Jo Woonkee S, Curtis Brian J, Rehan Mohammad, Adrover-Castellano Maria L, Sherman David H, Healy Alan R
Chemistry Program, New York University Abu Dhabi (NYUAD), Saadiyat Island, Abu Dhabi 129188, United Arab Emirates (UAE).
Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
JACS Au. 2024 May 9;4(5):2058-2066. doi: 10.1021/jacsau.4c00257. eCollection 2024 May 27.
The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from -to- is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from -to-, as a method to convert stable chiral amides into more reactive thioesters. To this end, we developed a novel cysteine-derived oxazolidinone that serves as both a chiral imide auxiliary and an acyl transfer agent. This auxiliary combines the desirable features of rigid chiral imides as templates for asymmetric transformations with the synthetic applicability of thioesters. We demonstrate that the auxiliary can be applied in a range of highly selective asymmetric transformations. Subsequent intramolecular -to- acyl transfer of the chiral product and in situ trapping of the resulting thioester provides access to diverse carboxylic acid derivatives under mild conditions. The oxazolidinone thioester products can also be isolated and used in Pd-mediated transformations to furnish highly valuable chiral scaffolds, such as noncanonical amino acids, cyclic ketones, tetrahydropyrones, and dihydroquinolinones. Finally, we demonstrate that the oxazolidinone thioesters can also serve as a surrogate for SNAC-thioesters, enabling their seamless use as non-native substrates in biocatalytic transformations.
对自然界中硫酯介导的酰基转移过程的观察激发了新型蛋白质合成和功能化方法的发展。从……到……的酰基化学选择性转移是几种强大连接策略的基础。在这项工作中，我们试图应用逆向过程，即从……到……的酰基转移，作为将稳定的手性酰胺转化为反应性更高的硫酯的方法。为此，我们开发了一种新型的源自半胱氨酸的恶唑烷酮，它既作为手性酰亚胺助剂又作为酰基转移剂。这种助剂将刚性手性酰亚胺作为不对称转化模板的理想特性与硫酯的合成适用性结合起来。我们证明该助剂可应用于一系列高度选择性的不对称转化。随后手性产物的分子内从……到……的酰基转移以及所得硫酯的原位捕获使得在温和条件下能够获得多种羧酸衍生物。恶唑烷酮硫酯产物也可以分离出来并用于钯介导的转化反应，以提供高价值的手性骨架，如非天然氨基酸、环酮、四氢吡喃和二氢喹啉酮。最后，我们证明恶唑烷酮硫酯还可以作为SNAC硫酯的替代物，使其能够作为非天然底物在生物催化转化中无缝使用。
