Silylation Lithium amides, chiral

By analogy, the acetylene aldehyde 500 gives, on addition of the chiral Li-enolate 501 [79-82], the chiral //-lactams 502 and 503 in 75% yield [80-82]. Similar (fhc-tam-forming reactions are discussed elsewhere [70, 83-88]. The ketone 504 affords, with the lithium salt of the silylated lithium amide 505, the Schiff base 506, in 74% yield (Scheme 5.27). The Schiff base 506 is also obtained in 25% yield by heating ketone 504 with (C6H5)3P=N-C6H4Me 507 in boiling toluene for 7 days... 

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). 

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). ... 

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). 

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... 

Both dimethylphenylphosphine-borane (107) and -sulfide (108) are enantio-selectively deprotonated by a lithiumalkyl (—)-sparteine complex as demonstrated by subsequent reaction with electrophiles to give products with e.e. values of 80-87% (Scheme 8). Oxidative coupling of (109) in the presence of copper(II) pivalate gives the (S. S)-isomer (110) as the major product. Asymmetric metalla-tion and silylation of diphenylphosphinyl ferrocene (111) using the chiral lithium amide base derived from di(l-methylbenzyl)amine has been reported to give an... 

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 synthesis of an enantiomerically enriched chromium complex via asymmetric lithiation of a prochiral tricarbonyl(ri -arene)chromium complex using a chiral lithium amide base was first demonstrated in 1994 by Simpkins [88]. Arene complex 44 was treated with C2-symmetric chiral base ent-39 in the presence of TMSCl as an internal quench and silylated complex 45 was obtained in 84% ee (Scheme 24). 

The diastereoselective lithiation of 74 shows that ferrocenes bearing electron-withdrawing directors of lithiation are sufficiently acidic to allow deprotonation with lithium amide bases. By replacing LDA with a chiral lithium amide, enantioselectivity can be achieved in some cases. The phosphine oxide 82, for example, is silylated in 54% ee by treatment with N-Hthiobis(a-methylbenzyl)amine 83 in the presence of Me3SiCl (Scheme 20) [58]. 

For monosubstituted arenes, kinetically controlled discrimination between the two enantiotopic ortho hydrogens of the planar chiral benzene chromium tricarbonyl complex leads to nonracemic products. Asymmetric lithiation is more efficient when one or more oxygen atoms, such as ether linkages, are present in the starting prochiral complex (Scheme 26.14). Treatment of Cr(CO)j-anisole complex 52 with the chiral lithium amide 53, in the presence of TMSCl under ISQ conditions, affords (+)-orfho-silylated complex 54 with good chemical yield and ee value [143-145]. The isobenzofuran system 55 reacts as well to give a-sUylated product 56 [146]. 

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]. 

Scheme 2.42 Conjugate addition of chiral lithium amide 142 and under formation of c/s-lithium enolates 43b and quenching as silyl ketene acetal (Z)-144.

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%... 

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. 

Enol silylations. With the superhindered iithium t-butyl(trityl)amide (and related tritylamides) ketones give more ( )-siloxyalkenes than lithium 2,2,6,6-tetramethyl-piperidide. Asymmetric enolization is possible using chiral V-(l-phenethyl) analogue. ... 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

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