Amines synthesis from carboxylic

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

The same reagents can be used to form amides from carboxylic acids and amines, a method which is applicable to peptide synthesis. Condensation of A-benzyloxycarbonyl-L-phenylalanine and ethyl glycinate hydrochloride gave an 85% yield of purified dipeptide. 

Another kind of combinatorial synthesis can be applied to reactions that assemble the product from several components in a single step, a multicomponent reaction. A particularly interesting four-component reaction is the Ugi reaction, which generates dipeptides from an isocyanide, an aldehyde, an amine, and a carboxylic acid. 

This synthesis also gives a small glimpse at the chemistry of heterocyclic compounds. Most active compounds in today s pharmaceuticals or agrochemicals include heterocycles, as well as most vitamins and natural products. The chemistry of heterocycles is thus very important and lectures or textbooks should be consulted.6 Formation of amide bonds also plays a large role in this problem. It was demonstrated that the strong amide bond can be formed from an amine and a carboxylic acid only after the acid has been activated. This can be done by transformation into the carboxylic halide or imidazolide or by application of an activating agent developed for peptide synthesis. 

The synthesis of amides directly from carboxylic acids is not easy because the reaction of an amine with a carboxylic acid is a typical acid-base reaction resulting in the formation of a salt (Following fig.). Some salts can be converted to an amide by heating strongly to expel water. 

Amides can be synthesized directly from carboxylic acids, using heat to drive off water and force the reaction to completion. The initial acid-base reaction of a carboxylic acid with an amine gives an ammonium carboxylate salt. The carboxylate ion is a poor electrophile, and the ammonium ion is not nucleophilic, so the reaction stops at this point. Heating this salt to well above 100 °C drives off steam and forms an amide. This direct synthesis is an important industrial process, and it often works well in the laboratory. 

Carbodiimides are the diimides derived from carbon dioxide, and they are extensively used in the formation of peptide amide bonds from carboxylic acids and amines. This reaction was utilized by the Nobel laureate Sheehan in the total synthesis of penicillin. He also was the first to use water soluble carbodiimides to crosslink gelatin. Khorana, another Nobel laureate, demonstrated that carbodiimides can also be used in the synthesis of nucleotides. Today, carbodiimides are used extensively in the synthesis and modification of proteins. Proteomics is the new frontier of chemical research. 

Capson, T. L., Poulter, C. D. A facile synthesis of primary amines from carboxylic acids by the Curtius rearrangement. Tetrahedron Lett. 1984, 25, 3515-3518. 

Amide synthesis. The reagent lisa dehydrating agent compatible with water. It mediates the formation of amides from carboxylic acids and amines. 

In a general sense exopeptidases should be the enzymes of choice for stepwise chain assembly since once formed the internal peptide bonds of the growing chain can no longer be proteolytically cleaved from this type of peptidase. Carbox-ypeptidase exhibit superior properties for the stepwise synthesis, especially, carbox-ypeptidase Y (CPD-Y)12101 or other serine peptidases of this type. In principle, aminopeptidases can also be used starting from the C-terminus. Because under these conditions not only the carboxyl component but also the amine component has a free a-amino function, product isolation is more difficult, particularly, if one component is used in excess. Otherwise, stepwise synthesis from the C-terminus is not a problem in chemical peptide synthesis. 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

---