Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
Org Lett. 2022 Jun 3;24(21):3867-3871. doi: 10.1021/acs.orglett.2c01436. Epub 2022 May 19.
Chiral γ-branched aliphatic amines are present in a large number of pharmaceuticals and natural products. However, enantioselective methods to access these compounds are scarce and mainly rely on the use of designed chiral transition-metal complexes. Herein, we combined an organocatalytic method for the stereospecific isomerization of chiral allylic amines with a diastereoselective reduction of the chiral imine/enamine intermediates, leading to γ-trifluoromethylated aliphatic amines with two noncontiguous stereogenic centers, in excellent yields and high diastereo- and enantioselectivities. This approach has been used with primary amine substrates. This approach also provides a new synthetic pathway to chiral trifluoromethylated scaffolds, of importance in medicinal chemistry. Additionally, a gram-scale reaction demonstrates the applicability of this synthetic procedure.
手性γ-支链脂肪族胺大量存在于许多药物和天然产物中。然而，获得这些化合物的对映选择性方法很少，主要依赖于设计的手性过渡金属配合物的使用。在此，我们将手性烯丙基胺的立体特异性异构化的有机催化方法与手性亚胺/烯胺中间体的非对映选择性还原相结合，在手性三氟甲基化脂肪族胺中以优异的收率和高非对映选择性和对映选择性得到了两个非连续的手性中心。这种方法已用于伯胺底物。该方法还为手性三氟甲基化支架提供了新的合成途径，在手性药物化学中具有重要意义。此外，克级反应证明了该合成方法的适用性。
