Esters P-hydroxy

3 Electrophilic Animation of Chiral Ester Enolates 3.3.3.1 p-Hydroxy Esters 

Chiral P-hydroxy esters and l,3-dioxan-4-ones are well-known substrates for diaster-oselective a-alkylation reactions developed by Frater [20] and Seebach [21]. These chiral compounds are available in both enantiomeric forms, and have been also ami-nated at the a-carbon with high stereoselectivity. 

Subsequently, as an application of this method, D-ribo-C18-phytosphingosine has been prepared stereoselectively from (S)-malic acid dimethyl ester 50. The electrophilic animating reaction with DTBAD proceeded with 62 % yield and the anti a-hydrazino P-hydroxy ester 51 was obtained as the major diastereomer (anti syn = 67 33). After separation of the two isomers, the synthesis of the enan-  

This method gives the aminated products with complete control of stereochemistry, and the subsequent deprotection and hydrogenolysis of the hydrazine functionality yield the desired a-amino P-hydroxy acid derivatives. 

Dropwise addition of a P-hydroxy ester THF solution to a THF solution of MeZnBr (1 equiv.) at 0°C. 

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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. 

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). 

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)... 

In the presence of a base such as l,4-diazabicyclo[2.2.2]octane (DABCO) or tri-alkylphosphines, conjugated carbonyl compounds such as esters and amides add to aldehydes via the a-carbon to give a-alkenyl-P-hydroxy esters or amides. This sequence is called the Baylis-Hillman reaction and a simple example is... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

A further example of highly diastereoseleetive and enantioseleetive C-H insertions performed in similar eonditions to those deseribed above was the reaetion between aryldiazoacetates and allylsilyl ethers, yielding p-hydroxy ester derivatives that are equivalents to aldol products. " An illustrative reaction between an aryldiazoacetate and trani-2-butenylsilyl ether is shown in Scheme 10.78. This reaction led to the diastereoseleetive formation of the equivalent of a syn-a do product in both high yield and enantioselectivity. 

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 hydrogenation of fi-keto esters.7 The Ru(OAc)2(BINAP) complexes are ineffective catalysts for asymmetric hydrogenation of (i-keto esters, but on treatment with HX (2 equiv.) are converted into complexes with the empirical formula RuX2(BINAP), which are effective catalysts for this enantioselective hydrogenation. Complexes of (R)-BINAP catalyze hydrogenation to (R)-(S-hydroxy esters in >99% ee, whereas the enantiomeric (S)-P-hydroxy esters are obtained... 

Reduction of a. -epoxy esters to fi-hydroxy esters. Sml2 alone reduces these esters to a mixture of a- and p-hydroxy esters. The reaction rate and yield is increased by addition of HMPT. Addition of a chelating agent, TMEDA or N,N-dimethylaminoethanol (DMAE), results in regioselective reduction to p-hydroxy esters (equation I). The system reduces optically active epoxy esters with complete... 

Other classes of alcohols are unreactive. Ethyl 3-hydroxybutyrate (a p-hydroxy ester) went to the phosphate stage, but would not undergo azide displacement. In this example about 30% of the crotonate was formed because of p-elimination. 

Sharpless and his group have also studied a series of selective transformations of r/jreo-2,3-dihydroxy esters (6) -prepared by catalytic ADH of a,P-unsaturated esters 5- which lead to very useful and highly elaborated synthetic intermediates [36], such as a-(sulfonyloxy)-P-hydroxyesters (2), P-acetoxy-a-bromo esters or a-acetoxy-p-bromo esters (8 and 9), threo- and erythro-glycidxc. esters QO and U.) and P-hydroxy esters (12). The substituent at the p-position plays an important role in determining the regiochemistry of the bromination of the 2,3-dihydroxy esters whereas a P-alkyl substituent leads to p-acetoxy-a-bromo esters, a phenyl group directs formation of the a-acetoxy-P-bromo esters (Scheme 10.5). 

In 2004, Bode and Rovis independently and concurrently reported the catalytic coupling of reducible aldehydes and alcohols. This mode of reactivity is most closely related to the work published by Wallach, who generated dichloroacetic acid from chloral under cyanide catalysis in aqueous media [108]. Bode and coworkers reported the catalytic, diastereoselective synthesis of P-hydroxy esters from a,P-epoxy aldehydes using thiazolium pre-catalyst 173 Eq. 16a [109]. MeOH, EtOH, and BnOH are effective nucleophiles providing upwards of >10 1 diastere-oselectivity. Aziridinylaldehyde 174 has also been shown to provide the desired iV-tosyl-P-aminoester 175 in 53% yield Eq. 16b. 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

The y-amino-p-hydroxy acid derived oxazolidinones 55 are prepared from the corresponding N-unprotected y-amino-p-hydroxy ester derivatives by reaction with phosgene,1119,391 carbonyl diimidazole,[41] or benzyl chloroformate.[86] Alternatively, cyclization is obtained from the N-carbamate protected derivatives, i.e. from the TV-isopropenyloxycarbonyl derivatives under heating,[381 or from the TV-Boc or N-Z derivatives under basic conditions. [68 81 87] By analogy, the p,y-diamino acid analogue is converted into the imidazolidinone 57 by treatment of the unprotected compound with phosgene.[83 88]... 

To a suspension of the compound obtained above (500mg, 1.57 mmol) and NaHCOj (1.58 g, 18.84 mmol) in MeOH/H20 (26 ml, 12 1), cooled in an ice bath, was added NBS (1.96g, ll.OOmmol). The reaction mixture was stirred at 5°C for 5 min, then at ambient temperature for 10 min. A solution of aqueous 10% Na Os (5 ml) was added, then the mixture was concentrated under reduced pressure to remove most of the MeOH. The reaction mixture was partitioned between HzO and Et20/hexane (1 1), then washed with water, dried (MgS04), filtered and evaporated under reduced pressure. Silica gel chromatography (35% EtOAc/hexane) afforded the p-hydroxy ester as a colourless oil (310 mg, 88%). 

Some efficient syntheses have been reported such as those of p-hydroxy esters from tris(methylthio)methyllithium and epoxides. The case of a malate derivative from a commercially available chiral epoxide is described [286]. 

This variation was used for an enantioselective synthesis of anti-a-methyl-p-hydroxy esters using the silylketene acetal derived from (1R, 2S)-N-methylephed-rine-O-propionate (equation II).12... 

The resulting alkylation products 66 can easily be converted into the corresponding P-hydroxy esters and P-amino esters, respectively. 

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