Diastereoselectivity in aldol reactions

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

The scope and diastereoselectivity of reactions with various electrophiles are shown below. The only weak point is the poor diastereoselectivity in aldol reactions with aldehydes. These methods have been widely used as they are robust and reliable. Nevertheless the methods we have so far described for chiral enolates are less significant than the Evans chiral oxazolidinones in the next section. 

Heathcock has demonstrated the utility of double stereodifferentiation to enhance 1,2-diastereoselectivity in aldol reactions. ... 

Acyl Silanes. Although acyl trimethylsilanes are known, they are usually unstable and lead to poor diastereoselectivity in aldol reactions. TBDMS acyl silanes, however, were prepared in 50% yield from 1-methoxy- 1-lithiopropene in the presence of TMEDA at rt (eq 20). The lithium enolates of TBDMS acyl silanes were treated with aldehydes to give the corresponding aldol products in reasonable yields. 

Another application of diastereoselective nitro-aldol reactions catalyzed by Bu4NF-3H20 is demonstrated in a simple synthesis of l,4-dideoxy-l,4-imino-D-mannitol (DIM) and amino analogues (Eq. 3.85).134 The nitro-aldol reaction of nitro compounds bearing a-oxy or a-amino function with glyceraldehyde leads to nitrohexitols, which can be reduced to the corresponding amino compounds. Cyclization gives iminopolyols, as shown in Eq. 3.85. 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

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]. 

There is an important difference between Horeau s and Heathcock s examples in that the aldol reaction generates two chirality elements in the bond-forming step. In principle, analysis of such a reaction requires evaluation of two aspects, i.e., the effect of double asymmetric induction on simple and induced diastereoselectivity. The aldol reaction is not particularly suited for this... 

The simple diastereoselectivity of aldol reactions was first studied in detail for the Ivanov reaction (Figure 13.45). The Ivanov reaction consists of the addition of a carboxylate enolate to an aldehyde. In the example of Figure 13.45, the diastereomer of the /1-hydroxycarboxylic acid product that is referred to as the and-diastereomer is formed in a threefold excess in comparison to the. vy/j-diastereoisomer. Zimmerman and Traxler suggested a transition state model to explain this selectivity, and their transition state model now is referred to as the Zimmer-man-Traxler model (Figure 13.46). This model has been applied ever since with good success to explain the simple diastereoselectivities of a great variety of aldol reactions. 

Treatment of chiral oxazolidinone with Bu2BOTf and Et3N quantitatively produced a novel doubly borylated enolate, which afforded the double aldol products with high diastereoselectivity in the reaction with aldehydes (Equation (182)).687 688... 

The Et3SiH-promoted diastereoselective reductive aldol reaction proceeds by using InBr3 as a catalyst. This three-component reaction affords only silyl aldolates as products without any side-reaction. The //-selectivity obtained here is higher than that of any other reductive aldol reactions (Scheme 111).382 A catalytic amount of In(OAc)3 also promotes... 

Ghosh et al. reported that the chiral oxazolidinone 87, derived from (1S,2R)-cis-l-amino-2-indanol (86), underwent a highly diastereoselective. vyn-aldol reaction with a variety of aldehydes30 (Scheme 2.1cc). Reaction of the indanolamine 86 with disuccinyl carbonate in acetonitrile gave the oxazolidinone 87, which was deprotonated with -BuLi and reacted with propionyl chloride to provide the N-propionyl derivative 88. Reaction of 88 with n-BioBOTf and... 

In the synthesis of RK-397 (18), Denmark and Fujimori prepared an anft -diol using the Evans-Chapman-Carreira protocol5 (Scheme 4.2f). The (3-hydroxy ketone 21, obtained by a diastereoselective boron aldol reaction between 19 and 20, was reduced with tetramethylammonium triacetoxyborohydride to afford the anti-diol derivative 22 in greater than 19 ldiastereoselectivity. 

A kinetic study of the Ph2BOH-catalysed reactions of several aldehydes with 2 revealed that the rate of the disappearance of 2 followed first-order kinetics and was independent from the reactivity of the aldehydes used. Taking into account this result, we have proposed the reaction mechanism in which a silyl enol ether is transformed to the corresponding diphenylboryl enolate before the aldol addition step takes place (Scheme 13.1). The high diastereoselectivity is consistent with the mechanism, in which the aldol step proceeds via a chair-like six-membered transition state. The opposite diastereoselectivity in the reaction with the geometrical isomers of the thioketene silyl acetal shown in Table 13.3 also supports the mechanism via the boron enolate, because this trend was also observed in the classical boron enolate-mediated reactions in dry organic solvents. Although we have not yet observed the boron enolates directly under the reaction conditions, this mechanism can explain all of the experimental data obtained and is considered as the most reasonable one. As far as we know, this is the first example of... 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

Development of diastereoselective and enantioselective aldol reactions has had a profound impact on the synthesis of two important classes of natural products—the macrolide antibiotics and the poly ether ionophores. The aldehyde and the enolate involved in aldol reactions can be chiral, but we shall discuss only the case of chiral enolates. 

Matsumoto et al. have reported the first example of a diastereoselective nitro-aldol reaction of optically active A,(V-dibenzyl a-amino aldehydes 150 with nitroalkanes 151 under high pressure without a catalyst (Scheme 7.38). The reactions occurred at 0.8 GPa (room temperature, 12h) and gave mixtures of diastereomers 152 and 153 in good yields and with high optical purity under atmospheric pressure 150 did not react with 151. Very high diastereoselectivity (152/153 = 99) was observed in the reaction of 150a with 2-nitropropane (151c). 

Dicarbonyl compounds may be converted into dianions, which react with electrophiles at the more basic site. Huckin and Weiler found that 3-keto ester dianions undergo aldol addition reactions at the more basic methyl position (equation 32). The lithium/sodium dianion shows surprisingly weak reactivity, giving the aldol in only 11% yield after 1 h at -78 °C In contrast, the lithium enolates of simple ketones and esters, which should be much less basic than the 3-keto ester dianion, react with aldehydes to give nearly quantitative yields of aldols in THF in seconds at -78 °C. ° Seebach and Meyer also studied this reaction, and obtained the oxolactone (equation 33). Simple diastereoselection in the reaction of 3-keto ester dianions has also been studied (vide infra). 

A highly diastereoselective acetate aldol reaction that uses an L-tert-leucine-derived N-acetyl thiazolidinethione auxiliary 125 and dichlorophenylborane has been reported <04OL23>. Thiazolidinethione reagent 127, pseudoenantiomeric to 125, is also found to be effective in diastereoselective asymmetric aldol reactions, thus obviating the expensive D-tert-leucine <04OL3139>. Asymmetric aldol additions of A-propionyl thiazolidinethione... 

As the previous chapters have demonstrated, chiral auxiliaries have found a widespread application in the asymmetric synthesis of lignans. Among them, chiral oxazolidinones have been used extensively due to their ability to produce excellent diastereoselectivities in aldol as well as in numerous other reactions. For example, Kise et al. reported the use of (5)-4-isopropyl-3-(phenylacetyl)-2-oxazolidinone (141) in oxidative homocoupling reactions and its application in the asymmetric synthesis of dibenzylbutyrolactones and dibenzylbutandiols, Scheme (26) [86,87]. Treatment of 3-arylpropanoic acid derivative 142 with LDA in the presence of TiCU yielded a mixture of the dimeric compounds 143 in a ratio of 85 15 to 87 13. The major product having (R,R) configuration was converted into dibenzylbutyrolactones 145 in a three step sequence... 

A.L Alkylation. If the aldol condensation reaction that produces 330 could be controlled, one diast-ereomer might be formed in preference to the other, making the reaction diastereoselective. There are two essential factors that control diastereoselectivity in this reaction the face from which the two reagents approach and the relative orientation of the two molecules. 

A.ii. Diastereoselection in the Aldol Condensation. In addition to the alkylation reaction, enolates react with other carbonyl compounds to give aldol or Claisen products, as discussed in previous sections. An aldol condensation with the enolate of 1-phenyl-1-propanone and benzaldehyde generates two new stereocenters and gives two racemic diastereomers (four stereoisomers). These two diastereomers are the racemic anti diastereomer (340 and 343) and the racemic syn diastereomer (341 and 342). Diastereoselectivity in this reaction is dependent on the reaction conditions and the enolate and aldehyde partners, and this section will explore the origins of that diastereoselection. 

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