Total Synthesis of Phenanthropiperidine Alkaloids by Sequential Alkylation of N,N‐Dibenzylaminoacetonitrile

Abstract

Two representative members of the phenanthropiperidine alkaloid family, tylophorine (1) and cryptopleurine (2), were synthesized by a bidirectional alkylation strategy employing dibenzylaminoacetonitrile as a substrate. This approach relies on the unprecedented condensation of metallated α-aminonitriles with bromomethylphenanthrenes to provide fully substituted α-aminonitriles, which are subjected to a NaBH 4 -mediated reductive decyanation process to form homobenzylic amines. From these intermediates, a terminal leaving group was introduced by simple chemical manipulation, and its displacement by a free primary amine under two favorable cyclization processes led to the formation of the future E-ring of both alkaloids in high yields. Finally, a late Pictet-Spengler cyclization ensured the formation of a D-ring for the alkaloids 1 and 2.

Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven-Membered Nitrogen-Containing Heterocyclic Systems

“…This work began with the synthesis of α-aminonitriles 6c−h (Table 1) according to a reaction sequence that has been reported previously for the preparation of α-aminonitriles 6a,b. 25 To gain further insight into the reactivity of lithiated αaminonitrile 4, several condensation experiments were carried out in the presence of iodides with increasing length (5d−h). There are two distinct steps for this process: the initial deprotonation of α-aminonitrile 4 and the alkylation of the resulting carbanion.…”