Chiral lithium amides rearrangements

A high level of enantioselectivity in an acyclic system has been reported in the rearrangement of tricarbonylchromium(O) complexes of allyl benzyl ethers using chiral lithium amide base 73 (equation 38) . Upon treatment with 1.1 equivalents of lithium amide 73 and 1 equivalent of LiCl at —78 to —50°C, ether 74 afforded the rearrangement product R)-75 in 80% yield with 96% ee. The effect of substituents on the chemical yields and enantioselectivity of the [2,3]-Wittig rearrangement was also studied (see Table 3). 

Phosphate-derived a-oxycarbanions can rearrange into a-hydroxy phosphonates. This class of rearrangement is known to proceed with retention of configuration at the carban-ion terminus. The enantioselective version of this rearrangement has been developed using a chiral lithium amide as a base (equation 115) . The reaction of benzyl dimethyl phosphate 182 with amide R,R)-63 in THF gave the hydroxy phosphonate (5 )-183 in 30% in enantioenriched form (52% ee). 

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. 

The catalytic asymmetric rearrangement of functionalized cyclohexene and cyclopentene oxides to give chiral allylic alcohols has been studied using sub-stoichiometric amounts of a chiral lithium amide in combination with a stoichiometric amount of different lithiated imidazoles (Scheme 47).79... 

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

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). 

Phosphoramidates rearrange into a-aminophosphonates using chiral lithium amide bases e.g. 31 afforded aminophosphonate 86 from phosphoramidate 85 in 13% ee and 65% yield (Scheme 61)104. A slightly higher optical purity of 26% (55% yield) was obtained with chiral (R. R)-3 as base. The application of (—)-sparteine and BuLi gave 13% ee and a yield of 30%. A higher level of enantioselectivity was reached when a bisphosphonate (87) was reacted with (R,R) 3 in THF. Although the yield was only 30%, aminophosphonate 88 was obtained in 35% ee (Scheme 61). 

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. 

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. 

Asymmetric rearrangement of cyclohexene oxide. Cyclohexene oxide is rearranged to (S)-2-cyclohexene-l-ol in 92% ee by the chiral lithium amide (2) prepared from n-butyllithium and 1. Several related (S)-2-(disubstituted aminomethyOpyrrolidines prepared from (S)-proline are almost as stereoselective. ... 

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-... 

Scheme 6.21. Asymmetric [2,3]-Wittig rearrangements using a chiral lithium amide base [70,87-89]. The transition structure leading to the major enantiomer is illustrated.

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. 

The first examples of chiral lithium amides to be used to generate a chiral organolithium species were reported by Marshall in 1987 [81] in his pioneering work into [2,3]-sigmatropic rearrangements (Hodgson et al,in this volimie) for which the Hthiiun amide 39 (Fig. 4) was used (up to 60% ee) the amine precursors to both 39 and enf-39 are commercially available. 

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]. 

More recently, they have reported an enantioselective reaction via an a-sulfi-nyl carbanion involving rearrangement to a vinyl sulfoxide [Eq. (16)] [61]. Treatment of an episulfoxide with a chiral lithium amide followed by methyla-tion yielded a methysulfinylcyclopentene with high enantioselectivity. In this reaction, the enantioselection occurs in the first deprotonation step. 

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... 

In an effort to develop a more efficient method to S5mthesize enantioenriched allylic amine substrates for [2,3]-rearrangements, Davies and Smyth reported an asymmetric conjugate addition with chiral lithium amide 74 tScheme 1S.16T ° The resulting aminoester 75 was reduced to alcohol 76, which was treated with m-CPBA to furnish chiral amine iV-oxide 77. 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

Chiral bis-lithium amide bases have been used for enantiotopic deprotonation of the sulfonium salt of 1,4-oxathiane 86. The anion undergoes an enantioselective thia-Sommelet rearrangement to afford the 3-substituted-1,4-oxathiane 87. Only bis-lithium amide bases were effective, giving products with high diastereoselectivity and with low to moderate enantioselectivity (Equation 13) <2003TL8203>. 

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