Reductively cleaved linkers

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]. 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

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]. 

A new solid-phase technique used a relatively nontoxic cleaving agent for peptide aldehydes, which would prevent lithium aluminum hydride reduction byproduct contamination 51 A support-bound threonine or serine was treated with the substrate aldehyde to give an imine intermediate that immediately cyclized to give the stable oxazolidine linker, which was stable to Fmoc conditions including treatment with TFA. The peptide was cleaved under mild aqueous conditions at 60 °C 51 ... 

The cross-linker used to form the bond between the antibody and toxin must be able to survive in vivo and not be cleaved by enzymatic or reductive means before reaching the targeted cells. 

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

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. 

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 first linker systems designed to be cleaved using Sml2 were based on the reduction of N-O bonds. For example, Abell prepared amides (including 19) and ureas using an N-0 linker cleaved by Sml2,47 and Taddei used a similar strategy in a solid-phase synthesis of p-lactams such as 20 (Scheme 7.13).48... 

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-... 

One important variation of this linker is Barany s B AL linker 13, which contains a formyl group [45-51]. Primary amines [45] and O-protected hydroxylamines [52] are attached to this linker by reductive animation. The resulting secondary amines can be acylated and the corresponding secondary amides or hydroxamates cleaved with TFA. Anilines [53] and enamines [54] can be cleaved without needing to be acylated. 

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]. 

Spengler and coworkers [173] have used p-nitromandelic acid (Pnm) as a safety-catch linker for the synthesis of depsipeptides by Boc/Bzl chemistry. The hexafluo-roacetone (HFA)-protected Pnm is loaded on the resin with concomitant deprotection of the hydroxy unit. After the depsipeptide is constructed, reduction of the nitro group with 6M SnCl2/1.6mM HC1 gives the p-aminomandelic (Pam) linker, which can be cleaved in acidic media (5% TFA in dioxane, 50°C, lh), thereby obtaining the target depsipeptides in good yields and purities (Scheme 18.7). 

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