3- Alkylalkanoic acids

Alkylations of lithiated chiral 4,5-dihydrooxa7oles with 2.0 equivalents of a racemic secondary alkyl halide proceed under kinetic resolution10-16. The (S)-alkyl halide is assumed to react preferentially, and, after quenching with water, the excess (7 )-alkyl halide is isolated in 92-99% purity (determined by GC) and in 5 49% optical purity10. Hydrolysis of the alkylated 4,5-di-hydrooxazoles provides the chiral 3-alkylalkanoic acids in 99-99.8% purity (determined by GC) and 13-47% optical purity10. 

Alkylalkanoic acids (6, 386-387). Full deta ils including improved procedures have been published for the synthesis of thes e acids in high optical purity from 1, The oxazoline is converted into 3 by Wittig-Hor ner olehnation via 2 only the (E)-isomer is formed. Remaining steps are addition of sm alkyllithium to 3, followed by hydrolysis to 5. One limitation is that use of stabilized carbanions (LiCH2COOC2Hs, LiCH2CN, etc.) results in essential ly racemic products. 

Alkylalkanoic acids, This chiral oxazoline (1) can be converted into an... 

ALKYLALKANOIC ACIDS (4S,5S)-2-Methyl-4-methoxymethyl-5-phenyl-2-oxazoline. 

Alkylalkanoic acids, 388 Alkyl oj-alkenoates, 313 3-Alkyl-l-alkynes, 85 6-N-Alkylaminouracils, 185 Alkyl aryl ethers, 645 Alkyl aryl ketones, 24 N-Alkylarylsulfonamides, 578 o-Alkylbenzaldehydes, 443 Alkyl benzoates, 347 o-Alkylbenzoic acids, 368 2-Alkyl-l-f-butylaziridines, 118 Alkyl f-butylperoxyglyoxalates, 82 Alkyl chlorides, 22, 259 6-Alkyl-A -cyclohexenones, 236... 

General Synthesis.—One of the more significant publications of 1976 is a full report 1 from Meyer s group on the preparation of chiral a-alkylalkanoic acids (2) in up to 80% optical yield, by alkylation of chiral 2-oxazolines (1) (Scheme 1). The thorough study has revealed that alkyl iodides or activated halides afford maximum yields, and that no racemization occurs on hydrolysis thus the propanediol derivative (3) can be recycled. In addition, it is possible to predict which enantiomer of acid (2) will be obtained on double alkylation of oxazoline (4) by due consideration of the order of alkylation. The carbanion from (4) has also been found to be capable of chiral recognition of racemic secondary alkyl iodides to afford 3-alkylalkanoic acids in ca. 40% optical purity. In similar studies, oxazoline... 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

Lithiated chiral oxazolines have been shown to react with various electrophiles, generating a new asymmetric center with considerable bias. This process has led to the synthesis of optically active a-alkylalkanoic acids,47 n-hydroxy(methoxy)alkanoic acids,48 / -hydroxy(methoxy)alkanoic acids,49 n-substituted y-butyrolactones,50 and 2-substituted-l,4-butanediols (Fig. 2-4).50... 

The crude, alkylated product mixture can be either hydrolyzed with acid to give nonracemic 2-alkylalkanoic acids 5 of good optical purities (as80% ee) or reacted with methyl- or ethyl-lithium to furnish the corresponding 3-substituted 2-alkanones and 4-substituted 3-alkanones 6, respectively, in moderate yield and enantiomeric excess2. 

Alkylalkanoic Acids 5 by Hydrolysis of Alkylated A -Acylephedrines General Procedure2 ... 

Alkylation of the enolates of the amides derived from these chiral auxiliaries is a very useful method for the enantioselective preparation of chiral 2-alkylalkanoic acid derivatives. 

Table 5. 2-Alkylalkanoic Acids and a-Alkyl Lactones by Alkylation of Enolates from l-Acyl-2-pyrrolidinemethanols and Their Ethers, Followed by Hydrolysis...

Alkylalkanoic Acids by Hydrolysis of l-(2-Alkyl-l-oxoalkyl)-2-(methoxymethyl)pyrrolidines General Pro-cedure2,13 ... 

Table 7. 2-Alkylalkanoic Acids by Alkylation of Enolates from (2R,5R)-1-Acyl-2,5-bis(methoxymethyl)pyrrolidines, Followed by Hydrolysis7...

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

The mixtures of alkylation products can be purified by chromatography or, alternatively, by alkaline hydrolysis to afford the dcmethoxycarbonylated heterocycles 5 which can be purified to high diastereomeric purity by recrystallization. The purified major diastereomer can then be hydrolyzed (lithium hydroxide/hydrogen peroxide) followed by protonation to afford the corresponding 2-alkylalkanoic acids 6 with >99% ee4. 

Chiral oxazolines have been used in the chiral-selective assembly of carboxylic acids and lactones. The chiral oxazoline (407) was prepared using a commercially available chiral aminodiol. Metallation at -78 °C gave a lithiooxazoline which was alkylated with a variety of alkyl halides to afford on acid hydrolysis a-alkylalkanoic acids (409) of the (S)-configuration (72-82% e.e.). The methoxyamino alcohol released during the hydrolysis could be recycled to produce again the chiral oxazoline (Scheme 91) (79PAC1255). 

Meyers AI, Knaus G, Kamata K, Ford ME. Asymmetric synthesis of R and S a-alkylalkanoic acids from metalation and alkylation of chiral 2-oxazolines. J. Am. Chem. Soc. 1976 98 567-576. 

The chiral irans-2,5-disubstituted 1-acylpyrrolidines have been used in many diastereoselective reactions, in particular alkylation reactions. Thus, the amide enolates have been used in the preparation of a wide variety of chiral acid derivatives, e.g., 2-alkylalkanoic acids7,8 and other 2-substituted acids, such as 2-hydroxy-9, 2-cyano-2-methyl10, and 2-aminoalkanoic acids112 and their derivatives (see Tables 7 and 8), in high chemical yield. The induced diastereoselectivity is usually very high (mostly d.r. >97.5 2.5). 

A general method for the synthesis of a-amino-a-alkylalkanoates has been exemplified by reacdon of 1,2-monoacetoneglucose with (/ )-(+)-S-ethyl-S-methyl-l,3-dioxdane-2,4-dione as shown in Scheme 3." Methyl a-D-gluco-, a-D-galacto-, and a-D-manno-pyranosides esterified at 0-2, -3. and -4 with basic amino acids (lysine, cmuthine, o,P-diaminopropionic acid) have been prepared, via 6-0-trityl intermediates, to invesdgate the reladonship between chemical structure and taste. ... 

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