Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Org Biomol Chem. 2013 Nov 14;11(42):7342-9. doi: 10.1039/c3ob41583j.
The high antiplasmodial activity of racemic benzylamines rac-1 and rac-2 stimulated the synthesis of pure enantiomers. Ellman's chiral sulfinamides (S)-6 and (R)-6 were used as chiral auxiliaries. Condensation of prochiral ketone 5 with enantiomerically pure sulfinamides (S)-6 and (R)-6 and subsequent NaBH4 reduction provided predominantly unlike configured diastereomers (S,R)-8 and (R,S)-8 (ratio unlike-8:like-8 = 90:10). The same transformation of phenol 4 led to the diastereomeric sulfinamides (S,R)-12 and (S,S)-12 in the ratio 60:40. Acid hydrolysis of the diastereomerically pure sulfinamides followed by monobenzylation yielded the enantiomerically pure benzylamines (R)-1, (S)-1, (R)-2 and (S)-2. The enantiomeric purity of the products was proven by chiral HPLC and the absolute configuration by CD-spectroscopy. Generally, benzylamines with (R)-configuration show higher antiplasmodial activity than their corresponding (S)-configured enantiomers. Phenol (R)-2 represents a very potent lead against P. falciparum, with an IC50 value of only 0.026 μM against the NF54 strain. The very high eudismic ratio of 34 indicates the enantioselective interaction of phenol (R)-2 with a particular target protein of P. falciparum.
外消旋苯甲胺 rac-1 和 rac-2 的高抗疟活性刺激了纯对映异构体的合成。埃尔曼手性亚磺酰胺 (S)-6 和 (R)-6 被用作手性助剂。将前手性酮 5 与对映体纯的亚磺酰胺 (S)-6 和 (R)-6 缩合，然后用 NaBH4 还原，主要得到构型不同的非对映异构体 (S,R)-8 和 (R,S)-8（非对映异构体 8:对映异构体 8 的比例为 90:10）。酚 4 的相同转化导致非对映异构体亚磺酰胺 (S,R)-12 和 (S,S)-12 的比例为 60:40。非对映异构体纯亚磺酰胺的酸水解，然后单苄基化，得到对映体纯的苯甲胺 (R)-1、(S)-1、(R)-2 和 (S)-2。产物的对映体纯度通过手性 HPLC 证明，绝对构型通过 CD 光谱证明。一般来说，具有 (R)-构型的苯甲胺比其相应的 (S)-构型对映异构体具有更高的抗疟活性。酚 (R)-2 对 P. falciparum 具有很强的抗药性，对 NF54 株的 IC50 值仅为 0.026 μM。非常高的外消旋比 34 表明酚 (R)-2 与 P. falciparum 特定靶蛋白的对映选择性相互作用。
