Construction Of Spiroannulated Compounds Based On β-Oxo-Thioamide Derivatives

Spiroannulated compounds attract a large number of medical and chemical researchers’ attention for their special place as building blocks in natural products, pharmaceutical agents and materials. Especially optically active and sulfer-containng polyfunctionalized compounds are of considerable interest as they possess a wide range of biological properties. This paper provides two methods about the synthesis of enantioselectivities polyfunctional sulfur-containing spiroannulated compounds based on β-oxo-thioamide derivatives:(1) Enantioselective construction of polyfunctionalized spiroannulated dihydrothiophenes via a formal thio[3+2]cyclization; (2) Enantioselective organocatalytic construction of ring-fused spiroannulated 1,2,3-thiadiazole derivatives. These two methos build the sulfur-containing spiroannulated structure via reversal of standard functional group polarity or umpolung of intermediates successfully. The reversal of standard functional group polarity or umpolung have opened up an novel avenue to a new set of sulfur-containing spiroannulated.Polyfunctionalized spiroannulated dihydrothiophenes have very great medicinal potential. We have successfully demonstrated an efficient and highly enantioselective thio[3+2]-cyclizations of thioamide derivatives to (E)-α-nitrostyrenes to afford the chiral polyfunctionalized spiroannulated dihydrothiophene with excellent regio-, chemo-, diastereo- and enantioselectivities (up to 94% ee, up to 99:1 dr) and high yield (up to 88%). Takemoto’s organocatalyst was used to be the chiral catalyst which can control the stereo configuration of products. The key step of the reaction is Michael addition and int- ramolecular oxidative umpolung of intermediate. The reaction is broader substrate scope, and we made certain the absolute configuration of the dihydrothiophene compound by the single-crystal X-ray analysis.Umpolong is a well known reversal of expected chemical reactivity and has been proven to be a powerful strategy in chemistry that facilitates the construction of organic molecules in unusual ways. We report, for the first time, an organocatalytic domino α-amination/oxidative umpolung/cyclization of β-oxo-thioamides to azodicarboxylates and its direct application in an atom-economic synthesis of chiral spirol,2,3-thiadiazole derivatives. The asymmetric reaction is smoothly effected by using simple and green oxygen as the oxidant as well as using NBS. This versatile, atom-economic and environmentally friendly domino α-amination/oxidation Umpolung/cyclization affords chiral spiroannulated 1,2,3-thiadiazoles in high yields(up to 94%) and enantioselectivities (up to 98% ee) in the presence of an easily available organic catalyst demethylated quinine for the first time. Notably, the asymmetric synthesis of chiral spiroannulated 1,2,3-thiadiazoles can be fulfilled on a gram-scale (>4 g) without any decrease in yield or enantioselectivity at low cost, and enantiopure products could be obtained by a single recrystallization.