Noyori asymmetric transfer hydrogenation

The Noyori asymmetric transfer hydrogenation was utilized in the synthesis of the chiral 1,2,3,4-tetrahydroisoquinolines by R.A. Sheldon et al. These compounds are important intermediates in the Rice and Beyerman routes to morphine. The "Rice imine" was exposed to a series of chiral Ru " complexes, which was prepared from r -arene-Ru " chloride dimeric complexes and A/-sulfonated 1,2-diphenylethylenediamines along with the azeotropic mixture of HCOOH/NEts. With the best catalyst the desired tetrahydroisoquinoline was isolated in 73% yield and the enantiomeric excess was 99%. 

Noyori Asymmetric Transfer Hydrogenation Noyori s well-designed chiral Ru -arene complexes catalyze the asymmetric transfer hydrogenation of ketones and imines (not shown) with stable organic hydrogen donors such as 2-propanol [69]. The reaction is reversible, and the involved chiral ruthenium species and the proposed transition state are depicted in Scheme 2.140. 

The stereochonical outcome of Noyori asymmetric transfer hydrogenation is predictable and depends on the particular diamine S,S or RJi) used. Two other challenging examples of Noyori asynunetric transfer hydrogenation during the course of cytostatin total synthesis are depicted in Figure 2.3 [71]. 

Several approaches toward the syntheses of quinolacta-cins were published. ° In 2008, Silva Santos and coworkers applied Noyori asymmetric transfer hydrogenation of cyclic imine 218 to the total synthesis of (5)-(—)-quinolactacin B, which showed activity against mmor necrosis factor production. The hydrogenation of imine 218 was accomplished with the (/ ,/ )-Ts-DPEN-Ru(ll) complex in DMF and a HC02H/Et3N mixture to obtain amine (5)-(—)-219 in 89% yield and >90% ee (Scheme 30.43). 

SCHEME 30.43. Noyori asymmetric transfer hydrogenation in the synthesis of (/f)-trypargine, (S)-(—)-quinolactacin B, and RWJ387273, a PDE5 inhibitor. 

Pilli RA, Trindade Rodrigues JrM. The asymmetric total synthesis of (+) and (—)-trypargine via Noyori asymmetric transfer hydrogenation. J. Braz. Chem. Soc. 2009 20 (8) 1434-1440. 

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... 

As another successful application of Noyori s TsDPEN ligand, Yan et al. reported the synthesis of antidepressant duloxetine, in 2008. Thus, the key step of this synthesis was the asymmetric transfer hydrogenation of 3-(dime-thylamino)-l-(thiophen-2-yl)propan-l-one performed in the presence of (5,5)-TsDPEN Ru(II) complex and a HCO2H TEA mixture as the hydrogen donor. The reaction afforded the corresponding chiral alcohol in both high yield and enantioselectivity, which was further converted in two steps into expected (5)-duloxetine, as shown in Scheme 9.17. 

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

Jiang et al.113 synthesized another tridentate ligand 121 for asymmetric transfer hydrogenation. Ru-121-catalyzed asymmetric transfer hydrogenation gives comparable enantioselectivity to Noyori s catalyst 109 but shows more... 

Ikariya and Noyori et al. also reported the synthesis of new chiral Cp Rh and Cp Ir complexes (13 and 14) bearing chiral diamine ligands [(R,R)-TsCYDN and (R,R)-TsDPEN] (Scheme 5.10) these are isoelectronic with the chiral Ru complex mentioned above, and may be used as effective catalysts in the asymmetric transfer hydrogenation of aromatic ketones [42], The Cp Ir hydride complex [Cp IrH(R,R)-Tscydn] (14c) and 5-coordinated amide complex (14d), both of which would have an important role as catalytic intermediates, were also successfully prepared. 

The mixture of 40a and 40b was directly converted to the corresponding acetonide 41 (Scheme 8). Then, the asymmetric transfer hydrogenation was performed following Noyori s procedure.28 The... 

J. Gao, T. Ikariya, and R. Noyori, Aruthe-niumjii) complex with a C2-symmetric diphosphine/diamine tetradentate ligand for asymmetric transfer hydrogenation of aromatic ketones, Organometallics 1996, 15, 1087-1089. 

Noyori, R. and S. Hashiguchi, Asymmetric Transfer Hydrogenation Catalyzed by Chiral Ruthenium Complexes, Accounts of Chemical Research, 30, 97-102 (1997). 

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). 

Noyori R, Hashiguchi S, Iwasawa Y. Asymmetric transfer hydrogenation catalyzed by chiral ruthenium complexes. Acc. Chem. 

We therefore quickly turned our attention to the ruthenium-catalyzed asymmetric transfer hydrogenation recently reported by Noyori. Without any optimization, 95% yield and 96% e.e. were obtained with 0.25 mol% catalyst and formic acid-triethylamine 5 2 azeotropic mixture (2.5 mL/g) in CH2CI2 at room temperature for 8 h (Scheme 6.17). - Apart from the high yield, enantiomeric excess, and turnover, this procedure is particularly simple to carry out. It also allows an easy recovery of the optically active amine by filtration, as its formiate salt at the end of the reaction, if needed, would offer an additional improvement in optical purity. 

Other chiral diamine-( -arene)ruthenium catalysts were developed by Noyori where the chirality was centred at the metal (see Figure 3.18). These complexes were effective catalysts for asymmetric transfer hydrogenation of carbonyl compounds and a mechanism involving a metal-ligand bifunctional process was proposed. 

Enantioselective hydroacylation of 1,5-ketoalcohols using Noyori s transfer hydrogenation catalyst 32 provides a series of tetrahydro-2H-pyran-2-ones (Scheme 54) (13JA5553). 6-Iodomethyltetrahydro-2H-pyran-2-ones are achieved by asymmetric iodolactonization of 5-arylhex-5-enoic acid with a catalytic amount of iodine using a PyBidine-Ni(OAc)2 complex as catalyst (13SL2045).A similar iodolactonization is the key step in the... 

Scheme 1.46 A revised catalytic cycle for the asymmetric transfer hydrogenation of aromatic ketones in propan-2-ol by the Noyori-Ikariya (pre)catalyst 2 demonstrates crossover of the reaction pathways the product is obtained via a H"/H+ outer-sphere hydrogenation mechanism and/or step-wise metal-ligand bifunctional mechanism (see text). Formation of the major enantiomeric product is shown. (Adapted from Dub, P. A. et al., /. Am. Chem. Soc., 135, 2604-2619. Copyright 2013 American Chemical Society.)...

Hashiguchi, S. Fujii, A. Takehara, J. Ikariya, T. Noyori, R. Asymmetric transfer hydrogenation of aromatic ketones catalyzed by chiral Ruthenium(Ii) complexes. /. Am. Chem. Soc. 1995,117, 7562-7563. 

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