Acetate ester aldol addition

One of the pervasive problems in asymmetric synthesis has been the development of stereoselective acetate ester aldol reactions. Although a number of chiral auxiliaries perform superbly well in diastereoselective propionate aldol additions, these have, with rare exceptions, been unsuccessful in the corresponding additions of unsubstituted acetate-derived enolates [19, 63, 64). Braun s disclosure of a stereoselective acetate aldol addition reaction with 103 was an important milestone in the development of the field (Scheme 4.11) [63, 65]. The diol auxiliary can easily be prepared from mandelic acid esterification of the secondary alcohol is obsei ved, without interference from the tertiary counterpart. Its use has been showcased in a number of syntheses [53]. The high yield and diastereoselectivity generally obtained with 103 were highlighted by investigators at Merck in the construction of the chiral lactone fragment that is common in a number of HMG-CoA reductase inhibitors, such as compactin (105) [66]. 

A confusing picture emerges from the stereochemical outcome of the Mukaiyama variation of the aldol addition. The titanium(IV) chloride mediated addition of silylketene acetals to isobutyraldehyde confirms this statement while there is a reasonable correlation between the predominance of the (/t)-silylkctenc acetal 2 over the (Z)-acetal, and the favored formation of the an/t -carboxylic ester over the. svn-product, the pure (Z)-diastereomer displays no syn selectivity26. 

When /V-arenesulfonyl-a-amino acid derived boranes 13 and 14 are used in substoichiometric amounts in order to mediate enantioselective aldol additions of a,a-dimethyl substituted ketcnc acetal 15, /J-hydroxycarboxylic esters 16 are obtained in enantiomeric excess of 84 to > 99 %3fi. 

The predominant formation of ann -carboxylic esters and thioesters results when the additives 13 or 14 are used to mediate aldol additions of silylketene acetals derived from propionates and propanethioates37. The enantioselective addition of a-unsubstituted esters or thioesters is also feasible with the borane 1437. 

The Evans Cu(II)- and Sn(II)-catalyzed processes are unique in their ability to mediate aldol additions to pyruvate. Thus, the process provides convenient access to tertiary a-hydroxy esters, a class of chiral compounds not otherwise readily accessed with known methods in asymmetric catalysis. The process has been extended further to include a-dike-tone 101 (Eqs. 8B2.22 and 8B2.23). It is remarkable that the Cu(II) and Sn(II) complexes display enzyme-like group selectivity, as the complexes can differentiate between ethyl and methyl groups in the addition of thiopropionate-derived Z-silyl ketene acetal to 101. As discussed above, either syn or anti diastereomers may be prepared by selection of the Cu(II) or Sn(II) catalyst, respectively. 

Three molecules of acetyl-coenzyme A are used to form mevalonic acid. Two molecules combine initially in a Claisen condensation to give acetoacetyl-CoA, and a third is incorporated via a stereospecific aldol addition giving the branched-chain ester P-hydroxy-P-methylglutaryl-CoA (HMG-CoA) (Figure 5.4). This third acetyl-CoA molecule appears to be bound to the enzyme via a thiol group, and this linkage is subsequently hydrolysed to form the free acid group of HMG-CoA. In the acetate... 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

Aldol Reactions of Ester Derivatives. The Titanium(IV) C/tlor/dc-catalyzed addition of aldehydes to 0-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Formation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THF and silyl trapping, with a corresponding aldehyde in the presence of TiCU (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the anti-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

Introduction. Ti-TADDOLates are a,a,a, a -tetraaryl-2,2-disubstituted l,3-dioxolane-4,5-dimethanolatotitanium derivatives. The most common substituents are R, R = Me/Me and Ph/Me, Ar=Ph and 2-naphthyl, X, Y = C1/C1, t-PrO/Cl, Cp/Cl, and i-PrO/i-PtO. The corresponding TADDOLs (2) are available in both enantiomeric forms from tartrate esters which are acetalized (R R CO) and allowed to react with aryl Grignard reagents. The reactions performed in the presence of Ti-TADDOLates or with Ti-TADDOLate derivatives include nucleophilic additions to aldehydes - - and nitroalkenes of alkyl, aryl, and allylic - groups aldol additions hydrophosphonylations and cyanohydrin reactions of aldehydes inter- and intramolecular Diels-Alder additions ... 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

In the reaction of y -keto esters with a-halo ketones, the possible competition between C-alkylation (followed by reaction of the Paal-Knorr type) and aldol addition (followed by reaction of the Feist-Benary type) can result in mixtures of isomeric fiirans. Regioselectivity can, however, sometimes be controlled by the reaction conditions, as for instance in the interaction of chloroacetone with an aceto-acetic acid ester, leading to the furan-3-carboxylates 18/19 ... 

Increasing the oxidation state from enol ether to ketene acetal allows one to gain access to syn-P,y-dihydroxy esters (522) when the aldol addition is carried out under chelation control (Table 1.3). An excellent replacement for the standard Lewis acids in this type of reaction is Eu(fod)3 [92]. 

Hoffmann-La Roche used for their initial syntheses the Mukaiyama variant. [271] The aldehyde component is obtained by reduction ofthe corresponding enantiomericaUy pure )S-hydroxy-ester with diisobutylaluminium hydride. The silylketene acetal is accessible from the ester of (-)-N-methylephedrine by sUylation. The titanium tetrachloride-catalysed Mukaiyama aldol-addition gives the desired anti-product in a 3 1 ratio. After saponification of the ester, the... 

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