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

Abstract

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.

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

“…Therefore, we performed this comparison by applying three different peptide synthesis strategies (BM, solution and solid support) to the production of the VVIA peptide sequence, protected or not, depending on the strategy (all amino acids bearing L absolute configuration, Figure 1). The sequence has been chosen as it corresponds to the Aβ (39-42) tetrapeptide, a promising small therapeutic peptide that inhibits Aβ42-induced neurotoxicity [21,22], and that is known to be difficult to produce due to high hydrophobicity and steric hindrance [23]. …”

Synthesis of β‐Amino Alcohols Using Ethyl 2‐Cyano‐2‐(2‐nitrobenzenesulfonyloxyimino)acetate (o‐NosylOXY)

“…Finally, the activated Oxyma ester of the carboxylic acid ( III ) reduced to the corresponding alcohols by NaBH 4 . The intermediate III in the reaction mixture was well characterized …”

“…Recently, we have reported the use of ethyl‐2‐cyano‐2‐(2‐nitrobenzenesulfonyloxyimino) acetate ( o ‐NosylOXY, I , Figure ) as a new and efficient coupling reagent. We have achieved the conversion of the carboxylic acids to amides, peptides, esters, thioesters, hydroxamates, ureas, heterocyclic compounds such as benzoxazoles and benzthiazoles by using I . Conversion of aldoximes to nitriles was also possible by using I .…”

“…Conversion of aldoximes to nitriles was also possible by using I . Excellent racemization suppression capability, ease of preparation and recyclable nature, of the reagent are major advantages of this reagent. We herein report a simple approach for the synthesis of β ‐amino alcohols from the corresponding carboxylic acids using o ‐NosylOXY–NaBH 4 reduction condition.…”

FeCl3‐Mediated Boc Deprotection: Mild Facile Boc‐Chemistry in Solution and on Resin

“…In our method, Boc can be removed from methyl ester of Boc protected amino acid within 30 min using the stoichiometric amount of eco‐friendly Lewis acid, FeCl 3 . The Boc deprotected methyl ester of amino acid can be coupled with the next Boc protected amino acid using eco‐friendly coupling reagent ( o ‐NosylOXY) and Hünig's base (DIPEA). Usually, Boc chemistry is performed on Merrifield resin, PAM‐resin, and BHA resin from which the final peptide is cleaved by strong acid HF .…”