0-Hydroxy esters

Hydroxy-esters. - Once again, most contributions to this area involve the synthesis of chiral hydroxy-esters. Almost complete enantioselectivity is achieved in the reduction of a-keto-esters to a-hydroxy-esters using Alpine-Borane (B-(3-pinanyl)-9-BBN) derived from either (+)- or (-)-a-pinene when the reactions are carried out at relatively high concentrations ( 2M). Many other types of prochiral ketones are also reduced with excellent asymmetric inductions although 3-keto-esters may not be particularly suitable substrates as ethyl acetoacetate is reduced to ethyl 3-hydroxybutanoate with an enantiomeric excess of only 

a-Keto-esters can also be reduced asymmetrically using di-isobutylaluminium hydride modified by the addition of SnCl2 and a chiral pyrrolidine, although in these examples, optical yields are variable. Asymmetric induction has also been 

Lewis acid (RAICI2 or TiCl ) modified by the addition of (-)-menthol reacts with various phenols to give hydroxy-esters (110), in some cases with remarkably high stereoselectivities (up 

Extremely high selectivities have also been obtained 

0-silyl-enolates of methyl o-alkoxyacetates, catalysed by zinc 

Hydroxy-esters. - The asymmetric oxidation of ester enolates using, 

A wide range of a-keto-esters can be reduced to the corresponding 

An alternative way to exploit the steric screening principle in the elaboration of chiral a-hydroxy-esters is by asymmetric alkylations of the dioxolanones (140) and (141) [R=H] derived in a 

After chromatographic separation, (the major drawback of the method) 

Complimentary diastereoselectivities have been observed in condensations of methyl pyruvates with various organometallic nucleophiles, the allylborane (142) giving largely the threo- adducts 

Hydroxy-esters.—Ethyl 5-3-hydroxybutanoate is obtained in 87% optical purity by the reduction of ethyl acetoacetate with Bakers yeast. Two independent chiral synthesis of the leukotriene intermediates (46), R = CHO and R = CH2OH, have appeared. An effective large-scale conversion of arachidonic acid into 5-hydroxy-6-fran5-8,ll,14-cis-eicosatetraenoicacid (5)HETE, including its resolution, is also reported by Corey and Hashimoto.  

Enantioselective aldol reactions with high threo- or erythro-scleciivity are obtained with boron azaenolates derived from chiral and achiral oxazolines, respectively. Moving the chirality from the boron in (50), to the heterocyclic in (51), causes the reaction to switch from threo- to eryt/iro-products with high 

Hydroxy-esters.—Some success has been achieved with asymmetric reduction of a-ketoesters to the corresponding i -hydroxy esters using chiral Hantzsch esters in the presence of mono-zinc species formed in a standard Reformatsky reaction. Although yields, both chemical and optical, are variable the method offers some synthetic utility, and is also interesting as a model of biological NAD(P)H reductions. 

An attractive method for the generation of ester enolates involves treatment of a-trimethylsilyl esters with quaternary ammonium fluorides. Enolates thus formed couple with ketones to form j3-hydroxy esters in 70—90% yield, although strangely no reaction was observed with j8-ionone or benzylacetone. The same group has reported the preparation of the silylated base (115), which can be used to effect specific ester enolate formation in the presence of an aldehyde leading 

Nakamura, M. Shimizu, and I. Kuwajima, Tetrahedron Letters, 1976, 1699. I. Kuwajima, N. Minami, and T. Sato, Tetrahedron Letters, 1976, 2253. 

Optically pure a- and j8-hydroxy esters and amides have been produced from the corresponding keto-deiivatives by reduction with the yeast Saccharomyces cerevisiae yields are good in many cases but overall conversions are often low. 

Improved syntheses of t-butyl o -mercapto-carboxylates by aminolysis of the corresponding co-acetoxy- and oj-xanthogen- analogues have been documented.  

---

Reformatski reaction Aldehydes and ketones react with a-bromo- fatty acid esters in the presence of zinc powder to give -hydroxy-esters which may be dehydrated to give a-, 0-unsaturated esters. a-Chloroesters will react if copper powder is used in conjunction with the zinc. 

It may be pointed out that dehydration of p hydroxy esters with fused potassium hydrogen sulphate, acetic anhydride, phosphoric oxide or with tliionyl chloride in benzeue solution leads to ap unsiiturated esters containing some PY-unsaturated ester the proportion of the latter depends not only upon the structure of the ester but also upon the dehydrating agent used. Elehydration occasionally occurs during the reaction itself or upon attempted distillation. 

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

Alkynyl)oxiranes also react with carbon nucleophiles to afford furan derivatives. Furanes of different types are obtained depending on the structure of the substrates. 7-Methyl-2-ethynyloxirane (95) reacts with acetoacetate to give the furan 97 by the elimination of formaldehyde from the cyclized product 96. The hydroxy ester of the alkylidenefuran 98 and the corresponding lactone 99 are obtained by the reaction of i-methyl-2-(2-propynyI)oxirane[40, 42]. 

Ester enolates generated by proton abstraction with dialkylamide bases add to aldehydes and ketones to give (3 hydroxy esters... 

The reaction of ketene itself with tettaalkyl titanates followed by a ketone R R C=0 gives P-hydroxy-esters, R R C0HCH2C02R. Polyinsertion of ketene and aldehyde into the Ti—O bond leads to di-, tri-, and tetraesters, eg, H0CR R CH2C02CR R CH2C02R (200). 

Naphthyl)ethyl isocyanate 2 for chromatographic resolution of alcohols, hydroxy esters thiols via diastereomenc derivatives. 

The reaLUons of phenyltetrafluorophosphorane with numerous silylated secondary or tertiary a- or (1-hydroxy esters, ketones, nitriles, ethers, nitro, and trichloromethyl derivatives have been investigated, the corresponding a or p fluoro derivatives are obtained in yields varying from reasonable to nearly quantitative [24, 25, 26, 27 The application of phenyltetrafluorophosphorane for fliiorination of silyloxy steroids has also been reported [28]... 

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)... 

Fluormation of tertiary benzylic hydroxy esters with the Ishikawa reagent gives somewhat lower yields of fluorides because of the formation of dehydrated products, 2-aryl acrylates [87] (equation 54)... 

The reactions of 1,1,2,3,3,3-hexafluoropropyldiethylamine with secondary aliphatic p-hydroxy esters give reasonable to good yields of their corresponding fluondes, whereas aliphatic a-hydroxy esters yield mostly 2,3,3,3-tetrafluoropro-pionates [55] (equations 55 and 56)... 

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)... 

CL Amino-(i-hydroxy esters in which the amino group is protected as a 4,5 diphenyl-3-oxazohne-2-one moiety undergo fluontiation with DAST to give the corresponding (1 fluoro compounds as the main products along with the dehydrated compounds [/2(5] (equation 64)... 

A fluorinated keto ester reacts as an electrophile with hydrides, giving a hydroxy ester in a highly stereoselective reduction [30] (equation 25). 

FIGURE 14.25 Catalytic antibodies are designed to specifically bind the transition-state intermediate in a chemical reaction, (a) The intramolecnlar hydrolysis of a hydroxy ester to yield as products a S-lactone and the alcohol phenol. Note the cyclic transition state, (b)... 

Butylethylidene and 1-phenylethylidene ketals were prepared selectively from the C4-C6, 1,3-diol in glucose by an acid-catalyzed transketalization reaction [e.g., Me3CC(OMe)2CH3, TsOH/DMF, 24 h, 79% yield PhC(OMe)2Me, TsOH, DMF, 24 h, 90% yield, respectively]. They are cleaved by acidic hydrolysis AcOH, 20°, 90 min, 100% yield, and AcOH, 20°, 3 days, 100% yield, respectively. Ozonolysis of the /-butylmethylidene ketal affords hydroxy ester, albeit with poor regiocontrol, but a more sterically differentiated derivative may give better selectivity, as was observed with the ethylidene ketal. ... 

The reaction with a carbonyl substrate 3 is similar to a Grignard reaction. Hydrolytic workup then yields the /3-hydroxy ester 4. Sometimes product 4 easily eliminates water to yield directly an o ,/3-unsaturated ester. 

The anion produced by VNS of nitroarenes andct-chloro esters is hydroxylated by the ac of air and benzaldehyde, thereby producing ct-hydroxy esters fEq 9 37,... 

A terpene yielding isofenchyl alcohol on hydration, which Wallach considers to be one of the fenchenes, was artificially prepared by converting nopinone into a hydroxy ester by means of bromoacetic ester and zinc-dust. The hydroxy ester is dehydrated by potassium bisulphate, and so yields an unsaturated ester, which on saponification yields an acid from which the terpene results by distillation. This fenchene has the following characters —... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

The hydroxy ester (12, R = Et, n = 3) is hydrolyzed with 1 M aq NaOH. After acidification of the alkaline solution with 2 M H2S04 and extraction, the crude product is bulb-to-bulb distilled (bath temp. 130 °C/... 

---