Synthesis chiral lithium amide deprotonations

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

The high propensity of organolithium compounds to form mixed complexes with other organolithium species in solution has been utilized successfully in synthesis using chiral lithium amides. Either the chiral lithium amides have been added to organolithium reagents in an effort to achieve asymmetry in addition reactions, or various additives have been introduced to alter the reactivity or selectivity of the chiral lithium amides themselves, e.g. in deprotonation reactions. 

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). 

The crucial role of the secondary liberated amine was also reported in experiments involving deprotonation with lithium (/ )-A -ethyl(l-phenylethyl)amide and reprotonation at —70°C with 2R,3R, racemic, and meso-DPTA, yielding, respectively, 70, 39, and 24% ee of the (5)-enantiomer. In the two last cases, significant inductions were obtained with the sole secondary chiral amine as chiral inductor in the medium. Since these first results, chiral lithium amides have been widely used for asymmetric synthesis. 

The organic synthesis of alkaloids has a long history and numerous synthetic approaches of the tropane skeleton have been developed, from the classical synthesis of tropine by Willstatter at the beginning of the century and comprehensively reviewed by Holmes [46], to the most recent developments dealing with asymmetric deprotonation of tropinone, with chiral lithium amide bases for the enantioselective synthesis of a range of tropanes [47]. New synthetic methods are periodically reviewed and readers interested in this area may refer to specialized literature. 

Ma, L. and WiUiard, P.G. (2006) Synthesis of polymer-supported chiral lithium amide bases and application in asymmetric deprotonation of prochiral cyclic ketones. Tetrahedron Asymmetry, 17, 3021-3029. 

Aggarwal and Olofsson have developed a direct asymmetric a-arylation of prochiral ketones using chiral lithium amide bases and diaryliodonium salts [881]. In a representative example, the deprotonation of cyclohexanone derivative 684 using chiral Simpkins (/ ,/ )-base followed by reaction with the pyridyl iodonium salt gave the arylated product 685 in 94% ee (Scheme 3.275). This reaction has been employed in a short total synthesis of the alkaloid (-)-epibatidine [881]. 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Before the emergence in the mid-1980s of the asymmetric deprotonation of cA-dimethyl cyclohexanone using enantiomerically pure lithium amide bases, few reports pertaining to the chemistry of these chiral reagents appeared. Although it is not the focus of this chapter, the optically active metal amide bases are still considered to be useful tools in organic synthesis. Readers are advised to consult the appropriate literature on the application of enantiomerically pure lithium amides in asymmetric synthesis.6... 

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. 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

Before embarking on a discussion of new reactions, it will be useful to describe recently reported examples of the synthetic utility of the reducing capabilities of the LABs. Myers has recently described a practical synthesis of chiral alcohols employing pseudoephedrine as a chiral auxiliary (4). An amide of pseudoephedrine is first deprotonated with LDA and then alkylated with the appropriate alkyl halide to give the substituted amide with 97-99% de. The amide is then reduced to the alcohol with lithium pyrrolidinoborohydride to give... 

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