Enantioselective reduction acetophenone

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

The hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

Riant et al. in 2006 reported an enantioselective reductive aldol reaction of acetophenone and methyl acrylate mediated by PhSiH3 (140 mol %) and catalyzed by a complex generated in situ from [CuF(Ph3P)3]2MeOH (1-3 mol %) and a chiral bisphosphine (1-3 mol %) [57]. According to Mori s... 

In 1969, Fiaud and Kagan[U1 tested ephedrine boranes but achieved only 3.6-5% enantiomeric excess in the reduction of acetophenone. Itsuno et a/.[121 reported in 1981 an interesting enantioselective reduction of a ketone using an amino alcohol-borane complex as a catalyst. Buono[131 investigated and developed the reactivity of phosphorus compounds as ligands in borane complexes for asymmetric hydrogenation. 

A detailed kinetic study of the enantioselective reduction of acetophenones, ArCOMe, to arylethanols, using a propan-2-ol-acetone couple and a chiral rhodium diamine catalyst, has been undertaken.Non-linear effects on the % ee are observed, e.g. addition of achiral ketones can both slow the reaction and raise the ee. These effects can be rationalized in terms of the difference in reactivity of diastereomeric catalytic sites. The scope for exploiting such mechanistic insights so as to maximize the enantioselectivity is discussed. 

Scheme 5.4 shows some examples of enantioselective reduction of ketones using I. Adducts of borane with several other chiral /i-aminoalcohols are being explored as chiral catalyst for reduction of ketones.102 Table 5.6 shows the enantioselectivity of several of these catalysts toward acetophenone. 

Figure I.IAJ shows that after addition of NADP, reductions were more efficient. Gonversion of acetophenone was complete after a reaction time of 20 min. ADH activity in E. coli BL21(DE3)/pAW-3 is threefold higher than in E. coli BL21(DE3)/ pAW-4 cells. Enantioselective reductions of various ketones are more efficient using E. coli BL21(DE3)/pAW-3 than with pAW-4. All ketones were reduced completely in a stereoselective manner alcohols were formed with >99% ee and de.

A modified oxazaborolidine 2 catalyzing the enantioselective reduction of acetophenone or tetralone with borane proved to give ttn values in the same order of magnitude [10, 11]. Using a special hydroxyproUne-based polymer-enlarged oxazaborolidine 3, a ttn of 1400 for the reduction of tetralone was achieved (Fig. 3.1.3, 3) [5, 12]. 

Enantioselective reduction of acetophenone was achieved in a ruthenium-catalysed hydrogen transfer reaction using isopropanol as the hydrogen source in the presence of mono-tosylated (R, R)-diphenylethylenediamine, ephedrine or norephedrine as chiral auxiliary ligands. Under optimised conditions, ( R)-l-phenylethanol was obtained in 90% yield and 82% enantiomeric excess (ee) within 9 min. f-Butylphenylketone was reduced under similar conditions in almost quantitative yield but in moderate ee... 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

In 1987, Corey and co-workers proved that highly enantioselective reduction of ketones could be achieved by using stoichiometric borane in the presence of catalytic amounts of the oxazaborolidine 28a11 (Scheme 4.3j). Compound 28a, synthesized by heating (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine at reflux in THF with 3 equivalents of BH3 THF, shows excellent catalytic activity for the asymmetric reduction of acetophenone and other ketones. The B -methylated analog 28b was later synthesized to improve the air and moisture sensitivity associated with 28a. The third analog, 28c, with a 2-naphthyl substituent on the oxazaborolidine ring, has proven to be the best to afford the alcohol 29 with superb levels of enantioselectivity. 

The enantioselective reduction of acetophenone using pyrrolidine-oxazoline-derived ligand 6.77 and [IrCl(COD)]2 gave optically pure alcohol (41-49% ee). n OH... 

The ee s of the obtained alcohols increase according to the increase in steric bulkiness of the alkyl substituents of prochiral ketones. Thus the reduction of t-butyl phenyl ketone occurs with 86% ee whereas reduction of acetophenone gives 51% ee. The enantioselective reduction of f-butyl phenyl ketone and a-tetralone (86 and 88% ee, respectively) are among the most selective of those reported. ... 

The enantioselective reduction of cyclic conjugated enones may be best accomplished using a complex of LAH with (11) to which EAP has been added.Optimum conditions for these reductions involve treatment of the ketone with 3 equiv of a 1 1 2 complex of LAH-(—)-(ll)-EAP in ether at —78 °C for 3 h (Table 3). However, under these conditions, acetophenone is reduced to the (R)-alcohol in only 54% ee. 

Chiral modification is not limited to boronate and aluminate complexes. Boranes or alanes are partially decomposed with protic substances such as chiral amines, alcohols or amino alcohols to form useful reagents for enantioselective reduction of carbonyl compounds. For example, reduction of acetophenone with borane modified with the amines (65) to (67) gives (5)-l-phenylethyl alcohol with 3.5-20%... 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

The extent of asymmetric induction with chiral Rh(I) complexes remains unsatisfactory. Enantioselective reduction of acetophenone catalyzed by a Rh complex of the chiral phenanthroline 11 in 2-propanol containing KOH at 60 °C af-... 

Although the catalytic asymmetric borane reductions mentioned above are a powerful tool to obtain highly enantio-enriched alcohols, these require the use of a rather expensive and potentially dangerous borane complex. Sodium borohydride and its solution are safe to handle and inexpensive compared to borane complexes. Thus sodium borohydride is one of the most common industrial reducing agents. However its use in catalytic enantioselective reductions has been limited. One of the most simple asymmetric catalysts is an enantiopure quaternary armnonium salt that acts as phase-transfer catalyst. For instance, in the presence of the chiral salt 81 (Fig. 9), sodium borohydride reduction of acetophenone gave the secondary alcohol in 39% ee [124]. The polymer-supported chiral phase-transfer catalyst 82 (Fig. 10) was developed for the same reduction to give the alcohol in 56% ee [125]. 

A detailed kinetic study of the enantioselective reduction of acetophenones, ArCOMe, to arylethanols, using a propan-2-ol-acetone couple and a chiral rhodium diamine catalyst, has been undertaken.Non-linear effects on the % ee are observed,... 

The first attempt to use a chiral ligand to modify borane was Kagan s attempt at enantioselective reduction of acetophenone using amphetamine-borane and desoxy-ephedrine-borane in 1969 [18]. However, both reagents afforded 1-phenyl ethanol in <5% ee. The most successful borane-derived reagents are oxazaborolidines, introduced by Hirao in 1981, developed by Itsuno, and further developed by Corey several years later (reviews [19,20]). Figure 7.2 illustrates several of the Hirao-Itsuno and Corey oxazaborolidines that have been evaluated to date. All of these examples are derived from amino acids by reduction or Grignard addition. Hirao... 

In order to discover new modifiers in the hydrogenation of both C=0 and C=C bonds we have tested fS7-Qr,a-diphenil-2-pyrrolidinmethanol (DPPM) (Scheme 1), which was used as a ligand in the transition metal complex catalyzed enantioselective reduction of prochiral ketons, like acetophenone and pinacolone [8, 9, 10]. 

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