One-Pot Total Synthesis of Cannabinol via Iodine-Mediated Deconstructive Annulation

Caprioglio, Diego; Mattoteia, Daiana; Minassi, Alberto; Pollastro, Federica; Lopatriello, Annalisa; Muñóz, Eduardo; Taglialatela‐Scafati, Orazio; Appendino, Giovanni

doi:10.1021/acs.orglett.9b02258

Cited by 31 publications

(33 citation statements)

References 33 publications

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“…Thus, the reaction using water with or without the presence of SDS and NH 4 Cl led to the exclusive formation of ortho -THC derivatives ( 9 – 10 ) 12 ( Table 2 , entries 1–3), whereas the reaction performed in toluene originated the CBC analogue 11 . 13 The only difference with respect to the use of orcinol was that now the presence of additives such as NH 4 Cl or the surfactant sodium dodecyl sulfate (SDS) improved the efficiency of the corresponding reactions increasing the final yield to 30% in the presence of the former and an increase of 10% in the presence of the latter. The lower polarity of orcinol can be argued to rationalize these results.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

et al. 2021

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We have proven that the biomimetic-like synthesis of cannabinoids from citral and the corresponding phenolic counterpart may well be carried out using water as a solvent. The influence of different additives such as surfactants was also analyzed. Rationalization of the reaction mode and regiochemistry of the processes were provided in terms of “on water” and “in water” reactions. The same reactions were conducted in organic media using Ga(III) salts as catalysts. Worthy of being underlined, an unprecedented formal [2+2+2] process was found to occur between two citral molecules and the corresponding phenolic species in both aqueous and organic environments. Computational studies were performed in order to gain a comprehensive mechanistic and energetic understanding of the different steps of this singular process. Finally, the influence of SDS micelles in the chemical behavior of olivetol and citral was also pursued using PGSE diffusion and NOESY NMR studies. These data permitted to tentatively propose the existence of a mixed micelle between olivetol and SDS assemblies.

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Section: Resultsmentioning

confidence: 99%

“…The organic layer was dried with Na 2 SO 4 and concentrated under a vacuum. Purification with silica gel chromatography yielded 68% of 11 ( 13 ) as a colorless oil (H/MTBE, 5:1) (93 mg, 0.36 mmol).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

et al. 2021

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“…The molecules in the 1 -series (see Figure 2 ) were previously reported [ 44 , 45 ], and were used as the starting material to prepare the compounds from the 2 -, 3 -, 4 - and 5 -series, containing a 1′-aldehyde, 1′-methyl ketone, 3-methylbutanoic acid ester, and 9-methyl functionalities, respectively (see Figure 2 ). Compound 5f (cannabinol) and its analogue 5e were obtained through iodine-mediated deconstructive annulation in a one-pot synthesis, using citral and resorcinol analogues as the starting material [ 46 ]. In total, 12 molecules were prepared and assayed in vitro against T. cruzi epimastigotes, as well as L. braziliensis and L. amazonensis promastigotes (see Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

SARs for the Antiparasitic Plant Metabolite Pulchrol. 3. Combinations of New Substituents in A/B-Rings and A/C-Rings

et al. 2021

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The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.

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“…Cannabichromene (CBC, 15a ) shows a remarkable reactivity associated to valence tautomerism. [ 17 ] Thus, the regiochemistry of the oxidation could be the result of this tautomeric manifold, declined in terms of a) electrocyclic opening of the o ‐quinone chromene ring to an alkylidientrione, b) re‐aromatizative isomerization of the proximal olefin double bond, and, c) eventual electrocyclization on the α‐dicarbonyl system to a p ‐quinone (Scheme 4). This mechanistic rationale was backed up by the formation of a mixture of the o ‐quinone 17 and p ‐quinone 16c from the oxidation of 15c , the bis‐prenylogue analogue of 15b .…”

Section: Resultsmentioning

confidence: 99%

Regiodivergent Synthesis of ortho‐ and para‐Cannabinoquinones

et al. 2020

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Spurred by the remarkable biological profile of cannabinoquinoids, we have systematically investigated the periodinane oxidation of their resorcinolic precursors, discovering that the regiochemistry of oxidation, a critical maneuver for bioactivity, depends not only on the nature of the oxidant (λ3‐ vs. λ5‐iodanes), but also on post‐oxidative prototropic‐ and valence tautomeric equilibria that isomerize ortho‐quinones to para‐quinones. By complementary selection of the periodinane oxidant and by freezing prototropic equilibration with O‐methylation, isomeric ortho‐ and para‐quinones could be obtained from mono‐ and diphenolic cannabinoids, setting the stage for the exploration of novel areas of the biological space, and establishing a blueprint for the extension of this strategy to other classes of bioactive alkylresorcinols.

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One-Pot Total Synthesis of Cannabinol via Iodine-Mediated Deconstructive Annulation

Cited by 31 publications

References 33 publications

Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

SARs for the Antiparasitic Plant Metabolite Pulchrol. 3. Combinations of New Substituents in A/B-Rings and A/C-Rings

Regiodivergent Synthesis of ortho‐ and para‐Cannabinoquinones

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