Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Automated Synthesis Facility, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Angew Chem Int Ed Engl. 2018 Sep 3;57(36):11634-11639. doi: 10.1002/anie.201805191. Epub 2018 Aug 10.
Facile synthesis of C-terminal thioesters is integral to native chemical ligation (NCL) strategies for chemical protein synthesis. We introduce a new method of mild peptide activation, which leverages solid-phase peptide synthesis (SPPS) on an established resin linker and classical heterocyclic chemistry to convert C-terminal peptide hydrazides into their corresponding thioesters via an acyl pyrazole intermediate. Peptide hydrazides, synthesized on established trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily proceed to the peptide acyl pyrazoles. Acyl pyrazoles are mild acylating agents and are efficiently exchanged with an aryl thiol, which can then be directly utilized in NCL. The mild, chemoselective, and stoichiometric activating conditions allow this method to be utilized through multiple sequential ligations without intermediate purification steps.
C 端硫酯的简便合成是用于化学蛋白质合成的天然化学连接（NCL）策略的重要组成部分。我们引入了一种新的温和肽激活方法，该方法利用固相肽合成（SPPS）在已建立的树脂连接子和经典杂环化学上，通过酰基吡唑中间体将 C 端肽酰肼转化为相应的硫酯。在已建立的三苯甲基氯树脂上合成的肽酰肼可以在溶液中用化学计量的乙酰丙酮（acac）进行激活，很容易转化为肽酰基吡唑。酰基吡唑是温和的酰化剂，可与芳基硫醇有效地交换，然后可直接用于 NCL。温和、选择性和化学计量的激活条件允许该方法在没有中间纯化步骤的情况下，通过多次连续连接进行使用。
