Submonomer solid-phase synthesis

Zuckermann RN. Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis. J. Am. Chem. Soc. 1992 114 10646-10647. 

Ric1995 Richter, L.S. and Zuckermann, R.N., Synthesis of Peptide Nucleic Acids (PNA) by Submonomer Solid Phase Synthesis, Bioorg. Med. Chem. Lett., 5 (1995) 1159-1162. 

Key words Peptoids, N-substituted glycines. Submonomer solid-phase synthesis, Antimicrohial... 

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). 

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. 

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

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

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. 

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

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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