N-Acylsulfonamide Linker Activation by Pd-Catalyzed Allylation

Abstract

N-Acylsulfonamide safety-catch linkers are versatile tools in solid-phase organic synthesis because of their stability. This stability necessitates linker activation prior to compound cleavage. Here, we demonstrate that the N-acylsulfonamide group can react with a pi-allyl palladium complex and that these mild and neutral conditions can be exploited for linker activation. The advantages of this process are illustrated by its use in the efficient synthesis of thioesters. We anticipate that this activation method will extend the utility of the N-acylsulfonamide group. [reaction: see text]

Chemoselective Ligation and Modification Strategies for Peptides and Proteins

“…The second required building block is a C-terminal thioester of the N peptide. [40,41] A prominent example is the use of the alkanesulfonamide "safety-catch" resin, [42] which allows the resulting peptides to be activated with diazomethane, [43] iodoacetonitrile, [44] or by palladiumcatalyzed allylation [45] to yield the secondary sulfonamide 23. [37] The Boc strategy, however, requires HF to cleave the resin-bound thioester 21 and deliver thioester 22 (Scheme 4 A).…”

“…[37] Various strategies which take into account the high electrophilicity of thioesters have been developed for the Fmoc-based synthesis of peptide thioesters. [40,41] A prominent example is the use of the alkanesulfonamide "safety-catch" resin, [42] which allows the resulting peptides to be activated with diazomethane, [43] iodoacetonitrile, [44] or by palladiumcatalyzed allylation [45] to yield the secondary sulfonamide 23. The addition of nucleophilic thiols leads to a cleavage of the protected peptides as thioesters (Scheme 4 B).…”

Chemoselektive Ligations‐ und Modifikationsstrategien für Peptide und Proteine

“…[40,41] Ein bekanntes Beispiel ist die Verwendung von Safety-Catch-Alkansulfonamidharzen, [42] die nach Beendigung der Fmoc-SPPS mit Diazomethan, [43] Iodacetonitril [44] oder durch Pd-katalysierte Allylierung [45] in ein sekundäres Sulfonamid 23 überführt werden. Die anschließende Zugabe von nucleophilen Thiolen führt zur Abspaltung der geschützten Peptide als Thioester 24 (Schema 4 B), [43,46] die nach globaler Entschützung in der NCL eingesetzt werden können.…”

Tsuji–Trost Cyclization of Disulfonamides: Synthesis of 12-Membered, 11-Membered, and Pyridine-Fused Macrocyclic Triamines

“…The exocyclic double bond in the 3-position of the 1,5,9-triazacyclododecane ring, which is important for activity, enables an alternate macrocyclization strategy involving double N -allylation, as shown in Scheme (method B). Tsuji–Trost − N -allylation is well-precedented, − and hydroxyl groups in erythromycin A and other macrolide antibiotics have been bridged with an isobutylene unit by palladium-catalyzed reaction with 3-methylene-1,3-propanediyl bis­( t -butylcarbonate) in THF or toluene. − In addition, palladium-catalyzed C -allylation with similar dielectrophiles has been used in natural product total syntheses. , …”