Stereochemistry of aldol reaction

TABLE 5. Stereochemistry of aldol reaction of magnesium enolates derived from thioamides with aldehydes... 

Aldol reactions of simple amide enolates give poor stereoselection. Stimulated by the interest in /3-lactams, the stereochemistry of aldol reactions of chiral magnesium enolates of /3-lactams has been studied . The best results have been obtained with 6,6-dibromopenams 85 (equation 108). After bromine-magnesium exchange with MeMgBr,... 

Methodology and stereochemistry of aldol reactions with participation of heterocycles 00MI7. 

There have been more than 20 aldolases isolated, eight of which have been explored for organic synthesis (6). Aldolases possess two interesting common features the enzymes are specific for the donor substrate but flexible for the acceptor component, and the stereochemistry of aldol reaction is controlled by the enzyme not by the substrates. In our previous study, we have described the use of lipases, hexokinases, glycosyl transferases and rabbit muscle aldolase for the synthesis of certain fluorosugars (7). This review describes our recent development in aldolase-catalyzed reactions for the synthesis of fluorosugars. 

Table 5 Stereochemistry of Aldol Reactions of Cyclopentanone with Aliphatic Aldehydes (equation 93)...

Control of Regiochemistry and Stereochemistry of Aldol Reactions of Ketones... 

Long-range Structural Effects on the Stereochemistry of Aldol Reactions... 

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. 

The stereogenic centers may be integral parts of the reactants, but chiral auxiliaries can also be used to impart facial diastereoselectivity and permit eventual isolation of enantiomerically enriched product. Alternatively, use of chiral Lewis acids as catalysts can also achieve facial selectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been well developed for simple molecules, the application of the principles to more complex molecules and the... 

Scheme 2.6. Control of Stereochemistry of Aldol and Mukaiyama Aldol Reactions Using...

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... 

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

In addition to the structural effects due to the geometry of a substituted magnesium enolate, the stereochemistry of the reaction with a chiral aldehyde can be controlled, as described in equation 85. The aldol reaction based on the addition of magnesium enolate 56 to aldehyde 55 has been applied to the synthesis of monensin. The chiral center in the aldehyde induces the preferential approach of one diastereotopic face of the aldehyde by... 

Further examination of the fluoride ion-catalyzed asymmetric aldol reaction of the enol silyl ethers prepared from acetophenones and pinacolone with benzaldehyde using 4b and its pseudoenantiomer 4c revealed the dependence of the stereochemistry of the reactions on the hydroxymethyl-quinudidine fragment of the catalyst (Table 9.3) [10,15]. 

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

The mechanism of the reaction is well-known. The first step is formation of a carbanion, followed by nucleophile addition to the carbonyl carbon atom halo-hydrin alcoholates are produced finally, ring-closure takes place by intramolecular substitution. The stereochemistry of the reaction is much disputed the reason why a unified viewpoint has not emerged is that the configuration of the end-product is influenced by the structure of the starting compound (including steric hindrance), the base employed, and solvation by the solvent, sometimes in an unclear manner. The stereochemical course of the reaction is controlled by the kinetic and thermodynamic factors in the second step the structure of the oxirane formed is decided by the reversibility of the aldolization and the reaction rate of the ring-closure. 

The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiomer of 50 that was used in the previous aldol reaction. The stereochemistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome of the reaction ... 

Kinetic enolates are obtained by slow addition of the ketone (1.00 eq) to an excess of a hindered strong base (1.05 eq) at low temperature in an aprotic solvent (nonequilibrating conditions). It should be noted that deprotonation of acyclic ketones may furnish ( )/(2)-mixtures of enolates. Since the stereochemistry of enolates plays a pivotal role in controlling the product stereochemistry in aldol reactions, methodologies used for selectively preparing either one of the isomers are discussed in the following subsections. 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

We shall discuss further aspects of the aldol reaction in the next two chapters where we shall see how to control the enolisation of unsymmetrical ketones, and how to control the stereochemistry of aldol products such as 121. We shall return to a more comprehensive survey of specific enol equivalents in chapter 10. In this chapter we are concerned to establish that chemoselective enolisation of esters, acids, aldehydes, and symmetrical ketones can be accomplished with lithium enolates, enamines, or silyl enol ethers, and we shall be using all these intermediates extensively in the rest of the book. 

Introduction and stereochemical control syn,anti and E,Z Relationship between enolate geometry and aldol stereochemistry The Zimmerman-Traxler transition state Anti-selective aldols of lithium enolates of hindered aryl esters Syn-selective aldols of boron enolates of PhS-esters Stereochemistry of aldols from enols and enolates of ketones Silyl enol ethers and the open transition state Syn selective aldols with zirconium enolates The synthesis of enones E,Z selectivity in enone formation from aldols Recent developments in stereoselective aldol reactions Stereoselectivity outside the Aldol Relationship A Synthesis ofJuvabione A Note on Stereochemical Nomenclature... 

Phillips RS, Dua RK (1991) Stereochemistry and mechanism of Aldol reactions catalyzed by kynureni-nase. J Am Chem Soc 113 7385-7388... 

The powerful control of stereochemistry in aldol reactions that is available through boron enolates has been amply demonstrated [122, 160, 169, 253],... 

Assuming ready availability of the a-halo ester component, the Reformatsky reaction is often a convenient and economical alternative to base-promoted aldol procedures. Since its discovery in 1887, over SOO research articles and six reviews of the reaction have been published. Heathcock has recently reviewed the stereochemistry of the reaction of a variety of zinc enolates with aldehydes and ketones. ... 

The aldol condensation, one of the oldest organic reactions, is emerging as a powerful method for control of relative and absolute stereochemistry in the synthesis of conformationally flexible compounds. Some of the research which has been carried out at Berkeley over the past five years is reviewed in this article. Points discussed are the factors that control simple erythro, threo diastereoselection, the use of double stereodifferentiation to influence the "Cram s rule" preference shown by chiral aldehydes, and some recent experiments that shed light on the role that the solvent and other nucleophilic ligands play in determining the stereochemistry of the reaction. 

You saw in Chapter 33 that it is possible to use aldol reactions to create two new chiral centres in a single step, and that the relative stereochemistry of the two chiral centres depends in many cases on the geometry of the enolate used to do the aldol reaction. The power of an asymmetric aldol reaction is easy to see it creates two new chiral centres with control over their absolute stereochemistry, and also constructs a new C—C bond. What is more, the products of aldol reactions are very common features in a huge number of natural products known as polyketides—as you will see in the next chapter, polyketides are made by living things using a series of successive enzyme-controlled aldol reactions. 

As for the characteristic controlling of stereochemistry during aldol reaction, the Evans aldol reaction has been extensively modified through the application of Lewis acids, chiral auxiliaries (e.g., oxazolidone, oxadiazinones, thiazolidinethione " ), chelating metals, etc. 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

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