Hydroxy diester

The first asymmetric synthesis of (—)-Y-jasmolactone, a fruit fiavor constituent, vas achieved via the enantioselective lactonization (desymmetrization) of a prochiral hydroxy diester promoted by porcine pancreas lipase (PPL) (Figure 6.23) [71]. 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

Enzymatic enantioselective oligomerization of a symmetrical hydroxy diester, dimethyl /Lhydroxyglutarate, produced a chiral oligomer (dimer or trimer) with 30-37% ee [24]. PPL catalyzed the enantioselective polymerization of e-substituted-e-hydroxy esters to produce optically active oligomers (DP < 6) [25]. The enantioselectivity increased with increasing bulkiness of the monomer substituent. Optically active polyesters with molecular weight of more than 1000 were obtained by the copolymerization of the racemic oxyacid esters with methyl 6-hydroxyhexanoate. 

Their hydrophobicity and their plasticity were appreciated and used for a long time in a wide range of activities. To our knowledge, the first wax to have been exploited is beeswax. Beeswax is produced by various species of bees in the world, and it has a melting point between 62°C and 64°C. It mainly contains homologous series of even-numbered fatty acids (C22 C34, C2 being the predominat compound), odd-numbered ra-alkanes (C2i C33, C27 being the major compound) and even-numbered palmitic esters from C40 to C52 (Tulloch and Hoffman, 1972 Kolattukudy, 1976). Hydroxy esters, diesters and hydroxy diesters also form part of beeswax to a lesser extent. 

The keto group of a keto ester may be preferentially reduced by catalytic hydrogenation. Excellent yields of hydroxy esters are obtained. Copper-chromium oxide catalyst has been employed in the preparation of methyl p-(a-hydroxyethyl)-benzoate and several aliphatic -hydroxy esters. The last compounds have also been made by hydrogenation over nickel catalysts.Substituted mandelic esters are prepared by catalytic reduction of aromatic a-keto esters over a palladium catalyst. Similarly, platinum oxide and copper-chromium oxide have been used in the aliphatic series for the preparation of the a-hydroxy diester, diethyl... 

Prochiral y-hydroxy diesters underwent enantioselective lactonization with PPL to afford the (S)-lactone in a highly enantioselective fashion (eq 17). Formation of macrocyclic lactones by the condensation of diacids or diesters with diols, leading to mono- and dilactones, linear oligomeric esters, or high molecular weight optically active polymers, depending upon type of substrates as well as reaction conditions, has also been described. 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

The same methodology has been extensively developed for the synthesis of optically active p-ketophosphonates from (3/ ,l 7 )-methyl T-phcnylethyl 3-hydroxypentanedioate. Low-temperature condensation of this unprotected hydroxy diester with dimethyl 1-lithiomethylphosphonate in excess in THF gives the desired optically active functionalized P-ketophosphonate in fair yield (43%). It has been observed that the methyl ester reacts faster than the I -phenethyl ester, and it is necessary to operate without the silyl protecting group to avoid a P-elimination reac-tion. - 2< By an analogous route, the reaction of dimethyl 1-lithiomethylphosphonate (1.3 eq) with the corresponding protected hydroxy ester-amide (Nahm-Weinreb amide) provides the... 

The concentration-time curve for the reactants is shown in Fig. 2, and the concentration-time curve for the products is depicted in Fig. 3. Examination of Fig. 3 shows that as well as the desired reaction product (the chlorohydrin ester), there are two other major product components. These were identified as 1,3-dichloropropan-2-ol (OL dichlorohydrin) and glycerol -1,3-di(2-ethylhexanoate) (hydroxy diester). The structure of the hydroxy diester was confirmed by its independent synthesis from glycidyl 2-ethyl hexanoate and 2-ethyl hexanoic acid. The yield of chlorohydrin ester was only 50.4%, the remainder of the 2-ethylhexanoic acid being converted to the undesirable hydroxy diester. Fig. 4 shows the structure of the products obtained in the 1 1 reaction. Fig. 5 depicts the formation of the hydroxy diester from glycidyl 2-ethylhexanoate and 2-ethyl-hexanoic acid. 

The reaction of epichlorohydrin with 2-ethylhexanoic acid in a 1 1 molar ratio gives rise to only 50% of the desired product, the chlorohydrin ester. The mechanism depicted above indicates that the undesirable hydroxy diester is formed by reaction of 2-ethylhexanoic acid with glycidyl 2-ethylhexanoate. It appears therefore that formation of the hydroxy diester competes directly with the chlorohydrin ester formation (Fig. 9). 

It is apparent therefore that an increase in the epichlorohydrin concentration should promote the formation of the chlorohydrin ester, at the expense of the hydroxy diester. 

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