Using (+)-carvone to access novel derivatives of (+)-ent-cannabidiol: The first asymmetric syntheses of (+)-ent-CBDP and (+)-ent-CBDV

Golliher, Alexandra E.; Tenorio, Antonio J.; Dimauro, Nina O.; Mairata, Nicolas R.; Holguín, F. Omar; Maio, William A.

doi:10.1016/j.tetlet.2021.152891

Cited by 10 publications

(5 citation statements)

References 36 publications

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“…Each of these corresponding substituted resorcinol derivatives, 10 – 13 , were coupled with geraniol in the presence of catalytic amounts of p -toluenesulfonic acid monohydrate as shown in Scheme 2 to give the corresponding CBG analogs, 14 – 17 , in 20–30% yields [ 36 ]. The solubility of CBGV and CBG is between 25–50 mg/mL or around 80–180 mM in pure DMSO; the solubility drops by 100-fold or more when the compounds are in 25% DMSO [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain

et al. 2022

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(1) Background: Recently, a number of side chain length variants for tetrahydrocannabinol and cannabidiol have been identified in cannabis; however, the precursor to these molecules would be based upon cannabigerol (CBG). Because CBG, and its side chain variants, are rapidly converted to other cannabinoids in the plant, there are typically only small amounts in plant extracts, thus prohibiting investigations related to CBG and CBG variant therapeutic effects. (2) Methods: To overcome this, we developed an efficient synthesis of corresponding resorcinol fragments using the Wittig reaction which, under acid catalyzed coupling with geraniol, produced the desired side chain variants of CBG. These compounds were then tested in an animal model of chemotherapeutic-induced neuropathic pain and to reduce colorectal cancer cell viability. (3) Results: We found that all side-chain variants were similarly capable of reducing neuropathic pain in mice at a dose of 10 mg/kg. However, the molecules with shorter side chains (i.e., CBGV and CBGB) were better at reducing colorectal cancer cell viability. (4) Conclusions: The novel synthesis method developed here will be of utility for studying other side chain derivatives of minor cannabinoids such as cannabichromene, cannabinol, and cannabielsoin.

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Section: Resultsmentioning

confidence: 99%

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain

et al. 2022

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“…In Figure 4, we show the three-wave mixing spectrum for a mixture of terpenes. Terpenes are naturally occurring chiral building blocks that have been used for decades as starting materials for the synthesis of natural products and active ingredients in pharmaceuticals, due to their abundance and low cost [34][35][36]. All transitions in Figure 4 belong to enantiopure (-)-β-pinene, (R)-fenchone, and (R)-carvone.…”

Section: Resultsmentioning

confidence: 99%

Assignment-free chirality detection in unknown samples via microwave three-wave mixing

Koumarianou

Wang

Satterhwaite

et al. 2021

Preprint

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Straightforward identification of chiral molecules in multi-component mixtures of unknown composition is extremely challenging. Current spectrometric and chromatographic methods cannot unambiguously identify components while the state of the art spectroscopic methods are limited by the difficult and time-consuming task of spectral assignment. Here, we introduce a highly sensitive generalized version of microwave three-wave mixing that uses broad-spectrum fields to detect chiral molecules in enantiomeric excess without any prior chemical knowledge of the sample. This method does not require spectral assignment as a necessary step to extract information out of a spectrum. We demonstrate our method by recording three-wave mixing spectra of multi-component samples that provide direct evidence of enantiomeric excess. Our method opens up new capabilities in ultrasensitive phase-coherent spectroscopic detection that can be applied for chiral detection in real-life mixtures, raw products of chemical reactions and difficult to assign novel exotic species.

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“…Matched literature data. , R f = 0.468 [hexanes:Et 2 O (4:1)]; [a] D 20 +74.9 ( c 0.810, CHCl 3 ); 1 H NMR (500 MHz, chloroform- d ) δ 6.41–6.08 (m, 2H), 5.97 (s, 1H), 5.57 (dt, J = 2.9, 1.6 Hz, 1H), 4.66 (p, J = 1.6 Hz, 1H), 4.56 (d, J = 2.0 Hz, 1H), 3.90–3.80 (m, 1H), 2.49–2.33 (m, 3H), 2.32–2.17 (m, 1H), 2.10 (ddt, J = 17.8, 5.0, 2.4 Hz, 1H), 1.90–1.70 (m, 6H), 1.66 (t, J = 1.1 Hz, 3H), 1.56 (p, J = 7.6 Hz, 2H), 1.41–1.18 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13 C NMR (126 MHz, chloroform- d ) δ 154.1, 149.5, 143.2, 140.2, 124.3, 113.9, 110.9, 108.2, 46.3, 37.4, 35.6, 31.7, 30.8, 30.6, 28.6, 23.8, 22.7, 20.7, 14.2; TOF-MS (EI+) m / z [M] + calculated for C 21 H 30 O 2 (M) + 314.2240, found 314.2242.…”

Section: Methodsmentioning

confidence: 92%

Structure–Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor

Bosquez-Berger,

Gudorf,

Kuntz

et al. 2023

J. Med. Chem.

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The US faces an unprecedented surge in fatal drug overdoses. Naloxone, the only antidote for opiate overdose, competes at the mu opioid receptor (μOR) orthosteric site. Naloxone struggles against fentanyl-class synthetic opioids that now cause ∼80% of deaths. Negative allosteric modulators (NAMs) targeting secondary sites may noncompetitively downregulate μOR activation. (−)-Cannabidiol ((−)-CBD) is a candidate μOR NAM. To explore its therapeutic potential, we evaluated the structure–activity relationships among CBD analogs to identify NAMs with increased potency. Using a cyclic AMP assay, we characterize reversal of μOR activation by 15 CBD analogs, several of which proved more potent than (−)-CBD. Comparative docking investigations suggest that potent compounds interact with a putative allosteric pocket to stabilize the inactive μOR conformation. Finally, these compounds enhance naloxone displacement of fentanyl from the orthosteric site. Our results suggest that CBD analogs offer considerable potential for the development of next-generation antidotes for opioid overdose.

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Using (+)-carvone to access novel derivatives of (+)-ent-cannabidiol: The first asymmetric syntheses of (+)-ent-CBDP and (+)-ent-CBDV

Cited by 10 publications

References 36 publications

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain

Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain

Assignment-free chirality detection in unknown samples via microwave three-wave mixing

Structure–Activity Relationship Study of Cannabidiol-Based Analogs as Negative Allosteric Modulators of the μ-Opioid Receptor

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