Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, China.
Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China.
Nat Chem. 2023 May;15(5):647-657. doi: 10.1038/s41557-023-01179-0. Epub 2023 Apr 13.
β-Amino acids are structural motifs widely found in therapeutic natural products, novel biomimetic polymers and peptidomimetics. As a convergent method, the synthesis of stereoenriched β-amino amides through the asymmetric Mannich reaction requires specialized amide substrates or a metal catalyst for enolate formation. By a redesign of the Ugi reaction, a conceptually different solution to prepare chiral β-amino amides was established using ambiphilic ynamides as two-carbon synthons. The modulation of ynamides or oxygen nucleophiles concisely furnished three classes of β-amino amides with generally good efficiency as well as excellent chemo- and stereo-control. The utility is verified in the preparation of over 100 desired products that bear one or two contiguous carbon stereocentres, including those that directly incorporate drug molecules. This advance also provides a synthetic shortcut to other valuable structures. The amino amides could be elaborated into β-amino acids, anti-vicinal diamines, γ-amino alcohols and β-lactams or undergo transamidation with amino acids and amine-containing pharmaceuticals.
β-氨基酸是在治疗性天然产物、新型仿生聚合物和肽模拟物中广泛存在的结构基序。作为一种会聚方法，通过不对称曼尼希反应合成立体富集的β-氨基酰胺需要专门的酰胺底物或金属催化剂来形成烯醇化物。通过对 Ugi 反应的重新设计，使用两性亲核试剂作为二碳合成子，建立了一种概念上不同的制备手性β-氨基酰胺的方法。通过调节炔酰胺或氧亲核试剂，可以简洁地制备三类β-氨基酰胺，通常具有良好的效率和出色的化学和立体选择性。该方法的实用性在 100 多个具有一个或两个相邻碳立体中心的所需产物的制备中得到了验证，包括那些直接包含药物分子的产物。这一进展还为其他有价值的结构提供了合成捷径。氨基酰胺可以被修饰成β-氨基酸、反式二胺、γ-氨基醇和β-内酰胺，或者与氨基酸和含胺药物进行转酰胺化反应。
