HOMEGROWN In-house research and development at fine chemicals companies continues to be a major route for inventing and developing chiral technologies, complementing partnerships and inlicensing. RHODIA PHARMA SOLUTIONS PHOTO

These days, with biopharmaceuticals the hot topic of the day, Peter Nagler sometimes brandishes the structure of apoptolidin. This natural product, originally isolated in 1997 from an actinomycete by researchers at the University of Tokyo, in Japan, is the subject of intense interest as a potential antitumor agent. A total synthesis was reported in 2001 by the group of K. C. Nicolaou at Scripps Research Institute. Worldwide, at least 10 other groups are developing more efficient routes.

"Amid the biopharma frenzy, we tend to forget that there are still many unsolved problems in chemistry," says Nagler, president of Degussa Fine Chemicals. Apoptolidin, which contains 25 chiral centers, exemplifies the complexity of molecules in pharmaceutical pipelines, he continues. "Everybody would prefer a flat, nonchiral molecule prepared in one step from benzene, but it doesn't work that way."

Chirality in drugs is as old as the first natural-product therapeutic agents. Isolated as products of biological synthesis, drugs such as quinine and morphine always have been available as single enantiomers. But as products of synthetic chemistry, chiral drugs until recently have had to be manufactured and used usually as racemates. Now, single-enantiomer drugs have a commanding presence in the global pharmaceutical landscape.

The top two drugs in terms of global sales--Lipitor and Zocor, with combined sales of almost $14 billion in 2002--are single-enantiomer small-molecule drugs. Last year, worldwide sales of single-enantiomer drugs reached more than $159 billion. Of this, about two-thirds was due to small molecules and only one-third to biopharmaceuticals, according to Sandra E. Erb, manager of research for chiral and fine chemicals consulting at Technology Catalysts International, Falls Church, Va.

The growth of single-enantiomer small-molecule drugs is tracked by pipelines and revenues that are due to the application of chiral technology. At DSM Pharmaceutical Products, for example, chiral compounds currently account for at least 50% of sales. But they are expected to grow to 80% within five to 10 years, based on the compounds now in the drug pipelines, says Ellen M. de Brabander, senior vice president for global R&D. And according to a new study by Frost & Sullivan, worldwide revenues due to chiral technology, which amounted to $4.8 billion in 1999, will more than triple to $14.9 billion by 2009. With these numbers, it isn't surprising that, despite the exuberance for biopharmaceuticals, pharmaceutical suppliers are fortifying their chiral chemistry capabilities.

Large-scale production of single enantiomers of compounds as complex as apoptolidin takes creativity, innovation, technology, and development. But even relatively simple building blocks can be trouble, says Hans-Jürgen Federsel, head of project management for process R&D at drugmaker AstraZeneca. He cites (S)-azetidinecarboxylic acid as an example.

A search of the literature indicates that many therapeutic agents, including analgesics and anticoagulants, incorporate (S)-azetidinecarboxylic acid. AstraZeneca and others now possess process patents for the compound. But in the early 1990s, according to Federsel, (S)-azetidinecarboxylic acid was available only in gram quantities from established sources, probably as an isolate from plant protein hydrolysates.

"The reality was quite different when we required multikilogram quantities," Federsel tells C&EN. A warehouse in Europe delivered 75 kg, isolated from several hundred tons of molasses. That precious amount kept projects going for awhile. But the manufacturer would not repeat the tedious isolation, and a way to make the compound in large scale had to be developed. At present, AstraZeneca has at its disposal several routes to the compound.

Pharmaceutical companies expect suppliers to be up to the chiral challenges in the pipeline, and fine chemicals companies have been gearing up. They face tough decisions because single enantiomers can be reached through many routes, which can be traversed in myriad ways. Which technologies should be adopted? How broad should the portfolio be? How will the know-how be acquired? Because it's impossible to solve all problems, which tools will solve most of the problems? Timing is another question: Should a technology be ready before signing up a project that requires it? Or should a company wait for the right project before developing the technology?

ROUTES TO SINGLE enantiomers of small molecules can be classified into four groups: chiral pool technology, resolution, biological asymmetric methods, and chemical asymmetric techniques. According to the new Frost & Sullivan study, among 40 companies specializing in chiral technology, only 12% have competence in all areas. For most major players, having a broad portfolio and competencies in all the technology groups is very important, and companies are racing to fill gaps in their portfolios, says Matthew Moorcroft, the study's author.

Companies generally agree that a broad portfolio is desirable. "The market is fiercely competitive," says David J. Moody, director of new technology ventures at Avecia's pharmaceuticals unit. "Trying to shoehorn a customer's problem to fit a particular solution is never going to be good enough. To arrive at the best solution objectively and rigorously, you need a broad spread of options."

Avecia is one of the few companies in the Frost & Sullivan survey that has a full house of chiral technology options. The final piece--chiral pool technology--was put in place in January with the acquisition of Synthon Chiragenics' chiral business. The deal gives Avecia access to a range of C₃, C₄, and C₅ chiral compounds, including (S)-hydroxy--butyrolactone, a key building block for cholesterol-lowering drugs such as Lipitor.

"The deal is impressive, a major boost for Avecia, given that it competes with the likes of BASF, Degussa, and Bayer, which boast sales of many billions of dollars," Moorcroft says. Avecia reported sales of $858 million in 2002.

According to Moody, the acquisition was not based on a desire to gain a position in chiral pool per se, but on the complementarity of technologies. The acquisition makes Avecia more competitive in projects that interest it, he says. Nevertheless, Avecia touts the full house of chiral options that the acquisition has allowed.

Others say a broad chiral portfolio is not a goal by itself. "We feel no strong need to be in all the chiral technology categories," says Ralf Pfirmann, global business director of Clariant's pharmaceutical business unit. "But we do feel a need to be able to address all the major structural elements in active pharmaceutical ingredients."

Lonza takes a similar attitude. For example, large-scale resolution is not viewed as a must-have technology, because "we prefer to design syntheses that do not require a resolution at the end," says John F. McGarrity, director of R&D outsourcing at Lonza Exclusive Synthesis. And in case a chiral resolution cannot be avoided, Lonza can do it through companies that offer it, he adds.

"Sometimes it is better to have excellent competence in the important areas than an average competence all around," Moorcroft says. "Lonza, for example, is very good in biocatalysis and asymmetric synthesis, leaps and bounds ahead of [the Israeli company] FCRD, which has a broad portfolio but only skims the surface."

THE ITEMS that make up the chiral technology portfolio ideally should be decided after carefully evaluating various parameters, says Marc A. Hennebert, a partner in the London office of Strategic Decisions Group, a global strategy consulting firm specializing in decision analysis and risk management. These include the factors influencing the value of the technology, such as costs, customers, investments, and revenues, and their associated risks and uncertainties, as well as a range of alternatives. A deliberate approach is especially critical for chiral technology portfolios, because these cannot be bought or sold overnight, he says. "Once you bet on a technology, it is often difficult to withdraw or change course rapidly." In practice, however, many chiral technology portfolios have developed through a combination of historical happenstance and carefully considered choice.

According to the Frost & Sullivan study, chiral pool and resolution together currently contribute most to revenues due to the application of chiral technology (55%), followed by chemical (35%) and biological (10%) asymmetric methods. The data reflect the continuing importance of the traditional methods, which, Moorcroft says, form the backbone of many chiral portfolios.

"That's the picture through the rearview mirror," Moody says. "Ten years ago, almost every technology in our portfolio today was not available. The dominant solutions for chiral problems were chiral pool and resolution technologies."

It has been estimated that more than half of the chiral drugs in the market are produced by crystallization of diastereomeric salts, says Ian C. Lennon, a technology leader at Dowpharma. Resolutions of this type can be done quickly, they don't require special plants, and resolving agents are available inexpensively in bulk, he explains. Pharmaceutical and fine chemicals companies have a lot of experience and feel comfortable with these methods, he adds.

IN MANY CASES, though, traditional methods have been modernized for current needs. Classic resolutions, for example, are being invigorated by new methodologies, such as those developed by chemists at DSM and Syncom (C&EN, Nov. 18, 2002, page 60, and Feb. 14, 2000, page 91).

Likewise, although classic diastereomeric resolutions are still being applied at Degussa, the company is collaborating with partners to develop, for example, simulated moving-bed (SMB) systems to resolve racemates by continuous chiral chromatography, according to Karlheinz Drauz, vice president for technology and R&D management. Similarly, Degussa's amino acid chiral-pool platform, originally based on protein hydrolysis followed by ion-exchange chromatography, is now largely based on biocatalysis.

According to the Frost & Sullivan study, contributions to chiral revenues due to traditional methods will decrease between 2002 and 2009, whereas those due to chemical and biological asymmetric methods will increase. Nevertheless, traditional methods are projected to continue their dominance through 2009, reflecting the user friendliness of chromatography and the growing success of continuous chiral chromatography.

New chiral drugs coming to market will initially be manufactured with a chiral chromatographic step, because chiral chromatography is the fastest technology to develop and scale up, says Jean Blehaut, chief executive officer of Novasep Inc. The economics are comparable with that of asymmetric routes in some cases and often can be improved by recycling and reracemization of the undesired enantiomer, he adds.

At an ACS ProSpectives conference last March, Joel M. Hawkins, a research adviser at Pfizer Global Research & Development, confirmed the economic viability of SMB systems, citing the case of Zoloft. Zoloft (sertraline) is Pfizer's single-enantiomer blockbuster antidepressant, with sales of almost $2.7 billion in 2002.

Hawkins did not say how SMB is applied to sertraline, but it may be to resolve a readily available racemate to get a key building block, a chiral tetralone. A 1995 Pfizer patent describes a method to prepare the required S enantiomer by asymmetrically reducing the racemate to a mixture of diastereomeric alcohols, separating the required alcohol, and oxidizing it back to the desired ketone. A 1999 Pfizer patent describes a method to produce the optically enriched S-tetralone by chromatography with an SMB system. In this case, economics favors resolution.

Chiral chromatography can also make the difference for chiral drugs that must be produced at the lowest production costs possible, such as those that are off patent or are in the late stages of the product life cycle. "SMB can be the lowest cost process for making chiral drugs," says Thomas B. Lewis, president and CEO of Chiral Technologies, a supplier of chiral chromatographic products. "Part of our agenda is to assist companies with chiral-switch compounds," he adds. Switching from a racemic to a single-enantiomer drug extends a product's life cycle, but it depends on an efficient way to get the single enantiomer.

Meanwhile, Jane Zhou, a senior research associate at Technology Catalysts, will not be surprised to see phenomenal growth in biological routes to chiral small molecules. Last year, in surveying trends in chiral technologies, she observed a high interest in biocatalysis. That trend has continued, she says.

RELIABLE Preparative chiral chromatography is a fast and effective route to single enantiomers. CHIRAL TECHNOLOGIES PHOTO

ONE REASON is the increasing acceptance of biocatalysis. Companies that develop and produce enzymes--such as Altus Biologics, Diversa, and Maxygen--are succeeding in convincing chemists of the industrial potential of biocatalysis. As de Brabander says, getting the right enzyme in the right quantities is no longer as rate limiting as it used to be.

Another reason is the generally lower cost of developing biocatalytic methods compared with metal-catalyzed syntheses--"provided you have a really, really good enzyme," Drauz adds. After an enzyme has been developed, the running cost is low, he explains. "And you have the flexibility of bringing together several enzymes in resting cells for reaction cascades in one pot." For this reason, Drauz believes biocatalysis will be the dominant technology in the future.

DSM researchers Hans E. Schoemaker, Daniel Mink, and Marcel G. Wubbolts also foresee impressive growth in biocatalysis. Biocatalysis, they write, is poised for wider industrial use in applications ranging from resolutions to chiral syntheses [Science, 299, 1694 (2003)]. In particular, they suggest that biocatalysis may be the answer to certain problems that have not been satisfyingly solved by organic chemistry--for example, stereoselective carbon-carbon bond formations.

Further evidence of the importance of biocatalysis is admission by various companies of gaps in this area. Bayer does not develop its own biocatalysts but may develop expertise in-house or through collaboration with a partner. And Dowpharma is strengthening its position in enzyme technologies through collaboration with Diversa and others. Clariant has installed a biocatalysis group in Frankfurt to quickly fill Clariant's experience gap in biocatalysis. The group is working with enzyme suppliers and testing applications for potential customer inquiries.

Meanwhile, Rhodia is considering its position in biotransformations. According to Michel Spagnol, vice president for strategic and technical marketing for Rhodia Pharma Solutions, biocatalysis is not enough to set a company apart anymore. Biocatalysis, he explains, involves nothing more than a one-step catalytic transformation in a reactor mediated by an isolated enzyme. Biotransformations that convert simple substrates to complex small-molecule products in one pot are more challenging, he says. "The differentiation comes when you move from biocatalysis to biotransformations," he adds.

Despite the current middle-of-the-road contribution to chiral revenues by chemocatalytic asymmetric methods, these are the most popular tools in contemporary chiral toolboxes, according to the Frost & Sullivan study. The popularity reflects the high hopes people have for these technologies.

"We're probably at the point where chemocatalytic asymmetric methods will be used more and more," Lennon says. "More catalysts are available. We understand better how to scale up. Loss of half the yield of a complex-molecule product after resolution is untenable."

"Intellectually and logically, any synthesis of a single enantiomer will be superior to one that requires resolution," Moody says. "However, those asymmetric technologies must work very well in terms of selectivity and scalability to multiton quantities."

Surprisingly, Moody says, Avecia has found some of its chemocatalytic asymmetric technologies to be relatively straightforward to scale up. The catalytic asymmetric transfer hydrogenation (CATHy) technology, for example, he says, has not presented unusual challenges in moving from the lab to 100-kg scale and beyond. "We are now comfortably manufacturing late-phase and launched products with these technologies," he adds.

Likewise, the proprietary ClMeOBIPHEP ligand for metal-catalyzed asymmetric reductions is now being used by Bayer in a multiton enantioselective hydrogenation, and development of a continuous process is under way.

At Lonza, catalytic asymmetric hydrogenation as a key step in the manufacture of (+)-biotin has been carried out in multiton scale. Enantioselective alkylation of substituted acetophenones with alkyllithium reagents has also been carried out in multiton quantities. However, that reaction is noncatalytic because the chiral ligand is used in stoichiometric amounts. And at Rhodia Pharma Solutions, the hydrolytic kinetic resolution (HKR) technology licensed from Harvard University is also applied in industrial scale.

Other reactions are ready to go but not practiced on large scale because the right projects aren't there. Lonza, for example, had scaled up the Sharpless-Kagan technology for making chiral sulfoxides by oxidation of thioethers. Unfortunately, the drug it was intended for was not commercialized, McGarrity says. Nevertheless, the technical experience is in-house.

Likewise, the Sharpless dihydroxylation technology licensed by Rhodia is now being used only in pilot scale because there is no customer demand to go to larger scale. "Technology is great, but at some point it needs to converge with a customer demand," Spagnol says.

Other commercial-scale chiral reactions are not based on chiral catalysis. For example, Lonza uses chiral auxiliaries to direct chiral transformations, whereas Clariant practices a chemistry in which the substrate is its own chiral auxiliary.

Clariant's chemistry uses supported nonchiral metal catalysts. With the right combination of metal, support, metal distribution, and metal activation, the chiral nature of a chiral substrate can be used to the extent that it can direct selectivity of reactions at other centers, Pfirmann explains. This leveraging of the molecule's existing chirality to direct chirality of subsequent reactions is effective and economical but underestimated in its importance, he says.

For preparing chiral molecules, asymmetric synthesis is the best way forward in principle, Hawkins said at the ACS ProSpectives meeting. But he also emphasized that whatever methods are used, the bottom line is always economics.

The pharmaceutical pipeline forecasts the chiral problems that fine chemicals companies will have to solve. On the basis of corporate history and position in chiral chemistry, companies decide what technologies to acquire. How to do so, and when, present another range of options.

CLARIANT REITERATES COMMITMENT TO PHARMA Clariant is committed to its business activities in the pharmaceutical industry, says Roland Lösser, the company's chief executive officer. Lösser became CEO on March 12, after the abrupt departure of former CEO Reinhard Handte (C&EN, March 17, page 11). Shortly before, Handte had been reported elsewhere as having considered Clariant's life sciences operations, which includes the pharmaceutical business and custom synthesis units, "of less strategic importance" and as looking to divest them. Clariant's pharmaceutical business unit includes the company's regulated manufacturing sites and is responsible for servicing the pharmaceutical market. "It is our intention to continue to develop these businesses and to provide the resources necessary to confirm our reputation with customers as a reliable supplier," Lösser says.

REGARDING TIMING, most companies acquire and develop technology to attract clients. Clariant, for example, has arranged for access to the pool of ligands for asymmetric synthesis at Chiral Quest, a provider of chiral catalysis products. This move was based on anticipating customer inquiries and deciding to build the know-how to solve those problems, Pfirmann says. "We cannot just say we know how to develop a technology," he adds. "Customers are looking for someone with solutions."

It's important to be able to react quickly, Drauz says. "When you have technology that's ready, you don't have to spend years developing a method. That's not what the customer wants to see."

Lonza is different. "We prefer to take on a project and then develop or acquire the technology during the working of the project," McGarrity says. "Clients tell us that they are anxious about being locked to one supplier. Rather than being stuck with a technology offered by a particular supplier, customers prefer to get around the technology by developing their own."

As to how to acquire technology, academia is a major route. Licensing of intellectual property developed by academic groups is popular, especially now that universities have more realistic expectations of the value of intellectual property. "There was a period when universities overvalued their technology, when they saw faster returns than were actually available," Lennon says. "Things have swung back. I think academia now understands better how to outlicense appropriately."

Partnering with academic groups is also common. A recent example for Degussa is the development of a new family of asymmetric hydrogenation catalysts in collaboration with Armin Börner at the University of Rostock, in Germany. "We asked him to develop something as good as, and perhaps better than, the benchmark catalyst, and we paid for the work," Drauz says.

Börner's group came up with MalPHOS, a new bisphospholane ligand characterized by a maleic anhydride backbone. Particularly for asymmetric hydrogenation of Z-configured -acylamido acrylates, MalPHOS is better than the benchmark, MeDuPHOS [J. Org. Chem., 68, 1701 (2003)]. Malphos should be very interesting to the pharmaceutical industry, Drauz says, because it can be used under normal pressures and needs no special equipment.

LIKE OTHERS, Avecia seeks out new inventions from academia and elsewhere. In addition, it claims to be a technology attractor. "People have come to think routinely of Avecia as the right partner to exploit their invention," Moody says. "It's very helpful to be in that situation."

Two things are key to attracting technology, Moody explains. "First is a reputation for fairness. Potential technology suppliers must believe that working with us will lead to an agreement that is both fair and realistic. Second, it is helpful to have people who are well respected internationally as scientists." As an example, Moody cites Avecia process chemist John Blacker, who was instrumental in Avecia's acquisition of catalytic asymmetric cyanohydrin (CACHy) technology from King's College, London, and the Russian Academy of Sciences. "Blacker is held in such high regard that we have had to put him in a safe every night," he jokes.

DSM also believes that internationally recognized scientists strengthen a company's technology position. This belief is evident in its strong publication record and high visibility in scientific meetings. "Many companies still have the attitude that research results should be secret," de Brabander says. "Of course, we have to be careful, but without breaching customer confidentiality, we believe it is necessary to communicate our position in certain fields."

Mergers and acquisitions are another route to acquiring technology, but they are perhaps not so favored now, after the costly acquisitions of recent years. In fact, according to SDG's Hennebert, acquisition prices are fairly low compared with those of three or four years ago. It's the right time to buy. As Moody says of Avecia's acquisition of Synthon Chiragenics' fine chemicals business, "We're happy with the price we paid, obviously."

In-house R&D remains a major route to chiral technology. Even though technology now comes easily from outside, companies maintain active R&D groups, some of which are widely recognized. That's partly because, as Moody explains for Avecia, "in some areas, we believe that some of the best innovations will in fact be done by our scientists, if we allow it." But on balance, he notes, companies will concentrate more on commercializing technologies rather than inventing new ones.

When the in-house R&D effort is huge and complex, measuring its effectiveness is especially critical, de Brabander says. At DSM, she explains, the progress of R&D is meticulously monitored for two reasons: "To know yourself as a research organization: how effective you are and where you can improve. And to determine what R&D is adding as value, compared with activities that have more transparent indicators, such as manufacturing."

THE EFFECTIVENESS of DSM's chiral technology R&D, for example, is measured in part by the extent that chiral competencies are contributing to new projects. For example, the current business hardly uses homogeneous catalysis, because that competence is in a relatively early stage of development, de Brabander says. "But in our new-business portfolio, a substantial fraction of projects require homogeneous catalysis. That supports our idea about the role of homogeneous catalysis."

DSM also looks at financial indicators, such as sales of new products in relation to cost of generating the business. According to de Brabander, the data guide R&D decisions and provide hard evidence of R&D effectiveness, because the data quantify how knowledge generated from basic R&D programs is used in revenue-generating business.

"We also look at numbers of patents, publications, and lectures by our scientists," de Brabander says. But she emphasizes, "We are not about amassing as many patents as possible. We are really investing in technologies that can be applied to large scale."

With so much technology available, the question remains: Will customers come because of chiral technology? Opinions vary.

Two to five years ago, chiral chemistry was highly differentiating; chemical companies that had the expertise were sought by pharmaceutical companies that did not want to invest in chiral chemistry themselves, observes SDG's Hennebert. The landscape has changed. Customers expect chiral chemistry. "It is more commonplace, increasingly a part of the basic portfolio if you want to be the outsourcing partner," he says.

Whether chiral chemistry sets a firm apart may depend on what it has. Rhodia, for example, considers its HKR technology as truly differentiating. "It is a key factor for customers coming to Rhodia," Spagnol says. "Very often, HKR allows us to do more than just the chiral chemistry."

But the consensus seems to be that chiral technology is only part of a supplier's attractiveness to drugmakers.

"The purchasing behavior of pharmaceutical companies is a very complex equation," Hennebert says. "Technology is one of the few hard facts of that equation. And people use very different 'soft' criteria, such as delivery of service, contractual relationships, ease of communications, and effectiveness of problem resolution. The experience of working together as partners is often what leaves the impression on the pharmaceutical company. These criteria may offset the breadth of the portfolio."

"Chiral technology is only one hook to attract customers," Degussa's Drauz says. "Being good in chiral technology may not be enough. But if you are good and reliable and you can also offer a good portfolio of chiral technologies, then you really would be an interesting partner for pharma companies."

"We don't try to attract clients with a chiral technology badge or any other badge," Lonza's McGarrity says. "We attract clients because we have a broad technology base and are dependable, rapid, and flexible, and that involves a lot more than chiral technology.

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COVER STORY

CHIRAL BUSINESS Fine chemicals companies are jockeying for position to deliver the increasingly complicated chiral small molecules of the future CONTEST Vying For Chiral Hydroformylation Advantage NICHE PLAYER Chiral Quest Sees Advantages In Independence STEADY SHARE Worldwide sales of single-enantiomer pharmaceutical products approach $160 billion BLOCKBUSTERS Top 10 single-enantiomer products belong to billion-dollar club CHIRALITY AT WORK Drug developers can learn much from recent successful and failed chiral switches REALITY CHECK When Chemistry Bows To Economics HARVEST Research in Chiral Fine Chemicals Reaps Recognition CONSTANT Chiral separations are enduring items in the toolbox CASE HISTORIES History and choice shape portfolios CALENDAR Events Of Interest

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