Lithium enolates transition states

Transmetalation of lithium enolate 1 a (M = Li ) by treatment with tin(II) chloride at — 42 °C generates the tin enolate that reacts with prostereogenic aldehydes at — 78 °C to preferentially produce the opposite aldol diastereomer 3. Diastereoselectivities of this process may be as high as 97 3. This reaction appears to require less exacting conditions since similar results are obtained if one or two equivalents of tin(ll) chloride arc used. The somewhat less reactive tin enolate requires a temperature of —42 C for the reaction to proceed at an acceptable rate. The steric requirements of the tin chloride counterion are probably less than those of the diethyla-luminum ion (vide supra), which has led to the suggestion26 44 that the chair-like transition state I is preferentially adopted26 44. This is consistent with the observed diastereoselective production of aldol product 3, which is of opposite configuration at the / -carbon to the major product obtained from aluminum enolates. 

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 reaction is believed to proceed via a six-membered cyclic transition state, analogously to the carbonyl addition of enolates, but the energy differences between boat- and chair-like arrangements are lower for x-sulfinyl carbanions69. Tor tert-butyl sulfoxides only anti- and, vn-products are obtained, arising from the approach onto the same diastereotopic face of the anion, but with different relative topicity. The exchange of lithium by zinc causes an increase of the anft-produci, but attempts to titanate the anion failed (see Table 3)69. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

Four different orientations are possible when the enantiofaces of (E)- and (Z)-enolates and an ( )-enone combine via a closed transition state, in which the olefinic moieties of the donor and the acceptor are in a syn arrangement. It should be emphasized that, a further four enan-tiomorphous orientations of A-D are possible leading to the enantiomers 2 and 3. On the basis of extensive studies of Michael additions of the lithium enolates of esters (X = OR) and ketones (X = R) to enones (Y = R) it has been concluded ... 

The initial addition step is reversible allowing isomerization of the ( )- and (Z)-nitroalkenes and equilibration between the initially formed syn- and ann -imminium ion adducts. The spn-ad-duct is identical to that obtained from the lithium enolate of cyclohexanone and ( >(2-nitro-cthenyl)benzenc. The preference for the. yyu-adduct can be rationalized by inferring the transition state 1 which is similar to that proposed for the reaction of (-E)-nitroalkcnes with ( )-eno-lates11, l2. 

Studies show that the Zr-bearing bulky ligand is exclusively located in the bottom hemisphere with respect to the plane of the (Z)-enolate. The aldehyde molecule coordinates with the Zr atom and approaches from the same side, adopting a chair-like transition state. This leads to the formation of erythro-aldols (Scheme 3-9 and 23). For lithium enolate, the attack of alkyl or acyl halides in alkylation or acylation occurs directly on the top face of the enolate. 

Diastereoface selection has been investigated in the addition of enolates to a-alkoxy aldehydes (93). In the absence of chelation phenomena, transition states A and B (Scheme 19), with the OR substituent aligned perpendicular to the carbonyl a plane (Rl = OR), are considered (Oc-or c-r transition state R2 Nu steric parameters dictate that predoniinant diastereoface selection from A will occur. In the presence of strongly chelating metals, the cyclic transition states C and D can be invoked (85), and the same R2 Nu control element predicts the opposite diastereoface selection via transition state D (98). The aldol diastereoface selection that has been observed for aldehydes 111 and 112 with lithium enolates 99, 100, and 101 (eqs. [81-84]) (93) can generally be rationalized by a consideration of the Felkin transition states A and B (88) illustrated in Scheme 19, where A is preferred on steric grounds. 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Diastereoselectivity in the aldol and the conjugate additions of 2 -hydroxy-1,T-binaphthyl ester enolates with a variety of carbonyl electrophiles has also been explored the tendency of the ester enolates, generated by BuLi, to react with aldehydes to give threo products preferentially with high diastereoselectivity has been interpreted in terms of an acyclic transition state of chelated lithium enolate involving the aldehyde carbonyl and the 2 -hydroxy group. 

The favourable effect of lithium bromide on facial enantioselective protonation of methyl tetralone enolate by a-sulfinyl alcohols has been attributed to coordination of lithium to both enolate and sulfinyl alcohol followed by competition between diastere-omeric paths involving intramolecular proton transfer the proposed transition-state model is supported by results of PM3 semiempirical calculations. ... 

In 1998, Hasanayn and Streitwieser reported the kinetics and isotope effects of the Aldol-Tishchenko reaction . They studied the reaction between lithium enolates of isobu-tyrophenone and two molecule of beuzaldehyde, which results iu the formation of a 1,3-diol monoester after protonation (Figure 28). They analyzed several aspects of this mechanism experimentally. Ab initio molecular orbital calculatious ou models are used to study the equilibrium and transition state structures. The spectroscopic properties of the lithium enolate of p-(phenylsulfonyl) isobutyrophenone (LiSIBP) have allowed kinetic study of the reaction. The computed equilibrium and transition state structures for the compounds in the sequence of reactions in Figure 28 are given along with the computed reaction barriers and energy in Figure 29 and Table 6. 

Entries 1—4 in Scheme 2.3 represent cases in which the nucleophilic component is converted to the enolate under kinetically controlled conditions by the methods discussed in Section 1.2. Such enolates are usually highly reactive toward aldehydes so that addition occurs rapidly when the aldehyde is added, even at low temperature. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. The guiding mechanistic concept for reactions carried out under these conditions is that they occur through a cychc transition state in which lithium or another metal cation is coordinated to both the enolate oxygen and the carbonyl oxygen. i. 4... 

Boron Enolates. Another important version of the aldol reaction involves the use of boron enolates. A cyclic transition state is believed to be involved, and, in general, the stereoselectivity is higher than for lithium enolates. The O—B bond distances are shorter than the O—Li bond in the lithium enolates, and this leads to a more compact transition state, which magnifies the steric interactions that control stereoselectivity. 

A comprehensive comparison of the anti syn diastereoselectivity of the lithium, dibutylboron, and (Cp)2Zr enolates of 3-methyl-2-hexanone with benzaldehyde has been reported.38 The order of stereoselectivity is Bu2B > (Cp)2Zr > Li. These results are consistent with reactions proceeding through a cyclic transition state. 

Analysis of results for a-substituted aldehydes with E- and Z-enolates indicates that the cyclic transition states shown below are favored with lithium and boron enolates.64a... 

If HMPA is included in the solvent, the Z-enolate predominates.162 DMPU also favors the Z-enolate. The switch to the Z-enolate with HMPA or DMPU can be attributed to a loose, perhaps acyclic, transition state being favored as the result of strong solvation of the lithium ion by HMPA or DMPU. The steric factors favoring the E transition state are therefore diminished.163 These general principles of solvent control of enolate stereochemistry are applicable to other systems.164... 

The ester I gives alternative stereoisomers when subjected to Claisen rearrangement as the lithium enolate or as the trimethylsilyl enol ether. Analyze the respective transition states and develop a rationale for this observation. 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

The authors proposed a chelating transition state model to explain these results (Fig. 8.14). The thermodynamically more stable intermediate resulting from initial lithium amide addition should have the amino group on the face opposite to the bulky tert-butyl group. Due to the same steric effect, the HMPA ligand should also occupy a position on the p face. The electrophile approaches the enolate from the ot face and gives the trans product. For bulky amines, either the aza enolate does not form due to severe steric hindrance or the aza enolate is inactive for the same reason. 

However, the more hindered, less basic lithium hexamethyldisilazamide reacts slowly with 1 at 0 °C to provide chemoselectively the desired enolate species 5. The a-protons of these rhenium-acyl complexes are believed to have a lower pKa than the cyclopentadienyl protons, but unless treated with hulky, selective hases the cyclopentadienyl protons exhibit greater kinetic acidity due to statistical factors and an earlier, reactant-like transition state since minimal rchybridiza-tion is required at the anionic center after cyclopentadienyl deprotonation. Equilibration of the cyclopentadienyl anion to the thermodynamically more stable enolate species cannot compete with the rapid acyl migration84. 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

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