Reduction of prochiral ketones

Chiral aluminium hydride for the asymmetric reduction of prochiral ketones... 

Enantioselective reductions of prochiral ketones by means of oxazaborolidines 97CLY9. 

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 ... 

Probably the first non-covalent immobilization of a chiral complex with diazaligands was the adsorption of a rhodium-diphenylethylenediamine complex on different supports [71]. These solids were used for the hydride-transfer reduction of prochiral ketones (Scheme 2) in a continuous flow reactor. The inorganic support plays a crucial role. The chiral complex was easily... 

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. 

Enantiometrically pure alcohols are important and valuable intermediates in the synthesis of pharmaceuticals and other fine chemicals. A variety of synthetic methods have been developed to obtain optically pure alcohols. Among these methods, a straightforward approach is the reduction of prochiral ketones to chiral alcohols. In this context, varieties of chiral metal complexes have been developed as catalysts in asymmetric ketone reductions [ 1-3]. However, in many cases, difficulties remain in the process operation, and in obtaining sufficient enantiomeric purity and productivity [2,3]. In addition, residual metal in the products originating from the metal catalyst presents another challenge because of the ever more stringent regulatory restrictions on the level of metals allowed in pharmaceutical products [4]. An alternative to the chemical asymmetric reduction processes is biocatalytic transformation, which offers... 

Complexation of (124) and (125) with [ Rh(COD)Cl 2] in the presence of Si(OEt)4, followed by sol-gel hydrolysis condensation, afforded new catalytic chiral hybrid material. The catalytic activities and selectivities of these solid materials have been studied in the asymmetric hydro-gen-transfer reduction of prochiral ketones and compared to that of the homogeneous rhodium complexes containing the same ligands (124) and (125) 307... 

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. 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

Since the discovery of the CBS catalyst system, many chiral //-amino alcohols have been prepared for the synthesis of new oxazoborolidine catalysts. Compounds 95 and 96 have been prepared93 from L-cysteine. Aziridine carbi-nols 97a and 97b have been prepared94 from L-serine and L-threonine, respectively. When applied in the catalytic borane reduction of prochiral ketones, good to excellent enantioselectivity can be attained (Schemes 6-42 and 6-43). 

TABLE 6-9. Asymmetric Reduction of Prochiral Ketones Using 10 mol% of ( + )-94... 

In summary, many attempts have been made at achieving enantioselective reduction of ketones. Modified lithium aluminum hydride as well as the ox-azaborolidine approach have proved to be very successful. Asymmetric hydrogenation catalyzed by a chiral ligand-coordinated transition metal complex also gives good results. Figure 6-7 lists some of the most useful chiral compounds relevant to the enantioselective reduction of prochiral ketones, and interested readers may find the corresponding applications in a number of review articles.77,96,97... 

TABLE 12. The asymmetric reduction of prochiral ketones under catalysis of chiral urea derivative 8173 (in all reactions 5% catalyst was used)... 

Attempts to induce stereochemical control in the reduction of prochiral ketones and imines have been reported using chiral ammonium borohydrides [e.g. 16] (see Chapter 12). 

Cervinka and co-workers have extensively investigated the asymmetric reduction of prochiral ketones with LAH modified with alkaloids and related amino alcohols. Most of this work has been reviewed in detail by Morrison and Mosher (1) and will not be discussed extensively here. Modification of LAH was effected with (-)-quinine (65), (- )-cinchonidine (66), (- )-ephedrine (67), (-)-A-ethyl-ephedrine (68), (-)- l-phenyl-2-dimethylaminoethanol (69), (+ )-quinidine (70), (+ )-cinchonine (71), and (+ )-pseudoephedrine (72). 

Chiral terf-diamines complexed with LAH gave very low optical yields in reductions of prochiral ketones. A/,/V,A/, /V -Tetramethyl-l,2-cyclohexanedi-amine complexed with LAH or LiAlD4 reduced phenyl alkyl, dialkyl ketones or benzaldehyde in <15% optical yields (109). 

Early studies of the asymmetric reduction of prochiral ketones by chiral aluminum alkoxides have been reviewed by Morrison and Mosher (1). Doering and Young (123) reported the reduction of methyl cyclohexyl ketone with chiral 3-methyl-2-butanol in the presence of a catalytic amount of aluminum alkoxide to give the (S)-( + )-carbinol in a 22% optical yield. Jackman and co-workers (124) similarly reduced methyl n-hexyl ketone with chiral 3,3-dimethyl-2-butanol to the (S)-( - )-carbinol in a 6% optical yield. Other attempts resulted in similar low optical yields or gave only racemic products. Since the reductions were carried out under equilibrium conditions, racemization could have accounted for the low optical yields. 

The chiral trialkylaluminum reagent used in the majority of asymmetric reduction studies is (+ )-tris[(S)-2-methylbutyl]aluminum (119) or its etherates. This reagent is readily prepared from (S)-( + )-2-methyl-l-chlorobutane (152,153). Results of the reductions of prochiral ketones with these reagents and other chiral organoaluminum reagents are shown in Table 15. 

Hydrogenation The enantioselective reduction of prochiral ketones to chiral alcohols has been intensely investigated. The highest enantioselectivity has been found for 2-acetylpyridine, which was reduced in buffered EtOH (pH 4.5), in the presence of strychnine to l-(2-pyridyl[-ethanol with 48% ee. The selectivity was... 

The asymmetric reduction of prochiral ketones to their corresponding enantiomerically enriched alcohols is one of the most important molecular transformations in synthetic chemistry (20,21). The products are versatile intermediates for the synthesis of pharmaceuticals, biologically active compounds and fine chemicals (22,23). The racemic reversible reduction of carbonyls to carbinols with superstoichiometric amounts of aluminium alkoxides in alcohols was independently discovered by Meerwein, Ponndorf and Verley (MPV) in 1925 (21—26). Only in the early 1990s, first successful versions of catalytic... 

Enantioselective borane reduction of prochiral ketones catalysed by chiral oxabor-olidines is of considerable synthetic utility, but the catalytic cycle has to compete with direct borane reduction of the ketone. Accordingly, precise kinetic data on the latter would help optimize conditions for the former. Such a study has been... 

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. 

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

In work concerning the directed evolution of enantioselective enzymes, there was a need for fast and efficient ways to determine the enantiomeric purity of chiral alcohols, which can be produced enzymatically either by reduction of prochiral ketones (e.g., 26) using reductases or by kinetic resolution of rac-acetates (e.g., 19) by lipases (111). In both systems, the CD approach is theoretically possible. In the former case, an LC column would have to separate the educt 26 from the product (A)/(J )-20, whereas in the latter, (5)/(J )-20 would have to be separated from (S)/(R)-19. 

One popular method that has been apphed to industrial processes for the enantio-selective reduction of prochiral ketones, leading to the corresponding optically active secondary alcohols, is based on the use of chiral 1,3,2-oxazaborolidines. The original catalyst and reagent system [diphenyl prolinol/methane boronic acid (R)] is known as the Corey-Bakshi-Shibata reagent. Numerous examples... 

Corey and Reichard described a more efficient synthesis of the fluoxetine enantiomers.This synthesis features a catalytic reduction of prochiral ketone 12 to install the correct absolute stereochemistry at C-3. In this respect this method is very similar to the one previously described by Robertson et However, the major... 

Some chiral oxazaphospholididine-borane catalysts can be used for enantioselective reduction of prochiral ketones by borane-THF or bor-ane-dimethyl sulfide complex (Scheme 19) (44). 

The BINAL-H reagents exhibit exceptionally high enantioface-dif-ferentiating ability in the reduction of prochiral ketones that have unsaturated substituents such as aromatic rings, olefinic and acetylenic groups, etc. The general sense of asymmetric induction of simple car-... 

Borane and aluminum hydrides modified by chiral diols or amino alcohols are well-known, effective reagents for the stoichiometric enan-tioselective reduction of prochiral ketones and related compounds (34). Reduction of prochiral aromatic ketones with the Itsuno reagent, which is prepared from a chiral, sterically congested /3-amino alcohol and borane, yields the corresponding secondary alcohols in 94-100% ee... 

Asymmetric reduction of ketones.2 A reducing agent prepared by treatment of a mixture of SnCl2 and (S)-l-[l-methyl-2-pyrrolidinyl]methylpiperidine (11, 525, 12, 490) with DIBAH effects asymmetric reduction of prochiral ketones in 60-80% ee (equation I). 

Rates of hydroboration of (61 R = Me, Et, Pr, Bu, and Ph) with 9-borabicyclo-[3.3.1]nonane have been elucidated and found to decrease with increasing steric bulk of R no reaction was observed for R = Pr1. The products (62) are potentially valuable for the asymmetric reduction of prochiral ketones.61... 

The use of oxazaborolidines as asymmetric reduction catalysts257 and the enantioselectivity of diphcnyloxazaborolidinc reduction of ketones have been reviewed.258 Large-scale practical enantioselective reduction of prochiral ketones has been reviewed with particular emphasis on the Itsuno-Corey oxazaborolidinc and Brown s 5-chlorodiisopinocampheylborane (Ipc2BCl) as reagents.259 Brown himself has also reviewed the use of Ipc2BCl.260 Indolinoalkylboranes in the form of dimers have been confirmed by 11B NMR as the products of the reduction of trifluoroacetylindoles by diborane.261... 

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