Optically active 3-hydroxy acid chiral building blocks

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

C4 chiral synthetic units are also important for the syntheses of pharmaceuticals and their intermediates. For example, optically active 4-chloro-3-hydroxybutyrate (CHB) and 4-chloro-3-hydroxybutyronitrile (BN) are key compounds as C4 chiral building blocks for the syntheses of L-carnitine [16], l-GABOB [17], / -hydroxybuty-ric acid, 3-hydroxy-y-butyrolactone, and 4-hydroxy-2-pyrrolidone. Recently, CHB has been reported as being used for synthesizing an intermediate for HMG-CoA reductase inhibitor for hyperlipidemia (Fig. 11) [18]. 

An interesting chiral building block for the synthesis of optically active unusual amino-hydroxy acids is (+)-8-phenylmenthyl isocyanoacetate 1532 [1170]. It is prepared in optically pure form in 95% yield by dehydration of the corresponding formamide with diphosgene within ca. 10 h at room temperature. 

Emil Fischer s result involving cyanide additions to carbohydrates had demonstrated the power of diastereoselective synthesis early as the 1890s (Equation 1) [4, 34,162]. The corresponding enantioselective formation of cyanohydrins has been the subject of immense efforts. It has long been appreciated that optically active cyanohydrins are synthetically useful intermediates that can be elaborated into a number of chiral building blocks, such as hydroxy acids. In general, there are three main classes of catalysts for the preparation of chiral cyanohydrins enzymes, cyclic dipeptides, and transition metal complexes [163-166]. 

In this chapter, we review the production methods for optically active -hydroxy-carboxylic acids (esters), and chiral building blocks derived from optically active 3-hydroxy acids and their use in the synthesis of optically active bioactive compounds. 

A. Useful Chiral Building Blocks Derived from Optically Active p-Hydroxy Acids... 

---