Chelating compounds aldol reaction

As a result of a chelation-controlled aldol reaction exclusive formation of compound 43 tvith the desired 6(R),7(S),8(R)-triad tvas observed. The structure has been confirmed by X-ray analysis after transformation to a crystalline six-membered lactone. In their macro-lactonizsation strategy to synthesize epothiione B Nicolaou et al. used the same ketone 41 in an aldol reaction vith aldehyde 19. The diastereoselectivity in the aldol addition vas only moderate, giving a ratio of 3 1 in favor of the natural epothiione configuration [33]. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

The use of chiral chelating agents in reactions of organometallic reagents with carbonyl compounds has been intensively investigated (134-138). However, the influence of such chiral addends in the aldol process has not met with much success. In the presence of the... 

As a Stereochemical Prohe in Nucleophilic Additions. Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-l,3-dioxolane-4-carhoxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions. Nevertheless, several studies have employed the (45)-aldeh-yde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording anti products. This preference for addition is predicted by Felkin-Ahn transition-state analysis, and stands in contrast to that predicted by the Cram chelate model. Thus addition of the lithium (Z)-enolate shown (eq 1) to the reagent affords an 81 19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition, while the 2,3-syn relationship in each of the diastere-omers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction. ... 

Under kinetic control the aldol reaction is very stereospecifie (Fig. 8.5). The lithium enolate is generated in an aprotic solvent, and then the carbonyl compound is added. The reaction proceeds via the metal-chelated minor path 6e. The minimization of steric effects in the chair transition state and the stereochemistry of the enolate (Section 9.3) determine the stereochemistry of the product. 

Much tvork in the field of aldol reactions of ketones tvas performed by Evans to enable the synthesis of polypropionate natural products. They demonstrated that j5-ketoimides like 159 vere selectively and completely enolized at the C4 position rather than the potentially labile methyl-bearing C2 position, most probably because steric factors prohibited alignment of the carbonyl groups necessary to activate the C2 proton. As sho vn in Table 2.29, it vas demonstrated that these compounds vould react vith aldehydes to provide syn-syn product 161, via titanium enolates, vith good yield and excellent selectivity, and the corresponding syn-anti product 162 could be favored by use of a tin enolate reaction [58]. They invoked the chelated transition state assembly 160 to explain the product stereochemistry observed, in vhich the C2-methyl group directs diastereofacial selectivity. Interestingly, reduction vith Zn(BH4)2 provided the syn diol diastereoselec-tively. 

Silks and co vorkers reported anti-selective aldol reactions in conjunction vith their investigations on chiral selenium compounds [39]. They discovered that bidentate oxyaldehydes precomplexed vith TiCl4 led to anti aldol products in good yield and vith excellent stereoselectivity, as sho vn in Table 2.35, entries 1 and 2. Presumably, this chelation-controlled reversal of syn/anti selectivity is a phenomenon similar to that vhich Ghosh and co vorkers exploited to produce syn aldols from aminoindanol chiral auxiliaries. Both benzyl and isopropyl oxazolidineselone chiral auxiliaries have comparable anti diastereoselectivity. 

An aldol reaction of preformed enolates requires three individual steps the irreversible generation of the metal enolate 143 (mostly by deprotonation but also by alternative methods outlined in Chapter 2), the addition of the aldehyde that leads to a metal aldolate 144, and, finally, the hydrolysis that yields the fi-hydroxy carbonyl compound (Scheme 4.28). Usually, the first two steps are performed in a one-pot reaction and the third one in the course of a quenching operation at the beginning of the work-up procedure. In the aldolate 144, the metal is generally chelated, a feature that contributes to its thermodynamic stability and... 

Silyl enol ethers undergo reaction with carbonyl compounds promoted by Lewis acids, but especially titanium tetrachloride. The reaction is thought to proceed via a titanium chelate which inhibits the reverse aldol process and the regiochemical integrity of the starting silyl enol ether is retained (Scheme 102).373... 

It should be noted here that Corriu and co-workers have reported on organosilicon compounds containing C,N-chelating ligands in which the silicon atom is penta- or hexacoordinate (55-58). Such organosilicon compounds are models for the intermediates proposed for the activation of enoxysilanes by F leading to cross-aldolizations or Michael reactions (59). 

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