Chiral lithium amides epoxide rearrangement

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. 

A. Chiral Lithium Amides Employed in Epoxide Rearrangement. 460... 

II. CHIRAL LITHIUM AMIDES IN ASYMMETRIC SYNTHESIS A. Rearrangement of Epoxides to Allylic Alcohols... 

Using the methodology previously developed by Stella and coworkers22 and by Wald-mann and Braun23 to synthesize 2-substituted aza-norbornanes (see Section II.C), Ander-sson and coworkers prepared chiral lithium amide 1824,25. This chiral base has been reported to rearrange several epoxides in up to 98% ee in the absence or presence of high concentrations of DBU (Scheme 13). 

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. 

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. 

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-... 

Asami, M., Ishizuka, T. and Inoue, S. (1994) Catal3ftic enantioselective deprotonation of mejo-epoxides by the use of chiral lithium amide. Tetrahedron.Asymmetry, 5, 793-796 Seki, A. and Asami, M. (2002) Catalytic enantioselective rearrangement of mejo-epoxides mediated by chiral lithium amides in the presence of excess cross-linked polymer-bound hthium amides. Tetrahedron, 58, 4655 663. 

A more recent example of chiral lithium amide-induced enantioselective deprotonation-rearrangement is the conversion of exo-norbornene oxide to nor-tricyclanol which proceeds via the Hthiated epoxide 43 (Scheme 22) [82]. 

In the above case no P-elimination can occur. Reversibility observed during the a-deprotonation of such an epoxide with a lithium amide (vide supra) might result in lowering the ee when using a chiral lithium amide, since reversible deprotonation could compromise the kinetic control in enantioselective deprotonation. Nevertheless deprotonation of exo-norbornene oxide 91 with lithiiun (S,S)-bis(l-phenyl)ethylamide 11 [Eq. (7)] gave tricyclanol 92 in good yield (73%) and moderate ee (49%) (Scheme 16). When the rearrangement of exo-norbornene oxide 91 is carried out with s-BuLi in pentane from -78°C to room... 

The lithium derivative of the chiral chelating diamine (3 )-2-(l-pyrrolidinylmethyl)-pyrrolidine (6) has been used extensively in stereoselective synthesis, i.e. in the deprotonation of ketones and rearrangement of epoxides to homoallylic alcohols. The lithium amide has been crystallized from toluene solution, and X-ray analysis revealed that it forms a ladder-type tetramer with the two pyrrolidine nitrogens solvating the two lithiums at the end of the ladder38, (Li-6)4. 

Lithium amide deprotonation of epoxides is a convenient method for the preparation of allylic alcohols. Since the first deprotonation of an epoxide by a lithium amide performed by Cope and coworkers in 19585, this area has received much attention. The first asymmetric deprotonation was demonstrated by Whitesell and Felman in 19806. They enantioselectively rearranged me.vo-cpoxidcs to allylic alcohols for example, cyclohexene oxide 1 was reacted with chiral bases, e.g. (S,S) 3, in refluxing TFIF to yield optically active (/ )-2-cyclohexenol ((/ )-2) in 36% ee (Scheme 1). 

Other Enantioselective Reactions. Enantioselective epoxide elimination by chiral bases has been demonstrated. More recently, the enantioselective [2,3]-Wittig rearrangement of a 13-membered propargylic ally lie ether has been performed using the lithium amide of (f ,f )-(l) as the base for deprotonation (eq 15). For this particular substrate, THF is a better solvent than ether, although pentane produces better results in a related transformation (eq 16). In fact, a change in solvent in this type of reaction has been shown to lead to a reversal of the stereoselectivity of the transformation. ... 

Sddergren, M.J. and Anderson, PG. (1998) New and high enantioselective catalysts for the rearrangement of mejo-epoxides into chiral allylic alcohols. Journal of the American Chemical Society, 120, 10760-10761 S6dergren, M.J., Bertilsson, S.K. and Anderson, P.G. (2002) Allylic alcohols via catalytic asymmetric epoxide rearrangement. Journal of the American Chemical Society, 122, 6610-6618 Bertilsson, S.K. and Anderson, P.G. (2002) Asymmetric base-promoted epoxide rearrangement achiral lithium amides revisited. Tetrahedron, 58, 4665-4668. 

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