Journal
ACS CATALYSIS
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.3c015156518
Keywords
asymmetric catalysis; crystallization-induced diastereomer transformation; Mannich reaction; organocatalysis; stereoconvergence
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A simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction was disclosed for the synthesis of stereodefined alpha-monosubstituted-keto esters, dissymmetric diesters, dissymmetric diketones, and keto amides that productively leveraged product epimerization in solution. Mechanistic studies suggested that the initial enantioselective, diastereodivergent skeletal assembly was catalyzed by a chiral tertiary amine organocatalyst, which then facilitated second stage crystallization-induced diastereoconvergence to provide the challenging alpha-stereocenter in excellent stereoselectivity.
The synthesis of chiral alpha-monosubstituted-ssdicarbonyls 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 pi electrophiles are unusual. Herein, we disclose a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined alpha-monosubstituted-ssketo 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 alpha-stereocenter in excellent stereoselectivity.
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