Zirconium enolates diastereoselectivity

A comparison of the anti.syn diastereoselectivity of the lithium, dibutylboron, and (Cp)2Zr enolates of 3-methyl-2-hexanone with benzaldehyde has been reported.34d The order of stereoselectivity is Bu2B > (Cp)2Zr > Li. These results suggest that the reactions of the zirconium enolates proceed through a cyclic TS. 

Earlier studies had demonstrated that such enolates would participate in aldol condensations with aldehydes however, the stereochemical aspects of the reaction were not investigated (68). For the cases summarized in Table 25, the zirconium enolates were prepared from the corresponding lithium enolates (eq. [54]). Control experiments indicated that no alteration in enolate geometry accompanies this ligand exchange process, and that the product ratio is kinetically controlled (35). From the cases illustrated, both ( )-enolates (entries A-E) and (Z)-enolates (entries F-H) exhibit predominant kinetic erythro diastereoselection. Although a detailed explanation of these observations is clearly speculative, certain aspects of a probable... 

Nucleophiles such as enolates or substituted allylmetal compounds are known to react with prochiral aldehydes and ketones to form mixtures of threo or erythro adducts. In case of aldehydes, high degrees of diastereoselection have been achieved 48 91,108). In the following three Sections, reactions of titanium and zirconium enolates as well as allyl derivatives are presented. 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

Anti diastereoselectivity gives the optically active (S)-p-hydroxy ester while syn diastereoselectivity leads to the (/ )-P-hydroxy ester, via a chelated six-membered transition state (eq 3). Since the anti intermediate is more stable, the (S)-P-hydroxy ester predominates under thermodynamic conditions (Table 1, entry 1). Higher diastereoselectivity is achieved by changing the counterion from lithium to a more chelating one such as zinc (Table 1, entry 2). On the other hand, in order to obtain diastereoselection under kinetic control, zirconium enolates (prepared by treating the lithium enolate with Dichlorobis(cyclopentadienyl)zirconium) are used, leading to the (/ )-p-hydroxy ester (Table 1, entry 3) in high yield. 

Zirconium enolates can also be derived from amides. It is of particular interest that diastereoselective functionalization of /3-lactams has been performed in high yields (Eq. 2) [2d],... 

With regard to asymmetric synthesis, the possibility that a stereogenic center outside the sigmatropic framework can direct the stereochemical outcome of the electrocyclic process has been intensively exploited recentlyOne method for asymmetric induction has been realized with X representing a chiral carboxylic acid derivative. From the various chiral auxiliaries studied, the C2 symmetrical amide (32) seems to be the most effective, giving via its zirconium enolate) essentially 100% diastereoselectivity and erythro selection, thus permitting ready access to optically active a-hydroxycarboxylic acids (equation 40). 

In contrast, aldol condensation with (Z)- and (E)-chlorobis(cyclopenladienyl)-zirconium enolates results in ery/Iiro-diastereoselection regardless of the geometry of the enolate.2 3 These enolates are prepared from lithium enolates by metal exchange with Cp,ZrCl, at —78°. The effect is particularly marked with amide enolates (equation II). 

The a -enolate of cyclopentenone reacts with aldehydes to give anti and syn aldols in ratios of 70 30 to 9S S, with the degree of stereoselectivity being related to the size of R (equation 62). Similar yields, with reversed diastereoselectivity, are observed with the corresponding zirconium enolates. 

Aldol reactions of chiral dioxolanones (113) and (114) are summarized in Scheme 6 and Table 9. ° With both (113) and (114), essentially perfect diasterofacial selectivity is observed. The simple dia-stereoselection is modest to good, and is dependent on the enolate counterion. For the lithium and magnesium enolates, the sense of simple diastereoselection is the same as is observed with the achiral dioxolanone (107) and the chiral dioxolanone (110). Use of the zirconium enolate generally reverses the sense of simple diastereoselection, although the isomer ratios are not very high in some cases. 

As indicated by Entry 5 in Table 6.2, the lithium enolates of pyrrolidine amides show excellent simple diastereoselectivity, and rearrange in excellent yields [69]. These amides also show a slight dependence of selectivity on the structure of the amide base used [69]. Monosubstituted pyrrolidine amides were poor auxiliaries for this reaction (<76% ds) [69], but C2-symmetric pyrrolidines are highly selective, as shown in Scheme 6.22 [90]. The Si facial selectivity of the lithium enolate and the illustrated zirconium enolate were comparable, but only the zirconium enolate also showed a high preference for the ul topicity illustrated. The two views of the transition structure rationalize both the topicity and the absolute configuration of the product. The enolate Si face is favored because the closer of the two pyrrolidine stereocenters blocks the Re face. The ul topicity is favored because when the enolate moiety is on the concave face of the cyclopentane envelope, a severe interaction between a pseudoaxial hydrogen and a cyclopentadiene is avoided cf. Scheme 6.14 a for another illustration). 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

Procter et al. reported a novel anti-selective aldol process using titanium enolates of N-propionylpyrrolidine [61]. The aldol products vere obtained in good yield and anti diastereoselectivity. The aldolates vere produced in racemic form, ho vever. As sho vn in Table 2.30, formation of the titanium enolate of 172 vas achieved by transmetalation of the lithium enolate vith Cp2TiCl2 in THE. The resulting titanium enolate reacted vith a range of aldehydes. Interestingly, the lithium enolate of 172 has stereoselectivity and the corresponding zirconium enolate afforded syn diastereoselectivity. 

The group of Badia in Spain also explored the possibility of using other types of electrophiles [39]. Interestingly, the aldolization of zirconium enolates with various electrophiles afforded excellent i yn-diastereoselectivities. Imines were also employed as electrophiles in Mannich reaction... 

With (Z)-amide enolates and (Z)-thioamide enolates a strong preference for sm-adducts is also observed. In general, boron or zirconium (Z)-enolates of ketones and amides display a higher simple diastereoselectivity in favor of syn-products than the corresponding lithium or magnesium enolates6,7. 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

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