RESUMO
Herein, we disclosed the asymmetric construction of an oxa-quaternary stereocenter via an intramolecular oxa-Michael (IOM) reaction in ß-substituted ortho-hydroxymethyl chalcone by the formation of 1,1-disubstituted-1,3-dihydroisobenzofuran using cinchona alkaloid-based chiral amino-squaramide catalyst. Both the (E- and Z)-ß-substituted ortho-hydroxymethyl chalcone provide (S)- and (R)-enantiomers of the 1,1-disubstituted-1,3-dihydroisobenzofuran with excellent stereospecificity. In general, excellent yields (up to 95 %) and enantioselectivity (up to 98 % ee) were obtained. Furthermore, the resulting 1,1-disubstituted isobenzofuran or phthalan was converted to corresponding chiral 3,3-disubstituted phthalides without losing the enantioselectivity. This methodology provides the core moiety of the (S)-citalopram drug.
RESUMO
A unified strategy has been developed to utilize hydrazine hydrate in asymmetric organic synthesis by overcoming the rapid background reaction with dienone. The H-bond donor ability of the cinchona-alkaloid-derived squaramide catalyst unlocks this previously deemed infeasibility. The dissymmetric hydrazine addition to symmetrical dienones tolerates various substitutions, resulting in the formation of optically pure fused pyrazoline derivatives under mild reaction conditions. Furthermore, the scalability of this methodology and a successful demonstration of postsynthetic transformations have been accomplished.