School of Chemistry , University of Bristol , Cantock's Close , Bristol BS8 1TS , United Kingdom.
J Am Chem Soc. 2019 Mar 20;141(11):4573-4578. doi: 10.1021/jacs.9b01513. Epub 2019 Mar 11.
Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.
氮杂环丁烷是药物化学中的重要结构单元，但目前合成氮杂环丁烷的方法有限。在此，我们提出了一种新的方法，通过利用氮杂双环[1.1.0]丁烷相关的高环张力来实现氮杂环丁烷的模块化构建。氮杂双环[1.1.0]丁基锂的生成，接着用硼酸酯捕获，得到一个硼酸酯中间体，然后用乙酸质子化，经历 1,2-迁移，同时切断中环的 C-N 键以释放环张力。该方法适用于伯、仲、叔、芳基和烯基硼酸酯，且立体选择性完全。同系化的氮杂环丁基硼酸酯可以通过氮杂环丁基 N-H 的反应以及硼酸酯的转化进一步官能化。该方法应用于含有氮杂环丁烷的药物考比替尼的短程、立体选择性合成。
