Linkers for amides

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). 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

Boas U, Brask J, Jensen KJ (2009) The backbone amide linker for solid-phase synthesis. Chem Rev 109 2092-2118... 

Minkwitz R, Meldal M (2005) Application of a photolabile backbone amide linker for cleavage of internal amides in the synthesis towards melanocortin subtype-4 agonists. QSAR Comb Sci 24 343-353... 

Polyfunctional 2-hydtoxyalk5iamides can serve as cross-linkers for carboxyHc acid-terrninated polyester or acryHc resins (65). The hydroxyl group is activated by the neighboring amide linkage (66). SoHd grades of hydroxyamides are finding use as cross-linkers for powder coatings (67). 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

Henkel B, Zeng W, Bayer E. 9-Hydroxy-9-(4-carboxyphenyl)xanthene- a new linker for the synthesis of peptide amides. Tetrahedron Lett 1997 38 3511-3512. 

Meisenbach M, Echner H, Voelter W. New methoxy-substituted 9-phenyl-xanthen-9-ylamine linkers for the solid phase phase synthesis of protected peptide amides. Chem Commun (Cambridge) 1997 849-850. 

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. 

Brown EG, Nuss JM. Alkylation of Rink s amide linker on polystyrene resin a reductive amination approach to modified amine-linkers for the solid phase synthesis of /Y-substiuited amide derivatives. Tetrahedron Lett 1997 38 8457-8460. 

Scheme 4. Use of diversification linkers for the synthesis of (a) amides, (b) amines, (c) aromatic, and (d) heteroaromatic compounds.

To 100 MicroTubes in 100 mL of DCM, the following were added sequentially 4.96 g (9.2 mmol) Rink amide linker (note 6), 3.20mL (18.4mmol) DIEA, and6.9g (18.4mmol) HATU (note 7). The reaction mixture was shaken at room temperature for 48 h. After the supernatant was removed by aspiration, the MicroTubes were washed sequentially with DMF, MeOH, and DCM for three cycles. The MicroTubes were dried under vacuum for 5 h after a final washing with ethyl ether. 

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

FIGURE 5.18 Resins and linkers for synthesis of peptide amides using Fmoc/tBu chemistry. Chain assembly is effected after removal of the Fmoc group. Treatment with CF3C02H releases a peptide amide by cleavage at the NH-CH/CH2 bond. 

RESINS AND LINKERS FOR SYNTHESIS OF PROTECTED PEPTIDE ACIDS AND AMIDES... 

H-donor for both the intramolecular hydrogen bond with the amide linker carbonyl the carboxylic acid group is deprotonated. 

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). 

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