Paul H. Moran, PhD, is a research specialist at Chirotech Technology Ltd.

Paul H. Moran

			Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis. Asymmetric hydrogenation is an atom economical and scaleable method for the manufacture of commercial chiral compounds.  Developing efficient methods to produce the chiral ligands and catalysts on a large scale is essential to effectively commercialize this technology. The authors examine methods to manufacture select catalyst systems and their application in commercial-scale asymmetric hydrogenation.			

Single-enantiomer compounds accounted for 75% of the new small molecule pharmaceuticals approved by the US Food and Drug Administration in 2006. Half of these products are made by purely synthetic means, and asymmetric chemocatalytic methods such as asymmetric hydrogenation are being used more frequently to synthesize single-enantiomer compounds.  

Asymmetric hydrogenation was first demonstrated almost 40 years ago, with the landmark literature reports published independently by the groups of Knowles and Horner in 1968. Both groups indicated that a rhodium catalyst, modified with a chiral phosphine ligand, was capable of inducing asymmetric hydrogenation in a suitable prochiral substrate. While working for Monsanto, Knowles developed the first commercial application for the manufacture of L-DOPA (see Figure 1), a drug used for treating Parkinson's disease (1). This pioneering work led to Knowles sharing the 2001 Nobel Prize for Chemistry with Noyori and Sharpless. 

During the 1970s, there were no more than a handful of chiral ligands reported, and none of these were commercially available on large scale. The ligand system and synthesis for any given application had to be developed 

, thereby creating significant barriers in using asymmetric hydrogenation. Most systems also were neither modular nor widely applicable over a broad range of substrates, making systematic selection of a suitable catalytic system difficult to predict. Noyori introduced the BINAP catalysts in the 1980s, and these catalysts led to Takasago developing many commercial processes for manufacturing β-hydroxy esters [used in the Lipitor (atorvastatin) side chain], alcohols, and carbapenem intermediates using ruthenium-BINAP systems (2).  

During this period, a greater range of catalytic systems and substrates was established, so systematic employment of chiral catalytic technology was possible to a significantly greater extent. The largest-scale rhodium-BINAP process is the allylic isomerization of diethylgeranylamine to provide (R)-citronellal, an intermediate used to manufacture (–)-menthol, which is produced on a scale exceeding 1000 metric tons per year (2).  

The commercial success of the BINAP technology encouraged many companies and research institutes to search for novel ligands outside the scope of the BINAP patents. Hoffmann-La Roche, for example, developed the MeO-BIPHEP ligands and catalysts and applied these ligands in the manufacture of vitamins and pharmaceutical intermediates. The side chain of tetrahydrolipstatin (orlistat) (see Figure 1) is manufactured using an asymmetric hydrogenation process, with a ruthenium MeO-BIPHEP catalyst (3).  

By the 1990s, there were many more catalyst systems established for asymmetric hydrogenation, applying a diverse range of ligands, using rhodium, ruthenium, and iridium metals, and finding applications in pharmaceutical, agrochemicals, nutraceuticals and the flavor and fragrance industries. The two ligand systems with the greatest impact developed in the 1990s were DuPhos (1,2-bis(2,5-dialkylphospholano)benzene) by Burk (4) and Josiphos by Togni and Spindler (5). The JosiPhos ligand system is used in the largest-scale asymmetric hydrogenation process known to date: for the manufacture of the herbicide Dual Magnum[(

)-metolachlor] (see Figure 1), which is produced on a 20,000-metric-ton scale per year (6). The actual iridium Josiphos catalyst required was not known at the start of the research project, but was discovered as the development of (

)-metolachlor proceeded. Chirotech, now part of Dowpharma, obtained the exclusive license to the DuPhos, BPE (1,2-bis(2,5-diphenylphospholano)ethane) and 5-Fc (1,1'-bis (2,5-diphenyl-phospholano) ferrocene) technology for commercial pharmaceutical applications from DuPont. Chirotech subsequently developed numerous asymmetric hydrogenation processes, and the DuPhos ligands and catalysts were also offered for sale on commercially relevant scales (>100 g–multi-kilograms) (7).   

There are in excess of 3000 ligands known for asymmetric hydrogenation processes, though only a handful of these are truly available on a kilogram scale within a reasonable lead time (8). Four drugs, recently approved by FDA are reported to use asymmetric hydrogenation in their manufacture (see Figure 2). Rozerem (ramelteon) (9) and Aptivus (tipranavir) (7) were approved in 2005, Januvia (sitagliptin) (10) in 2006, and Tekturna (aliskiren) (11) in 2007. These approvals confirm that asymmetric hydrogenation has matured and become an accepted addition to commercially relevant technologies for pharmaceutical manufacture. 

Rhodium DuPhos applications and ligand synthesis

The DuPhos technology has a broad substrate scope, and Chirotech has reported asymmetric hydrogenation processes for tipranavir (7), candoxatril (7), pregabalin (7), unnatural α-amino acids (12), and succinates (13) (see Figure 3). To further develop and potentially commercialize such processes, however, require the Me-or Et-DuPhos rhodium precatalysts to be produced on multikilogram scales. 

Prior to the commercialization of the DuPhos technology, Chirotech developed methods to produce the ligands and catalysts on a multigram scale, with practical but moderate yields. These methods satisfied the laboratory scale and early development needs for the compounds shown in Figure 3. As demand for these catalyst systems increased toward multi-100s grams and then to kilograms, it was clear that the initial synthetic methods were not practical in terms of yield, purity, and economics. In the first instance, Chirotech addressed the ligand synthesis and made improvements over the original routes. Hexane-2,5-diol was originally obtained using an electrochemical Kolbe coupling of single enantiomer 3-hydroxybutyric acid, but this method did not scale up well with severe fouling of the electrodes being observed (14). 

Chirotech then developed an in-house method constituting a bioresolution approach starting with the 1:1 racemic/meso diol (15). Using inversion techniques on a monobutyrate derived from the meso diol, a good yield of the (

) enantiomer was obtained, but the yield of the (

) entantiomer was lower. With the introduction of highly efficient alcohol dehydrogenase enzymes and ready availability of hexane-2,5-dione, both enantiomers of hexane-2,5-diol are commercially available on the requisite scales. For security of supply reasons, Dowpharma still operates its own protected bioresolution route. 

In the original synthetic protocol for the DuPhos ligands, 1,2-bis (phosphino) benzene was deprotonated with 

-BuLi, followed by addition of the cyclic sulfate and then further 

-BuLi (see Figure 4) (14). This approach gave the ligands in good yields and purities. Upon scaling up this process to produce kilogram amounts, yields were not reproducible, and higher levels of impurities were formed. These problems were readily solved by an inverse addition procedure, whereby 

-BuLi is added to a mixture of 1, 2-bis (phosphino) benzene and the cyclic sulfate. This process is readily scaleable, giving high purity ligand in excellent yields on multikilogram scales (16). This process also has been applied to other 1,4-diols to give access to ethyl and isopropyl phospholane ligands, as well as the related 1,3-diols for the proprietary phosphetano ligands, FerroTANE (Dowpharma, Midland, MI) (17). 

For some asymmetric hydrogenation catalyst systems, it is acceptable to make the precatalyst 

 from a metal complex and the ligand. We have the general approach that it is better to preform and isolate the ligand–metal catalyst complex so it can be charged to the reactor as a defined species. This approach results in more robust and reproducible reactions, with greater quantification (important for CGMP manufacture) and no debate as to whether the precatalyst complex has completely formed. Initially, standard established literature methods were used to make the Rh-DuPhos complexes: (1,5-cyclooctadiene) Rh(I) acetylacetonate] is converted into the sparingly soluble Rh bis(1,5-cyclooctadiene) tetrafluoroborate complex (18), and the ligand reacts with this intermediate to provide the precatalyst complex in solution. Addition of an antisolvent is required to precipitate the desired product (see Figure 5). This method worked well for a range of diphosphine ligands, but provided material in modest yields (~70%) and variable product form. Obviously, failing to isolate 30% of valuable ligand and metal precursor is neither desirable nor economical.  

A further problem with this method was that the product form was variable, from robust deep red crystals to orange-yellow amorphous powders. Although all of these forms performed well in asymmetric hydrogenation reactions, the powdered materials had shorter shelf life and were prone to degrade more easily than the crystalline material. Further process development led to a scaleable process that delivers crystalline rhodium precatalysts in very high yields (91–97%) with excellent chemical purity and substantially improved chemical and physical stability.  

The new process involves taking [(1,5-cyclooctadiene) Rh(I) acetylacetonate] in an ethereal solvent (see Figure 6a), treating it with an alcohol solution of strong acid, such as tetrafluoroboric acid, to give a soluble bis-solvato species (see Figure 6b), which is then reacted with an ethereal solution of the bisphosphine ligand (see Figure 6c). Shortly after the addition of the ligand crystallization of the precatalyst complex is observed. This protocol controls the rate of nucleation at higher temperatures through rate of ligand addition, such that granular, free-flowing precatalyst is deposited in exceptionally high yields (19).  

The difference in quality of the precatalyst formed using this process is noteworthy (see Figure 7). The original catalyst fabrication process often provided an orange amorphous powder that performed well in the asymmetric hydrogenation reaction, but had poor long-term stability. This material had to be handled very carefully under rigorously inert conditions, as the larger surface area made it more prone to atmospheric oxidative decomposition. The new process provides a deep red crystalline material, and allows the crystal size and reproducibility to be controlled to produce high-quality product (see Figure 7). This material can be readily weighed in air, as long as it is stored under nitrogen, has a long shelf life (>12 months), and provides reproducible results in asymmetric hydrogenation. 

As our early needs were for both enantiomers of [Me-DuPhos Rh (COD)]BF

, we first applied this procedure in manufacture. Very high yields of crystalline precatalyst (>95 %) on batch sizes from 2–2.5 kg per run (see Figure 8) were obtained, with the ability to increase the batch size as required. This process is operated routinely and consistently produces high-quality product, a major advance when compared with the original precatalyst synthesis.  

With this process working well for rhodium Me-DuPhos complexes, Dowpharma investigated the synthesis of other related bisphosphine complexes. This methodology could be applied to the manufacture of a wide range of precatalysts, all giving crystalline products in high yield and quality (see Figure 9). Unsurprisingly, the crystalline form in each case is subtly different, and the crystallization protocol requires tailored optimization for each product. The basic process, however, is retained for each precatalyst produced. To date, we have applied this method to more than 20 bis-and mono-phosphine systems (19). 

Applications of ruthenium- based catalysts

Ruthenium catalysis is complementary to rhodium catalysis as it is effective in differing substrate classes. Dowpharma's position in this area includes ruthenium DuPhos/BPE systems and Diphosphine RuCl

 Diamine systems for asymmetric ketone hydrogenation, developed by professors Noyori and Ikariya. Chirotech in-licensed the Noyori technology from the Japan Science and Technology Corporation (JST) in December 2000. 

Limited representatives of the DuPhos ligand family have been developed for ruthenium catalysis. Among these ligands, the i-Pr-DuPhos Ru (TFA)

 system is good for the asymmetric hydrogenation of acrylate derivatives. This catalyst outperforms other ruthenium-based catalysts, including biaryls, for the asymmetric hydrogenation of tiglic acid, a γ-amino acid derivative (20) and furoic acid (see Figure 10). The latter process to (

)-3-furoic acid was scaled up for clinical supplies. 

Regarding asymmetric ketone hydrogenation, the technology in-licensed from the JST is a valuable method for producing chiral alcohols on an industrial scale. These catalyst systems were originally based on the BINAP ligand with an extremely expensive non-C2 symmetric diamine, DAIPEN (1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine). As there are several patents covering the use of ruthenium-BINAP complexes, especially for the more relevant precatalysts employing Xyl-and Tolyl-BINAP ligands, our strategy was to develop novel systems, leading to the development of the HexaPHEMP RuCl

 Diamine systems, both of which are highly active and selective catalysts. Both systems use readily available and relatively inexpensive diamines, and are an alternative to BINAP-based systems. The PhanePhos precatalyst systems have been used to manufacture many 1-phenylethanols on multi-100 kg scales. For example, 4'-fluoroacetophenone is hydrogenated at a molar substrate-to-catalyst ratio of 100,000/1, equivalent to a weight/weight ratio of 13,000/1 (or 1 kg of catalyst for 13 metric tons of product) (see Figure 11) (21). To achieve the high substrate-to-catalyst ratios, the substrate was purified using short-path distillation. A further distillation of the product afforded pure material and completely removed the catalyst complex. 

The number of large-scale applications for the in-licensed JST technology necessitated the ability to manufacture the precatalysts efficiently. We originally prepared these complexes using the procedures of Noyori (22), whereby the ligand was reacted with an [(arene)RuCl

 species in dimethylformamide at 100 °C, followed by treatment with a suitable diamine, typically DPEN (1,2-diphenylethanediamine), DACH (1,2-diaminocyclohexane) or DAIPEN to provide the desired product. When this methodology was applied for the larger scale manufacture of these catalyst systems, significant byproduct formation and yields lower than desired for precatalyst manufacture were observed.  

As these complexes contain valuable chiral phosphines, chiral diamines, and metal precursors, we sought a more efficient synthetic method. Quite surprisingly, we found that an isolated [diphosphine(arene)RuCl]Cl complex could be reacted with a diamine at moderate temperatures in ethereal solvents, routinely leading to >95% yield of the desired complexes in excellent purity (see Figure 12) (23). 

Although the JST technology works well with aryl ketones or enones, it is of little utility for the asymmetric hydrogenation of alkyl-alkyl systems. Professor Reetz  recently published an asymmetric transfer hydrogenation (ATH) catalyst that gives excellent results for a range of alkyl-alkyl ketones, thus making these alcohols more readily available (24). The catalyst consists of a xanthyl-based chiral diphosphonite and a [RuCl

(p-cymene)] complex. Dowpharma recently obtained a license to this technology for the manufacture of chiral alcohols using ATH, which complements the JST technology (see Figure 13). 

Asymmetric hydrogenation is a fully accepted method for the manufacture of a wide range of chiral compounds in the pharmaceutical, agrochemical, fragrance, and fine-chemical industries. The design of an effective catalyst system relies on manufacturing metal precatalysts and ligands.With effective design, a range of catalytic systems and substrates may be developed to allow for the systematic use of chiral catalytic technology. 

 is a business development and marketing manager, and 

is a research specialist at Chirotech Technology Ltd., Dowpharma, Unit 162, Cambridge Science Park, Milton Road, Cambridge, UK, tel. + 44 (0) 1223.728037, fax +44 (0)1223.506701 

*To whom all correspondence should be addressed. 

 1.  W.S. Knowles, "Asymmetric Hydrogenations," 

s (John Wiley & Sons Inc, New York, 1994). 

 3. M.A. Schwindt et al., "Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization," 

 4. M.J. Burk, "Modular Phospholane Ligands in Asymmetric Catalysis," 

Articles

Single-enantiomer drugs represent an increasingly large share of new chemical entities, leading to approaches in asymmetric synthesis.