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III. RESINS AND LINKERS FOR GENERATION OF AMIDE FUNCTION

III. RESINS AND LINKERS FOR GENERATION OF AMIDE FUNCTION

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Figure 8



thoxyphenoxy)valeric acid) 27 [33], Rink amide support (RAM) 28 [34]

and 4-(4V-methoxyvenzhydryl)phenoxyacetic acid (Dod) linker 29 [35]

contain more electron-donating groups and were designed on the same

principles as discussed above for the hydroxymethyl supports (Fig. 8).

These three linkers are the most widely used in SPOS and require TFA for

cleavage. Xanthone-based handles XAL (xanthenyl amide linder) 30 [36]

and Seiber 31 [37] resin were designed to release amides using low

concentrations of TFA (Fig. 9). Handles which contain an aminomethyl

and o-nitrobenzyl function (Nb [nitrobenzyl] 32 [38], NBHA [nitrobenzylamine] 33 [39], and a-methyl-6-nitroveratrylamine) 34 [40] are cleaved by

photolysis and are based upon the same principles discussed for hydroxyl

resins (Fig. 10).



Figure 9



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Figure 10



In an extension to the xanthenyl theme, the benzyl hydrogen was

replaced with a substituted p-methoxyphenyl ring to give linker 35 (Scheme

10) [41]. Peptide amides were cleaved rapidly and in high purity with TFADCM (1:9) for 15 min or as a protected fragment with TFA-DCM (1:99)

for 3–10 min.

Silyl-derived linker 36 was prepared in three steps from a silyl ether of

serine and incorporated for Fmoc/tBu-based assembly of protected glycopeptide blocks (Scheme 11) [42]. The a-carboxylic acid function of serine

was protected as an allyl ester. Deprotection by a Pd(0) catalyst in the

presence of dimedone liberated the carboxylic acid in order for subsequent



Scheme 10



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 11



coupling with amines, alcohols, and carbohydrates. The final glycopeptide

product was released from the support by fluoridolysis (CsF).

As an extension to the p-carboxybenzenesulfonamide ‘‘safety-catch’’

linker [43,44], alkanesulfonamide handle 37 was developed [45]. This linker

tethers carboxylic acids to the solid support to give an acylated sulfonamide which is stable to both basic and acidic conditions (Scheme 12).

Products were released by treatment with iodoacetonitrile followed by the

addition of a nucleophile.

Aryl hydrazide linker 38 stable to both acid and base was utilized in

SPPS [46]. Treatment of the resin with a copper(II) catalyst in the presence

of a base and nucleophile gave the corresponding acid, amide, or ester

(Scheme 13).



Scheme 12



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 13



IV. RESINS AND LINKERS FOR N-SUBSTITUTED

AMIDE GENERATION

Linker 39 with an aldehyde attachment point permits amine anchoring

via reductive amination (Fig. 11) [47]. In peptide synthesis, the handle

attaches the amino as opposed to carboxylic acid function of the Cterminal residue to the support followed by chain elongation (attachment

to the peptide occurs via a backbone nitrogen). The same strategy for

developing handles functionalized with an aldehyde is similar to the

concepts described above. Backbone amide linker (BAL) 40 was prepared from the Fmoc-based tris(alkoxy)benzylamide handle PAL [48]. In

peptide synthesis, BAL allows the preparation of sequences having a

variety of C-terminal functionalities such as alcohols, N-alkyl amides,

and head-to-tail cyclic peptides that are devoid of a trifunctional amino

acid. Due to the electron-donating groups contained in the handle,

release of the peptide is accomplished with a high concentration of

TFA. Based upon the BAL concept, the acid sensitive methoxybenzal-



Figure 11



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 14



dehyde polystyrene resin (AMEBA) 41 was reported for the solid-phase

synthesis of sulfonamides, amides, ureas, and carbamates [49]. Reductive amination of aldehydes and ketones with sodium cyanoborohydride

to Rink amide linker generated N-alkyl amines. Acylation followed by

cleavage with TFA provided a method to generate a series of difunctional amines and N-substituted amide derivatives [50]. Subsequently,

backbone linker 42 for Boc-based peptide was developed from a 4alkoxybenzyl derivative in which products were released upon HF

treatment (Scheme 14) [51].

Contrary to an alkoxy benzene scaffold, secondary amides were

generated via novel aldehyde linker 43 based upon an indole scaffold

(Scheme 15) [52]. The indole resin was prepared from indole-3-carboxyaldehyde in two steps and reacted with amines under reductive conditions

to generate resin-bound secondary amines. Treatment of the resin with



Scheme 15



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



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