School of Chemistry, Gate 2 High Street, Dalton 219, University of New South Wales, Sydney, NSW 2052, Australia.
J Org Chem. 2012 Dec 7;77(23):10596-616. doi: 10.1021/jo3017499. Epub 2012 Nov 16.
We report the first synthesis of sanguinamide B analogues. Substituting N-methylated (N-Me) amino acids, glycine (Gly), and L- or D-phenylalanine (Phe) into the backbone of sanguinamide B showed that only l- and d-Phe residues controlled the macrocycle conformation. The N-methylated and glycine analogues all had multiple conformations, whereas the L- and D-Phe derivatives only had a single conformation. Testing of all conformer analogues showed that inclusion of an L- or D-Phe was a superior design element than incorporating the N-Me moiety that is often utilized to control macrocyclic conformation. Finally, we show that there is an ideal Phe residue (in this case L-Phe) for generating compounds that have the greatest inhibitory effect on bacterial motility. Our data support the hypothesis that the macrocyclic conformation is dictated by the benzyl moiety requiring a "pseudoequatorial" position, and all other energy considerations are secondary.
我们首次合成了血根碱 B 类似物。在血根碱 B 的骨架中取代 N-甲基化（N-Me）氨基酸、甘氨酸（Gly）和 L-或 D-苯丙氨酸（Phe），结果表明只有 L-和 D-Phe 残基控制着大环构象。N-甲基化和甘氨酸类似物都有多种构象，而 L-和 D-Phe 衍生物只有一种构象。对所有构象类似物的测试表明，包含 L-或 D-Phe 是优于引入 N-Me 部分的设计元素，后者常用于控制大环构象。最后，我们表明存在一个理想的 Phe 残基（在这种情况下是 L-Phe），用于生成对细菌运动具有最大抑制作用的化合物。我们的数据支持这样一种假设，即大环构象由苄基部分决定，需要处于“假赤道”位置，而所有其他能量因素都是次要的。
