Deprotonation Lithium amides, chiral

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

Table 1. Chiral Lithium Amides for Asymmetric Deprotonation and Elimination5 57,59,60...

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

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]. 

Table 4. Asymmetric Deprotonation of 1 with Chiral Lithium Amides in THF and in situ Trapping of the Lithium hnolatc with (CH3)3SiCl...

Deprotonation of tropinone (1) with various chiral lithium amides and external quenching of the lithium enolate with benzaldehyde gives the aldol product 2 in moderate to good yield with moderate enantiomeric excess but high diastcrcosclcctivity. The aldol product 2 is a single diastereomer with the relative configuration as depicted, but of unknown absolute configuration19. Recrystallization of the aldol product leads to enantiomerically pure material. 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

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. 

Enantioselective deprotonation.2 The rearrangement of epoxides to allylic alcohols by lithium dialkylamides involves removal of the proton syn to the oxygen.3 When a chiral lithium amide is used with cyclohexene oxide, the optical yield of the resulting allylic alcohol is 3-31%, the highest yield being obtained with 1. 

Similar results have been obtained for related compounds 174 for example, 404 is asymmetrically deprotonated by chiral lithium amide bases.81 Dearomatising cyclisation... 

A dearomatising asymmetric cyclisation initiated by deprotonation with a chiral lithium amide base is discussed in section 5.4. 

The high propensity of organolithium compounds to form mixed complexes with other organolithium species in solution has been utilized successfully in synthesis using chiral lithium amides. Either the chiral lithium amides have been added to organolithium reagents in an effort to achieve asymmetry in addition reactions, or various additives have been introduced to alter the reactivity or selectivity of the chiral lithium amides themselves, e.g. in deprotonation reactions. 

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. 

Incorporation of the (2/ ,5/ )-dimethylpyrrolidinyl substituent gave the chiral lithium amide 1926. This chiral base was found to give improved enantioselectivities e.g. cyclohexene oxide could be deprotonated to give the allylic alcohol in 99% ee (Scheme 14). For a more detailed use of chiral bases 18 and 19, see Section n.E.l. 

Davidsson, Johansson and Abrahamsson reported the use of polymer-supported chiral lithium amides in the deprotonation of cyclohexene oxide30. Interestingly, polymer base A provided allylic alcohol 2 in 67% yield and 91% ee of the (S )-enantiomer, after 12 h, which was a higher enantioselectivity than the non-polymer corresponding lithium amide which gave only 47% yield and 19% of the (S )-enantiomer (Scheme 17). In contrast, polymer B was found to show low efficiency 12% yield and 70% ee of the (S )-enantiomer... 

A kinetic investigation using 20 in the deprotonation of cyclohexene oxide revealed that the composition of the activated complexes was different from that assumed in the theoretical model. The reaction orders showed that an activated complex is built from one molecule of chiral lithium amide dimer and one molecule of epoxide 1. Such activated complexes have been computationally modeled by the use of PM3 and optimized structures are displayed in Figure A44. 

FIGURE 4. PM3-optimized THF-solvated diastereoisomeric TSs for deprotonation of 1 with chiral lithium amide 20. Most hydrogen atoms are omitted for clarity... 

Using Corey and Gross s internal quench method48 with TMSC1, silylenol ethers have been generated upon deprotonation of 4-substituted cyclohexanone with chiral lithium amides as shown in Scheme 20. It has been noted that the internal quench condition is crucial for achieving high level of enantioselectivity. 

TABLE 3. Deprotonation of 69 by various chiral lithium amides... 

Employing the chiral lithium amide (R,R)-3 as a base in THF at —78°C gave the hydroxy phosphonate 84 in 30% yield and 52% ee upon deprotonation of phosphate 83 (Scheme 60)102,103. The use of BuLi as base with (—)-sparteine as chiral ligand in ether at —78 °C resulted in a lower optical activity (8% ee) and 65% yield102. 

Similarly, phospholane 89 could be deprotonated by chiral lithium amides in the presence of LiCl, followed by quenching with various electrophiles (Scheme 62)105. The enantioselectivity was found to range from 82% up to 92% ee, and in each case only one... 

Since most chiral lithium amides are expensive to produce, an effective, readily available and cost-efficient catalytic system using a catalytic amount of chiral lithium amide is currently a significant challenge. The chiral lithium amide should also be available in both enantiomeric forms. Asami and coworkers reported in 1994110 the first catalytic enantioselective deprotonation using chiral lithium amides. 

The finding that the use of LDA as bulk base results in non-enantioselective deprotonation indicated that bulk bases which are much less reactive toward the epoxide substrate compared with the chiral lithium amide are needed. But they should be strong enough to regenerate the chiral amide from the amine formed in the epoxide rearrangement. 

Asami and coworkers synthesized and applied the chiral lithium amide 14, which appeared to be more reactive than 4. It was successfully used in catalytic enantioselective deprotonation of both cyclic and acyclic epoxides (Scheme 69). Interestingly, the addition of DBU lowered the enantioselectivity ... 

In order to further develop the field of enantioselective catalytic deprotonation, it was necessary to develop bulk bases that show low reactivity toward the epoxide but have the ability to regenerate the chiral catalyst. Thus, the bulk bases should show low kinetic basicity toward the substrate, but be thermodynamically and kinetically basic enough to be able to regenerate the chiral lithium amide from the amine produced in the rearrangement. 

Ahlberg and coworkers have found that lithiated 1-methylimidazole (21) and lithiated 1,2-dimethylimidazole (22) work as such bulk bases in the presence of catalytic amounts of a readily accessible homochiral lithium amide 20 (both enantiomers are readily available) (see Section III.C)45,46. These new bulk bases are easily accessible by deprotonation of 1-methylimidazole and 1,2-dimethylimidazole by, e.g., n-BuLi (Scheme 72). Using chiral lithium amide 20 (20 mol%) and bulk base 21 or 22 (200 mol%) in the deprotonation of cyclohexene oxide 1 gave (S)-2 with the same enantiomeric excess (93%) as under stoichiometric conditions (Scheme 15). Apparently, any background reactions of the bulk bases are insignificant. Interestingly, no addition of DBU was needed to obtain the high enantioselectivities under these catalytic conditions. 

Ahlberg and coworkers noted that in some cases the enantioselectivity was increased when running the deprotonations with equimolar amounts of the novel bulk bases and the chiral lithium amide113. This finding initiated a detailed mechanistic investigation using isotopically labeled compounds and multinuclear NMR spectroscopy and kinetics, to elucidate the nature of the reagents and transition states in the deprotonations. They discovered that mixed dimers 23 and 24 are formed in solution from monomers of chiral lithium amide 20 and bulk base 21 and 22, respectively (Scheme 73). 

Since Asami7 presented his seminal ligand (4) in 1984 based on a diamine, most of the ligands developed and used as chiral lithium amides have been based on bidentate ligands. Malhotra s results clearly show that monodentate bases can also be used for highly selective deprotonations. 

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