Transamidation carboxylic acids

GatCAB amidotransferase.This natural product mimics the charged 3 -terminus of aa-tRNA and has been used as a tool for the study of protein biosynthesis. The parent compound 22 is a very weak inhibitor of AdT. The amino acid chain is related to tyrosine and differs from the glutamic and aspartic side chains transformed in the kinase or the transamidase steps. Replacement of the methoxyphenyl moiety of puromycin by carboxylic acid derivatives (23-26) improved the ability to inhibit this AdT. Stable analogues of the transition state in the last step of the transamidation process (27-29) where the carbonyl to be attacked by NH3 is replaced by tetrahedral sulfur or phosphorus atom with a methyl group mimicking ammonia exhibited the highest activity. 

Cefoxitin Cefoxitin, 3-(hydroxymethyl)-8-oxo-7-methoxy-7-[(2-thienylacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid carbamate (32.1.2.30), is synthesized in various ways starting from cefamicin C-7)3-(D-5-amino-5-carboxyvaleramido)-3-aminocarbonylhydroxymethyl-7-methoxy-3-cefem-4-carboxylic acid, in which a methoxy group is initially present at C, and the task of making the desired drug essentially consists of a transamidation reaction. 

Carboxylic acids with strongly electron-withdrawing groups, for example trifluoro-acetic or 2,4,6-trinitrobenzoic acid [22], are readily converted into esters or amides. The products can, however, be unusually sensitive toward attack by nucleophiles and can readily undergo hydrolysis, transesterification, or transamidation. 2,4,6-Tris(trifluoromethyl)benzoic acid has been reported to undergo conversion into the acyl chloride or esters only with difficulty [23]. 

NH3 or RNH2 or R2NH Amide formation from carboxylic acid derivatives (mild) or from carboxylic acids (A technical synthesis of nylon-6,6) transamidation [capro-lactame —> nylon-6 (perlon)] Peptide synthesis (Section 6.4.3)... 

In a later development by Bedenbaugh et methylamine was used as solvent and lithium as electron donor. No proton donor was required, suggesting that the lithium salt (28) of hemiaminal (27) is stable under the reaction conditions (both aldehydes and aldimines are reduced by the reagent cf. the analogous reduction of carboxylic acids, Section 1.12.2 and Scheme 2). Yields of aldehydes produced by this method are shown in Table 8. It is notable that only tertiary amides are reduced satisfactorily. A major limitation of the reaction is the substantial formation of side products resulting from transamid-ation by the methylamine solvent (/. e. RCONHMe from RCONR 2). 

Acylation of amines by carboxylic acids occurs in excellent yield at room temperature if carried out in the presence of the calculated amount of 1,1 -carbonyldiimidazole in an inert solvent such as tetrahydrofuran.701 It involves formation of the acylimidazole as intermediate which is transamidated by the amine.702,703 It is necessary to use dry reagents and to exclude moisture. 

Concerning carboxylic acids and their derivatives, transformations of practical value are restricted to oxidative hydrolysis such as the conversion of hydrazides back to carboxylic acids, transamidation of iV-acyl-5,6-dihydrophenanthridines, and decarboxylative processes, especially the degradation of a-hydro-xymalonic acids (eq 9). In some cases the Ce oxidation is much superior to periodate cleavage. A related reaction is involved in a route to lactones. ... 

Carboxylic acid amides from carboxylic acids by transamidation... 

Aside from the outstanding and reliable diastereoselectivity, two more advantageous features helped the method to success the easy, one-step preparation of various N-acylated derivatives from the parent oxazolidinones and the cleavage of the auxiliary by hydrolysis, transamidation to the Weinreb amide, esterification, and reduction, as outlined in Section 4.1. A typical Evans aldol procedure with phenylalanine-derived oxazolidinone (S)-47, including the preparation of propionic imide 73 and cleavage of the auxiliary, is shown in Scheme 4.47. Typically, the boron aldolate resulting from the addition to the aldehyde has to be cleaved by an oxidative work-up. The hydrolysis of the aldol adduct 211 occurs without detectable epimerization that liberates diastereomerically and enantiomerically pure carboxylic acid 212 besides the auxiliary (S)-47 [110]. 

Transamidations of amides with amines, as well as of carboxylic acids with amides, have been reported. 

Altering the iV-substitution of an amide by the introduction of an amine is termed transamidation it offers an interesting approach to the construction of functionalised amide bonds. It can allow alternative disconnection pathways that may suffer from decarboxylation if carboxylic acids are... 

The amide transfer reactions can be distinguished from the transamidation reactions studied by Fruton et al. as follows. The enzyme is not a peptidase or protease. The amide (or hydroxylamine) transfer is restricted to the /3-carboxyl of aspartic acid or the y-carboxyl of glutamic acid the transfer is not associated with hydrolysis of the amide it does depend on ATP or ADP, arsenate or phosphate, and Mn++, but this dependence notwithstanding, it shares with the peptidase-protease type of transamidation its independence of energy or phosphate transfer. 

H2N< C00H Polyamides 1. Amine (PA) + anhydride or acid (modifier) 2. Amine/carboxyl (PA) + epoxy (modifier) 3. Amine/carboxyl (PA) + isocyanate (modifier) 4. Carboxyl (PA) + oxazoline (modifier) 5. Carboxyl (PA) + nitrile (modifier) 6. Transamidation reactions (between PA and usually diamine type modifier)... 

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