Amino alanine derivatives

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Szymanska A, Wegner K, Lankiewitz L (2003) Synthesis of N-[(tert-Butoxy)carbonyl]-3-(9, 10-dihydro-9-oxoacridin-2-yl)-L-alanine, a new fluorescent amino acid derivative. Helv Chim Acta 86 3326-3331... 

As early as 1905 Abderhalden (Al) isolated from the hydrolyzate of the nondiffusible fraction of human urine four amino acids, i.e., leucine, alanine, glycine, and glutamic acid, and detected two others phenylalanine and aspartic acid. Some amino acids derived from this fraction have been quantitatively determined by Albanese et al. (A3) who found in the amount of the nondiffusible fraction corresponding to one liter of urine as much as 32.8 mg tryptophan, 18.0 mg phenylalanine, 16.2 mg methionine, 15.2 mg cystine, 13.1 mg arginine, 6.7 mg histidine, and 3.9 mg tyrosine. 

The behavior of 2-alkylthiohydantoins 428 and 3-chlorobenzopyrano[2,3-c]pyrazole 430 toward er-amino acid derivatives was studied. 2-Alkylthiohydantoins 428 condensed with alanine at high temperature, and the reaction of 3-chlorobenzopyrano[2,3-z]pyrazole 430 with ethyl glycinate was carried out in DMF at reflux to give the cycloadduct 431 in 62% yield (Equations 197 and 198) <2000PS77, 2000FA641>. 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

In the heterocyclic series, racemic 3-(fur-2-yl)alanine has been prepared from furfural using this approach. In addition, (3-(pyrid-3-yl)alanine, ° p-(quinol-3-yl)alanine, ° a p-(benzofuranyl)alanine derivative, 2-amino-3-(2,2 -bipyridi-nyl)propanoic acid, and some interesting derivatives of histidines—in particular 1-alkylhistidines with amphiphilic properties have all been synthesized using this methodology. The complete reaction sequence starting from an aldehyde and an A-acylamino acid derivative is shown in Scheme 7.150. 

Optically pure or almost pure a-methyl a-amino acids (alanine derivatives) can be prepared by reacting 5-substituted 2,5-dihydro-3,6-dimethoxy-2-methylpyrazines 1, which are derived from alanine and various amino acids as the chiral auxiliary, with alkylating agents, followed by hydrolysis (see Table 2). 

Table 2. a-Substituted a-Amino Propanoates (Alanine Derivatives) by Alkylation of 5-Substituted 2,5-Di-hydro-3,6-dimethoxy-2-mcthylpyrazines, Followed by Hydrolysis... 

The co-polymerization of D-alanine-derived A-propargylamide 22, L-valine-derived 23, and pyrene-based monomer 24 gives helical poly(22 -< o-23-c -24) carrying pyrene. The secondary structure of the co-polymer is tunable by the composition of the optically active amino acid units and solvent, which makes it possible to control the direction of the pyrene groups in the side chain. The interaction between the pyrene groups is small when the co-polymer takes a helical structure. The pyrene groups are regularly positioned in the polymer side chain. The co-polymer emits weak... 

You have a peptide that is a potent inhibitor of nerve conduction and you wish to obtain its primary sequence. Amino acid analysis reveals the composition to be Ala(5) Lys Phe. Reaction of the intact peptide with FDNB releases free DNP-alanine on acid hydrolysis. e-DNP-lysine (but not a-DNP-lysine) is also found. Tryptic digestion gives a tripeptide (composition Lys, Ala (2)) and a tetrapeptide (composition Ala(3), Phe). Chymotryptic digestion of the intact peptide releases a hexapeptide and free alanine. Derive the peptide sequence. 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

An ion-pair derived from the substrate and solid NaOH forms a cation-assisted dimeric hydrophobic complex with catalyst 39c, and the deprotonated substrate occupies the apical coordination site of one of the Cu(II) ions of the complexes. Alkylation proceeds preferentially on the re-face of the enolate to produce amino acid derivatives with high enantioselectivity. However, amino ester enolates derived from amino acids other than glycine and alanine with R1 side chains are likely to hinder the re-face of enolate, resulting in a diminishing reaction rate and enantioselectivity (Table 7.5). The salen-Cu(II) complex helps to transfer the ion-pair in organic solvents, and at the same time fixes the orientation of the coordinated carbanion in the transition state which, on alkylation, releases the catalyst to continue the cycle. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

A major breakthrough in the use of Nobin as an asymmetric phase-transfer catalyst came when Belokon and coworkers applied it to the alkylation of glycine-derived nickel(II) complex 11a under the conditions shown in Scheme 8.13 [25], Representative results are given in Table 8.1, which illustrate that benzylic and allylic halides react very rapidly and highly enantioselectively to produce a-amino acids. Intrigu-ingly, in this case (R)-Nobin catalyzes the formation of (R)-amino acids, which is the opposite enantioselectivity to that observed for the alkylation of alanine derivative 16b [21,24],... 

Catalyst screening experiments resulted in the discovery that copper(salen) complex 33 was a highly effective catalyst for the conversion of alanine derivative 16b into (f )-a-methyl phenylalanine 17 under the conditions shown in Scheme 8.16. The presence of just 1 mol% of catalyst 33 was sufficient to induce the formation of compound 17 with up to 92% ee and in >70% yield [33]. Allyl bromide, 1-chloromethylnaphthalene and ethyl iodide also reacted with substrate 16b to give the corresponding (H)-a-methyl a-amino acids in the presence of 2 mol % of complex 33 [34], Complex 33 also catalyzed the asymmetric mono-alkylation of glycine-derived substrate 34 by benzylic or allylic halides, to give (H)-a-amino acid derivatives 35 with 77-81% ee. and in greater than 90% yield, as shown in Scheme 8.17. 

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