Aldols ketone donors

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

Scheme 17 Asymmetric aldol reactions with ketone donors...

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

The formation of C-C bonds by aldol condensation is a very useful method in synthesis. Besides the chemical synthesis, aldolases can be used to perform this reaction. The reaction yields a stereoselective condensation of an aldehyde with a ketone donor. 

To a mixture of anhydrous dimethyl sulfoxide (4 mL) and ketone donor (1 mL) was added the corresponding aldehyde (0.5 mmol) followed by L-proline (20-30mol%) and the resulting mixture was stirred at room temperature for 4—72 h. The reaction mixture was treated with saturated ammonium chloride solution, the layers were separated, and the aqueous layer was extracted several times with ethyl acetate, dried with anhydrous MgS04, and evaporated. The pure aldol products were obtained by flash column chromatography (silica gel, mixture of hexanes and ethyl acetate). 

S)-Proline (1), its derivatives, and related molecules catalyze aldol reactions of ketone donors [6], For example, (S)-proline, (2S,4R)-4-hydroxyproline (2), and... 

General Procedure for O-tert-Butyl-L-Threonine Catalyzed Cross-Aldol Reactions of Ketone Donors and Aldehyde Acceptors [2] (p. 23)... 

In addition to broad-scope substrate specificity, 38C2 exhibits high enantioselectivity for the aldol reaction. Although this high degree of enantioselectivity has been observed for antibody-catalyzed ester hydrolysis reactions, it is certainly not a feature common to all such catalysts (Janda et al., 1989 Lo et al., 1997 Pollack et al., 1989 Tanaka et al., 1996 Wade and Scanlan, 1996). Furthermore, the rules for the enantioselectivity for 38C2-catalyzed aldol reactions are both simple and general (Hoffmann et al., 1998). For most ketone donors, attack occurs on the si side of the acceptor. However, when a ketone with an a-hydroxy substituent (such as hydroxyacetone) acts as donor, attack occurs on the reside (Scheme 5). 

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). 

The as)rmmetric proline-catalyzed intramolecular aldol cyclization, known as the Hajos-Par-rish-Eder-Sauer-Wiechert reaction [106,107], was discovered in the 1970s [108,109,110,111]. This reaction, together with the discovery of nonproteinogenic metal complex-catalyzed direct asymmetric aldol reactions (see also Sect 5.5.1) [112,113,114], led to the development by List and co-workers [115,116] of the first proline-catalyzed intermolecular aldol reaction. Under these conditions, the reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used. For example, acetone reacts with several aldehydes in dimethylsulfoxide (DMSO) to give the corresponding aldol in good yields and enantiomeric excesses (ee) (O Scheme 17) [117]. 

O Scheme 25) [150]. The latter acts as an acceptor only because of its good electrophilic and non-nucleophilic character. The a-thioacetal functionality in this enantioselective crosscoupling allows access to highly oxidized, stereo-defined synthons of broad versatility. Moreover, the observed reactivity profile makes them pre-eminent substrates for highly selective cross-aldol reactions with ketone donors. 

Reactions between ketone donors and aldehyde acceptors strrMigly depend on the nature of the aldehyde. While a-disubstimted aldehydes normally react easily, unbranched ones often undergo self-addition reactions. List et al. reported one of the first examples of a direct aldol addition of ketones to a-unbranched aldehydes en route to a natural product in 2001 (44). The operationally simple reaction between 13 and 19 in the presence of catalytic amounts of (5)-12 furnished the enantiomerically enriched p-hydroxy-ketone 20 in moderate yield. The reduced yield can be rationalized by the concomitant formation of the crmdensation product 21, which is one of the limiting factors in such reactions (besides the self reaction of a-unbranched aldehydes). Intermediate 20 can then be further converted to the bark beetle pheromone (5)-ipsenol (22) in two more steps (Scheme 6). 

The amine-catalyzed aldol reaction between ketone donors and a-disubstituted aldehydes normally proceeds much more easily and with excellent enantios-electivity, which was demonstrated impressively in the synthesis of the southern part of the highly cytotoxic potential anticancer drug epothilone B (29) 47,48) by Avery and Zheng (49) (Scheme 8). In this case (/ )-proline was the catalyst of choice to introduce the secondary alcohol group in high enantioselectivity early in the synthesis sequence. 

This example demonstrates the strength and versatility of enamine-catalyzed aldol reactions between ketone donors and aldehydes for the synthesis of key natural product synthons in a very impressive way. Like other routinely used asymmetric organic transformations that are applied commonly in total synthesis, this type of reaction today belongs to the standard repertoire for the introductirm of chiral alcohols by aldol-type reactions in natural product synthesis (50—54). 

The high versatility of proline-catalyzed aldol reactions with ketone donors for the selective introduction of adjacent steieogenic centers was also applied... 

Total synthesis of the potential anticancer drug salinosporamide A (56) represents an example where a proline-catalyzed aldol reaction between an achiral ketone donor and an a-chiral aldehyde was carried out with high selectivity. 

Some secondary amine-catalyzed intermolecular aldolizations with ketone donors. 

Ketone donors have only rarely been used in amine-catalyzed aldolizations. Selected examples that have been published over the last 70 years are shown in Scheme 4.7 [57-68]. 

As in intermolecular aldol reactions, amine-catalyzed 5-enolexo aldolizations can either lead to aldol condensation (Eqs. (l)-(4)) or addition products (Eq. (5)). These reactions usually involve an aldehyde group as the aldol donor the corresponding amine-catalyzed 5-enolexo aldolizations of ketone donors have so far not been realized. The acceptor carbonyl group can either be an aldehyde or a ketone. 

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