Zirconium enolates

Enols and alkoxides give chelates with elimination of alcohol. For example, in the reaction of the enol form of acetylacetone [123-54-6] all four alkoxide groups attached to zirconium can be replaced, but only two of the four attached to titanium (Fig. 3). Acetoacetic esters react similarly. 

Thenoyltrifluoroacetone(TTA), C4H3S,CO,CH2,COCF3. This is a crystalline solid, m.p. 43 °C it is, of course, a /1-diketone, and the trifluoromethyl group increases the acidity of the enol form so that extractions at low pH values are feasible. The reactivity of TTA is similar to that of acetylacetone it is generally used as a 0.1-0.5 M solution in benzene or toluene. The difference in extraction behaviour of hafnium and zirconium, and also among lanthanides and actinides, is especially noteworthy. 

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. 

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. 

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. 

Chelation of the enolate and orientation of the acceptor chain away from the chclatc, seems to be essential as the use of potassium tert-butoxide in to / -butyl alcohol (nonchelated enolate) results in a 1 1 mixture of cis- and tram-2132-I33. The diastereomeric ratio furthermore depends on the alcohol (R20) moiety134- 136-386, whereas the use of zirconium(IV) isopropoxide also results in high tram-selectivity (cisjtrans ratio, 1 25) 137. 

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. ... 

Reaction conditions that involve other enolate derivatives as nucleophiles have been developed, including boron enolates and enolates with titanium, tin, or zirconium as the metal. These systems are discussed in detail in the sections that follow, and in Section 2.1.2.5, we discuss reactions that involve covalent enolate equivalents, particularly silyl enol ethers. Scheme 2.1 illustrates some of the procedures that have been developed. A variety of carbon nucleophiles are represented in Scheme 2.1, including lithium and boron enolates, as well as titanium and tin derivatives, but in... 

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. 

Zirconium enolates can also prepared by reaction of lithium enolates with (Cp)2ZrCl2, and they act as nucleophiles in aldol addition reactions.34... 

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. 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Additionally, various zirconium-assisted aldol condensations between different types of zirconium enolates and aldehydes have been reported.141-145... 

Finally, Lipshutz and co-workers developed catalytic copper(i)-assisted polyfunctionalizations of zirconacyclopen-tenes of type 93 by trapping the intermediary zirconium enolates 94 with an aldehyde to form the corresponding 2,3-disubstituted cyclopentanones 95 (Scheme 40).146... 

Zirconium enolates of various carbonyl compounds have also been investigated for Mannich-type reactions with different electrophiles. According to Shibasaki s method,148 the coupling reaction between a 3-acetoxy-4-alkyl-/3-lactam and the in r(/ -generated zirconium enolate 96 of a cyclohexanone derivative was realized as a key step during the total synthesis of an anitibiotic (Scheme 42).117,149... 

For a representative example of the preparation of a zirconium (3-keto ester enolate, see Stuhldreier, T. Keul, H. Hocker, H. Englert, U. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Aldol reactions of 1 and 2 can be used to obtain any one of the four possible stereoisomers of a,3-dihydroxy esters.3 Thus 1 reacts with aldehydes to provide (2S)-aldols, and 2 reacts to provide (2R)-aldols. The syn/anti ratio of the aldols can be controlled by the choice of the enolate counterion. Thus lithium or magnesium enolates provide mainly an/i-aldols, whereas 5yn-aldols predominate with zirconium enolates. Ethanolysis of the purified adducts yields the optically pure a,p-dihydroxy esters without epimerization with recovery of 8-phenylmenthol. 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

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... 

Kinetically Controlled Aldol Condensations of Zirconium Enolates with Benzaldehyde... 

It should also be noted that there is a strong conformational bias for only one of the product chelate conformers. For example, erythro chelate D should be strongly disfavored by both 1,3-diaxial Rj L and CH3 Xq steric control elements. Consequently, it is assumed that the transition states leading to either adduct will reflect this conformational bias. Further support for these projections stems from the observations that the chiral acetate enolates derived from 149a exhibit only poor diastereoface selection. In these cases the developing Rj CH3 interaction leading to diastereomer A is absent. Similar transition state allylic strain considerations also appear to be important with the zirconium enolates, which are discussed below. 

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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