Journal
ACS CATALYSIS
Volume 13, Issue 10, Pages 6518-6524Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.3c01515
Keywords
asymmetric catalysis; crystallization-induceddiastereomertransformation; Mannich reaction; organocatalysis; stereoconvergence
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We report a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined alpha-monosubstituted-ss-ketoesters, dissymmetric ss-diesters, dissymmetric ss-diketones, and ss-keto amides. This method efficiently leverages product epimerization in solution. Mechanistic studies suggest that the initial enantioselective, diastereodivergent skeletal assembly is catalyzed by a chiral tertiary amine organocatalyst, followed by crystallization-induced diastereoconvergence to provide the challenging alpha-stereocenter in excellent stereoselectivity.
Thesynthesis of chiral alpha-monosubstituted-ss-dicarbonylsis a challenging task in asymmetric catalysis due to the rapid, typicallyuncontrolled, product racemization or epimerization under most reactionconditions. For this reason, diastereoselective additions of unsubstitutedss-dicarbonyls to pi-electrophiles are unusual. Herein, wedisclose a simple catalytic crystallization-driven enantio- and diastereoselectiveMannich reaction for the synthesis of stereodefined alpha-monosubstituted-ss-ketoesters, dissymmetric ss-diesters, dissymmetric ss-diketones,and ss-keto amides that productively leverages product epimerizationin solution. Mechanistic studies suggest a scenario where the initialenantioselective, diastereodivergent skeletal assembly is catalyzedby a chiral tertiary amine organocatalyst, which then facilitatessecond stage crystallization-induced diastereoconvergence to providethe challenging alpha-stereocenter in excellent stereoselectivity.
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