Stereoselection enolate geometry

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

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... 

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... 

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

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 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. 

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... 

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). 

Up to this point, we have considered primarily the effect of enolate geometry on the stereochemistry of the aldol condensation and have considered achiral or racemic aldehydes and enolates. If the aldehyde is chiral, particularly when the chiral center is adjacent to the carbonyl group, the selection between the two diastereotopic faces of the carbonyl group will influence the stereochemical outcome of the reaction. Similarly, there will be a degree of selectivity between the two faces of the enolate when the enolate contains a chiral center. If both the aldehyde and enolate are chiral, mutual combinations of stereoselectivity will come into play. One combination should provide complementary, reinforcing stereoselection, whereas the alternative combination would result in opposing preferences and lead to diminished overall stereoselectivity. The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation,67... 

Stereoselective Michael additions. In the absence of strong steric effects, the stereochemistry of Michael addition of amide enolates depends on the enolate geometry, with (Z)-enolates giving mainly antf-adducts and (E)-enolates giving mainly syn-adducts.1 Ester enolates show higher stereoselectivity than amide enolates, as shown by the (E)- and (Z)-enolates of r-butyl propionate (1). The (E)-... 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Complex substitution is tolerated in the rearrangement of divinylcyclopropanes 68. Stereoselectivity is achieved by altering the enolate geometry in situ. 

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... 

Boron enolates (other names are vinyloxyboranes, enol borinates, or boron enol ethers) are often employed in the aldol reaction because they show higher stereoselectivity than alkali and magnesium enolates. Extensive developmental work in this area has been carried out by Evans, Masamune and Mukaiyama, and their respective coworkers. - - The correspondence between enolate geometry and aldol stereochemistry is exceptional (Z)-enolates give syn/erythro aldol products, whereas ( )-enolates give anti/threo aldol products, albeit with slightly lower selectivity. 

The kinetic stereoselectivity of the aldol is a function of the enolate stereochemistry and its structure. One often reads the over-generalization that (Z)-enolates gives syn aldols and (E)-enolates give anti al-dols. However, the situation is much more complex than this in addition to enolate geometry, several variables are involved. The following generalizations may be made at this time (refer to equation 37 for definition of R , R- and R ). 

In an application to asymmetric monobactam synthesis. Overman and Osawa observe a high level of 1,4-diastereofacial selectivity in the reaction of (5)-cyanoamine (235) with the enolate of STABASE-protected glycine ester (234), affording diastereomeric 3-amino-2-azetidinones (236) and (237) in a 10 1 ratio, respectively, and in 65% yield (Scheme 49). Based on the (E)-enolate geometry of glycine ester (234), determined in trapping experiments with TMSCl, the authors postulate a chelated, chair-like transition state (238) that is consistent with the observed stereoselectivity. 

Kinetic control. The Zimmerman-Traxler model, as applied to propionate and ethyl ketone aldol additions, is shown in Scheme 5.7 (note the similarity to the boron-mediated allyl additions in Scheme 5.3). Based on this model, we would expect a significant dependence of stereoselectivity on the enolate geometry, which is in turn dependent on the nature of X and the deprotonating agent (see section... 

While more plentiful, alcohol-based chiral auxiliaries have been limited in their ability to direct the diastereoselective hydroxylation for the preparation of tertiary a-hydroxy acids. Among these, the best results in this series were obtained when oxidation of the enolate of chiral ester substrate 24 with (+)-5 yielded (5)-25.ub The use of (-)-S as the hydroxylating agent, provided a reversal in stereoselectivity, providing (i )-25. Interestingly, when substoichiometric amounts (0.5 equiv) of (+)-5 were used, stereoselectivity improves (94% de), a fact attributed to the matching of the enolate geometry to the oxidant. This speculation is credible, as evidenced by the fact that oxidation with 0.50 equivalent of (-)-5 produces (5)-25 in only 37% de in a stereochemically mismatched case. 

The simplest asymmetric induction involves a reaction of an achiral enolate with a chiral aldehyde. In this case, if the boron enolate geometry and facial selectivity to the aldehyde are well controlled, the stereoselective aldol reaction will proceed. For example, treatment of (Z)-boron enolate 11 with chiral aldehyde 12 effected stereoselective aldol reaction to give sy -aldol adduct 13 as a single product [3]. 

---