Ketones with BINAL

TABLE 6-4. Enantioselective Reduction of Aromatic Ketones with BINAL-H (R"0=C2H50) ... 

BINAL-H reagents 45 are not effective in the enantioselective reduction of dialkyl ketones.53 For example, reaction of benzyl methyl ketone with (S)-45 gives (S )-l-phenyl-2-propanol in only 13% ee (71% yield). Reaction of 2-octanone with (R)-45 produces (S )-2-octanol in 24% ee (67% yield).53 This drop of ee values in the reaction may be explained by the lower energy difference between the favored transition state 48 and unfavored transition state 49 caused by the lack of the above-mentioned n-n repulsion between the reductant and the substrate dialkyl ketone. 

Another method for ketone reduction, BINAL-H asymmetric reduction, can also be used in co-side chain synthesis. An example of applying BINAL-H asymmetric reduction in PG synthesis is illustrated in Scheme 7-27. This has been a general method for generating the alcohol with (15. -configuration. The binaphthol chiral auxiliary can easily be recovered and reused. As shown in Scheme 7-27, when the chiral halo enone 91 is reduced by (S -BINAL-H at — 100°C, product (15S)-92 can be obtained with high enantioselectivity. 

BINAL-H is prepared by adding binaphlhol to a solution of LiAlH., in THF followed by one equivalent of either methanol or ethanol. The reagent generally is used in threefold excess to achieve optimal selectivities. It reduces acetylenic ketones,aromatic ketones, and a, 3-iinsaturated ketones with high optical purities. 

Aj-l-Phenylbutanol Typical Procedure for the Reduction of Ketones with a BINAL-II Reagent49 ... 

The reduction of dialkylketones and alkylaryl ketones is also conveniently accomplished using chiral oxazaborolidines, a methodology which emerged from relative obscurity in the late 1980s. The type of borane complex (based on (,V)-diphenyl prolinol)[39] responsible for the reductions is depicted below (10). Reduction of acetophenone with this complex gives (/ )-1 -phenylethanol in 90-95% yield (95-99% ee) [40]. Whilst previously used modified hydrides such as BiNAL-H (11), which were used in stoichiometric quantities, are generally unsatisfactory for the reduction of dialkylketones, oxazaborolidines... 

The hydride donor of the Noyori reduction of ketones is the hydrido aluminate K-BINAE-H shown in Figure 10.23 or its enantiomer S-BINAL-H. The new C—H hond is presumably formed via a cyclic six-memhered transition state of stereostructure A. Unfortunately, there is no easy way to rationalize why enantioselectivity in this kind of addition is limited to substrates in which the carbonyl group is flanked by one conjugated substituent (C=C, aryl, C=C). The suggestion that has been made is that a lone pair on the axial oxygen of the BINOL unit in the transition state undergoes a repulsive interaction with pi electrons in the unsaturated ketone if the latter is also axial. 

In 1979, Noyori and co-workers invented a new type of chiral aluminum hydride reagent (1), which is prepared in situ from LiAlEE, (S)-l, E-bi-2-naphthol (BINOL), and ethanol. The reagent, called binaphthol-modified lithium aluminum hydride (BINAL-H), affects asymmetric reduction of a variety of phenyl alkyl ketones to produce the alcohols 2 with very high to perfect levels of enantioselectivity when the alkyl groups are methyl or primary1 (Scheme 4.3a). 

The binaphthol-modified lithium aluminum hydride reagents (BINAL-Hs) are also effective in enantioselective reduction of a variety of alkynyl and alkenyl ketones2 (Scheme 4.3b). When the reaction is carried out with 3 equivalents of (S)-BINAL-H at —100 to —78 C, the corresponding propargylic alcohol 3 and allylic alcohol 4 are obtained in high chemical yields with good to excellent levels of enantioselectivity. As is the case with aryl alkyl ketones, the alcohols with (.V)-con figuration are obtained when (S)-BINAL-H is employed. 

Marko et al. employed an enantioselective Noyori BINAL-H reduction in the synthesis of methyl monate C (11), the methyl ester derivative of the potent antibiotic pseudomonic acid C6 (Scheme 4.3e). The a,(3-unsaturated ketone 12 underwent the Noyori reduction with the (S)-BINAL-H reagent to give the product desired (13) in 70% yield and 95% ee. The chiral alcohol was then condensed... 

Noyori et al. demonstrated the effectiveness of the BINAL-H reduction method by synthesizing the Japanese beetle pheromone (R)-167 (Scheme 4.3f). The alkynyl ketone 17 was treated with 3 equivalents of (Wj-IJINAL-H at —100 C for 1 hour and then held at —78 C for 2 hours. The propargylic alcohol 18 was obtained in good yield and with moderate enantioselectivity of 84% ee. Exposure... 

A number of structurally diverse ketones have been reduced using BINAL-H. Some of the results are summarized in Table 1. Aryl alkyl ketones, alkynic ketones, and a, -unsaturated ketones are reduced to alcohols with good to excellent % ee, while aliphatic ketones give products with lower optical purities. The asymmetric reduction of a number of acylstannanes with (7) gives synthetically valuable a-alkoxystannanes with high optical purities after protection of the initially formed unstable alcohols as their MOM or BOM ethers. ... 

BINAL-H has also been used for the asymmetric reduction of methylaryl- and methylalkylphosphinylimines to the corresponding phosphinylamines in high % ee (Table 2). Similar to the reduction of ketones, reduction of the imines with (S)-(7) produces the (S)-amine and reduction with (R)-(7) gives the (R)-amine. 

The BINAL-H reduction works well with alkenic - and alkynic ketones affording alcohols with satisfactory optical purities (Scheme It is noteworthy that (S)-BINAL-H [(S)-(28)] reduces 1-halo-l-octen-3-one and 2-cyclopentene-l,4-dione to give the corresponding carbinols, which are important chiral building blocks for the synthesis of prostaglandins by the conjugate addition approach. ... 

The preparation of enantioenriched Q -(alkoxy)allylstannanes has been advanced by the asymmetric Noy-ori reduction of the stannyl ketone 264 with 2,2 -dihydroxy-l,T-binapthyl lithium aluminum hydride (BINAL-H) reagents affording the non-racemic (5 )-265 with > 95% ee, upon O-alkylation with common protecting groups (Scheme 5.2.57, top). °... 

Asymmetric reduction of ketones. A reagent 2, prepared by reaction of LiAlH4 with 1 and C2H5OH (1 equiv. each) in THF at 20°, effects asymmetric reduction of dialkyl ketones or alkyl aryl ketones in 53-93% yield and 60-97% ee. The enantioselectivity is generally greater than that obtained with Noyori s reagent BINAL-H (9,169-170), particularly in reduction of dialkyl ketones in which the alkyl groups have similar steric effects. 

Similarly, asymmetric reduction of alkylaromatic ketones gives high optical yields (Table 26.26) [7], It is noteworthy that the optical yields obtained by K-glucoride in the reduction of hindered ketones such as pivalophenone is 97-100% ee and 87% ee for isobutyrophenone are considerably higher than the values (44 and 71% ee, respectively) obtained with highly promising Binal-H reagent [8] (Eq. 26.27). 

The reagent itself may be chiral. Enantiopure forms of l,l -bi-2-naphthol are readily available [35] and can be complexed with lithium aluminum hydride (LAH) to form the selective reducing agent BINAL-H, which reduces a variety of ketones, including the precursor to Pirkle s alcohol, 3.13, a chiral solvating agent mentioned in Section 3.3 (Eq. 3.7) [36]. 

The conjugated ketone 138 was then reduced diastereose-lectively with (S)-BINAL-H to the allyhc alcohol 139 (Scheme 3.34). Hydrolysis with dilute aqueous hydrochloric acid in THF gave the lactone 140 that was converted in a... 

A wide variety of chiral modifications of the commonly employed reducing agent lithium aluminum hydride have been examined [23, 111, 112). Noyori described one of the most effective reagents namely BINAL-H (176), produced upon treating LiAlH4 with BINOL (Equation 17) [122, 123]. BINAL-H has been shown to be particularly useful in the enantioselective reduction of aromatic and unsaturated ketones [111]. For example, reduction of 175 with (S)-BINAL-H furnishes 177 in 92% yield and with >99% ee [122]. 

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