Enolate alkylation conformational effects

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

The prediction and interpretation of alkylation stereochemistry requires consideration of conformational effects in the enolate. The decalone enolate 3 was found to have a strong preference for alkylation to give the cis ring junction, with alkylation occurring cis to the f-butyl substituent.58... 

Alkylations of P-substituted 6-lactone enolates occur anti to the substituent with high dia-stereoselectivity unless bulky groups are present at the a-position. " Then, conformational effects may lead to a reversal of the diastereofacial differentiation. Other 8-lactone enolates are alkylated with poor diastereoselectivity unless they are cu-disubstituted at the 7- and 6-positions. Still and Galynker have shown that remote substituents may exert a considerable amount of asymmetric induction in mediumring lactone enolate alkylations. The remote substituent can determine which of the lower energy conformations of the enolate are available for alkylation. ... 

Scheme 33 illustrates the use of two standard persistent auxiliaries. The Evans oxazolidinone 33-1 [83] is highly versatile, i.e., suitable for enolate reactions and double bond additions alike. In the enolate alkylation case [reaction (99)] the high diastereoselectivity depends on the formation of a chelate 33-2 which fixes the reaction site in a defined conformation in which one of the diastereofaces is efficiently shielded. The removal of the auxiliary requires the chemoselective cleavage of the exo cyclic amide bond which is sometimes difficult to achieve. In boron mediated aldoltype additions [Scheme 34, reaction (100)] no chelate can be formed so that the extremeley high diastereoselectivity with which the syn-adduct 34-1 is formed must be due to some other effect, presumably allyl 1,3-strain on the stage of the enol borinate 34-1. 

A study of the lithium enolate of pinacolone with several a-phenyl aldehydes gave results generally consistent with the Felkin model. Steric, rather than electronic, effects determine the conformational equilibria.77 If the alkyl group is branched, it occupies the large position. Thus, the f-butyl group occupies the large position, not the phenyl. 

The effect of crown ethers on the rates and stereochemistry of the alkylation of metal acetoacetates has been studied by Cambillau et al. (1976, 1978) and Kurts et al. (1973, 1974). Since the enolate can adopt various conformations ([96]—[99]), O-alkylation may produce either the cis ([100]) or the trans ([101]) isomer, whereas C-alkylation affords [102]. The reaction of the sodium... 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

Among several chiral cyclic and acyclic diamines, (R,R)-cyclohexane-l,2-diamine-derived salen ligand (which can adopt the gauche conformation) was most effective in providing high enantioselectivity [38]. Further, the introduction of substituents at the 3,4, 5 and 6 positions on the aromatic ring of catalyst 39c was not advantageous, and resulted in low enantioselectivity [32,37,39]. The metal ions from first-row transition metals - particularly copper(II) and cobalt(II) - that could form square-planar complexes, produced catalytically active complexes for the asymmetric alkylation of amino ester enolates [38]. 

It has also been found that in medium-sized (8- to 12-membered) lactones containing a single chiral center at a remote position, highly stereoselective formation of a new chiral center adjacent to the carbonyl group occur (equation 79). This effect falls off as the distance between the enolate and the controlling asymmetric center increases561. Such stereocontrol is caused by the conformational properties of the particular lactone being alkylated. 

In the alternative, equatorial, sulfoxide conformation 20, one face of the enolate is effectively shielded by the bulk of the dithiane ring, the other face being exposed unless a very large 2-alkyl substituent is present. Stereoselectivity is therefore expected to become poorer as the relative size of the (equatorial) 2-alkyl substituent is increased, an effect which can be observed in the results outlined in Table 4 on moving from R = Me to R = Ph. 

Alkylation of fl-aryleyclopentanones. Addition of 10 mole% of CuCN to the lithium enolate prepared from /3-arylcyclopentanones and LDA increases the amount of the less stable product of alkylation. Polyalkylation is also suppressed. Similar results are obtained when methyl- or phenylcopper is added to the enolate prepared by alkyUithium cleavage of trimethylsilyl enol ethers. The mechanism by which Cu(I) influences these alkylations is not as yet understood. The regiospecificity of enolate formation in the example Illustrated in equation (I) has been attributed to a directing efiect of the proximate phenyl group. This effect is also observed in the deprotonation of -arylcyclohexanones. Quantitative, but not qualitative, differences exist between five- and six-membered rings, probably because of conformational differences. ... 

In certain cases, seemingly simple enolates can have a chiral memory effect . For example, treatment of a-imino lactam (5)-88 with f-BuOK in CD3OD for 6-13 days at 25°C gave the corresponding enantiomerically deuteriated a-imino lactam l-d-(S)-89 in quantitative yield with 98% D incorporation and ee 97% (equation 15) , via a conformationally chiral enolate. This methodology has been extended towards enan-tioselective alkylation of enolates. Excellent levels of enantioselectivity (ee 88%) were achieved for a-imino lactam (S)-SS using KHMDS as Brpnsted base and benzyl iodide as the electrophile . Interestingly, to prevent unwanted racemization of the intermediate enolate, the reaction time for deprotonation was lowered to 10 seconds, and to ensure rapid alkylation, 20 equivalents of Bnl were used . 

There is a lot to explain here. It looks very odd that syn-66 is preferred and even more so that alkylation of the enolate 67 occurs on the same face as the undoubtedly large /-butyl group. Both these issues matter as the original chiral centre in proline is destroyed in 67 and only the newly introduced chiral centre in 66 retains the stereochemical information from proline. This centre acts as a relay for the stereochemical information. Others call this a memory effect. The acid-catalysed formation of the N, O-acetal 66 is under thermodynamic control (acetal formation is reversible) and the conformation 66a shows that the molecule folds about the necessarily cis ring junction and the /-butyl group prefers to be on the outside (or exo- face).8 The enolate 67 has a flattened conformation 67a (probably more flattened than this ) and its alkylation is under kinetic control. Attack is preferred on the outside, exo-face. Note that this happens to restore the original configuration at the ex-proline chiral centre. 

The reaction of endocyclic enamines with a,p-unsaturated ketones to afford cu-fused hydroindolones or hydroquinolones constitutes a complementary and highly useful annulation sequence developed extensively by Stevens and coworicers, see the reaction of (5) to give (6) in Scheme 7. ° The importance of stereoelectronic effects is highlighted in the reaction of (7) with methyl vinyl ketone, which provided only the alkylated product (8) and none of the expected ci5-hydroindolone (9)." The failure of intermediate (8) to cyclize in this case was attributed to nonbonded interactions between the aryl group and the side chain. This destabilizing allylic interaction s disfavors formation of conformer (10), the intermediate required for antiperiplanar addition of the enol nucleophile (Scheme 8). Cyclization via the alternate conformation would require a double boat-like transition state. 

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