E-enolate

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

A consequence of this mechanism is that the reaction is stereospecific with respect to the E- or Z-configuration of the enolate. The E-enolate will give the anti aldol product whereas the Z-enolate will give the syn aldol. 

The early stages of the reaction of the quaternary salt can be regarded as proceeding in a manner exactly analogous to that by which the isoxazoles themselves are degraded, the j8-oxoketene imine structure (148) being one mesomeric form of a compound which could alternatively be formulated as a nitrilium betaine. However, by contrast with the products from the isoxazoles (i.e., enolates of /3-keto-nitriles), this is electrically neutral and susceptible to further nucleophilic attack. 

The fact that (Z)-lithium enolatcs generally display a higher simple diastereoselectivity giving. vyn-aldols compared to (E)-enolates affording nn/i-aldols is a challenge to the Zimmer-man-Traxler model, and has become the source of extended speculation. 

Due to their tendency to form (Z)-enolates, ketones usually provide syn-aldols, and anti-se ec-tive chiral ketone enolates are rare. When, however, (S)-5,5-dimethyl-4-trimethylsiloxy-3-hex-anone is deprotonated with (V-(bromomagnesio)-2,2,6,6-tetramethylpiperidine, the (E)-enolate la is assumed to be formed. Subsequent addition to aldehydes delivers anh-aldols 2a and 3a in ratios of between 92 8 and 95 5 and yields of 75-85%53b. 

On the other hand, syn-carboxylic acids are obtained from a deprotonation of the /5-silyl ester, giving the (E)-enolate, followed by reaction with different aldehydes and subsequent hydrogenolysis. No diastereomers of the aldol product are detected720. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

The cycloaddition of photoenol of o-methylbenzaldehyde 66 with 5-alkyli-dene-l,3-dioxane-4,6-dione derivatives 67 is an example of a photo-induced Diels Alder reaction in which one component, the diene in this case, is generated by irradiation [48]. The yields of some cycloadducts 68, generated by photo-irradiation of a benzene solution of 66 and 67 at room temperature, are reported in Table 4.14. The first step of the reaction is the formation of (E)-enol 69 and (Z)-enol 70 (Equation 4.7) by an intramolecular hydrogen abstraction of 66 followed by a stereo- and regioselective cycloaddition with... 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

Some E enols can inhibit nitrosamine formation in a similar manner, (Challis and Bartlett, 1975),... 

Thus, a reversal of the diastereoseleetivity of the reaetion was observed if the enolate was prepared in the presenee of a lithiated base. The different behaviour of the base could be attributable to the geometry of the enolate. It was assumed that the use of KOH as a base would give predominantly the E enolate, whereas the Z enolate would be formed with a lithiated base such as LiN(TMS)2- This methodology was applied to the asymmetric synthesis of quaternary a-amino acids starting from an imino alaninate compound. 

These and other related enolate ratios are interpreted in terms of a tight, reactantlike cyclic TS in THF and a looser TS in the presence of HMPA. The cylic TS favors the E-enolate, whereas the open TS favors the Z-enolate. The effect of the HMPA is to solvate the Li+ ion, reducing the importance of Li+ coordination with the carbonyl oxygen.13... 

E-enolate syri.anti Z-enolate syri.anti... 

E-enolate 2,3-anti, 3,4-weak Z-enolate 2,3-syn,3,4-anti Y13 = alkoxy 3,5-anti... 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

Entry 2 is an example of the polar (3-oxy directing effect. Entries 3 and 4 involve formation of E-enolates using dicyclohexylboron chloride. The stereoselectivity is consistent with a cyclic TS in which a polar effect orients the benzyloxy group away from the enolate oxygen. 

The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. Z-enolates favor anti adducts and E-enolates favor syn adducts. These tendencies can be understood in terms of an eight-membered chelated TS.299 The enone in this TS is in an s-cis conformation. The stereochemistry is influenced by the s-cis/s-trans equilibria. Bulky R4 groups favor the s-cis con former and enhance the stereoselectivity of the reaction. A computational study on the reaction also suggested an eight-membered TS.300... 

Cyclization of 8, e-enols is controlled by a conformation-dependent strain in the exo TS.107 The C(5)-C(6) bond is rotated to minimize A1,3 strain. 

It has been found that when 8,e-enolates bearing (3-siloxy substiments are subject to iodolactonization, the substituent directs the stereochemistry of cyclization in a manner opposite to an alkyl substituent. Suggest a TS structure that would account for this difference. 

Asymmetric alkylation. Deprotonation of (-)-l provides exclusively an (E)-enolate, which is alkylated to provide a single diastereomeric product. De-complexation by oxidation [Br, I2, Ce(IV)] in the presence of water provides the corresponding acid with the same configuration. This sequence has been used for synthesis of the drug (- )-captopril (3). In this case liberation of the acyl group in the presence of the amine provides the amide 2. 

Michael additions of ketone enolates. The stereochemistry of Michael additions of lithium enolates of ketones to a,(3-enones is controlled by the geometry of the enolate. Addition of (Z)-enolates results in anti-products with high diaster-eoselectivity, which is not changed by addition of HMPT. Reaction of (E)-enolates is less stereoselective but tends to favor syn-selectivity, which can be enhanced by addition of HMPT. 

E)-Enol silyl ethers.1 A new highly stereoselective route to (E)-enol silyl ethers involves addition of CH,Li to silyl ketones substituted at the a -position by a SC6H5 group such as 1. The adduct (a) undergoes a Brook rearrangement and... 

The carbocupration of methoxyallene affords a (Z)- or (E)-enol ether depending on the solvent used [52], In THF, the reaction exhibits Z-selectivity because the coordination ability of THF excludes the intramolecular chelation effect of the methoxy group, which may be responsible for the E-selectivity for the reaction in ether (Scheme 10.49). 

The preferential -configuration of the enol esters, derived from p-dicarbonyl compounds under phase-transfer conditions, contrasts with the formation of the Z-enol esters when the reaction is carried out by classical procedures using alkali metal alkoxides. In the latter case, the U form of the intermediate enolate anion is stabilized by chelation with the alkali metal cation, thereby promoting the exclusive formation of the Z-enol ester (9) (Scheme 3.5), whereas the formation of the ion-pair with the quaternary ammonium cation allows the carbanion to adopt the thermodynamically more stable sickle or W forms, (7) and (8), which lead to the E-enol esters (10) [54],... 

The kinetic enolization of esters with amide bases such as lithium diisopropylamide (LDA) and the resultant aldol condensations with representative aldehydes have been investigated by several groups (2,32,33). The enolate stereochemical assignments were determined by silylation in direct analogy to studies reported by Ireland (34). The preponderance of (E )-enolate observed with LDA (THF) in these... 

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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