Aziridine-2-carboxylic acid, ring opening

The C-2 proton in an aziridine-2-carboxylate is acidic, due to the adjacent carboxylic group. Upon treatment with base, such aziridines may undergo ring-opening reactions to give a-amino-a, 3-unsaturated carboxylates [74, 94, 95]. As an example, treatment of 111 (Scheme 3.39) with TMSI/Et3N gave 116 in 64% yield [74]. 

With Sulfur Nucleophiles N-Carboxy-protected aziridine-2-carboxylates react with thiols to give P-mercapto-ot-amino acid derivatives. The reaction is usually catalyzed by BF3 and the yields range from fair to excellent [15, 16, 108-111]. With N-unprotected 3-substituted aziridine-2-carboxylates, the ring-opening with thiols usually takes place with anti stereoselectivity, especially in the case of the C-3 aliphatic substituted substrates. In cases in which C-3 is aromatic, however, the stereoselectivity has been found to be a function of the substitution pattern on the aromatic ring 3-p-methoxy ph eri yl-su bs li In led aziridines 143a (Scheme 3.51) and... 

Similar to the epoxides, the most frequently encountered synthetic transformation for aziridines is nucleophilic ring-opening, whereby carbon- and heteroatom-based nucleophiles are comparably important. As an example of the former type, aziridine-2-carboxylates 100 can be ring-opened with higher order cuprates to give the protected amino acid derivatives 101, corresponding to attack at the less-substituted aziridine carbon [95TL151],... 

Starting from ethyl 4, 4, 4-trifluorocrotonate, racemic aziridine carboxylic acid 96 was prepared as shown in Scheme 9.22 [46] and was then subjected to lipase-catalyzed esterification. Methyl ester 97 was obtained in 35% yield with excellent enantiomeric purity. Acid-catalyzed ring opening of aziridine 97 proceeded regio- and stereoselectively, affording 2-substituted (2R,3R) or (2/ ,3S)-3-amino-4,4,4-trifluorobutanoates 98 in high yields [47]. 

Carboxylic acids have also been investigated as nucleophiles in the ring-opening of aziridine-2-carboxylates [103]. Solvation of compounds 129 (Scheme 3.46) in acetic acid, for example, gave 130a and 130b in 83% and 89% yields, respectively. 

S,3R)-Aziridine-2-carboxylic amide 258 (Scheme 3.95) has been used in the synthesis of the cyclic guanidino amino acid, L-epicapreomycidine (260) [145]. Treatment of 258 with saturated ammonia in methanol at 30 °C for 4 days in a pressure bottle resulted in the aziridine ring-opening product, which afforded 259 in 52 % yield after removal of the Cbz protecting group. 

The regioselective reductive ring opening of, V-substitutcd aziridine-2-carboxylates gives either a- or //-amino acids.122 Heteronucleophiles such as nitrogen,123 oxygen,124 sulfur,125 and chloride preferably attack the C-3 position to provide a-amino acid derivatives. However, a mixture of products will result when carbanion or azide is used as the nucleophile (Scheme 4-62). 

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... 

Ethyl l-azabicyclo[3.1.0]hexane-5-carboxylate 6 with hydrochloric acid gives 3-chloropiperidine-3-carboxylic acid hydrochloride 53 by ring opening with concomitant hydrolysis. Catalytic reduction with hydrogen over palladium on charcoal causes cleavage of both aziridine N—C bonds of the parent azabicyclohexane 1, to give 2-methylpyrrolidine (54) and piperidine (55) in the ratio 2 1. ... 

Carboxylic acids are well known nucleophiles for opening epoxides and aziridines. Recently the stereoselective epoxide ring opening has also been achieved via palladium catalyzed formal 1,4 addition <05TL7243>. 

Carboxylic acids also add to the C=N double bond and the products rearrange to more stable compounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions [15] ... 

J. Legters, J. G. H. Willems, L. Thijs, and B. Zwanenburg, Synthesis of functionalized amino acids by ring-opening reactions of aliphatically substituted aziridine-2-carboxylic esters. Reel. Trav. Chim. Pays-Bas-J. Roy. Neth. Chem. Soc., Ill (1992) 59-68. 

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