Lactic acid, chiral methyl

If we convert (+)-lactic acid into its methyl ester, we can be reasonably certain that the ester will be related in configuration to the acid, because esterification should not affect the configuration about the chiral carbon atom. It happens that the methyl ester so obtained is levorotatory, so we know that (+)-lactic acid and (—)-methyl lactate have the same relative configuration at the asymmetric carbon, even if they possess opposite signs of optical rotation. However, we still do not know the absolute configuration that is, we are unable to tell which of the two possible configurations of lactic acid, 2a or 2b,... 

Oxidation of thioethers derived from the natural chirality pool , the readily available lactic acid and 3-hydroxybutyric acid, has been used in molar-scale preparation of enantiomerically pure sulfoxides methyl ( )-2-(phenylsulfinyl)acrylate and (K)-isopropenyl p-tolyl sulfoxide [107]. 

The ring was built up from a cetyl a ted (S)-lactic acid, and a cy clization step introduced the second chiral centre—the methyl group goes pseudoequatorial while the pseudoaxial position is preferred by the methoxy group because of the anomeric effect (Chapter 42). 

Fig. 9 Comparison of VCD spectra for the S form of (a) propylene oxide, (b) glycidol, (c) lactic acid, and (d) methyl lactate in aqueous solutions. The chirality transfer spectral windows are indicated with dotted lines. Adapted with permission from [132]. Copyright (2009) American Institute of Physics...

This technique played a big role in the synthesis of all possible isomeric forms of lactic acid in which the methyl contains all three hydrogen isotopes and the hydrogen at C-2 can be either H, 2H or 3H. Each of the three structures, CH3CHOHCOOH, CH3C2HOHCOOH and CH3C3HOHCOOH, contains two chiral centers when the methyl is CH2H3H. Each structure thus exists in four forms, for a total of 12 isomers. They can all be prepared in substantial amounts and with high optical purity [133]. 

The use of these asymmetric hydrogenation catalysts gives the C-2 chiral center in about 80% optical purity. The same value would apply also to the chiral methyl. For further purification, a crystallization process was used. The optically impure lactic acid (an oil) was dissolved in an approximately equal volume of boiling diethylether diisopropyl ether, 1 1 on standing at 5°C large, colorless, crystals of optically pure chiral methyl chiral lactic acid, 162, were deposited. The recovery of the purified material was 60%. Because of the inherent relationship between the two chiral centers, optical purity at C-2 guarantees optical purity at C-3. 

The chiral methyl isobutyrates were prepared by a syn specific catalytic hydrogenation of metacrylic acid derivatives, 166. The catalyst used was not chiral (as in the work on chiral methyl chiral lactic acid) so a diastereoisomeric mixture of 167 and 168 was obtained. Since they contain 3H on the C-2 carbon atom, and assuming... 

Chiral methyl chiral lactic acid (5). This labeled molecule, useful for study of stereospecificity of enzymic reactions, has been prepared in a way that allows for synthesis of all 12 possible isomers. One key step is the stereospecific debromination of 1, accomplished by conversion to the vinyl-palladium cr-complex 2 followed by cleavage with CF3COOT to give the tritium-labeled 3. The next step is the catalytic deuteration of 3, accomplished with a rhodium(I) catalyst complexed with the ligands norbornadiene and (R)-l,2-bis(diphenylphosphino)propane. This reaction gives 4 with an optical purity of 81%. The product is hydolyzed to 5, which is obtained optically pure by cr3rstallization. 

Most of the syntheses of chiral methyl groups reported to date involve the use of purely chemical methods, purely enzymic methods, or various combinations of the two. Most of these routes produce acetic acid, pyruvic acid, or lactic acid, which can then be converted into more complex molecules. 

This method was proposed by P. Husek (ref. 5) and involves the analysis of the lactic acid in the form of dioxolanone using GC on a chiral stationary phase comprising a derivative of the p-cyclodextrine heptakis (2,3,6 tri O methyl) p-cyclodextrine. The derivatization reaction is as follows ... 

The enantiomers of methyl, ethyl, isopropyl esters of lactic acid can be directly separated using a "Pirkle" chiral stationary phase. 

Halopropionic acid derivatives are readily accessible from lactic acid via its mesylate. Thus, treatment of 156a with AICI3 affords methyl (i )-2-chloropropionate (162) with 88% ee [59]. Reaction of 156a with KF in formamide produces methyl (R)-2-fluoropropionate (163) (96% ee). The use of formamide as solvent not only increases the reaction rate but also favors Sn2 reaction due to its high polarizability. The ti ji is approximately 30 min, and reaction is complete in 3 h [57]. (R)-2-Fluoropropionic acid is prepared from 163 by transesterification with formic acid. Amberlyst A-26 (F ) can be used as an alternate fluoride source in the conversion of mesyl lactates to chiral a-fluoroesters. This polymer-supported reagent produces clean Sn2 reactions [60]. 

Ethyl-2-methyl-l,6-dioxaspiro[4.5]decane is a constituent of the antiaggregative pheromone produced by several varieties of bees. All of the four thermodynamically stable stereoisomers of this spiroacetal have been synthesized using (5)-malic acid and (5)-lactic acid as the sources of chirality [15]. 

The doublet structure of the methyl signal at 17 ppm is caused by the stereochemistry. Polylactides, not yet described in any pharmacopoeias, are rather new biodegradable polyesters derived from the chiral lactic acid and used, e. g., in drug delivery systems. The stereochemistry of the polymer is important to the physical and chemical behavior, especially the polymer properties. Pure tactic polymerization can be differentiated from atactic or mixed polymers by simple comparison of the C NMR spectra (Figure 3-10) [4]. 

Scheme 23.1. Synthesis of metalaxyl-M 1 starting from (S)-lactic acid methyl ester (chiral pool).

We ll use as an illustration a synthesis of a rare sugar, methyl mycaminoside, containing five chiral centres. Only one chiral centre comes directly from the chiral pool—the rest are introduced diastereoselectively. The naturally derived, enantiomerically pure compound used as the starting material is (S)-lactic acid. The starting chiral centre, preserved right through the... 

The zwitterionic monocyclic A. Si-silicates la and lb were synthesized by reaction of the zwitterionic A, 5 -trifluorosilicate 4 with one molar equivalent of the 0,0 -bis(trimethylsilyl) derivatives of glycolic acid and 2-methyl lactic acid, respectively (Scheme 1). Compounds 2a and 2b were prepared analogously starting from the zwitterionic X Si-trifluorosilicate 5 (Scheme 1). As shown for compound la in Fig. 1, the zwitterionic X i i-silicates la, lb, 2a, and 2b are chiral and exist as pairs of enantiomers [(A)- and (C)-enantiomers]. All compounds were isolated as racemic mixtures. 

By replacing a hydrogen —H in the PGA repeating unit with methyl group —CH3, we can mm PGA into PLA (Fig. 7.4). This substimtion gives chirality to PLA s structure, hence different stmcmral variations are possible, such as poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), and poly(D,L-lactic acid) (PDLLA). PLLA and PDLLA have been extensively smdied for medical applications. The replacement of —H with methyl group —CH3 also makes PLA a stiffer polymer than PGA because the methyl group —CH3 limits the rotation of the PLA chain. PLA is therefore classified... 

Optically active lactones are valuable building blocks in organic synthesis (4) and in the preparation of optically active biodegradable polymers (7,5). Several chemical methods for producing these compounds and their corresponding polymers have been explored (6) but unfortunately all of these methods are either experimentally cumbersome or afford the lactones with only modest enantioselectivities. Examples of chemically prepared optically active polyesters include poly(a-phenyl-P-propiolactone) (7), poly(a-ethy(-a-phenyl-P -propiolactone) (S, 9), poly(a-methyl-a-ethyl-P-propiolactone) (70) and poly(lactic acid) (77, 72). Use of enantioselective polymerization catalysts to carry out stereoelective polymerizations of racemic lactones has produced mixed results. For example, stereoelective polymerization of [/ ,S]- P-methyl-P-propiolactone with a catalyst from Zn ( 2115)2 and [7 ]-(-)-3,3-dimethyl-l,2-butanediol showed only a small enantiomeric enrichment in the final polymer (75). Stereoselective copolymerizations of racemic (LL/DD monomers) and meso (LD monomer) lactides using chiral catalyst that gives heterotactic and syndiotactic PLA, respectively have also been studied (77). 

Hydroxy-acids.—A full report has been published on the preparation of chiral a-hydroxy-acids in optical yields of up to 98% from a, -unsaturated acid chlorides by sequential N-acylation of an optically pure a-amino-acid, bromo-lactonization, dehydrobromination, and hydrolysis " (2, 23). Enolates of /-menthyl mandelate can be alkylated in ca. 50% yield with typical enantiomeric excesses of less than 40%, An elegant use of the prophos ligands in rhodium(i)-catalysed asymmetric hydrogenation (see 3,322) is in the preparation of all twelve isomers of chiral methyl chiral lactic acid the method is illustrated for one isomer in Scheme 5. The other isomers are obtained by changing the order of introduction of H, D, and T and the chirality (i.e. R or S) of the prophos ligand. 

The separation of methyl lactate enantiomers is recommended using an Agilent J W CycloSil-B column, which is 30% hepatkis (2,3-di-0-methyl-6-0-t-butyl dimethylsilyl)-(3-cyclodextrin in DB-1701— stationary phase. (3-cyclodextrin is suitable for chiral separation due to the fact that its cyclic oligosaccharide units forms inclusion complexes with different equilibrium constants with respect to methyl lactate enantiomers, leading to easy GC separation. This method has a wide detection range of 0.05—50% D-lactic acid in PLA. 

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