Anhydrides with amino acids

The analgesic and anti-inflammatory Indoprofene (42) can be made by several routes, two of which involve cyclisations. Treatment of phthalic anhydride with amino acid (43) gives imide (45) in one step - the cyclisatlon of (44) must be faster than the inter-molecular reaction by which it is formed. Reduction of (45) give.s Indoprofene as the reactive imide is easily reduced as far as the unreactive amide. 

In order to eliminate the influence of temperature on the rate of a chemical reaction, a reaction mixture of phthalic anhydride with amino acids was placed in a block of ice and then irradiated under microwave conditions. Ice was used to cool the reaction mixture because opposite to water it is transparent to microwaves (e 3.2, c" 0.0029 at 25°C for 2.45 GHz) [26]. The reaction product was formed after 3 min. of irradiation while under conventional conditions the reaction was conducted in a boiling toluene solution for 1.5 h. However, since in such a case microwaves interact directly with the reaction mixture and temperature was not monitored during the experiments, it was stated that the increase of the reaction rate is not only due to thermal effects [27]. 

The palladium(O) catalysed tandem cyclisation of a bromoallene tethered with a sulfamide group 124 gives bicyclic azepines 125. The analogous reaction with Af-tethered bromoallene sulfamide 126 afforded bicyclic diazepine 127 <07CEJ1692>. Condensation of thiaisatoic anhydride with -amino acids proved to be a straightforward method for the synthesis of thieno[3,2-< ][l,4]diazcpin-2,5-dionc analogues 128 <07JOC2662>. 

The reaction of pyromellitic dianhydride or benzophenone-3,3, 4,4 -tetra-carboxylic anhydride with amino acids or lactams followed by condensation of the resulting diacids with diacetates of hydoquinone, 2,6-dihydroxynaph-thalene or 4,4 -dihydroxybiphenyl produced layer polymers (42). With the exception of the polymer with y=ll, all the polymers based on Ar = 4,4 -biphenylyl exhibit a smectic mesophase. The polymer with y = 10 and Ar = 1,4-phenylene exhibits a smectic mesophase. Polymers based on Ar = 1,4-phenylene or 2,6-naphthalene melt directly into an isotropic phase. 

Fig. 5.2 Peptide synthesis using Leuchs anhydrides amino acid 1 (with residue Ri) is reacted with phosgene to give the Leuchs anhydride. This reacts with amino acid 2 (residue R2) to give the peptide carbamate. The dipeptide is obtained after cleavage of C02...

In addition to the more or less popular methods of depsipeptide synthesis discussed vide supra, there are also a limited number of complementary and effective synthetic procedures that have been described for this purpose. Among these, the well-known method of symmetric anhydrides from N-protected amino acids has to be considered. This method has found successful use in the esterification of hydroxy acids in the presence of some catalyst additives. Initially, the addition of pyridine11091 or 1-hydroxybenzotriazole in pyridine1 101 to a symmetric anhydride was utilized for ester bond formation. As an example, Katakai has prepared a number of didepsipeptides in 85-96% yield by means of a 2-nitrophenylsulfenyl /V-carboxy anhydride with lactic acid derivatives in the presence of pyridine.1 09 ... 

Carboxylic acids (8.54) are frequently conjugated with amino acids, especially glycine (Scheme 8.18). The carboxylic acid is first activated as a mixed anhydride (8.55). Reaction of the anhydride with the thiol of coenzyme A forms an intermediate (8.56) that reacts with the amine of an amino acid. The new conjugate (8.57) has increased water solubility to improve elimination. 

Weber [61,62] has developed in the context of prebiotic chemistry an original pathway for a-aminothioester synthesis [180], which can start from hydroxyaldehydes 30 intermediates in the formose reaction (a likely prebiotic pathway to carbohydrates). Obviously, thioesters themselves are not observed as products because of their fast hydrolysis in the medium, but they could be converted into peptide bonds in the presence of amino acids or peptide free amino groups, and into mixed anhydride with phosphoric acid in the presence of inorganic phosphate. The reaction involves two key-steps the condensation of ammonia and of the mercaptan on a-keto aldehyde 31... 

Silyl esters are stable to nonaqueous reaction conditions, but are often too labile to mild acid or base or even neutral aqueous media to survive many simple manipulations. Thus, they have not found wide application in peptide synthesis. Due to easy formation and cleavage they may play an important role as intermediates in the synthesis of amino acid derivatives and for temporary carboxy protection in the preparation of small peptide fragments. The TMS group has been used for the solubilization of H-Arg-OH for the synthesis of Z-Arg(Z2)-OHP l and in the synthesis of Al -Nps- and Al -Tfa-protected amino acids.P Amino acid trimethylsilyl esters as well as the related A1 -TMS derivatives react rapidly with acylating agents and are used for the preparation of peptides with amino acid active esters, e.g. A-hydroxysuccinimide-, 4-nitrophenyl-, or 2,4,5-trichlorophenyl esters, or mixed anhydrides. 

The fact that Fmoc amino acids are relatively simple to prepare, are obtained in high yield in a crystalline form, and are stable, has added to the attraction of the method. Several reagents have been proposed for the addition of the Fmoc group.f l Initially Carpinof l proposed the chloroformate 1 and this was used predominantly until it was discovered that there was a potential side reaction occurring to a small extent with amino acids such as Gly and Ala. This resulted in the formation of Fmoc dipeptides and in some cases tripeptides were en-countered.P 1 A plausible mechanism for the formation of these products is via the mixed anhydride 2 which can react at either activated carboxy to give the expected product or the unwanted dipeptide (Scheme 2). 

The acid reduces ammoniacal. silver nitrate solution, and with sodium nitrite gives a yellow diazo-compound, which couples with resorcinol to give a bluish-red dye. Wren dissolved in sodium hydroxide and treated with acetic anhydride, the amino-acid yields an acetyl derivative, which separates in colourless prisms from water, and yields amorphous calcium and magnesium salts. ... 

For peptide chemistry, protected amino acid chlorides are too highly activated and therefore not used due to their racemization tendency, reactions with amino acid side chains e.g. asparagin), loss of selectivity against nucleophiles and the formation of internal Leuchs anhydrides. ... 

Maleic and phthalic anhydrides condense with amino acids under MW to afford the desired products in excellent yields [Eq. (78)] ... 

The reagent promotes the coupling in high yields of acylamino acids with amino acid esters in benzene, ethanol, or THF at room temperature. No racemization was detected in the supersensitive Young test, and Bz-Leu-Gly-OEt, an 33.5°, was synthesized in 95% yield. Activation of the carboxyl group involves the transient formation of a mixed carbonic anhydride.3... 

The further attempts to again prepare this substance did not succeed, since the exact conditions leading to its formation could not be repeated, but in 1906 Fischer and Abderhalden obtained the anhydride of this body by a new method which they had discovered for isolating such compounds when mixed with amino acids and higher polypeptides. This method depends upon the different behaviour of the esters of these compounds those of the simple mono-amino acids are easily volatile in vacuo and are therefore easily removed, whereas those of the dipeptides are converted by the action of ammonia into their anhydrides or diketopiperazines which crystallise readily and are therefore easily separated from the esters of the higher polypeptides. They thus obtained a methyl diketopiperazine. 

The synthesis of 2,3,4,5-tetrahydro-lH-2-benzazepine-l,5-diones by the photochemical addition of alkenes to phthalimides has been known for a number of years. More recently this method has been extended to the reaction of N-alkylphalimides prepared from phthalic anhydride and amino acids, with a further example being published during the period under review <94T3627>. 2,3-Dihydro-l/f-2-benzazepine-l,3-diones have been prepared by the reaction of... 

The acylation of the carboxylate anions is assumed to lead to formations of mixed anhydrides of the acids with amino acids and subsequent rearrangements ... 

N-carboxy anhydrides of amino acids (326), obtained fromN-benzyloxy-amino acids as crystalline derivatives by reaction with phosgene. Acylation of glycine methyl ester by (326) gave the corresponding peptides... 

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