Stereochemical outcomes aldol reactions

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

Both of the 4,5-tran.v-diaslereomers of 4,5-dihydro-4-(4-methoxyphenyl)-5-methyl-3-[(7 )-(4-methylphenylsulfinyl)methyl]isoxazole (24) show excellent stereoselection in reactions with aldehydes. Despite the bulky substituents at the 4,5-dihydroisoxazole nucleus, the stereochemical outcome of the reaction is controlled by the sulfoxide stereogenicity. The pairs of 4,5-dihydro-3-(2-hydroxyalkyl)-4-(4-methoxyphenyl)-5-methylisoxazoles, obtained by desulfurization of the corresponding aldol adducts, have the same configuration at the hydroxy-substituted carbon (C-2 ) and opposite configuration in the 4- and 5-positions of the dihydroisoxazole ring24. 

When the aromatic group of the sulfoxide is replaced by a heteroaromatic group (e.g., N-methylimidazole), the internal coordination between Li—N to form a five-membered metallocycle apparently predominates over Li—O coordination to form a four-membered metallocycle . Reaction of imidazole (S)-sulfoxide 16 with benzaldehyde produces aldol 17 as the major product in which the a-H and the sulfoxide lone pair are syn (equation 14) imidazole (R)-sulfoxide 18 reacts similarly (equation 15). The stereochemical outcome of these reactions is rationalized in terms of a-lithiosulfoxides in which the reactive diastereomer (i.e., 20 and 21) is that having one diastereotopic face of the five-membered Li—N metallocycle carrying both H and sulfoxide lone pair. 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

Predict the stereochemical outcome of the following aldol addition reactions involving chiral auxiliaries. 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

Up to this point, we have considered primarily the effect of enolate geometry on the stereochemistry of the aldol condensation and have considered achiral or racemic aldehydes and enolates. If the aldehyde is chiral, particularly when the chiral center is adjacent to the carbonyl group, the selection between the two diastereotopic faces of the carbonyl group will influence the stereochemical outcome of the reaction. Similarly, there will be a degree of selectivity between the two faces of the enolate when the enolate contains a chiral center. If both the aldehyde and enolate are chiral, mutual combinations of stereoselectivity will come into play. One combination should provide complementary, reinforcing stereoselection, whereas the alternative combination would result in opposing preferences and lead to diminished overall stereoselectivity. The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation,67... 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

The stereochemical outcome of the aldol addition reactions to pyruvate and glyoxylates catalyzed by Sn(II) were complementary to the Cu(II)-catalyzed process, giving the anti stereoisomers. Thus, aldol adducts were isolated as mixtures of 10 90-1 99 syn anti diastereom-ers in 92-99% ee. 

The stereochemical outcome was rationalized by a Zimmerman-Traxler type transition state 45.64 Assuming the titanium enolate of 42 has a Z-geometry and forms a 7-membered metallacycle with a chairlike conformation, a model can be proposed where a second titanium metal coordinates to the indanol and aldehyde oxygens in a 6-membered chairlike conformation. The involvement of two titanium centers was supported by the fact that aldehydes that were not precomplexed with titanium tetrachloride did not react (Scheme 24.7).63 Ghosh and co-workers further hypothesized that a chelating substituent on the aldehyde would alter the transition state 46 and consequently the stereochemical outcome of the condensation, leading to. vyn-aldol products 47.64 Indeed, reaction of the titanium enolate of 42 with bidentate oxyaldehydes proceeded with excellent. s v -diastereo-selectivity (Scheme 24.8).65... 

The cyclic transition state explains how enolate geometry controls the stereochemical outcome of the aldol reaction. But what controls the geometry of the enolate For lithium enolates of ketones the most important factor is the size of the group that is not enolized. Large groups force the enolate to adopt the cis geometry small groups allow the fram-enolate to form. Because we can t separate the lithium enolates, we just have to accept that the reactions of ketones with small R will be less dias ter eoselective. 

The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazoline) copper(II) complexes resulting in excellent enantioselectivities (Fig. 7) [23]. A wide range of silylketene acetals 46 and 49 were added to (benzyloxy[acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. 

Docking simulations carried out with the aldol adducts bound into the active center of RAMA and RhuA suggested that in all cases the bulky N-protecting group cannot get into the catalytic site of the protein. That would explain the small effect of the N-protecting groups with different sizes and shapes on the stereochemical outcome of the reactions, since those groups would remain far from the reactive atoms. 

There are two important conclusions to be carried forward first, that solvation is likely to be of critical importance and should be included in the computations, and second, that focusing on the C-C forming step is appropriate. This C-C forming step is critical in accounting for the stereochemical outcome of the aldol reaction. 

The Mannich reaction is a close relative of the aldol, whereby an imine replaces the aldehyde acceptor. Proline has been demonstrated to be an excellent catalyst of the Mannich reaction, inducing high enantiomeric excess, as shown in Table 6.13. ° " Pertinent to this discussion is that the stereochemical outcome of the proline-catalyzed Mannich reaction is opposite to that of the proline-catalyzed aldol reaction. 

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