Chiral lithium amides ketones

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... 

Reaction of the chiral lithium enolate of meso-2,6-dimethylcyclohexanone (6), generated by deprotonation with (R)-l-phenylethylamine and (/ )-camphor/(R)-l-phenylethylaniine derived chiral lithium amides (Table 1, entries 17 and 64) with 3-bromopropene, leads to homoallyl ketones of opposite absolute configuration in acceptable yield with poor to modest enantiomeric excess14, which can be determined directly by H-NMR spectroscopy in the presence of tris [3-(heptafluorohydroxymethylene)-D-camphorato]europium(III) [Eu(hfc)3]. 

Asymmetric eliminations of mew-configurated epoxides to give chiral allyl alcohols may most successfully be achieved using the chiral lithium amides which are also successful for the asymmetric deprotonation of ketones (see previous section). Problems in interpretation of asymmetric induction are also similar to those found in deprotonation of the ketones finding the optimal chiral lithium amide and reaction parameters remains largely empirical. 

So far, chiral lithium amides for asymmetric deprotonation have found use only with a few types of substrates. The following sections deal with deprotonation of epoxides to yield chiral allylic alcohols in high enantiomeric excess, deprotonation of ketones, deprotonation of tricarbonylchromium arene complexes and miscellaneous stereoselective deprotonations. These sections are followed by sections in which various chiral lithium amides used in stereoselective deprotonations have been collected and various epoxides that have been stereoselectively deprotonated. The review ends with a summary of useful synthetic methods for chiral lithium amide precursors. 

The exploration of chiral lithium amide bases to desymmetrize conformationally locked cyclic ketones began with Koga and coworkers 14 work and has been followed by... 

New bases have also been proposed to extend the arsenal presented in Scheme 16. In particular, conformational constraints have been introduced on the amide. It was shown, for instance, that e.e. values up to 81% can be returned for the deprotonation of 4-f-butylcyclohexanone in a THF/HMPA mixture by a lithium amide derived from a tetrahydroquinoline bearing a heterocycle at C3102. Note that the same ketone can be converted in its (S)-enolate in 90% e.e. resorting to the bulky lithium A-trityl-A-(/ )-l-phenethylamide79. Interestingly, chiral lithium amides on polymeric solid support have also been successfully employed to deprotonate bridged cycloheptanones103. 

This volume, which complements the earlier one, contains 9 chapters written by experts from 7 countries. These include a chapter on the dynamic behavior of organolithium compounds, written by one of the pioneers in the field, and a specific chapter on the structure and dynamics of chiral lithium amides in particular. The use of such amides in asymmetric synthesis is covered in another chapter, and other synthetic aspects are covered in chapters on acyllithium derivatives, on the carbolithiation reaction and on organolithi-ums as synthetic intermediates for tandem reactions. Other topics include the chemistry of ketone dilithio compounds, the chemistry of lithium enolates and homoenolates, and polycyclic and fullerene lithium carbanions. 

Simpkins and co-workers were the first to use an asymmetric catalytic process in (-)-anatoxin-a synthesis (Newcombe and Simpkins, 1995) instead of resorting to the chiral pool strategy. Their total synthesis of (-)-anatoxin-a relied on an enantioselective enolisation reaction of a readily available ( )-3-tropinone (33), by a chiral lithium amide base (34) (Bunn et al. 1993a, 1993b) and subsequent cyclopropanation/ring expansion reaction giving the ketone 37 (Scheme 7.8). 

Bunn, B.J., Simpkins, N.S., Spavol4 Z., and Crimmin, M.J. 1993b. The effect of added salts on enantioselective transformations of cyclic ketones by chiral lithium amide bases. J Chem Soc Perkin Trans 1, 3113-3116. 

Cain, C.M., Cousins, R.P.C., Coubarides, G., and Simpkins, N.S. 1990. Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases. Tetrahedron 46, 523—544. 

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50]. The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 % yield and 92 % ee. The amount... 

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). 

Lithium enolates of ketones and esters can be generated by the action of chiral lithium amides. If the base is used in stoichiometric amounts, the lithium cation of the endate bears the chiral amine as a ligand. If the amide is used in excess, chiral mixed aggregates can be formed [77, SS7, 558, 559], These lithium... 

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... 

Scheme 3.23. Enantioselective deprotonation of achiral ketones with chiral lithium amide...

Ma, L. and WiUiard, P.G. (2006) Synthesis of polymer-supported chiral lithium amide bases and application in asymmetric deprotonation of prochiral cyclic ketones. Tetrahedron Asymmetry, 17, 3021-3029. 

Aggarwal and Olofsson have developed a direct asymmetric a-arylation of prochiral ketones using chiral lithium amide bases and diaryliodonium salts [881]. In a representative example, the deprotonation of cyclohexanone derivative 684 using chiral Simpkins (/ ,/ )-base followed by reaction with the pyridyl iodonium salt gave the arylated product 685 in 94% ee (Scheme 3.275). This reaction has been employed in a short total synthesis of the alkaloid (-)-epibatidine [881]. 

A chiral reagent can also be used as the source of stereoinduction in the s)mthesis of an enantioenriched compound. They are used in stoichiometric quantities and some typical examples are chiral lithium amide bases to asymmetrically deprotonate a ketone, chiral reducing reagents, such as BINAL-H, to asymmetrically reduce a... 

Enolization of racemic ketone 122 with the chiral lithium amide 123 produced a mixture of regioisomeric enol silanes 124 and 125 [78]. A treatment with PhSeCl and subsequent oxidation with dimethyldioxirane afforded the enones 126 and 127. This result shows a regiodivergent KR of racemic ketone 122. 

Enantioselective deprotonation has been reviewed " and further explored " for cyclic ketones and for L-dihydroorotate ° and alkyl carbamates.Conformationally rigid chiral lithium amide bases, based on 1,3-disubstituted tetrahydroisoquinoline, deprotonate 4-r-butylcyclohexanone with high enantioselectivity (81%... 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

A variety of other chiral lithium amides, for example 106 and 108, have been applied more recently to bring about enantioselective aldol additions. As sho vn in Eqs. (48) [179] and (49) [180], both simple diastereoselectivity and induced stereroselectivity can be induced by these reagents. In the latter reaction, the enolate itself becomes chiral, because of desymmetrization of ketone 107 on deprotonation. 

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