Download PDF
Synlett 2005(19): 3008-3010  
DOI: 10.1055/s-2005-921902
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Two New Azabicyclophosphinic Acids as Constrained Analogues of TPMPA

David Orain*, Henri Mattes
Global Discovery Chemistry-NeuroScience, Novartis Institute for Biomedical Research Basel, WKL-122.2.43, Basel 4002, Switzerland
Fax: +41(61)6968250; e-Mail: david.orain@novartis.com;
Further Information

Publication History

Received 3 October 2005
Publication Date:
04 November 2005 (online)

    Permissions and Reprints All articles of this category

Abstract

Utilization of the Polniaszek reagent Cl2PNi-Pr2/AlCl3 was used on amino dienes to generate new azabicyclophosphinic acid as constrained analogues of TPMPA.

Key words

phosphorus - bicyclic compounds - cyclizations - ­medicinal chemistry - receptors

    References

  • Most recent reviews on GABAC and references herein:
  • 1a Johnston GAR. Chebib M. Hanrahan JR. Mewett KN. Curr. Drug Targets: CNS Neurol. Disord.  2003,  2:  260 
    CrossrefGoogle Scholar
  • 1b Johnston GAR. Curr. Top. Med. Chem.  2002,  2:  903 
    CrossrefGoogle Scholar
  • 2 Hanrahan JR. Mewett KN. Chebib M. Burden PM. Johnston GAR. J. Chem. Soc., Perkin Trans. 1  2001,  2389 
    CrossrefGoogle Scholar
  • 3 Chebib M. Vandenberg RJ. Johnston GAR. Br. J. Pharmacol.  1997,  122:  1551 
    CrossrefGoogle Scholar
  • 4 Chebib M. Chem. Aust.  2001,  68:  19 
    Google Scholar
  • 5 Quin LD. Middlemas E. Rao Nandakumar S. Miller RW. McPhail AT. J. Am. Chem. Soc.  1982,  104:  1893 
    CrossrefGoogle Scholar
  • 6a Polniaszek RP. J. Org. Chem.  1992,  57:  5189 
    Google Scholar
  • 6b Conway SJ. Miller JC. Bond AD. Clark BP. Jane DE. J. Chem. Soc., Perkin Trans. 1  2002,  14:  1625 
    Google Scholar
  • 9a Huwe CM. Blechert S. Tetrahedron Lett.  1994,  35:  9537 
    Google Scholar
  • 9b Trost BM. Chen S.-F. J. Am. Chem. Soc.  1986,  108:  6053 
    Google Scholar
  • 10 Protocol for purification over DOWEX resin see: Dumond YR. Montchamp J.-L. J. Organomet. Chem.  2002,  653:  252 
    CrossrefGoogle Scholar
7

Typical Procedure for Cyclization/Oxidation.
To a suspension of AlCl3 (1.3 g, 10 mmol) in CH2Cl2 was added dropwise, at -20 °C and under N2, Cl2PNi-Pr2 (2.0 g,10 mmol) in CH2Cl2. Then, the mixture was stirred at r.t. for 1 h. The mixture was cooled down to -20 °C and N-benzyl diallylamine (936 mg, 5 mmol) in CH2Cl2 was added dropwise. The mixture was allowed to warm up to r.t., stirred at r.t. for 16 h and refluxed for 1 h. The mixture was cooled down to 0 °C and 10 mL of a solution of 0.2 M EDTA-sat. NaHCO3 (1:1) was added carefully. The mixture was then stirred at r.t. for 5 h. Then, 100 mL of H2O were added and the aqueous phase was extracted several times with CHCl3. The organic phases were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a crude yellow oil (2 g). Purification was achieved by flash chromatography over silica gel using EtOAc-MeOH (100:0 to 80:20) as eluent. After concentration of the fractions, a yellow paste (1.05 g, 63%) was obtained.

8

1H NMR (400 MHz, D2O): δ = 3.55 (m, 2 H), 3.03 (m, 2 H), 2.85 (m, 2 H), 1.82 (m, 2 H), 1.40 (m, 2 H).

11

1H NMR (400 MHz, D2O): δ = 5.87 (d, J = 31.7 Hz, 1 H), 3.79 (d, J = 14.0 Hz, 1 H), 3.56 (d, J = 15.9 Hz, 1 H), 3.42 (dd, J = 12.8 Hz, J = 2.4 Hz, 1 H), 3.01 (m, 1 H), 2.30 (m, 1 H), 2.15 (m, 2 H), 2.00 (m, 1 H), 1.63 (m, 1 H).