Amide bases, chiral, deprotonation

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

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... 

Snapper and Hoveyda reported a catalytic enantioselective Strecker reaction of aldimines using peptide-based chiral titanium complex [Eq. (13.11)]. Rapid and combinatorial tuning of the catalyst structure is possible in their approach. Based on kinetic studies, bifunctional transition state model 24 was proposed, in which titanium acts as a Lewis acid to activate an imine and an amide carbonyl oxygen acts as a Bronsted base to deprotonate HCN. Related catalyst is also effective in an enantioselective epoxide opening by cyanide "... 

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>. 

The 3-acyl-2-oxazolidinones are readily deprotonated by strong, sterically hindered amide bases in dry telrahydrofuran at low temperature to afford the. vyn-enolates. Alkylation then provides products with induced chirality in the a-position of the amide with good to excellent di as tereo selectivities. 

Recently, Henderson has investigated the effect of Lewis base additives such as HMPA in enantioselective deprotonation of ketones mediated by chiral magnesium amide bases. In almost all reactions investigated, the additive HMPA could be replaced by DMPU without any undue effect on either selectivity or conversion (equation 69) ... 

Deprotonation of carbonyl compounds by chiral amide bases followed by trapping with silylating agents or aldehydes has become a common method for de-symmetrizing prochiral and conformationally locked 4-substituted cyclohexanones and bicyclic ketones. The literature through 1997 has been reviewed [45]. 

Similar results have been obtained for related compounds 174 for example, 404 is asymmetrically deprotonated by chiral lithium amide bases.81 Dearomatising cyclisation... 

A dearomatising asymmetric cyclisation initiated by deprotonation with a chiral lithium amide base is discussed in section 5.4. 

Davidsson, Johansson and Abrahamsson reported the use of polymer-supported chiral lithium amides in the deprotonation of cyclohexene oxide30. Interestingly, polymer base A provided allylic alcohol 2 in 67% yield and 91% ee of the (S )-enantiomer, after 12 h, which was a higher enantioselectivity than the non-polymer corresponding lithium amide which gave only 47% yield and 19% of the (S )-enantiomer (Scheme 17). In contrast, polymer B was found to show low efficiency 12% yield and 70% ee of the (S )-enantiomer... 

Cain, C.M., Cousins, R.P.C., Coubarides, G., and Simpkins, N.S. 1990. Asymmetric deprotonation of prochiral ketones using chiral lithium amide bases. Tetrahedron 46, 523—544. 

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. ... 

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. 

Novel and readily accessible polymer-supported chiral magnesium amide reagents have been prepared and shown to be effective in the asymmetric deprotonation of a series of prochiral cyclohexanones, affording good to excellent conversion and enantiomeric ratio (up to 93 7) the Merrifield-based chiral amine species has been shown to be readily recyclable (Scheme 3.39) [29]. 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

The first successful chiral deprotonation was reported in 1980 by Whitesell, who found that epoxides could be deprotonated with chiral amide bases to generate optically active allylic alcohols with ee s up to 31% [54]. In 1986 Simpkins and Koga independently reported stoichiometric asymmetric deprotonations of ketones. Koga studied the deprotonation of prochiral 4-alkyl-cyclohexanones... 

Simpkins examined the deprotonation of 2,6-dimethylcyclohexanone using a series of chiral amide bases. Enantioselectivity up to 74% was achieved using the bicyclicbase 13,Eq. (17) [57]. 

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-... 

Enantioselective deprotonation by chiral lithium amide bases has been reported. The degree of asymmetric induction depends on the base and on the bulkiness of the alkyl group in the cyclohexanone (Scheme U) ... 

Deprotonation of the chiral 1,2-oxazine (34) by n-butyllithium proceeds with a high degree of stereoselectivity cis to the C-6 substituent subsequent capture of this carbanion with carbonyl compounds also proceeds syn to the C-6 substituent, so that the overall process occurs with retention of configuration at C-4 (Scheme 16). Although the related 1,2-oxazine (3 has not been condensed with carbonyl compounds, it is useful to note that the regioselectivity of its deprotonation can be easily controlled by the size of the base employed. Bulky amide bases preferentially abstract the proton at the exocyclic methyl group, whereas small amide bases such as lithium dimethyiamide preferentially abstract a proton at C-4. ... 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

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. 

Both dimethylphenylphosphine-borane (107) and -sulfide (108) are enantio-selectively deprotonated by a lithiumalkyl (—)-sparteine complex as demonstrated by subsequent reaction with electrophiles to give products with e.e. values of 80-87% (Scheme 8). Oxidative coupling of (109) in the presence of copper(II) pivalate gives the (S. S)-isomer (110) as the major product. Asymmetric metalla-tion and silylation of diphenylphosphinyl ferrocene (111) using the chiral lithium amide base derived from di(l-methylbenzyl)amine has been reported to give an... 

Remarkable improvements in chiral base-mediated reactions of prochiral ketones under external quench (EQ) conditions with TMS-Cl, furnishing enantiomerically pure enol silanes, were found upon deprotonation in the presence of LiCl. [22, 24] Simpkins et al. studied for instance the conversion of 4-tert-butylcyclohexanone 9 into enol silane 10 by employing the chiral amide base 11 (Scheme 9). [24] Applying the TMS-Cl in situ quench (TMS-Cl-ISQ) protocol a higher level of enantiomeric excess was observed compared to external quench conditions (EQ). However, under external quench conditions in the presence of LiCl (EQ-i-LiCl procedure) significantly higher levels of asymme-... 

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