Homochiral lithium

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. 

Garrido and coworkers116 have demonstrated the use of homochiral lithium (a-methyl-benzyljbenzylamide 175 to initiate the highly stereoselective conjugate addition-cyclization of dimethyl ( , )-octa-2,5-dienoate, 174, to generate the homochiral cyclopentane derivative (—)-(lR,2R,5R,aR)-176 with complete control over the configuration of C-l and C-2 and excellent control over C-5 (Scheme 54). 

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. 

The Diels-Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2 1 mixture of endo/exo adducts was obtained with 75% yield. Only 15% of ee was observed, which compares well with the results quoted for Diels-Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels-Alder reaction. 

When Michael additions of chiral enolates to nitroalkenes were studied, it was found that lithium enolates (132) of l,3-dioxolan-4-ones (131), derived from the corresponding a-hydroxy acids, afford the adducts (133) with high diastereoselectivity (Scheme 50).144 Recrystallization leads, in general, to diastereomerically pure products, which in turn can efficiently be converted to homochiral compounds like (134), (135) or (136). A number of other chiral enolates (137M140) were also shown to undergo highly selective additions to nitroalkenes however, product configurations were not determined in these cases. 

This synthesis featured a four-component coupling involving an oxidative dimerization process. Treatment of homochiral acyl silane 56 with vinyl lithium at low temperature, followed by the addition of half an equivalent of iodine to the reaction mixture, furnished tetraene 58 in high yield and with a very high level of stereoselectivity. The TBS ether was then converted to its triflate equivalent 59 in a... 

The chiral discrimination in the 2 1 complexes (homo vs. heterochiral ones) indicates that, in all the cases, the heterochiral complexes are more stable than the homochiral ones, except for the tert-butyl derivatives. The chiral discrimination energies were discussed on the basis of different parameters related to the lithium atom, such as the N-Li distance, the orbital interaction between the lone pair of the nitrogen and an empty orbital of the lithium, and its atomic contribution to the total energy of the complexes. 

The first issue confronted by Myers was preparation of homochiral epoxide 7, the key intermediate needed for his intended nucleophilic addition reaction to enone 6. Its synthesis began with the addition of lithium trimethylsilylacetylide to (R)-glyceraldehyde acetonide (Scheme 8.6).8 This afforded a mixture of propargylic alcohols that underwent oxidation to alkynone 10 with pyridinium dichromate (PDC). A Wittig reaction next ensued to complete installation of the enediyne unit within 11. A 3 1 level of selectivity was observed in favour of the desired olefin isomer. After selective desilylation of the more labile trimethylsilyl group from the product mixture, deacetalation with IN HC1 in tetrahydrofuran (THF) enabled both alkene components to be separated, and compound 12 isolated pure. 

Lithium phosphites also can catalyze the silyl benzoin reaction of acylsilanes. Its asymmetric version is successfully achieved by a lithium phosphite derived from a homochiral diol.236 Thiazolium salt 32 effectively promotes conjugate acylation of a, 3-unsaturated carbonyls with acylsilanes in the presence of DBU (Equation (61)).237,237a The active catalyst of this sila-Stetter reaction would be a carbene species generated from 32 by deprotonation. 

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... 

---