Imino esters formation

However, the analogous reductive amination process involving in situ imino ester formation was not efficient yet. 

Tin(Il) shows considerable affinity towards nitrogen, therefore is expected to activate the imino group. The diastereoselective addition of tin(II) enolates derived from thioesters 1 to x-imino-esters 2 is reported12. This reaction proceeds smoothly to afford. vi w-/j-amino acid derivatives 3 (d.r. 95 5) in good yields. Lithium, magnesium, and zinc enolates do not react while titanium enolates give the adducts in low yield with preferential formation of the anti-isomer. 

The formation of tluorinated Q -hydroxy-jS-imino esters (180) by treatment of fluorinated imino ethers (179) with lithium 2,2,6,6-tetramethylpiperidide has been reported. A possible explanation for this interesting intramolecular rearrangement is proposed in Scheme 64. Acyclic imides derived from primary benzylic amines and amino acid esters have been found to undergo a novel nitrogen to carbon acyl migration via a base-generated carbanion to yield the corresponding a-amino... 

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

We were particularly interested to see whether a regio- and stereoselective hy-droxyalkylation and amrnoalkylation of 1 and 2 with aldehydes and imino esters, perhaps by choice of the substituent X at the Ti atom, with formation of the corresponding sulfonimidoyl-substituted homoallyl alcohols 4-7 and the homoallyl amines 8-11 (Fig. 1.3.3) could be achieved. Reggelin et al. had already demonstrated that the sulfonimidoyl-substituted mono(allyl)titanium complexes 3, the... 

The synthesis of ortho esters from nitriles is usually a two-step process involving first the formation of the imino ester hydrochloride and subsequent reaction with an alcohol. Several examples are described in Table I, even a glycol such as ethylene glycol can be used to obtain heterocyclic ortho esters, as shown in Eq. (11). 

PINNER REACTION. Formation of imino esters (alkyl imidates) by addition of dry hydrogen chloride to a mixture of a nitrile and an alcohol. Treatment of alkyl imidates with ammonia or primary or secondary amines affords amidines. while treatment with alcohols yields ortho-esters. 

Under optimized reaction conditions this two step synthesis for asymmetric preparation of /1-lactams is performed as follows. First, the organocatalyst 46 is added as a shuttle base to a solution of the acid chloride, 47, and the proton sponge , 49, at low temperature. Within a few minutes the soluble ketene and the hydrochloride salt, 49 HC1, as a white precipitate, are formed. Subsequently, the imino ester 44 is added to this solution at —78 °C, which results in the asymmetric formation of the /Mactam. Thus, the alkaloid 46 acts both as a dehydrohalogena-tion agent and as an organocatalyst for subsequent lactam formation [49, 52]. 

Molecular mechanics calculations also led to an explanation of the diastereose-lective course of the reaction. Several assemblies of the imino ester, 44, and the zwitterionic enolate were investigated [52]. In accordance with the experimental results it was found that the assembly leading to the cis diastereomer was of lowest energy. Because the lowest-energy trans assembly is several kilocalories higher, or-ganocatalytic / -lactam formation proceeds with an excellent cis diastereoselectivity. 

In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

The search for a catalyst suitable to promote addition of the less reactive silyl enol ethers of ketones has identified a novel class of cationic transition metal complexes in two independent laboratories. The use of a chiral palladium(II) di-aquo complex in the catalytic asymmetric addition of silyl enol ethers to aldehydes (first demonstrated by Shibasaki, Sodeoka et al. [52a, 52b]) provided a clear precedent for their subsequent use with a-imino esters [53] (Scheme 27). Initial experiments focused on the reaction of various a-imino esters 82a-c with silyl enol ether 83 (1.5equiv) in the presence of the Pd diaquo complex 80a (10 mol %) in DMF. Extensive experimentation led to the formation of 84c in 67% ee, and also underscored the importance of suppressing the generation of tetrafluoroboric acid during the course of the reaction. 

Towards that end,binuclear p-hydroxo complexes 81a,b could be made by the treatment of the diaquo complexes 80a,b with 4 A molecular sieves in acetone. These complexes were expected to prevent the formation of HBF4 when treated with silyl enol ether 83. In the presence of the novel complex 81b (5 mol %), the reaction of silyl enol ether 83 with a-imino ester 82c proceeded smoothly at 25 C to give the acylalanine derivative (S)-84c in 95% yield and 90% ee (Scheme 27). The reaction of other silyl enol ethers with a-imino ester 82c afforded the corresponding acylalanine derivatives with good asymmetric induction (53-84% ee). 

The radiation-induced N-O shift represented by Equation 1 leads to formation of a labile imino ester which species is readily hydrolyzed to yield ammonia and the hydroxyacid, lactic acid... 

The first highly enantioselective synthesis of the p-lactam ring with Cinchona alkaloids was demonstrated by Lectka and coworkers in 2000. They employed 10 mol% of benzoylquinine (O-Bz-Q) or benzoylquinidine (O-Bz-QD), to condense electron-deficient a-imino esters and ketenes (Scheme 15.12). To ensure in situ ketene formation (in fact a chiral ketene enolate is the reactive species.), proton sponge (PS) was used as a... 

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