Hydroxy esters, conversion

Hexafluoropropyldiethylamine is a particularly useful reagent for conversion of secondary benzylic hydroxy esters into the corresponding secondary benzyl fluorides The reactions proceed with inversion of configuration and a high degree of stereospecificity [86, 87] (equation 53)... 

Huonnations with DAST proceed with high chemoselectivity In general, under very mild reaction conditions usually required for the replacement of hydroxyl groups, other functional groups, including phenolic hydroxyl groups [112], remain intact This provides a method for selective conversion of hydroxy esters [95 97] (Table 6), hydroxy ketones [120, 121], hydroxy lactones [722, 123], hydroxy lactams [124] and hydroxy nitriles [725] into fluoro esters, fluoro ketones, fluoro lactones, fluoro lactams, and fluoro nitnles, respectively (equations 60-63)... 

The rhodium-catalyzed conversion of a-diazo-p-hydroxy carbonyl into P-dicarbonyl compounds (Table 23, Entries 6-8) in general seems to be preferable to the acid-catalyzed reaction because of higher yields and absence of side-reactions 37S,377). From a screening of 20 metal salts and complexes, Rh2(OAc)4, RhCl(PPh3)3, PdCl2 and CoCl2 emerged as the most efficient catalysts for the transformation of a-diazo-P-hydroxy esters into P-ketoesters 376). This reaction has become part of... 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

The next stage would involve conversion of 18 to a tetra acylated pentaol with a uniquely exposed axial alcohol at C5. Early difficulties were encountered in attempts to cleave the lactone to its corresponding hydroxy ester. Difficulties were also experienced in manipulating the highly polar compounds arising from attempted reductive opening of 18. 

When racemic methyl a-(l-hydroxyethyl)aciylate is hydrogenated by using the (S)-BINAP-Ru catalyst, the R substrate is depleted more easily than the S. At 76% conversion, the unreacted S enantiomer is obtained in greater than 99% ee, as well as a 49 1 mixture of the threo (2R,3R) and the erythro saturated products. Hydrogenation of the S substrate with either antipodal Ru catalyst results in 2S,3S hydroxy ester with equally high threo selection (>23 1). These data indicate operation of overwhelming substrate control in this particular reaction. 

Diastereoselective protonation of arylmethylketenes. Merck chemists1 have described a conversion of (R,S)-2-arylpropionic acids (1) into the optically active forms. Thus 1 is converted into the corresponding arylmethylketene (2). Addition of a chiral alcohol can give optically active a-hydroxy esters 3 (and the acids). Of a... 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

In another study, screening was carried out for reduction of substituted benzazepin-2,3-dione 23 to a 3-hydroxy derivative 24 (Scheme 19.14). This was accomplished by a bacterial strain of Rhodococcus fascians ATCC 12975 (Norcardia salmonicolor SC 6310) with a conversion of 97% and an optical purity of >99.9%. This reaction product 24 is a key intermediate in the synthesis of the calcium antagonist SQ 31,765 (25).104 105 The Bristol-Myers Squibb group has also shown the selective reduction of the (3-keto ester, methyl-4-chloro-3-oxobutanoate, by the fungus Geotrichum candidum SC 5469 to the corresponding (,S )-hydroxy ester.106... 

There are two common ways to accomplish an asymmetric reaction. Either a second chiral center is created in a molecule under the influence of an existing chiral center in that molecule or a chiral reagent acts on a prochiral substrate to create a new chiral center. The conversion of chiral a-keto esters to di-, astereomeric a-hydroxy esters is an example of the first type of asymmetric reaction, and the asymmetric hydroboration of alkenes with chiral boranes is an example of the second type (Fig. 1). 

Asymmetric oxidoreductions performed in isopropyl ether allow syntheses of optically active alcohols with ee >95% on a 1-10 mmol scale. Nakamura et al. investigated the effect of organic solvents on the reduction of ot-keto esters mediated by bakers yeast [140]. The reduction of ethyl 2-oxoheptanoate was tested in various solvents. Best results were achieved with benzene so further experiments were performed with benzene. Conversion only takes place in the presence of small amounts of water. The reduction of six ot-keto esters was examined regarding the stereoselectivity of the corresponding ot-hydroxy esters. The reactions were performed in aqueous systems as well as in benzene. In aqueous systems, the formed hydroxy esters show (S)-stereoselectivity while the stereochemistry of the reaction shifts markedly towards the production of (/ )-ot-hydroxy esters in benzene. 

Imines can be hydrolyzed in quantitative yield by use of boric acid in ethanol under reflux [1]. Imines that are susceptible to intra- and intermolecular attack in the presence of other catalysts have been successfully hydrolyzed by use of boric acid [2], The conversion of isoxazolines into y3-hydroxy ketones and yS-hydroxy esters involves hydrogenolysis of the N-O bond and imine hydrolysis in a single step [3]. In the presence of boric acid, racemization is inhibited (Eq. 1) [3a]. 

An indirect conversion of halides to alcohols involved triethylborane. The reaction of an a-iodo ester with BEt3, followed by reaction with dimethyl sulfide in methanol, gave an a-hydroxy ester. 

An extremely efficient synthesis of lactone [41] is provided (33,34) by asymmetric synthesis (Fig. 10). Alkylation of the anion of cyclopentadiene with methyl bromoacetate gave the unstable diene [59], Immediate asymmetric hydroboiation with (+)-di-3-pinanylborane gave, after oxidative workup, the hydroxy ester [60] in about 95% e.e. Lactonization involved conversion to mesylate [61] and saponification. The crystalline lactone [41] was readily brought to an enantiomerically pure state. This route is apparently the basis for commercial quantities of compound [41], the Corey lactone, and other prostaglandin intermediates offered by the Hungarian firm Chinoin. 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

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