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Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

ABSTRACT: The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1'-bi-2,2'-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9'-bianthracenyl-based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2-bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4-ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.

SUBMITTER: Dauvergne G

PROVIDER: S-EPMC10087792 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

Dauvergne Guillaume G Naubron Jean-Valère JV Giorgi Michel M Bugaut Xavier X Rodriguez Jean J Carissan Yannick Y Coquerel Yoann Y

Chemistry (Weinheim an der Bergstrasse, Germany) 20220929 68

The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1'-bi-2,2'-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9'-bianthracenyl-based atropisomers could be prepared enantiospecifically ...[more]

PMID: 35943888

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Project description:Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB1 and CB2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC50 (a measure of potency) and Emax (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB2 receptor than at the CB1 receptor and (S)-enantiomers had an enhanced potency to both receptors over the (R)-enantiomers. The relative potency of the enantiomers to the CB2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of (R)-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials (n = 16), found 5F-MDMB-PINACA (<1.0-91.5 mg/g herbal material) and AMB-FUBINACA (15.5-58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the (S)-enantiomer predominated in all samples (93.6-99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the "intrinsic" potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.

Dataset Information

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

Publications

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

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