Kolb Benedikt, Schmid Fabian, Weng Jessica, Altevogt Luca, Pereira Rebelo Ruben, Wank Bianca, Baro Angelika, Zens Anna, Shekhar Aditya, Bilitewski Ursula, Sax Sibylle, Wittlin Sergio, Taylor Dale, Müller Rudolf, Laschat Sabine
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569, Stuttgart, Germany.
AG Compound Profiling and Screening, Helmholtz Zentrum für Infektionsforschung, Inhoffenstr. 7, D-38124, Braunschweig, Germany.
Chemistry. 2024 Dec 18;30(71):e202403408. doi: 10.1002/chem.202403408. Epub 2024 Nov 12.
A total synthesis of the enantiopure syn,syn-tosyl-samroiyotmycin A, a C-symmetric 20-membered antimalarial macrodiolide with syn,syn-configuration of the 8,24-dihydroxy-9,25-dimethyl units and it's enantiopure anti,anti-derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield via a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized seco-acids. By a similar approach we gained access to several samroiyotmycin analogues and precursors. Antimalarial activity was tested on multi-resistant (K1) and sensitive (Nf54) P. falciparum strains providing insight into structure activity relationships. Both tosyl-oxazol unit as well as the syn-configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, syn,syn-tosyl-samroiyotmycin A showed 3.4 times higher activities than the "tosyl-free" natural product.
描述了对映体纯的顺式、顺式-甲苯磺酰基-桑罗伊霉素A的全合成，它是一种具有C对称性的20元抗疟大环二内酯，其8,24-二羟基-9,25-二甲基单元具有顺式、顺式构型，以及其对映体纯的反式、反式衍生物。该合成通过线性方法，经超季铵恶唑烷酮辅助剂的非对映选择性甲基化、交叉复分解和全功能化开链酸的山口大环内酯化序列，以7步反应和3%的总收率完成。通过类似方法，我们获得了几种桑罗伊霉素类似物和前体。在多重耐药（K1）和敏感（Nf54）恶性疟原虫菌株上测试了抗疟活性，从而深入了解构效关系。结果表明，甲苯磺酰-恶唑单元以及两个相邻立体中心的顺式构型对抗疟活性均有益。例如，顺式、顺式-甲苯磺酰基-桑罗伊霉素A的活性比“无甲苯磺酰基”的天然产物高3.4倍。
