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Synlett 2010(12): 1775-1778  
DOI: 10.1055/s-0030-1258110
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Expeditious Method for the First Asymmetric Synthesis of Dexoxadrol from the Chiral Pool

Pablo Etayo, Ramón Badorrey, María D. Díaz-de-Villegas*, José A. Gálvez*, Pilar López-Ram-de-Víu
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Instituto Universitario de Catálisis Homogénea, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Fax: +34(976)761202; e-Mail: loladiaz@unizar.es; e-Mail: jagl@unizar.es;
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Publication History

Received 19 April 2010
Publication Date:
30 June 2010 (online)

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Abstract

A new, straightforward and high-yielding methodology for the asymmetric synthesis of 2-(1,3-dioxolan-4-yl)piperidines is described. This approach involves a highly stereoselective addition of vinylmagnesium bromide to N-(3-butenyl)imines derived from d-glyceraldehyde diphenyl ketal and a ring-closing metathesis reaction as key steps. This procedure was used for the first asymmetric synthesis of (S)-2-[(S)-2,2-diphenyl-1,3-dioxolan-4-yl]piperidine (dexoxadrol) starting from conveniently protected d-mannitol in six steps in 43% overall yield.

Key words

imines - piperidines - metathesis - ring-closure - stereo­selective synthesis

    References and Notes

  • 2 Hardie WR. Hidalgo J. Halverstadt JF. Allen RE. J. Med. Chem.  1966,  9:  127 
    CrossrefSearch in Google Scholar
  • See for example:
  • 3a Lasagna L. Pearson JW. Proc. Soc. Exp. Biol. Med.  1965,  118:  352 
    Search in Google Scholar
  • 3b Williams MW. Williford EA. Williams CS. Towne JC. Arch. Int. Pharmacol. Ther.  1969,  178:  26 
    Search in Google Scholar
  • 3c Tang AH. Kirch JD. Anesth. Analg.  1973,  52:  577 
    Search in Google Scholar
  • 3d Frederickson EL. Longnecker DE. Allen GW. Anesth. Analg.  1976,  55:  335 
    Search in Google Scholar
  • 3e Coan EJ. Collingridge GL. Br. J. Pharmacol.  1987,  91:  547 
    Search in Google Scholar
  • 4a Jacobson AE. Harrison EA. Mattson MV. Rafferty MF. Rice KC. Woods JH. Winger G. Solomon RE. Lessor RA. Silverton JV. J. Pharmacol. Exp. Ther.  1987,  243:  110 
    Search in Google Scholar
  • 4b Thurkauf A. Zenk PC. Balster RL. May EL. George C. Carroll FI. Mascarella SW. Rice KC. Jacobson AE. Mattson MV. J. Med. Chem.  1988,  31:  2257 
    Search in Google Scholar
  • 5a Thurkauf A. Mattson MV. Richardson S. Mirsadeghi S. Ornstein PL. Harrison EA. Rice KC. Jacobson AE. Monn JA. J. Med. Chem.  1992,  35:  1323 
    Search in Google Scholar
  • 5b Sax M. Wünsch B. Curr. Top. Med. Chem.  2006,  6:  723 
    Search in Google Scholar
  • 5c Sax M. Ebert K. Schepmann D. Wibbeling B. Wünsch B. Bioorg. Med. Chem.  2006,  14:  5955 
    Search in Google Scholar
  • 5d Sax M. Fröhlich R. Schepmann D. Wünsch B. Eur. J. Org. Chem.  2008,  6015 
  • See for example
  • 6a Etayo P. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. Synlett  2006,  2799 
  • 6b Etayo P. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. Tetrahedron: Asymmetry  2007,  18:  2812 
    Search in Google Scholar
  • 6c Etayo P. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. J. Org. Chem.  2008,  73:  8594 
    Search in Google Scholar
  • 6d Etayo P. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. Eur. J. Org. Chem.  2008,  3474 
  • 6e Badorrey R. Portaña E. Díaz-de-Villegas MD. Gálvez JA. Org. Biomol. Chem.  2009,  7:  2912 
    Search in Google Scholar
  • 7 Sydorenko N. Hsung RP. Vera EL. Org. Lett.  2006,  8:  2611 
    CrossrefPubMedSearch in Google Scholar
  • 8a Díez R. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. Eur. J. Org. Chem.  2007,  2114 
  • 8b Allepuz AC. Badorrey R. Díaz-de-Villegas MD. Gálvez JA. Eur. J. Org. Chem.  2009,  6172 
  • 8c Badorrey R. Díaz-de-Villegas MD. Gálvez J. Tetrahedron: Asymmetry  2009,  20:  2226 
    Search in Google Scholar
  • For recent papers on the asymmetric synthesis of piperidine heterocycles using RCM, see for example:
  • 9a Rengasamy R. Curtis-Long MJ. Seo WD. Jeong SH. Jeong IY. Park HH. J. Org. Chem.  2008,  73:  2898 
    Search in Google Scholar
  • 9b Lebron S. Couture A. Deniau E. Grandclaudon P. Tetrahedron: Asymmetry  2008,  19:  1245 
    Search in Google Scholar
  • 9c Nomura H. Richards CJ. Org. Lett.  2009,  11:  2892 
    Search in Google Scholar
  • 9d Venkataiah M. Rao BV. Fadnavis NW. Tetrahedron: Asymmetry  2009,  20:  198 
    Search in Google Scholar
  • 9e Shaikh TM. Sudalai A. Tetrahedron: Asymmetry  2009,  20:  2287 
    Search in Google Scholar
  • 9f Kamal A. Vangala SR. Reddy NVS. Reddy VS. Tetrahedron: Asymmetry  2009,  20:  2589 
    Search in Google Scholar
  • 9g Srivastava AK. Das SK. Panda G. Tetrahedron  2009,  65:  5322 
    Search in Google Scholar
  • 9h Venkataiah M. Fadnavis NW. Tetrahedron  2009,  65:  6950 
    Search in Google Scholar
  • 9i Davies SG. Fletcher AM. Roberts PM. Smith AD. Tetrahedron  2009,  65:  10192 
    Search in Google Scholar
  • 9j Ghosh S. Shashidhar J. Tetrahedron Lett.  2009,  50:  1177 
    Search in Google Scholar
  • For reviews on the synthesis of heterocycles using RCM, see:
  • 10a Felpin FX. Lebreton J. Eur. J. Org. Chem.  2003,  3693 
  • 10b Compain P. Adv. Synth. Catal.  2007,  349:  1829 
    Search in Google Scholar
  • 10c Villar H. Frings M. Bolm C. Chem. Soc. Rev.  2007,  55 
  • 10d Majumdar KC. Muhuri S. Islam RU. Chattopadhyay B. Heterocycles  2009,  78:  1109 
    Search in Google Scholar
  • 11 Schwab P. France MB. Ziller JW. Grubbs RH. Angew. Chem. Int. Ed. Engl.  1995,  34:  2039 
    Search in Google Scholar
  • 13 Hardie WR, Creek W, and Halverstad IF. inventors; PCT Int. Appl. US  3262938.  ; Chem. Abstr. 1996, 65, 12207d
1

Present address: Institute of Chemical Research of Catalonia (ICIQ), Avgda. Països Catalans 16, 43007 Tarragona, Spain

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CCDC 773631 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or 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