Stereospecific aldol condensation

The enzymatic aldol reaction represents a useful method for the synthesis of various sugars and sugar-like structures. More than 20 different aldolases have been isolated (see Table 13.1 for examples) and several of these have been cloned and overexpressed. They catalyze the stereospecific aldol condensation of an aldehyde with a ketone donor. Two types of aldolases are known. Type I aldolases, found primarily in animals and higher plants, do not require any cofactor. The x-ray structure of rabbit muscle aldolase (RAMA) indicates that Lys-229 is responsible for Schiff-base formation with dihydroxyacetone phosphate (DHAP) (Scheme 13.7a). Type II aldolases, found primarily in micro-organisms, use Zn as a cofactor, which acts as a Lewis acid enhancing the electrophilicity of the ketone (Scheme 13.7b). In both cases, the aldolases accept a variety of natural (Table 13.1) and non-natural acceptor substrates (Scheme 13.8). 

Stereospecific aldol condensations are of prime importance in synthesis, particularly so in construction of the polyether-related antibiotics. In an effort to develop product-selective aldol condensations which are independent of enolate... 

Apparently, the aldol condensation proceeds with the same stereochemical results. In any case, this approach permits a stereospecific synthesis of litsenolide B2(l) and related Lauraceae lactones, as outlined in equation (I).5... 

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... 

The use of enzymes for the aldol reaction complements traditional chemical approaches. In the early twentieth century a class of enzymes was recognized that catalyzes, by an aldol condensation, the reversible formation of hexoses from their three carbon components.3 The lyases that catalyze the aldol reaction, are referred to as aldolases. More than 30 aldolases have been characterized to date. These aldolases are capable of stereospecifically catalyzing the reversible addition of a ketone or aldehyde donor to an aldehyde acceptor. Two distinct mechanistic classes of aldolases have been identified (Scheme 5.1).4... 

A tandem aldol condensation-radical cyclization sequence has been developed for the preparation of functionalized bicyclo[3.3.0]octane systems [116]. Conjugate addition of Me2AlSePh to dimethylcyclopentanone (118) followed by trapping of the resulting enolate with aldehyde gave predominantly the trans, erythro aldol 119 this then underwent radical cyclization with BusSnH and catalytic AIBN yielding the bicyclic ketol 120 stereospecifically (Sch. 80). 

The synthesis began, as shown in Scheme 2.16, with the alkylation and subsequent hydrolysis of compounds 160 and 161 to afford aldol precursor 162. An enantioselective aldol condensation, using D-proline as a catalyst, gave a 70% yield of 163 and 164 in a 1 1 ratio, both diastereomers being formed in 36% ee. Isolation of the desired 164 followed by dehydration and recrystallization then gave optically pure (-I-) 165 in 10-12% yield from the racemates 160 and 161. A stereospecific sequence involving ketone reduction and protection as the MOM ether followed by bishydroxylation of the olefin and subsequent acetonide formation gave the key intermediate 166 (74%). 

A simple approach to a difficult alkene might be to make whatever mixture results from the easiest synthesis and convert it stereoselectively into one isomer or, with more precise control, to make the wrong isomer, if that is easier to make, and convert that stereospecifically into the other. A simple example is the enone E-5 made by an aldol condensation. It is easy to see why E-5 is the thermodynamic product there is a steric clash in the Z-isomer between the carbonyl oxygen and one of the ortho-Hs on the benzene ring. 

Stereoselective aldol condensation. Aldol condensation has been shown to be subject to kinetic stereoselection, with (Z)-enolates giving mainly the erythro-aldol and (E)-enolates giving mainly the (Areo-aldol. This observation has been extended to preformed (Z)- and (E)-lithium enolates generated under kinetic control with LDA in THF or ether at — 72°. When one of the alkyl groups is sterically demanding, complete kinetic stereospecificity can be obtained. As the bulk of the alkyl group decreases, stereoselection also decreases. Thus the kinetic enolate of ethyl /-butyl ketone (1) is the (Z)-isomer a, and it reacts with benzalde-hyde to form the erythro-aldol (2) with no detectable amounts of the threo-aldol. 

Further details and examples of the introduction of a 2-C-hydroxymethyl group by aldol condensation of aldose derivatives with formaldehyde have been published (Vol. 12, p. 114). Condensation of 2,3 5,6-di-O-isopropylidene-D-mannose with formaldehyde afforded the 2-C-hydroxymethyl derivative (17) which was converted into 2,3-C-isopropylidene-D-apiose by standard reactions (Scheme 4). The L-enantiomer was similarly prepared from a derivative (18) of hamamelose. The same derivative (18) has also been employed in a stereospecific synthesis of the di-O-isopropylidene derivative (19) of L-dendroketose (Scheme 5). Similar methods have been used to synthesize 4-C-hydroxy-methyl-D-ribose and its derived nucleoside derivatives. ... 

Dialkylborinyl triflateslethyldiisopropylamine Stereospecific aldol-type condensation with a-alkoxycarboxylic acid esters under mild conditions 5> /f-a-Alkoxy-p-hydroxycarboxylic acid esters... 

Stereospecific double ring closure of aminodiacetals via tandem Mannich-aldol condensation 7-Hydroxyindolizidines... 

The literature describes number of methods for the generation of enolborinates [1]. Enolborinates are valuable intermediates [2] and react with high stereospecificity in aldol condensation [3-8]. Brown and coworkers [9] have carried out a detailed study of the stereochemistry of ketone enolization with B-C1-9-BBN [10], B-OTf-9-BBN [3c], Chx BCl [10], and ChXjBOTf [9] to get ( )- or (Z)-enolborinates. It is found that stereochemical outcome of the reaction varies not only with the steric requirements of RjB and steric requirements of the amine [4, 5b, c], but also with the nature of the leaving group. Cl or OTf (Table 20.1) [9]. 

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