Alkylation of Chiral Imide Enolates

Evans and Oppolzer s auxiliaries are of comparable efficacy with regard to chemical yields and the stereoselectivities they induce in the a-alkylation process. In some cases Oppolzer s imide enolates are superior because they give slightly higher stereoselectivities, the resultant a-branched iV-acylsultams are often more easily purified by simple crystallization, and the auxiliary is easier and cleaner to remove. For both auxiliaries, the iV-acylated derivatives required for alkylation are readily accessible by treatment of the deprotonated auxiliaries with the respective acyl halides or mixed anhy-drides , generated in situ from the free acid (or the sodium salt) and pivaloyl chloride in 

In the first example, the sodium enolate of (S)-4-benzyl-3-[ 1 - C]butyryl-1,3-oxazolidin-2-one (93) was treated with a tenfold excess of methyl iodide to afford a 95 5 mixture of the two a-methylated diastereomers 94 and 95. Preparative HPLC separation of 94 followed by cleavage of the auxiliary provided the free (S)-2-methyl[l- C]butyric acid (96) in overall 58% yield from sodium [l- C]butyrate. Acid 96 was a key intermediate in the carbon-14 labeling of pravastatin, an antihyperlipoproteinemic drug, as well as for investigation of the biosynthesis and the biological labeling of avermectin Bia, currently marketed as a miticide/ insecticide . 

Reaction conditions la. NaHMDS, THF -78 °C, b. Bromide, n-Bu4NI, HMPA, 

So far only one example for the successful use of acetals in diastereoselective a-functionalization of chiral isotopically labeled imides has been published. Though this reaction was performed with carbon-13 material, there is little doubt that it is also applicable in carbon-14 synthesis. The titanium enolate prepared from (45)-4-benzyl-3-[(2R)-2-[ C, H3]methylpropionyl]-l,3-oxazolidin-2-one (111) reacted with trioxane to afford the corresponding a-hydroxymethyl derivative 112 in 83% yield and 96% 

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Optically active 2-alkylbutanedioates are also available from the stereoselective alkylation of chiral imide enolates. Thus, prepared by means of nondestructive and reusable chiral auxiliaries (e.g. chiral oxazolidinones ), dimethyl (7 )-2-terr-butylbutanedioate (>99 /oee)... 

General Synlliesis.— An enantioselective synthesis of a-substituted carboxylic acids and their derivatives has been described involving the asymmetric alkylation of chiral imide enolates. Yields are good, and the optical purity of the purified products is >99% for each case. The method (Scheme 1) has been... 

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