Carboxyl component

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

There are two basic strategies for enzyme-catalyzed peptide synthesis equiUbrium- and kineticaHy controlled synthesis. The former is the direct reversal of proteolysis and involves the condensation of an amino component with unactivated carboxyl component. The latter proceeds by the aminolysis of an activated peptide ester. 

Special emphasis has been laid on structural studies of Cd compounds with dicarboxylic acids, because these combinations form coordination polymers of differing dimensionalities depending on the carboxylate component and on coligands coordinated to Cd. The simplest compound of this type, namely Cd oxalate CdC204, adopts a 3-D framework structure, with CdOe octahedra linked by oxalate groups.272 Further interesting structures containing Cd, oxalate and other components have been described recently.273,274... 

For example, U-Sn2[7][MnAe] indicates a nucleophilic aliphatic substitution following an Ugi reaction to give a 7-membered ring, where the additional nucleophile is embedded in the amine component and the leaving group (electrophile) is introduced in the carboxylic component. When more than one new ring is formed,... 

Starting from ethanolamines 72, benzoxazepinones 73 [84—86], benzodiazepi-nones 74 [47, 86] and diazepanones 75 [47] have been produced depending on the starting carboxylic components. In the last case, classical Mitsunobu conditions gave unsatisfactory yields, and the conditions developed by Hanessian (SDI and NaH) were used instead. Using a-hydroxyacids 76, both benzoxazinones 69 [55] and benzoxazepinones 77 [55] have been accessed. The same compounds can also... 

Finally, by placing the additional carbonyl in the carboxylic component, a synthesis of pyridinones 131 has been realized [115]. In this case, the nucleophilic carbon is not the one derived from the acid, but the one initially embedded in the starting aldehyde. Moreover, here a vinylogous Knoevenagel is operating, which is clearly favoured over the reaction involving the carbon a to the amide, thanks to the formation of a stable aromatic 6-membered ring. 

Intramolecular Diels-Alder (IMDA) is a very powerful reaction, which converts an acyclic system into a bicyclic one, often with high stereocontrol. By positioning a good dienophile (typically in the carboxylic component) and a highly... 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

However, they have not yet found many applications in asymmetric Ugi reactions [41-43], and this is probably due to the fact that diastereomeric excesses are often only moderate and strongly influenced by the structure of the side chain of the a-amino acid. A thorough study was carried out by Yamada et al. [42], who observed that the configuration of the newly generated stereocenter of the major diastereoisomer is always opposite to that of the amino ester. Representative examples are shown in Scheme 1.15. Although Yamada often also used chiral protected aminoacids as the carboxylic component, they were proved to have a negligible influence on the stereoselectivity. 

Earlier biochemical studies had reported that the Krebs cycle in mitochondria are closely associated with the intramitochondrial precipitation of electron-dense mineral granules,138 which have been suggested as ACP containing OCP-carboxylate components.139 Previous studies have shown that succinate ions (00CC2H4C002 ) can be incorporated into the lattice of OCP,139-142 leading to the formation of the OCP-succinate (OCPS) compound.139 Consequently, OCPS prepared in vitro could serve as a model system to mimic the biomineralization process in mitochondria. The XRD... 

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnCl2 as promoting Lewis acid, a-amino acid amides are obtained [13,45] with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19 1 in favor of the D-amino acid amides 30 (Scheme 20). 

Mechanization and automation are possible in the synthesis of peptides using solid polymeric active esters also. By passing a solution of the amine component in a suitable solvent through a column packed with the solid polymeric activated carboxyl component, mechanization could be effected. The product, the protected peptide, which is in the eluent, is then N-deprotected, and the product in solution is passed... 

Thus, in this method the stepwise synthesis proceeds on the soluble polymer, as in the liquid phase method the only difference is in the coupling step where the carboxyl component is an insoluble polymeric active ester. The use of the solubilizing C-terminal macromolecular protecting group overcomes the limitations encountered in the original application of the polymer reagent method of peptide synthesis. However, due to the steric limitations characteristic of the polymer-polymer interactions, the attainment of quantitative coupling in each step of the synthesis can be difficult in this method. 

The inconveniences of DCC, A-acylurea formation, dehydration of Asn and Gin residues, and racemization, can be reduced by performing the acylation step in the presence of a suitable nucleophile which reacts very quickly with the G-acylisourea before side reactions can occur. An acylating agent of lower potency but still sufficiently reactive toward aminolysis and more resistant towards side reactions and racemization is formed. The additive is usually applied in equimolar amount with the two components to be coupled. As a result, there are two moles of nucleophiles, the additive and the amino component, present in the reaction mixture for each mole of carboxylic acid component or carbodiimide. Therefore the lifetime of highly reactive intermediates, such as G-acylisoureas and symmetrical anhydrides is considerably reduced. The concentration of the additive that acts as a second nucleophile increases with respect to the carboxylic component during the coupling reaction, because it is continuously regenerated. The most commonly used additives used in combination with DCC are shown in Scheme 2. 

The advantage of these reagents relies on their simplicity of use. An equivalent of the reagent is added to a 1 1 mixture of the carboxylic component and tertiary base in an inert solvent at room temperature. The mixing can be carried out in the presence of the amino component. These coupling reagents are compatible with Z, Boc, and Fmoc chemistry, solution and solid-phase synthesis, polystyrene, polyamide, and continuous flow resins. 

The solubilizing capacity of the choline residue is so pronounced that even substrates combining two hydrophobic amino acids are homogeneously soluble in aqueous buffer without any additional cosolvent. These favorable physical properties were also used in the enzymatic formation of peptide bonds. The amino acid choline ester 38 acts as the carboxyl component in kinetically controlled peptide syntheses with the amino acid amides 39 and 40 [52] (Fig. 11). The fully protected peptides 41 and 42 were built up by means of chymotrypsin in good yields. Other proteases like papain accept choline esters as substrates also, and even butyrylcholine esterase itself is able to generate peptides from these electrophiles. 

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