Total Synthesis of Tosyl-Samroiyotmycin A and Its Biological Profiling

IF 3.9 2区化学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Chemistry - A European Journal Pub Date : 2024-09-30 DOI:10.1002/chem.202403408

Benedikt Kolb, Fabian Schmid, Jessica Weng, Luca Altevogt, Ruben Pereira Rebelo, Bianca Wank, Angelika Baro, Anna Zens, Aditya Shekhar, Ursula Bilitewski, Sibylle Sax, Sergio Wittlin, Dale Taylor, Rudolf Müller, Sabine Laschat

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Abstract

A total synthesis of the enantiopure syn,syn-tosyl-samroiyotmycin A, a C₂-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.

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Tosyl-Samroiyotmycin A 的全合成及其生物学分析。

该化合物是一种 C2 对称 20 元抗疟大环内酯，具有 8,24 二羟基-9,25-二甲基单元的对映对映配置。该合成采用线性方法，通过 SuperQuat噁唑烷酮助剂的非对映选择性甲基化、交叉偏析和完全官能化的仲酸的 Yamaguchi 大内酯化等一系列步骤，在 7 个步骤中完成，总收率为 3%。通过类似的方法，我们获得了几种翅果霉素类似物和前体。我们对具有多重抗药性（K1）和敏感性（Nf54）的恶性疟原虫菌株进行了抗疟活性测试，以深入了解其结构与活性之间的关系。结果表明，甲苯磺酰噁唑单元和两个连续立体中心的同步构型都有利于提高抗疟活性。例如，合成、合成-对甲苯磺酰基-三代洋蓟素 A 的活性比 "不含对甲苯磺酰基 "的天然产物高 3.4 倍。

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来源期刊

Chemistry - A European Journal 化学-化学综合

CiteScore

7.90

自引率

4.70%

发文量

1808

审稿时长

1.8 months

期刊介绍： Chemistry—A European Journal is a truly international journal with top quality contributions (2018 ISI Impact Factor: 5.16). It publishes a wide range of outstanding Reviews, Minireviews, Concepts, Full Papers, and Communications from all areas of chemistry and related fields. Based in Europe Chemistry—A European Journal provides an excellent platform for increasing the visibility of European chemistry as well as for featuring the best research from authors from around the world. All manuscripts are peer-reviewed, and electronic processing ensures accurate reproduction of text and data, plus short publication times. The Concepts section provides nonspecialist readers with a useful conceptual guide to unfamiliar areas and experts with new angles on familiar problems. Chemistry—A European Journal is published on behalf of ChemPubSoc Europe, a group of 16 national chemical societies from within Europe, and supported by the Asian Chemical Editorial Societies. The ChemPubSoc Europe family comprises: Angewandte Chemie, Chemistry—A European Journal, European Journal of Organic Chemistry, European Journal of Inorganic Chemistry, ChemPhysChem, ChemBioChem, ChemMedChem, ChemCatChem, ChemSusChem, ChemPlusChem, ChemElectroChem, and ChemistryOpen.