Solid-phase-bound dipeptide

Jackson et al. furthermore prepared the solid-phase-bound ligand libraries 23 shown in Scheme 9 (27). The ligands consist of a solid-phase-bound dipeptide which is capped by a salicylic aldehyde. The screening of a number of... 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Fig. 3. Solid-phase synthesis of hydantoin and thiohydantoin libraries from resin-bound dipeptides.

Fig. 4. Solid-phase synthesis of an indolepyridoimidazole library and an imidazo-imidazolone hbrary from resin-bound acylated dipeptides.

In connection with an interest in generating /i-turn dipeptide mimetics, Piscopio and co-workers developed a solid-phase approach to the Freidinger lactam 86 via a solid-phase Ugi condensation and ring-closing metathesis (RCM) methodology [72], The resin-bound amine 85 is the equivalent of a traceless linker and the two-step protocol proceeds in good yield (Scheme 11.17). 

To overcome the problems associated with these reaction conditions, Backes et al. developed an alkanesulfonamide safety-catch linker for solid-phase s)rnthesis [34]. In this method, acylation of a sulfonamide support affords a support-bound iV-acylsulfonamide that is able to withstand the basic and strongly nucleophilic reaction conditions required for Fmoc-based SPPS. On completion of the solid-phase synthesis sequence, iodoacetonitrile treatment yields iV-cyanomethyl derivatives that can be cleaved under mild nucleophilic reaction conditions to afford the target compounds. Coupling conditions of alkanesulfonamide resin with Boc- and Fmoc-amino acids were developed to minimize the racemization. Using this method, a short synthesis sequence, followed by iodoacetonitrile activation and nucleophilic displacement is able to form dipeptide products from a number of support-bound amino acids incorporating diverse side-chain functionalities. 

Various solid-phase syntheses have been reported including the phosphinic acid dipeptide analogues 209 which were constructed by coupling the appropriate Wang Resin-bound amino acid to the phosphinate carboxylic acid 210 using Fmoc chemistry. Similar phosphinate carboxylic acid derivatives (211) protected at phosphorus as their 1-adamanyl esters have also been used in solid-phase synthesis directed towards zinc metallo protease inhibitors. ... 

Fig. 7.9. Representation of a combinatorial parallel synthesis of a 96-member library of dipeptides in a typical plastic microtiter plate of eight rows and 12 columns only the upper left three rows and three columns are shown. Step 1 shows three rows of wells containing three different amino acids that are already attached to a polymeric solid phase, as represented by the solid circles. In step 2, all eight rows are treated with the particular protected amino acids shown in each of the 12 columns, giving rise to 96 different polymer-bound dipeptides. In step 3, the dipeptides are cleaved from the solid support in preparation for testing them for biological activity.

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