Noyori asymmetric reduction, ketones

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 use of a chiral hydride complex has been central to the asymmetric reduction of ketones such as acetophenone (58). A number of excellent chiral metal hydride complexes have been introduced by many researchers, including Noyori (59,60), Meyers (61), Mukaiyama (62,63), Terashima (64,65), and others (58). It is apparent that there is a close similarity in structure between acetophenone and the proposed intermediate in enamide photocyclization, therefore suggesting the possibility of undergoing photocyclization in an asymmetric manner. 

Asymmetric reduction The ruthenium(II)-BINAP catalysts developed by Noyori s group in 1980s were the most successful for the asymmetric hydrogenation of functionalized ketones such as a-ketoesters, a-hydroxyketones and a-aminoketones because the second... 

Figure 7.1. Postulated transition structures for the asymmetric reduction of unsaturated ketones by BINAL-H [12]. Structures (a) and (b) differ in the orientation of Rjat and Run, the saturated and unsaturated ketone ligands, respectively, (a) UI topicity P reagent attacking Re face of ketone, (b) Lk topicity P reagent attacking Si face of ketone, (c) Alternate chair that is destabilized by the gauche pentane conformation accented by the bold lines (c/. Figure 5.5). Transition structures containing this conformation were considered by Noyori to be unimportant [12].

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. 

This methodology using Ru/dpenTs complexes with HCOOH/NEta as the reducing system was essentially developed by the Noyori group (for a recent account, see [87]) and is now widely used by synthetic chemists for the asymmetric reduction of ketones... 

Complementary to the oxidative diol lactonization approach, a substrate containing both ketone and ester functionalities may undergo reduction to liberate the desired lactone product following ring closure. Noyori and coworkers demonstrated that Ru-BINAP complexes were excellent catalysts for the asymmetric reduction of ketones with neighboring carboxylic acid and ester functionalities capable of undergoing the desired lactonization in high yields and selectivities (Scheme 2.50) [103, 104],... 

Directed and Asymmetric Reduction The principles of directed and asymmetric reactions were first developed for hydrogenation, as discussed in Section 9.2. Asymmetric hydrosilation of ketones can now be carried out cata-lytically with rhodium complexes of diop (9.22). The new chiral ligand Et-duPHOS, made by Burk at du Pont, allows chiral amination of ketones via Eq. 14.50. Note how the use of the hydrazone generates an amide carbonyl to act as a ligand, as is known to favor high e.e. (see Section 9.2). Noyori s powerful BINAP ligand has been applied to a large number of asymmetric reactions. 

Oxidation of the hydro>yl group followed by the highly enantioselective asymmetric reduction of the resulting ketone (in the presence of the Noyori s catalyst 52) yielded alcohol (i )-54 (ee>96%). Subsequent... 

Noyori is largely responsible for the development and evolution of Ru-based asymmetric reductions of ketones in various important new directions [115-118]. Indeed, a number of different protocols and catalysts have been crafted. In the earliest systems, Ru"-BINAP-complexes, such as 211 in alcohol solvents and at moderate H2 pressures, were shown to effect the reduction of a wide range of keto esters, hydroxy ketones, chloroketo esters, and amino ketones with superb enantiocontrol (Figure 2.8) [117, 118, 137]. A key feature of this system is the requirement for the substrate to incorporate a polar functional group that can putatively participate in chelate formation. A particularly attractive feature of the system was disclosed early in the history of the catalyst the catalyst need not be prepared and purified extensively... 

The power of Noyori s Ru -BINAP system in ketone reductions has been amply demonstrated in numerous complex molecule syntheses. Schreiber, for example, has disclosed a route to the macrolide antibiotic mycoticin A (221, Scheme 2.27) [139] that relies on a strategy involving two-directional chain synthesis [140]. Catalytic asymmetric reduction of diketone 216 affords the C2-symmetric diol 217. Conversion of 217 into bis(ketoester) 218 then allows double ketone reduction to furnish 219, which was subsequently elaborated into the skipped polyol chain 220 of mycoticin A (221). 

On the other hand, one of the first chiral sulfur-containing ligands employed in the asymmetric transfer hydrogenation of ketones was introduced by Noyori el al Thus, the use of A-tosyl-l,2-diphenylethylenediamine (TsDPEN) in combination with ruthenium for the reduction of various aromatic ketones in the presence of i-PrOH as the hydrogen donor, allowed the corresponding alcohols to be obtained in both excellent yields and enantioselectivities, as... 

After extensive developmental studies, [35] the final crucial element in our most recent synthesis of epothilone B involves an asymmetric catalytic reduction of the C3 ketone of 67 proceeding via a modified Noyori procedure (Scheme 2.8, 67—>68). In the event, Noyori reduction of ketone 67 afforded the desired diol 68 with excellent diasteresdectivity (>95 5). The ability to successftdly control the desired C3 stereochemistry of the late stage intermediate 68 permitted us to introduce the Cl-C7 fragment into the synthesis as an achiral building block. 

The discovery by the recent Nobel-laureate, Ryoji Noyori, of asymmetric hydrogenation of simple ketones to alcohols catalyzed by raras-RuCl2[(S)-binap][(S,S)-dpen] (binap = [l,l -binaphthalene-2,2/-diyl-bis(diphenylphosphane)] dpen = diphenylethylenediamine) is remarkable in several respects (91). The reaction is quantitative within hours, gives enantiomeric excesses (ee) up to 99%, shows high chemoselecti-vity for carbonyl over olefin reduction, and the substrate-to-catalyst ratio is >100,000. Moreover, the non-classical metal-ligand bifunctional catalytic cycle is mechanistically novel and involves heterolytic... 

One place to look for good alcohol racemization catalysts is in the pool of catalysts that are used for hydrogen transfer reduction of ketones. One class of complexes that are excellent catalysts for the asymmetric transfer hydrogenation comprises the ruthenium complexes of mono sulfonamides of chiral diamines developed by Noyori and coworkers [20, 21]. These catalysts have been used for the asymmetric transfer hydrogenation of ketones [20] and imines [21] (Fig. 9.9). 

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