Synthesis of Chiral Aziridines

In addition, these authors have developed the synthesis of chiral aziridine... 

For reviews about the asymmetric synthesis of chiral aziridines, see (a)... 

The addition of aldehydes to carbenoids derived from the Cu-catalyzed decomposition of ArCHNj to form stilbene epoxides is subject to asymmetric induction by 1,3-oxathiane 47 prepared from 10-mercaptoisobomeol and acetaldehyde. The attack of sulfonium ylides derived from 48 on aldehydes also affords epoxides of high optical purity. The same principle underlies a synthesis of chiral aziridines. ... 

Chiral aziridine-2-carboxylates. The generation of enolates and their subsequent cyclization occur when P-benzyloxyamino carbonyl compounds are treated with TiCl -EtjN. Since the chiral substrates are readily available, this reaction realizes a valuable synthesis of chiral aziridines. 

At the same time, Antilla et al. developed a vaulted biphenanthrol (VAPOL)-based magnesium phosphate 20b mediated asymmetric aza-Darzens reaction for the synthesis of chiral aziridine derivatives. The catalyst was prepared in an identical procedure to the previously described process with VAPOL-derived phosphate and magnesium fert-butoxide, and applied in the enantioselective aza-Darzens reaction of N-benzoyl imines 23 and ot-chloro-1,3-diketone 24. The process formed a series of substituted aziridines 25 bearing various substituents at the aromatic ring, with good... 

Through the ester enolate-imine route, we have been able to prepare with high diastereo-and enantio-selectivity carbapenems such as PS-5 and PS-6 as well as ip-methyl carbapenems and monobactams. A promising application is represented by the stereospecific synthesis of chiral aziridines, potential starting materials for the preparation of a- and P-amino acids. Metallo imines also undergo reaction with a number of organometallic compounds to give primary amines and chiral 1,2-aminols. 

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]. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

The synthesis of chiral w-amino phosphonic acids (analogues of natural amino acids) may be accomplished from imines. The key step in this synthesis is the formation of an aziridine by reaction of a phosphonamide with an imine (equation 153)555. The reaction occurs in very good yield in THF, at —78 °C with BuLi. 

McCoull, W., Davis, F. A. Recent synthetic applications of chiral aziridines. Synthesis 2000,1347-1365. 

As part of an ongoing research program directed toward the use of chiral aziridines in asymmetric synthesis [36], Andersson, Tanner and co-workers have recently reported the detailed results of their own findings in the field of catalytic asymmetric dialkylzinc alkylation of imines [37dj. Tanner et al. had previously communicated their success in the catalytic asymmetric addition of organolith-ium reagents to imines with C2-symmetric bis(aziridines) [37a, 37b]. This was followed by a preliminary report on the use of aziridino alcohols as well as simple aziridines for the addition of diethylzinc to M-diphenylphosphinoylimines [37c]. The most recent report is an extension of this study, and includes the detailed preparation of the ligands [37d]. 

Elimination. Sometimes zinc dust alone is inadequate for achieving organic reactions. Surface modification can have dramatic effects. The Zn-Cu couple is useful for the synthesis of chiral allylic alcohols from epoxy tosylates and of ally-lamines from 2-(bromomethyl)aziridines (with sonication). 

Iska, V.B.R., Gais, H.-J., Tiwari, S.K. er a/. (2007) Asymmetric aziridination with chiral allyl aminosulfonium ylides synthesis of alkenyl aziridine carboxyaltes and palladium-catalysed E, trans/ , cis-isomerization of an alkenyl aziridine. Tetrahedron Letters, 48, 7102-7107. 

Maikov, Kocovsky, and co-workers have developed different L-valine-based Lewis basic catalysts such as 81 [176, 177], for the efficient asymmetric reduction of ketimines 76 with trichlorosilane 2, or catalyst 82 [178] with a fluorous tag, which allows an easy isolation of the product and can be used in the next cycles, while preserving high enantioselectivity in the process. Sigamide catalyst 83 [179, 180] and Lewis base 84 [181] were employed in a low amount (5 mol%) affording final chiral amines 80 with high enantioselectivity (Scheme 30) [182]. Interestingly, 83 was used for the enantioselective preparation of vicinal a-chloroamines and the subsequent synthesis of chiral 1,2-diaryl aziridines. In these developed approaches the same absolute enantiomer was observed in the processes. 

The memory of chirality concept has been employed in a strategy for the synthesis of chiral a,/ -diamino- and a-amino-/ -hydroxy ester derivatives via asymmetric imino-aldol and aldol reactions, starting from protected aminoesters. The route can 0 be extended to the enantioselective synthesis of aziridines. 

Example 9.4 Complete asymmetric synthesis of —)-chloramphenicol, (l/ ,2/ )-TM 9.2 is outlined in Scheme 9.6. An exemplary application of chiral organocatalysts is present in symmetric catalytic cyclization to aziridine 4 in the key step of the synthesis [11, 12]. Scheme 9.7 presents the detailed mechanism of chemo- and stereoselective rearrangement of chiral aziridine daivative 4 in the final intermediate 5. 

Synthesis of chiral SES aziridines was also performed by using a chiral nitridomanganese complex activated by silver salt and SES-Cl (3) (eq 26 and Table 6). Like that for the sulfonyl-iminoiodinane process, this reaction proceeds via nitrogen atom... 

The first sulfide-catalyzed aziridination via an alkylation/deprotonation route was reported by Dai and coworkers in 1996 for the synthesis of vinyl aziridines through the reaction of N-sulfonylimines with cinnamyl bromide using dimethyl sulfide (0.2 equiv) as a catalyst (Scheme 20.14). PhSMe and PI12S failed to promote this reaction due to the slow alkylation reaction. Chiral sulfide 2 was also tried in this reaction and gave the aziridination product in 23% yield without diastereoselectiv-ity (49 51), but no optical yield was reported [35]. 

Compound 14b catalyzed the aziridination of aliphatic and aromatic a,P-unsaturated aldehydes with similar results to catalyst 14a [15]. Worse results were achieved by using catalyst 14c in the synthesis of terminal N-tosylaziridines [16]. The further oxidation of products 15 allowed the synthesis of chiral p-amino esters derivatives [14—16], whereas their reduction permitted the synthesis of chiral protected amino alcohols [16]. 

After 18 rounds of evolution and the introduction of at least 35 mutations, the volumetric activity of the mutant was increased 4000-fold and this allowed a process having a space-time yield greater than 360 gp, d L/d. The optical purity of the desired product was higher than 99.5%. As a result of this extensive protein engineering study, several new and usefiil HHDHs became commercially accessible. The synthetic applicability of these HHDHs was demonstrated on several examples in the past [30,82-85]. Kosjek and coworkers published the resolution of 2,2-disubstituted epoxides 50 via biocatalytic azidolysis and subsequent synthesis of chiral amino alcohols 52 and aziridines 53 containing a tertiary center (Scheme 9.17) [86]. 

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