Catalytic Asymmetric Transfer Hydrogenation: an Industrial Perspective

Home , Asymmetric hydrogenation, Transfer hydrogenation

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 for the synthesis of the key intermediate trans-(S,S)-hydroxysulfone 23 from the corresponding ketone with an ee and de greater than 99 percent (21). Among the numerous attempts at reducing the starting (S)-ketosulfone 24 via a chemical approach, just a single report describes the preparation of the desired trans diastereoisomer, this being obtained in 76 percent de using the Corey technology (22). The steric hindrance of the methyl group at C-6 prevents most reducing agents from approaching the required face for a trans selective reduction to occur. With the objective of enhancing the Scheme 8. Ruthenium-catalyzed asymmetric transfer productivity of this step and the overall cost efficiency a ruthenium- hydrogenation of ketosulfone 24 and ketosulfide 25 (hundreds kg catalyzed asymmetric transfer hydrogenation process has been scale per batch). developed by ZaCh System- Zambon Chemicals (Scheme 8) (23). Surprisingly, catalyst control efficiently overcame substrate control an asymmetric transfer hydrogenation for the production of (S)-1- affording the desired (S,S)-hydroxy sulfone 23 with high selectivity (3-trifluoromethylphenyl)ethanol 13 as a key step to the fungicide (98 percent de after isolation) and with no loss of the starting S (S)-MA20565 14 (Scheme 4) (16). configuration at C-6. The optical purity of the starting ketone is in The work has been pioneering in terms of scale-up. This fact prone to erosion in basic media by the retro-michael required investigating the importance of temperature and the mechanism shown in Scheme 9.

HCO2H/Et3N ratio with respect to reaction rate and the For this reason both the Asymmetric Hydrogenation (AH) approach resulting ee. In the 100 kg scale-up they observed an using Noyori catalysts and the ATH employing i-PrOH/base, could increased reaction rate in comparison to small scale not be considered as viable alternative approaches to experiments. This observation can be ascribed to a more hydroxysulfone 23, instead leading to complete racemization at efficient agitation which results in a more effective C-6. Interestingly the ATH reaction does proceed very slowly if the disengagement of carbon dioxide from the reaction mixture. sulfide 25 is subjected to ATH conditions, although still in favour of Zhang et al. at Pfizer have devised an efficient and highly the trans stereochemistry. This poorly selective transformation may enantioselective method for producing N-propyl be explained either by an epimerization of the hydroxyl pantolactam 16 (Scheme 5) (17). functionality at C-4 occurring in acidic media after selective Enantioselectivity was increased during development studies by reduction, or by stereo-electronic differences of the substrates. changing the tertiary amine base in the HCO2H/Et3N (5:2) system, still the most widely used hydrogen source since the initial report by Leitner and Brunner (18). Best results were obtained ATH OF IMINES TO AMINES using HCO2H:(-)-sparteine (5:2) or HCO2H:Hünig’s (5:2) combinations, the latter being an excellent hydrogen source for Asymmetric transfer hydrogenation of imines is more effectively

ATH affording comparable results to those of the optically active carried out on aryl-fused cyclic imine substrates, using HCO2H/Et3N

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Interested in more information about Ru-721? Please visit http://jmcct.com Scheme 9. Epimerization occurring at C-6 via retro-michael mechanism. Scheme 11. Ruthenium-catalyzed intramolecular asymmetric reductive amination as a key step to Suvorexant 33 (>100 kg scale).

Scheme 10. ATH of a dihydroisoquinoline methanesulfonate salt Scheme 12. Asymmetric reduction of o-hydroxyaryl Imine for the large-scale production of Almorexant (> 100 kg scale). 35 as a key step to MK-8742 37 (gram scale)

conditions since i-PrOH could not serve as hydrogen source as and triethylamine produced the desired diazepane ring in 90 described in Noyori’s seminal paper (3d). Recently it was also percent ee and 88 percent yield, using 3 mol percent catalyst 34, reported that the imine ATH can only be performed under with dichloromethane as the co-solvent and precipitating the acidic conditions which is in line with the inapplicability of final product 32 as the HCl salt (Scheme 11). i-PrOH in the presence of a base (24). ATH of imines is less In order to decrease the amount of catalyst and increase the commonly utilized than the corresponding ATH of ketones from reaction rate, the authors studied the profound effect that CO2 an industrial perspective. Three remarkable and very recent had on the equilibrium between the Ru-hydride and Ru-formate examples of ATH of a dihydroisoquinoline system and of an catalyst forms and the huge negative impact on reaction rate o-hydroxyaryl imine, and a reductive amination by hydrogen (27). Purging of the CO2 not only greatly improved the reaction transfer are described in this section. rate, allowing reduction in the amount of catalyst to S/C 50, but A catalytic asymmetric transfer hydrogenation of also reduced the potential for formation of carbamates of the 3,4-dihydroisoquinoline for the large-scale production of product, increasing the overall yield. Studies on the ATH of

Almorexant 30 was developed by researchers at DSM, Actelion acetophenone, either efficiently purging CO2, or trapping it with a Pharmaceuticals and GlaxoSmithKline (Scheme 10) (25). secondary amine, exemplified these as useful techniques to Key to obtaining high ees and lowering the amount of the formyl enhance the efficiency of the reaction. impurity formed was to conduct the reaction starting from the Recently a very efficient asymmetric transfer hydrogenation of an imine salt 27•MsOH without prior formation of the free base. The o-hydroxyaryl imine 35 has been developed by Mangion et al. at mesylate salts were less prone to react with HCO2H without any Merck towards the synthesis of the NS5a inhibitor MK-8742 37 negative impact on ee and reaction rate, which were indeed (Scheme 12) (28). improved. A further change of the HCO2H/Et3N ratio to 1:1 from 5:2, allowed a decrease in the amount of catalyst to S/C = 2000. The reduction of acyclic imine 35 had been initially performed via Also, the asymmetric hydrogenation (AH) process from catalytic asymmetric hydrogenation in the presence of iridium, 3,4-dihydroisoquinoline free base was investigated and scaled-up and rhodium catalysts in conjunction with a range of to ton quantities using Ir/TaniaPhos as the catalyst of choice. A bisphosphine ligands, furnishing promising results in terms of ees detailed comparison of AH and ATH approaches for the (80-87 percent) but modest yields (13-30 percent) due to production of the key amine intermediate 28 is reported. ATH competing hydrolysis of the imine back to the ketone, and proved superior to AH in terms of number of steps (freebase subsequent reduction of the ketone to the corresponding formation avoided), cost of the catalyst, flexibility, productivity alcohol. Even the traditional Noyori-type ruthenium transfer and variable costs. The main driver for the final choice was mainly hydrogenation catalysts furnished poor results in terms of yield. the cost of goods, taking into consideration the availability of However it was discovered that the “tethered” (R,R) Teth-TsDPEN plant units and delivery times of raw materials. RuCl catalyst 38, pioneered by Wills, improved both Recently the first example of intramolecular asymmetric reductive enantioselectivity (78-98 percent ee) and yield (81-96 percent), amination of a dialkyl ketone containing an aliphatic amine has the best results being achieved in DCM using NH4CO2H as been developed as a key step to the dual Orexin antagonist hydrogen source at S/C 333. The result was consistent with existing Suvorexant by Merck (MK-4305) (26). Modifications to the TsDPEN studies suggesting the role of the tethered ligand in stabilizing the ligand architecture were executed in order to fine tune both catalyst and providing faster Ru hydride generation (29). reactivity and enantioselectivity. The 2,4,6-triisopropylsulfonyl-DPEN complex (Ru-TIPPS-DPEN, 34) proved to be the most effective, using a HCO2H/Et3N ratio of 1. The most significant improvements CONCLUSIONS to both enantioselectivity and yield were obtained when no effort was made to preform the imine prior to reduction. The free base Recent applications of ruthenium-catalyzed asymmetric transfer formation with potassium carbonate had the beneficial effect of hydrogenation of ketones and imines have been reported as key precipitating the mesyl counteranion as the potassium salt, steps in the synthesis and large-scale production of increasing the ee. A mixture of formic acid, potassium carbonate pharmaceuticals or agrochemicals. The ATH process employing

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