Aldehyde enolates, problem with

The problem is how to protect the ketone rather than the aldehyde and the answer is like that for 20 protect it when the aldehyde isn t there. Reconnection to the alkene 25 achieves this and the ketone 26 can be made by reaction of some enolate 27 with allyl bromide. 

With the Corey lactone four of the stereocenters (8,9,11,12) are defined in the lactone synthon, although there could be a slight concern with the integrity of the stereocenter at position 12 because as an aldehyde intermediate there is some chance of epimerization at that center via its enol. The main problem with this approach is the control of the stereocenter at position 15, which has to be introduced late into the process. Inevitably, there is some diastereoisomer formed, which can be... 

The enol content of simple ketones is much lower than that of /1-ketoesters or /3-diketones. For a number of electrophiles it is often too low. Hence, functionalizations with the respective electrophile via the enol form do not succeed in these cases. This problem can be managed, though, by converting the ketone (Formula A in Figure 12.16) into an enamine D with the aid of a condensation with a secondary amine that is in line with Figure 9.29 and the mechanism given there. Enamines are common synthetic equivalents for ketonic and aldehyde enols. 

Reminder of the problems with lithium enolates of aldehydes. 

Aldehydes are so electrophilic that, even with LDA at -78°C, the rate at which the deprotonation takes place is not fast enough to outpace reactions between the forming lithium enolate and still-to-be-deprotonated aldehyde remaining in the mixture. Direct addition of the base to the carbonyl group of electrophilic aldehydes can also pose a problem, reactions which compete with aldehyde enolate formation... 

An interesting observation from organocuprate chemistry is that the initial step in 1,4-addition to enones may be electron transfer. Thus the relative reactivity of enones toward conjugate addition parallels their ease of reduction. One problem with any reaction between a ketone or aldehyde and a metal alkyl is deprotonation, when a hydrogens are present, to yield an enolate. Given the considerable basicity of metal alkyls, this side reaction should be anticipated. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

Unsaturated aldehydes and enones with heavy P-substitution in particular often give poor results either by competing 1,2-addition or by aldol condensation of the enolate products. Thus the enone18 42 and most aldehydes give predominantly 1,2-adducts 44 even with Me2CuLi. These problems can be avoided if the reaction is carried out in the presence of Me3SiCl. 

There is an inherent problem with either type of enzyme as the reactions are reversible. One way to make the reaction run in the direction of ester formation is to use a non-aqueous solvent (you may be surprised that enzymes function in, say, heptane, in which they are insoluble, but lipases do). One way to make the reaction run in the other direction is to make the alcohol component an enol so that, on hydrolysis, it gives the aldehyde or ketone and does not reverse. 

We have examined a purely logical way in which the "Cram s rule problem" can be attacked — double stereodifferentiation. For example, either reactant in an aldol condensation can be chiral and exhibit diastereoface selectivity. Suppose we have an aldehyde which reacts with achiral enolates to give the two possible erythro adducts in a 10 1 ratio ... 

Fig. 6.40. Eschenmoser s interpretation of glycolaldehyde phosphate aldomerisation reactions [37] It is generally appreciated... that the BUrgi-Dunitz trajectory... for nucleophilic addition to C = 0 groups must be taken into account as steric interactions between reaction center substituents are evaluated. The drawings in (this figure) remind the reader why. While it can be difficult to weigh the contributions of the four relevant interactions for an aldehyde/ketone-enolate pair, the problem for the case of an aldehyde/aldehyde-enolate pair turns out to have a unique solution the one indicated in (this figure), where none of the interacting substituents is juxtaposed with a non-H-atom partner ...

In Section 9.4.A, it was noted that there were problems with aldol-type reactions, especially with the directed aldol condensation. In particular, aldehydes with an a-hydrogen have great difficulty adding to ketones due to their propensity for self-condensation. The ability to use kinetic control conditions in enolate reactions of ketones and aldehydes often solves this problem. There are also several alternative approaches that involve the use of carbanions derived from imines and hydrazones and these can be very useful. l... 

As just discussed, the condensation of an enolate derived from one aldehyde or ketone with a different aldehyde or ketone is a desirable reaction. In the reaction of acetone and benzaldehyde to give 26, the reaction gave 26 because benzaldehyde has no a-proton. Therefore, the only enolate possible is the one from acetone (see 27). Self-condensation of acetone may be a problem, but it is not possible from benzaldehyde because there is no enolate anion. The reaction of acetone and 3-pentanone is not this simple because an enolate anion may be formed from both ketones. Before this reaction is discussed (in Section 22.4.3), it is useful to describe a method that allows selective formation of the enolate anion of acetone or the enolate anion of 3-pentanone. 

Branched hydroformylation inttoduces a new stereogenic centre and, therefore, there is the opportunity to control the new centre by the use of chiral ligands. An early application of this concept is in an industrial synthesis of the anti-inflammatory drug, naproxen 4.193 from the corresponding styrene (Scheme 4.69). The ligand for the hydroformylation reaction, chiraphite 4.194, consisted of two bulky phosphates linked by a chiral tether. Many other chiral ligands have been developed. A problem with generating aldehydes with an a-chiral centre is their facile racemization via their enol or enolate form. One solution to this problem is to protect the product as its acetal 4.195 in situ (Scheme 4.70). ... 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles like chloromethyl methyl ether and trimethylorthoformate proceed smoothly in the presence of 2 mol% of 1 (eq 1) (3, 5). These reactions can be carried out in aqueous media, so that the reaction of silyl enol ethers with an aqueous solution of formaldehyde does not present any problems. Triphenylboron catalyzes no aldol-type reactions. 

If a chiral aldehyde reacts with an achiral enolate the induced stereoselectivity is determined by the inherent preference of the aldehyde to be attacked from its Re or Si face. If, however, a chiral aldehyde is combined with a chiral enolate one must consider whether the inherent selectivities of the two reagents will be consonant in one of the combinations ( matched pair ), but dissonant in the other combination ( mismatched pair ). Thus, different diastereoselectivity results from each combinations. The problem of insufficient stereoselectivity in the mismatched combination can be solved by means of highly efficient chiral enolates which can outplay the inherent selectivity of the aldehyde. The concept has been applied extensively in the context of boron enolates, a topic that has been reviewed comprehensively [52] and is discussed in detail in Chapter 3 of Part I of this book. 

Aldehyde enolates present another problem. They tend to give selfcondensation before an electrophile can be added. This may be solved again by use of imine enolates or A,A-dimethylhydrazones, which are themselves of low electrophihcity and allow good crossed aldol condensations and alkylations. For example, the terf-butyl imine of propanal was converted to the enolate with LDA and used in a crossed aldol condensation (Eq. 7.16) [30]. 

Now we look at enones from the opposite point of view—how do we disconnect them If we look at the bond that has been made in each of the previous examples (highlighted in red), it is clear that we must dissect the enone or enal through the double bond to give two carbonyl compounds or a dicarbonyl compound. Consider 20.11 (Figure 20.20). We disconnect the double bond so that there is a carbonyl group at one side of it and an enolizable site at the other. If we consider the forward reaction in this case, there should be no problem with it, because only the ketone is able to enolize, but the aldehyde is the more electrophilic component. Most bases will be appropriate here in practice, sodium hydroxide in aqueous ethanol was used. 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

---