Aziridines chirality

Aziridines have been prepared stereospecifically by the nucleophilic addition of the nitrogen residue to alkenes <80T73). Introduction of the nitrene is accomplished readily via a Michael-type addition with free diphenylsulfilimine (Scheme 12), and where a chiral sulfilimine is used the chirality is transferred to the aziridine with optical yields in excess of 25%. 

Reagent-controlled aziridination using camphor-derived chiral sulfide 47 has been reported with ee values of 84-98% for the trans isomer although the tram cis ratio was... 

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... 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

Jorgensen has recently reported similar enantioselective reactions between N-tosylimines 107 and trimethylsilyldiazomethane (TMSD) catalyzed by chiral Lewis acid complexes (Scheme 1.32) [57, 53]. The cis-aziridine could be obtained in 72% ee with use of a BINAP-copper(i) catalyst, but when a bisoxazoline-copper(i) complex was used the corresponding trans isomer was fonned in 69% ee but with very poor diastereoselectivity. 

Table 1.15 Chiral guanidylium ylides for asymmetric synthesis of aziridines.

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... 

The sense of asymmetric induction could be tuned in two ways firstly through the chirality of the sufinyl group, and secondly through the use of dimethylox-osulfonium methylide (n = 1) or of dimethylsulfonium methylide (n = 0), which was found to provide aziridines with opposite diastereoselectivity. This was interpreted by assuming the process to be under thermodynamic control in the former... 

Table 1.16 Chiral tert-butylsulfinylimines in asymmetric aziridine synthesis.

Saito has recently reported high yields and enantioselectivities in aziridine synthesis through reactions between aryl- or vinyl-substituted N-sulfonyl imines and aryl bromides in the presence of base and mediated by a chiral sulfide 122 (Scheme 1.41) [66]. Aryl substituents with electron-withdrawing and -donating groups gave modest transxis selectivities (around 3 1) with high enantioselectiv-... 

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]. 

Aziridination remains less well developed than epoxidation. Nevertheless, high selectivity in inline aziridination has been achieved through the use of chiral sulfi-nimines as auxiliaries. Highly successful catalytic asymmetric aziridination reactions employing either sulfur ylides or diazo esters and chiral Lewis acids have been developed, although their scope and potential applications in synthesis have yet to be established. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Another example is indium(0)-induced electron transfer to aziridines 270 incorporating allyl iodide moieties (Scheme 2.66). Treatment with indium(O) in MeOH at reflux gave the corresponding chiral (E)-dienylamines 271 in excellent yields [98]. It should be noted that indium was found to be more effective for this transformation than other metals such as zinc, samarium, and yttrium. 

The chemistry of aziridine-2-carboxylates and phosphonates has been discussed in part in several reviews covering the literature through 1999 [1-3], This chapter is intended to give an overview of asymmetric syntheses using chiral nonracemic aziridine-2-carboxylates and -phosphonates with particular emphasis on their applications as chiral building blocks in asymmetric synthesis since 2000. Some overlap with earlier reviews is necessary for the sake of continuity. 

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... 

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. 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

Aziridine-2-carboxylates are playing important roles in the synthesis of natural products and pharmaceutically useful molecules. In this section, applications of chiral nonracemic aziridine-2-carboxylates in the synthesis of natural products are discussed. 

These reagents may be considered to be one of the elusive aza-analogues of peroxyacids, and there are significant mechanistic similarities between the Rees-Atkinson reaction and the Bartlett epoxidation. Chiral Q-reagents have been used to effect highly stereoselective aziridination of alkenes (Scheme 4.13) [1],... 

Chiral N-(2-bromo)crotonoyl imidazolidinones react with ammonia to give N-unsubstituted aziridines (Scheme 4.24) [31]. 

Probably the most widely applicable asymmetric imine aziridination reaction reported to date is that of Wulff et al. These workers approached the reaction from a different perspective, utilizing the so-called vaulted , axially chiral boron Lewis acids VANOL and VAPOL [35] to mediate reactions between ethyl diazoacetate and N-benzhydrylimines (Scheme 4.29) [36]. The reactions proceed with impressive enantiocontrol, but there is a requirement that the benzhydryl substituent be present since this group is not an aziridine activator there is, therefore, a need for deprotection and attachment of a suitable activating group. Nonetheless, this method is a powerful one, with great potential for synthesis, as shown by the rapid synthesis of chloroamphenicol by the methodology [37]. 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

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