Chiral lithium amide base

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

A high level of enantioselectivity in an acyclic system has been reported in the rearrangement of tricarbonylchromium(O) complexes of allyl benzyl ethers using chiral lithium amide base 73 (equation 38) . Upon treatment with 1.1 equivalents of lithium amide 73 and 1 equivalent of LiCl at —78 to —50°C, ether 74 afforded the rearrangement product R)-75 in 80% yield with 96% ee. The effect of substituents on the chemical yields and enantioselectivity of the [2,3]-Wittig rearrangement was also studied (see Table 3). 

C—H insertion reaction occurs in a stereoselective manner. Various attempts based on chiral lithium amide bases gave only moderate enantioselectivities. More efficiently, the reaction is carried out by means of s-butyl- or wo-propy 1-lithium in the presence of (—)-sparteine under these conditions, the bicyclic alcohol 92 was obtained in 74% yield and 83% ee. This concept has been extended to various meio-epoxides, an example of which is shown in equation 52. ... 

Tetr Asym 2 1 (1991) (chiral lithium amide bases)... 

Given that this was apparently the first time an enantiomerically enriched benzyllithium had been made using a chiral lithium amide base, we tried trapping it with an external electrophile. Only by carbonation did we manage to obtain any enantioselectivity in the product 41 (Scheme 11) slower electrophilic quenches (such as, evidently, methyl iodide) presumably allow time for organolithium to racemise.48... 

An enantioselective synthesis of the substituted tetrahydroazepines 323 was achieved on treatment of 322 with a chiral lithium amide base (Equation 49) <1997JOC7080>. 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

Price, D. Simpkins, N. S. Concerning the asymmetric metalation of ferrocenes by chiral lithium amide bases. Tetrahedron Lett. 1995,... 

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

Desymmetrisation of the enantiotopic methyl groups of 432 with a chiral lithium amide base leads to atropisomeric amides in good enantiomeric excess.186... 

Desymmetrisation by enantioselective ortholithiation has been achieved with ferrocenylcarboxamides 434,187 and also (with chiral lithium amide bases) a number of chromium-arene complexes.188 The chromium arene complex 435, on treatment with s-BuLi-(-)-sparteine, gives 436 enantioselectively, and reaction with electrophiles leads to 437. However, further treatment with r-BuLi generates the doubly lithiated species 438, in which the new organolithium centre is more reactive than the old, which still carries the (-)-sparteine ligand. Reaction of 438 with an electrophile followed by protonation therefore gives ent-431.m... 

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

Stereoselectivity in dearomatising cyclisations may be controlled by a number of factors, including rotational restriction in the organolithium intermediates202 203 and coordination to an exocyclic chiral auxiliary.197 Most usefully, by employing a chiral lithium amide base, it is possible to lithiate 441 enantioselectively (see section 5.4 for similar reactions) and promote a cyclisation to 442 with >80% ee.204... 

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... 

Phosphoramidates rearrange into a-aminophosphonates using chiral lithium amide bases e.g. 31 afforded aminophosphonate 86 from phosphoramidate 85 in 13% ee and 65% yield (Scheme 61)104. A slightly higher optical purity of 26% (55% yield) was obtained with chiral (R. R)-3 as base. The application of (—)-sparteine and BuLi gave 13% ee and a yield of 30%. A higher level of enantioselectivity was reached when a bisphosphonate (87) was reacted with (R,R) 3 in THF. Although the yield was only 30%, aminophosphonate 88 was obtained in 35% ee (Scheme 61). 

A particularly interesting extension of this work is offered by the observed enandoselective hydrogen abstraction from the prochiral cyclohexanone (47) on treatment with chiral lithium amide bases (Scheme 27). Thus, quenching the initially formed enolate afforded the asymmetric trimethylsilyl ether (48) which gave the chiral enone (49) in 65% enantiomeric excess on dehydrogenation. Further woilc in this area should provide valuable methodology for the formation of chiral a,3-unsaturated carbonyl systems. 

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. 

Research by M. Majewski et al. showed that the enantioselective ring opening of tropinone allowed for a novel way to synthesize tropane alkaloids such as physoperuvine. The treatment of tropinone with a chiral lithium amide base resulted in an enantioslective deprotonation, which resulted in the facile opening of the five-membered ring to give a substituted cycloheptenone. This enone was subjected to the Wharton transposition by first epoxidation under basic conditions followed by addition of anhydrous hydrazine in MeOH in the presence of catalytic amounts of glacial acetic acid. 

McComas, C. C., Van Vranken, D. L. Application of chiral lithium amide bases to the thia-Sommelet dearomatization reaction. Tetrahedron Lett. 2003, 44, 8203-8205. 

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). 

While several stoichiometric chiral lithium amide bases effect the rearrangement of raeso-epoxides to allylic alcohols [1], few examples using catalytic amounts of base have been reported. Asami applied a pro line-derived ligand to the enantioselective deprotonation of cyclohexene oxide to afford 2-cyclohexen-... 

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