New Synthesis of Δ9- and Δ8-Tetrahydrocannabinol Using [2,3]Sigmatropic Rearrangement and the Intramolecular Diels-AIder Cyclization Reaction

Abstract

New Synthesis of cis-Δ9-tetrahydrocannabinol [2a] and trans-Δ8-tetrahydrocannabinol [lb], the main physiologically active constituent of Hashish or Marijuana, is reported starting from olivetol monoacetate and 3-methyl-3-butenyl isopropyl sulfide via [2, 3]sigmatropic rearrangement and intramolecular [2+4]cyclization. The [2, 3]sigmatropic rearrangement of oxysulfonium ylid derived from olivetol monoacetate and 3-methyl-3-butenyl isopropyl sulfide gave a separable mixture of 2-substituted [3 a] and 6-substituted olivetol [3 b] in 74% combined yield in 1: 1.2 ratio (Scheme 3), which, after separation by column chromatography, were acrylated and transformed into sulfoxides [5 a] or [5b], respectively. Upon heating in xylene in the presence of calcium carbonate under reflux, sulfoxides [5] underwent β-elimination followed by intramolecular Diels-Alder cycloaddition reaction, resulting in the formation of tetrahydrodibenzo[6,d] pyrans [7 a] or [7 b] in good overall yields (Scheme 4). These fused-ring compounds turned out to be cis indicating endo-mode cycloaddition, which is clearly contrast to unsubstituted model compound, o-(l,3-butadienyl)phenyl acrylate, which gave mainly a trans isomer. Dibenzopyranone [7a] was methylated and dehydrated to give Cis-Δ9-cannabidiol [12 a] in good overall yield, which was converted to cis-Δ9-THC [2a] on treatment with boron trifluoride etherate at -25 °C (Scheme 6). On the other hand, dibenzopyranone [7b] was similarly converted to abn-cis-Δ9-cannabidiol [12b] (Scheme 7), which was treated with P-toluenesulfonic acid in benzene at reflux to give trans-Δ8-THC [1 b] (Scheme 7). © 1992, The Chemical Society of Japan. All rights reserved.