We report the first crystallization-induced diastereomer transformations (CIDTs) of donor-acceptor (D-A) cyclopropanes, providing access to important chiral nonracemic building blocks for stereospecific and stereoselective transformations. Lewis acids rapidly epimerize aniline-substituted D-A cyclopropanes through reversible C-C bond cleavage. Formation of the conjugate acid anilinium salt concurrently slows epimerization and enhances the crystallinity of the cyclopropanes. We present the first example of a temperature-dependent switchable stereoselective crystallization, which enables isolation of either diastereomer with high yield and diastereoenrichment. As a complement to the Lewis acid activation paradigm, solvent-promoted epimerization is demonstrated to enable a spontaneous CIDT of an aniline-substituted D-A cyclopropane in the absence of a Lewis acid. In both approaches, products can be isolated by direct filtration of the reaction mixture without the need for further purification. The latter approach was demonstrated on a multidecagram scale. Through manipulation of the aniline and ester functional handles, this method enables access to diastereo- and enantiopure cyclopropanes and derivatives thereof.
Clarkson et al. (Wed,) studied this question.