Aziridines enantiopure

Ruano has reported substrate-controlled asymmetric ylide aziridination by treatment of enantiopure sulfinyl imines 117 with dimethyloxosulfonium methylide 118 to form terminal aziridines [63], The chiral tert-butylsulfinyl group was shown... 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

It may be concluded that the conversion of functionalized oxiranes into the corresponding aziridines by an azide ring opening followed by a Staudinger ring closure with triphenylphosphine constitutes a general method for the preparation of aziridines with high enantiopurity. 

Although the Sharpless asymmetric epoxidation is an elegant method to introduce a specific defined chirality in epoxy alcohols and thus, in functionalized aziridines (see Sect. 2.1), it is restricted to the use of allylic alcohols as the starting materials. To overcome this limitation, cyclic sulfites and sulfates derived from enantiopure vfc-diols can be used as synthetic equivalents of epoxides (Scheme 5) [12,13]. 

A modified Payne rearrangement of amino epoxides catalyzed by Lewis acid or induced by base, represents an interesting but a limited method for the synthesis of fonctionalized aziridines of high enantiopurity. The limitations are primarily due to the accessibility of the starting materials (Scheme 6) [15]. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

Coates used [Cp2Ti(THF)2] and [(salphen)Al(THF)2] as Lewis acid to convert a variety of epoxides to racemic p-lactones, and substituted aziridines to p-lactams in high yields under mild conditions. PO is selectively converted to p-BL in 95% yield in 4 h at 60°C [117]. However, only racemic p-BL can be obtained from racemic PO. In order to get enantiopure molecules from racemic precursors, the catalytic system has to be stereoselective. This can generally be achieved by the use of a chiral stereo-inducing Lewis acid, which effects a kinetic resolving activation [119, 120]. However, examples of the chiral resolution of PO are rare. 

The chiral dipolarophiles of Garners and Dogan, which were derived from Oppolzer s sultam, have been previously discussed in Section 3.2.1 and, in an extension to these results, the sultam moiety was used as the stereodirecting unit in enantiopure azomethine ylides (56). The ylides were generated either by thermo-lytic opening of N-substituted aziridines or by the condensation of the amine functionality with benzaldehyde followed by tautomerism. These precursors were derived from the known (+)-A-propenoylbornane-2,10-sultam. Subsequent trapping of the ylides with A-phenylmaleimide furnished the cycloaddition products shown in Schemes 3.60 and 3.61. 

The enantiopure 3-amino-2-(l-hydroxyethyl)quinazolinone 258 upon alkylation with cinnamyl bromide afforded O-alkylated product 259 as minor and N,0-dialkylated product as major (Scheme 58). Further iV-acetoxylation of 259 led to the formation of 260, which underwent intramolecular aziridination to give the 1,4,5-oxadiazepine 261 as a single diastereomer <1995J(P2)205>. 

The ring opening of enantiopure IV-tosyl aziridines 215 with 2-substituted 2-lithio-l,3-dithianes takes place at the less substituted carbon atom in good yields (59-92%)321. The corresponding adducts gave /9-tosylamino carbonyl compounds after reaction with methyl iodide under acetone reflux. 

Aziridines can be readily prepared utilizing 1,2-amino leaving groups as precursors. Traditionally an amine lone pair or an amide anion facilitates an intramolecular nucleophilic displacement to generate the aziridine ring. Utilization of enantiomerically pure 1,2-amino leaving groups renders the possibility of enantiopure aziridines via asymmetric synthesis. 

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>. 

Addition of (S)-dimethylsulfonium-(/>-tolylsulfinyl)methylide to V-tosyl imines provided sulfinyl aziridines with excellent diastereo- and enantioselectivity. Desulfinylation using EtMgl or MeLi afforded enantiopure 2-substituted aziridines without ring opening <07TL3907>. 

Aziridines can also be synthesized from their unsaturated azirine counterparts or existing aziridine rings. The first examples of enantiopure 2-substituted 2Z/-azirine 3-carboxylates 46 were prepared via dehydrochlorination of methyl 2-chloroaziridine-2-carboxylates. Bicyclic and tricyclic aziridines such as 47 were then generated via an aza-Diels-Alder reaction with the corresponding dienes <070L1707>. A related azomethine cycloaddition in the presence of an aziridine has also been reported <07JOC8506>. 

Biotransformation can serve as an alternative route towards enantiopure aziridines. (1R,25)-1 -Benzyl- and l-arylaziridine-2-carboxamides were obtained in enantiomerically pure form via kinetic resolution of their racemates by Rhodococcus rhodochrous IFO 15564 catalyzed hydrolysis <07OF521>. Rhodococcus erythropolis AJ270 was reported as an efficient whole cell catalyst for the synthesis of highly enantiopure 5,-l-arylaziridine-2-carboxamides and A-l-arylaziridine-2-carboxylic acids <07JOC2040>. Enantiopure 2-... 

Nitrogen-based nucleophiles continue to remain popular in ring-opening reactions of aziridines. a-Substituted-a-methoxycarbonyl-V-nosylaziridines were opened with a variety of functionalized amines to provide access to enantiopure a,a -disubstituted (3-lactam scaffolds for ditopic peptidomimetics <07OL101>. A related intramolecular regioselective 3,Y-aziridine ring opening with an a-amino functionality was reported in the synthesis of... 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

Chiral 2//-azirines have been prepared by dehydrochlorination of 7V-chloroaziridines, Swem oxidation of aziridines and elimination from A -sulfinylaziridines. These reactions require the use of high enantiopure aziridine esters as starting materials <03T2345>. Chiral enriched ethyl 3-methyl-2//-azirine-2-carboxylate was found to act as an efficient alkylating agent for the preparation of a variety of five-membered aromatic nitrogen heterocycles <03TL6277>. 

Access to enantiopure oxazolidinones was afforded by treatment of the corresponding aziridines 207 or 209 with phosgene or methyl chlorocarbonate <03JOC104,03JOC43>. 

A dynamic kinetic asymmetric transformation (DYKAT) of racemic vinyl aziridine 347 yielded the enantiopure imidazolidinone 348 (Scheme 90) <20050L823>. This transformation was the initial step in a total synthesis of (+)-pseudodistomin D. 

Chiral azomethine ylides were prepared and used for the preparation of ferrocenyl-substituted pyrrolidines <2002TA2099>. Other enantiopure azomethine ylides were produced from aziridines by thermolysis <2001T71> and an enantiopure nitrile oxide was trapped by alkenes <2001GH629>. 

Enantioselective aziridination has also been achieved by use of an enantiopure ligand [70]. Reaction of a variety of N-enoyl oxazohdinones with N-aminophthalimide and lead tetraacetate in the presence of camphor-derived chiral ligands provided the N-phthahmidoaziridines in good to high enantiomeric excess (Scheme 13.49). The oxazohdinone moiety of the substrate played an indispensable role in this reaction. The use of aryl acrylates led either to low stereoselectivity or low chemical yield. Coordination of the hgand-mediated Lewis acid to the bidentate acyl oxazohdinone might account for these results. 

Davis, F.A., and McCoull, W., Asymmetric synthesis of aziridine 2-phosphonates and azirinyl phosphonates from enantiopure sulfinimines. Tetrahedron Lett., 40, 249, 1999. 

More recently, Takeda et reported [Pd(SlPr)(cin)Cl)] (39) to be highly efficient in the regioselechve and stereospecific cross-coupling of enantiopure 2-arylaziridines with arylboronic acids. Using 4 mol% of the pre-catalyst, a variety of chiral 2-aryl-phenethylamine derivatives were produced under mild reaction conditions in high yield and with excellent enantioselectivity (up to 99% ee, Scheme 17). Electron neutral and electron deficient aziridines and sterically encumbered and/or funchonalized aryl boronic acids were all well tolerated under the developed conditions. 

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