Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary.
Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Eötvös utca 6, Hungary.
Int J Mol Sci. 2017 Dec 28;19(1):81. 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.
从 (-)-2-蒈烯-3-甲醛和市售的 (-)-桃金娘烯醛氧化得到的α,β-不饱和羧酸出发，完成了单萜基 1,2,4-和 1,3,4-噁二唑衍生物的立体选择性合成。1,2,4-噁二唑通过相应的酰基羟胺中间体两步制备，然后在温和的反应条件下，四丁基氟化铵（TBAF）诱导环化。用 OsO₄/NMO（-甲基吗啉 -N-氧化物）体系进行高度立体特异性反应的立体选择性二羟化，生成α,β-二羟基 1,2,4-噁二唑。同样，从酸与酰肼偶联，然后用 POCl₃介导脱水环合，得到来自蒎烷的 1,3,4-噁二唑。在芳环对应的情况下，在相同条件下，受约束的蒈烷系统发生重排，失去手性。用 OsO₄/NMO 进行立体选择性二羟化，生成α,β-二羟基 1,3,4-噁二唑。制备的二醇被用作手性催化剂，用于在醛的二乙基锌对映选择性加成反应中。通过 MTT 测定法，用 -酰化羟肟中间体对四种恶性人贴壁细胞系进行了体外抗增殖活性筛选，所有化合物均显示出显著的抗增殖作用。
