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A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

preprint
submitted on 07.01.2019 and posted on 08.01.2019 by Victor Bloemendal, Floris P. J. T. Rutjes, Thomas J. Boltje, Daan Sondag, Hidde Elferink, Jan C.M. van Hest

In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-trans8-THC derivatives, which can be used to modulate the pharmacologically important CB1 and CB2 receptors. This pathway involves a one-pot Friedel-Crafts alkylation/cyclization protocol, followed by Suzuki-Miyaura cross-coupling reactions and gives rise to a series of new Δ8-THC derivatives. In addition, we demonstrate using extensive NMR evidence that similar halide-substituted Friedel-Crafts alkylation/cyclization products in previous articles were wrongly assigned as the para-isomers, which also has consequence for the assignment of the subsequent cross-coupled products and interpretation of their biological activity.

Considering the importance of the availability of THC derivatives in medicinal chemistry research and the fact that previously synthesized compounds were wrongly assigned, we feel this research is describing a straightforward pathway into new cannabinoids.

Funding

H2020-FETOPEN: 737266-ONE FLOW

History

Email Address of Submitting Author

floris.rutjes@ru.nl

Institution

Radboud University

Country

The Netherlands

ORCID For Submitting Author

0000-0003-1538-3852

Declaration of Conflict of Interest

No conflict of interest

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