Linker allylic

Fig. 2.22 Combination of chiral imidazolidin-2-ylidenes and biphenyl linkers in the chiral catalysts or catalyst precursors for the asymmetric allylic alkylations...

The choice of diallylphtalate as the cross-linker is somewhat surprising, because allylic compounds are not very reactive in radical polymerizations due to the stability of the allyl radicals. 

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). 

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... 

FIGURE 5.23 Synthesis of cyclic peptides by head-to-tail cyclization of resin-bound peptides using Boc/Bzl chemistry59 and Fmoc/tBu chemistry.60 The carboxy-terminal protectors are orthogonal to the other protectors. The nature of the linker determines the nature of the product. Both chemistries are compatible with the two types of linkers. All = allyl. 

Glycol Bis(allyl Phthalates) as Cocross-linkers for Diallyl Phthalate Resins... 

Obviously, the coordination of the new ligands is not affected by the additional linker groups at the bridging carbon atom. No coordination of the linker to the metal center instead of the carboxylate donor takes place and the geometries of the allyl group in 53 (Fig. 33a) as well as of... 

The group of allyl-based linkers was developed by Kunz et al. [49] Linkers of the general allyl type are particularly valuable, because they are removable under almost neutral conditions using palladium catalysis and are orthogonally stable towards the commonly used acid and base-labile protecting groups (Tab. 3.2). 

New allylic anchors as the HYCRAM (19) (hydroxycrotonylamide) [50] and HY-CRON (21) (hydroxycrotyl-oligoefhylene glycol-n-alkanoyl) [51] linker have been developed, which exhibit excellent properties for the solid-phase synthesis of protected peptides and glycopeptides. A more flexible spacer was inserted in the HY-CRON (21) linker between the anchor and the polymeric support in order to facilitate an efficient access to the Pd(0) complex during the detachment reaction. 

Recently, the semi-synthesis of Vancomycin (48) on solid supports was accomplished using an allylic linker (Scheme 3.2) [123, 124]. Polymer-bound chiral electrophilic selenium reagents have been developed and applied to stereoselective se-lenylation reactions of various alkenes (Tab. 3.9) [125]. 

Resin-bound (4-acyloxy-2-buten-l-yl)silanes, which can be prepared from resin-bound allylsilanes and allyl esters by cross-metathesis, react with dilute TFA to yield free carboxylic acids (Figure 3.7 [75]). However, the scope of this strategy remains to be explored. Similarly, esters of polystyrene-bound (2-hydroxyethyl)silanes readily undergo acidolysis and have been used as acid-labile linkers (Figure 3.7 [76]). 

Allyl esters, carbonates, and carbamates readily undergo C-O bond cleavage upon reaction with palladium(O) to yield allyl palladium(II) complexes. These complexes are electrophilic and can react with nucleophiles to form products of allylic nucleophilic substitution. Linkers based on this reaction have been designed, which are cleavable by treatment with catalytic amounts of palladium complexes [165,166], For the immobilization of carboxylic acids, support-bound allyl alcohols have proven suitable (Figure 3.12, Table 3.7). 

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. 

Table 3.7. Linkers cleavable by palladium(0)-catalyzed allylic nucleophilic substitution.

Polystyrene-derived phenylboronic acids have been used for the attachment of diols (carbohydrates) as boronic esters [667]. Cleavage was effected by treatment with acetone/water or THF/water. This high lability towards water and alcohols severely limits the range of reactions that can be performed without premature cleavage of this linker. Arylboronic acids esterified with resin-bound diols can be oxidatively cleaved to yield phenols (Entry 8, Table 3.36). Alcohols have also been prepared by nucleophilic allylation of aldehydes with polystyrene-bound, enantiomerically enriched allyl-silanes [668], as well as by Pummerer reaction followed by reduction of resin-bound sulfoxides [669]. 

C-Alkylations have been performed with both support-bound carbon nucleophiles and support-bound carbon electrophiles. Benzyl, allyl, and aryl halides or triflates have generally been used as the carbon electrophiles. Suitable carbon nucleophiles are boranes, organozinc and organomagnesium compounds. C-Alkylations have also been accomplished by the addition of radicals to alkenes. Polystyrene can also be alkylated under harsh conditions, e.g. by Friedel-Crafts alkylation [11-16] in the presence of strong acids. This type of reaction is incompatible with most linkers and is generally only suitable for the preparation of functionalized supports. Few examples have been reported of the preparation of alkanes by C-C bond formation on solid phase, and general methodologies for such preparations are still scarce. 

Most of these procedures are incompatible with common linkers, and are therefore unsuitable for the transformation of support-bound substrates into carboxylic acids. A more versatile approach for this purpose is the saponification of carboxylic esters. Saponifications with KOH or NaOH usually proceed smoothly on hydrophilic supports, such as Tentagel [19] or polyacrylamides, but not on cross-linked polystyrene. Esters linked to hydrophobic supports are more conveniently saponified with LiOH [45] or KOSiMe3 in THF or dioxane (Table 13.11). Alternatively, palladium(O)-mediated saponification of allyl esters [94] can be used to prepare acids on cross-linked polystyrene (Entries 9 and 10, Table 13.11). Fmoc-protected amines are not deprotected under these conditions [160],... 

MI139, 2004MI773>. Bis(thioureas) [CH2NHC(S)NHR]2 (R = allyl, Ph, benzyl) with ethylene instead of 1,2-phenylene linker cyclized to thiadiazepines 108 in the presence of tetracyanoethylene in THF at ambient temperature <2004ZNB910> or neat on conventional heating or under microwave irradiation <2003HAG535>. 

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