The spiroisoxazolidinyl-benzoisothiazoline derivatives were synthesized through a highly diastereoselective 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes with nitrones. The regiochemistry of cycloaddition was assigned on the 1H NMR chemical shift of methane-H in 3 and 5. The relative stereochemistry of cycloadducts was determined from the single-crystal X-ray crystallography.Download high-res image (177KB)Download full-size image

A facile synthesis of 1′,4′-dihydro-2′H-spiro[azetidin-2,3′-quinolin]-2′-one is described. Synthetic highlights include simultaneous construction of azetidine ring by intramolecular alkylation and formation of spirocarbon center in excellent yield plus removal of p-methoxybenzyl (PMB) amide protective group in mild condition with good yield.

A straightforward synthesis of 3,4,5-trisubstituted isoxazole derivatives via 1,3-dipolar cycloaddtion/SO2 extrusion of benzoisothiazole-2,2-dioxide-3-ylidenes with nitrile oxides is reported using 4 Å molecular sieves as a dehydrochlorinating agent. This tandem ring closing/ring opening synthesis of 3,4,5-trisubstituted isoxazoles is the first of its kind. This methodology would enrich the synthetic chemistry of isoxazoles from easily available starting materials and benefit the discovery of novel isoxazoles with potential biological activities.

An improved and scalable process for substituted 3,8-diazabicyclo[3.2.1]octane was developed. N-Benzyl-2,5-dicarbethoxy-pyrrolidine 2 was reduced to N-benzyl-2,5-dihydroxymethylpyrrolidine 9 and subsequently debenzylated to afford N-Boc-2,5-dihydroxymethylpyrrolidine 10. After mesylation of the diol 10 and cyclization with benzylamine, a diversity of scaffold, 3,8-diazabicyclo[3.2.1]octane analogue 12 was obtained in a total yield of 42% in five steps.

A new synthesis of spirocyclic oxindole analogue spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one 1 is described. The key steps involve dialkylation of arylacetonitrile and cyclization of the azaoxindole ring by an intramolecular Buchwald–Hartwig amidation of carboxylic amide and aryl chloride. A small library was obtained by reductive amination of 1 with various aldehydes and was screened against human lung cancer cell A549, human liver cancer cell BEL7402, and human colon cancer cell HCT-8. The results show that most of the library compounds 2 have some inhibitory activities. 2-(Trifluoromethoxy) benzylic substituted spirocyclic azaoxindole 2e was identified as a nanomolar inhibitor against human lung cancer cell A-549 (IC50 = 50 nmol/L).