Crossed aldol reactions asymmetric

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Benito Alcaide, Pedro Almendros The Direct Catalytic Asymmetric Cross-Aldol Reaction of Aldehydes, Angew. Chem. 115(8), 884-886 (2003), Angew. Chem. Int. Ed. 42(8), 858-860 (2003)... 

Asymmetric Cross Aldol Reactions via Divalent Tin Enolates.155... 

Figure 1. Model proline-catalyzed asymmetric cross aldol reaction.

Of course, a systematic comprehensive analysis of all literature published on the asymmetric cross aldol reaction goes beyond the purpose of this chapter, thus attention is focused on the best achievements reported for catalysts working under neat conditions in the presence of an aqueous phase (Scheme 1.2). Generally, zzzZz-diastereoselectivity is observed, while the opposite. sv/z-diaslcr-eoselectivity is often exhibited by oc-hydroxyketones. 

Beside the cross aldol reaction, the Mannich reaction, too, has been the object of successful efforts using organocatalysis. The use of small organic molecules such as proline, cyclohexane diamine and Cinchona alkaloid-derived catalysts has proven extraordinarily useful for the development of asymmetric Mannich reactions in traditional polar solvents such as DMSO, DMP, DMF, etc. However, very few studies have been conducted so far in non-conventional solvents. 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

The fact that many published homochiral intermediates lack any functionality at the future 7-position makes these less than ideal for the efficient synthesis of aglycones. Kishi has developed a synthesis of 11-deoxyanthracyclinones in which both 7- and 9-hydroxyl functions are introduced stereoselectively during the construction of ring-A. Thus asymmetric crossed aldol reaction of the acetal 193 with 194 gave a 17 1 mixture of 195 and its C-7 epimer. Base catalysed cyclisation followed by removal of the C-10 ester function yielded the trans-dioxygenated product 197. This was epimerised to give an 8 1 mixture of 198... 

Cross-aldol reactions involving the optically active keto-esters menthyl pyruvate and phenylglyoxylate and either silyl enol ethers or keten silyl acetals have been shown to result in appreciable asymmetric induction, considerably larger than that observed in the reactions of the same chiral a-keto-esters with Grignard... 

Scheme 5.7 Asymmetric cross-aldol reaction of a-amino aldehydes.

Almost inevitably, a method to eany out a proline-eatalysed, asymmetric cross-aldol reaction was shortly after described by Tanaka and Barbas et al. The reaction of the protected a-amino aldehyde 8 with branched aldehyde 9 gave access to y-branched p-hydro gr-a-amino aldehyde 10, which was further used to generate the respective amino acid derivative 11 (Scheme 5.7). The surrounding study showed that the roles of the individual aldehydes as donor or acceptor were invertible, depending on whether branched or nonbranched aldehydes were applied. When a-nonbranched aldehydes were... 

Catalyst 15n is able to promote asymmetric cross-aldol reactions of acetone with activated ketones, to generate a quaternary carbon stereogenic centre bearing an OH function, whereas catalysts 15b-d are very active in the reaction of acetone and p-nitrobenzaldehyde in a series of solvents and catalyst loadings. Ley and coworkers reported the synthesis of the parent members of the sulfonamide family - proline methyl sulfonamide... 

To extend the operation period of prolinamide-derived IL-supported catalysts, bis-amides 58a-e were synthesised from (25, 4R)-4-hydro yproline and various diamines. C2-Symmetric compounds 58c-e bearing p-phenyle-nediamine, l,2-diaminocyclohexane or 1,2-diphenyl ethylenedia-mine ° structural units exhibited excellent catalytic performance in asymmetric cross-aldol reactions between ketones 8 and aldehydes 9 in the aqueous medium and could be recycled 15 times without any decrease of activity or loss of enantiocontrol. Furthermore, bis-amide 58e efficiently catalysed aldol reactions of acetone with a-ketoesters 62 to afford a-hydrojqr-y-ketoesters 63 in a nearly quantitative yield, yet with moderate enantioselectivity (Scheme 10.14). 

The ability of amino acids to catalyse the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions was reported one year later. Cordova et al. demonstrated that O-benzylglycoaldehyde 1 could react with protected dihydrojqracetone or with itself in the presence of enantio-pure Alanine, valine or phenylalanine, leading, respectively, to 2 and 3 (Scheme 12.1). ... 

The cross-aldol reaction between propionaldehyde (5a, R =Me in Scheme 4.12) and p-nitrobenzaldehyde gave the corresponding compound anti-29 (> 88% yield, 88% de and 99% ee), which has been used as the asymmetric key step in the synthesis of trichostatin A [76], In a similar way, using propionaldehyde (Sa, R =Me in Scheme 4.12) and an excess isobutyraldehyde (4 equiv, R =j-Pr) catalyzed by proline (10 mol%), product anti-29 (98% de and 99% ee) was obtained. Subsequent diastereoselective Mukaiyama aldol reaction followed by lactonization gave prelactone B [77]. The synthesis of (-)-enterolactone has been achieved by a cross-aldol reaction between methyl 4-oxobutyrate and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) as a key step [78],... 

The cross-aldol reaction between two aldehydes is a very difficult transformation. Since ahphatic aldehydes can act both as nucleophiles and as electrophiles, a successful cross-reaction requires two aldehydes with a significant difference in the rate of enamine formation (Scheme 3.20). (3-Hydroxy-aldehydes can be easily synthesized in an amine-catalyzed direct asymmetric cross-aldol reaction between two aldehydes only when one enolizable aldehyde is used and self-aldolization is somehow prevented. 

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