Copper-Mediated Three-Component Reaction for the Synthesis of N-Acylsulfonamide on DNA

Abstract

The DNA-encoded library (DEL) technology is a new method for discovering hit compounds for target proteins in the pharmaceutical industry. The N-acylsulfonamide functional group has been reported to exhibit various pharmacological activities, and based on this, the demand for a method that allows its introduction into the DEL platform has increased. In this report, a procedure for synthesizing N-acylsulfonamide functional groups applicable to DEL construction was developed in the presence of a copper reagent and water as a nucleophile from simple alkynes or sulfonyl azides, which are widely commercially available. Furthermore, we prove that a new alternative procedure can be used to construct a DNA-encoded library.

Ferric Chloride-Mediated Transacylation of N-Acylsulfonamides

“…N-acylsulfonamides can also be prepared through sulfonylation of amides with a sulfonyl chloride. 23 Alternative procedures include preparations from sulfonyl isocyanates 24,25 or sulfonyl azides 26,27 and amidation of aldehydes. 28,29 Transacylation is a transformation that replaces the N-acyl group with a new one and represents an attractive approach to N-acylsulfonamides because it allows making a diverse set of analogues from one N-acylsulfonamide.…”

“…N -acylsulfonamides can also be prepared through sulfonylation of amides with a sulfonyl chloride . Alternative procedures include preparations from sulfonyl isocyanates , or sulfonyl azides , and amidation of aldehydes. , …”

Groebke–Blackburn–Bienaymé Reaction for DNA-Encoded Library Technology

“…Several representative examples of MCRs that ensure the chemical diversity of DELs in a single step are available (Figure a). These include the Povarov reaction and Biginelli reaction mediated by the sulfonic-acid-substituted block copolymer, the Van Leusen imidazole synthesis, the copper-mediated three-component reaction (involving water, alkynes, and sulfonyl azides), the synthesis of a 4 H -pyran scaffold via a three-component reaction (involving aldehydes, enolates, and malononitrile), the synthesis of an annelated 1,5-benzodiazepine scaffold via a three-component reaction (involving aldehydes, o -phenylenediamines, and diketones), and the lactam scaffold synthesis via the Ugi reaction …”

“…6 Several representative examples of MCRs that ensure the chemical diversity of DELs in a single step are available (Figure 1a). These include the Povarov reaction and Biginelli reaction mediated by the sulfonic-acid-substituted block copolymer, 7 the Van Leusen imidazole synthesis, 8 the copper-mediated three-component reaction (involving water, alkynes, and sulfonyl azides), 9 the synthesis of a 4H-pyran scaffold via a three-component reaction (involving aldehydes, enolates, and malononitrile), 10 the synthesis of an annelated 1,5-benzodiazepine scaffold via a three-component reaction (involving aldehydes, o-phenylenediamines, and diketones), 11 and the lactam scaffold synthesis via the Ugi reaction. 12 The Groebke−Blackburn−Bienaymé(GBB) reaction is a versatile method for synthesizing N-fused 3-aminoimidazoles from aldehydes, amines, and isocyanides 13 and has emerged as a crucial strategy for constructing the core scaffold of bioactive molecules, including kinase inhibitors and HIV-1 reverse transcriptase inhibitors (Figure 1b).…”