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Catalytic Asymmetric Transfer Hydrogenation: an Industrial Perspective

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CHIRAL TECHNOLOGIES LIVIUS COTARCA, MASSIMO VERZINI, RAFFAELLA VOLPICELLI* *Corresponding author ZaCh System SpA, via Dovaro 2, 36045 Lonigo (Vi), Italy Raffaella Volpicelli Catalytic asymmetric transfer hydrogenation: an industrial perspective KEYWORDS: catalytic asymmetric transfer hydrogenation, ATH, industrial applications, ketones, imines, reductive amination. Asymmetric transfer hydrogenation (ATH) of ketones and imines has emerged as a powerful alternative to Abstractasymmetric hydrogenation (AH) for the production of optically active alcohols and amines. The Noyori- type catalysts are still the most widely applied for industrial manufacture, because of their modularity, efficiency, stability and cost- effectiveness. The present review presents an account of recent examples of ATH reactions reported for the production of pharmaceuticals and agrochemicals. Particular attention will be given to a case study on the ATH process developed as a key step in the synthesis of the Active Pharmaceutical Ingredient (API) Dorzolamide HCl. INTRODUCTION remarkable advances, in terms of molar substrate to catalyst ratio (S/C) are the tethered catalysts 1 and 2 developed by Catalytic asymmetric reduction of double and triple bonds Wills and Ikariya. These systems are active at S/C as high as has received much attention in recent years. In particular, 30,000 in the transfer hydrogenation of ketones using catalytic asymmetric hydrogenation of ketones and imines HCO2H/Et3N mixtures as hydrogen source (Figure 1) (5-8). has been at the forefront of research due to the importance Another significant advance in the field of transfer of optically active amines and alcohols as pharmaceuticals hydrogenation includes the development of Ru catalysts and agrochemicals (1). Amongst the available methods, containing a monoanionic meridional C,N,N ligand of the asymmetric transfer hydrogenation (ATH) of ketones and type 3 and 4, displaying great activity with TOF over 105 h-1 imines using stable hydrogen donors has operational and S/C 20,000 (Figure 1) (9). advantages by avoiding the use of hydrogen gas (2). In this context, the seminal research of Noyori on ATH mediated by The present review will focus on recent applications of ATH in N-sulfonated diamine-η6-arene ruthenium catalysts the pharmaceutical and agrochemical industry for the represents a breakthrough, transforming ATH into a viable, synthesis of enantio-enriched amines and alcohols. These efficient and cost effective technology (Scheme 1) (3). examples are characterized by the use of Noyori type catalysts Since the publication of the first catalytic system, several such as TsDPEN RuCl (p-cymene) 5, which are the most widely other catalysts have been developed (4). Amongst the most applied in industrial manufacturing processes (Figure 1). Scheme 1. Asymmetric transfer hydrogenation (ATH) of ketones and imines catalyzed by Noyori-type catalyst. Figure 1. Asymmetric Transfer Hydrogenation catalysts. 36 Chimica Oggi - Chemistry Today - vol. 32(5) September/October 2014 Drivers for the vast utilization of Noyori sulfonyl-diamine Ru(arene)Cl catalysts are firstly their modularity, which allows for fine tuning of reactivity by simply changing substituents on the arene and sulfonyl moieties; a further benefit is their stability and efficiency allowing for scale-up to ton quantities and finally their competitive cost due to availability from several suppliers on the market. These systems may be also employed in a variety of conditions giving a reversible reaction in i-PrOH/base and an irreversible reaction with various combinations of HCO2H/NEt3 in organic media or sodium formate in aqueous or biphasic systems. This review Scheme 2. Catalytic ATH of pyridyl ketone 6 as a key step to the asymmetric will focus on both the reduction of ketones to alcohols and synthesis of (11S,12R)-(+)-erythro-mefloquine HCl 9 (gram scale). of imines to amines. A particular attention will be given to a case study on the ATH process developed as a key step in the synthesis of the Active Pharmaceutical Ingredient (API) Dorzolamide HCl. ATH OF KETONES TO ALCOHOLS Most of the reported examples of ATH reactions of ketones using toluene-sulfonyl-1,2-diphenylethylenediamine (TsDPEN) type ligands, involve differentiation between Scheme 3. Preparation of both C5’ epimers of 5’-methyladenosine via ATH (gram scale). ketone groups which can be saturated or unsaturated in the α,β position. Unsaturated substrates have usually an aromatic or heteroaromatic ring, but examples involving alkenes and alkynes are also described (10). During the past decade reports have started to appear in which heteroatoms attached to the α-carbon of the ketone, such as α-ketoesters or tri-halomethyl ketones, serve as effective control elements (11). In the following section industrial applications of ATH on unsaturated and saturated ketones will be discussed. In an attempt to devise an asymmetric and cost effective Scheme 4. Synthesis of (S)-1-(3-trifluoromethyl)ethanol via route to (+)-erythro Mefloquine HCl, the single enantiomer ruthenium-catalyzed ATH (100 kg scale). of the commercial racemate used for the treatment and prophylaxis of malaria, an ATH process was developed by Bryant et al., starting from pyridyl ketone 6 and using (S,S)- TsDPEN RuCl (p-cymene) 5 as catalyst (12). Recently the absolute configuration of (+)-erythro mefloquine was unambiguously determined (13-14), confirming the erroneous assignment by all previous asymmetric syntheses comprising the one from Bryant. Therefore the optically active alcohol S-(+)-8 was obtained in the ATH process instead of the reported R-8, in full conversion and with 96 Scheme 5. Use of (R;R)-5 Ru-TsDPEN with HCO2H/Hünig’s base for the ATH percent ee in 5:2 HCO2H/Et3N, using DMF as reaction to the enantiomerically enriched N-propyl pantolactam (kg scale). solvent. A further catalyst screening concluded that using TsDACH ligand resulted in a product having the same ee (96 percent and 98 percent after isolation), but adding an stoichiometric reductant. This example represents an ATH in economic benefit due to the lower catalyst cost which a non-aromatic heterocycle serves as an effective contribution (Scheme 2). control element. Despite the general sensitivity of ATH to Further increase of the S/C ratio to 1000 was obtained when stereoelectronic effects from contiguous stereogenic the molar ratio of HCO2H/NEt3 was 1. Excess of NEt3 proved centres, as well as the difficulty of retaining the detrimental, resulting both in rate decrease and lower ee of stereochemistry at (4’R) because a dynamic kinetic the product. resolution process can take place, the ATH process (5’S)-C-Methyladenosine 11a and its (5’R) diastereoisomer proceeded remarkably well with either enantiomer of the 11b, which are long-standing and important structural catalyst (S,S)-5 and (R,R)-5. The resulting absolute probes in molecular biology and enzymology, have been configuration was the same as the one obtained in the ATH synthesized by asymmetric catalytic transfer hydrogenation of aromatic substrates. Therefore the stereochemical result from methyl ketone 10 by Nugent et al. at Vertex was tentatively ascribed to an attractive interaction Pharmaceuticals (Scheme 3) (15). between the electron density around the lone electron pairs 6 Noyori’s catalyst η -(p-cymene)-(R,R)-N-toluene-sulfonyl-1,2- of the THF oxygen atom and the partial positive charge diphenylethylenediamine(1-)Ruthenium(II), (R,R)-5 was used, surrounding the η6 aromatic ring. replacing the HCO2H/Et3N system with aqueous HCO2Na as Okano et al. at Mitsubishi Chemical Corporation developed Chimica Oggi - Chemistry Today - vol. 32(5) September/October 2014 37 amine at lower cost. In this particular case a comparison with other metals - iridium and rhodium - has been performed. However, the ruthenium based systems proved to be superior. An efficient method to synthesize the enantiopure anti Alzheimer’s drug Ladostigil 19 (TV3326) was devised using ATH as the key step via the HCO2Na/H2O system as hydrogen donor and dichloromethane as organic solvent (Scheme 6) (19). The use of (S,S)-TsDPEN 20 and (S,S,S)-Cs-DPEN 21 as ligands, in conjunction with surfactants, permitted an efficient recycling of the catalyst which remained in the aqueous phase after separation. Surfactant OTAC (Octadecyl Trimethyl Ammonium Chloride) and ligand 21 furnished the product 18 in 63 percent Scheme 6. Efficient method to prepare Ladostigil via ATH yield with 98 percent ee, even on the fifth run. catalyzed by Ru-Ts-DPEN and Ru-Cs-DPEN in a HCO2H-H2O- ATH in water, proves to be an effective and versatile method for surfactant system (gram scale). fast and enantioselective reduction of prochiral ketones. In fact it may be carried out with unmodified homogeneous catalysts, tailor-made water-soluble catalysts or supported heterogeneous catalysts, with no organic solvents and without the need of surfactants (2f-2l). Ruthenium catalyzed asymmetric transfer hydrogenation as a key step to Dorzolamide Scheme 7. Retrosynthetic approach to Dorzolamide HCl. Dorzolamide HCl 22 is a Carbonic Anhydrase Inhibitor indicated for the treatment of high intraocular pressure. The total asymmetric synthesis of Dorzolamide described by Blacklock et al. envisaged trans-(S,S)-hydroxysulfone 23 as a key intermediate, bearing the correct stereochemistry at C-4 and C-6 for the active pharmaceutical ingredient, which is then retained during the following 7 steps (Scheme 7) (20).Several bioreductive methods had been proposed previously
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  • Highly Selective Vapor and Liquid Phase Transfer Hydrogenation of Diaryl and Polycyclic Ketones with Secondary Alcohols in the Presence of Magnesium Oxide As Catalyst

    Highly Selective Vapor and Liquid Phase Transfer Hydrogenation of Diaryl and Polycyclic Ketones with Secondary Alcohols in the Presence of Magnesium Oxide As Catalyst

    catalysts Article Highly Selective Vapor and Liquid Phase Transfer Hydrogenation of Diaryl and Polycyclic Ketones with Secondary Alcohols in the Presence of Magnesium Oxide as Catalyst Marek Gli ´nski*, Anna Markowska, Laura Wro ´nska , Anna Jerzak and Magdalena Tarkowska Faculty of Chemistry, Warsaw University of Technology, 00-664 Warsaw, Poland; [email protected] (A.M.); [email protected] (L.W.); [email protected] (A.J.); [email protected] (M.T.) * Correspondence: [email protected] Abstract: MgO has been shown to catalyze an almost quantitative hydrogen transfer from 2-octanol as the hydrogen donor to benzophenone to form benzhydrol, a useful intermediate product in the pharmaceutical industry. The hydrogen transfer from a series of alcohols to the carbonyl group of benzophenone, its ten derivatives, four polycyclic ketones, and 2-naphthyl phenyl ketone was carried out in liquid (LP) or vapor phase (VP). The dependence of reactivity on the structure of the hydrogen donor, reaction temperature, donor-acceptor ratio, amount of catalyst, and the type and position of substituents has been established. For both reaction modes, optimal conditions for selective synthesis Citation: Gli´nski,M.; Markowska, of the alcohols were determined and side reactions were investigated. The results indicate that the A.; Wro´nska,L.; Jerzak, A.; Tarkowska, M. Highly Selective reactivity of the ketone is suppressed by the presence of a methyl substituent in the ortho position to Vapor and Liquid Phase Transfer a much greater extent in LP mode. A scale-up was demonstrated in the liquid phase mode. Hydrogenation of Diaryl and Polycyclic Ketones with Secondary Keywords: magnesium oxide; transfer hydrogenation; benzophenones; 2-octanol; selective reduction Alcohols in the Presence of Magnesium Oxide as Catalyst.