Enolate geometry

Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 

Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. 

Partial control of enolate geometry occurs also when the enol phosphate, prepared by treatment of fluoroalkyl ketones with sodium diethyl phosphite, is... 

The stereochemical outcome of the Michael addition reaction with substituted starting materials depends on the geometry of the a ,/3-unsaturated carbonyl compound as well as the enolate geometry a stereoselective synthesis is possible. " Diastereoselectivity can be achieved if both reactants contain a stereogenic center. The relations are similar to the aldol reaction, and for... 

The diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

The diastereoselectivity of the copper enolate 2b may be rationalized by suggesting that the chair-like cyclic transition state J is preferred which leads to the major diastereomer 4. The usual antiperiplanar enolate geometry and equatorial disposition of the aldehyde substituent are incorporated into this model. Possible transition states consistent with the stereochemistries of the observed minor aldol products are also illustrated. 

Excellent chemical yields, high regio- and, in several cases, high diastereoselectivities are observed. A correlation between enolate geometry and product stereochemistry is found, with (Z)-eno-lates producing ////// -adducts and (L )-cnolates yielding. vvw-adducts preferentially, if these reactions are performed with kinetic control (see Table 1, entries 1 -10)21 -23. 

The enolate geometry can be controlled, in the case of esters, by the addition of HMPA without HMPA the enolate has predominantly the. E-geometry, while with HMPA mainly Z-geometry is observed. Similar additions with magnesium and zinc enolates are observed24"32 373 374. 

Consecutive Michael additions and alkylations can also be used for the diastereoselective synthesis of 5- and 6-membered ring systems. For instance when 6-iodo-2-hexenoates or 7-iodo-2-heptenoates are employed the enolate of the Michael adduct is stereoselectively quenched in situ to provide the cyclic compound with trans stereochemistry (>94 6 diastereomeric ratio). As the enolate geometry of the Michael donor can be controlled, high stereoselectivity can also be reached towards either the syn or anti configuration at the exocyclic... 

Enolate Enolate Geometry Nitroalkanc Geometry d.r. (synjanti) Yield (%)... 

Despite the ability to control ester enolate geometry, the aldol addition reactions of unhindered ester enolate are not very stereoselective.37... 

Much attention has been devoted to the examination of chiral enolate systems in which metal ion chelation may play an important role in establishing a fixed stereochemical relationship between the resident chirality and the enolate moiety. This has resulted in the conclusion that enolate geometry is critical in the definition of 7r-l acial selection. The following sections discuss this effort in several different chemical systems. 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

One of the first important studies to address the implications of enolate geometry on aldol product stereochemistry was reported by Dubois and Fellmann (eq. [14]) (5c). The condensation of the (Z)-... 

The observed aldol stereoselection as a function of both enolate geometry and enolate ligand Rx is summarized in Table 5. It is clear from these results that the increasing steric requirements of the substituent Ri appear to confer greater kinetic stereoselection from the (Z)- as opposed to the ( )-enolate geometry (Scheme 2). 

The correlation of metal enolate geometry and aldol product stereochemistry via diastereomeric chair-preferred transition states has been widely accepted (2,5,6,16). The observations that the steric bulk of the enolate ligand Rj and attendant aldol diastereoselection are directly coupled are consistent with the elaborated Zimmerman model illustrated in Scheme 3 for chair-preferred transition states. For example, for ( )-enoIates, transition state Q is predicted to be destabilized relative to Ci because of the Rj R3 variable steric... 

The basic assumption of the chair-preferred transition state (for tetrahedral metal centers) is clearly tenuous, and diastereomeric boat transition state geometries should not be discounted. For example, the diastereomeric chair and boat transition states for (Z)-enolates are illustrated in Scheme 4, For this enolate geometry it is entirely reasonable to consider that the heat of formation of boat transition state B2 might actually be less than chair transition state C4 for certain combinations of substituents Ri, R2, and R3. For example, boat transition state B2 not only disposes substituents R2 and R3 in a staggered conformation as in chair transition states C3 and C4, but also minimizes Rj R3 eclipsing, which must be significant in chan-transition state C3. The change in kinetic aldol diastereoselection of... 

Enolate geometry is an important stereochemical aspect of the problem. 

The steric influence of the enolate substituents Ri and Rj plays a dominant role in the alteration of kinetic stereoselectivity, whereas the aldehyde ligand appears to contribute to a minor extent. Good correlation between enolate geometry and aldol stereochemistry is possible when Rj is sterically demanding and Rj.is sterically subordinate (Rj = methyl or n-alkyl). In this case dominant path A stereoselection is observed. When R2 becomes sterically demanding (R2 = t-Bu) path B stereoselection is observed and becomes dominant. 

Dominant Ri R2 steric control elements are predicted to disfavor transition state T and promote enolization to give the (Z)-geometry, whereas dominant R2 L nonbonded interactions should disfavor transition state C and promote enolization to afford the ( )-enolate geometry. As summarized below in Table 10, under conditions of apparent kinetic control, esters and thioesters afford largely ( > enolates (transition state T ), and the dialkylamides exhibit predominant to exclusive (Z)-enolization (transition state C ). 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

Although simple alkyl esters (ethyl propionate) fail to enolize with the boryl triflate reagents under normal conditions, the more acidic acyloxyboranes 66 readily form the diboryl enediolates 67 (eq. [52]) (6a,66). Several interesting trends are noted in the data included in Table 23. Since previous studies have demonstrated that enolate geometry strongly correlates with product stereochemistry, enediolate 67 has been employed to directly compare the reactivities... 

In large measure, the problem associated with the execution of a stereoselective aldol condensation has been reduced to the generation of a specific enolate geometry. The recent results of Kuwajima (66a), which demonstrate that enolsilanes may be transformed into boryl enolates without apparent loss of stereochemistry (eq. [53]), should enhance the utility of vinyloxyboranes in stereoselective synthesis. The only current drawback to this procedure is associated with the presence of trimethylsilyl triflate (69), which must be removed from the reaction medium before the aldol condensation. It has recently been established that 69 is an effective catalyst for the aldol process (4). 

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... 

It was postulated that the role of the triflate reagent 69 is to activate the acetal, with the possible intervention of either 79 or 80 as the putative electrophUic species, which undergoes reaction with the enolsilanes via the extended acyclic transition state 81 (4). Based on the assumption that transition state R2 R3 interactions from either enolate geometry dictate the stereochemical course of... 

Enolate Geometry Imine Geometry Transition State Product Stereochemistry... 

The correlation between allylboronic ester stereochemistry and aldehyde diastereoface selection stands in contrast to the behavior of stereochemicaUy defined lithium enolates, which generally exhibit a preference for the Cram mode of addition to chiral aldehydes from either enolate geometry (cf, eqs. [72]-[77]). The stereochemical... 

The same natural product was synthesized by Paterson et al. [45] who assembled the carbon skeleton of the macrolide from three larger subunits as well. Instead of the Evans-Metternich variant they used their boron-mediated antz-selective aldol strategy which relies as the Evans-Metternich aldol on stereo-induction from the a-chiral center and translates the E-enolate geometry, established due to the use of Cy2BCl, to the anti aldol product (Scheme 33). 

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