Abstract
Highly functionalized spirocyclic ketals were synthesized through asymmetric oxidative spirocyclization via carbanion-induced ring transformation of 2H-pyran-2-ones with 1,4-cyclohexandione monoethyleneketal under alkaline conditions. Further acidic-hydrolysis of obtained spirocyclic ketals yields highly substituted 2-tetralone in good yield. Computational analysis based on the DFT calculations and MD simulations has been performed in order to predict and understand global and local reactivity properties of newly synthesized derivatives. DFT calculations covered fundamental reactivity descriptors such as molecular electrostatic potential and average local ionization energies. Nitrogen atom and benzene rings have been recognized as the most important molecular sites from these aspects. Additionally, to predict whether studied compounds are stable towards the autoxidation mechanism, we have also studied the bond dissociation energies for hydrogen abstraction and identified the derivative which might form potentially genotoxic impurities. Interactions with water, including both global and local aspects, have been covered thanks to the MD simulations and calculations of interaction energies with water, counting of formed hydrogen interactions, and radial distribution functions. MD simulations were also used to identify which excipient could be used together with these compounds, and it has been established that the polyvinylpyrrolidone polymer could be highly compatible with these compounds, from the aspect of calculated solubility parameters.
Highlights
A well-known aromatic bicyclic ketone derived from tetralin, 2-Tetralone, has been identified as an essential intermediate for the synthesis of natural products and biologically valuable compounds [1,2,3,4]
Using 2H-pyran-2-ones 5 as synthons, we recently reported synthesis of highly functionalized spirocyclic ketals 7 through carbanion-induced ring transformation of 2H-pyran-2-ones 5 with 1,4-cyclohexanedione monoethylene ketone under ultrasound irradiation condition [52]
The studied molecules are relatively large, it has been observed that all of them have only 2–4 atoms with radial distribution functions (RDF) worth of mentioning when the size and profile of g(r) curves are taken into account
Summary
A well-known aromatic bicyclic ketone derived from tetralin, 2-Tetralone, has been identified as an essential intermediate for the synthesis of natural products and biologically valuable compounds [1,2,3,4]. Idarubicine, an antileukemic glycoside [14], and (±) daunomycinone [15], a potent antibiotic with anticancer activity, are tetralin-cored drug molecules derived from 2-tetralones. Another interesting drug molecule, Nepinalone, synthesized by reacting 1-methyl-2-tetralone with 1-N-(2-chloroethyl)piperidine, is a compound exhibiting antitussive activity [16]. Rotigotine is as a dopamine agonist used in the treatment of Parkinson’s disease [17] while treprostinil is used to treat pulmonary hypertension [18] Compounds of this type are potential candidates for the development of drug molecules for the treatment of different diseases related to the central nervous system (CNS). In view of the above important facts, a number of organic chemists are actively engaged in the asymmetric synthesis of spirocyclic skeletons having cyclohexane, cyclohexene, and cyclohexanone motifs
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