Chloroacetophenones, asymmetric

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8-30).69... 

ASYMMETRIC REDUCTION OF CHLOROACETOPHENONE USING A SULFOXIMINE CATALYST S]... 

Related catalysts for asymmetric borane reduction of ketones are open chain and cyclic phosphoric amides, in the oxidation state +3 or +5 (Scheme 11.3) [10, 11]. Early examples are the phosphonamides and phosphinamides 5a and 5b of Wills et al. [12] and the oxazaphospholidine-borane complex 6a of Buono et al. [13]. In the presence of 2-10 mol% catalysts 5a,b, co-chloroacetophenone was reduced by BH3 SMe2 with 35-46% ee [12]. For catalyst 6a a remarkable 92% ee was reported for the catalytic reduction of methyl iso-butyl ketone and 75% ee for acetophenone... 

Several absolute asymmetric Norrish type II cyclizations have been reported in the solid state. Achiral a-(3-methyladamantyl)-/ -chloroacetophenone 114 formed a chiral crystal in space group P2i2i2i. Irradiation of these crystals caused Norrish/Yang cyclization to afford the cyclobutenol-type photoproduct 115 (six chiral centers) with respectable enantiomeric excess at low conversion (Scheme 27) [101]. Photolysis in solution phase led to mixtures of four of the six possible cyclobutanols, and no trace of optical activity could be detected in the mixtures. 

Other selected examples are summarized in Table 2. In addition to aldehydes, both cyclic and acyclic ketones can be reduced equally well. sec-Phenethyl alcohol (11, R = Ph) as hydride source works more effectively than t-PrOH. On the basis of this finding, the asymmetric MPV reduction of unsymmetrical ketones with chiral alcohol in the presence of catalyst 10 was examined [30]. Treatment of 2-chloroacetophenone (12) with optically pure (R)-(+)-sec-phenethyl alcohol (1 equiv.) under the influence of catalytic 10 at 0 °C for 10 h afforded (5)-(+)-2-chloro-l-phenylethanol (13) with moderate asymmetric induction (82 %, 54 % enantiomeric excess, ee Sch. 8). Switch-... 

An asymmetric MPV reduction that uses i-PrOH, MCjAl, and a chiral bi-naphfhol has also been reported [169]. (P)-BINOL and Me Al were mixed in a 1 1 ratio in toluene and the resulting white precipitate was treated with a prochiral ketone (tenfold excess) and i-PrOH (40-fold excess) (Scheme 6.129). This simple method was found to effect the catalytic reduction of 2-chloroacetophenone at r.l. to give the alcohol in 80% ee and 99% yield. 

Equilibrium distribution coefficient (log P or log D) is an important parameter to assess the solvent effect. Asymmetric reduction of 4-chloroacetophenone to (R)-l-(4-chlorophenyl)ethanol by Lactobacillus kefir showed an increase in product yield with increase in log D value of the ILs [104]. However, auother study [117], which used ILs as coating of lipase (Novozyme 435) for esterification of methyl a-o-glucopyranoside with fatty acids, showed a remarkable increase in the product yield with increase in the polarity of the IL used for coating which is opposite in trend to that observed when ILs were used as solvent as discussed above. This altered effect of more polar IL coating on product yield was attributed to their better absorption ability on the polyacrylate beads used for immobilization of enzymes in this case [117]. 

Catechol is an intermediate for the synthesis of racemic adrenaline which, although quite medicinally active, can be resolved (ref. 36) in 71% yield to afford the more active R(-) enantiomer, the natural form, which can also be derived quantitatively by asymmetric reduction (ref. 37) of the synthetic precursor, adrenalone as the hydrochloride by catalytic hydrogenation in methanol containing the rhodium complex of (R)-o[(S)-1 ,2-bis(diphenylphosphine)ferrocenyl]ethyl alcohol. Adrenalone is obtained by the acylation of catechol with chloroacetyl chloride to afford 3,4-dihydroxy-w-chloroacetophenone followed by reaction with methylamine. 

Figure 6. Asymmetric reduction of 2-chloroacetophenone with various boron based asymmetric reducing agents...

A more appealing feature is that one-pot synthesis of chiral styrene oxides can be performed by sequential asymmetric reduction of chloroacetophenones with the chiral Rh in 2-propanol followed by treatment of the reaction mixture with NaOH aqueous solution, leading to the desired products in isolated yields of 80-90% with 96-98% ee in a single reactor (Fig. 7) [37]. For example, (5)-w-chlorostyrene oxide, which is a key intermediate for the preparation of several p3-adrenergic receptor agonist compounds, is easily obtained from a one-pot procedure. 

Fig. 7 Asymmetric reduction of a-chloroacetophenones and one-pot procedure for the synthesis of chiral epoxide...

Biphasic systems that include ionic liquids can also be applied to whole-cell biocatalysis. The ability of these solvents to act as a substrate reservoir and in situ extracting agent was demonstrated by an efficient asymmetric ketone reduction. 4-Chloroacetophenone was reduced to the key pharmaceutical intermediated (k)-l-(4-chlorophenyl) ethanol using Lactobacillus kefir cells in ILs. The indigenous cellular cofactor regeneration system remained active, which allowed high product concentrations without cofactor supplementation [34]. 

A proline-derived catalyst effectively works for the asymmetric synthesis of cyclopropanes fi om a-chloroketones. Ye and coworkers reported that a-chloroacetophenone derivatives underwent asymmetric MIRC cyclopropanation by treatment with substituted cinnamaldehyde in the presence of chiral pyrrolidine 3 and that optically active cyclopropanes 5 were obtained in good yields (Scheme 1.3) [6]. 

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