Enolate alkylation, stereochemical

The idea that the stereochemical outcome of an intramolecular enolate alkylation is determined by chelation in the transition state was recently demonstrated by Denmark and Henke, who observed a marked preference for a "closed transition state (coordination of the cationic counterion to an enolate and the developing alcohol) resulting in a syn product. For example, the highest syn anti ratio (89 11) was obtained in toluene and the lowest syn.anti ratio (2 98) was obtained with a crown ether. These observations parallel the facial selectivities described herein and in ref 11 on the intramolecular SN2 reaction see (a) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1991, 113, 2177. (b) Denmark, S. A. Henke, B. R. J. Am. Chem. Soc. 1989, 111, 8022. 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

Recent studies have suggested that coordination with a lithium cation may be responsible for the stereochemical outcome in Meyers-type enolate alkylations . In fact, the hypothesis that the diastereofacial selectivity observed in these reactions might result from specific interactions with a solvated lithium cation was already proposed in 1990 . Nevertheless, the potential influence exerted by solvation and lithium cation coordination was not supported by a series of experimental results reported by Romo and Meyers , who stated that it would appear that neither the aggregation state of the enolate nor the coordination sphere about lithium plays a major role in the observed selectivity. This contention is further supported by recent theoretical studies of Ando , who carried out a detailed analysis of the potential influence of solvated lithium cation on the stereoselective alkylation of enolates of y-butyrolactones. The results showed conclusively that complexation with lithium cation had a negligible effect on the relative stability of the transition states leading to exo and endo addition. The stereochemical outcome in the alkylation of y -butyrolactones is determined by the different torsional strain in the endo and exo TSs. 

As with our discussion of the reduction of carbonyl compounds in Chapter 10, f-butyl-cyclohexanone makes an interesting structure to probe stereochemical preferences in carbonyl chemistry. Let s look at two specific cases of enolate alkylation the alkylation of 4-f-butylcyclohexanone, and the alkylation of 4-f-butylcyclohexyl methyl ketone. 

For lead references see Yamamoto, Y. Maruyama, K. The Opposite Diastereoselectivity in Alkylation and Protonation of Enolates J. Chem. Soc., Chem. Commun. 1984, 904-905. Fleming, I. Lewis, J. J. A Paradigm for Diastereoselectivity in Electrophilic Attack on Trigonal Carbon Adjacent to a Chiral Center The Methylation and Protonation of Some Open-Chain Enolates J. Chem. Soc., Chem. Commun. 1985, 149-151. McGarvey, G. J. Williams, J. M. Stereoelectronic Controlling Features of Allylic Asymmetry. Application to Ester Enolate Alkylations J. Am. Chem. Soc. 1985, 107, 1435-1437. Hart, D. J. Krishnamurthy, R. Investigation of a Model for 1,2-Asymmetric Induction in Reactions of a-Carbalkoxy Radicals A Stereochemical Comparison of Reactions of a-Carbalkoxy Radicals and Ester Enolates J. Ors. Chem. 1993, 57, 4457-4470. 

Predict the stereochemical course of the following enolate alkylations. (Calcimycin-4)... 

Notable diastereoselectivity was observed in the conjugate addition of Me2CuLi to cyclooctenone 35, which afforded the trans product 26 with >99 1 dr (Equation 2) [3]. Thus, enolate alkylation provides cis products (cf. 20—>25) with a stereochemical pattern complementary to that observed in conjugate additions (35—>26). 

There are numerous examples of diastereoselective alkylations of chiral enolates, in which the extant asymmetry of the substrate exerts suitable stereochemical control in the alkylation step [15, 20]. Several useful guiding principles have been determined to aid in predicting the stereochemical outcome. The examples discussed in the following sections have been selected to showcase the power of enolate alkylations for the stereoselective formation of new C-C bonds, as well as to highlight selected historical aspects in the development of the field. 

It is possible to change the stereochemical result of the alkylation by replacing the 3-ketal protecting group with a A -enol ether. This structural change eliminates a severe 1,3-diaxial interaction to a-face methylation and results in the formation of the 5a-methyl steroid (15) in about 35% yield, ... 

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

Other studies have provided additional data on the relative stabilities of the lithium aldolates 14 and 15 derived from the condensation of dilithium enediolates 13 (Rj = alkyl, aryl) with representative aldehydes (eq. [ 10]) (16). Kinetic aldol ratios were also obtained for comparison in this and related studies (16,17). As summarized in Table 4, the diastereomeric aldol chelates 14a and ISa, derived from the enolate of phenylacetic acid 13 (R = Ph), reach equilibrium after 3 days at 25° C (entries A-D). The percentage of threo diastere-omer 15 increases with the increasing steric bulk of the aldehyde ligand R3 as expected. It is noteworthy that the diastereomeric aldol chelates 14a and 15a (Rj = CH3, C2HS, i-C3H7) do not equilibrate at room temperature over the 3 day period (16). In a related study directed at delineating the stereochemical control elements of the Reformatsky reaction, Kurtev examined the equilibration of both... 

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

By contrast, lithium enolates derived from tertiary amides do react with oxiranes The diastereoselectivity in the reaction of simple amide enolates with terminal oxiranes has been addressed and found to be low (Scheme 45). The chiral bicyclic amide enolate 99 reacts with a good diastereoselectivity with ethylene oxide . The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case ) interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103. By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the hthium enolate 104 with the chiral oxiranes 105 and 106 °. It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselec-tivities can be achieved. 

In particular, there is only one review which places special emphasis on the stereochemical aspects of the alkylation of enolates, i.e., on the influence of a resident asymmetric center on the course of the reaction6. 

It has been shown in the previous examples of 5-lactone alkylations that a substituent in the /(-position strongly induces attack of the electrophile from the opposite side (e.g., see references 60 and 61). These findings correspond to common sense first approximations. However, an interesting example has been reported where this effect is nearly completely suppressed by a second stereochemical barrier. Alkylation of the enolate 18 can either give 19a or 19b. 

Hydridotris(3,5-dimethyl-l-pyrazolyl)borate]molybdenum-(i72-acyl) complexes, such as 1, are deprotonated by butyllithium or potassium hydride to generate enolate species, such as 488.8> jjie overa]] structure of these chiral complexes is similar to that of the iron and rhenium complexes discussed earlier the hydridotris(3,5-dimethyl-l-pyrazolyl)borate ligand is iso valent to the cyclopentadienyl ligand, occupying three metal coordination sites. However, several important differences must be taken into account when a detailed examination of the stereochemical outcome of deprotonation-alkylation processes is undertaken. 

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