Ketones Noyori reduction

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 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. 

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... 

An unusual enolate of the 3-triethylsilyl-pro-tected 1,3,5-tricarbonyl compound 69 was applied to aldehyde 70 by Danishefsky et al., forming aldol 71 in 74 % yield and with a 5.5 1.0 ratio - remarkable considering that in this case no double stereodifferentiation improves the induction [10, 52J. A systematic study with different aldehydes revealed that an interaction between the double bond and the carbonyl group of the aldehyde is superior to minimization of steric hindrance in the transition state, thus leading to the desired C7-C8 anti relationship [53]. Later in the synthesis of epothilone B, in Danishefsky s approach, the triethylsilyl group was removed and the C3 ketone converted to the desired C3 alcohol by enantioselective catalytic Noyori reduction [10]. 

An alternative route by the Danishefsky group was developed [142e-g] (Scheme 84). The aldol reaction of ethyl ketone 580, prepared from P-keto ester 579, with aldehyde 581 stereoselectively afforded 582 (dr = 5.4 1). After Troc protection followed by hydrolysis of the enol ether, Suzuki coupling with 583 followed by TBS deprotection gave the desired (12Z)-olefin 584. The Noyori reduction of the P-keto ester 584 gave 3a-alcohol with high stereoselectivity, which was converted into hydroxy carboxylic acid 585. Macrolactonization of 585 was accomplished by the Yamaguchi method, and subsequent deprotection and DMDO oxidation efficiently afforded epothilone B (5b). 

Tanis, S. R Evans, B. R. Nieman, J. A. Parker, T. T. Taylor, W. D. Heasley, S. E. Herrinton, P. M. Perrault, W. R. Hohler, R. A. Dolak, L. A. Hester, M. R. Seest, E. P. Solvent and in situ catalyst preparation impacts upon Noyori reductions of aryl-chloromethyl ketones Application to syntheses of chiral 2-amino-l-aryl-ethanols. Tetrahedron Asymmetry 2006, 17, 2154-2182. 

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... 

Scheme 9.20 Ru-catalysed reductions of ketones with water-soluble analogues of Noyori s and Knochel s ligands.

The hydrogenation of a number of aromatic ketones is shown in Figure 37.30. Noyori s very effective Ru-diphosphine-diamine technology was developed by several companies. It is not clear on which scale the processes developed by Takasago (dm-binap = 3,5-xylyl-binap) [16] and Dow/Chirotech [109-111] for the reduction of substituted acetophenones are actually applied commercially. Using the Xyl-PhanePhos-dpen catalyst, a highly efficient bench-scale process was developed for the hydrogenation of p-fluoroacetophenone (ee 98%, TON 100000, TOF 50000 IT1 at r.t., 8 bar) [109]. Ru-P-Phos (licensed to Johnson Matthey [112]) achieved ee-values >99.9% and TON up to 100000 for sev-... 

BrXuPHOS (1) may be prepared (Figure 3.4) from bis(dimethylamino)phos-phine (2), the preparation of which has been described in a previous volume in this series,in a condensation with BINOL (3). The preparation procedure for the ruthenium(II) complex (S, S, 55)-BrXuPHOS-Ru-DPEN (4) is a modification of that reported by Noyori. All reactions described below must be carried out under an inert atmosphere of argon or nitrogen. Examples of ketone reductions using (4) as the catalyst are given in Figure 3.5 and Table 3.5. 

For a review of reductive dehalogenalion of polyhalo ketones, see Noyori Havakawa Org. React. 1983, 29, 163-344. 

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... 

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). 

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... 

Enantiopure alcohols can be produced using chiral hydrogenation catalysts for the reduction of ketones. A major breakthrough in this area was achieved in the mid-1980s by Takaya and Noyori, following the initial work of Ikariya s group... 

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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