Carboxamide linker

Similarly, the coupling of LA to arylthiophene imidamide derivative 355, via a carboxamide linker, led to lipoic acid analogue 354, acting as a metabolic antioxidant and a nitric oxide synthase (NOS) inhibitor as well <2002BMCL1439>. 

Note that many of the hnker units described above are available in multiple forms, aUowing a range of substrates to be attached and cleaved. A discussion of all these related linker units is outside the scope of this chapter, but Kurosu has written a comprehensive review. By way of example, multiple versions of the Rink (Table 1.1, Entries 2 and 3) and trityl hnker units (Table 1.1, Entries 5 and 6) are commercially available and can be selected according to the desired substrate. However, beyond these general hnker units, there are also examples of substrate-specific hnker units. Eor example, the benzhydrylamine (BHA, Table 1.1, Entry 8) and Sieber (Table 1.1, Entry 9)" linkers find widespread use as acid labile carboxamide linker units, while the DHP (Table 1.1, Entry 10)" and sUyl linker units (e.g.. Table 1.1, Entry 11) can be used to attach alcohols to polymer supports. ... 

Fluorenone derived linker 17 prepared in two steps was coupled to aminomethyl-PS via DIPCDI [21]. Due to the presence of an electron-withdrawing carboxamide group, the release of carboxylic acids from this support requires strong acids, such as trifluoromethanesulfonic acid (TFMSA) (Scheme 1). Insertion of an oxygen adjacent to the biphenyl rings to the fluorenone scaffold provides xanthene 18 handle [22]. The oxygen is strategically located to decrease the acid concentration required... 

Hirayama et al. [90] made the efforts to discover FXa inhibitors, containing carboxamide and sulfonamide linkers (36-41). From their data Eq. 22 was formulated [72], where MRb is the most significant term followed by the indicator variable I-NAPH, used for the presence of a naphthyl group in the compound. Group B is indicated in the structures. 

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)... 

Coupling of 4-(4-hydroxymethyl-3-methoxyphenoxy)-butyric acid (HMPB, for synthesis of peptide acids) or p-[(R S)-a-[l- (9H- fluorenyl- methoxyform-amido]- 2,4- dimethoxybenzyl] - phenoxyacetic acid (modified Rink linker, for synthesis of carboxamide peptides) linkers to MBHA resin For Fmoc chemistry several types of solid supports are available, which include hydroxymethyl-based, aminomethyl-based, and trityl chloride resins. We describe the use of the MBHA resin. In this case the respective linker (to achieve peptide acid or amide) is coupled to the resin and first amino acid is then coupled to the linker. Attachment of the linker to the resin is a reaction between the carboxyl-group of the linker and amino-group of the MBHA resin. Commercially available resins with linkers already attached could also be used. 

Adamczyk M, Chen YY, Fishpaugh JR, et al. Linker-mediated modulation of the chemiluminescent signal from N(10)-(3-SuIfopropyl)-N-sulfonylacridinium-9-carboxamide tracers. Bioconj Chem 2000 11 714-24. 

Most of the linkers employed for attachment of carboxylic acids have originated from peptide chemistry. These linkers are modified hydroxy, amino or trityl units. Thus, after cleavage from fhe linker, fhe final products contain either a carboxyl or a carboxamide function. Depending on fhe type of linker, cleavage usually proceeds with the TFA concentration varying from 1 % to undiluted ( neat ) TFA. As TFA is volatile, evaporation of fhe solution applied for the release yields fhe product wtifhout impurities. These linkers are described in great detail in the peptide chemistry literature, and most are available commercially. 

Amines derived from p-alkoxybenzyl-type linkers, despite not being acid cleav-able, still have synthetic utility. Anilines anchored to Wang resin, once converted into carboxamides or sulfonamides by reaction with the appropriate electrophile, can be cleaved with TFA (Figure 14.6) [34]. Sulfonamides of aliphatic amines may also be cleaved with TFA [36]. Stronger acids are generally required for acyl derivatives of amines but this can cause cleavage of the linker benzylic ether bond, leading to formation of p-hydroxybenzylated by-products. 

Several linkers have been developed that rely on the formation of highly stabilized aromatic carbocations. The most frequently used are the eponymous Sieber amide linker 36 [3] and Barany s 3-XAL linker 6 [4]. Both are based on a 3-methoxyxanthine scaffold, which owing to the highly stabilized nature of the xan-thenium ion can provide primary amides on treatment with 1% TFA in DCM, making them excellent tools for the synthesis of protected peptide carboxamides. The Sieber amide resin has also been used to prepare secondary amides via reductive alkylation of the amino group, acylation of the resultant amine and cleavage with dilute TFA [88]. Brill et al. [67] have effected transamination of trifluoroacety-lated Sieber amide resin in good yield. This approach offers considerable potential for the immobilization of amines on this support. 

Fig. 3 Bis(vancomycin)carboxamides. The curved line locates the linker that could be a simple hexyl chain or a dipropyl- or diethyl-disulfide chain or a dipropylamine chain. Reprinted by permission of the American Chemical Society [20]...

The general scheme that outlines the strategy of Boc synthesis is shown in Fig. 2, which is principally similar to the scheme for Fmoc synthesis (Chapter 2). Prior to the synthesis, the appropriate resins and linkers (Table 3), as well as appropriately protected building blocks (Table 2), should be selected. Generally, two resins, the chloromethyl (or Merrifield) [1] or phenylacetamido-methyl (PAM) [9] resin, are used to generate peptide carboxylates, whereas 4-methylbenzhydrylamine (MHBA) [10] resin is the principal resin for making peptide carboxamides. Boc synthesis is particularly attractive for the synthesis of peptide thioester. 

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