Application of a Double Mannich Reaction Using Bis(aminol) Ethers in the Synthesis of AE Ring Analogues of Methyl Lycaconitine

Abstract

An efficient method for the construction of azabicy­clo[3.3.1]nonanes and azabicyclo[3.2.1]octanes is reported via double Mannich reaction of cyclic ketoesters with bis(aminol) ethers. This method is applied to the synthesis of AE ring analogues of ­methyl lycaconitine.

Key words

Mannich reaction - aminoalkylation - bis(aminol) ethers - methyl lycaconitine - alkaloids

References

• For reviews see:
• 1a Kleinman EF. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Heathcock CH. Pergamon Press; Oxford: 1991.  p.893 
• 1b Hart DJ. Ha D.-C. Chem. Rev.  1989,  89:  1447 
• 1c Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed.  1998,  37:  1044 
• 1d Kobayashi S. Ishitani H. Chem. Rev.  1999,  99:  1069 
• 1e Tramontini M. Synthesis  1973,  703 
• 1f Tramontini M. Angiolini L. Tetrahedron  1990,  46:  1791 
• 2a Tramontini M. Angiolini N. Mannich-Bases, Chemistry and Uses   CRC; Boca Raton / FL: 1994. 
• 2b Overman LE. Ricca DJ. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Heathcock CH. Pergamon Press; Oxford: 1991.  p.1007 
• 3a Barker D. Brimble MA. McLeod MD. Savage GP. Wong DJ. J. Chem. Soc., Perkin Trans. 1  2002,  924 
• 3b Barker D. Brimble MA. McLeod MD. Savage GP. Org. Biomol. Chem.  2004,  2:  1659 
• 4a Pelletier SW. Joshi BS. In Alkaloids: Chemical and Biological Perspectives   Vol. 7:  Pelletier SW. Springer-Verlag; New York: 1991.  p.297 
• 4b Manske RH. Can. J. Res.  1938,  16B:  57 
• 4c Goodson JA. J. Chem. Soc.  1943,  139 
• 5a Shimizu B. Ogiso A. Iwai I. Chem. Pharm. Bull.  1963,  11:  333 
• 5b Kraus GA. Shi J. J. Org. Chem.  1990,  55:  5423 
• 5c Coates PA. Blagbrough IS. Rowan MG. Potter BVL. Pearson DPJ. Lewis T. Tetrahedron Lett.  1994,  35:  8709 
• 6 Heaney H. Papageorgiou G. Tetrahedron  1996,  52:  3473 
• 7a Robinson GM. Robinson R. J. Chem. Soc.  1923,  123:  532 
• 7b Stewart TD. Bradley WE. J. Am. Chem. Soc.  1932,  54:  4172 
• 7c Gaines JR. Swanson AW. J. Heterocycl. Chem.  1971,  8:  249 
• 7d Rochin C. Babot O. Dunogues J. Duboudin F. Synthesis  1986,  228 
• 9 Heaney H. Papageorgiou G. Wilkins RF. Tetrahedron  1995,  51:  10737 
• 10 Gravel D. Labelle M. Can. J. Chem.  1985,  63:  1874 
• 11 Barker D. McLeod MD. Brimble MA. Savage GP. Tetrahedron Lett.  2002,  43:  6019 
• 12 Nicole L. Berlinguet L. Can. J. Chem.  1962,  40:  353 
• 13 Bergmeier SC. Lapinsky DJ. Free RB. McKay DB. Bioorg. Med. Chem. Lett.  1999,  9:  2263 
• 14 Schepartz A. Breslow R. J. Am. Chem. Soc.  1987,  109:  1814 
• 15 Barker D. McLeod MD. Brimble MA. Savage GP. Tetrahedron Lett.  2001,  42:  1785 
• 16 Neises B. Steglich W. Angew. Chem., Int. Ed. Engl.  1978,  17:  522 
• 17 Ismail KA. Bergmeier SC. Eur. J. Med. Chem.  2002,  37:  469 
• 18 Blagbrough IS. Coates PA. Hardick DJ. Lewis T. Rowan MG. Wonnacott S. Potter BVL. Tetrahedron Lett.  1994,  35:  8705 

8

General Procedure for the Preparation of the Azabicyclic Compounds 4, 12-18, 20-27, and 30-32 by Double Mannich Reaction: To a mixture of β-ketoester (100 mg, 1 equiv) and N,N-bis(ethoxymethyl)amine (2 equiv) in MeCN (2 mL) was added MeSiCl₃ (2 equiv). The reaction mixture was stirred for 20 h at r.t., then quenched with aq NaHCO₃ (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc-hexane). All products were characterized by ¹H NMR and ¹³C NMR spectroscopy and mass spectrometry.