Submonomer

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

Burkoth, T. S., Faearman, A.T., Char-YCH, D. H., Connolly, M.D., and Zuckermann, R.N. Incorporation of unprotected heterocyclic side chains into peptoid oligomers via solid-phase submonomer synthesis. J. Am. Chem. Soc. 2003 125, 8841-8845. 

Scheme 41 SPPS of a Peptoid-Peptide Hybrid (A) The Premade Monomer Method 122-2151 (B) The Submonomer Method1216-2171...

Two methods are used for the SPPS of peptoids and peptoid-peptide hybrids (Scheme 41). The first method 122,215 (Scheme 41, route A) called the premade monomer method involves the preparation of a Fmoc-protected monomer in solution (see Section 10.1.1.4.1 and Table 8) and its incorporation into the peptoid or the peptoid-peptide hybrid using Fmoc/SPPS. The second method1216217 (Scheme 41, route B) called the submonomer method involves the formation of the peptoid monomer on the solid support by first forming a bromoacetylated peptide-resin and then substituting the alkyl halide with the appropriate alkyl- or side-chain protected co-functionalized alkylamine. 

The submonomer method has two distinct advantages over the premade monomer method (1) the formation of the monomer on the resin eliminates the need for -protection (2) this method simplifies the synthesis of peptoid libraries, especially those that contain nonfunctionalized N-alkylated side chains, by using commercially available amines. Moreover, the diversity of these libraries is huge. 

The first step in the submonomer method involves the acylation of a halogenated acetic acid on the resin under standard conditions. In the second step the side chain of the peptoid is introduced by nucleophilic substitution of the halide with an excess of the primary amine. 

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

Fig. 10 Solid-phase synthesis of cationic lipids using submonomer (a) [147, 148] and monomer (b) [151, 152] linear assembly...

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). 

Scheme 7.1. Synthesis of a NSG peptoid dimer using the submonomer method 8 on a solid support carrying amide linker.

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-... 

R.N. Zuckermann, J.M. Kerr, S.B.H. Kent, W.H. Moos, Efficient method for the preparation of peptoids [oligo(n-substituted glycines)] by submonomer solid-phase synthesis,... 

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

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... 

SCHEME 9.6 Schematic of solid-phase submonomer peptoid synthesis method. 

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... 

The main reason for the wider adoption of peptoids relative to many other types of peptidomimetic polymers is their relative synthetic accessibility and versatility, both fmits of the commonly used submonomer synthesis protocol (Figure 3). Peptoids were reported originally as individually synthesized N-substimted Fmoc amino adds for use in Fmoc solid-phase peptide synthesis. It was noted at the time that two such amino adds were already commercially available (Npm and sarcosine. Figure 4), and 20 years later those same two amino acids are joined by only one more commerdally available Fmoc-protected peptoid amino add, NLys. Thus, dearly the adoption of peptoids by dozens of research groups worldwide has not been spurred by commerdal availability of synthesis-ready Fmoc-protected N-substituted glydne monomers. 

Instead, peptoids are synthesized using the submonomer synthesis protocol first reported by Zuckermann and coworkers. In conventional peptide synthesis, whether of natrual a-peptides or otherwise, both the amine and add moieties of the amino acid are installed in one synthetic step, followed by a deprotection step that paves the way for the next cyde (Figure 3). However, in the submonomer protocol, the amine and add moieties are installed in two separate... 

Figure 3 Solid-phase peptide synthesis (a) and solid-phase peptoid synthesis using the submonomer protocol 1...

Additionally, the submonomer process enables installation of nearly any commercially or synthetically accessible primary amine as a side chain in peptoids. To date, 230 different amine monomers have been incorporated into peptoids as side chains, a number that likely equals or exceeds all possible commercially available a-amino acids, and yet represents a mere fraction of the possible chemical diversity of peptoids. The synthesis of any new a-amino acid requires either asymmetric synthesis or chiral separations, both of which contribute to high costs associated with synthesizing new amino acids. With peptoids, however, new residues can in principle use any of the thousands of commercially available primary amines, which also include a plethora of a-chiral amines (inexpensive due to their use in industrial chiral separations) that have... 

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