Enantioselective Synthesis of Spiro Chroman-Isoindolinones via Formal (4+2) Cycloaddition of In Situ-Generated ortho-Quinone Methides with 3-Methylene Isoindolinones

Using chiral phosphoric acids as organocatalysts, a formal asymmetric (4+2) cycloaddition of 3-methylene isoindolinone and in situ-generated ortho-quinone methide substrates is disclosed. This reaction exhibited a broad substrate scope with various substituted cyclic enamides and ortho-hydroxybenzyl alcohol derivatives to construct a series of spiro chroman-isoindolinones containing spiro-N,O-heterocycles with 56 to 93% ee. This strategy demonstrates significant potential towards establishing a chiral spiro-N,O-aminal systems bearing two chiral carbon centers, including a tetrasubstituted carbon stereocenter.

Automated summary

Using chiral phosphoric acids as organocatalysts, a formal asymmetric (4+2) cycloaddition of 3-methylene isoindolinone and in situ-generated ortho-quinone methide substrates is achieved. This reaction allows the construction of spiro chroman-isoindolinones containing spiro-N,O-heterocycles with high enantioselectivity, with a broad substrate scope.