Chiral lithium amides chelation

In summary, chelating chiral lithium amides exist in either of four major structural motifs or mixtures of them (Scheme 3). Non-coordinating solvents generally favor cyclic trimers, A. Ladder tetramers are favored for pyrrolidide amides in the absence of coordinating solvents. 

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. 

Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithioacetonitrile, lithium n-propylacetylide, and lithium (g) phenylacetylide) to aldehydes result in decent to excellent ee% (65-98%) when performed in the presence of a chiral lithium amido sulfide [e.g. (14)], 75 The chiral lithium amido sulfides invariably have exhibited higher levels of enantioselectivity compared to the structurally similar chiral lithium amido ethers and the chiral lithium amide without a chelating group. 

B. Chiral Lithium Amides with Chelating Amino Groups. 385... 

The interest in chiral lithium amides and their structures was sparked in the beginning of the 1990s when they proved useful in asymmetric synthesis. Over the years several chiral lithium amides have been structurally characterized. In this section the chiral lithium amides are discussed separately, depending on their structural basis. The chiral lithium amides with chelating groups constitute a central class of chiral amides widely used in various enantioselective reactions. 

Stoddart and coworkers40 have synthesized a chiral lithium amide with C2-symmetry and two chelating methoxy groups from the amine (R,R)-di(a-methoxymethylbenzyl)amine (7). This lithium amide was crystallized from a hexane solution and X-ray analysis revealed a dimeric structure where both lithiums are tetracoordinated, (Li-7)2. 

Chiral lithium amides with chelating sulfur atoms (Li-11) have also been prepared and studied51. The sulfur atom is less electronegative and has a larger radius than oxygen... 

SCHEME 3. The most common stmctural motifs of chiral lithium amide chelates... 

B. Mixed Complexes between Alkyllithiums and Chiral Lithium Amides with Chelating Ether Groups... 

In the development of chiral lithium amides which result in higher ee, the effect of a diverse set of substituents R and R in 38 was examined. It was shown that ee increases as the size of substituent R becomes bulkier, and also as the amount of fluorine in R increases. In THF, 38a occurs as a monomeric structure M-38a in either the presence or absence of HMPA. Fluorinated base 38b has also been shown to be monomeric in THF, consistent with structure M-38b where the fluorine atoms do not act as internal chelating ligands. In the presence of LiCl, the solution structure of labeled 38b was examined by Li and NMR in THF-ds- The Li- N coupling patterns showed that mixed dimer MD-6 was formed, as also illustrated with 38a. The absolute configuration of the products renders the OD-1 structure of transition state TS-1 most likely (Fig. 7) [58]. 

The 6Li, 15N and 13C NMR spectra of the a-aminoalkoxide-LiHMDS mixed dimer, where LiHMDS = lithium hexamethyldisilazide, showed the presence of a pair of conformers.7 6Li and 15N couplings and 6Li, ll HOESY data gave structural information for chiral lithium amides with chelating sulfide groups, e.g. (3).8... 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

Similar to the LDA dimers 52 in solution and in the crystal, the chiral amide 72a forms a bis-solvated dimer 82 as shown by the crystal structure [92] and NMR studies in THF [93]. The dimeric structure 83 was found in the case of Koga s base 75 (X = CH2) wherein hthium adopts a threefold coordination by chelation and not by coordination to THF [94] (Scheme 2.23). Similar dimeric structures were confirmed more recently by a variety of NMR techniques for chiral lithium amides derived from valinol [95]. 

The proUne-derived diamidobinaphthyl dilithium salt S,S,S)-66, which is dimeric in the sohd state and can be prepared via deprotonation of the corresponding tetraamine with n-BuLi, represents the first example of a chiral main-group-metal-based catalyst for asymmetric intramolecular hydroamination reactions of aminoalkenes [241], The unique reactivity of (S,S,S)-66, (Fig. 17) which allowed reactions at or below ambient temperatures with product enantioselec-tivities of up to 85% ee (Table 17) [241, 243] is believed to derive from the close proximity of the two lithium centers chelated by the proline-derived substituents. More simple chiral lithium amides required significantly higher reaction temperatures and gave inferior selectivities. 

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. 

In the presence of the corresponding pyrrolidine diamine, the chiral lithium pyrrolidide amide yields dimeric chelates composed of a lithium pyrrolidide amide dimer solvated by a pyrrolidine diamine, (Li-6)2 6, as shown by NMR spectroscopy39. The lithium amide gives two 6Li NMR signals in a 1 1 ratio. The addition of TMEDA to Li-6 results in a similar complex where TMEDA coordinates to the lithium pyrrolidide amide dimer, (Li-6)2 TMEDA. 

Li-C couplings have been collected for a series of lithium reagents by Reich and co-workers, who studied their chelation and aggregation with potential 5-, 6-, and 7-ring chelating ether and amine ortho substituents. The couplings have been also applied by Hilmersson and Malmros in their studies on mixed dimer and mixed trimer complexes of -BuLi and a chiral hthium amide. 

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