Shvo catalyst

Johnson and Backvall reported that the bimetallic Shvo catalyst can also catalyze the transfer dehydrogenation of alcohols (Eq. (48)) [83]. 

Of particular interest is the dinuclear Ru complex 34, the so-called Shvo catalyst [55, 56]. It has been established that, under the reaction conditions, this complex is in equilibrium with two monometal complexes (35 and 36) [57-59]. Both of these resemble catalytic intermediates in the concerted proton-hydride transfer pathway (Scheme 20.13), and will react in a similar way (Scheme 20.15) involving the six-membered transition state 37 and the reduction of the substrate via 38. 

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]. 

A significant improvement was achieved when Shvo s Ru-catalyst 2 (Fig. 12b) was employed in combination with the addition of DMP to suppress dehydrogenation reactions [106]. Poly-(R)-6-MeCL, with a promising ee of 86% and Mp of 8.2 kDa, was obtained after workup starting from optically pure (5 )-6-MeCL. The low rate of reaction compared to DKR (typically complete after 48 h with the Shvo catalyst) is attributed to the low concentration of the terminal alcohol as well as to the iterative nature of the system. Racemic 6-MeCL showed comparable rates of reaction for both enantiomers, which polymerized within 220 h with complete conversion of both enantiomers, yielding polymers of high ee (92%) and Mp (9.4 kDa). Successful polymerizations with more than 100 consecutive and iterative enzymatic additions and Ru-catalyzed racemizations on one polymer chain were realized. 

The Shvo catalyst is one of the most paradigmatic hydrogen-transfer catalysts due to its great versatility. It is able to hydrogenate polar (ketones, imines) and non-polar bonds (alkenes,... 

Fig. 6. Transition-states for the concerted outer-sphere mechanism for the hydrogenation of imines in both the model (left) and the complete Shvo catalysts (right) the former is for imine H2C=NH, whereas the latter is for (CH3)2C=N-CH3. Geometries optimized in solution (THF). Distances in A.

Screening several amine racemization catalysts, we found that the SCRAM and the Shvo catalyst would both racemize the (S)-enantiomer at temperatures above 11() G. Interestingly, no dimeric products were found. The best racemization conditions were found to be using toluene or TBME at 150°C in a pressure vessel with 1 mol% SCRAM or 5 mol% Shvo catalyst over 24 h, providing quantitative conversion. In the presence of (R, R)-dibenzoyltartaric acid the racemization slowed, possibly because of unfavorable coordination of the alkylammonium substrate or acid quenching of the iridium hydride catalyst intermediate. 

A chemical catalyst can be used to racemize an alcohol, whereas an enzyme is used to prepare an ester of one of the enantiomers of that alcohol. In this example, reduced pressure was used to remove the isopropanol by-product and drive the reaction to completion whereas the Shvo catalyst was used to racemize the alcohol (Fig. 13) (257). 

Racemisation can be achieved with a variety of homogeneous catalysts. We selected the well-known Shvo catalyst (Scheme 2). Since many DKR processes have been successfully developed with the combination Novozym 435 and this Ru-based catalyst, the two catalysts are both compatible and complementary. In-situ racemisation of the terminal secondary alcohol of the propagating polymer chain should provide reactive chain ends, theoretically resulting in an enantiopure polymer in a 100% yield starting from the racemic monomer (Scheme 2). If the less reactive (RJ-6-MeCL is incorporated (which will occur since the selectivity for lactones is moderate with an E value of 12, see Table 2) a reactive R-chain end is obtained and propagation occurs instantly. In this way, both enantiomers of the monomer are consumed. 

Figure 4. A) Conversion of (S)-6-MeCL as a function of time and B) development of MW during the ITC polymerisation of 6-MeCL. Reaction conditions Shvo catalyst (0.03 mmol), Novozym 435 (33 mg), (S)-6-MeCL (2.5 mmol), BA (0.05 mmol), DMP (0.25 mmol), and 1,3,5-tri tert-butylbenzene (0.20 mmol, internal standard) were stirred in toluene (2.5 mL) at 70 °C under Ar.

Lledos and coworkers [125] investigated several hypotheses of ISM and OSM for the hydrogenation reaction of formaldehyde catalyzed by the Shvo catalyst using a simplified model [126, 127]. They selected the two most likely hypotheses and conducted full DPT studies using the real Shvo catalyst, which confirmed the evidence obtained using the model catalyst. In all of their calculations, the solvent effect has been taken into account by means of a CPCM implicit model. The two stepwise reactions for the ISM and OSM are reported in Scheme 19. 

Fig. 18 Structures involved in the inner-sphere hydrogenation by the Shvo catalyst (a) franial-dehyde approach to the RuCp complex, (b) TS for the hydrogen transfer to the carbonyl, (c) alcohol interaction with the imsaturated Ru complex...

The immediate product from the reaction of the hydride complex with ketone has been a subject of debate. Some have proposed that an alkoxide complex is formed and that proton transfer between the coordinated amine and the alkoxide then forms the alcohol that is ultimately released. Others have supported a direct transfer to form free alcohol (or amine) and then coordination of this species to the open To accommodate the isotope effect data and the absence of an open coordination site for coordination of the ketone, the formation of the alkoxide from the hydride has been proposed to occur by hydride transfer assisted by hydrogen bonding of the amine in the case of the reactions with [Ru(BINAP)(diamine)(H)j], or by ring slip to allow coordination of the ketone (or imine) in the case of the reactions with the Shvo catalyst. ... 

Bifunctional rhenium complexes related to the Shvo catalyst have been used in TH reactions, including tests on three non-prochiral imines, with TOFs up to 79 h obtained for imines. In common with the Shvo catalysts, DFT calculations have indicated the operation of an outer-sphere mechanism for the reaction [118]. 

Recently, the Bell group applied similar conditions in the gas-phase hydroformylation-hydrogenation of propene by using a silica-supported Shvo catalyst. Under the most favorable conditions examined (CO/H2 =10 1 140 °C), an overall yield of 13% to butanol was achieved with 15% propene conversion and 90% aldehyde conversion. 

The aim of this chapter is to provide an overview of the mechanistic aspects and the applications of the Shvo catalyst 1 in hydrogen transfer reactions. Several reviews have recently appeared on the applications of the Shvo catalyst, and this topic was reviewed in 2005 [30], 2009 [31], and 2010 [32]. Mechanistic studies on the Shvo catalyst in hydrogen transfer reactions were reviewed in 2006 [33], 2009 [34] and 2010 [32]. 

The Shvo catalyst 1 can participate in the transfer of hydrogen from one molecule to another. Such hydrogen transfer reactions are useful in synthetic organic chemistry for the reduction of ketones (aldehydes) and imines, and for the oxidation of alcohols and amines. In the former case (transfer hydrogenation), a hydrogen donor such as isopropanol or formic acid is used, which reduces the carbonyl compound or imine to alcohol or amine, respectively. In the oxidation of alcohols and amines (transfer dehydrogenation), a hydrogen acceptor such as acetone or a quinone is used. 

The Shvo catalyst 1 was successfully used in the transfer hydrogenation of 1,3-diones to the corresponding 1,3-diols with isopropanol as the hydrogen donor (2) [36, 37], This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlIli preferentially gives the aUyUc alcohol [36]. Also piperidine-3,5-diones were efficiently reduced to the corresptMiding diols by isopropanol using 1 as catalyst [37], and these diols were subsequently used in dynamic kinetic asymmetric transformatimis (DYKATs) to provide stereodefined 3,5-disubstituted piperidines [36, 37],... 

However, there are reports on the hydrogenation of alkenes and alkynes using the Shvo catalyst 1 [6, 30, 31, 39]. The reactions were carried out at a hydrogen pressure of 500 psi at 145°C. 

In a recent application, the Shvo catalyst 1 was used to oxidize enantiomerically pure bicyclic diols (R,R)-3 to the hydroxyketones (/ )-4 in acetone [46]. The acetone acts as the hydrogen acceptor and, interestingly, under these conditions, it was possible to stop the reaction after oxidation of one of the hydroxyl groups to give the hydroxyketones 4 in 82-85% yield and 97-98% ee (5). The hydroxyketones obtained are useful starting materials for the synthesis of natural products and biologically active compounds, and (f )-4b was used for the synthesis of Sertraline [46]. 

The temperature used in the oxidation of the diols 3,35°C, is probably the lowest temperature reported for a hydrogen transfer reaction with the Shvo catalyst The aerobic oxidation of secondary alcohols using Shvo s catalyst 1 was recently combined with an efficient hybrid electron transfer mediator 5 (6) [47, 48], This leads to a facile aerobic oxidation via transfer dehydrogenation, whereas the previous system (cf. electron transfer system of Scheme 3) [41, 42] with separate quinone and metal macrocycle now has been modified by tethering the quinone to the metal macrocycle (Scheme 3). 

The Shvo catalyst has found many applications as a racemization catalyst in enzymatic resolutions of alcohols and amines leading to a DKR. Also diols and amino-alcohols have been used in these applications in DYKATs. 

The DKR procedure described above was improved by Meijer and coworkers in 2007 [87]. The protocol was improved both in terms of reaction time (26 h instead of 72 h) and the required amount of acyl donor (the excess acyl donor could be reduced to 1.1 equiv). This was accomplished using a more effective acyl donor isopropyl 2-methoxyacetate for the enzymatic acylation. CALB was used for the kinetic resolution, and the para-methoxyphenyl derivative of the Shvo catalyst was used for racemization (22). All the DKR reactions were performed under reduced pressure (750 mbar) to eliminate the isopropyl alcohol from the reaction mixture. The isopropyl alcohol can be oxidized to acetone, and the latter can in subsequent reaction steps form unwanted condensation products with the amine substrates. The revised protocol afforded the products with excellent selectivity (96-99% ee). The yields were slightly lower (56-80%) than those obtained with the Backvall protocol [86], mainly due to problems with purification. 

More recently, interest in the immobilization of catalysts has increased. Candida antarctica lipase A (CALA) immobilized in mesoceUular foam (MCF) showed a dramatic increase in the enantioselectivity, as well as an improved thermostability of the enzyme. The immobilized enzyme (CALA/GAmp-MCF) was combined with the para-methoxyphenyl derivative of the Shvo catalyst, in an efficient DKR of 3-amino-3-phenylpropanoate at 90°C (24) [90]. The chiral acy-lated p-amino ester was obtained in 85% yield and with an ee value of 89%. 

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