Chelates amino esters

The diastereofacial selectivity is explained by the proposed chelated intermediate 151. Internal delivery of the nucleophile takes place from the less hindered side. Removal of the chiral directing moiety with a catalytic amount of palladium hydroxide on carbon in absolute ethanol then furnishes the final product. This process yields the amino ester in 83-100% yield without observable racemization. 

Co(III)-chelated amino acid ester reactant and/or peptide product (Scheme 1). This basic difficulty was quickly pointed out (5), and has subsequently been examined and commented upon by others (6, 7). Such criticisms are well-founded since epimerization (or racemization) is a common problem, at least to some degree, in all chemical methods of synthesis where acyl-activation is employed. As a result, metal-activation methods have received little attention. However, since 1981 we have refined the Co(III) method such that very fast, clean, couplings can now be carried out using A-[Co(en)2((S)-AAOMe)]3+ reagents, which involve minimal (<2%) epimerization/racemization provided experimental conditions are strictly adhered to. 

Rate Constants (km0, kon) for Intermolecular Hydrolysis of Some Free and Co(III)-Chelated Amino Acid Esters at 25°C, I = 1.0 M... 

A stereochemical behavior similar to that of the 1-bromo-l-lithio aUcene 164 with regard to chiral aldehydes is shown by the hthiated methoxyallene 183. When added to iV,iV-dibenzylated a-aminoaldehydes 188, it reacts with non-chelate control so that awh -carbinols 189 are obtained predominantly. Diastereomeric ratios of 189 190 range from 80 20 to 95 5. As outlined above, the hydroxyalkylated allenes 189/190 can be converted into furanones 191/192 upon treatment with potassium f-butoxide and subsequent acid hydrolysis" . When, on the other hand, the adducts of 183 to the aldehydes 193 are submitted to an ozonolysis, A-protected a-hydroxy-/3-amino esters 194/195 result (Scheme 25)"" . 

These chelates are structurally similar to that postulated above for the metal ion-catalyzed hydrolysis of oj-amino esters the position of the protons in the transition state is different, but this is a completely arbitrary distinction. A further distinction is that the metal ion is facilitating attack in this instance not by a polarization of the substrate molecule, but rather by the positioning and fixation of the hydroxide ion at the reaction site. It is not clear which of these two representations—for the amino acid esters involving polarization or for the carboxylate esters involving fixation of the hydroxide ion—is the correct interpretation. It is conceivable that both are correct. A similar explanation will account for the large effect of calcium ions on the alkaline hydro ysis of acetylcitric and benzoyl-citric acids (53). 

The rapid aminolysis of cobalt(llI)-chelated glycine esters in aprotic solvents (Scheme 10 N4 = (en)2 or trien, R = Me, Et, R = H, CHR"C02Et) could be of value in peptide synthesis. The cobalt atom acts as both an N-protecting and an activating group. The synthesis of the chelated amino acid esters has presented some difficulties.207 A recent paper208 describes the use of methyl trifluoromethanesulfonate for the alkylation of chelated amino acids using dry trimethyl phosphate... 

Figure 3-11. The reaction of a chelated amino acid ester with an amine, R NH2, to yield an amino acid amide complex.

There are a number of useful synthetic applications of these reactions of chelated amino acid esters (Fig. 3-12). For example, if the attacking nucleophile is not a simple amine, but is another amino acid ester or an O-protected amino acid, then peptide or polypeptide esters are formed in excellent yields. This may be developed into a general methodology for the metal-directed assembly (and, in the reverse reaction, the hydrolysis) of polypeptides. 

We saw in Chapter 3 that the hydrolysis of chelated amino acid esters and amides was dramatically accelerated by the nucleophilic attack of external hydroxide ion or water and that cobalt(m) complexes provided an ideal framework for the mechanistic study of these reactions. Some of the earlier studies were concerned with the reactions of the cations [Co(en)2Cl(H2NCH2C02R)]2+, which contained a monodentate amino acid ester. In many respects these proved to be an unfortunate choice in that a number of mechanisms for their hydrolysis may be envisaged. The first involved attack by external hydroxide upon the monodentate A-bonded ester (Fig. 5-62). This process is little accelerated by co-ordination in a monodentate manner. 

The enhanced reactivity of chelated amino acid esters towards attack by other nucleophiles has been used to advantage in the sequential synthesis of small peptides equation (4l).225 Formation of the amide bond takes only seconds to minutes at room temperature in DMSO as solvent, and the peptide can be easily recovered by reducing the metal to the Co" state. Recent studies have shown that the A and A diastereoisomeric reactants are selective in their couplings to (2 ) and (S) amino acid esters and that mutarotation at the asymmetric centre of the chelated ester reactant varies from 0-6%.226 Isied and coworkers have described the use of the Co(NH3)3+ as a C-terminal protecting group for the sequential synthesis of peptides (equation 42).227 This procedure has advantages over other methods in some cases. 

Metal chelating amino acid derivatives of cellulose were recently obtained via modification of cellulose with 2,4-toluenediisocyanate, followed by treatment with amino acid ester derivatives [58,59]. Diisocyanates are able to crosslink cellulose chains and/or to yield reactive cellulose isocyanate, depending on the reaction conditions. Sato and his coworkers [60] examined the optimum conditions for the reaction between cellulose and 2,4-toluenediisocyanate and succeeded in introducing 0.30 mol of free isocyanate group per glucose unit. Cellulose isocyanate was further converted into isothiocyanate [61]. This derivative has also been synthesized by condensation of cellulose with 2,4-diisocyanototoluene, followed by hydrolysis and thiophosgene treatment [61]. 

Kobayashi and co-workers. used zirconium-based bromo-BINOL complex for the catalytic enantioselective Mannich-type reaction. The o-hydroxyphenyl imine 3.36 chelates the Zr(IV)(BrBINOL)2 to form the activated chiral Lewis acid complex A. The ketone acetal 3.37 reacts with the Lewis acid complex A to give the complex B. The silyl group is then transferred to the 3-amino ester to form the product 3.38 and the catalyst Zr(BrBINOL)2 is regenerated, which is ready for binding with another imine molecule (Scheme 3.16). 

Kazmaier, U. Synthesis of y,5-unsaturated amino acids via ester enolate Claisen rearrangement of chelated allylic esters. Amino Acids... 

Kazmaier, U. Reactions of chelated amino acid ester enolates and their application to natural product synthesis. Bioorg. Chem. 1999, 201-206. 

Van Koten and coworkers prepared zinc ester enolates of IV-protected a-amino esters from the corresponding lithium enolates and allowed them to react with imines at low temperature to obtain trans-3-amino-P-lactams, often with high stereoselectivity as shown in Scheme 19. Interestingly, the authors interpreted their results in terms of an internally chelated zinc-oxygen bonded enolate (37). 

A -Methylephedrine-derived silyl ketene acetals react with imines in the presence of 2 mol equiv. of TiCU to give P-amino esters (equation 15) significant results are summarized in Table 7. With benzyl-ideneaniline the reaction is anti selective (entry 1), while with imino esters that chelate TiCU to give complexes such as (41), the reaction is syn selective (entries 2 and 3), in agreement with the general prin-... 

The rates of alkaline hydrolysis of the half-esters, potassium ethyl oxalate, malonate, adipate, and sebacate were studied in the presence of potassium, sodium, lithium. thallium(I), calcium(II), barium(II), and hexamminecobalt(III) ions (106). On the basis of the results obtained, chelate formation between the metal ions and the transition state of the substrate was postulated. In these chelate structures (structures XXXVIII), formally similar to those postulated in the hydrolysis of a-amino esters (26), the metal ion facilitates the attack by the hydroxide ion by positioning it in a suitable manner. The rate of hydrolysis of the oxalate half-ester is greater than that of the malonate, which in turn is greater than that of the adipate. This is in the expected order of the stability of the metal chelates. The order for the rate of hydrolysis of the ethyl oxalate and ethyl malonate is Ca2+ Ba2+ > [Co(NH3)6]3+ > T1+. The hexamminecobalt(III) ion seems to be less effective than expected, since it is too large to satisfy the steric requirements of the chelate structures. The alkali metals were found to have marked negative specific salt effects on the rates of reaction of the adipate and sebacate, but only a small negative salt effect on the hydrolysis of potassium ethyl malonate. 

An asymmetric synthesis of amino alcohols by asymmetric addition of Grignard reagents to chiral a-bromoglycine esters provides a convenient synthesis of a-amino esters (Scheme 4.8, [99]). Hydrolysis of the product ester produces racemized amino acids, but reduction affords amino alcohols that can be subsequently oxidized to the amino acids with no loss of enantiomeric purity. Note that in the proposed transition structure, the phenyl effectively shields the Re face (toward the viewer) of the imine, which is chelated to the carbonyl by magnesium halide formed in the dehydrohalogenation. 

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