O-Protected Malates

Diethyl ( S)-malate (3) is readily acetylated with acetic anhydride in pyridine to give diethyl (5)-acetoxysuccinate (6) in good yield [7]. 

Alkylation of dimethyl ( S)-malate (2) at oxygen can be accomplished with an alkyl halide in the presence of silver oxide. The methoxy derivative 7a forms in 74% yield [3], while the benzyloxy analog 7b is produced in 84% yield [12]. Alternatively, 7b can be prepared by treating 2 with (9-benzyl trichloroacetimidate in the presence of trifluoroacetic acid (68% yield) [13]. Upon treatment of malate ester 7a with barium hydroxide, (iS)-methoxysuccinic acid (8) is obtained in high yield [3]. 

The 1-ethoxyethyl (EE) protecting group can be introduced by reaction of the appropriate malate ester with ethyl vinyl ether in the presence of an acidic catalyst, such as pyridinium p-toluenesulfonate [14] or trifluoroacetic acid [15,16]. In either case, the (AS)-malate ester EE ether 9 is isolated in quantitative yield. 

A third member of the family of acid-removable protecting groups is the 2-methoxy-2-methylpropyl functionality. This is introduced by treating the appropriate malate ester with 2-methoxypropene in the presence of a catalytic amount of phosphorus oxychloride [6,20]. The labile ketals 11 are formed in nearly quantitative yield, and are generally used immediately without purification. 

The fully silylated malate ester 12 is prepared from (5)-malic acid by treatment with a slight excess of hexamethyldisilazane containing one equivalent of trimethylsilyl chloride [21]. 

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