Achiral imines

Synthesis of aziridines by treatment of carbenes with imines was reported by Jacobsen [56]. A metallocarbene 104 derived from ethyl diazoacetate and copper fluorophosphate was treated with N-arylaldimines to form aziridines with reasonable diastereoselectivities (>10 1 in favor of cis) but with low enantioselectivities (about 44% ee). This was shown to result from a competitive achiral reaction path-... 

The classical aza-Darzens reaction (between bromoenolates and imines) has been investigated by several groups in recent years, especially with respect to the design and execution of asymmetric variants. Both stoichiometric and catalytic methods have been studied thus, the reactions between N-Dpp imines and chiral ot-bromoenolates [49] (derived from Oppolzer s sultams Scheme 4.35) and between S-chiral sulfmylimines and achiral bromoenolates [50] (Scheme 4.36) have been reported. 

Obviously, racemization occurred during the reduction step. For this benzylic alkoxyamine. racemization may occur by initial elimination of a metal alkoxide followed by reduction of the resulting achiral imine. 

Analogous to the closely related aldol reactions, reactions of achiral a-substituted enolates and imines lead to mixtures of syn- and rwd-diastereomers. The following diagram shows the postulated pericyclic transition states involved in enolate-iminc condensations10. 

Scheme 17 Asymmetric synthesis of 2,3-diaminoacids by the addition of a chiral imi-noester enolate to achiral imines...

The ionic liquid [bmim][BF ] is known to catalyze the aza-Diels-Alder reaction in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an endo. exo ratio of 60 40 (Scheme 69) [191]. The product was obtained as a race-mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky s diene was catalyzed by the salt 67 giving racemic product. The salt and its analogues could be easily prepared via the oxidation of the corresponding aminals [192]. Investigation of the influence of the counter anion in achiral C2-substituted imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the catalytic activity increased, the more lipophilic the counter anion and therefore the more hydrophobic the salt was [193]. 

In 2006, Akiyama and coworkers established an asymmetric Brpnsted acid-catalyzed aza-Diels-Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate (R)-3o (5 mol%, R = 2,4,6- Pr3-CgH2) bearing 2,4,6-triisopropylphenyl groups mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol with Danishefsky s diene 95 in the presence of 1.2 equivalents of acetic acid. Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-ties (76-91% ee). While the addition of acetic acid (pK= 4.8) improved both the reactivity and the selectivity, the use of benzenesulfonic acid (pK= -6.5) as an additive increased the yield, but decreased the enantioselectivity. A strong achiral Brpnsted acid apparently competes with chiral phosphoric acid 3o for the activation of imine 94 and catalyzes a nonasymmetric hetero-Diels-Alder reaction. The role of acetic acid remains unclear. 

Attempts to achieve an asymmetric 1,3-proton shift reaction of (/ )-33, obtained from ethyl 3,3,3-trifhioro-2-oxopropanoate and (f )-l-phenylethanamine in 81 % yield, resulted in conversion into 34 in 89% yield, but without any reliably delectable enantiomeric excess.26 Even at 10% conversion, the Shiff base 34 formed is completely racemic. Imine 34 undergoes isotopic exchange in triethylamine/methanoI-r/4 at a rate 10 times slower than the isomerization of 33 to 34. The authors reason that if a 1.3-proton shift mechanism is operating, some enantiomeric excess would have to be observable in product 34 at low conversion. Since this is not the ease, a 1,5-proton shift to the carbonyl oxygen, via stabilized anion 37, to form achiral intermediate enol 38, was proposed.26... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Asymmetric formation of /i-lactams (38) in high ee has been achieved by reaction of achiral imines (36) with a ternary complex of achiral lithium ester enolate (35), achiral lithium amide, and a chiral ether ligand (37) (in either stoichiometric or catalytic amount) 45 the size and nature of the lithium amide have a considerable effect on the enantioselectivity of the ternary complex. 

Thiruvazhi et al. [112] have shown interest in the area of (3-tum mimetics and the synthetic application of d- and L-proline for asymmetric synthesis of proline-derived spiro-(3-lactams. It has been shown that the asymmetric Staudinger reaction of optically active acid chloride of d- and L-proline with achiral imines is impossible due to the loss of stereochemistry at C-2. The authors have developed a strategy in which a chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of the reaction and is sacrificed later to obtain optically active spiro-(3-lactams (Scheme 38). 

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

The coupling of ketenes and imines has been reported to be catalyzed by a bifunctional system in which a chiral nucleophile was paired with an achiral Lewis acid metal salt [73, 74]. Optically enriched (3-lactam products were isolated in high yields, (Scheme 18). Among the various Lewis acids studied, such as Mg(OTf)2, Cu (MeCN)4C104, YbCL. La(OTf)3, AgOTf, Al(OTf)3, Sc(OTf)3, Zn(OTf)2,and In (OTf)3, this latter was the best overall cocatalyst for promoting the reaction. The best chiral nucleophiles used are reported in Scheme 18. 

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