Late Stage Diversification of Peptides by Transition Metal Mediated Cross-Couplings

溴化芳香氨基酸，特别是溴色氨酸，已经被我们确立为多肽后期多样化的中心合成平台。含有溴化氨基酸的多肽可以通过过渡金属催化的交叉偶联反应进行衍生化，如Suzuki-Miyaura交叉偶联、Mizoroki-Heck反应和根岸交叉偶联。在之前的资助期内，我们能够证明过渡金属催化的交叉偶联反应可以用于合成后期的氨基酸和肽修饰。基于这一经验，我们将阐明邻近的甲硫氨酸残基对含溴色氨酸肽的Suzuki-Miyaura交叉偶联的加速作用，并通过Mizoroki-Heck、Negishi和Hiyama交叉偶联研究后期肽的多样化。此外，我们将探索光氧化还原催化和金属催化的组合用于肽修饰。此外，还研究了用交叉偶联反应合成c -糖苷的方法。作为基准模型体系，系统研究后期多样化反应的官能团相容性以及修饰对rgd -多肽生物活性的影响。

Brominated aromatic amino acids, especially bromotryptophan, have been established by us as a central synthetic platform for late-stage diversification of peptides. Peptides containing a brominated amino acid can be efficiently derivatized using transition metal-catalyzed cross-coupling reactions, e.g. the Suzuki-Miyaura cross-coupling, the Mizoroki-Heck reaction, and the Negishi cross-coupling. In the previous funding period we were able to show that transition metal catalyzed cross-coupling reactions can be employed for amino acid and peptide modification on a late synthetic stage. Based on this experience we will elucidate accelerating effects of adjacent methionine residues on the Suzuki-Miyaura cross-coupling of bromotryptophan containing peptides and study the late stage peptide diversification by Mizoroki-Heck, Negishi, and Hiyama cross-couplings. Moreover, we will explore combinations of photoredox catalysis and metal catalysis for peptide modification. In addition, the synthesis of C-glycosides using cross-coupling reactions will be investigated. As a benchmark model system, the functional group compatibility of the late stage diversification reactions and the effect of the modification on the biological activity of RGD-peptides will be systematically studied.