Backbone amide linkers

Jensen KJ, Alsina J, Songster MF, Vagner J, Albericio F, Barany G. Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified and cyclic peptides. J Am Chem Soc 1998 120 5441— 5452. 

BACKBONE AMIDE LINKER (BAL) STRATEGY FOR SOLID-PHASE SYNTHESIS... 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Several different types of linker have been developed that yield amides upon cleavage. These linkers can often also be used to prepare sulfonamides, carbamates, or ureas. There are essentially three different strategies for the release of amides from insoluble supports (a) cleavage of the benzylic C-N bond of resin-bound N-alkyl-N-benzylamides (backbone amide linkers, BAL linkers), (b) nucleophilic cleavage of resin-bound acylating agents with amines, and (c) acylation/debenzylation of resin-bound /V-benzyl-/V,A -dialkylamines. 

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). 

Alternatively, sulfonamides can also be prepared by oxidation of sulfinamides with periodate (Entry 3, Table 8.8) or with MCPBA [125]. Polystyrene-bound sulfonyl chlorides, which can be prepared from polystyrene-bound sulfonic acids by treatment with PCI5, SOCI2 [126-129], CISO3H [130], or SO2CI2/PPI13 [131], react smoothly with amines to yield the corresponding sulfonamides (Entry 4, Table 8.8). Support-bound carbamates of primary aliphatic or aromatic amines can be N-sulfonylated in the presence of strong bases, and can therefore be used as backbone amide linkers for sulfonamides (Entries 5 and 6, Table 8.8). 

Ixpcrimental Procedure 10.2 Racemizalion-free loading of amino acid eslcrs on to. i backbone amide linker [152]... 

Polystyrene-bound diketopiperazines, such as those prepared with the aid of a backbone amide linker, can be N-alkylated by treatment with alkyl halides in the pres-... 

Cyclic peptides are of interest as turn mimetics or as conformationally constrained peptide analogs. The cyclization of peptides can either be performed after cleavage from the support in solution (see, e.g. [58]) or while still on the support. Besides cycli-zations of the peptide backbone, peptides can be cyclized through their side chains or by means of a non-natural spacer. To cyclize the backbone of a peptide on an insoluble support, the peptide must be attached to the support either by a backbone amide linker [59] or via the side chain of an amino acid [60] (Figure 16.7). 

AM-resin BAL BEMP resin Aminomethylated polystyrene Backbone amide linker Resin 2-ferf-Butylimino-2-diethylamino-l,3-dimethyl-perhydro-1,3,2-diazaphosphorine immobilized on polystyrene resin... 

Abbreviations BAL, backbone amide linker BSA, bis(trimethylsilyl)acetamide DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene DCE, dichloroethane DCM, dichloromethane DIC, 2-diisopropylcarbodiimide DIEA, diisopropylethyl amine DMAP, A,A-dimethylaminopyr-idine DMF, dimethylformamide DMSO, dimethyl sulfoxide EDC, l-(3-dimethylaminopro-pyl)-3-ethylcarbodiimide hydrochloride HBTU, [0-(7-azabenzotriazol-l-yl)-l, 1,3,3-tetramethyluronium hexafluorophosphate MCPBA, m-chloroperoxybenzoic acid NMP, N-methylpyrrolidinone NMM, A-methylmorpholine PfP, pentafluorophenol RT, room temperature TFA, trifluoroacetic acid THF, tetrahydrofuran. 

Two linkers particularly suitable for peptide amides and cyclopeptides are the peptide amide linker (PAL) and the backbone amide linker (BAL) [29] (Scheme 6.1.3). With these electronic and steric factors enable acylation of secondary ben-zylamines and relatively mild cleavage. 

Merrifleld 1,2,3-triazole resins 183 and 184 were prepared and utilized in the BAL (Backbone Amide Linker) strategy to synthesize amides 185 via sequential reductive aminations, amide couplings, and traceless resin cleavage with trifluoroacetic acid <03OL1753>. 

Backbone Amide Linker Strategies for the Solid-Phase Synthesis of C-Terminal Modified Peptides... 

Solid-phase synthesis (SPS) of peptides containing at their C-termini the usual carboxylic acid or carboxamide functionalities is a well-established process the peptide is traditionally attached to the resin through the a-carboxyl group of the C-terminal residue, and synthesis proceeds in the C A direction (1,2). However, synthetic peptides containing modifications at the C-termini are often desired because of their potential therapeutic properties and/or synthetic significance as intermediates in peptide and protein chemistry. Therefore, effective solid-phase methods are needed for the preparation of these peptide targets (3). The present chapter describes backbone amide linker (BAL) strategies (4)... 

Guillaumie, L., Kappel, J. C., Kelly, N. M., Barany, G., and Jensen, K. J. (2000) Solid-phase synthesis of C-terminal peptide aldehydes from amino acetals anchored to a backbone amide linker (BAL) handle. Tetrahedron Lett. 41, 6131-6135. 

Alsina, J., Yokum, T. S., Albericio, F., and Barany, G. (1999) Backbone amide linker (BAL) strategy for iV -9-fluorenylmethoxycarbonyl (Fmoc) solid-phase syn-... 

This approach was extended to solid-phase glycosylation of D-glucosamine derivatives anchored by the 2-amino group through a Backbone Amide Linker to a solid support [196]. 

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