Organolithium chiral bases

Siwek and Green have deprotonated arenechromium tricarbonyls bearing acidic ben-zylic protons with chiral bases in which the organolithium itself is chiral. Menthyllithium 452 (R = H) performed variably in terms of ee, but 8-phenyhnenthyllithium 452 (R = Ph) gave good yields and ee s (in the opposite enantiomeric series from 452 (R = H)) in the deprotonation of 412 (Scheme 181). Unlike most chiral bases, 452 (R = Ph) gives better results in THF than in ether. 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

Non-stabilised organolithiums - that is, organolithiums in which the lithium-bearing centre is tetrahedral - generally react with high stereospecificity. This fact is essential for the use of chiral bases such as s-BuLi-(-)-sparteine in the synthesis of enantiomerically enriched compounds by asymmetric deprotonation, as well as for the use of enantiomerically pure... 

A chiral auxiliary is a chiral molecule attached to the starting material of the reaction dia-stereoselective reactions of compounds from the chiral pool are likewise controlled by chirality in the starting material, and we call this type of stereocontrol substrate control. But is it also possible for enantioselective reactions to be controlled by chiral reagents. For example, a typical achiral base will just remove a proton from a substrate, but an enantiomerically pure chiral base can select one of two enantiotopic protons and form a product enantioselectively. The product of course has to be chiral, so we can t use a chiral base to make planar enolates enantioselectively, for example, but we can a chiral base to make chiral organolithiums. 

This chiral base can now choose to remove from the pyrrolidine substrate just one of the enantiotopic protons adjacent to nitrogen, and form a chiral, enantiomerically enriched organolithium. The stereochemistry of the organolithium is preserved through its reactions with electrophiles such as the ketone shown here. 

In recent years, enantioselective variants of the above transannular C-H insertions have been extensively stiidied. The enantiodetermining step involves discrimination between the enantiotopic protons of a meso-epoxide by a homochiral base, typically an organolithium in combination with a chiral diamine ligand, to generate a chiral nonracemic lithiated epoxide (e.g., 26 Scheme 5.8). Hodgson... 

The first successful approaches were based on the, often Cu-mediated, conjugate addition of organolithium and organomagnesium (Grignard) reagents to o ,/ -unsaturated systems covalently modified with chiral auxiliaries (Scheme 1 ). ... 

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... 

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... 

---