Enantio- and Diastereoselective Mannich Reactions of ss-Dicarbonyls by Second Stage Diastereoconvergent Crystallization
Enantio- and Diastereoselective Mannich Reactions of ss-Dicarbonyls by Second Stage Diastereoconvergent Crystallization
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DOI：
10.1021/acscatal.3c01515
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发表时间：
2023-04-27
期刊：
影响因子：
12.9
通讯作者：
Johnson, Jeffrey S. S.
中科院分区：
文献类型：
--
作者：
Cassels, William R. R.;Crawford, Evan T. T.;Johnson, Jeffrey S. S.
由于在大多数反应条件下产物会发生快速且通常不受控制的外消旋化或差向异构化，因此手性α-单取代-β-二羰基的合成在不对称催化中是一项具有挑战性的任务。由于这个原因，未取代的β-二羰基化合物与π-亲电试剂的非对映选择性加成是不常见的。在此，我们公开了一种简单的催化结晶驱动的对映体和非对映体选择性Mannich反应，用于合成立体定向的α-单取代的β-酮酯、不对称的β-二酯、不对称的β-二酮和β-酮酰胺，其有效地利用了溶液中的产物差向异构化。机理研究表明，在手性叔胺有机催化剂的催化下，初始的对映体选择性，非对映体发散的骨架组装，然后促进第二阶段结晶诱导的非对映体会聚，以提供具有挑战性的α-立体中心，具有优异的立体选择性。
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.