Reflective work

C&I Issue 9, 2007

Chiral synthesis is big and a growing business for the world’s pharmaceutical industry. In 2006, 75% of the drugs approved by the US Food and Drug Administration (FDA) were chiral, compared with 58% a decade earlier, according to analysis by Chirotech scientist and technology leader Ian Lennon. Roughly half of all drugs approved in 2006 were made by ‘chiral synthetic means’ – methods involving catalysts and biocatalysts, not including starting molecules derived from the natural pool of chiral biomolecules found in living organisms. In 1996, just 20% of molecules were made by chiral synthetic routes.

‘Nowadays, if there is a “chiral” – or strictly speaking, stereogenic centre as a centre or point that has no three-dimensionality and so can not be chiral – in a molecule, then at the very least it is highly desirable to make it enantiomerically pure,’ observes Laurence Harwood, head of organic chemistry at the UK’s University of Reading. ‘Otherwise you would have to prove that the other enantiomer has no adverse effects.’

Asymmetric advances
Traditional methods of generating chiral molecules via the corresponding racemates – and separating or resolving the two isomers by crystallography or chromatography approaches – still account for nearly half of all chiral syntheses. But direct asymmetric methods are rapidly gaining ground. Synthesising racemic mixtures is not only more costly than making the correct isomer outright, argues Harwood, ‘but more importantly it also raises quality control issues because you can never be sure that your resolution will be as good from one batch to the next’.

Actual figures are hard to find, but year-on-year growth of asymmetric synthesis is around 15-20%, estimates Fred Hancock, technical manager at Johnson Matthey’s Catalysis & Chiral division. Most of the major breakthroughs came in the 1980s and 1990s, with developments such as Noyori’s BINAP ligands, Sharpless’ expoxidation reactions and Evans’ asymmetric aldol reaction. ‘There’s not been anything on that sort of scale recently that affects a whole raft of substrates, nothing as broad based,’ Hancock says. ‘Nowadays the developments tend to be more gradual and more substrate defined.’

At Johnson Matthey, the emphasis is on developing catalyst systems for the classical synthetic routes, involving the ‘bread and butter’ ketone, alkene and amine intermediates through which the majority of asymmetric syntheses must proceed, Hancock says. ‘The only sensible way to go is to find successful processes involving large scale pharma intermediates that require kilogram quantities of organometallic catalyst. At the end of the day, the only practical catalysts are the ones you can make at tens of kilogram scale.’

For pharma companies looking for asymmetric manufacturing routes, the biggest issue is cost, he continues. ‘If a racemic synthesis worked quite well but then you invent an asymmetric route there is a barrier because you’d have to invest more money in developing that process, which may in the end be no better than the existing one.’

Developing an asymmetric route from the preclinical stage is a lot cheaper than switching later when all the validation studies, impurity profiles etc have already been carried out, he adds. Switching to an asymmetric route for a launched drug is almost never done, because as well as the extra development work, this would necessitate re-registering the entire manufacturing process, at a cost of roughly $2-$3m.

At Dowpharma subsidiary Chirotech, Lennon says, researchers have created a database that tracks the number of drugs in clinical development. Generally speaking, ‘what we are seeing is that fewer resolution methods – diastereoisomeric salt, enzyme etc – are being used and there is a move towards more efficient asymmetric methodologies’. Usefully, the database also allows researchers to identify which of the drugs currently in development could potentially be amenable to its own catalysts and synthetic routes. Lennon estimates, for example, that 15-20% of these drug candidates could have an intermediate made by asymmetric hydrogenation – arguably one of the most commercially important asymmetric synthesis steps.

The first commercial asymmetric hydrogenation reaction was the synthesis of L-dopa by Monsanto in the 1970s, using the Rh-DIPAMP catalyst system. While the rhodium controls the catalysis in this system, the DIPAMP ligand coordinated about the metal directs the chirality, Lennon explains. As in any asymmetric hydrogenation, he says, the success of the reaction hinges on finding the right catalyst-ligand system to carry it out. ‘There were less than 20 ligands available in the 1970s, so the number of substrates that could be tackled was small. Today, there are more than 1000 ligands known and around 100 are available to buy, fewer on a truly commercial scale.’

The largest commercial scale application is for manufacture of the agrochemical (S)-Metolachlor, using an iridium josiphos catalyst system; 20 000t of the herbicide are produced every year at two sites in Switzerland. Significantly, over the past three years, the FDA has approved four drugs manufactured via asymmetric hydrogenation steps, Lennon points out: Rozerem (2005), Tipranavir (2005), Sitagliptin (2006) and Aliskiren (2007).

Dowpharma has more than 10 asymmetric hydrogenation catalyst systems made on a >1kg scale and ‘as our ligands are modular, we can produce all of our catalysts and ligands on the scale that the customer requires,’ Lennon elaborates.

Alongside hydrogenation, he adds, the company also has a broad technology portfolio that includes Trost asymmetric allylic alkylation, asymmetric hydroformylation and biocatalysis. ‘With the current portfolio we provide potential solutions for more than 80% of the current chiral drugs in development.’

Biocatalytic inroads
Biocatalysis in particular is expected to make big inroads in drug manufacture in coming years. At the University of Manchester’s new Centre of Excellence for Biocatalysis, Biotransformations and Biocatalytic Manufacture (CoEBio3), researchers are working hard to transform fledgling laboratory biocatalytic syntheses using enzymes and biocatalysts into commercially viable processes. Operating in partnership with a consortium of 17 companies, the Centre works in collaboration with some of the world’s major pharma and fine chemicals companies – AstraZeneca, Pfizer, Merck, DSM, Lonza, Dowpharma etc – and also BASF, with which it announced a ¤1m collaboration earlier this year.

One of the Centre’s big strengths, says its director Nick Turner, is the availability of a 1000L pilot scale bioreactor for testing out the reactions at larger scale: ‘We are unique in that industry tells us they can’t get access to this type of research-to-pilot-scale facility themselves’.

Currently, Turner estimates that only about 5% of chemical – mostly pharma – processes employ biocatalysis. A few years ago, he points out, consultancy Frost & Sullivan predicted this figure will grow to 20% by 2010. While ‘this is almost certainly an over-estimate,’ Turner acknowledges, ‘over the past 15 years we have seen a slow but steady uptake of biocatalysts, mainly by pharma. My prediction is there’s going to be a big inflection because of renewables feedstocks. Enzymes work very well on carbohydrates, amino acids and other renewables.’

Asymmetric synthesis is ‘a huge focus’ of the Centre’s work, he continues: ‘at least half of the work we do concerns asymmetric synthesis’. In a recent survey of consortia members, aimed at finding out where companies would like the centre to focus its efforts, asymmetric transformations came out as the number two priority, he points out. The number one priority was identified as hydroxylation – both chiral and achiral.

‘Enzymes are chiral inherently and so are very good at asymmetric transformations naturally,’ Turner notes. What’s more, ‘fifteen years ago, if your enzyme wasn’t perfect for a reaction you couldn’t use it for practical applications. But a lot of new technologies have come along in the past five to 10 years, such as directed evolution, that have given the field a huge push because you can now tailor catalysts for these processes’.

Proof of the power of these new approaches came last year, with the development of an alternative commercial route to (R)-4-cyano-3-hydroxybutyrate, used to introduce the chiral side chain of the world’s best-selling drug, Lipitor. Developed on behalf of speciality chemicals firm Lonza by biotech company Codexis, the synthesis was last year awarded the US Environmental Protection Agency’s Greener Reaction Conditions award (C&I 2006, 16, 17).

Synthesis unscrambled
Whatever the advantages of direct synthesis, however, often the least costly route to a single isomer product is via the corresponding racemate. Analysis by custom manufacturer NPIL indicates that roughly 40% of drugs are currently made through syntheses involving the racemic mixtures, says John Blacker, technology director at NPIL. Alternative asymmetric syntheses involving so-called ‘deracemisations’ that convert the unwanted isomer back to the desired enantiomer are increasingly popular, and have the advantage of significantly reducing the wastefulness associated with traditional resolution processes, he continues.

‘Typically, the waste from a resolution process is more than 50%, and if multiple chiral centres are involved this can be much higher. The waste involves not only unwanted isomers but also a far greater volume of solvents.’

University of Edinburgh spin-off company Ingenza developed its proprietary deracemisation technology, primarily for the production of chiral amines and amino acids, several years ago. The company’s approach is based around a platform technology using a range of oxidase biocatalysts modified by directed evolution, says operations director Rob Speight. ‘This year will see the first commercial application of the technology. We believe our approach will be adopted as it offers access to a wide range of enantiopure amines and amino acids and will be cheaper than existing methods.’

NPIL announced its complementary catalytic technology Scram, in September 2006, for producing chiral amines and alcohols. The company recently received a £500 000 R&D grant, matching its own investment, from UK regional development agency Yorkshire Forward to develop and extend the technology. Under the two-year £1m programme, the project will look to develop Scram racemisation and linked resolution technologies to full commercialisation in pharma intermediate production. ‘We are aiming to have commercial application of this technology over the next 15 months,’ Blacker says.

Along with savings on waste, moreover, companies adopting such technologies will also benefit from increased productivity. ‘A drug made by resolution using diastereoisomeric crystallisation will typically require two or more isolations to achieve 100% isomer purity. Each crystallisation and isolation can be a lengthy process involving many vessels and manufacturing operations. As a result, the productivity of the manufacturing plant can be quite low.’

Future outlook
But despite the continuing progress, asymmetric synthesis is still not an option for all important drug intermediates. Looking to the future, experts say, key targets for asymmetric transformations include 1,4 additions to enones, the synthesis of quaternary centres, olefin metathesis, and CH/alkane activation reactions.

Across catalysis generally, meanwhile, another trend will be the drive to use fewer metals says the University of Reading’s Harwood. ‘One of the problems is that a lot of catalysts are based on organotransition metals, and the problem is that the acceptable level of transition metals in pharma is very low, so there is a crossways pull to have good material versus leaching of heavy metal into your product.’ While new organo-catalysts are still ‘very much in the development phases,’ they could promise better drug impurity profiles and product integrity, he adds. Together with developments in other academic laboratories around the world, it would appear that chiral synthesis has never been more fashionable.

Chiral catalysts in the pipeline…
Protecting interests
The thorny problem of adding silyl protecting groups to achiral diols has recently been solved by US researchers. Chemistry professors Amir Hoveyda and Marc Snapper and coworkers at Boston College have discovered a simple amino acid-based compound capable of catalysing the selective silylation reaction for symmetric diols, and in principle also for other compounds with more than two alcohol (OH or hydroxyl) groups.

Silylation reactions are ubiquitous in pharmaceutical synthesis, where silyl group caps are frequently used as protecting groups to prevent reactive alcohol groups from undergoing reaction during synthesis. ‘Our catalyst is very unique,’ says Hoveyda. ‘Finding a natural enzyme that could do this reaction is unlikely, because unlike acylation, phosphorylation reactions etc, silylation is not a natural process so there are no enzymes or blueprint for a biocatalyst.’
Chemicals supplier Sigma Aldrich has already confirmed that it has ‘just made a large batch of our catalyst’ and Hoveyda says he expects this will be commercially available in the next few months.

Asymmetric phase transfer
At the UK’s University of Nottingham, chemistry professor Barry Lygo was recently awarded the 2006 UK Prize for Process Chemistry for work that promises to promote the uptake of asymmetric phase transfer catalysis (PTC) by fine chemicals and pharma firms. Increasingly useful for bulk chemicals manufacture, PTC is carried out in two-phase systems involving both an organic and an aqueous (or solid) phase, helping to speed up reactions and reduce the costs of synthesis as well as offering environmental benefits.

To date, application of asymmetric catalysis in the pharmaceuticals sector has been limited, Lygo acknowledges. ‘Overall, there seems to be quite a lot of interest in this technology from pharmaceutical and fine chemical companies, but I don’t think that anyone is using it [at commercial scale].’ While GSK reported the scale up – ‘only to 6 mole’ - of an asymmetric PTC reaction earlier this year, he says, ‘the problem with asymmetric PTC is that it is still largely unproven for large scale application.’

The Lygo group’s breakthrough has been to speed the identification of the appropriate catalysts, chiral quaternary ammonium salts, by employing automated screening methods.

Halogenated steroids
Japanese chemists writing in Nature earlier this year (2007, 445, 900) have found a way of producing halogenated steroids, made in nature by marine organisms, in the laboratory. Many of the thousands of halogenated steroids found in nature show promise as medicinal leads for treating various diseases, while others have proved useful in treating skin diseases.

Now, chemistry professors Kazuaki Ishihara and coworkers at Nagoya University, in Japan, have reported the first non-enzymatic, highly enantioselective cyclisation reaction, induced by insertion of a halogen atom, to produce such compounds in the laboratory.

‘Before this work, there were no halocylisation methods that approached the exquisite enantioselectivity of enzymes,’ wrote Phil Baran and Thomas Maimone of The Scripps Research Institute in California, in an accompanying News & Views article in the same issue of Nature. ‘It seemed that such fine control could only be achieved with a complex biological catalyst.’

Key to the new reaction is a highly reactive reagent that acts as a halogen source and which gives only one chiral product in a halocyclisation reaction. Baran and Maimone describe it as a ‘chemical tuxedo’ that fits around the halogen atom – in this case iodine – creating a chiral environment for, and enhancing the reactivity of, that atom.

Organo-catalytic hopes
US researchers have hit upon a new route for carrying out a wide range of enantioselective additions to aldehydes – one of the most reactive and versatile groups in the organic chemist’s toolbox (C&I 2007, 7, 9). In work published earlier this year in the journal Science, researchers at Caltech and Princeton universities reported a new route to functionalise aldehydes at the alpha-position adjacent to the C=O group, by using nucleophiles rather than the traditional electrophiles that generally attach at this position.

David MacMillan of Princeton University and coworkers achieved the result using a metal-free chiral amine catalyst, mixed with the aldehyde before treatment with a single electron oxidant. The resulting transient radical intermediate is expected to be capable of carrying out a variety of previously impossible enantioselective catalytic transformations, the researchers report.

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