Asymmetric Aziridination of Imines

Early work on the use of chiral phase-transfer catalysis in asymmetric Darzens reactions was conducted independently by the groups of Wynberg [38] and Co-lonna [39], but the observed asymmetric induction was low. More recently Toke s group has used catalytic chiral aza crown ethers in Darzens reactions [40-42], but again only low to moderate enantioselectivities resulted. 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

Asymmetric transformation of imines into chiral aziridines remains less well developed than the analogous transformation of aldehydes into epoxides [49, 50, 51]. The reported methods can be divided into three conceptual categories involving 

Aziridines Bearing Electron-withdrawing Croups Esters and Amides 1.3.1.1 Aza-Darzens Route 

241 I Asymmetric Synthesis of Epoxides and Aziridines from Aldehydes ar]d imines 

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An alternative approach to aziridine synthesis involves transfer of a carbenoid species to imines. Jacobsen achieved the first asymmetric aziridination of imines by transfer of copper carbenoids derived from copper bis-oxazohne catalysts and ethyl diazoacetate onto imines, but this process only proceeds with moderate yield and selectivity. Better results have been achieved by addition of ethyl diazoacetate to imines in the presence of enantiopure Lewis acids such as the boron-based catalysts prepared from vaulted biaryls such as VAPOL (4.154) and B(OPh)3. A range of aryl and alkyl N-benzylaldimines, for example (4.155) and (4.156), undergo aziridination to give ds-aziridines with high ee using this procedure. 

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. 

Chiral dicarboxylic acid (R)-5g (5 mol%, R = Mes) bearing simpler mesityl-substituents at the 3,3 -positions was found to catalyze efficiently the trans-selective asymmetric aziridination of iV-aryl-monosubstituted diazoacetamides 177 and aromatic (V-Boc imines 11 (Scheme 75) [94], In sharp contrast to previous reports on this generally dx-selective sort of aziridination, this method exhibited unique fran -selectivity and afforded exclusively the fran -aziridines 178 in moderate to good yields along with excellent enantioselectivities (<20-71%, 89-99% ee). The 1,2-aryl shift products 179 were observed as side products in varying ratios (178 179= 56 44-90 10). Diazoacetamides were chosen instead of diazoesters. Due... 

Asymmetric variants of imine reduction have also been developed towards enantiopure aziridines. Reduction of chiral /V-tert-butanesulfinyl a-halo imines afforded enantiopure aziridines in good to excellent yields <07JOC3211>. Enantioselective catalytic reduction of a-chloroimines utilizing metal-free L-valine-derived formamide 45 followed by base-mediated ring closure provided aziridines with preserved enantiopurity <07AG(I)3722>. 

Chiral cychc and acyclic allylsulfoxonium ylides are generated from sulfoxonium-substi-tuted y,8-unsaturated a-amino acids (method A) and 1-alkenylsulfoxonium salts (method B) upon treatment with DBU (1) [51] (Scheme 3.31). Their apphcation to the asymmetric aziridination of A-ferf-butylsulfonyl imine ester, generated either in situ (method A) or externally added (method B), affords the corresponding alkenylaziridinecarboxylate with medium to high diastereoselectivity and enantioselectivity. 

A multi-component catalytic asymmetric aziridination of aldehydes employs a protected amine and ethyl diazoacetate as reactants and an (5)-VAPOL boroxinate catalyst, giving aziridine-2-carboxylic esters in up to 99% ee. It works for some cases where preformed imines failed. ... 

Asymmetric Aziridination of Alkenes. The copper-catalyzed aziridination reaction can be rendered enantioselective by the addition of chiral ligands. The first example of an enantioselective aziridination of an alkene employed the bis(oxazoline) ligand (4) (R = f-Bu) and copper(I) trifluoromethanesulfonate as the metal catalyst (eq 14). This catalyst system affords the aziridine in 97% yield and 61% ee. Other reports have appeared subsequently regarding the extended scope of this reaction. " Important contributions to this area include the copper/bis-(oxazoline)-catalyzed aziridination of aryl acrylate esters (eq 15) and the copper/bis(imine)-catalyzed aziridination of cyclic cis-alkenes with the bis(imine) ligand (5) (eqs 16 and 17). ... 

Scheme 20.31 Amine-catalyzed asymmetric aziridination of an imine.

Of course, the key limitation of the ylide-mediated methods discussed so far is the use of stoichiometric amounts of the chiral reagent. Building on their success with catalytic asymmetric ylide-mediated epoxidation (see Section 1.2.1.2), Aggarwal and co-workers have reported an aza version that provides a highly efficient catalytic asymmetric synthesis of trans-aziridines from imines and diazo compounds or the corresponding tosylhydrazone salts (Scheme 1.43) [68-70]. 

Reactions between imines and a-diazo carboxylates afford aziridine-2-carboxylates [55]. An asymmetric version of this reaction using chiral nonracemic catalysts has been described [53, 56-58]. As an example, catalytic aziridination of inline 44 (Scheme 3.14) with ethyl diazoacetate in the presence of 10% catalyst generated... 

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],... 

Tanner et al. also used an aziridine carbinol (viz. 54) as chiral ligand in asymmetric addition of diethylzinc to hT-(diphenylphosphinoyl)imines (Scheme 41) [54]. 

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. 

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