Unprecedented regiocontrol in synthesis of spirooxindolopyrrolizidines in both enantiomeric form via asymmetric [3+2] cycloaddition of azomethine ylides

Spirooxindoles and functionalized pyrrolizidines are an important class of naturally occurring substances characterized by highly pronounced biological properties and therapeutic applications. Thus, it might be expected that presence of a pyrrolizidine moiety at C-3 of the 2-indolinone system generates 3-spiroindolo pyrrolizidine that possess considerably enhanced biological activities. For example, horsfiline, elacomine and rhynchophylline, which exhibit significant biological activities.1 We herein report a highly regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction of (R)/(S)-camphorsultam cinnamate with azomethine ylides, which are generated from (S)-proline with isatins under optimized reaction conditions (Fig. 1). More importantly, for the first time an unusual regioselectivity was observed in this reaction, leading to the construction of novel 3-spiroindolopyrrolizidine derivatives in both enantiomeric form. The structures of cycloadducts were assigned from their elemental and spectroscopic analyses including IR, 1H NMR, 13C NMR, mass spectral data and by single-crystal X-ray analysis. The possible mechanism of the reaction was investigated using the DFT approach at the B3LYP/6-311G* level of theory.

Keywords:

1 , 3-Dipolar cycloadditions , Azomethine ylides , Chiral spiroindolo pyrrolizidine , Asymmetric Synthesis.