Synthesis of peptoids

Rapid Synthesis of Peptoid Macrocycles by Multi Component Reactions. . 163... 

As illustrated above, peptides have been used as tethering elements for the suitable positioning of carbohydrate moieties. Since the chemistry of glycopeptides is well under control, the approach may appear valuable, at least a priori. This is likely to be true for research investigations. However, as neoglycopeptides should eventually developed into useful therapeutics, the synthesis of novel and metabolically stable neoglycopeptidomitics was undertaken [110-113]. The approach chosen was commensurate to that used for the synthesis of peptoids. 

The synthesis of amino acids in which a nonfunctionalized alkyl group is covalently connected to the a-nitrogen has been discussed vide supra). In this section the synthesis of N-substituted amino acids in which the alkyl chain bears a protected functional group is discussed. The resulting amino acids have the general formula /Va-(m-functionalized alkyl) amino acids 28 (Scheme 17). These amino acids were developed for the solid-phase synthesis of backbone cyclic peptides 70 (see also Vol. E 22b, Section 6.8.3.2.4) [in this case they were called building units (BU)], for the synthesis of PNA 71 and for the synthesis of peptoids. 72 (In this case they were called monomers.)... 

Zuckermann et al.[216 217 have adapted the method developed by Fischer and Otto[268 for a convenient synthesis of peptoids and peptoid-peptide hybrids by SPPS. The peptoid monomer is built on the solid support by first preparing a bromoacetyl submonomer and then substituting the bromine with an alkyl- or side-chain-protected co-functional alkylamine (Scheme 41, route B). 

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 synthesis of peptoids and peptoid-peptide hybrids libraries is described in refsl210 217 254 2691 and in references cited in Table 12. 

Scheme 1. Multipin SPOC synthesis of peptoid libraries.

Using the Multipin SPOC systems, researchers at Chiron have demonstrated the automated solid-phase synthesis of peptoids 1 (Scheme 1) [12], while Ellman and co-workers have completed the synthesis of a combinatorial library of 11 200 spatially dispersed benzodiazepines 2 (Scheme 2) [13],... 

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

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). 

Approaches to the synthesis of peptoids are summarized in Scheme 21. In the original method, Simon et al. [55] reported a monomer approach analogous to peptide synthesis in which the appropriate Fmoc-protected N-substituted glycines (84) were activated and coupled to the secondary amino group of the resin-bound peptoid chain to yield 85 (Scheme 21). Several synthetic routes to A-Fmoc-protected precursors (84) that were utilized in this early work are summarized in Scheme 22. 

This approach was reinvestigated by Liskamp s group during the synthesis of peptoids and retro-peptoid analogues of Leu-enkephalin and substance R In this study, A-substituted glycine precursors were obtained by alkylation of appropriate primary amines with ethyl bromoacetate. Subse-... 

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

Peptoid oligomers are synthesized on a Rink amide resin (50 /Ltmol scale) to avoid diketopiperazine formation. In order to suppress the formation of diketopiperazine during the synthesis of peptoids with a C-terminal carboxylic group, one can use the 2-chloro tritylchloride resin [155]. Following Fmoc removal, the resin is bromoacylated by successively adding a solution of bromoacetic acid (83 mg, 600 tmol, 12 equiv.) in DMF (830 fiL) and 200 fiL of DIG (103 /xL, 660 tmol, 13 equiv.) in DMF (170 >L) to the resin. The reaction mixture is shaken for 30 min at room temperature. A double coupling is performed systematically. The resin is then filtered and washed three times with 2 mL of DMF. The nucleophilic substitution step... 

Three different types of building block strategies were developed for the efficient synthesis of peptoids as schematically shown in Scheme 2.4.1 (Approaches A-C)P ... 

The solid phase-supported synthesis of peptoids was first reported using protected and N-substituted amino acids [23], A major bottleneck of this approach was the difficult and expensive monomer synthesis. Accordingly, Zuckermann and coworkers developed a different approach in which a monomer unit is formed in two reaction steps. First, a haloacetic acid is coupled to the resin and, second, Sn2 substitution of the halogen with a primary amine takes place (Fig. la). The crucial... 

Zuckermann et aL published the hrst examples of SPS-hahde displacement in the synthesis of peptoids in 1992 [252] (Scheme 12). The utUized strategy is caJled sub-monomer synthesis and the hahde was introduced by amide formation of halogenated carboxyhc acids. To elongate the peptoid back-... 

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. 

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