A number of new chiral bispidines containing monoterpenoid fragments have been obtained. The bispidines were studied as ligands for Ni-catalyzed addition of diethylzinc to chalcones. The conditions for chromatographic analysis by HPLC-UV were developed, in which the peaks of the enantiomers of all synthesized chiral products were separated, which made it possible to determine the enantiomeric excess of the resulting mixture. It was demonstrated that bispidine-monoterpenoid conjugates can be used as the ligands for diethylzinc addition to chalcone C=C double bond but not as inducers of chirality. Besides products of ethylation, formation of products of formal hydrogenation of the chalcone C=C double bond was observed in all cases. Note, that this formation of hydrogenation products in significant amounts in the presence of such catalytic systems was found for the first time. A tentative scheme explaining the formation of all products was proposed.

Monoterpenes and their derivatives are important starting compounds in the design of new biologically active substances. In particular, cineole, isolated from eucalyptus essential oil, exhibits a wide range of biological activities. Here, the synthesis of new heterocyclic compounds containing a cineole fragment by the acid-catalyzed condensation of α-pinene-derived 8-hydroxy-6-hydroxymethyllimonene with monoterpene aldehydes was carried out for the first time. The reactions of 8-hydroxy-6-hydroxymethyllimonene with cuminaldehyde, perillylaldehyde, myrtenal, citral, and geranial were studied in the presence of heterogeneous K10 clay or Lewis acid BF₃·Et₂O. The main products of these reactions were compounds with the methanopyrano[4,3-b]pyran scaffold having a 1,8-cineole fragment. As a result of this work, five new compounds with the methanopyrano[4,3-b]pyran scaffold were synthesized. The use of BF₃·Et₂O led to an increase in the yields of target products, compared with the results obtained on K10 clay.

Monoterpenes, which have a unique diverse structure and are inexpensive, available and often enantiomerically pure, are an attractive renewable raw material for the development of physiologically active agents. One of the most important methods for the utilization of monoterpenes is their interaction with carbonyl compounds, which produces heterocyclic compounds. Often these products exhibit analgesic, antiviral or neuroprotective properties. Earlier, we discovered the anti-influenza A (H1N1) virus activity of several compounds with a hydro-2H-chromene scaffold, which were synthesized by the Prins reaction using p-menthane alcohols and carbonyl compounds; montmorillonite K10 or nanosized halloysite catalyst were used as the reaction catalysts [1]. Chromenols produced from an (–)-isopulegol and aliphatic ketones (acetone and cyclopentanone) demonstrated a high activity combined with a low toxicity against the influenza virus [1]. The introduction of the fluorine atom into the molecule is an important strategy in the development of new biologically active compounds, enabling lipophilicity and electrostatic interactions to change and increasing the metabolic stability of compounds, which affects their physiological activity. Here, we synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from an (–)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF₃∙Et₂O/H₂O system, acting as both an acid catalyst and a fluorine source. The activity of the synthesized compounds against the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- and hydroxy-containing 2,4,6-trimethoxybenzaldehyde derivatives. These compounds were supposed to be capable of binding to viral hemagglutinin, which is an agreement with data on the effect of compounds on viral fusogenic activity, as well as with molecular docking studies.

A large series of new chiral heterocyclic cineol-like methanopyrano[4,3-b]pyrans was prepared by reactions of the (+)- and (–)-isomers of 8-hydroxy-6-hydroxymethyllimonene, obtained from the corresponding α-pinenes with high optical purity, and aromatic aldehydes with OH and/or OMe substituents. The synthesized heterocycles were tested for analgesic activity in the in vivo tests. Some of cineol-like methanopyrano[4,3-b]pyrans synthesized from 4-methoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde and 2,4,5-trimethoxybenzaldehyde exhibit significant analgesic activity. Experiments in vivo with agonists and antagonists of several neurotransmitter systems helped to elucidate the probable mechanism of analgesic action mediated by these compounds. Thus, cannabinoid CB1 receptors do not appear to be involved in the development of the analgesic effect. Opioid and GABA_A receptors of the central nervous system likely play a significant role in the analgesic activity of the tested cineol-like methanopyrano[4,3-b]pyrans. (3R,4aR,5R,8S,8aS)-5-(4-Methoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran likely mediates its analgesic effect through both muscarinic and adrenergic receptors of the central nervous system. Serotonin receptors may be involved into the mechanism of analgesic action of (3R,4aR,5R,8S,8aS)-5-(2,3,4-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran and (3R,4aR,5R,8S,8aS)-5-(2,4,5-trimethoxyphenyl)-2,2,8a-trimethylhexahydro-2H,5H-3,8-methanopyrano[4,3-b]pyran.