Aldol reactions can be stereoselective

In Chapter 27 you met the aldol reaction reaction of an enolate with an aldehyde or a ketone. Many of the examples you saw approximated to this general pattern. 

Only one new stereo genic centre is created, so there is no question of diastereoselectivity. But with substituted enolates, two new stereogenic centres are created, and we need to be able to predict which diastereoisomer will be formed. Here is an example from p. 699. We did not consider stereochemistry at that stage, but we can now reveal that the syn diastereoisomer is the major product of the reaction. 

This is a very general rule and there are cis or tram. Which enolate is formed is an important factor controlling the diastereoselectivity 

Let s start by showing some examples and demonstrating how we know this to be the case. Some enolates can only exist as trara-enolates because they are derived from cyclic ketones. This enolate, for example, reacts with aldehydes to give only the anti aldol product. 

Tf we choose the group X , next to the carbonyl group, to be large, then we can be sure of getting just the ds-enolate. So, for example, the lithium enolate of this f-butyl ketone forms just as one geometrical isomer, and reacts with aldols to give only the syn aldol product. 

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Aldol reactions can be stereoselective 868 Ring expansion by fragmentation 963... 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

The observed stereoselectivity in the Evans aldol reaction can be explained by the ZImmerman-Traxler transition state model. There are eight possible transition states, four of which would lead to the anti aldol product. These, however, are disfavored due to the presence of unfavorable 1,3-diaxial interactions (not depicted below). The possible transition states leading to the syn aldol product are shown below. The preferred transition state leading to the product is transition state A, where the dipoles of the enolate oxygen and the carbonyl group are opposed, and there is the least number of unfavored steric interactions. 

In a similar manner, syn aldol reactions can be carried out with ethyl ketones using the Ipc2BOTf reagent. We showed that the asymmetric induction using diethyl ketone is reasonable (66-91% ee), with best results for a,jS-unsaturated aldehydes [35]. We also showed that this reaction could be extended to chiral ketones, for example, the stereoselective synthesis of either syn adduct 51 or 52 was achieved, depending on the configuration of IpciBOTf reagent (Scheme 9-17) [II]. 

If you would like to know more about how the existing chiral centre makes its influence felt then you are directed to the paper43 and a suggestion for transition states.44 For now we continue with the manipulations. The new hydroxyl group that has been formed in the aldol reaction can be used to direct a stereoselective reduction of the ketone in the way that we have already seen. So, P-hydroxyketone 179 is reduced to diol 181. 

In some cases, a stereoselective aldol reaction can be accomplished in a kineti-cally controlled process via kinetic resolution of the racemic a-substituted aldehyde. Thus, if the reaction is stopped before it reaches equilibrium, a single diastereomer is predominantly formed. However, as mentioned above, the selec-tivities of aldolases for such kinetic resolutions involving recognition of the (remote) chirality on the a-carbon atom of the aldehyde are usually low. 

Mechanistically, the stereoselective aldol reaction can be divided into several different subclasses. Aldol reactions of metal enolates follow some general mechanistic pathways that facilitate prediction of the relative configuration of the products. The reactions can be described as proceeding via chelated, closed, Zimmerman-Traxler transition states [33]. The positioning of substi-... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

Boron triflates 45a and 45b are very useful chiral auxiliaries. Boron azaenolate derived from achiral35 and chiral36 oxazolines gives good stereoselectivity in the synthesis of acyclic aldol products, particularly for the rarely reached threo-isomers. By changing the chiral auxiliary, the stereochemistry of the reaction can be altered.37... 

As the t-butyl group can readily be removed upon acidic or basic hydrolysis, this method can also be used for //-hydroxyl acid synthesis. In analogy with allylation reactions, the enolate added preferentially to the Re-face of the aldehydes in aldol reactions. Titanium enolate 66 tolerates elevated temperatures, while the enantioselectivity of the reaction is almost temperature independent. The reaction can be carried out even at room temperature without significant loss of stereoselectivity. We can thus conclude that this reaction has the following notable advantages High enantiomeric excess can be obtained (ee > 90%) the reaction can be carried out at relatively high temperature the chiral auxiliary is readily available and the chiral auxiliary can easily be recovered.44... 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

Mukaiyama aldol condensation (6, 590-591).8 This reaction can be effected in the absence of a Lewis acid catalyst under high pressure (10 kbar). Surprisingly the stereoselectivity is the reverse of that of the TiCl4-catalyzed reaction (equation I). The reaction can also be effected in water with the same stereoselectivity, but the yield is low because of hydrolysis of the silyl enol ether. Yields are improved by use of water-oxolane (1 1) and by sonication.9... 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

Stereoselective aldol condensation. Heathcock and Buse have previously employed 2-methyl-2-trimethylsiloxy-3-pentanone (1) in a highly stereoselective route to 3-hydroxy-2-methylcarboxylic acids (8, 295). Aldol condensation of the lithium enolate derived from 1 with a chiral aldehyde yields ery//iro-aldols, which are cleaved with periodic acid to -hydroxy carboxylic acids. However, when 1 is condensed with a chiral aldehyde such as 2, two eryt/iro-products (3 and 4) are produced. Heathcock and co-workers now report that the 1,2-diastereoselectivity of these aldol condensations can be enhanced by use of the ketone 5. Reaction of racemic 5 with racemic aldehyde 2 furnishes a single (racemic) adduct 6. 

In accordance with this model one finds diastereoselectively anti products on reaction of aldehydes with ( )-allyl compounds, whereas allyl systems with the (Z)-configuration give mainly syn products and it is even possible to effect asymmetric induction. As the double bond of the product can be oxidatively cleaved to a CW3 group, the reaction can be regarded as a stereoselective aldol reaction, an aspect which explains the widespread interest in this type of reaction. With heterosubstituted allylic anions it is sometimes possible to effect predominantly y-attack with different electrophiles by the choice of the heteroatom.2 For instance it is well known that with sulfur substituents like —SR, —SOR or —SOjR the a-attack dominates, but doubly lithiated allenethiol possesses high y-reactivity and can be used as a homoenolate anion equivalent in reaction with electrophiles such as alkyl halides (Scheme 7). ... 

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