Chemometric Optimization of BF3·OEt2‐Mediated Cyclization of Cannabidiol to Rare Δ⁴‐ and Iso‐THC Isomers

TL;DR

This paper uses chemometrics to optimize the conversion of cannabidiol into various tetrahydrocannabinol isomers using a BF3·OEt2 catalyst.

Contribution

The study demonstrates how chemometrics can be applied to selectively produce rare THC isomers by optimizing reaction parameters.

Findings

Chemometrics tools like PCA and DoE improved the chemoselectivity of CBD cyclization.

Optimal conditions for Δ⁴-iso-THC and Δ⁴(⁸)-iso-THC were successfully identified.

Cannabinoid derivatives incorporating the reaction medium were unexpectedly identified.

Abstract

The acid‐catalyzed conversion of cannabidiol (CBD) to tetrahydrocannabinol and iso‐tetrahydrocannabinol derivatives is a well‐established synthetic strategy. However, since the reaction outcome is strongly dependent on the conditions, a careful investigation is always required to achieve the optimal chemoselectivity. Chemometrics recently emerged as an effective approach for improving synthetic methods, especially when multiple parameters are involved. The present paper aims to apply chemometrics tools to the optimization of the procedures for the preparation of Δ⁹‐THC, Δ⁸‐THC, Δ⁸‐iso‐THC, Δ⁴‐iso‐THC, and Δ⁴(⁸)‐iso‐THC. All the reactions have been performed at room temperature by tuning the initial concentration of CBD, the equivalents of the model Lewis acid considered (BF3·OEt2), the reaction time, and the nature of the media to achieve the desired products. The kinetics of the process, followed over the course of 1 to 48 hours, were analyzed by means of Principal Component Analysis (PCA) to initially simplify the multidimensional dataset and help identify the best media for Δ⁹‐THC and Δ⁸‐THC. In order to optimize the conditions needed for Δ⁴‐iso‐THC, Δ⁴(⁸)‐iso‐THC, and Δ⁸‐iso‐THC, multiple Design of Experiment (DoE) were employed, leading to the successful isolation of the target compounds. During the investigation, cannabinoid derivatives incorporating a portion of the reaction medium were also identified.

Find the path! The present paper points out the potentialities of chemometrics tools to design selective BF3·OEt2 catalyzed procedures for the preparation of Δ⁹‐THC, Δ⁸‐THC, Δ⁸‐iso‐THC, Δ⁴‐iso‐THC, Δ⁴(⁸)‐iso‐THC, by simply tuning the initial concentration of CBD, the amount of the Lewis acid, the reaction time as well as the nature of the solvent employed.

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