Zirconium enolates stereoselectivity

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

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. 

Michael additions of organotitanium or zirconium reagents remain to be explored systematically. Recently, Stork described an interesting stereoselective intramolecular Michael addition in which zirconium enolates appear to be involved113). In another Michael type process, methyltitanium triisopropoxide 6 was added enantioselectively to a chiral a, p-unsaturated sulfoxide, but CH3MgCl was more efficient114). 

Introduction and stereochemical control syn,anti and E,Z Relationship between enolate geometry and aldol stereochemistry The Zimmerman-Traxler transition state Anti-selective aldols of lithium enolates of hindered aryl esters Syn-selective aldols of boron enolates of PhS-esters Stereochemistry of aldols from enols and enolates of ketones Silyl enol ethers and the open transition state Syn selective aldols with zirconium enolates The synthesis of enones E,Z selectivity in enone formation from aldols Recent developments in stereoselective aldol reactions Stereoselectivity outside the Aldol Relationship A Synthesis ofJuvabione A Note on Stereochemical Nomenclature... 

Some kinds of metal enolate also give highly stereoselective reactions in the same sense whatever the geometry of the enolate. At first sight the reactions of zirconium enolates seem like lithium enolates. Using the pyrrolidine amide 38 as an example, we get the Z-enolate 39 only and this gives syn aldol products 40 with aldehydes.13... 

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. 

The high syn stereoselectivity attained in zirconium enolate aldol reactions has proved useful in complex natural product synthesis. The zirconium-mediated aldol reaction of the chiral ethyl ketone (9) with a chiral aldehyde has been used by Masamune et al. to give selectively adduct (10), which was further elaborated into the ansa chain of rifamycin S (equation 1). Good enolate diastereofacial selectivity is also obtained here and leads to a predominance of one of the two possible syn adducts. A zirconium enolate aldol reaction also features in the Deslongchamps formal total synthesis of erythromycin A, where the di(cyclopentadienyl)chiorozirconium enolate from methyl propionate adds with high levels of Cram selectivity to the chiral aldehyde (11) to give the syn adduct (12 equation 2). A further example is... 

A similar chair and boat dual transition state model to that for zirconium enolates has been used by Reetz and Peter to explain the syn stereoselectivity, although acyclic transition states may also be operative. 

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. 

Further work on the preparation of cryt/iro-2-alkyl-3-hydroxy-esters (140) by various condensations between propionic acid derivatives and aldehydes has been reported " the use of zirconium enolates seems to be particularly efficacious. Rules for predicting the stereochemical outcome of condensations between lithium enolates of esters and ketones and a-alkoxy-aldehydes have also been delineated. Pure erythro-isomer (140) can also be obtained in some cases by reduction of the corresponding jS-keto-ester with zinc borohydride. In related work it has been found that sodium borohydride in isopropanol reduces t-butyl a-alkoxy-j8-keto-esters to the corresponding -hydroxy compounds with erythro-threo ratios of between 2 1 and 20 1 in favour of the eryt/iro-isomer. In an extension of his previous work, Frdter has reported that dianions derived from cyclohexanol (141) can be alkylated with 95% stereoselectivity, to give (142). When the starting alcohol (141) is optically pure, a sequence of alkylation and oxidation leads to 2-ethoxycarbonylcyclohexanones with 76% enantiomeric enrichments. 

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. 

Like alkaline and alkaline earth metals, the oxophilic metals in group 3 and 4 form O-bound enolates. For the most important of them from the point of view of stereoselective synthesis - titanium and zirconium enolates - the O-metal bond had been deduced from the stereochemical integrity of the enolate double bond, which was maintained upon transmetallation of cis- or traws-lithium into titanium or zirconium enolates [50]. The aggregation state depends on the individual ligands at the transition metals, which means their ligand-dependent Lewis acid character. 

Thus, jyn-adducts arise predominantly, as expected, according to the Zimmerman-Traxier model. Provided that either boron or zirconium is the enolate-metal atom, high syn selectivity is achieved. The total amount of anti-adducts is lower than 2% in the case of amides 1 and 2, and it approaches zero when the other reagents arc used94 . The induced stereoselectivities are impressive for the amides and remarkable in the case of the imides. 

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. ... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

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