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 Noyori reduction of various diketo esters in this series was very dependent upon the amount of add present in the reaction. Without the presence of a stoichiometric amount of add, the rate of reduction as well as the selectivity in the reduction dropped off. At higher pressures, the chemoselectivity of the reduction was poor resulting in die reduction of both alkene groups. Further, the carbonyl at C5 was never reduced under these reaction conditions but was absolutely necessary for the reduction of the C3 carbonyl. When C5 was in the alcohol oxidation state, no reduction was seen. A. Balog, unpublished results. 

Reviews on chiral hydride reagents M. Nishizawa and R. Noyori, Reduction of C=X to CHXH by Chirally Modified Hydride Reagents, in B. M. Trost and I. Fleming, eds., Comprehensive Organic Synthesis, Vol. 8, Chap. 1, p. 159, Per-gamon Press, Oxford, 1991 V. K. Singh, Synthesis, 605 (1992). 

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]. 

Scheme 5.2.57 Noyori reductions for preparation of enantioenriched a-(alkoxy)allylstannanes and y-( Ikoxylallylstannanes...

These furfliryl alcohols can be produced in either enantiomeric form via asymmetric catalysis. Our preferred method for the asymmetric synthesis of these fiiran alcohols 4.2 is by the highly enantioselective Noyori reduction of achiral acylfurans 4.1 (Scheme 4). Alternatively fiirfurly alcohols like 4.4 can be prepared by the Sharpless asymmetric dihydroxylation of vinylfuran 4.3. Key to this later approach was the recognition that vinylfuran 4.3 could be made by a Petersen olefination reaction. 

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). 

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

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. 

An important aspect of this approach is the ease with which fiiran alcohols can be prepared in enantiomerically pure form from achiral furans (e.g., 7 and 8). There are many asymmetric approaches to prepare furan alcohols. The two most prevalent approaches are (i) the Noyori reduction ofacylfurans (8 to 12) and (ii) the Sharpless dihydroxylation of vinyUurans (7 to 12) (Scheme 1.4) [17]. Both routes are readily adapted to 100 g scale synthesis and use readily available reagents. While the Sharpless route is most amenable to the synthesis of hexoses with a C-6 hydroxy group, the Noyori route distinguishes itself in its flexibility to virtually any substitution at the C-6 position. Herein, we review the development of the Achmatowicz approach to the de novo synthesis of carbohydrates, with apphcation to oligosaccharide assembly and medicinal chemistry studies. 

We have had great success at the preparation of optically pure furan alcohols from the Noyori reduction of the corresponding acylfuran, see Li, M., Scott, J.G., and O Doherty, G.A. (2004) Tetrahedron Lett., 45, 6407-6411. 

The reduction of the pre-fuctionalized, usually through the referred in the previous chapter aldols, asymmetric 5-hydroxy-3-ketoesters (72) can lead directly to functionalized 1,3-diols. This transformation can be achieved either by chemical reduction or by biotransformation. Since the Noyori reduction [72] is not only one of the most prominent and applied catalytic reductions but also highly applicable to P-keto esters, it was investigated by Shao et al. [73]. They used chiral ester 72 and performed Noyori reduction using both enantiomers of DINAR It was realized that the chiral... 

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