Aldehydes direct asymmetric aldol reaction

Direct asymmetric aldol reactions, that is between aldehydes and unmodified ketones has been accomplished using a lanthanum trilithium tri(binaphth-oxide) complex1 281. 

The direct asymmetric aldol reaction under phase-transfer conditions is a representative example of this class of phase-transfer reaction, which is known to proceed with a catalytic amount of base and to include an undesired retro-process (Scheme 1.6) [9]. Here, the onium enolate 4 reacts with aldehyde in the organic... 

Table 5.12 Direct asymmetric aldol reactions of 2 with aldehydes under phase-transfer conditions.

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 similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

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]. 

The direct asymmetric aldol reaction between unmodified aldehydes and ketones plays an important role in nature as a source of carbohydrates and it is used for the synthesis of chiral p-hydroxycarbonyl compounds. This reaction was performed by using (5)-proline/poly-(diallyldimethylammonium) hexafluorophosphate heterogeneous catalytic system 36. The catalyst was simply prepared by mixing a suspension of the commercially available polyelectrolyte 34 in methanol with a solution of (,S )-prolinc (35) in the same solvent (Scheme 3.11). 

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

In 2006, Takabe and Barbas et al. developed a water-compatible pyrrolidine-based diamine organocatalyst (Id) for direct asymmetric aldol reactions. The long hydrocarbon chain containing diamine (Id TFA) catalysed the aldol reaction in the presence of water at ambient temperature. Various ketones and isobutyraldehyde were treated with aromatic aldehydes to provide aldol products in high chemical yields, with favourable diastereos-electivity and high enantioselectivity (Scheme 9.5). ... 

Later Saito, Yamamoto, and coworkers used tetrazole 5a for the direct asymmetric aldol reactions of ketones to aldehydes. Interestingly, no product formation was observed when the reaction was performed under anhydrous conditions or with a catalytic amount of water (Scheme 9.8). The... 

Hartikka and Arvidsson demonstrated the high catalytic efficiency of catalyst 5a for the direct aldol reaction of acetone with various aldehydes. In the organocatalysed direct asymmetric aldol reaction, acetone reacted with aromatic and aliphatic aldehydes, resulting in formation of p-hydro) ketones with good yields and moderate to high enantiomeric excesses (Scheme 9.9). ... 

Scheme 9.9 Direct asymmetric aldol reaction of acetone with aldehydes.

A key role of the water-organie emulsion and/or heterogeneous reaetion conditions in reactivity and stereoselectivity of direct asymmetric aldol reactions of cyclic ketones 8 (R -R =-(CH2) -, -(CH2)2XCH2-) with aryl aldehydes 9 catalysed by amphiphilie, in particular surfactant-like, eatalysts 19a-e in the aqueous environment was later confirmed by Chinese and Italian researchers (Scheme 10.1). These catalytic reactions could be performed on a 0.2 mole seale with the enantiomeric purity of products 10 maintained at the same level, whieh shows great promise for industty. ... 

In 2001 Barbas III et al. reported the amino acid-catalysed direct asymmetric aldol reaction between ketones and aldehydes. Using the benchmark condensation reaction between acetone and p-nitro-benzalde-hyde, the authors tested many different amino acids as organocatalysts, including (5 )-ot-2-methyl-proline 7a (Scheme 11.2). In this reaction however 7a proved to be much less reactive than (S)-proline (1), as well as slightly less enantioselective. Compound 7a was also found to be less efficient than 1 in the direct organocatalytic asymmetric a-oxidation of cyclohexanone with iodosobenzene, as reported by Cordova et ah in 2005 (Scheme 11.3). ... 

Based on the observations and quantum mechanical calculations for proline-catalysed asymmetric aldol reactions Li and coworkers synthesised a series of L-proline-hased dipeptides for the direct asymmetric aldol reaction between substituted aldehydes and acetone in DMSO. Dipeptide 31 was successfully employed yielding the desired adducts in excellent yield and good to excellent enantioselectivity. Additionally, PGME 5000 was used as a surfactant additive in catalytic amounts, since prior reports showed an acceleration of aldol reactions hy such additives Xheme 13.20b). 

In this direction, Choudary et al. reported the direct asymmetric aldol reaction of aldehydes and ketones to afford the optically active [3-hydroxy carbonyl compounds in good yields and moderate ee s catalyzed by nanocrystalline magnesium oxide. 

TABLE 5.10. Direct Asymmetric Aldol Reaction of Aldehydes and Acetone with NAP-MgO ... 

In another work ZnS nanoparticles with an inducing chirality were used as a catalyst for asymmetric aldol condensation reactions. In this case ZnS nanoparticles (Fig. 9) have been synthesized by a coprecipitation of ZnS in the presence of r-proline. Then these nanoparticles were used as a catalyst for the direct asymmetric aldol reaction of several aldehydes with acetone to achieve chiral Z)-hydro>q carbonyl compounds in good yields and enantioselectivity at room temperature without using any co-solvent for solubility purposes. It was found that the selectivity of the ZnS nanoparticles enabled to produce only (i )-6-hydro q carbonyl compounds and restricted the reaction at the aldolization stage only. Importantly, notice that the ZnS catalyst was recovered and reused several times without any considerable loss in activity. 

Misaki, Sugimura and Takimoto reported a direct asymmetric aldol reaction between 5-H-oxazol-4-ones and aldehydes. The reaction is catalysed by bifunctional guanidines Misald-Sugimura-G with a tertiary alcohol functional group (Scheme 23.2). Misald-Sugimura-Gl is employed for a-branched (R2 group) aldehyde and Misald-Sugimura-G2 is used when R2 comprises a linear hydrocarbon chain [e.g. -octyl) (Scheme 23.3). 

Most reports in the field of organocatalytic, direct, asymmetric aldol reactions involve aldehydes as acceptors. Reactions where ketones act as electrophiles have been less explored, though they may provide efficient access to chiral tertiary alcohols. 

The combinational use of inorganic base and chiral phase-transfer catalyst provides an efficient process for the synthesis of -hydroxyl-a-amino acids via the aldol reaction (260-262). A representative and successful example was reported by Maruoka and co-workers (319) that a highly efficient direct asymmetric aldol reaction of a glycinate Schiff base with aliphatic aldehydes has been achieved under mild organic/aqueous biphasic conditions with excellent stereochemical control activity (Scheme 67) (96 99% ee). 

A plausible catalytic cycle for the direct asymmetric aldol reaction is shown in Fig. 7. Key to the success of the reaction is chemoselective enolate formation of ynones 8 in the presence of enolizable aldehydes, which is mediated by soft-soft interaction 10 between the ynone moiety and the copper catalyst. This interaction selectively acidifies the a-protons of ynones. The aldol addition of chiral Cu (I) enolate 12 to an aldehyde affords copper aldolate 13. The soft-soft interaction between the Cu(I) atom and the n electrons of the alkyne moiety in 13 would help suppress the imdesired retro-aldol reaction due to the existence of additional coordination. Nevertheless, facile protonation of imstable 13 and formation of aldol product 14 is crucial, rationahzing the inquiry of (sub)stoichiometric amounts of trifluoroethanol. Protonation of 13 regenerates the copper alkoxide catalyst. 

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

The highly chemoselective Lewis acid/hard Brpnsted base cooperative chiral catalyst used to promote anti-selective direct asymmetric aldol reaction of N-protected thiolac-tams permits the use of enolizable aldehydes as the aldol acceptor. ... 

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