Epoxides chiral lithium amides

C—H insertion reaction occurs in a stereoselective manner. Various attempts based on chiral lithium amide bases gave only moderate enantioselectivities. More efficiently, the reaction is carried out by means of s-butyl- or wo-propy 1-lithium in the presence of (—)-sparteine under these conditions, the bicyclic alcohol 92 was obtained in 74% yield and 83% ee. This concept has been extended to various meio-epoxides, an example of which is shown in equation 52. ... 

Asymmetric eliminations of mew-configurated epoxides to give chiral allyl alcohols may most successfully be achieved using the chiral lithium amides which are also successful for the asymmetric deprotonation of ketones (see previous section). Problems in interpretation of asymmetric induction are also similar to those found in deprotonation of the ketones finding the optimal chiral lithium amide and reaction parameters remains largely empirical. 

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. 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

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

So far, chiral lithium amides for asymmetric deprotonation have found use only with a few types of substrates. The following sections deal with deprotonation of epoxides to yield chiral allylic alcohols in high enantiomeric excess, deprotonation of ketones, deprotonation of tricarbonylchromium arene complexes and miscellaneous stereoselective deprotonations. These sections are followed by sections in which various chiral lithium amides used in stereoselective deprotonations have been collected and various epoxides that have been stereoselectively deprotonated. The review ends with a summary of useful synthetic methods for chiral lithium amide precursors. 

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). 

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. 

Asami and coworkers discovered that the chiral lithium amide 4 was more reactive toward epoxides than lithium diethylamide (LiNEt2) or lithium diisopropylamide (LDA) argil° pje reasonecj at an achiral lithium amide could be used to regenerate the chiral... 

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. 

Asami and coworkers synthesized and applied the chiral lithium amide 14, which appeared to be more reactive than 4. It was successfully used in catalytic enantioselective deprotonation of both cyclic and acyclic epoxides (Scheme 69). Interestingly, the addition of DBU lowered the enantioselectivity ... 

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. 

The chiral lithium amide 18 has also been used for catalytic kinetic resolution of epoxides117. Epoxide 104 was subjected for kinetic resolutions under the conditions shown in Scheme 75, which resulted in roughly enantiopure epoxide and allylic alcohol. 

Liu and Kozmin used the asymmetric deprotonation of hetero-epoxides such as 106 as key step in the synthesis of chiral polyols120. The deprotonation was carried out using the chiral lithium amide pool published in the literature and both stoichiometric and catalytic deprotonations gave satisfactory results (Scheme 78). 

Research by M. Majewski et al. showed that the enantioselective ring opening of tropinone allowed for a novel way to synthesize tropane alkaloids such as physoperuvine. The treatment of tropinone with a chiral lithium amide base resulted in an enantioslective deprotonation, which resulted in the facile opening of the five-membered ring to give a substituted cycloheptenone. This enone was subjected to the Wharton transposition by first epoxidation under basic conditions followed by addition of anhydrous hydrazine in MeOH in the presence of catalytic amounts of glacial acetic acid. 

Figure 4.46 summarizes our second synthesis of (+)-95.80 The key step was the asymmetric cleavage of mew-epoxide B with a chiral lithium amide to give allylic alcohol C (77% ee), which was purified as... 

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-... 

Two further contributions illustrate how chiral lithium amides can be used as catalysts in asymmetric deprotonation reactions (Schemes 2 and 3). The first example of catalytic chiral lithium amide chemistry was reported [13] by Asami (Scheme 2). In this process an achiral base, in this case LDA, provides a stoichiometric reservoir of amidoli-thium reagent. However, deprotonation of the epoxide is affected primarily by the chiral lithium amide 11 rather than the relative excess of LDA. Turnover is possible since the resulting chiral secondary amine 10 can be deprotonated by the remaining reservoir of LDA thus regenerating the chiral base 11. For example, the deprotonation of cyclohexene oxide 8 in the presence of DBU as an additive gives the allylic alcohol 9 in 74 % ee (82 % yield) using 50 mol% of chiral base 11. 

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. 

During the last decades, a number of chiral lithium amides have been developed for stereoselective deprotonation of, e.g., epoxides. For example, the lithium amide lithium (5 )-2-(pyrrolidin-l-yl-methyl)pyrroli-dide (4) was for a long time the most stereoselective base used in epoxide deprotonations. It gives 90% of the (5 )-enantiomer and 10% of the (/ )-enantiomer upon deprotonation of cyclohexene oxide 2 in THF solution (Scheme 2) [4-6]. 

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... 

Andersson developed chiral lithium amide 1 for the enantioselective base-mediated transformation of /neso-epoxides to allyl alcohols (Scheme 2.2). The combined use of lithium diisopropylamide (LDA) and 1,8-diazabicy-clo[5.4.0]undec-7-ene (DBU) with 1 was essential, and cyclic meso-epoxides 2 gave the corresponding 2-cycloalken-l-ol derivatives 3 with high enantioselectivities. 

Kinetic resolution can also be accomplished via eliminative pathways. Thus, the enantiomerically enriched allylic alcohol 102 can be prepared from the meso epoxide 96 with up to 96% ee by the action of LDA in the presence of the chiral diamine 101 and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The DBU is believed to function as an aggregation modifier, and the active catalyst is theorized to be a heterodimer of the lithium amide (deprotonated 101) and DBU, although some nonlinear effects have been observed at low DBU concentrations <00JA6610>. Dipyrrolidino derivatives (e.g., 104) have also demonstrated utility with regard to kinetic resolution <00H1029>. 

Subsequent work [55-65], in particular by Asami [56-60] and Andersson [61-65], has led to the development of catalytic methods in which a sub-stoichiometric amount of a chiral diamine such as 61 or 62 is used with an over-stoichiometric quantity of an achiral lithium amide base such as LDA (Scheme 13.29). Examples of catalytic epoxide isomerizations using the Asami diamine 61 or the Andersson... 

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. ... 

Acetals as Chiral Auxiliaries. There have been many applications of acetals of 2,4-pentanediol as chiral auxiliaries to control the diastereoselectivity of reactions on another functional group. Examples include cyclopropanation of alkenyl dioxanes, lithium amide-mediated isomerization of epoxides to allylic alcohols, and addition of dioxane-substituted Grignard reagents or organolithiums to aldehydes. 

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