Aldol reaction synthetic utility

It is worth pointing out that the stereochemistry of intermediate 147 at C-9 and C-10 is inconsequential since both positions will eventually bear trigonal carbonyl groups in the final product. The synthetic problem is thus significantly simplified by virtue of the fact that any or all C9-C10 diol stereoisomers could be utilized. A particularly attractive means for the construction of the C9-C10 bond and the requisite C8-C10 functionality in 147 is revealed by the disconnection shown in Scheme 41. It was anticipated that the venerable intermolecular aldol reaction could be relied upon to accomplish the union of aldehyde 150 and methyl glycolate (151) through a bond between carbons 9 and 10. 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

An important reaction of silylenol ethers is their use as enolate equivalent in Mukaiyama aldol additions. An example of the synthetic utility of this reaction with a magnesium enolate as starting reagent is shown below. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

The aldol reaction is of central importance to synthetic organic chemistry in carbon skeletal elaboration. Furthermore it generates at least one and often two new stereogenic centers. Since an abundance of natural aldolases have now been identified and characterized, interest in the application of aldolases as catalysts in synthetic organic chemistry continues to increase. However, despite the potential synthetic utility of aldolase chemistry, the lyase class of enzymes is still underutilized. In contrast, the oxido-reductase and hydrolase class of enzymes have demonstrated substantial synthetic utility and are the two most utilized class of biocatalysts. 

One cannot help but notice that the above reactions lead to related products characterized by the presence of two oxygens in a 1,3-relationship as either a jS-hydroxycarbonyl (if both components are aldehyde or ketones) or a )S-dicarbonyl system (in the case of esters). Both of these functionalities are useful in subsequent conversions and we see that the synthetic utility of the reactions used to prepare these adducts is broadened further. Typical transformations are shown in Scheme 2.26 for the product 70 of an acetone aldol condensation. Oxidation of 70 leads to the formation of the corresponding dicarbonyl compounds 71, while the 1,3-diol 72 is formed as a result of reduction of 70 and the a,j8-unsaturated carbonyl compound 73, formed via dehydration of 70. 

Swinholide A. The swinholides are a series of complex macrodiolides isolated from the marine sponge Theonella Swinhoei, which display potent cytotoxicity against a range of human tumour cell lines. Swinholide A (71) provided an excellent opportunity to showcase the synthetic utility of a range of aldol reactions. For its total synthesis by our group in 1994 [50] the fully protected preswinholide A 72 was considered to be an essential late-stage intermediate, which appeared accessible via two directed aldol reactions of a suitable butanone equivalent with aldehydes 73 and 74 (Scheme 9-24). 

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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