Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
Toward Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis
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DOI：
10.1021/ja512875g
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发表时间：
2015-04-08
影响因子：
15
通讯作者：
Aggarwal, Varinder K.
中科院分区：
文献类型：
--
作者：
Balieu, Sebastien;Hallett, Gayle E.;Aggarwal, Varinder K.
用手性锂化苯甲酸酯和氯甲基锂进行硼酸酯的迭代同系反应，已被应用于两种天然产物（+）-kalkitoxin和（+）-hydroxyphthioceranic acid的高效合成。手性锂化苯甲酸酯（> 99%ee）由相应的锡烷产生，锡烷本身通过在（+）-或（-）-鹰爪豆碱存在下用s-BuLi对2，4，6-三异丙基-苯甲酸乙酯进行HoppeBeak去质子化，并用Me 3SnCl捕获，然后重结晶来制备。此外，发现可以避免几种同系物之间的纯化，从而大大提高了化学和人力效率。在（+）-kalkitoxin的情况下，在市售的p-MeOC（6）H（4）CH（2）Bpin上进行六次迭代同源化，以在C-B键转化为所需的CN键之前构建分子的核心，而不纯化中间体。在（+）-羟基邻苯二甲酸的情况下，对p-MeOC（6）H（4）Bpin进行了16次迭代同系物化，在C-B键氧化成所需的醇之前仅进行了4次中间纯化。这些复杂分子的立体控制和高效合成突出了使用硼酸酯的迭代化学合成的能力。
The iterative homologation of boronic esters using chiral lithiated benzoate esters and chloromethyllithium has been applied to the highly efficient syntheses of two natural products, (+)-kalkitoxin and (+)-hydroxyphthioceranic acid. The chiral lithiated benzoate esters (>99% ee) were generated from the corresponding stannanes, which themselves were prepared by HoppeBeak deprotonation of ethyl 2,4,6-triisopropyl-benzoate with s-BuLi in the presence of (+)- or (-)-sparteine and trapping with Me3SnCl followed by recrystallization. In addition, it was found that purification between several homologations could be avoided, substantially increasing both chemical and manpower efficiency. In the case of (+)-kalkitoxin, six iterative homologations were conducted on commercially available p-MeOC(6)H(4)CH(2)Bpin to build up the core of the molecule before the C-B bond was converted into the desired CN bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC(6)H(4)Bpin with only four intermediate purifications before oxidation of the C-B bond to the desired alcohol. The stereocontrolled and efficient syntheses of these complex molecules highlight the power of iterative chemical synthesis using boronic esters.