Asymmetric cross aldol reactions

Having established the positive effect of the presence of water, let us examine which protocols are to be adopted and which are deleterious in terms of catalytic activity and overall stereocontrol.The first protocols reported in DMSO did not focus on the presence of water but it is likely that the required trace amount was present as contaminant of the solvent used. The procedure to avoid is a homogeneous reaction in water as solvent using water-soluble carbonyl compounds in this case reactions likely proceed under general base catalysis mechanisms, resulting in very poor conversions and lack of enantio-control. Thus, two useful approaches for reactions in water are available in the 

If maximizing catalyst hydrophobicity is the key to success in the organocatalysed aldol reaction under liquid/liquid biphasic aqueous conditions using catalysts 3-16, this property does not generally provide practical recycling procedures. 

Ionic liquids (ILs), beside affording new molecular supports for catalytically active species, are entering the field of organocatalysis as solvent by offering (i) a new medium for checking the performance of existing organocatalysis in 

Much stronger, however, is the electrostatic interaction of the ion pairs of an IL with a catalyst possessing an ionic tag installed on its scaffold, e.g. 17. In this coulombic environment either acceleration or inhibition can be observed with respect to the use of molecular solvents. In the absence of a robust theoretical 

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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. 

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... 

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 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. 

Direct asymmetric cross-aldol reactions of ketones with aromatic aldehydes proceed in the presence of an l-proline-derived tertiary diamine and additives using water as a solvent (Scheme 26). L-Proline-derived diamines give racemic product in the absence of an acid cocatalyst. While trifluoroacetic acid (TFA) is the most effective additive for the aldol addition of cyclohexanone to 4-nitrobenzaldehyde in the presence of L-proline-derived diamine, addition of scandium triflate is also effective for the reaction with similar enantioselectivity. 

Recently, EUman and coworkers have shown that chiral sulfinate 18 can catalyze asymmetric aldol reactions of acetone, whereas proline (1) itself gave poor results [80]. Nakamura and coworkers also explored this field, and found that 19 can promote the asymmetric cross-aldol reaction of acetone with activated ketones, to generate a quaternary carbon stereogenic center bearing an OH function [81],... 

SCHEME 8.47. The proline-mediated asymmetric cross-aldol reaction by List and co-workers. 

Maikov, A.V., Kabeshov, M.A., Bella, M., Kysdka, O.E., Malyshev, D.A., Pluhackova, K.N., and Kocovsky, P. (2007) Vicinal amino alcohols as organocatalysts in asymmetric cross-aldol reaction of ketones application in the synthesis of convolutamydine A. Org. Lett., 9, 5473-5476. 

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