Optically active 3-hydroxy acid synthesis

In their continuing studies Heathcock and his co-workers have reported that preformed lithium enolates of hindered aryl esters condense with aldehydes to give predominantly tf rco-/3-hydroxy-acids after hydrolysis. Optically active hydroxy-acids have been prepared from optically active propargyl alcohols, which are readily available in high optical purity by reduction of propargyl ketones with /3-3-pinanyl-9-borabicyclo[3.3.1]nonane. ° A 1,6-eliminative epoxide cleavage provides an effective synthesis of a naturally occurring aromatic hydroxy-acid, which is a metabolite of ibuprofen. ... 

K. Yonaha u. K. Soda, Ad v. Biochem. Eng./Biotcchnol. 33,95 -130 (1986) . .Applications of Stereoselectivity of Enzymes Synthesis of Optically Active Amino Acids and a-Hydroxy Adds and Stereospecific Isotope Labeling of Amino Acids, Amines, and Coenzymes". 

Ohfune and co-workers have developed several methodologies involving an asymmetric version of the Strecker synthesis called asymmetric transferring Strecker synthesis (ATS) which has been successfully applied to the synthesis of optically active / -hydroxy-a-substituted a-amino acids [20]. This technique was further applied toward the synthesis of the Corey intermediate of lactacystin [21]. 

K. Yonaha, K. Soda in Application of Stereoselectivity of Enzymes Synthesis of Optically Active Amino Acids and a-Hydroxy-Acids,... 

Saturated, unsaturated, and functionalized carboxylic acids are important classes of natural products. Moreover, optically active hydroxy carboxylic acids are important biological molecules [ 1 ] as well as intermediates for organic synthesis [2]. 

Further methods for the synthesis of optically active amino acids have appeared. A new, general route involves asymmetric alkylation of lithium enolates derived from a chiral SchifT s base of glycine (Scheme 56). Yields, both material and optical, are in the order of 70% furthermore, the chiral reagent, 2-hydroxy-... 

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. 

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). 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

Lithiated chiral oxazolines have been shown to react with various electrophiles, generating a new asymmetric center with considerable bias. This process has led to the synthesis of optically active a-alkylalkanoic acids,47 n-hydroxy(methoxy)alkanoic acids,48 / -hydroxy(methoxy)alkanoic acids,49 n-substituted y-butyrolactones,50 and 2-substituted-l,4-butanediols (Fig. 2-4).50... 

Optically active aldehydes are available in abundance from amino and hydroxy acids or from carbohydrates, thereby providing a great variety of optically active nitrile oxides via the corresponding oximes. Unfortunately, sufficient 1,4- or 1,3-asymmetric induction in cycloaddition to 1-alkenes or 1,2-disubstituted alkenes has still not been achieved. This represents an interesting problem that will surely be tackled in the years to come. On the other hand, cycloadditions with achiral olefins lead to 1 1 mixtures of diastereoisomers, that on separation furnish pure enantiomers with two or more stereocenters. This process is, of course, related to the separation of racemic mixtures, also leading to both enantiomers with 50% maximum yield for each. There has been a number of applications of this principle in synthesis. Chiral nitrile oxides are stereochemicaUy neutral, and consequently 1,2-induction from achiral alkenes can fully be exploited (see Table 6.10). 

Isoxazolines can be transformed into a,p-enones by several methods from the initial aldol product. This strategy was applied by Barco et al. (285) toward the synthesis of ( )-pyrenophorin (98), a macrocychc fow(enone-lactone) with antifungal properties. The hydroxy group was introduced from the nitrile oxide component (95), while the carboxy function was derived from the acrylate dipo-larophile. Thus, cycloaddition of the optically active nitropentyl acetate 94 to methyl acrylate 95 afforded isoxazoline 96 as a mixture of optically active diastereomers. Reductive hydrolysis using Raney nickel/acetic acid gave p-hydro-xyketone (97), which was subsequently utilized for the synthesis of (—)-pyreno-phorin (98) (Scheme 6.63) (285). 

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