Organocatalytic Enantioselective Cascade Michael-Alkylation Reactions: Synthesis of Chiral Cyclopropanes and Investigation of Unexpected Organocatalyzed Stereoselective Ring Opening of Cyclopropanes

The development of efficient methods for the facile construction of important molecular
architectures is a central goal in organic synthesis. An unprecedented organocatalytic asymmetric cascade
Michael-alkylation reaction of α,β-unsaturated aldehydes with bromomalonates has been developed. The
process, efficiently catalyzed by chiral diphenylprolinol TMS ether in the presence of base 2,6-lutidine,
serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes
in high levels of enantio- and diastereoselectivities. Remarkably, the power of the cascade process is fueled
by its high efficiency of the production of two new C−C bonds, two new stereogenic centers, and one
quaternary carbon center in one single operation, which otherwise is difficult to achieve by traditional
strategies. Moreover, the beauty of the cascade process is further underscored by the nature of the product
formation depending on the reaction conditions. With the alternation of base from 2,6-lutidine (1.1 equiv),
which is effective for the cyclopropanations, to NaOAc (4.0 equiv), the spontaneous ring-opening of
cyclopropanes takes place to lead to stereoselective (E) α-substituted malonate α,β-unsaturated aldehydes.
A possible reaction mechanism, which involves a Michael-alkylation−retro-Michael pathway, is proposed
and verified by experimental studies. This investigation represents the first example of an organocatalyst-promoted ring opening of the cyclopropanes, whereas such reactions have been intensively explored by
Lewis acid-based catalysis.