Prochiral acetophenone

Labande et al. tested the rhodium(I) complexes of diphenylphosphinoferrocenyl functionalised NHC ligands (Cp,Cp and Cp,Cp substitution) in the hydrosilylation of ketones finding these complexes of only moderate activity [186]. As no attempt was made for the chiral resolution of the catalysts prior to use in catalysis, the prochiral acetophenone could not be tested in asymmetric catalysis. 

Assuming that the enantioselection mechanism for artificial transfer hydroge-nases using biotinylated d -piano-stool complexes should be similar to the homogeneous systems, we initially focused on the reduction of prochiral acetophenone derivatives [57-59]. Systematic variation of the pH revealed that these systems perform best at pH 6.25. As the pH rises during catalysis, we used a mixed buffer consisting of a sodium formate and boric acid mixture. Addition of MOPS further contributed to stabilization of the pH and improved the selectivity of the system. 

Stable achiral or prochiral intermediate. For example. Geotrichum candidum IFO 5767 can transform a racemic mixture of 1-phenylethanol in water to give the (R)-enantiomer in 96% yield after 24h (Scheme 5.56) [146]. It is interesting to note that oxidation to prochiral acetophenone occurs in only 4% yield. The recovered 1-phenylethanol was shown to be a 99.5 0.5 mixture of the (R)- and (S)-enantiomers. The origin of the irreversibility, which provides the driving force to overcome the entropy balance, is still unknown. 

Zhang K, Wang H, Zhao S, Niu D, Lu J (2009) Asymmetric electrochemical carboxylation of prochiral acetophenone an efficient route to optically active atrolactic acid via selective fixation of carbon dioxide. J Elctroanal Chem 630 35-41... 

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 One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands.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. 

In order to broaden the field of biocatalysis in ionic liquids, other enzyme classes have also been screened. Of special interest are oxidoreductases for the enan-tioselective reduction of prochiral ketones [40]. Formate dehydrogenase from Candida boidinii was found to be stable and active in mixtures of [MMIM][MeS04] with buffer (Entry 12) [41]. So far, however, we have not been able to find an alcohol dehydrogenase that is active in the presence of ionic liquids in order to make use of another advantage of ionic liquids that they increase the solubility of hydrophobic compounds in aqueous systems. On addition of 40 % v/v of [MMIM][MeS04] to water, for example, the solubility of acetophenone is increased from 20 mmol to 200 mmol L ... 

Ruthenium complexes of (129) and (130)336 were investigated for the asymmetric hydrogenation of prochiral 2-R-propenoic acids (Scheme 62a) rhodium complexes of these ligands were used for hydrogenation of acetoamido-cinnamic acid methyl ester (Scheme 62c) and hydrogenation of acetophenone-benzylamine (Scheme 62b). The results obtained with these... 

A different MS-based ee-assay makes use of a proline-derived mass-tagged acylating agent.95 In the course of derivatization it is necessary that some degree of kinetic resolution comes about. The sensitivity of the method was reported to be 10% ee. It can also be applied to the reaction of a prochiral compound lacking enantiotopic groups, as in the transformation of acetophenone to phenylethanol. 

Related to these enzyme -catalysed reactions are electroreductions of acetophenone in the presence of chiral crown ethers. The low optical yields (<3%) are attributed to association of the prochiral substrate and the chiral crown ether salt complex in the electrochemical double layer (Horner and Brich, 1978). 

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. 

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... 

The involvement of trialkylboranes in these reactions was probed by use of the optically active trialkylborohydride 52, shown in Eq. (16) (59). In previous work, 52 had been demonstrated to reduce the prochiral ketone acetophenone to 1-phenylethanol of 17% optical purity (80). Compound 52 was then used to generate the unstable anionic formyls 6, 12, and 26 (Table I) subsequently, acetophenone was added to these reaction mixtures. If Eq. (16) were reversible and 52 were the active hydride transfer agent, 1-phenylethanol of 17% optical purity would be expected. In practice, optical purities of 3.1-11.7% were obtained (39). This indicates some type of trialkylborane involvement in the hydride transfer (the exact role cannot be readily determined by experiment). Therefore, it became important to attempt similar reactions with isolable, purified formyl complexes. 

Since the discoveries of Itsuno32 and Corey,33 remarkable advances have been made in the enantio-selective reduction of prochiral ketones using amino alcohol-derived oxazaborolidines (see Chapter 16).34 35 In most cases, these amino alcohols were obtained from chiral pool sources. Consequently, extensive synthetic manipulations were often necessary to access their unnatural antipode. Didier and co-workers were first to examine the potential of m-aminoindanol as a ligand for the asymmetric oxazaborolidine reduction of ketones.36 Several acyclic and cyclic amino alcohols were screened for the reduction of acetophenone (Scheme 17.2), and m-aminoindanol led to the highest enantioselectivity (87% ee). 

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. ... 

Recently, the preparation of the chiral biphenyl (6) and its use as a modifying agent with LAH has been reported." A complex of LAH-(6)-EtOH (1 1 1) at —78°C gives the best enantiose-lectivities in the reduction of prochiral ketones. Similar to Noyori s reagent, use of the LAH complex with (S)-(6) leads to the (S)-alcohol. Enantioselectivity is usually high for aromatic ketones (acetophenone 97% ee, 93% yield). This reagent reduces 2-octanone in higher enantioselectivity (76% ee) than 3-heptanone (36% ee). 

Enantioselective Hydrosilylation of C=0 Double Bonds in Ketones. The use of Rh-phosphorane catalyst systems to promote asymmetric hydrosilylation of prochiral ketones with silanes of the type RsSiH has met with only limited success. Thus, hydrosilylation of acetophenone with Ph2SiH2 promoted by [Rh(COD)Cl]2-(S,S)-DIOP catalyst afforded the (S)-(-)-phenylmethylcarbonyl with an optical yield of 32% ee. Similarly, the use of a Rh-NORPHOS catalyst in this reaction proceeded with an optical induction of only 16% ee. S... 

Reduction of acetophenone with the LAH complexes of nitrogen analogs of binaphthol, (/ )-(23) and (5)-(24), affords (R)-l-phenylethyl alcohol in 43% ee and 46% ee, respectively. Optical yields for the reduction of other prochiral ketones are similarly moderate. 

Enantioselective hydrogenation of prochiral carbonyl compounds with Wilkinson-type catalysts is less successful than the hydrogenation of prochiral olefins. Both rates and enantioselectivities are greatly diminished in the hydrogenation of ketones, compared with olefins. Enantioselectivities only occasionally reach 80% ee, e. g., in the hydrogenation of acetophenone with the in-situ catalyst [Rh(nbd)Cl]2/DIOP, where nbd = norbomadiene [71]. The Ru-based BINAP catalysts improved this situation, by allowing the hydrogenation of a variety of functionalized ketones in enantioselectivities close to 100% ee [72]. 

Organic molecules that contain sp2 hybridized carbons can also be prochiral if the substituent pattern is correct. An example is provided by phenylethanone (acetophenone, 9), which has three different groups attached to the carbonyl carbon. After reduction with, say, LiAlH4, the product is the chiral alcohol 10 and a 50 50 mixture of enantiomers is observed. The same racemic mixture is obtained from the reaction of the Grignard reagent MeMgBr with benzaldehyde (11). In contrast, the product of reduction of propanone (12) with LiAlH4 is propan-2-ol (13), which is not chiral. 

Reduction of acetophenone (9) with LiAIH4 gives an alcohol with a stereogenic carbon the alcohol Is racemic. The sp3-hybrid carbon is prochiral, and the faces of the carbonyl carbon are enantiotopic. 

Using the same catalyst, prochiral ketones and ketimines have been hydrogenated Acetophenone (15) gives the corresponding alcohol (16) with an ee of 8.1% for the 5-enantiomer. The best reaction conditions are toluene solution, 130°C, 100 bar, and 5 hr. The conversion is 40%, corresponding to a catalytic turnover of 280 it is essential that the chiral ligand R.R-DIOP is present in excess (81). 

Relatively high optical yields were achieved in the asymmetric reduction of acetophenone by these chiral hydride reagents however, the optimum enantiomeric excess (e.e.) achievable was 83% at that time. Two effective methods have been reported since then Thus, we initiated a study on the exploration of a new and efficient chiral ligand suitable for the asymmetric reduction of prochiral ketones, and found that a chiral hydride reagent formed in situ from LiAlHj and the chiral diamine (S)-2-(anilinomethyI)pyrrolidine la) is efficient for the reduction of acetophenone, affording (S)-l-phenylethanol in 92% e.e. . Examination of the effect of the N-substituent in the diamine la-m) on the enantioselectivity in the asymmetric reduction of acetophenone, revealed that when a phenyl or 2,6-xylyl substituent was employed, 1-phenylethanol was obtained in 95% e.e. (Table 1)... 

Polymer-supported chiral oxazoborolidines have also been used for the reduction of prochiral ketones. Enantiomeric excesses of 98% were obtained for the reduction of acetophenone using borane dimethyl sulfide as a stoichiometric reducing agent [77, 78]. 

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