1.3- diols, asymmetric aldol reactions stereoselective synthesis

Stereoselective Synthesis of 1,3-Diols Asymmetric Aldol Reactions... 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

Scheme 8.43)." The aldol reaction of aldehyde 272 and alkynylketone 273 catalyzed with Zn(ll)-265 complex gave (3-hydroxyketone 274 in excellent stereoselectivity. Noyori hydrogen transfer reaction provided the central diol moiety of fostriecin 278. They accomplished the asymmetric synthesis of 277, therefore, the formal synthesis of fostriecin 278. 

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]. 

The catalytic, enantioselective aldol addition reaction generates products that can serve as versatile precursors to useful building blocks for asymmetric synthesis (Eq. 26). For example, treatment of cinnamaldehyde adduct 177 with LiAl(HNBn)4178 afforded the crystalline amide 179 (73%). Heating in -BuOH converted 177 to ester 180 (81%). Heating in alkaline methanol yielded (79%) the crystalline lactone 181. The synthetic utility of adducts 179 and 180 is enhanced by the stereoselective reaction methods that have been developed for their reduction to the corresponding syn and anti 3,5-diols [103,104]. 

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