Reactions at Both Carboxylate Sites

In Section 3.2 we explored reactions directed to certain specific sites of the malic acid framework. In this section, reactions that include both of the carboxylic acid or ester groups of malates will be discussed. Actually throughout the chapter we have touched on reactions that fit into this category. Simple hydrolysis of malate esters to the respective malic acids, or conversion of malic acids to their anhydrides (e.g. 21, 33, 232), exemplifies these rudimentary transformations. Although presented in earlier sections, such reactions were in fact intended to introduce chemistry associated with a specific functional group of malic acid. Here we concentrate on more substantial transformations, ones that lead to extremely useful enantiomerically pure intermediates. 

Exhaustive reduction of malic acid or its esters furnishes —)-l,2,4-butanetriol (370). Direct treatment of 1 with BMS and trimethylborate at 0 °C gives 370 in quantitative yield [101]. Reduction of dimethyl ( S)-malate (2) with either sodium borohydride at room temperature [102] or lithium aluminum hydride at 65 °C [8] affords 370 in 96% and 100% yield, respectively. 

Nonactin is assembled by coupling the subunits 381 and 383 with inversion of configuration at the hydroxyl center of 381. After ester cleavage, the resulting dimeric acid is simultaneously dimerized and cyclized to provide the natural product 384. 

7-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 enantiomeric fragment ( S)-392 is available from 386 by mesylation (393) followed by base-catalyzed cyclization (with inversion of configuration) to the (R)-epoxide 388. A similar series of reactions transforms (i )-388 to the iodide (S)-392 with 100% ee. 

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