Sasrin linkers

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Because no treatment with acid is required during peptide assembly, peptide synthesis with Fmoc amino acids can be conducted on acid-sensitive supports (e.g. Tenta-gel) and with acid-labile linkers. Wang resin is suitable for most purposes, but other supports, such as Sasrin or 2-chlorotrityl resin, can also be used. CPG, macroporous... 

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

The Wang linker 1.1 (57) is a very popular choice that is based on ap-alkoxybenzyl alcohol moiety. It is typically cleaved by trifluoroacetic acid (TFA)-DCM 1/1 in 30 min at room temperature (rt) to produce carboxylic acids or alcohols. Two slight modifications to this linker have produced the super-acid-sensitive resin (SASRIN)... 

Fmoc-D-cycloserine (4-aminoisoxazolidine-3-one) and its enantiomer were immobilized on SASRIN resin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The loading of the resulting resins (0.59-0.69 mmol g) was determined by spectrophotometry of the in rr/ -generated piperidine-dibenzofulvene... 

Resins/linkers used Safety Catch, Rink amide, Wang, Sasrin, THP, traceless. 

Cl Cl 6 p r= /= MeNHOH OH r= Y nA/om 0 0 [26] Only one example of nucleophilic cleavage with hydrox-ylamine has been described. Recently, many different hydroxylamine-based linkers have been described based on attachement of hydrox-ylamine to trityl-, Wang-, Sasrin- or Rink-resin. [26] [33] [175-177]... 

Ms CN O DBU [56J thiophene Resins/linkers used Wang resin. Moderate to high yields. 4-thiazolidinone, thiazole thiazolidine thiazanone Tentagel or Sasrin resin one-pot reaction good yields [56] [241] [200] [204] [205] [242]... 

In resins where the linker is anchored by an ether bond, the ether plays an essential role as an electron-donating substituent, thereby enhancing the acid sensitivity of the linker. In many cases, such as the Wang [8] (1) and Sasrin [10] linkers (3), this ether is benzylic as it derives from chloromethyl polystyrene (8). With such resins, there is always the risk that during the cleavage reaction the benzylic ether may also cleave, resulting in a product modified or contaminated... 

Figure 14.2 Ether and amide linked variants of some hydroxymethylphenoxy linkers. Wang (1) [8] HMPA (2) [9] Sasrin (3) [10] HMPB (4) [11].

TFA in DCM cleaved the peptide acid from the resin whilst retaining tBu/ Boc-based side-chain protection. Riniker [11] later developed a version of this linker with enhanced acid sensitivity by insertion of two extra methylene groups into the linker spacer 4. The Sasrin linker 3, developed by Mergler [10], is also based on the same dialkoxybenzyl alcohol structure, but in this case the linker is attached directly to Merrifield resin via an ether bond. 

Carbamates and chloroformates are also shown in the cases reported (see text). Some linkers and resins are labile to other cleavage conditions such as Merrifield, HMPS, Wang and Sasrin (acidolysis) or Nbb (photolysis). 

Scheme 11.2. SASRIN resin-bound maleimide with an ester linker.

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