Submonomer approach

Cationic lipids (lipitoids [147, 148]) were assembled on solid phase by Zuckermann using a submonomer approach, based on the sequential incorporation... 

Zuckermann et al. [8] developed a successful protocol, defined submonomer approach , for the solid-phase synthesis of peptoids, starting from the readily available building blocks bromoacetic acid and primary amines (Scheme 7.1). 

The access to peptoids was simplified with the solid-phase submonomer approach (Scheme 21) reported by Zuckerman et al. [56]. As shown in Scheme 21, the first step consists of acylation of the resin-bound amine with bromoacetic acid and DIC as the coupling agent, and in a second step, the side chain is introduced by nucleophilic substitution of the halide with an excess of a primary amine. This method, which allows the preparation of a wide variety of oligomers, has been applied successfully to the generation of diverse combinatorial peptoid libraries [50]. Furthermore, A-hlkyl glycine residues containing peptide or peptoid-peptide hybrids can be read-... 

A solid-phase submonomer approach to A-substituted j8-aminopro-pionic acid oligomers or )8-peptoids has been developed by Hamper et al. [63]. It is based on a simple two-step acylation and Michael addition reaction sequence. Treatment of Wang resin with 2 equiv. of acryloyl chloride in the presence of triethylamine in excess afforded the corresponding acrylate resin 86 (Scheme 23) [63]. Michael addition of a 6- to 10-fold excess of a given primary amine in DMSO afforded polymer-bound A-substituted -alanines (87). Trimeric A-benzyl-j8-aminopropionic acid (88) was prepared in 67% overall yield by repetition of this two-step sequence. 

Peptoids are oligomers of A-substituted glycines that, similar to P-peptides, have enhanced stability toward proteolysis and can be used in the design of new biological probes and in drug discovery. Peptoids are typically synthesized via the submonomer approach that features iterative acylation and amination reactions as shown in Scheme 9.6. This can take up to 3 h per monomer unit, and longer pep-toid sequences exacerbate this problem. Monomer incorporation can be reduced to... 

Polypeptoids are similar to polypeptides except the side chains are attached to the amide nitrogen of the peptide backbone instead of the a -carbon (Figure 12.6). Peptoids are synthesized by solid-phase synthesis on a peptide synthesizer using a submonomer approach that proceeds by adding each monomer in a two-step process. With this method, many different side chain groups... 

Four methods for the solid-phase synthesis of peptoids have been reported (i) the monomer approach in which i -substituted glycine building blocks are synthesized and characterized and then coupled sequentially [1]. (ii) reductive alkylation of glycine with the appropriate aldehyde or ketone to obtain the desired N -alkylated glycine derivative [29], (iii) the photolithographic approach [30], and (iv) the submonomer approach [31]. Only the latter, which by far is the most popular, will be described in detail below. 

In the submonomer approach, peptoids are synthesized from the C to N terminus on a Rink amide linker resin using a two-step coupling cycle (Fig. 2). First step involves a DIC-mediated coupling of bromoacetic acid to the resin followed by a SN2-nucleophilic displacement by a primary amine. This cycle is repeated until the desired compound is obtained. The peptoid is then cleaved from the resin with 95 % aqueous TFA. Following removal of TFA by evaporation, the peptoid is precipitated and lyophilized. Finally, the identity of the product is verified by chromatography combined... 

Peptoids containing up to 50 residues have been synthesized in reasonable yield using the submonomer approach [17]. Different instrumentations have been used for peptoid synthesis such as manual synthesis in syringes equipped with a fritted filter [21], automated peptide synthesizers [28], automated microwave peptide synthesizers [12], and parallel synthesizers [34]. 

In contrast to the relative simplicity of the submonomer method , which can be fully automated using commercially available building blocks, a different approach to generate peptoids is based on the use of preformed Fmoc-N-protected NSG residues. The synthe-... 

Scheme 21 Solid-phase monomer [55] and submonomer [56] approach to the synthesis of peptoids.

Fig. 1 Synthetic approaches towards peptoids by either (a) solid-phase submonomer synthesis or (b-d) ring-opening polymerization initiated by nucleophiles such as (b) amines in solution, (c) amines on solid-phase resins, or (d) IV-heterocyclic carbenes in solution...

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