Application of N-acyliminium ions in the asymmetric synthesis of indole alkaloids

We have developed a new and highly stereoselective approach to indolizino[8,7-b]indole derivatives such as (A) and indolizino[2,3-a]quinolizidines (B). Our protocol involves the cyclisation of pendent aromatic substituents onto N-acyliminium intermediates as a key ring-forming step. The indolizino[2,3-a]quinolizidines are of great interest and significance since this heterocyclic template is found within a plethora of indole alkaloids. [Illustration omitted.] In order to demonstrate the synthetic potential of this methodology we have established conditions for removal of the pendent hydroxymethyl substituent from cyclisation products such as (A) and (B). Furthermore, we have demonstrated the functionalisation of our cyclisation products via conjugate addition chemistry. We have utilised this methodology and herein describe the asymmetric synthesis of both enantiomers of deplancheine (C), furnishing the natural product and its enantiomer with >95% e.e. Our route relies on a highly stereoselective cyclisation reaction to access the indolizino[2,3-a]quinolizidine template from a readily available non-racemic chiral template. [Illustration omitted.]