Ketonic Substrates

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 /8-amino alcohol and borane, yields the corresponding secondary alcohols in 94-100% ee 

A variety of prochiral aromatic and aliphatic ketones can be reduced by diborane in THF in the presence of 5-10 mol % of the chiral auxiliary to produce the secondary alcohols with high ee and in high chemical yields. A variety of related chiral auxiliaries have been developed. 

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Due to the high reactivity of sulfonium ylide 2 for a,P-unsaturated ketone substrates, it normally undergoes methylene transfer to the carbonyl to give the corresponding epoxides. However, cyclopropanation did take place when 1,1-diphenylethylene and ethyl cinnamate were treated with 2 to furnish cyclopropanes 53 and 54, respectively. 

The chiral BOX-metal(II) complexes can also catalyze cycloaddition reactions of other ketonic substrates [45]. The reaction of ethyl ketomalonate 37 with 1,3-conju-gated dienes, e.g. 1,3-cyclohexadiene 5c can occur with chiral BOX-copper(II) and zinc(II) complexes, Ph-BOX-Cu(OTf)2 (l )-21a, and Ph-BOX-Zn(OTf)2 (l )-39, as the catalysts (Scheme 4.29). The reaction proceeds with good yield and ee using the latter complex as the catalyst. Compared to the copper(II)-derived catalyst, which affects a much faster reaction, the use of the zinc(II)-derived catalyst is more convenient because the reaction gives 94% yield and 94% ee of the cycloaddition product 38. The cycloaddition product 38 can be transformed into the optically active CO2-... 

The ammoximation reaction involves the in situ formation of hydroxylamine via TS-1 catalysed oxidation of NH3 with H2O2. Hence, there are no size restrictions with regard to the ketone substrate, because the reaction of NH2OH with the latter occurs in the bulk solution. For example, TS-1 catalyses the ammoximation of / -hydroxyacetophenone (Le Bars et al., 1996). Beckmann rearrangement of the oxime product (see Fig. 2.18) affords the analgesic paracetamol (4-acetaminophenol). 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

The acetone-sensitized photodehydrochlorination of 1,4-dichlorobutane is not suppressed by triplet quenchers (20), but the fluorescence of the sensitizer is quenched by the alkyl chloride (13). These observations imply the operation of a mechanism involving collisional deactivation, by the substrate, of the acetone excited singlet state (13,21). This type of mechanism has received strong support from another study in which the fluorescence of acetone and 2-butanone was found to be quenched by several alkyl and benzyl chlorides (24). The detailed mechanism for alkanone sensitization proposed on the basis of the latter work invokes a charge-transfer (singlet ketone)-substrate exciplex (24) and is similar to one of the mechanisms that has been suggested (15) for sensitization by ketone triplets (cf. Equations 4 and 5). 

COD = cyclooctadiene) not only for the ketone substrate, but also for terminal and cyclic unactivated alkenes (Table 1). 

The course of the reaction of phenacyl bromides (39) with nickel carbonyl is markedly dependent on the solvent employed in tetrahydrofuran the products are 1,2-dibenzoylethanes (cf. 40) but in dimethylformamide, 2,5-diarylfurans (41) are obtained in moderate to excellent yield (Scheme 53).90 It is possible that the furan derivatives (41) arise via intermediate fi,y-epoxyketones which can be isolated as products from a number of a-bromo-ketone substrates [cf. 39 and Section II].28... 

Electron spin resonance (ESR) signals, detected from phosphinated polystyrene-supported cationic rhodium catalysts both before and after use (for olefinic and ketonic substrates), have been attributed to the presence of rhodium(II) species (348). The extent of catalysis by such species generally is uncertain, although the activity of one system involving RhCls /phosphinated polystyrene has been attributed to rho-dium(II) (349). Rhodium(II) phosphine complexes have been stabilized by steric effects (350), which could pertain to the polymer alternatively (351), disproportionation of rhodium(I) could lead to rhodium(II) [Eq. (61)]. The accompanying isolated metal atoms in this case offer a potential source of ESR signals as well as the catalysis. 

A series of non-f, -symmetrical ferrocene-based 1,5-diphosphane ligands (TaniaPhos) has been developed by Knochel.88,88a,88b The ligands have been effectively used in Rh- or Ru-catalyzed asymmetric hydrogenations. The ligand 39, which has an MeO group at the chiral carbon center, has shown excellent applications in the hydrogenation of several olefin and ketone substrates.89 Weissensteiner and Spindler have reported a series of structurally different... 

Recently, the silane-mediated reductive cyclization of activated alkynes with tethered ketones using Stryker s reagent as a catalyst was reported.112,90b Alkynyl ketone substrate 84a was treated with a catalytic amount of Stryker s reagent in the presence of polymethylhydrosiloxane (PMHS) to afford the cA-fused hydrindane 84b as a single diastereomer. This method is applicable to both five- and six-membered ring formation, but often suffers from competitive over-reduction of the reaction products (Scheme 59). 

In transfer hydrogenation with 2-propanol, the chloride ion in a Wilkinson-type catalyst (18) is rapidly replaced by an alkoxide (Scheme 20.9). / -Elimination then yields the reactive 16-electron metal monohydride species (20). The ketone substrate (10) substitutes one of the ligands and coordinates to the catalytic center to give complex 21 upon which an insertion into the metal hydride bond takes place. The formed metal alkoxide (22) can undergo a ligand exchange with the hydride donor present in the reaction mixture, liberating the product (15). 

The two production processes using a-amino ketone substrates depicted in Figure 37.24 were developed by Boehringer-Ingelheim to improve on existing resolution syntheses for adrenaline and phenylephrine [94]. Unfortunately, few details are available but both processes are carried out with a Rh-mccpm catalyst with very high TONs and TOFs, albeit with medium ee-values of 88% which increase to >99% after precipitation of the free base. 

The stereoselective reduction may be applied to a variety of ketones. Some examples of reductions, as a function both of ketone substrate and amino acid catalyst are provided in Table 11.9. The full scope of this procedure 26-281 has... 

Removal of the more reactive H2 of the 36d-LAH complex (Scheme 6) by reaction with one equivalent of ethanol led to transfer of H, to ketone substrates... 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

Enolization of ketonic substrates can be carried out under far milder conditions if the dialkylboryl trifluoromethanesulfonate esters 59 (eq. [24]) are employed in the presence of hindered tertiary amines (eq. [43]) (6,63). At low temperatures (-78 0°C),... 

Dusopropyl ether (2.5 mL), ketone substrate (750 ph) and trimethylsilylcyanide (1.25 mL) were added to 18 mL of 0.1 m pH 4.5 citrate buffer which was stirring at 5 °C. The mixture was prepared in a chemical fume hood with the use of a cyanide detector to measure for any release of cyanide vapor. 

The generalized procedure described here has been demonstrated with a large number of aromatic ketone substrates, including those described in Table 8.1. When the goal is the production of a particular (5)-cyanohydrin, specialized process improvements to parameters, such as the operating temperature and pH and the choice and concentration of organic solvent and cyanide donor, may further increase both the product ee and yield values. 

Ketoreductase enzymes KRED-104 (120mg) and KRED-108 (30mg) and NADP+ (30 mg) were added to 0.5 m potassium phosphate buffer pH 6.5 (9.5 niL) that was stirring at 35 °C. The reaction was started with the addition of a solution of ketone substrate (100 mg) in isopropanol (0.5 mL) and aged for 12h. 

A large number of diaryl ketone substrates, including those listed in Table 9.3, have been reduced with high enantioselectivity with the protocol described here. Unlike analogous chemical catalysts, the commercially available biocatalysts displayed no dependence on ortho substitutions or electronic dissymmetry, and produced diaryl methanols with good to excellent ee values in nearly all cases. 

Chapter 8 describes the application of hydroxyl nitrile lyases to the synthesis of new chiral cyanohydrins and a-hydroxy acids and includes new approaches to the transformation of difficult aldehyde and ketone substrates using substrate engineering and immobilization techniques. 

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