Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin
Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin
复制标题
DOI：
10.1002/anie.201605167
复制
发表时间：
2016-08-26
影响因子：
16.6
通讯作者：
Song, Choong Eui
中科院分区：
文献类型：
--
作者：
Bae, Han Yong;Kim, Mun Jong;Song, Choong Eui
在这项研究中，二硫代丙二酸酯（DTMs）被证明是非常有效的曼尼希捐助者的反应性和立体选择性在金鸡纳-基于方酰胺催化的对映选择性曼尼希反应的不同亚胺或-氨基砜亚胺替代品。由于DTMs的上级反应活性优于传统的丙二酸酯，催化剂的负载量可以降低到0.1mol%，而不损害对映选择性（高达99%ee）。此外，通过使用DTM，甚至一些高度挑战性的伯烷基-酰胺基砜也以优异的对映选择性（高达97%ee）顺利地转化为所需的加合物，而使用丙二酸酯或单硫代丙二酸酯在相同条件下不导致反应。抗糖尿病药物（-）-（R）-西他列汀的有机催化、无偶联试剂合成突出了从伯烷基底物获得的手性曼尼希加合物的合成效用。
In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or -amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1mol% without the erosion of enantioselectivity (up to 99%ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl -amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97%ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.