Linkers, oxidatively cleaved

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]. 

Floreancig [42] has described a new solid-phase linker system cleaved by oxidative electron transfer. The cleavage process is based on the oxidative fragmentation of homobenzylic ethers. Acetal 230, immobilized on a soluble oligonorbornene scaffold prepared by ROMP polymerization, was efficiently... 

For the complete solid-phase synthesis of H- and A-Ras peptides, the hydrazide linker turned out to be the linker of choice (14). This linker is cleaved by oxidation to an acyldiazene that is then attacked by a suitable nucleophile. The linker is orthogonal to classic urethane protecting groups such as Boc, Fmoc, and... 

While the most common examples of diversity cleavage using phosphorus linkers have focused on this powerful olefination chemistry, other pertinent examples should be mentioned. Noticeably, cyanophosphoranes can be oxidatively cleaved (ozone or dimethyl-dioxirane) in the presence of a nucleophile (alcohol or amine) to provide a-keto esters and a-keto amides (Table 1.13, Entry... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

Methoxyphenyl ethers can be cleaved by mild oxidants (Entry 10, Table 7.8). Because many acid-labile linkers are also readily oxidized, care must be taken when applying this deprotection strategy. Benzyl ethers have been removed from Tentagel-or PEGA-bound carbohydrates by catalytic hydrogenation using palladium nanoparticles [112],... 

Support-bound organoselenium compounds have mainly been used as synthetic intermediates and linkers. The use of organoselenium compounds as linkers for solid-phase synthesis has been investigated by several groups [1-4]. The selenium-carbon bond is stable under a broad variety of reaction conditions, but can be selectively cleaved by tin radicals or by oxidants (see Sections 3.15.1 and 3.16.4). 

The carbonyl-reactive functional group on these cross-linkers is a hydrazide group that can form hydrazone bonds with aldehyde residues. To utilize this functional group with carbohydrate-containing molecules, the sugars first must be mildly oxidized to contain aldehyde groups by treatment with sodium periodate. Oxidation with this compound will cleave adjacent carbon—carbon bonds that possess hydroxyl groups, as are abundant in polysaccharide molecules (Chapter 1, Sections 2 and 4.4). 

Figure 195 Cross-linkers containing a diol group in their cross-bridge design may be cleaved by oxidation with sodium periodate.

Recent solid-phase syntheses utilise light-sensitive linkers which can subsequently be cleaved photochemically. And oxidative and reductive cleavage concepts are also used. The support material is subsequently filtered off and reused after washing. 

Disulfides, diselenides, and ditellurides can be oxidized by hypervalent iodine compounds quite easily. Depending on the reaction conditions disulfides can be oxidized to sulfinic esters [59] or thiosulfonic S-esters [60,61]. Diselenides can be transformed into selenosulfonates [62]. Arenetellurinic mixed anhydrides are mild oxidants and can be obtained by oxidation of the corresponding ditellurides as shown in Scheme 9 [63]. Recently it was shown that a thioacetal based linker for solid-phase synthesis can be cleaved oxidatively using [bis(trifluoro-acetoxy)iodo]benzene 4 [64]. 

Besides electrophiles and nucleophiles, several linkers are designed to be cleaved by oxidative or reductive methods (Tables 6.1.5 and 6.1.6). Besides the feature of orthogonality with other cleaving methods, a drawback in the use of oxidative or reductive reagents is the need to remove excess reagents or by-products. 

The redox-sensitive linker 1.34 (91), obtained in several steps from Merrifield resin and a lactone precursor, was charged with a N-protected aminoacid, treated with NBS to debenzylate and oxidize the linker to quinone, and submitted to SPS. The quinone linker was reductively activated to dihydroquinone with NaBH4 in THF/MeOH for 30 min at rt, then cleaved by treatment with anhydrous TBAF in THF for 20 h at rt to provide the free acidic peptide via intramolecular cyclization of the linker moiety. 

De Clercq [38] has utilized a sulfide linker, cleaved by a radical process initiated by electron transfer, in a solid-phase Julia-type olefination process. Alkylation of an aryl thiol resin followed by mCPBA oxidation gave supported sulfone 217 (Scheme 54). Successive treatment of the resin with n-butylhthium and an aldehyde followed by trapping of the resultant alkoxide with benzoyl chloride gave resin-bound a-benzoyloxy sulfone 218. Olefins 219 and 220 were released from the sohd support upon reduction with a single-electron-transfer reagent and elimination of the sulfone link-... 

Villalgordo et al. [22, 23] as well as Gayo and Suto [25] developed a strategy to cleave pyrimidines from the solid support. After oxidation of the thioether-linkage 17, aromatic substitution of the sulfonyl unit was performed with different N-nucleophiles as amines and azides to give free amino- or azido-pyrimidines 19 (Scheme 16.5). To demonstrate the stability of the linker, the resin-bound derivatives were subjected to different reactions such as saponification, ester reduction, acid chloride formation or Mitsunobu alkylation. A similar approach was presented later on by Hwang and Gong in the SPOS of 2-aminobenzoxazoles [26]. 

Waldmann s safety-catch hydrazide linker is also part of the class of traceless linkers [55]. Starting from hydrazide resin 126, which is converted into an activated species by oxidation with Cu(OAc)2, the molecules are cleaved by the addition of nucleophiles like amines to give arenes 127 (Scheme 16.30). 

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