Aldehyde cross-aldol reactions

As demonstrated by MacMillan and coworkers, a-oxygenated aldehydes are very good reaction partners in the aldehyde-aldehyde crossed-aldol reaction. The products are tetroses, and one further aldol step affords a range of hexoses, i.e. differentially protected monosaccharides, in a two-step synthesis (Scheme 20) [203],... 

McMillan and co-workers [146] have reported the first example of direct enantioselective aldehyde-aldehyde cross-aldol reaction using small molecules as catalysts. Subsequently, they have described the enantioselective dimerization and cross-coupling of a-oxygenated aldehydes to provide eiythrose architecture. A second L-proline-catalyzed aldol reaction generates hexoses (O Scheme 22) [147]. 

One normally expects antibodies to have a low tolerance to substrate modifications, however an ongoing feature of these aldolase antibodies is their wide scope. They accept a remarkable range of aldol donors and acceptors and perform crossed-, intramolecular- and retro-variants of this reaction, with high yields, rates, and stereospecificities [81,82,83]. Substrate modification experiments have revealed that when acetone is the aldol donor in a ketone-aldehyde crossed aldol reaction, stereoinduction is linked to attack of the sz-face of a prochiral aldehyde with typically >95% ee and when hydroxyacetone is the donor substrate, attack occurs preferentially at the re-face of the aldehyde leading to a diastereomeric a,P-dihydroxy ketones with the two stereogenic centers having an a-syn configuration. This reaction leads to stereospecificities of typically 70 to >99% ee. 

Scheme 5.8 Proline-catalysed direct aldehyde cross-aldol reaction.

The trimethylsilyl (TMS) group is a widely used protecting group and Lewis acid, as well as an important functional group for numerous substrates. For these reasons, we deemed the TMS group to be generation one. As described earlier (Scheme 20), we have demonstrated that the use of triflimide as a catalyst initiator is very effective for the aldehyde cross-aldol reaction [34, 35]. The success of this reaction proved to be maximal with the use of triflimide as the catalyst as well as the use of tris(trimethylsilyl)silyl (TTMSS) enol ethers (Scheme 20) [36, 37]. The use... 

In the same year, Hayashi and coworkers [39] also reported the use of an amphiphihc L-proHne derivative bearing a long alkyl chain on the 4-position via an ether bond for the enantioselective aldehyde cross-aldol reaction without the need for an additional co-solvent or additives (Scheme 8.14). Probably, emulsions offer an ideal reaction environment in which organic molecules can be assembled through hydrophobic interactions, thus enabling the aldol reaction to proceed efficiently. As a result, the corresponding products, chiral 1,3-diols, could be obtained with high diastereo- and enantioselectivity. 

If only one of the two aldehydes has an a-hydrogen, only two aldols can be formed and numerous examples have been reported, where the crossed aldol reaction is the major pathway. For two different ketones, similar considerations do apply in addition to the unfavorable equilibrium mentioned above, which is why such reactions are seldom attempted. 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

Silylation using the silylacetate (3.1.14) [49] involves the initial formation of the acetate carbanion, which abstracts a proton from the carbonyl compound or alcohol (Scheme 3.2, Table 3.5). When the reaction with a ketone is conducted in the presence of an aldehyde, crossed aldol products are obtained (see Chapter 6). 

In the Mukaiyama cross-aldol reaction, an aldehyde and a ketene silyl acetal [e.g. (43)] react via Lewis acid catalysis to give a jS-silyloxy ester (44). The reaction... 

The aldol reaction as formulated above involves two molecules of the starting substrate. However, by a consideration of the mechanism, one can see that different carbonyl compounds might be used as nucleophile or electrophile. This would be termed a mixed aldol reaction or crossed aldol reaction. However, if one merely reacted, say, two aldehydes together under basic conditions, one would get a... 

A nondirect enantioselective cross-aldol reaction between two discrete aldehyde components has been achieved see Denmark, S. E. Ghosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759 762. 

The simplest possible aldehyde donor, acetaldehyde, can also be used as the donor Very recently, Hayashi and coworkers discovered how to use acetaldehyde in crossed-aldol reactions - the trick is to use diarylprohnol as the catalyst and to optimize the reaction conditions carefully to prevent oligomerization of acetaldehyde. However, so far the acetaldehyde aldol reactions appear to be limited to aromatic aldehyde acceptors [205],... 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

An aldol reaction/condensation occurs when the enolate ion from an aldehyde or ketone attacks a molecule of the parent compound. If, however, two different carbonyl compounds are present, a crossed aldol reaction/ condensation occurs. 

Reaction between two different aldehydes. In the most general case, this will produce a mixture of four products (eight, if the olefins are counted). However, if one aldehyde does not have an a hydrogen, only two aldols are possible, and in many cases the crossed product is the main one. The crossed aldol reaction is often called the Claisen-Schmidt reaction. 

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... 

It is thus possible to look at a molecule such as A below and recognize that it is a ft-hydroxy ketone and thus could be formed in a crossed-aldol reaction between enolate B and aldehyde C. Likewise D could potentially be produced by dehydration of the aldol product of cyclohexanone... 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Crossed aldol reaction between an aromatic aldehyde and the TMS enolate of another aldehyde proceeds smoothly in wet or dry DMF using a lithium carboxylate as Lewis base catalyst.158 One-pot conversion to 1,3-diols using sodium borohydride as reductant gives up to 87% yield. A similar report, using tetrabutylammonium phe-nolates as Lewis bases, is diaslereoselective.159... 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

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