Homochiral lithium amide

Both diastereoisomers of -homothreonine derivatives (109) and their 2-deuteriated analogues have been synthesized by 1,4-addition of homochiral lithium amides (107) as nitrogen nucleophiles to y-alkoxyenoates (108) (Scheme 13). The product distribution of the 1,4-addition depends strongly on the nature of the substrate (110) vs... 

The enantioselective base-promoted rearrangement of oxiranes was achieved by White-sell and Fehnan in 1980. Various homochiral lithium amides were used for the isomerization of cyclohexene oxide with an enantiomeric excess (ee) up to 36% with the employment of 50 in refluxing THF (Scheme 24). 

Although modest, the results obtained with nonracemic lithium dialkylamides demonstrated the feasibility of such enantioselective transformations and important work has been undertaken from this date to improve both the yield and the ee values as well as developing a catalytic process. With this objective, both the use of homochiral lithium amide (HCLA) bases and organolithium-homochiral ligand complexes have been explored. This field has been extensively reviewed " and the following section presents a selection of the most outstanding results and recent developments. 

The enantioselective formation of bicyclic ketones through enantioselective deprotonation of the bicyclooxiranes 147,148 and 149 (Scheme 64) by homochiral lithium amides (such as 50) and subsequent rearrangement have also been reported with moderate enantiomeric excesses and yields . 

Hammerschmidt, F. Hanninger, A. Enantioselective deproto nation of benzyl phosphates by homochiral lithium amide bases. Configurational stability of benzyl carbanions with a dialkoxyphosphoryloxy substituent and their rearrangement to optically active a-hydroxy phosphonates. Chem. Ber. 1995, 328, 823-830. Avolio, S. Malan, C. Marek, I. Knochel, P. Preparation and reactions of functionalized magnesium carbenoids. Synlett 1999, 1820-1822. 

More recently, along with an increased understanding of the mechanisms for stereoselective deprotonations more rational approaches, e.g. using computational chemistry, have been used. Easily accessible and inexpensive homochiral lithium amides have been designed having broad applicability. Products in high yields and enantiomeric excess have been obtained. These achievements are also reviewed below. 

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. 

Bunn, B.J., Cox, P.J., and Simpkins, N.S. 1993a. Enantioselective deprotonation of 8-oxabicyclo[3.2.1]octan-3-one systems using homochiral lithium amide bases. Tetrahedron 49,207-218. 

Chiral imidazolidinones have been kinetically resolved with the aid of homochiral lithium amide... 

It follows that the corresponding enol ethers can be ring-opened by treatment with Lewis acid [190]. Simpkins subjected the enantiomerically enriched silyl enol ether 224 (obtained by deprotonation using a homochiral lithium amide) to titanium tetrachloride [121]. Alkene 224 was obtained in 88% ee at -95°C, and the ring opened product is expected to be of comparable enantiomeric purity, Eq. 135. 

Simpkins has also applied the well-documented homochiral lithium amide (HCLA) base chemistry [102] to these substrates, and has found that upon treating franj-4-t-butyl(diphenyl)silyloxythiane oxide with an optically active, camphor-derived base followed by quenching with trimethylsilyl chloride, non-racemic products are isolable in up to 69% enantiomeric excess (Scheme 4.50) [102]. 

A homochiral lithium amide was used to introduce chirality in the synthesis of compound (165) from which C-nucleosides can be made (Scheme 46). Recrystallization of (166) permitted (167) to be obtained with >98% e.e. ... 

Cox PJ, Simpkins NS. Asymmetric synthesis using homochiral lithium amide bases. Tetrahedron Asymm. 1991 2 1-26. 

Computational chemistry has been employed to calculate energy differences between diastereomeric activated complexes in the stereoselective deprotonations of cyclohexene oxide by monomeric, homo- and heterodimeric lithium amides (see Section II.A.2). Computational chemistry has also been used as a tool for design of highly stereoselective amides. Such a design approach has resulted in the homochiral base 20 and its enantiomer. These are readily available from both enantiomers of norephedrine, by inexpensive routes... 

Alexakis and coworkers have developed several homochiral bis-lithium amides such as 13 and 101 (Scheme 70)19,m. Interestingly, efficient recycling of the chiral lithium... 

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