Ketones anti-aldols

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

From these and many related examples the following generalizations can be made about kinetic stereoselection in aldol additions of lithium enolates. (1) The chair TS model provides a basis for analyzing the stereoselectivity observed in aldol reactions of ketone enolates having one bulky substituent. The preference is Z-enolate syn aldol /(-enolate anti aldol. (2) When the enolate has no bulky substituent, stereoselectivity is low. (3) Z-Enolates are more stereoselective than /(-enolates. Table 2.1 gives some illustrative data. 

By the use of chiral oxazolidines derived from a chiral norephedrine and methyl ketones, an asymmetric aldol reaction proceeds in a highly enantioselective manner. In the case of ethyl or a-methoxy ketones, the corresponding anti aldol products were obtained with high diastereo- and enantioselectivities. A chiral titanium reagent, generated from... 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The CD-spiroacetal subunit of the spongistatins proved to be of an appropriate level of complexity that several different synthetic strategies were evaluated. Access to the desired spiroacetal 5 was readily achieved by acid catalysed equilibration of the mixture of spiroacetals in aprotic solvents, followed by separation and recycling of the undesired isomer. Furthermore, the 1,5-anti aldol reaction of methyl ketones proved invaluable for construction of certain portions of the target molecule. 

As outlined in Scheme 22, the synthesis of the C1-C6 subunit 95 commenced with the anti aldol reaction of the ethyl ketone 100, prepared in three steps from Roche ester 18, and acetaldehyde, with in situ reduction to give diol 103 (>30 ldr) [130, 132-136, 145, 146], Completion of 103 then required a series of protecting group manipulations... 

The 1,3-anti-selective reduction was utilized in the total synthesis of the structurally unique compound (+)-clavosolide A (23)6 (Scheme 4.2g). The 1,5-anti -aldol reaction of a dibutylboron enolate of 24 with the aldehyde 25 proceeded smoothly to afford the (3-hydroxy ketone 26 in 93% yield and >96 4 diastereoselectivity. Compound 26 was subsequently treated with... 

Let s start by showing some examples and demonstrating how we know this to be the case. Some enolates can only exist as trara-enolates because they are derived from cyclic ketones. This enolate, for example, reacts with aldehydes to give only the anti aldol product. 

We have talked mainly about aldol reactions of ketones (as the enolate component). Esters usually form the trans lithium enolates quite stereoselectively. You might therefore imagine that their aldol reactions would be stereoselective for the anti product. Unfortunately, this is not the case, and even pure frans-enolate gives about a 1 1 mixture of syn and anti aldols. 

TABLE 17. Reaction of the TiCR enolate of an a-Mef ketone (193) with an aldehyde RCHO, to yield an anti-aldol (194)... 

When an aldehyde is reacted with a ketone-derived enolate under equilibrating conditions, the thermodynamically more stable 2,3-anti product predominates regardless of the geometry of the enolate. If, however, the reaction is kinetically controlled, the (Z)- and ( )-enolates furnish 2,3-syn and anti aldol products, respectively. This behavior has been interpreted in terms of a chair-type transition state known as the Zimmerman-Traxler model. ... 

Since the reactions of lithium (El-iOl-enolates are not stereoselective (see Table 6.3b), formation of 2,3-anti aldol products is conveniently accomplished by ketone enolization using dicyclohexylboron chloride. Reaction of the resultant boron... 

Gennari, C., Hewkin, C. T., Molinari, F., Bemardi, A., Comotti, A., Goodman, J. M., Paterson, I. The rational design of highly stereoselective boron enolates using transition-state computer modeling a novel, asymmetric anti aldol reaction for ketones. J. Org. Chem. 1992, 57, 5173-5177. 

Ethyl ketones (/ )- and (5)-18 (Scheme 9-8), as introduced by our group, have been u.sed extensively as versatile dipropionate reagents in polyketide synthesis [11]. Selective formation of the (ZO-enol borinate 19 is possible using c-Hex2BCl and the resulting anti aldol products, e.g, 20, are formed with ca. 97% ds [6a]. Several different hydroxyl protecting groups can be accommodated, but benzyl or... 

The use of a,y -chiral ketones has been studied (Scheme 9-11). In general, the a-stereocenter of the ketone controls the sense of addition and this can be seen in the boron-mediated anti aldol reaction of ketone 30 where the configuration of the C5 stereocenter makes little difference to the selectivity of the reaction [15]. 

Several alternative auxiliaries for obtaining anti aldol products are available [26]. For example, the lactate-derived ketone (R)-39, as developed in our laboratories, displays high levels of stereocontrol in boron-mediated anti aldol reactions (Scheme 9-14) [27]. Simple manipulations of the aldol product 40 allows the gen-... 

As previously mentioned, certain methyl ketone aldol reactions enable the stereocontrolled introduction of hydroxyl groups in a, 5-anti relationship (Scheme 9-7) [9], and this was now utilized twice in the synthesis. Hence, methyl ketones 48 and 98 were converted to their respective Ipc boron enolates and reacted with aldehydes 97 and 99 to give almost exclusively the, 5-anti aldol adducts 100 and 101, respectively (Scheme 9-34). In the case of methyl ketone 48, the j -silyl ether leads to reduced stereoinduction however, this could be boosted to >97%ds with the use of chiral ligands. In both examples, the y9-stereocenter of the aldehyde had a moderate reinforcing effect (1,3-syn), thus leading to triply matched aldol reactions. Adducts 100 and 101 were then elaborated to the spiro-acetal containing aldehyde 102 and ketone 103, respectively. 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

In our synthesis, iterative aldol reactions of dipropionate reagent (R)-18 allowed for the control of the C3-C10 stereocenters (Scheme 9-72) [89]. Hence, a tin-mediated, syn aldol reaction followed by an anti reduction of the aldol product afforded 270. Diol protection, benzyl ether deprotection and subsequent oxidation gave aldehyde 271 which reacted with the ( )-boron enolate of ketone (/ )-18 to afford anti aldol adduct 272. While the ketone provides the major bias for this reaction, it is an example of a matched reaction based on Felkin induction from the... 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

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