High-Pressure Diels−Alder Cycloadditions between Benzylideneacetones and 1,3-Butadienes: Application to the Synthesis of (R,R)-(−)- and (S,S)-(+)-Δ⁸-Tetrahydrocannabinol

Abstract

High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the mild Lewis acid HfCl(4).2THF allows these reactions to efficiently and regioselectively produce a series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton. Application to the synthesis of Delta(8)-trans-THC in both enantiomeric pure forms is based on the successful resolution of selected cycloadduct by the SAMP-hydrazone method.

Cannabidiol Discovery and Synthesis—a Target‐Oriented Analysis in Drug Production Processes

“…The authors did not describe the yield of all steps;h owever, each Diels-Alder approach contributes to the stereoselective synthesis of future cannabinoids, [136][137][138] including( À)-2, [119] and provides key evidence for rationalizing MS spectra. [130,139]…”

“…Minuti and co-workers, [138] for example, combined [4+ +2] cyclization and kinetic resolution as key steps to obtain intermediate (À)-36 in af ive-step process (Scheme 26). H NMR spectroscopy after racemic resolution and isolation.A sr eported by Korte and co-workers, compound (À)-34 could be synthesized by aW ittig reaction of the corresponding ketone, (À)-36 (Scheme 10).…”

“…Minuti and co‐workers, [138] for example, combined [4+2] cyclization and kinetic resolution as key steps to obtain intermediate (−)‐ 36 in a five‐step process (Scheme 26). The synthesis starts with formylation of 21 through a Vilsmeier–Haack reaction by using BuLi and DMF, followed by aldol condensation of 35 with a ketone under basic conditions, furnishing benzylideneacetone 30 in 80 % yield after two steps.…”

Synthetic pathways to tetrahydrocannabinol (THC): an overview

“…47,48 Minuti and co-workers applied late stage hyperbaric Diels-Alder reactions giving rise to a variety of Δ 8 -THC derivatives. 64 The authors performed this reaction with six benzylidene acetone dienophiles (70) and two diene coupling partners (71a, 71b) promoted by mildly Lewis acidic conditions. This resulted in excellent yields, full trans-stereoselectivity, however, with additional formation of a regioisomeric product.…”

Total Synthesis of (±)-Sorocenol B Employing Nanoparticle Catalysis

“…Regioselective formylation of 15 was carried out employing n BuLi in the presence of TMEDA followed by quenching the resulting aryl lithium intermediate with DMF which provided benzaldehyde 18 in 83% yield. 13 Sequential base-catalyzed aldol condensation between 18 and acetone (92% yield) 14 and Wittig olefination of the resulting α,β-unsaturated ketone 19 (79% yield) afforded the desired diene 12 .…”