Silyl enol ethers Lithium amides, chiral

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

Deprotonation of 4-f-butyl cyclohexanone 28 with chiral lithium amide 39 (30 mol%) and bulk base 107 (240 mol%) in the presence of HMPA (240 mol%) and DABCO (150 mol%), under external quench conditions, resulted in 79% ee of the silyl enol ether 29 (Scheme 79)121. This stereoselectivity is only slightly lower than that of the stoichiometric reaction (81% ee). 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

Using this concept, the Koga group have developed [14] catalytic asymmetric deprotonation of 4-alkylcyclohexanones (Scheme 3). For example, deprotonation of 12 gives silyl enol ether 13 in good enantioselectivity. The reaction is accomplished by combining 30 mol% of chiral lithium amide 15 along... 

The deprotonation of conformationally locked 4-t-butylcyclohexanone became a kind of benchmark reaction to study the efficiency of appropriate chiral bases. As shown in Scheme 2.20, the enantiotopic axial hydrogen atoms in o-position of the carbonyl group can be removed selectively by the C2-symmetric lithium base R,R) or (S,S)-72a, and the enantiomeric enolates R)-73a and (S)-73a thus formed were trapped with chlorotrimethylsilane to give enantiomeric silyl enol ethers (/ )-73b and (S)-73b, respectively. It turned out that - symptomatically for the chemistry of lithium enolates - the conditions have a dramatic effect on the enantioselectivity. When internal-quench conditions were applied (i.e., chlorotrimethylsilane present in the mixture from the very beginning), R)-73 was obtained in 69% ee. The external-quench protocol (i.e., deprotonation with the lithium amide 72a first, followed by trapping with chlorotrimethylsilane) led to a collapse of enantioselectivity (29% ee). Thus, here again, the idea came up that lithium chloride that forms gradually under the internal-quench conditions influences dramatically the deprotonation mode. Consequently, the enolate formation was performed in the presence of lithium chloride (0.5 equiv.), and chlorotrimethylsilane was added thereafter. The result was an enhancement of the ee value to 83% [75]. 

A modified protocol was elaborated that starts from the corresponding silyl enol ether that is cleaved into the lithium enolate by methyl lithium in the presence of lithium bromide and the free amine 2 [2a]. Both procedures, however, suffer from the fact that either the lithium amide base 1 or the chiral amine 2 has to be applied in stoichiometric amounts. Fortunately, the presence of 1 equiv. of lithium bromide and 2 equiv. of the additive AfAfdV W -tetramethylpropylenediamme permitted to reduce the amount of the valuable chiral amine 2b to 5mol%... 

Asynunetric Deprotonation/Protonation of Ketones. Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones. The resulting optically active enols orenol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing Cj symmetry, such as (1). For example, reaction of 4-r-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective the resulting enol silyl ether possesses an 88% ee (eq 4). ... 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

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