# Selective Synthesis of Tetrahydroisoquinoline and Piperidine Scaffolds by Oxidative Ring Opening/Ring Closing Protocols of Substituted Indenes and Cyclopentenes

## TL;DR

A new method for making tetrahydroisoquinoline and piperidine compounds with precise stereochemistry is developed using oxidative and reductive reactions.

## Contribution

A stereocontrolled oxidative ring opening and ring closing protocol for synthesizing nitrogen-containing heterocycles is introduced.

## Key findings

- Oxidative cleavage of substituted indenes or cyclopentenes produces diformyl intermediates.
- Reductive amination with chiral amines enables stereocontrolled ring expansion into nitrogen heterocycles.
- The method allows synthesis of amino acid derivatives relevant to foldamer chemistry.

## Abstract

Novel tetrahydroisoquinoline and piperidine derivatives were selectively synthesized from substituted indenes or cyclopentenes. The process starts with an oxidative cleavage of the ring olefin bond, which gives reactive diformyl intermediates. By a ring‐closing step using chiral (R) or (S) α‐methylbenzylamine under a reductive amination protocol facilitated ring formation with ring expansion of the corresponding nitrogen‐containing heterocycles. The stereocontrolled methodology enabled accurate control of the stereochemistry of the final products. Additionally, the synthesized amino acid derivatives possessing an aryl moiety in their structure may be relevant building blocks for foldamer chemistry.

Synthesis under stereocontrol of some novel tetrahydroisoquinoline and functionalized piperidine derivatives from substituted indenes or cyclopentenes is described. The key steps of the transformation are an oxidative ring cleavage across the olefin bond, followed by cyclization under double reductive amination with primary chiral amines through ring expansion.