Concise Synthesis of (±)-Perrottetinene with Bibenzyl Cannabinoid

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Scheme 1. Retrosynthetic analysis of (±)-perrottetinene (4) Cannabinoids are widely distributed in nature and have been isolated from Indian hemp Cannabis sativa, which has been used as both a medicine and a psychotomimetic drug since ancient times (Figure 1). These compounds possess analgesic, antiemetic, psychotropic, and anti-inflammatory properties. They also have potential therapeutic applications in the treatment of asthma and glaucoma. Among these, ∆-tetrahydrocannabinol (1) (∆-THC) and ∆-tetrahydrocannabinol (2) (∆-THC) are the major psychopharmacological active constituents of marijuana (hashish). Their analogues have also attracted medical interest because of their promising biological and pharmacological activities including anthemetic, analgesic, and psychotropic effects. Additionally, hexahydrocannabinol (3) has attracted considerable attention since clinical tests have shown that these compounds have a similar psychotropic activity to natural ∆-tetrahydrocannabinol (1). Currently, synthesized ∆-tetrahydrocannabinol (2) (∆-THC) and its derivatives have been used as the medicines, Marinol and Cesamet, for patients with chemotherapy-induced nausea and vomiting (CINV), who have failed to respond adequately to conventional antiemetic treatments. Structurally related perrottetinene (4) and perrottetinenic acid (5) with a bibenzyl cannabinoid nucleus were isolated from the extract of the New Zealand liverwort Radula marginata (Figure 2). The structures of these natural products were determined using spectroscopic analysis. Interestingly, most of the naturally occurring tetrahydrocannabinols 1-3 possessed a trans-fused ring junction between cyclohexene (or cyclohexane) and the pyranyl ring, whereas perrottetinene (4) and perrottetinenic acid (5) exhibited a cis-stereochemisty. Although the total synthesis of perrottetinene (4) has already been reported in a 9-step process, simple and more concise synthetic approaches are still needed. A new methodology was reported for synthesizing a variety of benzopyrans and canabinoid analogues starting from substituted resorcinols and α,β-unsaturated aldehydes utilizing ethylenediamine diacetate as a catalyst. Naturally occurring hexahydrocannabinol (3) was synthesized using this methodology as a key step. As an expansion of the synthesis of benzopyrans and cannabinoid, (±)-perrottetinene (4) was concisely synthesized in this study.