Pyruvic acid esters, chiral

Especially high optical inductions have been achieved with catalysts which contain BPPM (13), PPM (14) or (15) as chiral ligands. Pyruvic acid esters were usually hydrogenated to lactic acid esters in quantitative chemical yield with an enantiomeric excess of 65-75%41 a,53). However, this method is not of technical significance, since chiral lactic acid derivatives may be produced more conveniently by biotechnological processes. 

Although cinchona alkaloids and especially cinchonidine, Cnd, proved to be the most effective chiral modifier for the catalytic system of Pt-alumina, in the liquid phase enantioselective hydrogenations of the carbonyl group in pyruvic acid esters, efforts to understand the mechanism of action of this catalyst system has continued to the present. The efforts may be divided into two categories finding natural modifiers other than cinchona alkaloids and examining new effective amino alcohols, which are modeled after the structure of known cinchona modifiers. 

A little dichlorotitanium diisopropoxide in toluene added to a mixture of activated, powdered, 4A molecular sieves and a little (R)-2,2 -dihydroxy-1,1 -binaphthyl in methylene chloride at room temp, under argon, the mixture stirred for 1 h, cooled to — 70°, isobutylene and methyl glyoxylate added, warmed to — 30°, and stirred for 8 h - (R)-product. Y 72% (e.e. 95%). Molecular sieves facilitate ligand exchange on the metal and play a role in maximizing the stereodifferentiating ability of the catalyst (e.e. ca. 20% without sieves). F.e.s. K. Mikami et al., J. Am. Chem. Soc. Ill, 1940-1 (1989) from chiral pyruvic acid esters with TiCl4 cf. J.K. Whitesell et al., J. Org. Chem. 54, 2258-60 (1989) review of C2-symmetry and asym. induction s. Chem. Rev. 89, 1581-90 (1989). 

The use of proline methyl ester as a chiral auxiliary in the asymmetric synthesis of alanine is shown on the following page. The idea is to start with 2-oxopropanoic acid (pyruvic acid), which has the correct carbon skeleton, and replace tire oxygen on carbon 2 with an amino group and a hydrogen. This must be done in such a manner as to produce only the S-enantiomer of the amino acid, that is, L-alanine. This is accomplished by first attaching a chiral auxiliary, the methyl ester of L-proline, to the acid. In the critical step of the process, the catalytic hydrogenation, the chirality of the... 

The enantiomeric excess (ee) of the hydrogenated products was determined either by polarimetry, GLC equipped with a chiral column or H-NMR with a chiral shift reagent. Methyl lactate and methyl 3-hydroxybutanoate, obtained from 1 and 2, respectively, were analized polarimetry using a Perkin-Elmer 243B instrument. The reference values of [a]o(neat) were +8.4° for (R)-methyl pyruvate and -22.95° for methyl 3-hydroxybutcinoate. Before GLC analysis, i-butyl 5-hydroxyhexanoate, methyl 5-hydroxyhexanoate, and n-butyl 5-hydroxyhexanoate, obtained from 1, 5, and 6, respectively, were converted to the pentanoyl esters, methyl 3-hydroxybutanoate was converted to the acetyl ester, and methyl 4-methyl-3-hydroxybutanoate obtained from 2 was converted the ester of (+)-a-methyl-a-(trifluoromethyl)phenyl acetic acid (MTPA). 

Based on these preliminary findings, related couplings to pyruvates and iminoacetates were explored as a means of accessing a-hydroxy acids and a-amino acids, respectively. It was found that hydrogenation of 1,3-enynes in the presence of pyruvates using chirally modified cationic rhodium catalysts delivers optically enriched a-hydroxy esters [102]. However, chemical yields were found to improve upon aging of the solvent 1,2-dichloroethane (DCE), which led to the hypothesis that adventitious HC1 may promote re-... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Evans, D.A. and Tregay, S. W. and Burgey, C.S. and Paras, N.A. and Vojkovsky, T. (2000). C2-Symmetric Copper(ll) Complexes as Chiral Lewis Acids. Enantioselective Glyoxylate-Ene Reaction with Glyoxylate and Pyruvate Esters. J. Am. Chem. Soc., 122, 7936-7943. 

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%. ... 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

Evans, D.A., Tregey, S.W., Burgey, C.S. er a/. (2000) C2-Symmetric copper(II) complexes as chiral Lewis acids. Catalytic enantioselective carbonyl-ene reactions with glyoxylate and pyruvate esters. Journal of the American Chemical Society, 122, 7936-7943. 

Evans DA, Kozlowski MC, Bnrgey CS, MacMillan DWC (1997) C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Catalytic Enantioselective Aldol Additions of Enolsilanes to Pyruvate Esters. J Am Chem Soc 119 7893... 

An interesting asymmetric addition of 1-napthol 81 to pyruvic esters 82 using a catalytic amount of a chiral (1R,4S,1 R,4 S) dibomacyclopentadienyl-zirconocene Lewis acid was reported by Erker in 1990. Treatment of 1-napthol (81, 1 equiv) to pyruvic esters (82a and 82b, 5 equiv) using 5 mol % of ZrCls-dibomacyclopentadienyl catalyst complex at -10 °C in DCM and water (27 mol %) afforded the corresponding substituted a-hydroxy esters 83a and 83b, respectively, in yields of 56-59%. The reported optical purity of 83a (84-89% ee) depended on the conversion of 82a (70-90%). The presence of a small amount of water appeared to increase the enantio-selectivity of the reaction on the order of 10% ee, even though it was... 

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