Scheme 27

The linker was prepared starting from serine benzyl ester 57 according to Scheme 27. First, the hydroxyl function was protected as silylether. The amino group was then reacted with phosgene to allow for the further reaction with a substituted phenol (the educt). Finally, the benzylester was hydrogenolyzed, yielding unit 58 that carried a carboxylic acid function for attachment to the solid support to yield 55 ready for use in combinatorial synthesis. Carboxy Functionalized Resins for the Attachment of Phenols

Polystyrene was modified with carboxyl groups to allow for an attachment of phenols via an ester bond [47]. Hence, the insertion of a special linker unit was not necessary. After combinatorial synthesis the phenol was released under basic conditions. A typical example was the preparation of a bis benzamidophenol library by this approach [56]. Acetal Linker for the Preparation of Aldehydes

This linker was originally developed by Leznoff and colleagues [57, 58], Its preparation is outlined in Scheme 28. Commercial Merrifield resin was functionalized with the sodium

QTa ♦"""T'V—- qt°ty -S- or~°ym


1. Combin. Chemistry .0 r

alkoxide of isopropylidenglycerol. Hydrolysis of the acetonide yielded the desired entity 59, to which an aldehyde was coupled as starting material for a combinatorial synthesis. The final product carrying an aldehyde function was released by mild acid treatment. The linker was applied successfully in Suzuki-Miyaura cross-couplings to yield biaryl and heterobiaryl aldehydes as products [59].

Procedure: Attachment of aldehyde to resin 59 [57]

Anhydrous resin 59 was suspended in 60 mL of anhydrous dioxane. Excess terephtha-laldehyde (2.0 g) and 0.1 g of m-benzenedisulfonic acid as catalyst were added as well as 2.0 g of anhydrous sodium sulfate to absorb the liberated water.The mixture was stirred at rt for 48 h under exclusion of moisture. The resin was filtered, neutralized with anhydrous pyridine and re-filtered.The resin was then washed twice with pyridine/water (1:1), with water (10 times), ethanol (three times) and with ether (three times). For cleavage of the aldehyde, the resin (3.43 g) was stirred with 40 mL of a 1:1 mixture of dioxane and dilute HCI for 48 h at rt.The resin was filtered and washed with water (six times), acetone (once), ethanol (three times) and ether (three times).The aqueous filtrate was extracted three times with ether.The combined ether extracts were washed with water, dried over Na2S04 and evaporated to give a solid which upon preparativeTLC yielded 86 % of the desired aldehyde.

Aldehydes could also be attached to resin-bound serine or threonine via oxazolidine formation [60], This linker was used for the preparation of peptide aldehydes. The cleavage occurred with mild aqueous acid at 60° C.

A further aldehyde linker was constructed using Wittig chemistry [61], The olefin 60 created by the Wittig reaction was cleaved via ozonolysis, followed by subsequent work-up with dimethyl sulfide yielding the aldehyde 61. The principle was demonstrated for the synthesis of a library of peptide aldehydes.

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