Optically active P-hydroxycarboxylic acids

P-Hydroxy carboxylic acids (12,3).2 This acetate on double deprotonation with LDA undergoes diastereoselective aldol reactions with aldehydes. The adducts are easily hydrolyzed to optically active P-hydroxycarboxylic acids with release of (R)-(+)-1,1,2-triphenyl-1,2-ethanediol, the precursor to 1. Optically pure acids can be obtained by crystallization of the salt with an optically active amine such as (S)-(—)-1 -pheny lethylamine. 

Optically active p-hydroxycarboxylic acids are versatile chiral synthons, due to their useful dual functionality. Thus, optically active P-hydroxycarboxyhc acids and their derivatives have been used as starting materials for the synthesis of optically active bioactive compounds such as vitamins, antibiotics, pheromones, and flavor compounds. 

The groups of Masamune [4] and Evans [5] reported the synthesis of optically active p-hydroxycarboxylic acids by means of stereoselective chiral aldol condensation via boron enolates. (S)- and (i )-p-Hydroxyisobutyric acid of high optical purity (98% e.e.) were obtained by means of Masamune s method. However, these methods do not seem favorable for industrial production of p-hydroxycarboxylic acids because these reactions need equal amounts of the chiral starting material for the synthesis of optically active p-hydroxycar-boxylic acids (Scheme 2). 

This transformation has been used widely to prepare optically active p-hydroxycarboxylic acids. This process takes place in two stages in initial dehydrogenation to the a,p-unsat-urated carboxylic acid and subsequent hydration. These steps utilize the enzymes of the P-oxidation pathway of lipid cataboUsm, and so the P-hydroxy acids produced are generally of the natural S) form. Both saturated carboxylic acids and their a,P unsaturated counterparts have been used as raw materials. For example, P-hydroxypropionic acid (HPA) has been prepared from acrylic acid through a process mediated by Fusarium [17], and Pseduomonas putida has been used to prepare (5)-P-hydroxyisobutyric acid from isobutyric acid [18]. The preparation of C -C (5)-P-hydroxycarboxylic acids from the corresponding tran -a,p-unsaturated carboxylic acids by microbial hydration catalyzed by resting cells of Mucor sp. has also been reported [19] (Scheme 7). 

The authors considered microbial P-hydroxylation to be particularly suitable for further refinement. The availability and low cost of carboxylic acid precursors would favor the large-scale use of processes based on this method, but one major disadvantage is that when optically active p-hydroxycarboxylic acids were obtained, only the (5) form was observed. As noted earlier, (/ )-p-hydroxycarboxylic acids exhibit potential as precursors of pharmaceuticals, and this was one of tiie incentives for the development of a robust, general method for the (R) forms of these intermediates. 

Kaneka developed industrial production methods not only for the (S) form but also (R) form of p-hydroxycarboxylic acids involving the microbial stereoselective p-oxidation of fatty acids. And now we are producing various kinds of optically active P-hydroxycarboxylic acids by means of this method and are using them for the synthesis of the intermediates of pharmaceuticals. 

In this section, we review the chemical and biochemical preparation methods that have been reported for optically active 3-hydroxycarboxylic acids, especially P-hydroxybut5nic acid (HBA), p-hydroxyisobutyric acid (HIBA), and 3-hydroxyvaleric acid (HYA), wWch are most versatile for organic syntheses. 

For utility of optically active /3-hydroxy esters D. Seebach, S. Roggo, and J. Zimmermann, Biological-Chemical Preparation of 3-Hydroxycarboxylic Acids and Their Use in EPC-Syntheses, in W. Bartmann and K. B. Sharpless, eds., Stereochemistry of Organic and Bioorganic Transformations, p. 85, Verlag Chemie, Weinheim, 1987. 

Cartoni et al. [88] studied perspective of the use as stationary phases of n-nonyl- -diketonates of metals such as beryllium (m.p. 53°C), aluminium (m.p. 40°C), nickel (m.p. 48°C) and zinc (liquid at room temperature). These stationary phases show selective retention of alcohols. The retention increases from tertiary to primary alcohols. Alcohols are retained strongly on the beryllium and zinc chelates, but the greatest retention occurs on the nickel chelate. The high retention is due to the fact that the alcohols produce complexes with jS-diketonates of the above metals. Similar results were obtained with the use of di-2-ethylhexyl phosphates with zirconium, cobalt and thorium as stationary phases [89]. 6i et al. [153] used optically active copper(II) complexes as stationary phases for the separation of a-hydroxycarboxylic acid ester enantiomers. Schurig and Weber [158] used manganese(ll)—bis (3-heptafiuorobutyryl-li -camphorate) as a selective stationary phase for the resolution of racemic cycUc ethers by complexation GC. Picker and Sievers [157] proposed lanthanide metal chelates as selective complexing sorbents for GC. Suspensions of complexes in the liquid phase can also be used as stationary phases. Pecsok and Vary [90], for example, showed that suspensions of metal phthalocyanines (e.g., of iron) in a silicone fluid are able to react with volatile ligands. They were used for the separation of hexane-cyclohexane-pentanone and pentane-water-methanol mixtures. 

Optically active 3-amino-2-hydroxycarboxylic acid derivatives are often key components of medicinally important compounds. The synthesis of isopropyl (2i ,35)-3-amino-4-cyclo-hexyl-2-hydroxybutyrate (126) (Scheme 28) takes advantage of a [2 + 2]-cycloaddition reaction of the chiral imines 123, prepared from 63, to assemble the important diastereomeric azetidinone 124 as the crucial precursor for completion of this novel synthesis. Protection of the hydroxy group of 63 as either the TBS ether 119 or the tert-buty ether 120, followed by a DIBAL reduction at —78 °C, produces smoothly one of the aldehydes 121 or 122. Condensation of these aldehydes with either di-p-anisylmethylamine or benzylamine in the presence of anhydrous magnesium sulfate affords the four possible chiral imines 123a—d (Scheme 26). 

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