New sulfur-based reactive intermediates for synthesis and catalysis

用于合成和催化的新型硫基反应中间体

• 批准号: EP/S03658X/1
• 负责人: Michael Willis
• 金额: $ 47.21万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS03658X%2F1
• 关键词: New; sulfur; based; reactive; intermediates

Sulfonyl units, that is the -SO2- arrangement of atoms, are functional groups that feature in a significant number of pharmaceuticals, argochemcials and materials. Variations in which one or more oxygen atoms of these groups are replaced with nitrogen atoms are also emerging as useful molecules for exploring biological processes. This proposal is focused on this latter class of compounds. The types of molecules this encompasses - primarily sulfoximines and sulfonimidamides - are less explored than then non-aza-equivalent, and this is largely due to the lack of convenient methods for their preparation. Conventional syntheses of these types of molecules usually involve three or four synthetic operations, and often feature low-yielding steps. The chemistry involved also limits the substrates that can be converted to aza-sulfonyl-containing molecules. This proposal seeks to develop new reagents and new reactions to this class of molecules; the proposed chemistry will be achieved in a single operation, employ readily available reagents and substrates, and be conducted under mild conditions. The key aspect of the proposal is the design of new nitrogen-containing reagents that will allow ready access to a little used class of reactive intermediates; sulfinylnitrenes. By delivering these reactive intermediates in a simple way, using readily available reagents, a host of new reactivity, and thus transformations, will be available. These reactions will be used to provide general routes to sulfoximines and sulfonimidamides, as well as primary sulfonamides. We will deliver user-friendly reactions. These transformations will significantly simplify the preparation of these molecules, and allow them to be routinely considered when new collections of molecules for biological evaluation are being designed. We will seek to make the reagents we develop commercially available, thus allowing the rapid take-up of the methods we develop.

磺酰基团，即原子的-SO2-排列，是大量药物、化工和材料中的官能团。这些基团中的一个或多个氧原子被氮原子取代的变化也成为探索生物过程的有用分子。这项建议的重点是后一类化合物。这类分子--主要是磺胺类和磺胺类--比非氮杂类化合物探索得更少，这在很大程度上是因为缺乏方便的制备方法。这些类型的分子的常规合成通常涉及三到四个合成操作，并且通常以低产率步骤为特色。所涉及的化学物质也限制了可以转化为氮磺酰基分子的底物。这项建议旨在开发针对这类分子的新试剂和新反应；所建议的化学将在一次操作中实现，使用容易获得的试剂和底物，并在温和的条件下进行。该提案的关键方面是设计新的含氮试剂，使其能够很容易地获得一类很少使用的活性中间体；亚磺基硝烷。通过使用现成的试剂，以一种简单的方式提供这些活性中间体，许多新的反应性，从而转化，将是可用的。这些反应将被用来提供合成磺胺和磺胺以及伯磺胺的一般路线。我们将提供用户友好的反应。这些转化将大大简化这些分子的制备，并允许在设计用于生物评估的新分子集合时常规考虑它们。我们将寻求使我们开发的试剂商业化，从而使我们开发的方法能够迅速得到应用。

项目成果

Identification of histone peptide binding specificity and small molecule ligands for the bromodomains of TRIM33a and TRIM33ß

TRIM33a 和 TRIM33™ 溴结构域的组蛋白肽结合特异性和小分子配体的鉴定

• DOI: 10.26434/chemrxiv-2022-vnf6p
• 发表时间: 2022
• 作者: Sekirnik A

Mutate and Conjugate: A Method to Enable Rapid In-Cell Target Validation.

• DOI: 10.1021/acschembio.3c00437
• 发表时间: 2023-11-17
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Thomas, Adam M.;Serafini, Marta;Grant, Emma K.;Coombs, Edward A. J.;Bluck, Joseph P.;Schiedel, Matthias;Mcdonough, Michael A.;Reynolds, Jessica K.;Lee, Bernadette;Platt, Michael;Sharlandjieva, Vassilena;Biggin, Philip C.;Duarte, Fernanda;Milne, Thomas A.;Bush, Jacob T.;Conway, Stuart J.
• 通讯作者: Conway, Stuart J.

Exploiting Configurational Lability in Aza-Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides.

• DOI: 10.1002/anie.202109160
• 发表时间: 2021-12-01
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Tilby, Michael J.;Dewez, Damien F.;Hall, Adrian;Martinez Lamenca, Carolina;Willis, Michael C.
• 通讯作者: Willis, Michael C.