TiCl₃‐Mediated Synthesis of 2,3,3‐Trisubstituted Indolenines: Total Synthesis of (+)‐1,2‐Dehydroaspidospermidine, (+)‐Condyfoline, and (−)‐Tubifoline

Abstract

2,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids.W er eport herein an unprecedented access to this skeleton by aTiCl 3-mediated reductive cyclization of tetrasubstituted alkenes bearing a2-nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing ac oncise total synthesis of (+ +)-1,2-dehydroaspidospermidine featuring alate-stage application of this key transformation. Asequence of reduction of nitroarene to nitrosoarene followed by 6pelectron-5-atom electrocyclization and a1 ,2-alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome.Asubsequent total synthesis of (+ +)-condyfoline not only illustrates the generality of the reaction, but also provides am echanistic insight into the nature of the 1,2alkyls hift. The exclusive formation of (+ +)-condyfoline indicates that the 1,2-alkyl migration follows ac oncerted Wagner-Meerwein pathway,r ather than as tepwise retro-Mannich/Mannich reaction sequence.C onditions for almost quantitative conversion of (+ +)-condyfoline to (À)-tubifoline by way of ar etro-Mannich/1,3-prototropy/transannular cyclization cascade are also documented.

Enantioselective Total Synthesis of (+)‐Nordasycarpidone, (+)‐Dasycarpidone, and (+)‐Uleine

“…Our group has recently accomplished an enantioselective total synthesis of condyfoline ( 11 ) [20] through a key TiCl 3 ‐mediated reductive cyclization of tetrasubstituted alkene bearing a 2‐nitrophenyl substituent [21] as well as alstilobanine C ( 8 ) and undulifoline ( 9 ) featuring a late stage construction of both the indole and the piperidine rings by way of a double reductive cyclization cascade ( Scheme 1 ,b ) [22] . As a continuation of our interest in the synthesis of indole alkaloids containing a bridged bicyclic ring system, [23–26] we envisaged to develop an alternative strategy to reach the tetracyclic compound 1 .…”