Enantioselective lithiation chiral lithium amide bases

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. 

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... 

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... 

As with atropisomeric biaryls, axial chirality in atropisomeric amides maybe introduced by stereochemical control in the atroposelective reactions of planar chiral complexes [115]. Enantioselective lithiation was reported in this context by Uemura, who showed that the achiral complexes 195,198,201 and 204 are de-protonated enantioselectively by treatment with chiral lithium amide bases (Scheme 50) [116-118]. The stereogenic C-C and C-N axes in these compounds are orientated such that the larger NR2 and acyl groups, respectively, are directed away from the chromium. A range of chiral lithium amides was investigated, and by careful selection it was possible to obtain products 196,199,202 and 205... 

To date, several dozens of chiral lithium amide bases have been applied for enantioselective enolate formation. A collection including only several of these bases (72, 74-78) is given in Scheme 2.21. The Overberger amine [76], introduced under its lithiated form 72a by Simpkins group, still seems to be the most widely applied for this type of enantioselective bond disconnection. 

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. 

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]. 

The chiral base 360 turns out not to be the best choice for enantioselective lithiation of the sulphur analogue 437 (Scheme 177) the bis-lithium amide 438 in the presence of LiCl at — 100°C gives better yields and enantioselectivity The base 438 often turns out to be a good choice as an alternative to 360 for reactions that fail to give good enantioselectivity. ... 

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