Fmoc linkers based

Silyl-derived linker 36 was prepared in three steps from a silyl ether of serine and incorporated for Fmoc/tBu-based assembly of protected gly-copeptide blocks (Scheme 11) [42]. The a-carboxylic acid function of serine was protected as an allyl ester. Deprotection by a Pd(0) catalyst in the presence of dimedone liberated the carboxylic acid in order for subsequent... 

Fig. 17.7 Solid phase synthesis to obtain aminoindoline alkaloid-like tricyclic compounds by in situ aza Michael approach - (a) alkylsilyl linker-based polystyrene macrobeads (1.0 equiv),TfOH (6.0 equiv), 2,6-lutidine (10.0 equiv), 14 (0.5 equiv) (b) (i) 20% piperidine (ii) N-Fmoc amino acid chloride, collidine (iii) 20% piperidine.

Of those in common usage, the 2-chlorotrityl 28 [74] and 4-carboxytrityl 29 [75] linkers give the least stabilized cations and are suitable for immobilization of carboxylic acids. They are ideal for Fmoc/tBu-based SPPS as their use avoids many of the side reactions that occur with standard benzyl-based linkers. Firstly, race-mization does not occur during loading of the resin with the C-terminal residue [79], as is the case with esterification to hydroxy-functionalized resins. Secondly, the bulky trityl cation does not cause alkylation side reactions with nucleophilic amino-acid side-chains. Thirdly, cysteine does not undergo racemization [80, 81]... 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Allylic hydroxycrotyl-oligoethylene glyco-n-alkanoyl (HYCRON) linker 25 was applied to the synthesis of protected peptides and glycopep-tides [31]. HYCRON is stable to both acidic and basic conditions and is compatible with Boc- and Fmoc-based chemistry. The preparation of this novel linker is only two steps from commercially available materials. H YCRON linker can be cleaved under neutral conditions using Pd catalyst (Scheme 9). 

A special group of base-labile linkers for carboxylic acids rely on cleavage by 3-elimination. Here, the resin-bound alcohol must bear an electron-withdrawing group in the [3 position (Figure 3.8), which facilitates elimination by acidifying this position. Mechanistically, these linkers are closely related to the Fmoc protective group, and... 

The two most commonly used types of allyl alcohol linker are 4-hydroxycrotonic acid derivatives (Entry 1, Table 3.7) and (Z)- or ( )-2-butene-l, 4-diol derivatives (Entries 2 and 3, Table 3.7). The former are well suited for solid-phase peptide synthesis using Boc methodology, but give poor results when using the Fmoc technique, probably because of Michael addition of piperidine to the a, 3-unsaturated carbonyl compound [167]. Butene-l,4-diol derivatives, however, are tolerant to acids, bases, and weak nucleophiles, and are therefore suitable linkers for a broad range of solid-phase chemistry. 

Support-bound triacylmethanes (e.g. 2-acetyldimedone) readily react with primary aliphatic amines to yield enamines. These are stable towards weak acids and bases, and can be used as linkers for solid-phase peptide synthesis using either the Boc or Fmoc methodologies, as well as for the solid-phase synthesis of oligosaccharides [456]. Cleavage of these enamines can be achieved by treatment with primary amines or hydrazine (Entries 2 and 3, Table 3.23 see also Section 10.1.10.4). 

The synthesis of peptides on a solid support, usually beads of either polystyrene (the Merrifield approach) or polyamide (the Sheppard approach) resins has become extremely important, because it allows peptides to be synthesized by machines, and a key feature of the Sheppard approach is the use of Fmoc-protected amino acid residues. The idea is that the C-terminus amino acid is tethered to the resin by means of a carbamate linker that is stable to mild acid or base. The peptide chain is then built up using the sorts of methods we have been discussing and, when complete, is released by cleaving the linker with strong acid. 

The wide use of acid-labile linkers and protecting groups in peptide SPS has reduced efforts toward the development of base-labile linkers. The commonly used SP Fmoc peptide coupling protocols require Fmoc deprotection under basic conditions during the synthesis, thus ruling out base-labile linkers. However, base-labile linkers are popular in oligonucleotide SPS and will be described in Section 2.2. Other examples of base- or nucleophile-labile linkers are shown in Fig. 1.10. 

---