Stereoselective Acetate Aldol Reactions Using Chiral Auxiliaries

Stereoselective Acetate Aldol Reactions Using Chiral Auxiliaries 

The early tvork in the field of titanium enolate acetate aldol reactions tvas conducted by Braun in a general investigation of acetate aldol reactions [12]. The enoiates tvere generated from chiral acetamide 16 by transmetalation of the lithium enolate tvith triisopropoxytitanium chloride or titanium tetrachloride, as sho vn in Table 2.3. They reported moderate selectivity for the reaction vith benzaldehyde. 

Shortly thereafter, acetate aldol reactions using camphor-derived imidazo-lidinone 27 vere reported by Palomo and co vorkers [15]. They reported moderate yields and enantioselectivity for a variety of unsaturated and aliphatic aldehydes (Table 2.4, entries 8-12). Interestingly, enantioselectivity for unsaturated aldehydes vas opposite that for aliphatic aldehydes. Also, enantioselectivity reported for titanium vas completely opposite that of the corresponding lithium enolate reactions. 

Survey of acetate aldol reactions employing chiral auxiliaries. 

Chiral auxiliaries used in the asymmetric acetate aldol reactions described in Table 2.4. 

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Urpi and Vilarassa investigated an asymmetric acetate aldol reaction in conjunction vith the synthesis of Macrolactin A [17]. They reported good yield and excellent stereoselectivity for a handful of unsaturated aldehydes using a valine-derived thiazolidinethione chiral auxiliary. 

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]. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

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