Aldol reaction starting compounds

The intramolecular aldol reactions reported so far can be divided into two different types. The first is a enantioselective aldol reaction starting from a dicarbonyl compounds of type 81. In these reactions, products with two stereogenic centers, 82, are formed. The reaction is shown in Scheme 6.39, Eq. (1). These products can be converted into derivatives, particularly lactones. 

It should be added that improved formation of products of type 126 was achieved by choosing a different reaction strategy [133], A typical proline-catalyzed aldol reaction (starting from aldehydes as donors and compounds 125 as acceptors), followed by conversion of the C=0 functionality of the aldol adduct into a nitrone group by condensation with a hydroxylamine component led to products of type 126 in good yield and with high enantioselectivity (up to 96% ee) [133],... 

For some condensations with silylated substrates as starting compounds, trimethylsilyl inflate can be used as a catalyst [103, 104, 105] Atypical example of such a reaction is the aldol type condensation of silyl enol ethers and acetals catalyzed by 1-5 mol% of trimethylsilyl inflate [103] (equation 53)... 

Especially with the ordinary aldol reaction a number of side reactions can be observed, as a result of the high reactivity of starting materials and products. For instance, the a ,/3-unsaturated carbonyl compounds 4 can undergo further aldol reactions by reacting as vinylogous components. In addition compounds 4 are potential substrates for the Michael reaction. 

Certain starting materials may give rise to the non-selective formation of regioisomeric enolates, leading to a mixture of isomeric products. Furthermore a ,/3-unsaturated carbonyl compounds tend to polymerize. The classical Michael procedure (i.e. polar solvent, catalytic amount of base) thus has some disadvantages, some of which can be avoided by use of preformed enolates. The CH-acidic carbonyl compound is converted to the corresponding enolate by treatment with an equimolar amount of a strong base, and in a second step the a ,/3-unsaturated carbonyl compound is added—often at low temperature. A similar procedure is applied for variants of the aldol reaction. 

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... 

Mow might you synthesize each of the following compounds using an aldol reaction Show the structure of the starting aldehyde(s) or ketone(s) you would use in each case. 

Another attractive domino approach starts with an aldol reaction of preformed enol ethers and carbonyl compounds as the first step. Rychnovsky and coworkers have found that unsaturated enol ethers such as 2-237 react with different aldehydes 2-238 in the presence of TiBr4. The process consists of an aldol and a Prins-type reaction to give 4-bromotetrahydropyrans 2-239 in good yields, and allows the formation of two new C-C-bonds, one ring and three new stereogenic centers (Scheme 2.56) [131]. In the reaction, only two diastereomers out of eight possible isomers were formed whereby the intermediate carbocation is quenched with a bromide. 

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. 

Synthesis of the common intermediate C (4), and its further conversion to 2 and 3 is illustrated in Scheme 7-3. Two racemic compounds, ( )-7 and ( + )-10, are prepared from readily available starting materials 5 and 8, respectively (Scheme 7-2). Coupling of 7 and 10 gives a mixture of diastereomers 11. An intramolecular aldol reaction of 11 catalyzed by D-proline yields diastereomers 12 and 13 in equal molar ratios (about 36% ee for each diastereomer). Compound 12, the desired ketone, is converted to 14, which is further purified by crystallization to give the compound in the desired stereochemistry in sterically pure form. Reduction of the ketone carbonyl group and subsequent methoxy... 

The aldol reaction as formulated above involves two molecules of the starting substrate. However, by a consideration of the mechanism, one can see that different carbonyl compounds might be used as nucleophile or electrophile. This would be termed a mixed aldol reaction or crossed aldol reaction. However, if one merely reacted, say, two aldehydes together under basic conditions, one would get a... 

Other groups beside nitro can be reduced in the same step. So the diamine 19, needed for polyamine manufacture, could come from the unsaturated nitro compound 20 that would in turn come from an aldol reaction between the anion of nitromethane 1 and the aldehyde 21. This has a 1,5-diX relationship and acrylonitrile 23 is excellent at conjugate addition (chapter 21) so we can use isobutyraldehyde 24 as a starting material. 

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9]. The desired anti-diols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a dia-stereomeric ratio up to dr > 20 1 and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20 1. 

An aldol reaction is a reaction between two carbonyl compounds in which one carbonyl compound plays the role of a nucleophile while the other carbonyl compound acts as an electrophile. The term aldol reaction covers two types of reactions, aldol additions (see Section 13.3) and aldol condensations. The aldol reactions that lead to /i-hydroxycarbonyl compounds belong to the class of aldol additions. Aldol condensations start from the same substrates but result in a,/l-unsaturated carbonyl compounds (Figure 13.49). 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

The second approach is easier practically (just mix the starting material, base, and electrophile), but works only if the base and the electrophile are compatible and don t react together. With the first approach, which is practically more demanding, the electrophile and base never meet each other, so their compatibility is not a concern. We shall start with some compounds that avoid the problem of competing aldol reactions completely, because they are not electrophilic enough to react with their own nucleophilic derivatives. 

This key intermediate has given its name to Nature s general route to aromatic compounds and many other related six-membeied ring compounds the shikimic acid pathway. This pathway contains some of the most interesting reactions (from a chemist s point of view) in biology. It starts with an aldol reaction between phosphoenol pyruvate as the nucleophilic enol component and the C4 sugar erythrose 4-phosphate as the electrophilic aldehyde. 

What starting material would be required for formation of the natural product ds-jasmone by an intramolecular aldol reaction (Chapter 27). How would you make this compound using a Stetter reaction ... 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

Microbes and plants synthesize aromatic compounds to meet their needs of aromatic amino acids (L-Phe, L-Tyr and L-Trp) and vitamins. The biosynthesis of these aromatics [69] starts with the aldol reaction of D-erythrose-4-phosphate (E4P) and phosphoenolpyruvate (PEP), which are both derived from glucose via the central metabolism, into DAHP (see Fig. 8.13). DAHP is subsequently converted, via a number of enzymatic steps, into shikimate (SA) and eventually into chorismate (CHA, see later), which is the common intermediate in the biosynthesis of the aromatic amino acids [70] and vitamins. 

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

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