Structure chiral lithium amides

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. 

In this chapter the focus is on a few structures that serve to highlight the key factors controlling the structures of chiral lithium amides in general. For a complete review on structures of lithium amides there are a number of excellent articles5-10. The structures of the chiral lithium amides discussed herein have been determined either by X-ray analysis or by multinuclear NMR spectroscopy of isotopically labelled compounds. The basics of lithium amide structures and in particular the structures and dynamics of chiral lithium amides will be presented. 

Since much of the knowledge about chiral lithium amides has been obtained from research on achiral amides, this section will give a short overview of the field of lithium amides. Furthermore, without the development of NMR techniques in the last two decades the structural knowledge of organolithium compounds would still be in its infancy. 

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. 

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 chiral lithium amides can also be part of cubic tetrameric structures as shown by the mixed complex, Li-6/(n-BuLi)3, consisting of the chiral lithium amide Li-6 and three molecules of n-BuLi61. 

The rate constant for the lithium-lithium exchange within the mixed complexes of chiral lithium amides and lithioacetonitrile also differ, depending on the structure. The C-lithiated structures are significantly less fluxional than the /V-lithiated mixed dimers. The activation energy, AG, has been determined for two C-lithiated nitrile complexes in Et20... 

A kinetic investigation using 20 in the deprotonation of cyclohexene oxide revealed that the composition of the activated complexes was different from that assumed in the theoretical model. The reaction orders showed that an activated complex is built from one molecule of chiral lithium amide dimer and one molecule of epoxide 1. Such activated complexes have been computationally modeled by the use of PM3 and optimized structures are displayed in Figure A44. 

This volume, which complements the earlier one, contains 9 chapters written by experts from 7 countries. These include a chapter on the dynamic behavior of organolithium compounds, written by one of the pioneers in the field, and a specific chapter on the structure and dynamics of chiral lithium amides in particular. The use of such amides in asymmetric synthesis is covered in another chapter, and other synthetic aspects are covered in chapters on acyllithium derivatives, on the carbolithiation reaction and on organolithi-ums as synthetic intermediates for tandem reactions. Other topics include the chemistry of ketone dilithio compounds, the chemistry of lithium enolates and homoenolates, and polycyclic and fullerene lithium carbanions. 

The enantioselectivity was dramatically affected by the structure of the lithium amide used for the deprotonation, indicating that the secondary amine liberated during the metalation step participates in the protonation step. - The utilization of chiral lithium amides allowed higher enantioselections than with classical LDA (eq 4) (Table 2). ... 

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]. 

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