N-Acylsulfonamide Linker Activation by Pd-Catalyzed Allylation

Significance

A new method for N-acylsulfon­amide activation by palladium-catalyzed allylation was developed. Thus, the resin-supported peptides 2 and 3 were readily prepared from Gly, Ala, Leu, Ile, Phe, Ser, Lys, and His on the commercially available arylsulfonamide resin 1 (loading 0.62 mmol/g) by the standard Fmoc method using HATU and DIPEA as coupling reagents. Palla­dium-catalyzed allylations of N-acylsulfonamide resins 2 and 3 were carried out with allyl ethyl carbonate, Pd(OAc)₂ and PPh₃ to give the allylated substrates 2a and 3a, where the sulfonamide unit was activated as a leaving group. The reactions of activated resins 2a and 3a with n-PrNH₂ released N-Boc-protected peptides were deprotected with TFA to give the peptides 4 and 5 with good crude purity and in good yield (54% and 40% yield from 1). Peptide thioesters 6 and 7 were also obtained via similar solid-phase transformations using ethyl 3-mercaptopropionate in 52% and 41% yields, respectively.