Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog.
Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog.
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DOI：
10.1038/ja.2016.7
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Yao L
中科院分区：
文献类型：
--
作者：
Friestad GK;Banerjee K;Marié JC;Mali U;Yao L
微管苯丙氨酸和微管缬氨酸是微管蛋白抑制剂家族抗有丝分裂化合物的 α-取代 γ-氨基酸结构单元，在未受保护的羟基官能团存在下，使用自由基加成反应改进了微管苯丙氨酸和微管缬氨酸的合成。关键的碳-碳键构建需要在手性N-酰腙的C=N键上进行烷基碘的立体选择性Mn介导的光解加成，并以完全立体控制的方式高产率地生成手性胺。还原性 N-N 键断裂和醇氧化将这些氨基醇转化为相应的 γ-氨基酸。获得微管缬氨酸的途径是通过肽与丝氨酸甲酯偶联，然后通过高产序列将丝氨酸酰胺转化为噻唑。最后，肽键构建以 C 端醇类似物的形式建立了微管溶素框架。尝试氧化 C 末端羧酸盐未成功；二肽 18 的对照实验表明环化干扰了所需的氧化过程。
Synthesis of tubuphenylalanine and tubuvaline, α-substituted γ-amino acid building blocks for tubulysin family of antimitotic compounds, has been improved using a radical addition reaction in the presence of unprotected hydroxyl functionality. The key carbon–carbon bond construction entails stereoselective Mn-mediated photolytic additions of alkyl iodides to the C=N bond of chiral N-acylhydrazones, and generates the chiral amines in high yield with complete stereocontrol. Reductive N–N bond cleavage and alcohol oxidation converted these amino alcohols into the corresponding γ-amino acids. The route to tubuvaline proceeded via peptide coupling with serine methyl ester, followed by a high-yielding sequence to convert the serine amide to a thiazole. Finally, peptide bond construction established the tubulysin framework in the form of a C-terminal alcohol analog. Attempted oxidation to the C-terminal carboxylate was unsuccessful; control experiments with dipeptide 18 showed a cyclization interfered with the desired oxidation process.