Aziridine-2-carboxylic acid

Aziridine-2-carboxylic acid, 3-methyl-, methyl ester H NMR, 7, 51 <6630 0390)... 

Several early reports dealt with the resolution of racemic aziridine-2-carboxylic acids [72, 73], Treatment of ( )-78 (Scheme 3.25) with (-)-trans-2,3-bis(hydroxydi-phenylmethyl)-l,4-dioxaspiro[5.4]decane (79), for example, afforded the 1 1 ratio inclusion compound 80. Upon distillation, the inclusion compound 80 gave en-antiomerically pure (-)-78 in 33% yield. 

Reactions between aziridine-2-carboxylic acids and thiols in aqueous solution have been explored by Hata and Watanabe [112]. The reactions occurred predominantly at C-2 instead of C-3 to afford 3-amino acids, with the reaction between 148 (Scheme 3.53) and thiophenol in 0.2 m sodium phosphate buffer at room tem-... 

On the other hand, other chiral dirhodium(II) tetracarboxylate catalysts based on azetidine- and aziridine-2-carboxylic acids have been prepared by Zwanenburg et al. and submitted to the cyclopropanation of styrene with... 

S)-Aziridine-2-carboxylic acid (1), also named azyline (Azy)J4L42] exhibits an electron-withdrawing or quasi-aromatic effect on the nitrogen and is therefore susceptible to an attack by nucleophiles. [41 43] Unprotected aziridine-2-carboxylic acid (1) is very labile, but the... 

Aziridine-2-carboxylic acid derivatives have gained considerable interest since they can be considered as a versatile synthetic equivalent of the (3-alanyl cation synthon suitable for transformation into (3-substituted 5-amino acids. 55-57 262 ... 

Aziridines can be detected by a color reaction with 4-(4 -nitrobenzyl)pyridine that was originally developed for the detection and/or determination of a wide range of alkylating substances. 58 It can be adapted to TLC. 59 60 Upon acid hydrolysis of aziridine-2-carboxylic acid containing peptides, as required for amino acid analysis, this amino acid is recovered as serine in varying yields. 47 Configurational characterization of aziridine-2-carboxylates is performed by NMR spectroscopy 47 51 61-63 and X-ray analysis. 61 In addition, optical rotation of the related benzyl Wtritylaziridine-2-carboxylate is also used 64 with [a]D —95.5 (c 1, THF) for the 25-enantiomer 44 as reference. 

For the enantioselective syntheses of stereochemically pure (25)-aziridine-2-carboxylic acid and (25,35)-3-methylaziridine-2-carboxylic acid, so far the precursors of choice are L-serine or L-threonine. Ring closure of these (3-hydroxy-a-amino acids via (3-elimination is per-... 

Scheme 2 Synthesis of Aziridine-2-carboxylic Acids via the Serine and Threonine C-Sulfonates 41 44 47 65"671...

An alternative route starting from serine 73 or threonine 68 74 makes use of diethoxy-triphenylphosphorane. Attempts to asymmetrically synthesize (25)-aziridine-2-carboxylic acid (1) by treating a, 3-dibromopropanoates with chiral amines 75 or by the Staudinger reaction from oxirane-2-carboxylic acid ester 70,76 leads to optically impure products, whereas 3-alkyl derivatives of tert-butyl aziridine-2-carboxylates can be prepared with high cis-selectivity from a-halo ester enolates and jV-trimethylsilyl imines. 77 Moreover, when optically... 

The Gabriel-Cromwell reaction of amines with chiral c/., 3-unsaturated a-bromo carbonyl compounds was exploited for the synthesis of aziridine-2-carboxylic acid derivatives. 79 This procedure was optimized for a solid support synthesis in which the peptide resin was acylated with 2,3-dibromopropanoic acid active ester in the presence of 3 equivalents of NMM to produce directly on resin the a-bromoacrylamide for the addition of amines to produce the aziridine ring. 80 ... 

Finally, saponification of the benzyl ester leads to the aziridine-2-carboxylic acid lithium salt as a stable compound.144 ... 

Table 3 Derivatives of (25 )-Aziridine-2-carboxylic Acid and (25,35 )-3-Meth-ylaziridine-2-carboxylic Acid 41-44-47-68-69-81-83-84-256-257 ...

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

Access to peptides with internally positioned aziridine-2-carboxylic acid is only possible by coupling N-protected amino acids to 2-carbonylaziridine amino acids or peptides, 63 since cyclization of Ala-aminoacylated (3-hydroxy a-aminoacyl peptides leads to oxazolines, as... 

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of c/s-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559. 

The unactivated aziridine-2-carboxylic acid methyl ester was found to react with two molecules of aromatic thiol47 Initial ring opening is followed by a faster reaction (since little mono substitution product is found), probably involving formation of an episulfonium ion which is then ring opened by the second ArSH. The same result... 

Aziridine-2-carboxylic acid, asymmetric derivatives of 87MI5. Aziridines, formation from nitrenes and unsaturated compounds 79ZVK485. 

Figure 3 Different approaches for the introduction of lipid functionalities, here exemplified via the farnesyl group, into peptides. (A) Lipidated amino acid building blocks. (B) Substitution of bromoalanine with a nucleophile. (C) Alkylation or acylation of a free thiol functionality of a cysteine. (D) Conjugate addition of a nucleophile (e.g., farnesylthiolate) to a dehydroalanine. (E) Conjugate addition of a nucleophile to aziridine-2-carboxylic acid containing...

Galonic DP, Ide ND, van der Donk WA, Gin DY. Aziridine-2-carboxylic acid-containing peptides application to solution- and solid-phase convergent site-selective peptide modification. J. Am. Chem. Soc. 2005 127 7359-7369. 

Sodium enolates of ketones and disodium enediolates of substituted phenylacetic acids reacted with activated aziridines to afford 7-amido ketones and 7-amidobutyric acids, respectively (Scheme 72). Aziridine-2-carboxylic acid esters can be utilized as versatile precursors for amino acid derivatives. Although the product distribution resulting from the reaction of activated aziridine-2-carboxylates with amines depends on the structure of the reactants, the reactions with alcohols or thiols in the presence of acidic cabilysts generally gave the a-amino acid derivatives (Scheme 73). ° On the other hand, free 3-methyl-2-aziridinecarboxylic acids (168) reacted with thiophenol, cysteine and glutathione to afford P-amino acid derivatives with sulfur substituents at the a-position as the main product (Scheme 73). ... 

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