Enantioselectivity ketone deprotonation

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Asymmetric deprotonation of prochiral cychc ketones (Scheme 50) was performed with chiral ureas in the presence of butylhthium. Yields were good (85-88%) with high enantioselectivities (83-87%). Moderate enantioselectiv-ity is obtained with the cyclopentyl-containing urea (Scheme 50 37% ee with R = Ph 7% ee with R = Me) [ 168,169]. 

Another application of the hydrazone method is the preparation of achy dr oxy carbonyl compounds (R4 = H in 37). The aldehydes/ketones 36 are first transformed into their corresponding SAMP-hydrazones 38, followed by deprotonation with f-butyllithium or LDA in THF. The resulting anion undergoes facile oxidation by treatment with 2-phenylsulfonyl-3-phenyloxaziridine (39), and the product can be obtained with good to excellent enantioselectivity (Scheme 2-23).39b... 

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

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 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 . 

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... 

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) ... 

The complex of Me2Zn with (5, 5 )-ebpe, 107, has been applied successfully as catalyst in the enantioselective reduction of ketones by polymethylhydrosiloxane and combines excellent product yields with high ee values . Its structure comprises the iV,iV-chelate coordination of the ebpe ligand to the MeiZn unit (Figure 51). It is remarkable that in this case the two secondary amine functionalities are coordinated to zinc and leave the Zn—C bonds unaffected. Indeed, usually secondary amines undergo a fast deprotonation reaction with dialkylzinc compounds. 

By means of a chiral base the compound shown below can be converted enantioselectively into its lithium enolate which can be transformed into an a,p-unsaturated ketone in two subsequent steps. If deprotonation of the initial ketone occurs preferentially at the pro-R group to the extent of 92 %, what is the configuration and the enantiomeric excess of the resulting a,p-unsaturated ketone ... 

Deprotonation of other bicyclic ketones in the presence of LiCl has shown similar results (Scheme 23). Interestingly, deprotonation of tropinone (32) by 27 and using benzyl chloroformate as the electrophile resulted in ring opening to yield the enone 34 (Scheme 23a)55,56. The ee increased from 45% up to 62% upon addition of LiCl. The effect of LiCl on the enantioselectivity is also displayed in the reactions of 35 and 37 to give 36 and 38, respectively, in Schemes 23b and 23c53,54,57. 

Knochel and coworkers have reported the use of lithiated /V,/V-dialkylurcas (such as 47), which have proved to be useful for enantioselective deprotonation and alkylation of ketones. Enantioselectivities up to 88% were achieved across a range of 4-substituted cyclohexanones in the absence of HMPA. On addition of HMPA, both yield and enantioselectivity were lowered (Scheme 31)71,72. 

In some cases, a third control to be secured is that of the enantioselectivity, such as for the deprotonation of prochiral ketones with nonracemic bases (Scheme 10). 

Ketones are rarely used as electrophiles in the enantioselective aldolization while they find application to enantioselective olefination reactions such as the Horner-Wadsworth-Emmons or the Peterson reaction. For instance, the deprotonation of an achiral phos-phonoacetate by a set of chiral 2-aminoalkoxides led to the corresponding enolate that... 

Aggarwal and co-workers nsed the same key strategy but with a different Simpkins base (A,A)-41 (Cain et al. 1990) to achieve the rare enantioselective deprotonation of an eight-membered ring ketone (40, Scheme 7.9) at die low temperature of 100°C to ensure the presence of only one cyclooctanone conformer and consequently increase the enantioselectivity of the process (Aggarwal etal. 1999). 

Majewski, M., Lazny, R., and Nowak, P. 1995. Effect of lithium salts on enantioselective deprotonation of cyclic ketones. Tetrahedron Lett 36, 5465-5468. 

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