Deprotonation enantioselective

In all examples of enantioselective deprotonation of meso-epoxides with organo-... 

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. 

Alkyldimethylphosphine-boranes 74 underwent enantioselective deprotonation employing (-)-sparteine/s-BuLi, followed by oxidation with molecular oxygen [91, 92] in the presence of triethyl phosphite (Scheme 12) to afford moderate yields of enantiomerically enriched alkyl(hydroxymethyl)methylphosphine-bo-ranes 76, with 91-93% ee in the case of a bulky alkyl group and 75-81% ee in the case of cyclohexyl or phenyl groups [93]. Except for the adamantyl derivative (in which the ee increased to 99%), no major improvement in the ee was observed after recrystallization. 

We further synthesized unsymmetrical MiniPHOS derivatives 13b (Scheme 13) [30]. Thus, enantioselective deprotonation of l-adamantyl(dimethyl)phos-phine-borane (74, R = 1 -Ad), followed by treatment with ferf-butyldichlorophos-phine or 1-adamantyldichlorophosphine, methylmagnesium bromide and bo-rane-THF complex afforded the optically active diphosphine-boranes 82b as a mixture with the corresponding raeso-diastereomer. Enantiomerically pure unsymmetrical MiniPHOS-boranes 82b were obtained by column chromatography on silica gel or separation by recycling preparative HPLC. 

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... 

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric hydrogens and the chiral base, resulting from differences in diastere-omeric TSs.27 For example, transition structure E has been proposed for deprotonation of 4-substituted cyclohexanones by base D.28 This structure includes a chloride generated from trimethylsilyl chloride. 

A second route to nonracemic /-oxygenated allylic stannanes utilizes an enantioselective deprotonation of allylic carbamates by BuLi in the presence of (—)-sparteine. The configurationally stable a-lithio carbamate intermediate undergoes enantioselective S/,-2 reaction with Bu3SnCl and Mc SnCI (Scheme 28)65. Once formed, the /-carbamoyloxy stannanes can be inverted by successive lithiation with. s-BuLi and stannation with R3SnCl (Scheme 29)65. The former reaction proceeds with S/.-2 retention and the latter by Sf2 inversion. Nonracemic allylic carbamates can also be used to prepare chiral stannanes. Deprotonation with. s-BuLi TMEDA proceeds stereospecifically with retention (Scheme 29)65. 

The ligand synthesis is straightforward, using amino alcohols as the source of chirality in the oxazoline ring, whereas the stereochemistry in the phospholane ring is controlled by an enantioselective deprotonation using sparteine (Scheme 29.2). 

A more recent application of this chemistry was reported by Oestreich and Hoppe [74] and involved the enantioselective deprotonation of the enyne carbamate ester 125 with sec-butyllithium in the presence of (-)-sparteine (Scheme 2.41). Removal of the pro-S hydrogen atom led to the corresponding organolithium intermediate, which then underwent a highly enantioselective intramolecular 1,4-addition to the enyne. Protonation of the resulting allenyllithium species 126 provided a 70 30 mixture of the two diastereomeric allenes 127. 

Enantioselective deprotonations of meso substrates such as ketones or epoxides are firmly entrenched as a method in asymmetric synthesis, although the bulk of this work involves stoichiometric amounts of the chiral reagent. Nevertheless, a handful of reports have appeared detailing a catalytic approach to enantioselective deprotonation. The issue that ultimately determines whether an asymmetric deprotonation may be rendered catalytic is a balance of the stoichiometric base s ability... 

The (—)-sparteine-induced enantioselective deprotonation and subsequent alkylation and hydroxy alkylation has been extended to 0-benzylcarbamates and cinnamylcarbamate. 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

The enantioselective deprotonation of the borane complex 248 of A-methylisoindoline was investigated by Simpkins and coworkers (eqnation 59) . Deprotonation with i-BuLi/(—)-sparteine (11) in diethyl ether at —78°C for 1 h, followed by quenching with chlorotrimethylsilane, yielded the silanes 251, ent-252, 252, ent-25 in a ratio of 86.3 0.4 6.3 7.0 after destroying the chiral centre at nitrogen by treatment of the whole mixture with triethylamine, an e.r. 253/ewf-253 of 86.7 13.3 is expected. 

By contrast with the enantioselective deprotonation of meso oxiranes, there is only a limited number of reports on the kinetic resolution of unsymmetrically substituted oxiranes. This reaction involves the preferential recognition of one of the two enantiomers of a racemic mixture by a chiral reagent to provide both the starting material and the product in enantioenriched form . Several HCLA bases developed for enantioselective deprotonation have been tested as chiral reagent in stoichiometric or catalytic amount for the kinetic resolution of cyclic and linear oxiranes. 

As for enantioselective deprotonation, the best results are obtained with HCLA bases of type 56 which can be employed as catalyst (10 mol%) in the presence of excess amounts of LDA (2 equivalents) . In such conditions, high levels of selectivity are reached with linear and cyclic oxiranes. The general study undertaken with this base toward cyclic oxiranes has shown the beneficial influence of bulky substituents branched directly on the oxirane ring (Table 10, entries 3, 5 and 6) or on the 3-position (Table 10,... 

The enantioselective formation of bicyclic ketones through enantioselective deprotonation of the bicyclooxiranes 147,148 and 149 (Scheme 64) by homochiral lithium amides (such as 50) and subsequent rearrangement have also been reported with moderate enantiomeric excesses and yields . 

Rearrangement of an achiral epoxide to give an optically active allyl alcohol, e.g., 1, induced by enantioselective deprotonation with a homochiral base (see p 436 for the determination of absolute configuration)55. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

Enantioselective deprotonation of 4-(p-tolyl)-4-methyl cyclohexanone with lithium bis[(S)-l-phenylethyl]amide in THF at 100 C in the presence of chlorotrimethylsilane gives (R)-4-methyl-4-... 

Enantioselective deprotonation has also been used for the kinetic resolution of 2-substituted cyclohexanones rac-298. This procedure has been applied to a number of related cyclohexanones and a high level of enantioselectivity has been obtained. 

Magnesium amides have also found good utility in enantioselective deprotonation processes. A range of chiral amines has been prepared by Henderson and coworkers and it was found after conversion to their Mg-bisamide derivatives that it react with 4- and 2,6-substituted cyclohexanones with good to excellent selectivities (see Section m). Structures of some chiral magnesium amides are given in Chart 1. 

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) ... 

One other prediction may be made. The camphor azine (Table 15) is reduced to give a chiral EGB the tetramenthyl ester of ethenetetracarboxylic acid behaves similarly Given that the bases may be generated at low temperature and in the presence of cations which may be chelated it is to be expected that efficient enantioselective deprotonation by EGB s will be realised. 

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. 

Lithium amides, chiral. Koga et al.x have prepared a series of lithium amides of the type in which one carbon atom adjacent to the nitrogen is chiral and bears a bulky group (phenyl, naphthalene, r-butyl). Highest enantioselective deprotonation... 

Honda T, Kimura N et al (1994) Chiral synthesis of lignan lactones, (—)-hinokinin, (—)-deoxypodorhizone, (—)-isohibalactone and (—)-savinin by means of enantioselective deprotonation strategy. J Chem Soc Perkin Trans 1 1043-1046... 

Sparteine appears to be the best ligand examined to date in studies on the effect of ligand structure on the enantioselective deprotonation.304 The f-butoxycarbonyl group stabilizes the anion and renders a-protons more acidic. 

---