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Total synthesis of 7-des-O-pivaloyl-7-O-benzylbryostatin 10
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-10-27 00:00:00 , DOI: 10.1039/c7ob02129a Anthony P. Green 1, 2, 3, 4 , Simon Hardy 1, 2, 3, 4 , Alan T. L. Lee 1, 2, 3, 4 , Eric J. Thomas 1, 2, 3, 4
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-10-27 00:00:00 , DOI: 10.1039/c7ob02129a Anthony P. Green 1, 2, 3, 4 , Simon Hardy 1, 2, 3, 4 , Alan T. L. Lee 1, 2, 3, 4 , Eric J. Thomas 1, 2, 3, 4
Affiliation
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The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17–C27 fragment with aldehydes corresponding to the C1–C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1–C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17–C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19–C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19–C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7.
中文翻译：
7 -des-O-新戊酰基-7 - O-苄基溴化他汀的全合成10
描述了20-脱氧bryostatin的衍生物，即7 -des-O-新戊酰基-7 - O-苄基bryostatin 10的第一全合成。初步研究表明，对应于C17–C27片段的2-苯并噻唑基砜与对应于C1–C16片段的醛基的修饰Julia反应，提供了具有（E的高级中间体的高效，立体选择性组装）-16,17-双键。然后修饰C1-C16片段的合成，以使C1酸以烯丙基酯的形式存在于Julia偶联反应之前。开发了一种更有效的C17-C27砜合成方法，其中关键步骤是在烯丙基溴中存在丙烯酸酯部分的情况下，铋介导的烯丙基溴与醛的偶联。使用修饰的Julia反应完成了大环内酯类化合物的可扩展合成，然后进行了选择性脱保护和大环内酯化。合成的最后阶段需要选择性的羟基脱保护和引入敏感的C19–C21不饱和酮酸酯官能团。在羟基脱保护的研究过程中观察到意外的选择性。尤其是，在C 19处存在仲醇的三乙基甲硅烷基醚的情况下，观察到环外伯烯丙基醇的三异丙基甲硅烷基醚的裂解。模型研究有助于设计用于引入C19–C21酮酸酯官能团的方法，并导致完成了bryostatin 10的紧密类似物的全合成，其中C7上存在苄氧基而不是新戊酰氧基。
更新日期：2017-11-16
中文翻译：
7 -des-O-新戊酰基-7 - O-苄基溴化他汀的全合成10
描述了20-脱氧bryostatin的衍生物，即7 -des-O-新戊酰基-7 - O-苄基bryostatin 10的第一全合成。初步研究表明，对应于C17–C27片段的2-苯并噻唑基砜与对应于C1–C16片段的醛基的修饰Julia反应，提供了具有（E的高级中间体的高效，立体选择性组装）-16,17-双键。然后修饰C1-C16片段的合成，以使C1酸以烯丙基酯的形式存在于Julia偶联反应之前。开发了一种更有效的C17-C27砜合成方法，其中关键步骤是在烯丙基溴中存在丙烯酸酯部分的情况下，铋介导的烯丙基溴与醛的偶联。使用修饰的Julia反应完成了大环内酯类化合物的可扩展合成，然后进行了选择性脱保护和大环内酯化。合成的最后阶段需要选择性的羟基脱保护和引入敏感的C19–C21不饱和酮酸酯官能团。在羟基脱保护的研究过程中观察到意外的选择性。尤其是，在C 19处存在仲醇的三乙基甲硅烷基醚的情况下，观察到环外伯烯丙基醇的三异丙基甲硅烷基醚的裂解。模型研究有助于设计用于引入C19–C21酮酸酯官能团的方法，并导致完成了bryostatin 10的紧密类似物的全合成，其中C7上存在苄氧基而不是新戊酰氧基。
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