Chiral lithium amides ether groups

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. 

Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithioacetonitrile, lithium n-propylacetylide, and lithium (g) phenylacetylide) to aldehydes result in decent to excellent ee% (65-98%) when performed in the presence of a chiral lithium amido sulfide [e.g. (14)], 75 The chiral lithium amido sulfides invariably have exhibited higher levels of enantioselectivity compared to the structurally similar chiral lithium amido ethers and the chiral lithium amide without a chelating group. 

C. Chiral Lithium Amides with Chelating Ether Groups. 388... 

E. Mixed Complexes between Lithioacetonitrile and Chiral Lithium Amides with Ether Groups... 

Bidentate base. The chiral lithium amide of (S)-l has been used to generate the anion of the ethyl o-toluate 2 and as a chiral complcxing agent in reaction of the anion with acetaldehyde to give optically active mellein methyl ether (3) in 53% optical yield. Optical yields are markedly lower when a chiral base similar to 1 but lacking the OCH, group is used. 

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... 

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... 

Asymmetric elimination in epoxycyclopentenones bearing a chiral ketal group 1 with achiral lithium amides to give hydroxycyclopentenones has been examined due to the utility of the latter in prostaglandin synthesis67. When lithium diethylamide in diethyl ether and (3S, 5S )-2,6-dimeth-yl-3,5-heptanediol as chiral auxiliary are used, the diastereomeric cyclopentenol derivatives 2 are obtained in a ratio of 87.7 12.3 in 80 % yield. The absolute configuration is based on chemical correlation and the diastereomeric ratio on GC analysis. No further examples are reported. 

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]. 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

---