Total Synthesis of (-)-Apratoxin A, 34-Epimer, and Its Oxazoline Analogue
Total Synthesis of (-)-Apratoxin A, 34-Epimer, and Its Oxazoline Analogue
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DOI：
10.1002/asia.200800365
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发表时间：
2009-01-01
影响因子：
4.1
通讯作者：
Doi, Takayuki
中科院分区：
文献类型：
--
作者：
Numajiri, Yoshitaka;Takahashi, Takashi;Doi, Takayuki
通过18步线性反应，完成了高细胞毒性海洋天然产物阿曲毒素A的一个简洁和收敛的全合成。在C35-位带有相邻P-羟基的噻唑啉的高灵敏度导致组装过程需要包括适当的保护基团和对所有单独转化的仔细优化。在3，7-二羟基-2，5，8，8-四甲基壬酸（Dtena）的合成中，通过三个试剂控制的不对称反应，我们在一个二羟基脂肪酸结构中引入了四个手性碳中心。成功地证明了受阻酯和空间上不利的N-甲基酰胺键的形成。通过Tf 2 O和Ph 3 PO介导的脱水环化反应，最终在N-甲基异亮氨酸和脯氨酸残基之间形成大环化反应，构建了Apratoxin A中的噻唑啉。此外，恶唑啉类似物和阿曲毒素A的C34差向异构体也已经以类似的方法进行了阐述。该合成路线将使得能够组装在Dtena及其氨基酸的立体中心上不同的其他类似物。
A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent P-hydroxyl group at the C35-position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization o all individual transformations. In the synthesis of 3,7-dihydroxy-2,5,8,8-tetra-methylnonanoic acid (Dtena), three reagent-controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically-unfavorable N-methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf2O and Ph3PO-mediated dehydrative cyclizatin, and final macrocyclizatin was achieved between N-methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereo-centers of Dtena and their amino acids.