Ketones prochiral aryl alkyl

In cases where Noyori s reagent (see p. 102f.) and other enantioselective reducing agents are not successful, (+)- or (—)-chlorodiisopinocampheylborane (Ipc BCl) may help. This reagent reduces prochiral aryl and tert-alkyl ketones with exceptionally high enantiomeric excesses (J. Chandrasekharan, 1985 H.C. Brown, 1986). The initially formed boron moiety is usually removed hy precipitation with diethanolamine. Ipc2BCl has, for example, been applied to synthesize polymer-supported chiral epoxides with 90% e.e. from Merrifield resins (T. Antonsson, 1989). 

In 2000, Woodward et al. reported that LiGaH4, in combination with the S/ 0-chelate, 2-hydroxy-2 -mercapto-1,1 -binaphthyl (MTBH2), formed an active catalyst for the asymmetric reduction of prochiral ketones with catecholborane as the hydride source (Scheme 10.65). The enantioface differentiation was on the basis of the steric requirements of the ketone substituents. Aryl w-alkyl ketones were reduced in enantioselectivities of 90-93% ee, whereas alkyl methyl ketones e.g. i-Pr, Cy, t-Bu) gave lower enantioselectivities of 60-72% ee. 

The asymmetric organosilane reduction of prochiral ketones has been studied as an alternative to the asymmetric hydrogenation approach. A wide variety of chiral ligand systems in combination with transition metals can be employed for this purpose. The majority of these result in good to excellent chemical yields of the corresponding alcohols along with a trend for better ee results with aryl alkyl ketones than with prochiral dialkyl 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. 

Sinou and coworkers evaluated a range of enantiopure amino alcohols derived from tartaric acid for the ATH reduction of prochiral ketones. Various (2R,iR)-i-amino- and (alkylamino)-l,4-bis(benzyloxy)butan-2-ol were obtained from readily available (-I-)-diethyl tartrate. These enantiopure amino alcohols have been used with Ru(p-cymene)Cl2 or Ir(l) precursors as ligands in the hydrogen transfer reduction of various aryl alkyl ketones ee-values of up to 80% have been obtained using the ruthenium complex [93]. Using (2R,3R)-3-amino-l,4-bis(benzyloxy)butan-2-ol and (2R,3R)-3-(benzylamino)-l,4-bis(benzyloxy)butan-2-ol with [lr(cod)Cl]2 as precursor, the ATH of acetophenone resulted in a maximum yield of 72%, 30% ee, 3h, 25 °C in PrOH/KOH with the former, and 88% yield, 28% ee, 120 h with the latter. 

Tris[ (l S,2i )-6,6-dimethylbicylo[3.1.1]heptan-2-yl methyl]gallium reacts with ketones above room temperature, and optically active alcohols are obtained as main products (Scheme 145).438 LiGaH4, in combination with an S,0-chelate ligand, 2-hydroxy-2 -mercapto-l,T-binaphthyl (MTBH2), forms an active hydride catalyst for an asymmetric reduction of prochiral ketones with catecholborane. Enantiofacial differentiation is based on the steric requirement of the ketone substituents. Aryl//z-alkyl ketones are reduced in 90-93% ee and branched ketones RC(0)Me (e.g., R = Pr , oC6H11 Bu ) in 60-72% ee (Table 43).439 440... 

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. 

Enantioselective Ketone Reduction. The major application of chiral oxazaborolidines has been the stoichiometric (as the oxazaborolidine-borane complex) (eq 1) and catalytic (in the presence of a stoichiometric borane source) (eq 2) enantioselective reduction of prochiral ketones. These asymmetric catalysts work best for the reduction of aryl alkyl ketones, often providing very high (>95% ee) levels of enantioselectivity. 

The outlined Nugent reductive amination protocol with (R) or (S) PEA and prochiral alkyl alkyl and aryl alkyl ketones (acydic or cyclic) allows higher yields and shorter reaction times than the previously practiced two step strategy via isolated (R) or (S) PEA, see Moss, N., Gauthier, J., and Ferland, J. M., (1995) Synlett, 142 144 ... 

The enantioselectivity in the TH of prochiral aryl ketones catalysed by (arene)Ru(II) complexes depends not only on the chiral nature of the amine ligand but also on the edge-face C-H/tc interaction which stabilises the electron-rich (usually aromatic) ring of a substrate in a specific orientation as presented with TSl (Fig. 5) [43]. This interaction may explain why aryl ketones usually give better ee values than simple unfunctionalised alkyl-alkyl ketones. 

In general, OAB-catalyzed reductions are mostly effective for prochiral ketones having significantly different steric bulk between the two groups adjacent to the carbonyl to give high enantioselectivities. For example, the reduction of aryl alkyl ketone and hindered aliphatic ketone such as acetophenone and pinacolone, respectively, provided high enantioselectivities, whereas that of unhindered aliphatic ketones, namely 2-hexanone and 2-octanone, provide low to moderate enantioselectivities (Table 11.1). 

Whereas, for example, the asymmetric hydrosilylation of 2-naphthyl methyl ketone with this catalyst was carried out with 99% yield and 91% ee, the enan-tioselectivities for most aryl alkyl ketones were found to be slightly below those of the most efficient phosphane-based systems. However, the system was found to be exceptionally selective in the hydrosilylation of unsymmetrical dialkyl ketones (Table 15.5), which are difficult substrates [58]. The selectivity for the reduction of prochiral dialkyl ketones was comparable or even superior to the best previously reported for prochiral nonaromatic ketones. 

Asymmetric reduction of prochiral diaryl ketones (33 34, Scheme 12) is an important chemical transformation due to the practical significance of the resulting diaryl methanol derivatives 34 for biochemical and pharmaceutical applications [24]. It is also a challenging problem due to the lack of sufficient stereochemical bias between the two aromatic groups and coupled with a lower reactivity of diaryl ketones compared to the related aryl alkyl analogues. Chan reported catalytic... 

Another class of ligands for ATH is represented by multidentate Schiff bases and their derivatives. Zassinovich and Mestroni reported on the effective reduction of alkyl aryl ketones catalyzed by a series of lr(l) complexes with chiral bidentate pyridylaldimines, of the form [lr(cod)(NNR )]C104 (76a-f see Scheme 4.31). It was observed that both the activity and selectivity depended heavily on the nature of the subshtuents at the chiral center of the ligand, and also at the prochiral center of the substrate. Optical yields of up to 50% (R-isomer) at 100% conversion were obtained in the ATH of BuC(0)Ph and PhCH2C(0)Ph using [lr(cod)(PPEl)]C104 as the precatalyst (0.1% mol, 83 °C, PrOH, KOH) [66]. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

Asymmetric reduction of ketonesLithium aluminium hydride in conjunction with this chiral ligand reduces prochiral aromatic ketones to (S)-secondary alcohols in 90-95% optical yields. Optical yields are lower (10-40% ee) in the case of alkyl aryl ketones. It is superior to (S)-2-(anilinomethyl)pyrrolidine for this reduction. Evidently the two methyl groups enhance the enantioselectivity. 

Application of this sequence to alkyl aryl ketones generally gives the tertiary alcohols in 85-99% optical purity. However, separation of the adducts of prochiral dialkyl ketones is generally difficult. The resolution of adducts of aldehydes by chromatography is impractical desulfuration of the unresolved adducts results in optically active secondary methylcarbinols in only 25-45% optical purity. 

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