Preparation of Aziridine-2-carboxylates

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

3 Cyclization of a-Halo- and a-Sulfonyloxy- l-amino Esters and Amides 

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An attractive and useful method for the preparation of aziridine-2-carboxylic esters makes use of the readily available amino acids serine and threonine. Essentially, this synthesis involves the ring closure of 1,2-amino alcohols. 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

FR900490 (264 Scheme 3.96), a new immunomodulator, has been prepared from aziridine-2-carboxylic ester 261 [146, 147]. This aziridine reacts with (S)-histi-dine (262) in the presence of 1 n sodium hydroxide, giving 263 in 31-44% yield... 

An optically pure cyclic analogue of aziridine-2-carboxylate ester was prepared from ribose via a Ph3P-promoted conversion of 3-azido-2-tosyl-D-xylofuranoside to its corresponding 2,3-aziridine (95) (Scheme 34) <93T90l>. The procedure is directly applicable to the synthesis of enantiomerically pure 2,3-aziridine carboxylate isomers from D-lyxose. 

Preparation.- 4.1.1. Cyclisation. Dehydrohalogenation of (228) in aqueous LiOH at roan tenperature gives (229) (95 ) . This method has been applied to the synthesis of a number of aziridine-2-carboxylic acid... 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Aziridine-2-carboxylates 12 (Scheme 3.4) have also been prepared from 3-hy-droxy-a-amino esters 9 by treatment with sulfuryl chloride in place of tosyl or mesyl chloride. Treatment of 9 with thionyl chloride in the presence of triethylamine, followed by oxidation of 10 with sodium periodate and a catalytic amount of... 

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

Recently, Lee and co-workers reported an efficient method for the preparation of enantiomerically pure oxazolidin-2-ones from aziridine-2-carboxylates 186 (Scheme 3.68) [128]. This one-pot aziridine ring-opening and subsequent intramolecular cyclization process was highly regio- and stereoselective, affording 187 in high yield. 

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... 

Oligopeptides and amino aci containing an aziridine 2-carboxylate group have been prepared using a solid phase version of the Gabriel-Cromwell reaction (i.e., 127 129) <99TL6503>... 

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 key intermediate in the preparation of derivatives suitable for peptide synthesis (Table 3) is the benzyl (25)-7V-tritylaziridine-2-carboxylate, since it is smoothly converted into the N-protected imino acid by catalytic hydrogenolysis.[47] Similarly, the related methyl ester is saponified by lithium hydroxide to produce A-tritylaziridine-2-carboxylateJ83 84 Detrit-ylation to benzyl (2S)-aziridine-2-carboxylate is more difficult, but the dibenzosulfimide salt is found to be perfectly stable on storage as a solid for longer periods of time (see Section 9.2.1.1) J47l In solution, upon addition of bases the benzyl ester is sufficiently stable to allow for peptide syntheses.[47]... 

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 ... 

A facile phase-transfer catalysis protocol was reported for the conversion of p-hydroxy-a-amino esters into enantiomerically pure /V-tosyl aziridine-2-carboxylates <07TL6509>. Utilization of the same methodology allowed for preparation of an aziridine carboxamide in essentially quantitative yield. 

Aziridine-2-carboxylates are also prepared in high yield by reaction of hexahydro-1,3,5-triazines or A-methoxymethylanilines with alkyl diazoacetates in the presence of SnCU or BFs EtzO (Eq. 66) [99]. 

L. Dubois, A. Mehta, E. Tourette, and R. H. Dodd, Preparation of p-substituted tryptophan derivatives—comparison of the reactivity of JV-methylindole toward aziridine-2-lactones and aziridine-2-carboxylic esters and interpretation of results using MNDO calculations, J. Org. Chem., 59 (1994) 434- 1. 

Aziridine-2-carboxylic acid derivatives 133 may be prepared in a stereochemically predictable method by using the Oppolzer camphor sultarn as achiral auxilliary. The standard protocol of amine addition onto an a/pha-bromoacrylate is imbued with stereodifferentiation by the face-selective a/pfia-protonation of enolate 131, a step which the chiral auxilliary dictates to occur in a -fashion [94TL1653]. 

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