Exploring the potential of engineered enzyme families for selective N-alkylation of heteroarenes: A convergent synthesis approach with SAM analogs as intermediates

杂芳烃的选择性n -烷基化可以大大缩短复杂分子的合成时间，特别是当两个较大的片段可以通过选择性C-N键的聚合方式偶联时。在这里，我们建议设计、理解和应用酶家族来合成和使用s -腺苷- l-蛋氨酸（SAM）类似物作为杂芳烃选择性n -烷基化的中间体。我们的目标是生成两个酶家族，即从s -腺苷- l-同型半胱氨酸和“现成的”卤代烷生成SAM类似物的硫离子合成酶，以及使用这些SAM类似物作为共底物与杂芳烃构建块选择性形成C-N键的n -烷基转移酶。本研究i)旨在开发一种受欢迎的化学转化的催化方法，ii)在硅诱变中用于突变文库的计算设计，以系统地探索氨基酸序列空间的大区域，以及iii)通过将容易获得的片段偶联到复杂分子来探索SAM类似物在聚合合成中的潜力。

The selective N-alkylation of heteroarenes could drastically shortcut synthesis of complex molecules, especially if two larger fragments could be coupled by selective C-N bond formation in a convergent approach. Here we propose to engineer, understand and apply enzyme families that synthesize and use S-adenosyl-L-methionine (SAM) analogs as intermediates for selective N-alkylation of heteroarenes. Our goal is to generate two enzyme families, namely sulfonium ion synthases that generate SAM analogs from S-adenosyl-L-homocysteine and "off the shelf" haloalkanes, and N-alkyltransferases that use these SAM analogs as co-substrates in selective C–N bond formations with heteroarene building blocks. This research i) aims to develop a catalytic method for a sought-after chemical transformation, ii) uses in silico mutagenesis for computational design of mutant libraries to systematically explore large regions of the amino acid sequence space, and iii) explores the potential of SAM analogs in convergent synthesis by coupling readily available fragments to complex molecules.