Asymmetric reactions acetate aldol equivalents

The first asymmetric total synthesis of xestodecalactone B and C was recently accomplished in 10 steps with an overall yield of 22%. The key step involves the use of Evans aldol reaction to establish the C-9 configuration. Initial attempts to use an N-acetyloxazolidinone boryl enolate afforded the corresponding aldol product as a nearly 1 1 ratio of diastereomers. A switch to the boryl enolate of thiomethylacetyloxazo-lidinone 68, which is an acetate aldol equivalent, generated the product 69 with high diastereoselectivity (92% de). Subsequent desulfiuization with n-BuaSnH and AIBN was required to remove the thiol functionality. 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Asymmetric Aldol Reaction of Bromofluoroketene Silyl Acetal 2 Catalyzed by Lewis Acids 6. We next examined the aldol reaction of the bromofluoroketene silyl acetal 2 mediated by the catalyst 6 (30). The reaction was carried out by the addition of an aldehyde in nitroethane to a solution of 1.2 equivalents of the acetal 2 and 20 mol% of the catalyst 6 in the same solvent over 3 h at -7S°C and stirring at that temperature for an additional hour prior to quenching. As shown in Table II, the reaction of benzaldehyde afforded a 69 31 mixture of (2S,31 )- and (2R,3/ )-2-bromo 2-fluoro-3-hydroxy-3-phenylpropanoates. The enantiomeric excess of fte syn-isomer is 98% ee and diat of die an/i-isomer is 90% ee (entry 1). Although die reactions are not diastereoselective in all cases (synlanti = 69/31 to 46/54), aU syn- and anri-aldol products were obtained with excellent-to good chemical and optical yields. 

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