The synthesis of chiral -monosubstituted-ß-dicarbonyls is a challenging task in asymmetric catalysis due to the rapid, typically uncontrolled, product racemization or epimerization under most reaction conditions. For this reason, diastereoselective additions of unsubstituted ß-dicarbonyls to -electrophiles are unusual. Herein, we disclose a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined -monosubstituted-ß-keto esters, dissymmetric ß-diesters, dissymmetric ß-diketones, and ß-keto amides that productively leverages product epimerization in solution. Mechanistic studies suggest a scenario where the initial enantioselective, diastereodivergent skeletal assembly is catalyzed by a chiral tertiary amine organocatalyst, which then facilitates second stage crystallization-induced diastereoconvergence to provide the challenging -stereocenter in excellent stereoselectivity.
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| http://dx.doi.org/10.1021/acscatal.3c01515 | DOI Listing |
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