†School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
‡Vertex Pharmaceuticals Limited, Milton Park, Abingdon OX14 4RW, United Kingdom.
J Am Chem Soc. 2015 Apr 8;137(13):4398-403. doi: 10.1021/ja512875g. Epub 2015 Jan 27.
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 Hoppe-Beak 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-MeOC6H4CH2Bpin to build up the core of the molecule before the C-B bond was converted into the desired C-N bond, without purification of intermediates. In the case of (+)-hydroxyphthioceranic acid, 16 iterative homologations were conducted on p-MeOC6H4Bpin 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.
使用手性锂化苯甲酸酯和氯甲基锂对硼酸酯进行迭代同系化，已应用于两种天然产物（+）-卡利托毒素和（+）-羟基菲替酸的高效合成。手性锂化苯甲酸酯（>99%ee）是由相应的锡烷衍生而来的，这些锡烷本身是通过 Hoppe-Beak 去质子化乙基 2,4,6-三异丙基苯甲酸酯与 s-BuLi 在（+）-或（-）-斯图尔特胺存在下制备的，并用 Me3SnCl 捕获，然后再进行重结晶。此外，人们发现可以避免在几个同系化之间进行纯化，从而大大提高了化学和人力效率。在（+）-卡利托毒素的情况下，在商业上可获得的 p-MeOC6H4CH2Bpin 上进行了六次迭代同系化，以构建分子的核心，然后再将 C-B 键转化为所需的 C-N 键，而无需对中间体进行纯化。在（+）-羟基菲替酸的情况下，在 p-MeOC6H4Bpin 上进行了 16 次迭代同系化，仅进行了四次中间纯化，然后再将 C-B 键氧化为所需的醇。这些复杂分子的立体控制和高效合成突出了使用硼酸酯进行迭代化学合成的威力。
