An Organocatalytic Highly Enantioselective Stereospecific Synthesis of 1,1‐Disubstituted‐1,3‐Dihydroisobenzofurans

The asymmetric construction of an oxa-quaternary stereocenter via an intramolecular oxa-Michael reaction in β-substituted ortho-hydroxymethyl chalcone is being disclosed. Both the (E- and Z)-β-substituted ortho-hydroxymethyl chalcone produce (R)-enantiomers of the 1,1-disubstituted-1,3-dihydroisobenzofuran using two pseudo-enantiomeric cinchona alkaloid-based chiral amino-squaramide catalysts, demonstrating excellent stereospecificity, high yields, and enantioselectivity. The resulting phthalan can undergo conversion into corresponding phthalides followed by oxidation.

Abstract

Herein, we disclosed the asymmetric construction of an oxa-quaternary stereocenter via an intramolecular oxa-Michael (IOM) reaction in β-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)-β-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.