Microwave-Enhanced Solid-Phase Synthesis of N,N′-Linked Aliphatic Oligoureas and Related Hybrids

Abstract

A practical and efficient microwave-assisted solid-phase method for the synthesis of N,N'-linked oligoureas and related amide/urea hybrid oligomers, featuring the use of succinimidyl (2-azido-2-substituted ethyl) carbamate monomers, is reported. The rate enhancement of urea formation under microwave irradiation combined with the mild conditions of the phosphine-based azide reduction makes this approach very effective for routine synthesis of oligoureas and possibly for library production.

Solid‐Phase Synthesis of Hybrid Urea Oligomers Containing Conservative Thiourea Mutations

“…[23] The same coupling/deprotection cycle was used for both monomers B and 7, with microwave irradiation to speed up and improve the coupling steps (see Exp. Section).…”

“…Section). [23] After the synthesis was complete, cleavage from the resin by treatment with hydrofluoric acid (HF) gave the ex-pected oligomer (i.e., 8a) in 19 % yield after semipreparative RP-HPLC purification.…”

“…To enable further applications, including thiourea scanning of biologically active oligourea helices, we decided to develop a solid-phase synthesis (SPS) approach. The synthesis of homooligoureas has been studied extensively over the last 15 years, and various methods for their solid-supported synthesis have been reported by our group [21][22][23] and others. [24][25][26][27][28] In our laboratory, the SPS of oligoureas with chain lengths ranging from 6-12 residues is now routinely achieved using succinimidyl (2-substituted 2-azidoethyl)carbamates of type A (Figure 2).…”

“…[24][25][26][27][28] In our laboratory, the SPS of oligoureas with chain lengths ranging from 6-12 residues is now routinely achieved using succinimidyl (2-substituted 2-azidoethyl)carbamates of type A (Figure 2). [23] The advantage of these activated monomers compared to corresponding N-Fmoc-and N-Boc-protected (Fmoc = fluorenylmethoxycarbonyl; Boc = tert-butoxycarbonyl) building blocks (B; Figure 2) is that they can be used with standard TFA-labile resins (TFA = trifluoroacetic acid), and also that they can be used in conjunction with microwave irradiation to accelerate the oligourea-chain extension. [23] Notably, this synthetic approach has been combined with classical solid-phase peptide synthesis (SPPS) to access α-peptide/oligourea chimeras containing fused peptide and oligourea domains.…”

“…[23] The advantage of these activated monomers compared to corresponding N-Fmoc-and N-Boc-protected (Fmoc = fluorenylmethoxycarbonyl; Boc = tert-butoxycarbonyl) building blocks (B; Figure 2) is that they can be used with standard TFA-labile resins (TFA = trifluoroacetic acid), and also that they can be used in conjunction with microwave irradiation to accelerate the oligourea-chain extension. [23] Notably, this synthetic approach has been combined with classical solid-phase peptide synthesis (SPPS) to access α-peptide/oligourea chimeras containing fused peptide and oligourea domains. [29] In contrast, methods to access thiourea oligomers are much less developed, even in solution.…”