Aldolate product

In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult... 

A consequence of this mechanism is that the reaction is stereospecific with respect to the E- or Z-configuration of the enolate. The E-enolate will give the anti aldol product whereas the Z-enolate will give the syn aldol. 

When chloral was usedasthealdehyde2equivalents reacted with 1 equivalent of the enamine (98) regardless of the ratio of reactants or order of addition to give 2,6-bis(trichloromethyl)-5,5-dimethyl-4-morpholino-/ i-dioxane (183) in 83 % yield (126). Hydrolysis of 183 with hydrochloric acid at room temperature gave the hemiaeetal (184), but when heated with acid, the aldol product (185) was formed. 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

They report that in the reaction between 5-chlorisatin 19 and 5,6-dimethoxindanone 20 under basic conditions at reflux for 16 hours, the desired quinolinic acid 22 is obtained in 38% yield with an unavoidable competing amount of the aldol product 21. However, if the same reaction is carried out using aqueous acid conditions, the quinolinic acid is obtained in a reproducible 86% yield. ... 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

From a mixture of two different aldehydes, each with a-hydrogens, four different aldols can be formed—two aldols from reaction of molecules of the same aldehyde -I- two crossed aldol products not even considering possible stereoisomers (see below). By taking into account the unsaturated carbonyl compounds which could be formed by dehydration from the aldols, eight different reaction products might be obtained, thus indicating that the aldol reaction may have preparative limitations. 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

The diastereoselectivity is observed in the Henry reaction using optical active niti o compounds or a-heteroatom substituted aldehydes. Lor example, the reaction of O-benzyl-D-lactal-dehyde with methyl 3-niti opropionate in the presence of neubal alumina leads to a mixture of three niti o-aldol products from which D-ribo isomer is isolated by direct crystallization. D-Ribo... 

The exact position of the aldol equilibrium depends both on reaction conditions and on substrate structure. The equilibrium generally favors condensation product in the case of aldehydes with no a substituent (RCH2CHO) but favors reactant for disubstituted aldehydes (R2CHCHO) and for most ketones. Steric Factors are probably responsible for these trends, since increased substitution near the reaction site increases steric congestion in the aldol product. 

What is the structure of the aldol product from propanal ... 

Protonation of the alkoxide ion intermediate yields neutral aldol product and regenerates the base catalyst. 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

We can extend this kind of reasoning even further by imagining that subsequent transformations might be carried out on the aldol products. For example, a saturated ketone might be prepared by catalytic hydrogenation of the enone product. A good example can be found in the industrial preparation of 2-ethyl-... 

In general, a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products. For example, base treatment of a mixture of acetaldehyde and propanal gives a complex product mixture containing two "symmetrical" aldol products and two "mixed" aldol products. Clearly, such a reaction is of no practical value. 

The ketone 2-methyfcycloliexanone, for instance, gives the mixed aldol product on reaction with benzaldehyde. 

How can you account for the fact thaf 2,2,6-trimelhylcyclohexanonc yields no detectable aldol product even though it has an acidic a- hydrogen ... 

Overall yield using yields of chromatographed, isomericaliy pure aldol products. b Elimination requires forcing conditions ( )-isomer probably formed by isomerization of the kineticaily formed (Z)-isomer. The anti.anti- and anti.svn-aldol products were not separable. 

If, on the other hand, the aldol addition is performed using either enolates with stereogenic units, which may be located in the a-substituent Y or in the ipso-substituent X, or using chiral aldehydes, the aldol products 4a, 5a and 6a arc diastcreomers with respect to 4b, 5b and 6b. Thus, both significant simple diastereoselectivity and induced stereoselectivity are highly desirable when ... 

R Yield of Aldol Product (%) ee (%) anti Ratio (antijsyn) Config. of 1.3-Diols... 

On the other hand, syn-carboxylic acids are obtained from a deprotonation of the /5-silyl ester, giving the (E)-enolate, followed by reaction with different aldehydes and subsequent hydrogenolysis. No diastereomers of the aldol product are detected720. 

---