Asymmetric alkylation of ketones

The efficiency of the palladium-catalyzed asymmetric alkylation of ketone enolates was shown by Trost and coworkers in their synthesis of hamigeran B (50), a potent antiviral agent with low cytotoxicity to host cells (equation 15). The quaternary center... 

For the asymmetric alkylation of ketones and aldehydes, a highly practical method was developed by the Enders group, and uses SAMP-RAMP hydrazones (reviews [104-107]). SAMP and RAMP are acronyms for orR-l-amino-2-methoxymethylpyrrolidine. This chiral hydrazine is used in an asymmetric version of the dimethylhydrazone methodology originally developed by Corey and Enders... 

Table 3.10. Koga s asymmetric alkylation of ketones (Scheme 3.25 [148])...

Ketone and aldehyde azaenolates. Perhaps the most versatile of the auxiliaries for the asymmetric alkylation of ketones and aldehydes are the SAMP/RAMP hydra-... 

Catalytic Asymmetric Alkylation of Ketones Using Grignard Reagents. 116... 

The experimental data collected so far indicate cuprate-carbonyl jr-complex as a viable intermediate in the 1,2-addition of organocuprate to carbonyl compounds. Thus, the jr-complex 93 and the transition state proposed by Harutyunyan et al. for their copper-catalysed asymmetric alkylations of ketones seems to be viable as well. With respect to a-substituted a,p-unsaturated carbonyl compounds, the picture is less clear, warranting further investigations (Scheme 33). The principal problems that need to be addressed are (1) the difference in stability of the intermediates (olefin-copper ir-complex and Cu(III)-species) formed either using non-a- or a-substituted a,p-unsaturated ketones and (2) the effective status of the equilibrium (if there is any) between the olefin-copper and the carbonyl-copper jr-complexes formed either using non-a- or a-substituted a,p-unsaturated ketones. 

Scheme 26.11 Asymmetric alkylation of ketones promoted by chiral Bronsted acids.

Figure 2. The tight ion pair 17 in the asymmetric alkylation of the cyclic ketones.

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

Substrate-induced diastereoselection is the most common principle in alkylations of enolates derived from ketones. There are numerous successful applications reported in the literature (for extensive reviews, see refs 1, 3, and 79). The following account does not cover this extensive field with all its applications in detail, but rather presents representative examples which provide a general overview of the different synthetic methods available for alkylations of ketone enolates of various structural types, as well as demonstrating that remote asymmetric induction can be efficient and predictable. 

There are few examples of asymmetric alkylations of enolates derived from open-chain ketones, presumably because alkylation proceeds with low stereoselectivity in such conforma-tionally flexible systems. 

In addition, the /erf-butyl esters of valine and tert-leucine are excellent chiral auxiliaries in asymmetric alkylation of their imines. These chiral auxiliaries are preferentially used in the alkylation of cyclic ketones (73 to >99% ee)17 and /i-oxo esters (44 to >99% ee)18,, 9 and the absolute configuration of the products can be safely predicted. 

Using diethyl ether as solvent, SAMP/RAMP-hydrazones of acyclic ketones are alkylated in good chemical yield and generally enantiomeric purities of > 90 % are achieved (see Table 3). Most prominent is the preparation of the alarm pheromone of the ant, ( + )-(5T)-4-methyl-3-hep-tanone, which proceeds with practically complete asymmetric induction5,38. Lower enantiomeric excesses (10-30%) are obtained in the alkylation of ketones which contain a phenyl substituent at the alkylated carbon3,8. 

Asymmetric reduction of ketones. Ipc BCl is somewhat superior to B-3-pin-anyl-9-borabicyclo[3.3.1]nonane (12, 397) for enantioselective reduction of alkyl aryl ketones at normal pressures to (S)-alcohols. In general, optical yields are 78-98%. It is also useful for asymmetric reduction of ketones in which one alkyl group is tertiary. Thus 3,3-dimethyl-2-butanone is reduced in 95% ee at 25°.1... 

Rhodium catalyzed asymmetric hydrosilation of ketones is an excellent route to chiral alcohols in reasonable chemical yields. The reaction occurs by treatment of alkyl... 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

A Et2Zn-(5, S)-linked-BINOL (21) complex has been found suitable for chemos-elective enolate formation from a hydroxy ketone in the presence of isomerizable aliphatic iV-diphenylphosphinoylimines.103 The reaction proceeded smoothly and /9- alkyl-yS-amino-a-hydroxy ketones were obtained in good yield and high enantioselectivity (up to 99% ee). A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL (22) has exhibited an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol% without deterioration in enantioselectivity.104... 

The asymmetric alkylation of cyclic ketones, imines of glycine esters, and achiral, enolizable carbonyl compounds in the presence of chiral phase-transfer organoca-talysts is an efficient method for the preparation of a broad variety of interesting compounds in the optically active form. The reactions are not only highly efficient, as has been shown impressively by, e.g., the synthesis of enantiomerically pure a-amino acids, but also employ readily available and inexpensive catalysts. This makes enantioselective alkylation via chiral phase-transfer catalysts attractive for large-scale applications also. A broad range of highly efficient chiral phase-transfer catalysts is also available. 

In the mid-1980s Merck chemists developed a method for asymmetric alkylation of a cyclic ketone in the presence of a simple cinchona alkaloid (see also Section 3.1) [50-52], The resulting product 23, bearing a quaternary stereogenic center, is an intermediate in the synthesis of indacrinone 20 (Scheme 14.9). It should be noted that this impressive contribution from Merck chemists was not only the first exam-... 

Asymmetric alkylation of benzaldehyde can be performed in a toluene/FC-72 biphasic system with Ti(0-iPr)4 and the fluorous BINOL ligand 7 (Figure 2) with reasonable yield and enantioselectivity [24]. The asymmetric hydrogen-transfer reduction of ketones works fairly... 

Complex 32 has been employed in the asymmetric hydrosilylation of ketones, displaying good activity and excellent enantioselectivities (92% < ee < 98%) for aryl-alkyl ketones, while the selectivity observed in the transformation of the more demanding dialkyl ketones is somewhat lower (67% < ee < 96%). 

Memory of chirality signifies asymmetric transformation in which the chirality of the starting materials is preserved in the configurationally labile intermediates (typically enolates) during the transformation. A typical example of memory of chirality is the alkylation of ketone 23 and a-amino acid ester 40. Before and after our first report on the memory of chirality in 1991, several related phenomena have been reported. 

Asymmetric reduction of ketones The reagent prepared from 1 and diborane reduces alkyl phenyl ketones to (R)-benzyl alcohols in 94-100% ee. Aliphatic methyl ketones can also be reduced to (R)-secondary alcohols in 55-78% ee. The enantioselectivity increases with the steric bulk of the alkyl group it is highest with a r-alkyl group. 

Asymmetric reduction of ketones (10, 429). Elevated pressures (6000 atm.) not only increase the rate of reduction of ketones, but also improve the enantioselectivity, which is largely dependent on differences in the size of the two alkyl groups. Although a highly hindered ketone (f-butyl methyl ketone) is not reduced even under pressure. 

Asymmetric reduction of ketones.1 Lithium aluminum hydride, after partial decomposition with 1 equiv. of 1 and an amine additive such as N-benzylmethylamine, can effect asymmetric reduction of prochiral ketones at temperatures of — 20°. The highest selectivity is observed with aryl alkyl ketones (55-87% ee), but dialkyl ketones can be reduced stereoselectively if the two groups are sterically different. Thus cyclohexyl methyl ketone can be reduced with 71% ee. 

Asymmetric induction occurs during the alkylation of ketones with the a-sulfinyl carbanion derived from optically active 1-chloroalkyl-p-tolyl sulfoxides (equation 18). The resulting chloro alcohol may be converted to an optically active epoxide under alk ine conditions and the sulfinyl group is removed with n-butyllithium. While the process benefits from high asymmetric induction in the alkylatitm reaction, it must be recognized that, when either R 91H and/or R R diasteretHnerk compounds are formed and require separation. 

Asymmetric synthesis of ketones (7, 17). Meyers and Williams have extended the asymmetric alkylation of cyclohexanones via the imines formed from 1 to acyclic ketones. Initially optical yields were only 3-44%, but they can be increased to 20-98% by heating the lithioenamines to reflux (THF) prior to alkylation at -78°. Evidently the lithioenamines formed at —20° are mixtures of (E)- and (Z)-isomers. The optical yields are lowered as the size of substituents on the ketone increases. Example ... 

Asymmetric synthesis of ketones and acids A new synthesis of chiral ketones and acids starts with the reaction of an anhydride or an acid chloride with either I-or li-ephedrin to form a chiral N,N-disubstituted amide (1) in almost quantitative yield. The amide (1) is then alkylated via the anion to give 2, which contains three asymmetric centers. Acid hydrolysis of 2 gives a carboxylic acid (3) with an optical yield of 75% (two examples). Cleavage of 2 with methyllithium gives a methyl ketone (4), in optical yields of 45-75%. 

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