olefin metathesis · 2016-06-09 · keywords: metathesis, ruthenium, active pharmaceutical...

22 Chimica Oggi - Chemistry Today - vol. 32(5) September/October 2014

KEYWORDS: metathesis, ruthenium, active pharmaceutical ingredient, catalysis, organometallic reagents, alkenes

AbstractOlefin metathesis is a powerful transformation based on catalytic reaction between alkenes. It allows a formation of a variety of structurally diverse molecules that cannot be easily prepared by alternative routes.

Recently developed methods require relatively low catalyst loading and enable easy removal of residual ruthenium from the reaction product. These developments have attracted the attention of process chemists who add metathesis reaction to a toolbox of reliable methods for production of pharmaceuticals. This review presents selected examples of successful application of olefin metathesis in the synthesis of active pharmaceutical ingredients from laboratories within the pharmaceutical industry.

Olefin metathesis: a versatile synthetic tool for use in preparation of Active Pharmaceutical Ingredients

INTRODUCTION

Olefin metathesis is a powerful transformation that has gained a real significance in advanced organic synthesis for the formation of C = C double bonds (1). The development of well-defined and stable catalysts along with the understanding of the reaction mechanism has revolutionized retro-synthetic planning (2). The importance of olefin metathesis was recognized in 2005, with the award of the Nobel Prize in Chemistry to Yves Chauvin, Richard R. Schrock, and Robert H. Grubbs (3).The success of this transformation was fully associated with the development of efficient and durable catalysts (Figure 1). Among them: the first generation Grubbs catalyst G-I, Hoveyda-Grubbs catalyst H-I and the indenylidene bearing complex Ind-II (4), are characterized with high activity, selectivity, and functional group tolerance. The replacement of the electron-rich phosphine group with N-heterocyclic carbene (NHC) ligand resulted in the formation of second-generation catalysts G-II, G-II’ and H-II, H-II’. These catalysts are characterized with even higher stability of the active species and therefore better catalytic performance, especially with sterically hindered olefins and olefins substituted with electron withdrawing groups (1). Further modifications and fine tuning around the benzylidene moiety resulted in the discovery of electron withdrawing group (EWG) activated catalysts exemplified here by N-II (now commercially available). A weaker O—>Ru coordination, which results from the presence of electron deficient substituent, favours a formation of the catalytically active, coordinatively unsaturated species that likely undergo reaction. This makes the N-II type catalysts very active and fast initiators. The N-II catalyst was thus far successfully

employed in the synthesis of several natural and bioactive compounds (2b, 5). Finally, modification of the isopropoxy fragment of the benzylidene ligand lead to the active so-called “Scorpio” catalysts, represented by E-II and E-II’ (6).

Olefin metathesis is a broad term that describes not only one reaction but a set of transformations. Among those transformations, the ring-closing metathesis (RCM) is of particular importance for pharmaceutical industry (Figure 2). RCM helps to transform linear substrates to cyclic olefins and therefore is frequently used to the preparation of biologically important compounds containing medium and large size rings (7). The second important transformation is cross metathesis (CM), which produces alkenes by fusing two olefins (8). Other transformations represent an additional opportunities mostly in synthesis of advanced materials via polymerization (Figure 2) (9).

APIsTOMASZ K. OLSZEWSKI1*, MAREK FIGLUS2, MICHAŁ BIENIEK2

*Corresponding author1. Wroclaw University of Technology, Faculty of Chemistry, Department of Organic Chemistry,

Wybrzeże St. Wyspiańskiego 27, 50-370 Wrocław, Poland2. Apeiron Catalysts Sp. z o. o., Duńska 9, 54-427 Wroclaw, Poland

Tomasz K. Olszewski

Figure 1. Selected modern ruthenium based olefin metathesis catalysts.

23Chimica Oggi - Chemistry Today - vol. 32(5) September/October 2014

from Pfizer developed reliable and elegant method of preparation of cyclic ketones 8 and 9 (Scheme 2) (14). The target compounds exhibit significant pharmacological activity at opioid receptors and provide useful intermediates for the synthesis of novel and selective opioid receptor ligands. The key transformation used in the synthetic pathway was the conversion of diallylpiperidine 6 to the bi-cyclic olefin 7 using RCM in the presence of G-I catalyst. Reaction was carried out in dichloroethane at 60°C (Scheme 2) and enabled an easy formation of intermediate 7 with high yield

(93 percent). Regioselective functionalization of the double bond led to the target cyclic ketones 8 and 9.Also, scientists from Merck demonstrated a successful application of RCM in the synthesis of biologically relevant benzazepinone derivatives known as sodium channel blockers and useful for the treatment of chronic and neuropathic pain (15) (Scheme 3). RCM was used for the construction of 7-membered cyclic part of the intermediate 12, that was further transformed into target inhibitor with general structure 14. For the RCM reaction a member of an EWG activated ruthenium metathesis catalyst, namely Z-I (5 mol percent) was used. Desired cyclic products were formed with an average 90 percent yield after 16 h reaction time at room temperature in DCM.

The progress in the field of olefin metathesis made over the last few years, was followed by increase of interest with the methodology by chemical industry worldwide. The availability of various metathesis catalysts together with research efforts focused on the development of more active complexes helps to improve economical outcome of industrial processes including those in the pharmaceutical industry (10).

RING CLOSING METATHESIS (RCM) IN THE PREPARATION OF ACTIVE PHARMACEUTICAL INGREDIENTS

RCM has become an essential tool for the synthesis of carbo- and heterocylic ring systems particularly well-suited for the efficient synthesis of small, medium and large macrocycles with biological properties (7, 11). The right choice of catalyst and reaction conditions helps to overcome the usual problems associated with this transformation such as isomerization, dimerization, and necessity of working with highly diluted reaction mixtures. This section presents some of the possibilities offered by RCM in the synthesis of active pharmaceutical ingredients.

Synthesis of small and medium ringsAgonism of sphingosine-1-phosphate (S1P) receptors has been linked to many diverse cellular functions including sequestration of lymphocytes into secondary lymph organs which prevent them from causing an autoimmune response (12). Medicinal chemists from Abbot Laboratories reported on a gram-scale, enantioselective synthesis of compound 4 that has been shown to induce sequestration of lymphocytes in mice (13). The formation of sterically hindered double bond presented in the five membered-ring scaffold of the key intermediate 3 was accomplished with RCM using G-II catalyst (Scheme 1) (13).

In another example, as part of a program aiming to design and synthesize novel opioid receptor ligands, researchers

Figure 2. Variants of olefin metathesis transformations. ROMP = ring-opening metathesis polymerization, ADMET = acyclic diene metathesis polymerization, RCM = ring-closing metathesis, ROCM = ring-opening cross metathesis, CM = cross-metathesis, RCEM = ring-closing enyne metathesis.

Scheme 1. Synthesis of compound 4, agonist of sphingosine-1-phosphate receptor with the use of RCM.

Scheme 2. Application of RCM in the synthesis of cyclic ketones 8 and 9.

Chimica Oggi - Chemistry Today - vol. 32(5) September/October 201424

Synthesis of large ringsChronic infection with hepatitis C virus (HCV) is a severe medical problem affecting more than 170 million people worldwide. The infection can cause cirrhosis of the liver and eventually liver cancer (19). Considerable effort has been devoted to the design and synthesis of substrate-based peptidomimetic inhibitors that target specifically the NS3 serine protease enzyme of HCV. Disrupting the catalytic function of its essential enzyme NS3 protease can provide a treatment option of significant socioeconomic benefit. Medicinal chemists at Boehringer Ingelheim, proposed the structure of macrocyclic peptide, BILN 2061 as potential drug candidate for treatment of HCV. BILN 2061 has shown oral bioavailability and antiviral effect in humans infected with HCV, and was the first compound of its class to have reached clinical trials (20).The key step in the final assembly of BILN2061 was the formation of the 15-membered macrocycle. This exceptionally challenging transformation was done with the support of RCM applying suitable catalyst (Scheme 5).

The first attempt on the RCM reaction was carried out in the presence of the G-I (2-5 mol percent) and resulted in the successful formation of desired macrocycle (as a Z-cycloalkene) however a significant amount of epimerization product at the chiral carbon of the cyclopropane ring was observed. Replacement of G-I with H-I allowed to circumvent the epimerization problem but high catalyst loading (5-7 mol percent), long reaction time and high dilution were required to complete the RCM step (21). Subsequent experiments with the use of second generation catalysts G-II and H-II produced large amounts of unwanted cyclic dimers. Modification of protecting groups used in the starting diene followed by further optimization of the reaction conditions allowed to improve the outcome of the RCM transformation and to obtain the desired macrocyclic product with 83 percent yield (approx. 10 percent dimers were observed) using H-I (3 mol percent added portionwise), in toluene at 80°C and during reaction time of 3 h. Unfortunately, the product was contaminated with significant amounts of residual ruthenium (500–1000 ppm) (22). Finally, a breakthrough came with the application of N-II catalyst (Scheme 5). Careful optimization of the reaction conditions allowed to reduce the catalyst loading to 0.1 mol percent and obtain

Another example on successful application of RCM in the synthesis of pharmaceutically active ingredient was reported by medicinal chemists from GlaxoSmithKline. They proposed an RCM approach to the synthesis of potent cathepsin K inhibitor SB-462795, a candidate for the treatment of osteoporosis and osteoarthritis (Scheme 4).

Unlike bisphosphonate therapeuticals that cause a death of osteoclasts, cathepsin K inhibition does not affect the osteoclastic function (16). The progression of SB-462795 into clinical trials forced synthetic chemist to develop reliable and amendable procedures suitable for larger scale synthesis.One of the main challenges in the synthesis of SB-462795 was associated with the formation of seven-membered highly functionalized azepanone ring. A scalable route based on a RCM disconnection of the C5–C6 bond proved to be efficient (Scheme 4). Preliminary experiments however were carried out with rather high catalyst loading namely 14 mol percent of G-II in the first attempt and 10 mol percent of H-II in the second attempt (17). Subsequently, careful optimization of the structure of the diene allowed to decrease the catalyst loading to 0.5 mol percent of the H-II and the reaction could be carried out at relatively high concentration (0.2 M)(Scheme 4). It is worth stressing that residual ruthenium was simply removed from the reaction product upon addition of tetrakis(hydroxymethyl)phosphonium chloride. This methodology was applied to a large-scale manufacturing process. The diene 15 underwent RCM reaction with as little as 0.5 mol percent of H-II catalyst (600 g) in toluene (880 L) at reflux (5 h) affording cyclic olefin 16 (71.8 kg) in 96 percent yield just after simple crystallization (18).

Scheme 3. The application of RCM strategy in the synthesis of benzazepinone derivatives 14.

Scheme 4. RCM in the synthesis of cathepsin K inhibitor SB-462795. Scheme 5. Optimized RCM synthetic step in the synthesis of BILN 2061.

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Cross metathesis (CM) reaction in the synthesis pharmaceuticalsUnderstanding of CM mechanism and catalyst–substrate interactions as well as development of more active, selective and tolerant to various functional groups catalysts have improved in recent years (2, 8). These advances brought CM to a stage where more and more researchers employ it to multistep procedures and in the synthesis of active pharmaceutical ingredients.Aiming to develop new efficient drugs for treatment of HIV infection medicinal chemists at Merck prepared a library of lysine sulfonamide derivatives 23 (Scheme 6) (29). The key synthetic transformation in the multistep synthesis of 23 was a formation of the ketone 22 by means of CM of appropriate diene 20 with crotyl ketone derivatives 21 in the presence of G-II catalyst (10 mol percent). Cross metathesis transformation carried out in DCM at reflux during 16 h furnished the desired products with an average 90 percent yield. Subsequent transformations led to the desired inhibitors 23. Using metathesis as key synthetic step authors prepared over a hundred of new potent inhibitors, with the IC50 up to 0.005 nM.

Very recently CM was successfully applied to the preparation of intermediate 27 in the synthesis of Aliskiren. This compound is antihypertensive drug, co-developed by Novartis and Speedel, and is known as the first in a class of drugs called direct renin inhibitors (30, 31). Hanessian and Chénard demonstrated that the olefin 25 reacts with enantiopure ester 26 (3 equiv.) in the presence of H-II (20 mol percent) to afford CM product 27 with 60 percent yield (as a 84:16 E/Z mixture)(Scheme 7) (32).

Although the reported results looked acceptable it should be possible to further improve this process. For example changing the catalyst and adding it slowly over a certain

the desired macrocyclic product 18 with 95 percent yield (no epimerization or dimerization was observed) after just 30 min reaction at 110°C in toluene (Scheme 5) (23).In summary, this very first and challenging macrocyclization reaction perfectly illustrates the major issues associated with the application of ring-closing metathesis in pharmaceutical industry, which includes: 1) high dilution required to minimize the intermolecular metathesis reactions, 2) high catalyst loadings and the subsequent removal of residual ruthenium from the reaction product, 3) long reaction times to reach a completion. Researchers from Boehringer Ingelheim showed that most of these problems could be elegantly overcome by a selection of appropriate catalyst and the reaction conditions. A switch from the initially utilized H-I to N-II catalyst shortened the RCM reaction time from several hours to just 30 minutes. The turnover number was 50–100 times higher for N-II catalyst than for H-I catalyst which allowed to use less catalyst, and consequently provided the desired product contaminated with smaller amount of residual Ru (usually <50 ppm without additional metal scavenging). A clear benefit of this approach was also the dramatic reduction of the solvent usage, for H-I up to 150,000 L of solvent per ton of diene compared to only 7500 L for the optimized process with appropriate diene and N-II catalyst.Since the disclosure of the first series of macrocyclic HCV inhibitors by Boehringer Ingelheim, many compounds characterized by the same macrocyclic ring peptidomimetic scaffold have appeared in the drug-discovery pipelines of the pharmaceutical industry including derivatives from Pfizer (24), Bristol-Myers Squibb (25), Enanta Pharmaceuticals (26) and Array Biopharma (Figure 3) (27).

The interest in the use of RCM for production of macrocyclic drug candidates by pharmaceutical industry is still very strong. Very recently scientists from Merck reported on the preparation of 20-membered macrocyclic compound a key structural feature of Vaniprevir (MK-7009) (Figure 3) (28). The product containing 20-membered ring was generated in 91 percent yield with 0.2 mol percent of H-II catalyst (simultaneous slow addition of catalysts) on a 17 g scale process at a relatively high concentration (0.13 M).

Figure 3. Structures of selected macrocyclic HCV inhibitors prepared with the use of RCM.

Scheme 6. Preparation of a library of lysine sulfonamide derivatives 23 applying CM.

Scheme 7. Application of CM in a synthesis of Aliskiren.


product combined with a possibility of catalysts recovery and their reuse in a cycle of transformation. However their synthesis is much more complicated and therefore preparation in bulk quantities for industrial applications very limited. Additionally, it has to be mentioned that the aforementioned catalysts were developed mostly in academic laboratories and are not commercially available.Inspired by literature reports we have designed and prepared two new catalysts GreenCat and StickyCat that allow very efficient removal of residual ruthenium from the metathesis product (Figure 4, Table 1) (45, 46).The GreenCat it is very reactive and robust and its structure relays on the concept of “Scorpio” type catalysts. The introduction of hydroxamic ester group as terminal substituent of the styrenyl ether resulted in high affinity to silica gel (45). After reaction completion the reaction mixture is filtrated through a short pad of silica gel (SiO2/substrate mass ration = 7). At this stage the catalyst stay attached to the silica gel and the reaction product is eluted with CH2Cl2. This procedure enables a preparation of product with very low residual ruthenium content (9-143 ppm) (Table 1) (45). Subsequently, the catalyst can be removed from silica using ethyl acetate and the recovered catalyst can be reused 5 times without the loss of activity. An additional advantage of the GreenCat is it high activity as the catalyst operates at low loadings 1.0-0.1 mol percent in non-degassed, non-destilled ACS grade solvents without the protective atmosphere of an inert gas. The catalyst is particularly effective in “green solvents” with very low environmental footprint such as ethyl acetate (EtOAc), cyclopentyl methyl ether (CPME) or isopropanol (i-PrOH) (45).

period of time could result in decreasing the catalyst loading and improving the reaction yield (33). The use of CM allowed the synthesis of compound 27 in five steps from 24 in 38 percent overall yield. The intermediate 27 could be further transformed to the Aliskiren applying the literature procedures (31, 34, 35).

REMOVAL OF RESIDUAL RUTHENIUM FROM THE PRODUCT AFTER METATHESIS REACTION

One of the major problems associated with application of olefin metathesis in pharmaceutical industry is removal of residual ruthenium. First, ruthenium hydride complexes, formed from decomposition of metathesis catalysts, can accelerate side reaction during the synthesis, product isolation and purification. Second, the acceptable ruthenium level in administrative drugs should be <5 ppm. Therefore, effective and economically viable ruthenium removal techniques are of significant importance for pharmaceutical industry (36). To this end several techniques were reported in the literature including extraction with supercritical carbon dioxide (37), treatment with aqueous hydrogen peroxide and filtration through silica gel (38) and use of various scavengers such as DMSO (39), isocyanide (40), or supported phosphines (41). These techniques allow to reduce the ruthenium content to 10-1200 ppm. Alternatively, two cycles of chromatography combined with 12 h incubation with activated charcoal was shown to reduce the amount of residual ruthenium to 60 ppm (42). Those methods however are time consuming and in some cases may induce side reactions.

An alternative approach to removal ruthenium residues is based on the use of specially designed ruthenium catalysts with high affinity to silica gel such as the “Scorpio” type catalysts E-I, E-2, Carb, or catalysts bearing polar ammonium group like Q or affordable catalyst A (43). Additionally heterogenic complexes such as Het-1 or Het-2 were also synthesized (Figure 4) (44).While the homogeneous catalysts with classical NHC ligand and modified benzylidene ligand allow to reduce the ruthenium content up to 12 ppm after single purification (filtration through a pad of silica gel), they usually bind strongly to silica gel and therefore their recovery and reuse is impossible. In contrast, the heterogenic catalysts can give superior results in terms of low residual ruthenium content in the

Figure 4. Selected heterogenic and homogenous olefin metathesis catalysts designed for easy removal of residual ruthenium from the reaction product.

Table 1. Catalytic activity and levels of residual ruthenium for model metathetical transformations catalyzed by GreenCat and StickyCat in comparison with N-II and H-II.(a, b)a. Reaction conditions:1 mol percent of catalyst, CH2Cl2, 40°C, C = 0.05 M. Reactions with GreenCat carried out in ACS grade solvents on air.b. Level of ruthenium contamination determine by inductively coupled plasma mass spectroscopy (ICP-MS) analysis.c. ICP-MS analysis after filtration through silica gel.


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7. For a comprehensive review on RCM see: S. Monfette, D. E. Fogg Chem. Rev. 109, 3783-3816 (2009).

8. For a comprehensive review on CM in the synthesis of biologically important molecules see: S. J. Connon, S. Blechert, Angew. Chem., Int. Ed. 42, 1900-1923 (2003).

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In contrast, the StickyCat catalyst is functionalized with a quaternary ammonium group in the NHC ligand, which makes this catalyst very polar and active in various metathetical transformations. Although it requires longer reaction times that the GreenCat (46), similar to GreenCat it can be easily removed from reaction mixture by simple filtration through a pad of silica gel (SiO2/substrate mass ration = 7). The reaction product thus obtained is characterized with very low ruthenium content (0.9-4.8 ppm) (Table 1).Importantly, both GreenCat and StickyCat catalysts can be easily synthesized and are commercially available in bulk quantities.

CONCLUSIONS

The olefin metathesis has had a glorious past and it promises to have an even brighter future. Recent advances in the development of efficient and active catalyst substantially enhanced the utility of this already very powerful set of transformations. With the selected pallet of most prominent examples we have shown that olefin metathesis can be considered as a very efficient tool in the synthesis of structurally diverse active pharmaceutical ingredients even on large scale. There is no universal catalyst for all metathetical transformations, and therefore during the optimisation of industrial processes it is advised to test all main types of catalysts (preferably those commercially available). For pharmaceutical application catalysts with high activity and offering the possibility of efficient ruthenium removal from the reaction product are now available in bulk quantities. Additionally it has been shown that olefin metathesis can be performed in an environmentally friendly fashion with low catalyst loading (0.25 mol percent) in green, ACS grade solvents on air (47). Additionally advanced techniques such as metathesis under continuous flow mode with the use of microreactors are now available (48). We are confident that with these advantages in hands olefin metathesis will soon become a popular tool in the process chemist’s toolbox of efficient methods for the large-scale production of many more pharmaceuticals.

ACKNOWLEDGEMENTS

T.K.O. acknowledges financial support from the city of Wrocław within the MOZART programme (II edition).

REFERENCES AND NOTES

1. For selected reviews and books on olefin metathesis, see: (a) Olefin Metathesis: Theory and Practice, ed. Grela, K., John Wiley & Sons, Inc., 2014 (b) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 110, 1746-1787 (2010); (c) C. Samojłowicz, M. Bieniek, K. Grela, Chem. Rev. 109, 3708-3742 (2009); (d) A. H. Hoveyda, A. R. Zhugralin, Nature 450, 243-251 (2007).

2. Selected recent reviews and books on synthetic applications of olefin metathesis: use of ruthenium based catalysts: (a) A. H. Hoveyda J. Org. Chem. 2014 doi.org/10.1021/jo500467z. (b) T. K. Olszewski, M. Bieniek, K. Skowerski, K. Grela, Synlett 24, 903-919 (2013); (c) K. C. Nicolaou, P. G. Bulger, D. Sarlah Angew. Chem. Int. Ed. 44, 4490-4527 (2005); (d) Handbook of Metathesis, ed. R. H. Grubbs, Wiley- VCH, Weinheim, 2003. For applications of molybdenum based catalysts see: (e) A. Fürstner Angew. Chem. Int. Ed. 52, 2794-2819 (2013).

3. For the Nobel Prize Lectures, see: (a) Y. Chauvin, Angew. Chem. Int.


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olefin metathesis · 2016-06-09 · keywords: metathesis, ruthenium, active pharmaceutical...

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