Ethyl 2‑Cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o‑NosylOXY): A Recyclable Coupling Reagent for Racemization-Free Synthesis of Peptide, Amide, Hydroxamate, and Ester

Ubiquitousness
of amide and ester functionality makes coupling
reactions extremely important. Although numerous coupling reagents
are available, methods of preparation of the common and efficient
reagents are cumbersome. Those reagents generate a substantial amount
of chemical waste and lack recyclability. Ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)­acetate
(o-NosylOXY), the first member of a new generation
of coupling reagents, produces byproducts that can be easily recovered
and reused for the synthesis of the same reagent, making the method
more environmentally friendly and cost-effective. The synthesis of
amides, hydroxamates, peptides, and esters using this reagent is described.
The synthesis of the difficult sequences, for example, the islet amyloid
polypeptide (22–27) fragment (with a C-terminal Gly, H-Asn-Phe-Gly-Ala-Ile-Leu-Gly-NH2) and acyl carrier protein (65–74) fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH),
following the solid-phase peptide synthesis (SPPS) protocol and Amyloid
β (39–42) peptide (Boc-Val-Val-IIe-Ala-OMe), following
solution-phase strategy is demonstrated. Remarkable improvement is
noticed with respect to reaction time, yield, and retention of stereochemistry.
A mechanistic investigation and recyclability are also described.

酰胺和酯官能团的普遍存在使得偶联反应显得尤为重要。尽管市面上存在多种偶联试剂，但制备这些常见且高效的试剂的方法却显得繁琐。这些试剂在反应过程中会产生大量的化学废弃物，且缺乏可回收性。乙基-2-氰-2-(2-硝基苯磺酰氧基脒基)乙酸酯（o-NosylOXY），作为新一代偶联试剂中的首个成员，其副产物易于回收并再次用于同一试剂的合成，从而使得该方法更加环保且经济效益显著。本描述中详细介绍了利用该试剂合成酰胺、羟肟酸、肽和酯的方法。以固体相肽合成（SPPS）协议合成的困难序列，例如胰岛淀粉样多肽（22–27）片段（C端为甘氨酸，H-Asn-Phe-Gly-Ala-Ile-Leu-Gly-NH2）和酰基载体蛋白（65–74）片段（H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH），以及采用溶液相策略合成的淀粉样β（39–42）肽（Boc-Val-Val-IIe-Ala-OMe）为例，展示了显著的反应时间缩短、产率提升和立体化学保留率的提高。此外，还对反应机理和可循环使用性进行了研究。