Synthesis of (-)-Δ⁹-trans-Tetrahydrocannabinol:  Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction

Abstract

AbstractΔ 9 -THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum catalyzed asymmetric alkylation reaction of the extremely sterically congested bis-ortho substituted cinnamyl carbonate in high regio-and enantioselectivity.(-)-Δ 9 -trans-Tetrahydrocannabinol (Δ 9 -THC) 1, isolated 1 from female Cannabis sativa L. in 1964 has been identified as the primary psychomimetic component of marijuana. It is also known to show antiemetic, antiglaucoma, and analgesic properties. Currently it is administered as an antinauseant to patients undergoing chemotherapy. Discovery of the cannabinoid receptors CB1 and CB2 and Δ 9 -THC analogues 2 that bind selectively to them has led to a need for the development of a flexible synthetic route which would yield target compounds easily in high yields and in sterochemically pure form.THC itself has been prepared numerous times, though most routes are either racemic or derive their chirality from chiral building blocks. 3 Only Evan's 4 route targets the natural product enantioselectively from achiral starting materials. The problems associated with the synthesis of THC involve the control of cis-trans stereochemistry at the cyclohexene ring and the position of the double bond i.e. Δ 9 vs. Δ 8 , the latter being thermodynamically more stable.Our reterosynthetic analysis of the molecule envisioned all of the stereochemistry resulting from a single Mo-catalyzed asymmetric allylic alkylation (AAA) reaction (See abstract). Alkylation of malonate adduct 4 with 3 should furnish the substrate for ring-closing metathesis (RCM). The RCM in itself results in a fixed geometry of double bond thus solving the problem of co-formation of Δ 8 -THC seen in many syntheses. Decarboxlylation of the malonate after RCM was planned to result in the required trans stereochemistry of 2. Grignard addition to ester 2 followed by demethylation to the free phenol and cyclization yields 1. aromatic group in 5, the alkylating partner 3, or the Grignard reagents one can potentially prepare different analogues of THC without fundamentally changing the chemistry involved.Allyl alcohol 9 was easily prepared in high yield from commercially available olivetol, 6 in 4 steps (Scheme 1). Lithiated dimethyl olvitol was quenched with dry DMF to yield the aldehyde 8 in 83% yield. Wadsworth-Horner-Emmons reaction of 8 with sodium triethylphosphonoacetate resulted in the corresponding α,β-unsaturated ethyl ester, which was subjected without further purification to DIBAL-H reduction to yield 97% of 9. Preparation of carbonate 5 proved to be a little tricky because the compound is sensitive to both acid and base, including silica chromatography conditions. A preparation of 5 clean enough to take into the Mo-alkylation reaction, was achieved by titrating alcohol 9 with BuLi at -78 °C in ether and quenching the resulting alkoxide with methyl chloroformate also at -78 °C. Washing the organic layer with ice-cold water followed by solvent removal gave carbonate 5 as a waxy solid,...

Cannabidiol – Recent Advances

“…Trost and Dogra [18] have shown that THC can be synthesized in enantiomerically pure form through molybdenum (Mo)-catalyzed asymmetric alkylation of a sterically congested doubly ortho-substituted entity. An important intermediate in their route was a hydroxylated dihydrocannabidiol, which presumably can be converted into CBD proper with synthetic ease.…”

Advances in the Krapcho Decarboxylation

“…It can be concluded that in future, the Krapcho decarboxylation will be used to synthesise futher intermediates for natural and non-natural products. This review has not discussed all the recent examples on Krapcho decarboxylation but it is worthwhile considering the articles [24][25][26] which describe the application of Krapcho decarboxylation. We hope that the present review will attract the attention of the readers who are actively engaged in organic synthesis, especially of natural products.…”

Discovery and resupply of pharmacologically active plant-derived natural products: A review

“…Yet, these synthetic endeavors are not reflected in the broad industrial manufacture of natural products. There is at least one total synthesis for each of the plant-derived natural products approved for therapeutic use in the last thirty years, presented in Table 1, with exemplary syntheses of (+)-artemisinin (Zhu and Cook, 2012), (+)-arglabin (Kalidindi et al, 2007), (−)-cannabidiol (Petrzilka et al, 1969), capsaicin (Kaga et al, 1989), (−)-colchicine (Lee et al, 1998), dronabinol ((−)-Δ 9 -trans-tetrahydrocannabinol (THC); (Trost and Dogra, 2007)), (+)-ingenol (as described in greater detail in the next paragraphs, ingenol is chemically converted to ingenol mebutate for therapeutic supply; (Liang et al, 2012)), masoprocol (meso-nordihydroguaiaretic acid; (Gezginci and Timmermann, 2001)), omacetaxine mepesuccinate ((−)-homoharringtonine; (Eckelbarger et al, 2008)), (−)-paclitaxel (Nicolaou et al, 1994), and (−)-solamargine (Wei et al, 2011a). Also found in this list is (−)-galanthamine, which is particularly notable because it is a rather complex plant-derived compound for which an entirely chemical industrial-scale production process exists (as described in detail in the next paragraphs).…”