A-Aminoacid

Free-radical reactions in the synthesis of diketopiperazines and other cyclic derivatives of a-aminoacids 97CRV53. 

This method is widely applicable to the unambiguous synthesis of quinoxalin-2-ones." It involves the intermediate preparation of a l,2,3,4-tetrahydro-2-oxoquinoxaline by the reductive ring closure of the o-nitrophenyl derivative of an a-aminoacid. These derivatives are formed readily from the aminoacid and an o-nitrohalogenobenzene. The final step of oxidation of the tetrahydro- to the dihydro-quinoxa-line is carried out with potassium permanganate or hydrogen peroxide. The preparation of 7-nitroquinoxalin-2-one illustrates the application of this synthesis ... 

Furthermore it can be shown that besides the direct influence of hydrophilic and hydrophobic hydration on the conformation, the interaction of charged groups with ions is also strongly influenced by the hydration of the groups involved. Such studies were made largely by using relatively simple poly-a-aminoacids with ionogenic side chains as model substances. 

Enaminosulphoxides 459 have been obtained in the reaction of the carbanion of methyl methylthiomethyl sulphoxide 324 with nitriles. This procedure has been applied for converting nitriles into a-aminoacids 460527 and a-ketoacids 461528 (equation 275). 

The cationic pathway allows the conversion of carboxylic acids into ethers, acetals or amides. From a-aminoacids versatile chiral building blocks are accessible. The eliminative decarboxylation of vicinal diacids or P-silyl carboxylic acids, combined with cycloaddition reactions, allows the efficient construction of cyclobutenes or cyclohexadienes. The induction of cationic rearrangements or fragmentations is a potent way to specifically substituted cyclopentanoids and ring extensions by one-or four carbons. In view of these favorable qualities of Kolbe electrolysis, numerous useful applications of this old reaction can be expected in the future. 

In spite of the fact that biotechnology rather than chemical processing will probably provide the future greatly needed chirally pure compounds (ref. 1), we believe that simple chemical reactions starting from chiral natural compounds and proceeding under stereochemical control will eventually retain full importance. On the above grounds, we report on simple reactions which start from a-aminoacids, as an example of utilization of natural compounds, and move to related bromine containing compounds (Fig. 1). 

To date most of the nitriles studied have been simple alkyl or aromatic derivatives with little other functionality. We recently attempted to extend the reaction to iV-protected a-aminonitriles, derived by dehydration of a-aminoacid amides (Path A, Scheme 25), but this proved unsatisfactory, and therefore we investigated an alternative diazocarbonyl based route in which the order of steps was reversed, i.e. a rhodium catalysed N-H insertion reaction on the amide followed by cyclodehydration to the oxazole (Path B, Scheme 25). 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

The rates of oxidation of a-aminoacids in aqueous acidic media by Co(IlI) perchlorate are comparable with those of carboxylic acids, whilst those of amines are much slower Accord ingly, the RCHNH3 fragment is considered to be formed from RCH(C02H)NH3, which then undergoes further oxidation to NH3 and RCHO. 

An especially important case is the enantioselective hydrogenation of a-amidoacrylic acids, which leads to a-aminoacids.29 A particularly detailed study has been carried out on the mechanism of reduction of methyl Z-a-acetamidocinnamate by a rhodium catalyst with a chiral diphosphine ligand DIPAMP.30 It has been concluded that the reactant can bind reversibly to the catalyst to give either of two complexes. Addition of hydrogen at rhodium then leads to a reactive rhodium hydride and eventually to product. Interestingly, the addition of hydrogen occurs most rapidly in the minor isomeric complex, and the enantioselectivity is due to this kinetic preference. 

Zinc borohydride, which is also a useful reagent,66 is prepared by reaction of ZnCl2 with NaBH4 in THF. Owing to the stronger Lewis acid character of Zn2+, Zn(BH4)2 is more reactive than NaBH4 toward esters and amides and reduces them to alcohols and amines, respectively.67 Zn(BH4)2 reduces carboxylic acids to primary alcohols.68 The reagent also smoothly reduces a-aminoacids to (3-aminoalcohols.69... 

Polyamides containing a-aminoacid units are readily obtained by reaction of bisazlactones (2-oxazolin-5-ones) with diamines. When polyamines such as diethylenetriamine (DETA) or triethylenetetramine (TETA) are used as the diamine component, the resultant polyamides readily cyclodehydrate above 200°C to produce polymers containing 2-imidazolin-5-one units in the backbone. Polyamides derived from simple diamines (e.g. 1,6-hexanedi amine) cyclodehydrate only in the presence of a suitable catalyst. Carboxylate salts and certain Lewis acids have been found to be efficient catalysts for this transformation. 

In summary, the preparation of polyimidazolinones from polyamides containing a-aminoacid units (3, X = NH) can now be considered to be a general reaction provided that Rz and/or R3 are not hydrogen. When the polyamide has additional secondary or tertiary amine functionality in the backbone, cyclodehydration appears to be exceptionally facile. In the absence of amine functionality however, a catalyst is necessary to promote cyclization. Further studies of this new heterocyclic polymer system are ongoing in our laboratories. 

In an attempt to form orally active penicillins unrelated to ampicillin, use was made of the fact that certain spiro a-aminoacids, such as 9, are well absorbed orally and transported like normal amino acids. Reaction of cyclohexanone with ammonium carbonate and KCN under the conditions of the Bucherer-Bergs reaction led to hydantoin 10. On acid hydrolysis, a-amino acid 11 resulted. Treatment with phosgene... 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

A-Thiazolyl a-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of a-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an a-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields A-thiazolyl a-amino acids 56 <00T3161>. 

Naphtho[l,8-de][l,2,3]triazine 114 can be alkylated with a variety of alkyl halides and lithium diisopropylamide (LDA) to give alkylated derivatives 115. Reduction of 115 with aluminium amalgam cleaves the naphthotriazine moiety to afford substituted a-aminoacids 116 in good overall yields <00TL6665>. 

Replacement of the p-aminoacyl moiety with an a-aminoacid derivative such as isoleucyl or cyclohexylglycyl led to a 2- to 4-fold decrease in potency. This was the first indication that SAR between this series and the a-amino acid series was distinct. Early on it was discovered that the "right hand side" amide could be replaced with an ester or acid moiety. This result led to a more systematic exploration of acid substitutions. Ortho-, meta- and para-substituted phenylacetic acid derivatives were prepared, and the latter analog (11, Figure 5) proved to be the first submicromolar inhibitor prepared in this series (IC50 = 510 nM). Grati-fyingly, 11 was devoid of thrombin inhibitory activity [31]. 

As the latter were not easily accessible by chemical synthesis at that time, new methods of preparing these ferrocene derivatives were developed and introduced in 1969. It was then proved that the U-4CRs of chiral a-ferrocenyl-alkylamines can form diastereomeric a-aminoacid derivatives stereo-selectively, and it was further shown that after the reaction the a-ferrocenyl groups of the products can be replaced by protons, thus resynthesizing the chiral a-ferrocenyl-alkylamines simultaneously." Later, the development of this ferrocene chemistry was given up since such syntheses cannot form the products in sufficient quantity and stereoselective purity. ... 

A few years later Goebel and Ugi formed a-aminoacid derivatives by the U-4CR with tetra-6)-aIkyl-l-glucopyranosylamines, 58, where any carboxylic acid component can participate. Lehnhoff and Ugi used the U-4CR with 1-amino-2-deoxy-2-Al-acetylamino-3,4,6-tri-6)-acetyl- 3-D-glucopyranose, 59, whose large variety of products could be formed stereoselectively in excellent yields. The desired selective cleavage of the auxiliary groups of these products was equally unefficient. 

Ross and Ugi" prepared l-amino-5-deoxy-5-thio-2,3,4-tri-6)-isobutanoyl-P-D-xylopyranose 61a from xylose via the 5-desoxy-5-thio-D-xylopyranose. The U-4CRs of this amine form a-aminoacid derivatives stereoselectively and in excellent yields. These products have the advantage that their products are stable and their auxiliary group 5-desoxy-5-thio-D-xylopyranose can be cleaved off selectively by mercury(II) acetate and trifluoroacetic acid. The expected steric structure of the corresponding U-4CR product was confirmed by X-ray measurement. 

In the last decade, Bossio et al. have formed cychc products of many different types by using a variety of new MCRs. Thus, 80 was made from 76-79 (Scheme 1.19). Recently, Domling and Chi prepared 83 from 81, 82, and 27, and synthesized similar polycyclic products from other a-aminoacids with 82 and 27. 

Miertus, S., Nair, A. C., Frecer, V., Chiellini, E., Chiellini, R, Solaro, R. and Tomasi, J. Modelling of 3-cyclodextrin with L-a-aminoacids residnes. J. of Inclusion Phenomena and Marcrocyclic Chemistry, 1999, 34, 69-84. 

From the chemical point of view, general anesthetics can be classified as esters of n-aminobenzoic acid and dialkylaminoalkanols, or as anilides of iV,iV-diaIkyl substituted a-aminoacids. 

Swansonine and castanospermine synthesis starts with the a-aminoacid, y-semialadehyde and, via piperidine-6-carhoxyhc acid synthetases, L-pipecolic acid. This compound is a substrate to HSCoA and acetyl-CoA. As a result of this activity, the second ring is established. Subsequently, it changes to 1 -indolizidinone and, by oxidation reaction, produces castanospermine or swansonine (Figure 50). 

Oxidative cleavage of 1,3-dicarbonyls to carboxylic acids in almost quantitative yields using Oxone was reported. The first example of oxidative decarboxylation of a-aminoacids RCH(NH2)COOH, in which a product other than an aldehyde or a carboxylic... 

This general process is illustrated by the addition of a range of a-aminoacid esters (374) to the nitrile imine 373 (R = Ac, C02Me, COPh R = -X—C6H4), which proceed with no detectable racemization to give the chiral l,2,4-triazin-6-ones (376) in high yields (213,214). 

A much older reaction of N-nitroso a-aminoacids is their cycli-zation to the mesoionic sydnones (39 0a l 2) more recently, N-nitroso a-aminonitriles have been cyclized to the corresponding sydnone imines (U0, l, 2,43) ... 

Figure 3.8 The two enantiomers of a-aminoacids. Here we follow the classic nomenclature of l- and D-aminoacids for indicating the two chiral forms. In terms of the S, R nomenclature, L-aminoacids correspond to the S absolute configuration -except for cystein, which is R.

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