Lithium amide enantiomerically pure

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... 

Deprotonation of tropinone (1) with various chiral lithium amides and external quenching of the lithium enolate with benzaldehyde gives the aldol product 2 in moderate to good yield with moderate enantiomeric excess but high diastcrcosclcctivity. The aldol product 2 is a single diastereomer with the relative configuration as depicted, but of unknown absolute configuration19. Recrystallization of the aldol product leads to enantiomerically pure material. 

Enantiomerically pure a-amino aldehydes containing nonpolar side chains such as Boc-Ala-H, Boc-Leu-H, and Boc-Phe-H are synthesized by lithium aluminum hydride reduction of the corresponding Weinreb amides, Boc-Ala-N(Me)OMe, Boc-Leu-N(Me)OMe, and Boc-Phe-N(Me)OMe, respectively (Table 4). The lithium aluminum hydride does not affect the Boc group due to the low temperature and short 15-minute reaction time. Successful synthesis of side-chain Bzl-protected Boc-Thr(Bzl)-H gives a 95% yield of crude product, however, reduction of N-protected aspartyl and glutamyl aldehydes from their corresponding A-methoxy-A-methylamides leads to overreduction and unreacted hydroxamateJ1920 ... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

This method was also used for the preparation of P-chiral phosphinoselenoic amides (Rp,5)-61 and (Sp,S)-62 (Scheme 19). Enantiomerically pure amides 61,62 were synthesized by reaction of racemic phosphinoselenoic chlorides rac-60 with opticaUy-active lithium amides. Two diastereomers of (Rp,S)-61 and (Sp,S)-62 were formed in a nearly equal ratio in high yields, and the two diastereomers were successfully separated by column chromatography on silica gel. The absolute configuration of phosphinoselenoic amide (/ p,S )-61 was determined by X-ray analysis. Using this reaction, enantiomerically pure salts of phosphinoselenoic acid 63 and P-chiral phosphinoselenoic chlorides ( )-(5)-60 were prepared (Scheme 20) [45, 46]. 

The preparation of enantiopure or enriched complexes possessing planar chirality has been accomplished either by resolution of racemic mixtures or by asymmetric syntheses. Reported methods for the resolution of planar chirality include both chemical and kinetic resolution procedures, whilst reported asymmetric syntheses of enantiomerically pure or enriched benchrotrenic complexes include enantioselective ort/io-deprotonations with chiral lithium amide bases, and the transfer of side chain chirality onto the arene ring mediated by diastereoselective orf/io-nucleophilic additions and o/tfeo-metalations. 

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. ... 

Alternatively, (trimethylenemethane)iron complexes can be synthesized by disproportionation of tricarbonyl(2-methallyl)ironJ Enantiomerically pure tricarbonyl-(trimethylenemethane)iron complexes can be obtained by resolution of the racemic mixture via diastereomeric esters or amides. (5)-(-)-Ethyl lactate and (/ I)-(+)-a-methyl-benzylamine are employed as resolving reagents for this piupose. The chiral auxiliaries can be removed by a variety of reagents leaving the (trimethylenemethane)iron fragment unaffected. Treatment of both the corresponding Boc-protected amides and the chiral esters with diisobutylaluminum hydride (DIBAL) or methyllithium provides the primary or tertiary alcohols, respectively. Saponification of the ester with lithium hydroxide in methanol and subsequent acidification of the mixture affords the methyl ester. Treatment of the ester with triethylsilane leads to complete reduction of the functionality to leave a methyl group (Scheme 4—85). ... 

Recently, many research groups have focused their efforts oti the development of stereoselective routes leading to optically pure aminophosphinic acids. With this aim, Yamagishi and co-workers recently devised a practical methodology for the preparation of optically pure A-protected 1,1-diethoxyethyl(aminomethyl) phosphinates (12) [39] and their participation in diastereoselective alkylation reactions [40] which were first studied several years ago by McCleery and Tuck [41] (Scheme 4). In particular, they managed to obtain on a gram-scale and 99 % enantiomeric excess (ee) compound 11, after addition of paraformaldehyde to l,l-diethoxyethyl-//-phosphinate (10) and subsequent lipase-catalyzed resolution of the resulting racemic alcohol. Conversion of 11 to substrate 12 in four steps afforded a valuable substrate suitable for lithium bis(trimethylsilyl)amide (LHMDS)-promoted alkylation performed in a diastereoselective fashion (dr = 10 1) (Scheme 4). 

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