Aldol reactions, asymmetric

In its most general form the aldol reaction can be represented by the general formula shown. 

There are three questions to be addressed first, the relative stereochemistry of the new stereogenic centres C-2 and C-3 with respect to each other second, the influence of asymmetry in the 

Let us consider first the 2,3-stereochemistry. There are two new stereogenic centres, giving rise to four possible outcomes  

The two syn aldols (57) and (58) are enantiomers (provided there is no additional asymmetry in A or B), as are the anti aldols (59) and (60). The syn anti outcome depends fundamentally on the geometry of the enolate and can be predicted on the basis of the six-membered cyclic transition state known as the Zimmermann-Traxler model. 

assuming that the oxygen atom of the enolate takes precedence over group B, we can see thatthe -enolate gives rise to the anri-aldol, and the Z-enolate to the syn. Note the resemblance to the chair conformer of cyclohexane, in which the bulky A group occupies the equatorial position. In practice, the best syn anti selectivity is obtained with M = Li, Mg or BR2. Thus the problem of relative 2,3-diastereoselection reduces to the preparation of the necessary E- or Z-enolate, which is not always simple. 

Kokotos and coworkers investigated the use of prolinamide-based thioureas as bifunctional organocatalysts for the direct aldol reaction. The amide and the thiourea functionalities, tethered by a chiral diamine motif, offered multiple hydrogen bonding sites for electrophile activation, while the pyrrolidine skeleton served to activate the nucleophile via enamine catalysis. Thiourea 61 proved to provide the best catalyst in the presence of 4-nitrobenzoic acid as cocatalyst at low temperature and delivered the anti-aXAoX products in moderate to high yields and in high to excellent 

Since the middle of the 198O s remarkable progress has been achieved in the development of asymmetric aldol reactions of silyl enolates. In the beginning of this evolution, chiral auxiliary-controlled reactions were extensively studied for this challenging subject [106]. As new efficient catalysts and catalytic systems for the aldol reactions were developed, much attention focused on catalytic enantiocontrol using chiral Lewis acids and transition metal complexes. Thus, a number of chiral catalysts realizing high levels of enantioselectivity have been reported in the last decade. 

The catalyhc efficiency of L-proline in ionic liquid was enhanced by the addition of DMF as cosolvent, which may be largely due to tlie increased mass transfer in the presence of DMF [79c]. Thus, the use of only 5 mol% L-proline was sufficient to accomplish the cross-aldol reactions of aliphatic aldehydes, affording a-alkyl-P-hydroxyaldehydes with extremely high enanhoselectivihes ( 99% ee) in moderate to high diastereoselectivities (diastereomeric raho 3 1 19 1). However, under the same reaction conditions, much lower ee-values and yields were observed in a one-pot synthesis of pyranose derivahves by sequential cross-aldol reachons. The L-proline immobilized in the ionic liquid layer could be recovered and reused without any deterioration in catalytic efficiency, with the diastereoselectivity, 

The catalyst leaching problem could be solved by incorporating an ionic tag onto the 4-hydroxyproline [82]. In teres lirigly, the imidazolium-tagged organo- 

Fig ure 9.1 Structures of various 2-substituted pyrrolidine-derived organocataiysts. 

A proton coordinated to the nitrogen of the pyrrolidine ring was proposed to activate one of the carhonyl groups in which the transition state A 

Major stereoisomer along with minor isomers 

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Asymmetric aldol reaction promoted by chiral oxazaborolidinone 97YGK313. 

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

Other reactions adapted from asymmetric aldol reactions suffer in comparison from the fact that (probably due to the strength of the boron-nitrogen bond) boron-mediated processes generally yield the intermediate 2-halo-3-aminoester products rather than aziridine products directly [51]. 

Aldol reactions of a-substituted iron-acetyl enolates such as 1 generate a stcrcogenic center at the a-carbon, which engenders the possibility of two diastereomeric aldol adducts 2 and 3 on reaction with symmetrical ketones, and the possibility of four diastereomeric aldol adducts 4, 5, 6, and 7 on reaction with aldehydes or unsymmetrical ketones. The following sections describe the asymmetric aldol reactions of chiral enolate species such as 1. 

A tin(II)-catalyzed asymmetric aldol reaction and lanthanide-catalyzed aqueous three-component reaction have been used as the key steps for the synthesis of febrifugine and isofebrifugine (Scheme 8.31).293... 

Aldolases catalyze asymmetric aldol reactions via either Schiff base formation (type I aldolase) or activation by Zn2+ (type II aldolase) (Figure 1.16). The most common natural donors of aldoalses are dihydroxyacetone phosphate (DHAP), pyruvate/phosphoenolpyruvate (PEP), acetaldehyde and glycine (Figure 1.17) [71], When acetaldehyde is used as the donor, 2-deoxyribose-5-phosphate aldolases (DERAs) are able to catalyze a sequential aldol reaction to form 2,4-didexoyhexoses [72,73]. Aldolases have been used to synthesize a variety of carbohydrates and derivatives, such as azasugars, cyclitols and densely functionalized chiral linear or cyclic molecules [74,75]. 

Silvestri, G., Desantis, G., Mitchell, M. and Wong, C.-H. (2003) Asymmetric aldol reactions using aldolases. 

Machajewski, T.D., Wong, C.-H. and Lemer, R.A. (2000) The catalytic asymmetric aldol reaction. Angewandte Chemie-International Edition, 39 (8), 1352-1374. 

As shown in Scheme 53, L-proline-catalyzed asymmetric aldol reaction between 3-methylbutanal and acetone was used by List for the synthesis of (S)-34 [79]. 

TiX4 is employed as an effective promoter for asymmetric aldol reactions. A chiral aldehyde or a chiral enolate reacts to afford homochiral aldol adducts with high selectivity (Scheme 20).78 79... 

Asymmetric reactions using chiral copper Lewis acids are also performed in aqueous media. It has been reported that an asymmetric Diels-Alder reaction proceeds smoothly in water using Cu(OTf)2 and abrine as a chiral ligand (Scheme 49).214 The Cu -bis(oxazoline) system is effective in asymmetric aldol reactions in an aqueous solvent such as water/ethanol and even in pure water.215... 

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Catalytic asymmetric aldol reactions of a-heterosubstituted substrates such as glyoxaldehyde, and methyl pyruvate have been reported (Scheme 81). High diastereo- and enantioselectivity have been obtained by using combined use of Sn(OTf)2 and bis(oxazoline) or pyridinebis(oxazoline) ligands.341... 

A lead(II) triflate-crown ether complex functions as a chiral Lewis-acid catalyst for asymmetric aldol reactions in aqueous media (Scheme 86).352 This is the first example of a chiral crown-based Lewis acid that can be successfully used in catalytic asymmetric reactions. 

Zinc-containing compounds have also been used as catalyst. Recently, Trost et al. reported asymmetric aldol reactions of methyl ynones 331 with pyruvaldehyde ketals 330 in the presence of a dinuclear zinc catalyst 329 generated from ZnEt2 and a pentadentate 0,N,0,N,0-ligand (328, Scheme 168).428 This reaction is a unique case of enantioselective autoinduction with product incorporation into the catalyst and a reversal of the absolute configuration. 

Silvestri, M. G., Asymmetric Aldol Reactions Using Aldolases, 23, 267. 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Starting from ketone(i )-/(S )-49, the asymmetric aldol reaction with aldehyde in the presence of 45a or 45b affords all four isomers of //-hydroxyl ketone 47, 48, 50, and 51 with high yields and stereoselectivities (Scheme 3-17). 

Double asymmetric aldol reaction has been widely used for the efficient construction of the, sr -unit.10b 42 With above-described organoboron compounds (Section 3.3.1), antz -selectivity can be obtained. 

CHIRAL CATALYST-CONTROLLED ASYMMETRIC ALDOL REACTION... 

In the presence of a chiral promoter, the asymmetric aldol reaction of pro-chiral silyl enol ethers 71 with prochiral aldehydes will also be possible (Table 3-6). In this section, a chiral promoter, a combination of chiral diamine-coordinated tin(II) triflate and tributyl fluoride, is introduced. In fact, this is the first successful example of the asymmetric reactions between prochiral silyl enol ethers and prochiral aldehyde using a chiral ligand as promoter. 

Perfect stereochemical control in the synthesis of sy -a-methyl-/ -hydroxy thioesters has been achieved by asymmetric aldol reaction between the silyl enol ether of. S -ethyl propanethioate (1-trimethylsiloxy-l-ethylthiopropene) and aldehydes using a stoichiometric amount of chiral diamine-coordinated tin(II)... 

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