A New Green Oxyma-Sulfonate Coupling Reagent for Sustainable Organic Transformations

In this dynamic era, waste accumulation due to population growth and industrialization threatens ecosystems and human health. Scientists now prioritize recycling and sustainable chemical practices to mitigate these challenges. Syntheses of amide and ester moieties, crucial in medicinal chemistry, rely on coupling reagents in academia and in industries. However, classical protocols fall short of Green Chemistry standards using excess reagents and toxic and expensive solvents. Moreover, widely used hazardous coupling reagents and solvents elevate environmental and human health risks. In our study, we focus on green amide, ester, and peptide synthesis, achieving racemization-free reactions using ethyl (E)-2-((((5-chlorothiophen-2-yl)sulfonyl)oxy)imino)-2-cyanoacetate (o-CTSOXY), a novel coupling reagent. We have developed a rapid, cost-effective, environmentally friendly synthetic protocol for this coupling reagent and explored sustainable solution-phase and solid-phase peptide synthesis. Notably, we replaced the hazardous N,N-dimethylformamide (DMF) with acetone in solution-phase synthesis and an EtOAc/DMSO mixture in solid-phase peptide synthesis, significantly enhancing overall sustainability. Furthermore, our efforts to recover and reuse byproducts after chemical transformations, reconstructing the same coupling reagent from them, and reusing it in the same pool have been successful. By reclaiming and recycling both solvents and coupling reagents, we actively reduced chemical waste and advanced toward greener, waste-free chemical synthesis.