Aminoester enolates

Maguesium aminoester enolates are of much iuterest for the syuthesis of complex amiuoacids aud peptides. These chelate euolates have beeu used as uucleophiles for a wide rauge of stereoselective transformatious, as diastereoselective Michael additious aud Claiseu rearrangement . Two typical examples are presented in equation 95. 

In the presence of HMPA, 1 1 dimers were observed with both lithium cyclohexenolate or 2,4-dimethylpentanolate and [6Li,15N]LDA or [6Li,15N]LiTMP297. The /S-aminoester enolate presented above (Scheme 60B) was also shown to provide a 1 1 mixed aggregate with LiHMDS in THF288. 

With trimethylsilyl iodide 17 the 0,N-acetal 457 gives the iminium iodide as reactive intermediate this converts the enol silyl ether 107 a in situ into the Man-nich-base 669, in 81% yield, and hexamethyldisiloxane 7 [195]. On treatment of the 0,N-acetal 473 (or the N-silylated Schiff base 489) with TMSOTf 20 (or Zny, the intermediate iminium triflate adds to the ketene acetal 663 to give mefhoxytri-methylsilane 13 a and silylated / -amino esters such as 670, which are readily transsilylated by methanol to give the free / -aminoester [70, 196] (Scheme 5.61). 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

A similar procedure for the synthesis of a-acyl aminoesters has been proposed using a MgCl2/R3N base system to generate the magnesium enolates of a series of a-carboxy aminoesters. These reagents react smoothly at 0 °C with a variety of acid chlorides to give a-acyl aminoesters in good to excellent yields (equation 58). 

This reaction sequence has been extended to lithium enolates. The deprotonation of the aminoester 54 with LDA followed by a transmetalation with zinc bromide in ether furnishes a zinc enolate, which readily adds to the double bond providing the proline derivative 55 in high diastereoselectivity (Scheme 23) . ... 

An efficient asymmetric synthesis of / -lactams, reported by van Koten and coworkers128, was based on a-aminoesters as chiral auxiliaries and on the preformed imine-ZnCl2 complex (e.g. structure 72 in equation 45), which was then added to the glycine zinc enolate 73. The presence of ZnCl2 as Lewis acid was essential to ensure complete lactamization. 

It is also worth mentioning that such cyclizations could be achieved for a-aminoesters bearing the amino group located outside of the chain. Indeed, Chemla and coworkers recently reported that the a-aminoester 421 successfully underwent a zinc-enolate cyclization, according to the standard conditions, and afforded after hydrolysis the five-membered ring tertiary amine 422 as a 80/20 mixture of diastereomers (equation 182)264. 

The zinc-enolate cyclizations are not restricted to a-aminoesters as /3-aminoesters have also been successfully involved in such reactions275. The preformed lithium enolate generated by treatment of the /J-arninoester 423 with LDA had to be added dropwise to an ethereal solution of ZnBr2 in order to avoid a competing /3-elimination reaction induced by the zinc enolate. this reverse addition protocol was respected, a smooth carbocyclization reaction occurred and provided, after hydrolysis, the substituted 3-carbomethoxypyrrolidine 424 as a 87/13 mixture of diastereomers (equation 183). 

Asymmetric protonations of prochiral enolates or enaroines by enantiopure carboxylic acids typically occur with low enantioselectivity, but there are some exceptions. P. Duhamel, L. Duhamel and coworkers accomplished the " deracemi-zation of Schiff bases of a-aminoesters [552], The best selectivities (ee 70%) are obtained when the substrates are deprotonated by Li (ify-A -ethylphene-thylamide, and then reprotonated at -70°C by (fy )-diacyltartaric add 2.2 (R = fert-BuCO) [154] (Figure 4.4). In another successful application, asymmetric protonation of the potassium enolale of racemic benzoin 4.7 by (RJR) 2.2 (R = terf-BuCO) gjves the (S)-enantiomer with a good enantiomeric excess [552] (Figure 4.4). 

Asymmetry in enolate alkylations can be induced by the presence of chiral imines formed from aldehydes, ketones or aminoesters. Chiral acetals or oxa-zolidines of keto- or aldehydo-esters can also be efficient reagents. 

Enantioselective methylation of imine enolates of aminoesters 5.41 by diace-toneglucose 1.48 methyl sulfate has been carried out by Duhamel and coworkers [154, 358], After hydrolysis, nonracemic a-alkyl alanines are obtained with enantiomeric excesses up to 76% (Figure 5.28). 

The use of chiral sulfoxitnines 1.136 (R = Ph, Tol, Y = ArCH=N) has allowed the enantioselective synthesis of p-aminoesters after cleavage of the S-N bond by CF3COOH [510], Preliminary studies showed that the reaction of C-arenechromium tricarbonyl imines and the lithium enolate of Me2CHCOOEt gave chiral p-lactams after decomplexation with an excellent enantiomeric excess [549, 1291]. 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

The first report on the synthesis of P-lactams through an ester enolate-imine condensation was reported by Gilman and Specter close to 45 years ago [68]. The method involved reaction between an a-bromoester and an imine in the presence of zinc and iodine as catalyst to give P-aminoesters or P-lactams, depending on the reaction conditions employed. The mechanistic and stereochemical features of this reaction have been widely studied [69], however its utility in the preparation of valuable P-lactams for carbapenem synthesis has received very little attention. Recently we [70a] demonstrated the utility of this reaction for the preparation of 3-alkyl-4-acetoxyazetidin-2-ones as precursors for the synthesis of ( ) PS-5 and ( ) PS-6 antibiotics. 

Parallel to the above approach efficient synthesis of P-amino acid derivatives by the use of Sn(II) enolates and a-aminoesters have been carried out by Japanese workers [90]. The most recent asymmetric synthesis of a (-h)-6-epi PS-5 carbapenem building block through this methodology (Scheme 33), involved... 

Recently, Ueno et al used the chiral zirconium catalyst 7.4.4 for asymmetric induction. Thus, reaction of imine 7.4.5 and silyl enol ether 7.4.6 in the presence of 10 mol% S-IAA gave the desired phenyl isoserine derivative 7.4.7 in 94% ee and 95% yield. The a-hydroxy-phenylamine which was required for the catalytic asymmetric induction was then cleaved oxidatively using CAN after being converted to an a-methoxy-phenylamine derivative. Aqueous hydrolysis of the resulting aminoester 7.4.8 yielded the amino acid quantitatively, which was benzoylated to give the taxol side chain (269). 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of P-aminoketones or p-aminoesters. Although the classical protocols include some severe side-reactions, new modifications using preformed iminium salts and imines have been developed [46]. Among them, reactions of imines with enolate components, especially silyl enolates, provide useful and promising methods leading to p-amino-ketones or p-aminoesters. The first report using a stoichiometric amount of TiCU as a promoter appeared in 1977 [47] and, since then, some efficient catalysts have been developed [48]. 

We tested the reactions of imines with silyl enolates in the presence of 5 mol% of lanthanide triflates (Ln(OTf)3) and scandium triflate (Sc(OTf)3), and selected examples are shown in Table 8.10 [49]. In most cases, the reactions proceeded smoothly in the presence of 5mol% of Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding p-aminoester derivatives in good to high yields. Yttrium triflate (Y(OTf)3) was also effective, and the yield was improved when Sc(OTf)3 was used as a catalyst instead of Yb(OTf)3. Not only silyl enolates derived from esters, but also... 

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