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Synlett 2010(4): 579-582  
DOI: 10.1055/s-0029-1219210
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Novel Asymmetric Azaspirocyclisation Using a Morita-Baylis-Hillman-Type Reaction

Jonathan C. Killena, John Leonardb, Varinder K. Aggarwal*a
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax: +44(0)1179298611; e-Mail: v.aggarwal@bristol.ac.uk;
b Process R&D, AstraZeneca plc, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK
Further Information

Publication History

Received 3 December 2009
Publication Date:
19 January 2010 (online)

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Abstract

A Morita-Baylis-Hillman-type reaction has been applied to the asymmetric preparation of azaspirocycles in high yield and diastereoselectivity. The optimisation of the reaction is discussed and a model for the origin of diastereoselectivity is proposed.

Key Words

Morita-Baylis-Hillman-type reaction - azaspirocyclisation - spiro compounds - asymmetric synthesis - diastereoselectivity

    References and Notes

  • For isolation of cylindricines, see:
  • 1a Blackman AJ. Li CP. Hockless DCR. Skelton BW. White AH. Tetrahedron  1993,  49:  8645 
    Google Scholar
  • 1b Li CP. Blackman A.
    J. Aust. J. Chem.  1994,  47:  1355 
    Google Scholar
  • 1c Li CP. Blackman A. J. Aust. J. Chem.  1995,  48:  955 
    Google Scholar
  • 1d Patil AD. Freyer AJ. Reichwein R. Carte B. Killmer LB. Faucette L. Johnson RK. Faulkner DJ. Tetrahedron Lett.  1997,  38:  363 
    Google Scholar
  • 1e Sauviat MP. Vercauteren J. Grimaud N. Juge M. Nabil M. Petit JY. Biard JF. J. Nat. Prod.  2006,  69:  558 
    Google Scholar
  • 1f For a review on synthesis, see: Weinreb SM. Chem. Rev.  2006,  106:  2531 
    Google Scholar
  • For isolation of histrionicotoxins, see:
  • 2a Daly JW. Karle I. Myers CW. Tokuyama T. Waters JA. Witkop B. Proc. Natl. Acad. Sci. U.S.A.  1971,  68:  1870 
    Google Scholar
  • 2b Karle IL. J. Am. Chem. Soc.  1973,  95:  4036 
    Google Scholar
  • 2c Tokuyama T. Uenoyama K. Brown G. Daly JW. Witkop B. Helv. Chim. Acta  1974,  57:  2597 
    Google Scholar
  • 2d Daly JW. Witkop B. Tokuyama T. Nishikawa T. Karle IL. Helv. Chim. Acta  1977,  60:  1128 
    Google Scholar
  • 2e Tokuyama T. Daly JW. Tetrahedron  1983,  39:  41 
    Google Scholar
  • 2f Tokuyama T. Nishimori N. Karle IL. Edwards MW. Daly JW. Tetrahedron  1986,  42:  3453 
    Google Scholar
  • 2g Spande TF. Garraffo HM. Daly JW. Tokuyama T. Shimada A. Tetrahedron  1992,  48:  1823 
    Google Scholar
  • 2h For a review on synthesis, see: Sinclair A. Stockman RA. Nat. Prod. Rep.  2007,  24:  298 
    Google Scholar
  • 3a For isolation of halichlorine, see: Kuramoto M. Tong C. Yamada K. Chiba T. Hayashi Y. Uemura D. Tetrahedron Lett.  1996,  37:  3867 
    Google Scholar
  • 3b For isolation of the pinnaic acids, see: Chou T. Kuramoto M. Otani Y. Shikano M. Yazawa K. Uemura D. Tetrahedron Lett.  1996,  37:  3871 
    Google Scholar
  • 3c For a review on synthesis, see: Clive DLJ. Yu ML. Wang J. Yeh VSC. Kang SZ. Chem. Rev.  2005,  105:  4483 
    Google Scholar
  • 4 Myers EL. de Vries JG. Aggarwal VK. Angew. Chem. Int. Ed.  2007,  46:  1893 
    CrossrefGoogle Scholar
  • 5 Myers EL. Butts CP. Aggarwal VK. Chem. Commun.  2006,  42:  4434 
    Google Scholar
  • The addition of dimethyl sulfide to cyclohexenone in the presence of TMSOTf is 1,4-selective and reversible. The silyloxysulfonium salt produced is thermally unstable above -40 ˚C. At -20 ˚C the equilibrium lies entirely on the side of the cyclohexenone:
  • 6a Kim S. Park JH. Kim YG. Lee JM. J. Chem. Soc., Chem. Commun.  1993,  1188 
    Google Scholar
  • 6b Lee K. Kim H. Miura T. Kiyota K. Kusama H. Kim S. Iwasawa N. Lee PH. J. Am. Chem. Soc.  2003,  125:  9682 
    Google Scholar
  • 7a Burgess LE. Meyers AI. J. Am. Chem. Soc.  1991,  113:  9858 
    Google Scholar
  • 7b Burgess LE. Meyers AI. J. Org. Chem.  1992,  57:  1656 
    Google Scholar
  • 7c Meyers AI. Brengel GP. Chem. Commun.  1997,  1 
    Google Scholar
  • 7d Amat M. Llor N. Hidalgo J. Escolano C. Bosch J. J. Org. Chem.  2003,  68:  1919 
    Google Scholar
  • 7e Amat M. Escolano C. Llor N. Huguet M. Perez M. Bosch J. Tetrahedron: Asymmetry  2003,  14:  1679 
    Google Scholar
  • 7f Amat M. Perez M. Llor N. Martinelli M. Molins E. Bosch J. Chem. Commun.  2004,  1602 
    Google Scholar
  • 7g Amat M. Perez M. Minaglia AT. Casamitjana N. Bosch J. Org. Lett.  2005,  7:  3653 
    Google Scholar
  • 7h Amat M. Escolano C. Gomez-Esque A. Lozano O. Llor N. Griera R. Molins E. Bosch J. Tetrahedron: Asymmetry  2006,  17:  1581 
    Google Scholar
  • 7i Amat M. Lozano O. Escolano C. Molins E. Bosch J. J. Org. Chem.  2007,  72:  4431 
    Google Scholar
  • 7j Amat M. Perez M. Minaglia AT. Peretto B. Bosch J. Tetrahedron  2007,  63:  5839 
    Google Scholar
  • 7k Amat M. Perez M. Minaglia AT. Bosch J. J. Org. Chem.  2008,  73:  6920 
    Google Scholar
  • 7l For a review on stereochemistry of nucleophilic addition to aminals using this auxiliary, see: Husson HP. Royer J. Chem. Soc. Rev.  1999,  28:  383 
    Google Scholar
  • 8 Bahajaj AA. Vernon JM. Wilson GD. Tetrahedron  2004,  60:  1247 
    CrossrefGoogle Scholar
  • 9 Bahajaj AA. Moore MH. Vernon JM. Tetrahedron  2004,  60:  1235 
    CrossrefGoogle Scholar
  • The following Lewis acids and nucleophile combinations were screened for the MBH-type reaction without success:
  • 10a HCl: Melching KH. Hiemstra H. Klaver WJ. Speckamp WN. Tetrahedron Lett.  1986,  27:  4799 
    Google Scholar
  • 10b TiCl4 + Bu4NI: Yagi K. Turitani T. Shinokubo H. Oshima K. Org. Lett.  2002,  4:  3111 
    Google Scholar
  • 10c TMSI: Roe SJ. Stockman RA. Chem. Commun.  2008,  3432 
    Google Scholar
  • 10d TfOH + SMe2: Kurasaki H. Okamoto I. Morita N. Tamura O. Org. Lett.  2009,  11:  1179 
    Google Scholar
  • 12a For α,β-unsaturated aldehyde reduction, see: Stevens RV. Lawrence DS. Tetrahedron  1985,  41:  93 
    Google Scholar
  • 12b

    For Birch reduction, see ref 7j.

  • 13a The original paper concerns the effect of conformation of a stereocentre a to a carbonyl group on facial selectivity of nucleophilic addition to the carbonyl: Cherest M. Felkin H. Prudent N. Tetrahedron Lett.  1968,  2199 
    Google Scholar
  • 13b Anh NT. Top. Curr. Chem.  1980,  88:  145 
    Google Scholar
  • 14 Chen MD. He MZ. Zhou X. Huang LQ. Ruan YP. Huang PQ. Tetrahedron  2005,  61:  1335 
    CrossrefGoogle Scholar
  • 15 Stocker BL. Teesdale-Spittle P. Hoberg JO. Eur. J. Org. Chem.  2004,  330 
    CrossrefGoogle Scholar
11

We were not able to obtain crystals of the 5,5-spirocycle for analysis by X-ray diffraction, and we were unsuccessful in finding NOE correlations to assign its stereochemistry. The spirocentre stereochemistry is therefore not known in this case.