{"title":"Tosyl-Samroiyotmycin A 的全合成及其生物学分析。","authors":"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","doi":"10.1002/chem.202403408","DOIUrl":null,"url":null,"abstract":"<p>A total synthesis of the enantiopure <i>syn,syn-</i>tosyl-samroiyotmycin A, a C<sub>2</sub>-symmetric 20-membered antimalarial macrodiolide with <i>syn,syn-</i>configuration of the 8,24-dihydroxy-9,25-dimethyl units and it's enantiopure <i>anti,anti-</i>derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield <i>via</i> a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized <i>seco</i>-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) <i>P. falciparum</i> strains providing insight into structure activity relationships. Both tosyl-oxazol unit as well as the <i>syn</i>-configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, <i>syn,syn-</i>tosyl-samroiyotmycin A showed 3.4 times higher activities than the “tosyl-free” natural product.</p>","PeriodicalId":144,"journal":{"name":"Chemistry - A European Journal","volume":"30 71","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202403408","citationCount":"0","resultStr":"{\"title\":\"Total Synthesis of Tosyl-Samroiyotmycin A and Its Biological Profiling\",\"authors\":\"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\",\"doi\":\"10.1002/chem.202403408\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>A total synthesis of the enantiopure <i>syn,syn-</i>tosyl-samroiyotmycin A, a C<sub>2</sub>-symmetric 20-membered antimalarial macrodiolide with <i>syn,syn-</i>configuration of the 8,24-dihydroxy-9,25-dimethyl units and it's enantiopure <i>anti,anti-</i>derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield <i>via</i> a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized <i>seco</i>-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) <i>P. falciparum</i> strains providing insight into structure activity relationships. Both tosyl-oxazol unit as well as the <i>syn</i>-configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, <i>syn,syn-</i>tosyl-samroiyotmycin A showed 3.4 times higher activities than the “tosyl-free” natural product.</p>\",\"PeriodicalId\":144,\"journal\":{\"name\":\"Chemistry - A European Journal\",\"volume\":\"30 71\",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/chem.202403408\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemistry - A European Journal\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/chem.202403408\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemistry - A European Journal","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/chem.202403408","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Total Synthesis of Tosyl-Samroiyotmycin A and Its Biological Profiling
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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