Taspinar Ömer, Leonard Daniel J, Picois Nathan, Göcke Cornelia, Žabka Matej, Sparkes Hazel A, Clayden Jonathan
School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
CY Cergy Paris Université, CNRS, BioCIS, Cergy Pontoise, 95000, France.
Angew Chem Int Ed Engl. 2025 Jul;64(29):e202507713. doi: 10.1002/anie.202507713. Epub 2025 May 24.
The α-arylation of amino acids may be achieved by intramolecular nucleophilic aromatic substitution (SAr) reactions of amino-acid derived enolates, but for amino acids bearing β-leaving groups, such reactions are complicated by competing E1cB elimination of the β-substituent. In this paper we report an approach to the arylation of the polar amino acids serine, cysteine, diaminopropionic acid, and allothreonine by inducing intramolecular SAr reactions of heterocycles, which the heteroatom substituent is stereoelectronically protected from elimination by incorporating it into the ring system of N-carbamoyl oxazolidines, thiazolidines, or imidazolidines. The sequence comprises the diastereoselective formation of a heterocyclic urea followed by an intramolecular N-to-C aryl migration, yielding bicyclic hydantoins that can be further hydrolysed to afford quaternary α-aryl amino acids. The method is practical and scalable, avoids the use of transition metals or chiral auxiliaries, and provides the opportunity to access a variety of α-arylated products bearing electronically diverse benzenoid or heterocyclic substituents (35 examples).
氨基酸的α-芳基化反应可通过氨基酸衍生烯醇盐的分子内亲核芳香取代（SAr）反应实现，但对于带有β-离去基团的氨基酸，此类反应会因β-取代基的竞争性E1cB消除反应而变得复杂。在本文中，我们报道了一种通过诱导杂环分子内SAr反应实现极性氨基酸丝氨酸、半胱氨酸、二氨基丙酸和别苏氨酸芳基化的方法，其中杂原子取代基通过将其并入N-氨基甲酰基恶唑烷、噻唑烷或咪唑烷的环系统中而受到立体电子保护，从而避免消除反应。该序列包括非对映选择性形成杂环脲，随后进行分子内N到C的芳基迁移，生成双环乙内酰脲，其可进一步水解以得到季α-芳基氨基酸。该方法实用且可扩展，避免了使用过渡金属或手性助剂，并且提供了获得多种带有电子性质多样的苯环或杂环取代基的α-芳基化产物的机会（35个实例）。
