Substrates stereoselective aldol reactions

Enzymatic synthesis relying on the use of aldolases offers several advantages. As opposed to chemical aldolization, aldolases usually catalyze a stereoselective aldol reaction under mild conditions there is no need for protection of functional groups and no cofactors are required. Moreover, whereas high specificity is reported for the donor substrate, broad flexibility toward the acceptor is generally observed. Finally, aldolases herein discussed do not use phosphorylated substrates, contrary to phosphoenolpyruvate-dependent aldolases involved in vivo in the biosynthetic pathway, such as KDO synthetase or DAHP synthetase [18,19]. 

Chiral 2-sulfinylcyclohexanones react with lithium alkyl acetates (i.e. lithium ester enolates) to produce alcohols with four contiguous chiral centres.57 This stereoselective aldol reaction is proposed to depend upon tricoordination by lithium of the enolate, sulfinyl, and carbonyl oxygens of the substrates. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Thus far, most of the stereoselective approaches to aldol reactions mentioned have depended on substrate-based asymmetric induction by employing chiral... 

Aldol reaction Over twenty aldehydes are known to be substrates for the aldolases from S. carnosus and S. aureus. Stereoselectivity of the aldolases must be... 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The carbene-bound alkyl groups are acidic pX [(CO)5Cr=C(OMe)Me in H2O] 12.3 and can be easily deprotonated and alkylated [45,211,212] or acylated [213] (Figure 2.16). Stereoselective aldol-type additions can be realized with the aid of Fischer-type alkylcarbene complexes [214-216]. In these reactions the metallic fragment can either play the role of a bulky carbonyl group or stabilize a given conformation of the substrate by chelate formation [216,217]. 

Thioamide enolates are also interesting substrates for the stereoselective aldol-type reactions. The aldol stereochemistry is very sensitive to the conditions of preparation of magnesium thioamide enolates and it generally gives different results depending on the procedure used. Illustrations of some aspects of the reactivity are provided in the examples presented below. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

In contrast to titanium enolates of ketones, titanium enolates of aldehydes exhibit practically no stereoselectivity in aldol reactions. However, titanation of dimethylhy-drazones of aldehydes with 1 results in substrates (2) that show high eryt/iro-selecti v i ty in aldol-type reactions with aldehydes (equation I). Bromotitanium tris(diethylamide) can be used in place of 1, but is less efficient, as is Ti(IV) isopropoxide.6... 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

Although attempts to catalyze bimolecular aldol condensations without resorting to enamine chemistry have not yet been successful, the Schultz group92 has prepared an antibody against the phosphinate hapten 115 that catalyzes the retro aldol reaction of 116 (kcJKm = 125 M-1 s l). The equilibrium in this case strongly disfavors the condensation product, and a histidine induced in response to the phosphinate may be involved in catalysis. Interestingly and in contrast to the previous examples, the stereoselectivity of the antibody is modest. The syn diastereomer of 116 was found to be the better substrate for the antibody by 2 1 over the anti diastereomer, but no evidence of enantioselectivity was observed. 

Stereoselective aldol condensations. Reaction of these substrates (1) with LDA results in decomposition, but the tin(II) enolates can be obtained by use of tin(II) triflate (11, 525) in the presence of N-ethylpiperidine. Addition of aldehydes to the enolates results in formation of p-hydroxy ketones (2) with high iyn-selectivity. 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

Allylation of allylsilacyclobutane with carbonyl substrates also proceeds bimole-cularly (Sch. 66) [107]. In contrast with the aldol reaction, a mechanism with penta-coordinate silicon intermediates in chair-like transition states resulted in high stereoselectivity. 

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