Stereoselective Synthesis, Synthetic and Pharmacological Application of Monoterpene-Based 1,2,4- and 1,3,4-Oxadiazoles

• Published in: International journal of molecular sciences 2017-12, Vol.19 (1), p.81
• Main Authors: Gonda, Tímea, Bérdi, Péter, Zupkó, István, Fülöp, Ferenc, Szakonyi, Zsolt
• Format: Article
• Language: English
• Subjects: Acids; Aldehydes; Aldehydes - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Carboxylic acids; Carboxylic Acids - chemistry; Catalysts; Cell Line, Tumor; Cell lines; Chemistry Techniques, Synthetic; Chirality; Cyclization; Dehydration; Diols; Enantiomers; Fluorides; Humans; Hydrazines; Hydrazines - chemistry; Hydroxylation; Inhibitory Concentration 50; Intermediates; Ligands; Monoterpenes - chemistry; NMR; Nuclear magnetic resonance; Oxadiazoles; Oxadiazoles - chemical synthesis; Oxadiazoles - pharmacology; Oxidation; Oxidation-Reduction; Pharmacology; Quaternary Ammonium Compounds - chemistry; Stereoisomerism; Stereoselectivity; Structure-Activity Relationship; Terpenes - chemistry
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19010081

Stereoselective synthesis of monoterpene-based 1,2,4- and 1,3,4-oxadiazole derivatives was accomplished starting from α,β-unsaturated carboxylic acids, obtained by the oxidation of (-)-2-carene-3-aldehyde and commercially available (-)-myrtenal. 1,2,4-Oxadiazoles were prepared in two steps via the corresponding -acylamidoxime intermediates, which then underwent cyclisation induced by tetrabutylammonium fluoride (TBAF) under mild reaction conditions. Stereoselective dihydroxylation in highly stereospecific reactions with the OsO₄/NMO ( -methylmorpholine -oxide) system produced α,β-dihydroxy 1,2,4-oxadiazoles. Pinane-based 1,3,4-oxadiazoles were obtained similarly from acids by coupling with acyl hydrazines followed by POCl₃-mediated dehydrative ring closure. In the case of the arane counterpart, the rearrangement of the constrained carane system occurred with the loss of chirality under the same conditions. Stereoselective dihydroxylation with OsO₄/NMO produced α,β-dihydroxy 1,3,4-oxadiazoles. The prepared diols were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. All compounds were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines by means of the MTT assay with the -acylated amidoxime intermediates exerting remarkable antiproliferative action.