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.

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

References

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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.

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