Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London, W12 0BZ, UK.
Bayer AG, Pharmaceuticals Division, Drug Discovery, Müllerstr. 178, 13353, Berlin, Germany.
Chemistry. 2020 Oct 1;26(55):12533-12538. doi: 10.1002/chem.202002265. Epub 2020 Sep 11.
Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 % es, es=enantiospecificity) generating sulfonimidamides with up to 99 % ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.
磺酰亚胺酰胺作为磺酰胺的手性等排体，具有额外的定向相互作用的潜力，这是令人兴奋的机会。在这里，我们首次提出了磺酰亚胺酰胺的模块化对映选择性合成方法，包括对映富集的磺酰亚胺酰氟的首次立体选择性合成，并对其反应性进行了研究。提出了一种从固体稳定的 Boc-磺酰胺（Boc=叔丁氧基羰基）盐砌块制备磺酰亚胺酰氟的新路线。证明手性富集的芳基磺酰亚胺酰氟很容易被氟离子消旋化。开发了条件，可以捕获氟离子，并使磺酰亚胺酰氟与伯胺和仲胺的立体特异性反应（100%es，es=对映体选择性），生成对映体过量高达 99%的磺酰亚胺酰胺。芳基和烷基磺酰亚胺酰氟试剂适用于温和的晚期功能化反应，例如与市售药物中的一系列复杂胺的偶联。
