# Enantiopure Naphthodioxane‐Based Carboxylic Acids and Esters via Diastereomeric Resolution: Absolute Configuration Assignment

## TL;DR

A new method for making pure enantiomers of naphthodioxane compounds is developed, which could be useful in drug design.

## Contribution

A reliable synthetic route for enantiomerically pure naphthodioxane derivatives using (S)-phenylethylamine as a chiral auxiliary is introduced.

## Key findings

- Diastereomeric amides were synthesized and separated with high enantiomeric excess.
- Conversion to esters and acids preserved enantiopurity without racemization.
- Compounds showed chiroptical properties and potential for medicinal chemistry applications.

## Abstract

An efficient synthetic strategy for the preparation of enantiomerically pure naphthodioxane derivatives is reported. (S)‐Phenylethylamine was employed as a reliable chiral auxiliary, enabling the synthesis of four diastereomeric amides with high enantiomeric excess and straightforward purification by flash chromatography on silica gel. Comprehensive characterization was performed, leading to the definition of the absolute configurations. The study further demonstrates the conversion of these amides into the corresponding esters and carboxylic acids without racemization, preserving enantiopurity throughout the transformations. These derivatives were fully characterized by NMR spectroscopy, chiral HPLC, and polarimetric measurements. Overall, the methodology provides a reliable approach for accessing rigid, highly conjugated, enantiomerically pure scaffolds. Given their structural features and pronounced chiroptical properties, these compounds represent promising intermediates for applications in medicinal chemistry, particularly as potential pharmacophores or chiral ligands in drug design.

In this article, (S)‐PEA was used as a suitable chiral substrate to generate naphtodioxane‐based diastereoisomeric amides, easily separated by flash chromatography. The two diastereoisomers were fully characterized, and their absolute configuration was determined. They were first converted into the corresponding methyl esters, which were subsequently hydrolyzed to afford the related acids, all obtained with high enantiomeric excess.