. Gao Q. Lee O.-Y. Org. Lett.  2002,  4:  1239 
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  • 6h For formation of quaternary center by radical combination see: Ellison ME. Ng D. Dang H. Garcia-Garibay MA. Org. Lett.  2003,  5:  2531 
  • 7a Imide: Sibi MP. Petrovic G. Zimmerman J. J. Am. Chem. Soc.  2005,  127:  2390 
  • 7b Sultam: Sibi MP. Sausker JB. J. Am. Chem. Soc.  2002,  124:  984 
  • 7c Oxazolidinones: Sibi MP. Ji J. Wu JH. Gurtler S. Porter NA. J. Am. Chem. Soc.  1996,  118:  9800 
  • 7d Pyrrolidinones: Sibi MP. He L. Org. Lett.  2004,  6:  1749 
  • 7e Chiral relay templates: Sibi MP. Prabagaran N. Synlett  2004,  2421 
  • 7f Pyrazoles: Sibi MP. Shay JJ. Ji J. Tetrahedron Lett.  1997,  38:  5955 
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  • 8c For the use of imide templates in conjugate additions see: Sammis GM. Jacobsen EN. J. Am. Chem. Soc.  2003,  125:  4442 ; and references cited therein.
  • 9a For addition/trapping experiments from our laboratory, see: Sibi MP. Ji J. J. Org. Chem.  1996,  61:  6090 
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  • For examples of radical reactions where stereocenter α to a carbonyl is established, see:
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  • For a reaction with tiglates see:
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11

The ethyl addition products were formed in minor amounts depending on the chiral Lewis acid and/or template employed for the reaction.

14

General Procedure for the Addition/Trapping Reaction
To a suspension of Lewis acid (0.2 mmol) in 1.5 mL of CH2Cl2 was added the chiral ligand (0.2 mmol) and stirred at r.t. for 2 h resulting in a clear solution. Substrate (0.2 mmol) in CH2Cl2 was added to above chiral Lewis acid and the reaction cooled to -78 °C and stirred for 1 h. The radical precursor (6 mmol) was added, followed by addition of allyltributyltin (0.62 mL, 2 mmol), Et3B (1 mL, 1 mmol) and 10 mL of O2. The reaction was allowed to reach r.t. over 12 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and silica gel (4 g) was added. After removal of the solvent, the silica gel was washed with hexane (30 mL), followed by hexane-EtOAc (1:1, 30 mL). The hexane-EtOAc solution was concentrated to give the crude, which was purified by flash chromatography to give pure product. The enantio-meric purity was determined by chiral GC. Conditions for GC analyses: Supelco β-Dex 225 column, 30 m in length, 0.25 mm inner diameter, isotherm temperature program, and He as carrier gas (1 mL/min).
2-Isobutyl-2-methylpent-4-enoic Acid (2,2-Dimethyl-propionyl)amide (4)
Mp 67-68 °C; R f = 0.3 (hexane-EtOAc, 4:1); 70% ee (1 mL/min, T = 80 °C, t R1 = 42 min, t R2 = 43.6 min). IR (film): 1758, 1478, 1453 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.25 (br s, 1 H), 5.76 (m, 1 H), 5.15-5.10 (m, 2 H), 2.39 (dd, J = 14.0, 7.0 Hz, 1 H), 2.18 (dd, J = 14.5, 7.5 Hz, 1 H), 1.72 (m, 1 H), 1.62 (dd, J = 14.5, 7.0 Hz, 1 H), 1.41 (dd, J = 14.5, 5.5 Hz, 1 H), 1.24 (s, 9 H), 1.21 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 175.0, 174.3, 133.1, 119.3, 48.5, 47.5, 44.7, 40.5, 27.1, 24.7, 24.5, 23.5, 21.3. HRMS: m/z calcd for C15H27NO2Na+: 276.1933; found: 276.1932.
2-(2,2-Dimethylpropyl)-2-methylpent-4-enoic Acid (2,2-Di­methylpropionyl)amide (18)
Mp 73-74 °C; R f = 0.33 (hexane-EtOAc, 4:1); 73% ee (1 mL/min, T = 75 °C, t R1 = 91.3 min, t R2 = 93.1 min). IR (film): 3054, 1758, 1478 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.29 (br s, 1 H), 5.73 (m, 1 H), 5.15-5.08 (m, 2 H), 2.39 (dd, J = 14.0, 6.5 Hz, 1 H), 2.13 (dd, J = 13.5, 8.0 Hz, 1 H), 1.87 (d, J = 14.5 Hz, 1 H), 1.45 (d, J = 15.0 Hz, 1 H), 1.29 (s, 3 H), 1.25 (s, 9 H), 0.96 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ = 174.9, 174.3, 132.8, 119.5, 52.7, 47.9, 47.1, 40.5, 31.7, 31.2, 27.1, 21.7. HRMS: m/z calcd for C16H29NO2Na+: 290.2090; found: 290.2080.
2-Cyclohexylmethyl-2-methylpent-4-enoic Acid (2,2-Dimethyl-propionyl)amide (20)Mp 90-91 °C; R f = 0.33 (hexane-EtOAc, 4:1); 64% ee (1.6 mL/min, T = 123 °C, t R1 = 46.3 min, t R2 = 46.9 min). IR (film): 3054, 1758, 1479 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.24 (br s, 1 H), 5.75 (m, 1 H), 5.16-5.08 (m, 2 H), 2.38 (dd, J = 14.0, 6.8 Hz, 1 H), 2.18 (ddt, J d = 14.0, 8.0 Hz, J t = 1.2 Hz, 1 H), 1.69-1.56 (m, 7 H), 1.40-1.35 (m, 2 H), 1.25 (s, 9 H), 1.20 (s, 3 H), 1.18-1.06 (m, 2 H), 0.99-0.88 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 175.0, 174.3, 133.1, 119.2, 47.38, 47.35, 44.7, 35.1, 34.3, 34.2, 27.1, 26.31, 26.27, 26.1, 21.5. HRMS: m/z calcd for C18H31NO2Na+: 316.2246; found: 316.2256.