Despite the unrelenting pace of research in catalytic asymmetric
chemistry, relatively few catalytic enantioselective processes
are currently operated on a commercial scale. Until more bio- and
chemocatalytic chiral routes are developed that are robust and
cost-effective for large-scale production, the bulk of optically
pure compounds will have to be prepared through traditional chemistry,
including conventional syntheses based on chiral substrates or
stoichiometric chiral induction and separations, such as chromatographic
||CHIRAL CHEMISTRY HOTBED In this production
unit in Kaisten, Switzerland, the agrochemical company Syngenta
operates what is currently the largest-scale catalytic enantioselective
hydrogenation plant in the world.
COURTESY OF SYNGENTA
A survey by Frost & Sullivan
estimates that in 2002, of the $7 billion in revenues worldwide
from chiral products, 55% was generated by traditional technologies
(chiral pool and separation), 35% by chemocatalysis, and 10% by
biocatalysis. The survey projects that by 2005, worldwide revenues
of $9.5 billion would be realized not much differently: 49% by
chiral pool and separation, 36% by chemocatalysis, and 15% by
Demand for enantiopure chiral compounds continues to rise,
primarily for use in pharmaceuticals but also in three other sectors:
flavor and aroma chemicals, agricultural chemicals, and specialty
materials. Demand from the drug industry is fueled by regulations
governing chiral active pharmaceutical ingredients (APIs) and
the recognition that enantiomers of a chiral compound could have
dramatically different biological activities. Whereas chiral APIs
previously were usually formulated as racemates, the preference
now is for single enantiomers. Furthermore, the switch from a
racemic to a single-enantiomer API is key to managing the life
cycle, as well as improving the efficacy, of racemic drugs (C&EN,
May 5, 2003, page 56). Such switches also contribute to the
demand for optically pure compounds.
of single-enantiomer compounds are expected to reach
$8.57 billion by the end of 2004 and $14.94 billion by the end
of 2009, growing annually by 11.4%, according to the Frost &
Sullivan survey. By 2009, the share of the market realized through
traditional technology would drop to 41%. The share of chemocatalysis
would rise to 36% and the share of biocatalysis, to 22%, the same
Meanwhile, in journals surveyed by Chemical
Abstracts Service, the number of papers per year that are
related to chiral technologies has tripled from just over 1,300
in 1994 to more than 4,400 in 2003, for a total of more than 24,000
chiral-technology-related papers published in the past 10 years.
An overwhelming majority (72%) are about stereoselective or asymmetric
Yet when Hans-Ulrich Blaser, chief technology officer of Solvias,
a Basel, Switzerland-based chemical company serving the life sciences
industry, surveyed the literature three years ago for catalytic
enantioselective processes, he found only 16 practiced on a commercial
scale [Appl. Catal. A: Gen., 221, 119
(2001)]. Blaser's survey did not include commercial biocatalytic
processes. More chemocatalytic processes may exist that he is
not aware of, he says, because most companies do not publicize
processes used in actual production. But clearly, the gap between
R&D output and commercial application is wide.
Research in academia is focused on molecule building at the
bench scale, comments Enrico Polastro, vice president and senior
industry specialist at Arthur D.
Little Benelux, in Brussels. "What is easy to achieve in a
flask might be extremely challenging in a reactor, given the heat-
and mass-transfer considerations."
Many factors contribute to the slow development of commercial-scale
catalytic asymmetric processes. But the bottom line is cost. At
the end of the day, the customer does not care what technology
produces the required material. And to win business, suppliers
must offer optically pure products at the most competitive price.
At the economic level, some observers believe that a major
damper to the practice of catalytic asymmetric chemistry is that
most catalysts are not in the public domain. Many technologies
are proprietary, exclusively available only to particular companies.
When people consider using them, their first thought is not how
wonderful the chemistry is but how much it will cost and how the
price will be negotiated, observes Mukund S. Chorghade, president
of the consulting company Chorghade Enterprises, Natick, Mass.,
and chief scientific officer of D&O Pharmachem, an intermediates
and fine chemicals supplier based in Paramus, N.J. Complex negotiations
turn off customers and prompt efforts to develop alternative methods,
The situation has sparked a technological race that has produced
a plethora of proprietary catalysts. Many of these catalysts are
now available in research quantities from Strem
Chemicals, Newburyport, Mass.: for example, ClMeOBIPHEP (Bayer
Chemicals); CatAXium and CatASium families (Degussa
AG); MonoPhos (DSM Pharmaceutical
Products); Josiphos, Walphos, Mandyphos, and Rhophos (Solvias);
and Synphos (Synkem).
Companies develop their own catalysts to get around other companies'
patents, says David Ager, competence manager for homogeneous catalysis
at DSM. Very often, new catalysts are not any better than those
already existing, but they give their inventors freedom to practice
chemistries that previously were off-limits, he adds.
COST OF using patented chiral technology can be prohibitive,
Polastro points out. And the right price can be hard to figure
out. Assigning a value to a specific technology in the overall
context of a final product being developed is not an exact science.
Suppliers and customers will not discuss how they calculate these
In the view of Ronald Brandt, interim chief executive officer
of the chiral catalyst developer Chiral
Quest, Monmouth Junction, N.J., the task is easier for customers,
because they set the price at which their molecule must be produced,
whereas technology providers must work within the pricing already
existing in the market. What's clear is that companies like Chiral
Quest can't survive by only selling catalysts, unless those are
very highly priced. For this reason, Brandt says, Chiral Quest,
like other technology providers, offers multiple pricing options:
Customers can buy a high-priced catalyst, pay royalties, or arrange
anything in between.
At the strategic level, customers have traditionally regarded
as unacceptable reliance on technology over which they have no
control or that is available from only one source. This attitude
may be changing as technology providers demonstrate flexibility.
Multiple sourcing can be arranged by sublicensing either to the
customer or to a third party, says Michel Spagnol, vice president
for strategic and technical marketing at Rhodia
Pharma Solutions, Cranbury, N.J. The need for multiple sourcing
also can be satisfied by production at multiple sites of a sole
supplier, he adds.
At the practical level from the technology developer's point
of view, commercialization of catalytic asymmetric methods is
tricky. For one thing, catalysis is still viewed as a high-risk
step in fine chemicals production. "People in production units
usually prefer noncatalytic reactions," Blaser says. "They have
more experience with stoichiometric reactions, which are usually
easier to control and more robust."
The bigger problem is the still highly empirical nature of
catalyst selection. When presented with a new molecule, no one
can tell what catalyst is right simply from the target structure.
That's because the understanding of reactions and catalytic mechanisms
is far from complete. Analogies work, however, and scientists
with a lot of experience in asymmetric catalysis are fairly successful
in narrowing the field. "Catalyst selection is not just science,
but also art. You need intuition, some luck, some feeling," Blaser
The availability of substrates is also key. Sometimes synthesizing
the appropriate substrate is more problematic than running the
catalytic reaction itself, Ager says. Likewise critical is the
availability of catalyst. A good catalyst is useless if one can't
get it in commercial quantities.
Many things can go wrong in process development, Polastro adds.
Even very low levels of impurities can poison the system. The
economics--of temperature control, mass transfer, agitation, solvent
and catalyst recovery, among others--may not be favorable. Or
the process may be so fragile that minor variations in operating
parameters lead to significant changes in yield or quality.
Time is another factor. Especially for products in development,
the time to develop a catalytic asymmetric process may not meet
the need to get materials out rapidly for testing. The window
of opportunity is wider for established or mature products, for
which developing a catalytic asymmetric step in the synthetic
route could vastly improve production economics.
good luck counts. In many cases, commercially viable
catalytic chiral processes do not make it to prime time because
the projects they support don't survive. When a product is not
approved, a candidate does poorly in trials, or a promising lead
is dropped, chiral chemistries that are ready to go are mothballed
Ironically, it is usually under these circumstances that many
successful process development stories are made public. For example,
Avecia, based in Manchester,
England, developed a commercial process to enantioselectively
reduce m-nitroacetophenone to (S)-1-(3-nitrophenyl)ethanol.
Everything was in place, ready to go to a 1,000-L scale, when
the project died, according to John Blacker, technical manager
for process technology.
The asymmetric synthesis was developed to achieve better economics
for a synthetic route in which the chiral alcohol is a key intermediate.
With Avecia's proprietary transfer-hydrogenation catalyst CATHy,
the conversion could be achieved in greater than 95% yield and
greater than 95% enantiomeric excess with less than 0.1 mol %
of catalyst; 25 kg of substrate could be converted in four hours
in a 100-kg reactor. Because the chiral alcohol is an early intermediate,
95% enantiomeric excess is sufficient, Blacker says. "It's not
worth spending a long time trying to get a perfect reaction at
involves enantioselective transfer of hydrogen from
formic acid to the substrate. The aromatic nitro group is highly
reducible and would have been attacked by other catalysts, Blacker
points out. "This reaction gives a good example of the selectivity
you can get with a catalyst."
Another recent example of a potentially commercially feasible
but aborted catalytic asymmetric chemical process comes from a
project Solvias carried out for the agrochemical company Syngenta,
based in Basel. Syngenta required a route to a chiral mandelamide
with fungicidal activity. After evaluating three enantioselective
methods, Solvias prepared kilogram quantities of the material
through reduction of methyl (4-chlorophenyl)glyoxalate with a
ruthenium-(R)-MeOBIPHEP catalyst. The product, methyl (S)-4-chloromandelate,
could be prepared in up to 94% enantiomeric excess. The free acid
could be recrystallized to more than 99% enantiomeric excess.
Reaction with the appropriate amine yields the required mandelamide.
The process is far from optimized, but the efficiency achieved
gives strong reason to believe that it would be feasible technically
and economically, Blaser says. Syngenta lost interest in the compound
class, however, and Solvias did no further work. But it is not
uncommon that compounds that have been dropped are picked up again,
he adds. If and when this project comes up again, the catalytic
asymmetric chemistry might finally be developed to its full potential.
According to Polastro, the method of choice at present for
industrial-scale application still is traditional resolution.
Others disagree, on the basis that the cost of resolution rapidly
escalates with scale-up.
However, recent advances in separations are making large-scale
resolutions more cost-effective, Chorghade says. He notes that
in some cases, simulated-moving-bed technology (SMB) is cost-effective
on a commercial scale.
SMB is a form of multicolumn continuous chromatography. Six
to eight columns are run in series. Feed enters specific columns
at particular times, material moves out from one column into the
next, and fractions are collected in separate evaporators. The
system operates in continuous mode with solvent recycling. The
equipment is commercially available from companies such as Novasep.
Depending on the size of columns, separations can range in scale
from grams to tons. The technology is used to make the APIs for
two approved single-enantiomer drugs, escitalopram and sertraline.
SMB is a winner at Aerojet
Fine Chemicals, according to Aslam A. Malik, vice president
for technology and business development. Whereas the past few
years have been rough for custom chemical companies, "our sales
have doubled over the past three years," he tells C&EN. The
success is due to the value Aerojet can offer because of SMB,
he says. In one exclusive-synthesis example that he mentions without
specifics because of confidentiality agreements, use of SMB reduced
six steps of chemistry required in a process to two. "That cut
cost way down," he says.
The biggest advantage of SMB is rapid development. Recalling
recent work, Malik says a process developed on a 50-mm-diameter-column
unit to everyone's satisfaction in October 2003 was operating
in a 200-mm-diameter-column unit by December. "In a few months,
we went from a few kilograms to 250 kg. But as far as the engineers
were concerned, we could have gone all the way to metric-ton quantities.
Because SMB is a physical separation, once it works, it works
at any scale," he says.
The biggest disadvantage is the high cost of acquiring the
technology. Malik says the bill can reach $15 million by the time
a facility is up and running. Strong justifications must be made
for that kind of spending. According to Malik, one of the most
convincing arguments was that SMB simultaneously involves engineering
and chemistry expertise, which Aerojet developed through the company's
long history in the defense business.
illustrate the economics of SMB, Geoffrey B. Cox, vice president
and general manager for separation solutions at Chiral
Technologies, Exton, Pa., prepared a case study for C&EN
on the commercial-scale synthesis of enantiopure miconazole from
a racemic intermediate.
Miconazole is an antifungal agent used to treat skin diseases.
For topical applications, a single-enantiomer formulation may
not be needed. However, miconazole may be considered for oral
treatment of other diseases, including tuberculosis. Should a
new oral-route use be found, the drug will likely have to be formulated
as a single enantiomer. Furthermore, structurally related antifungal
agents are taken orally, and some of those are produced as single
Chromatographic experiments were conducted to determine the
appropriate chiral stationary phase and mobile phase for separating
the enantiomers of the racemic intermediate, Cox explains. The
data then were used in computer simulations to optimize operating
conditions for separation at a scale of 15 metric tons per year.
The process was run on a small-scale SMB unit to confirm results.
The process was valuated on the basis of the costs of raw material
and other material and personnel inputs, as well as costs related
to the outsourcing of an SMB operation. The valuation also embodied
four key assumptions: Yield will be 96%. Product will be 99% enantiopure.
The undesired enantiomer cannot be reracemized. And the separation
will directly yield material of the required enantiopurity.
According to the calculations, the additional cost to make
one enantiomer of miconazole at 99% enantiomeric excess would
be $121 per kg. This is the extra cost over the procedure that
yields racemic product. The amount includes the cost of SMB operation
($95 per kg) and of the raw material that is discarded at the
end ($26 per kg).
To put that extra cost in context, Cox estimates that the chemical
step to convert the intermediate to miconazole costs around $200
per kg. In this case, it will be more expensive to run the fairly
straightforward chemical reaction than to separate the enantiomers.
beginning with the racemic raw material will likely
be more costly or more time-consuming to develop, Cox says. Crystallization
might be tricky because the stereogenic center does not have a
group that can readily undergo acid-base chemistry. Catalytic asymmetric
chemistry will necessitate converting the raw material to an appropriate
substrate and identifying effective, as well as usable, chemical
catalysts or biocatalysts.
||THE PRICE IS RIGHT Chiral Technologies estimates
that in a commercial route to single-enantiomer miconazole that
incorporates resolution by simulated-moving-bed chromatography,
the separation step, at about $95 per kg, will cost less than
half the chemical conversion step, at about $200 per kg.
What happens to the unwanted enantiomer also depends on the
economics. Reracemizing and feeding the racemate back into the
process is ideal but not always practical. In the miconazole case,
the raw material costs $32 per kg. It is unlikely that reracemizing
would be less costly in this example, Cox explains.
People should not forget that the goal of chiral technologies--enantiopure
product--also may be achieved with chemistry that already exists,
notes David R. Dodds, founder of Dodds & Associates LLC, Manlius,
N.Y., a consulting service for biotechnology and chemical companies.
Process chemists seek the most robust, most productive, and least
expensive synthetic route and aim to find it as fast as possible.
Any reaction that can help reach this goal is useful. It is the
overall process cost that will dictate which reactions will be
used. And that cost covers not only reagents but also waste streams,
utilities, equipment use, unit operations, and downstream requirements.
Thus, it may be more commercially attractive to replace an elegant
but expensive single reaction with several more mundane ones that
have a lower total cost, he says. Such a situation is likely to
arise when an asymmetric step requires an expensive chiral catalyst
or chiral auxiliary.
The power of conventional chemistry is reflected by routes
developed by companies such as Zambon,
based in Milan, Italy. An example provided by Livius Cotarca,
R&D manager for fine chemicals, is the separation of (R)-flurbiprofen
from flurbiprofen, a racemic nonsteroidal anti-inflammatory agent.
(R)-Flurbiprofen is being studied for the treatment of Alzheimer's
disease and various cancers. Zambon's patented process has been
scaled up to kilogram production. It requires no catalysts. The
resolving agent is (R,R)-thiomicamine, an advanced intermediate
in Zambon's route to thiamphenicol.
Another example of the clever use of stoichiometric chemistry
is the practical synthesis of l-ribose by HanChem,
a company based in Daejeon, Korea. Interest in l-sugars is high
for therapeutic and cosmetic applications, says Myung Joon Seo,
the company's vice president for custom manufacturing. Demand
for l-ribose is several metric tons per year, and prices range
from $700 to $1,000 per kg, he adds.
HanChem prepares l-ribose through a piperidine-induced, one-pot
inversion of 2,3,5,6-di-O-isopropylidene-d-mannono-1,4-lactone
[Tetrahedron Lett., 44, 3051 (2003)].
The reaction has been run at a scale of 5 kg. Seo hopes that the
process will be competitive with the best so far, an enzymatic
route from d-glucose. It would be competitive if HanChem can find
a low-cost supplier of d-mannose. The price of d-mannose has increased
since HanChem began the development work, he says.
Still, the consensus is that catalytic asymmetric routes are
the most desirable. When C&EN asked several companies about
their best commercial or commercially viable chiral chemistry,
most offered catalytic asymmetric chemistries.
For the intermediates division of BASF,
Ludwigshafen, Germany, the best story so far is (S)-methoxyisopropylamine,
according to Henning Althoefer, manager for new business development.
The compound is an intermediate for the single-enantiomer active
ingredient of the herbicide Outlook, a chiral-switch product.
Frontier, another BASF herbicide, contains the racemic active
A DEDICATED PLANT in BASF's facilities in Geismar,
La., produces (S)-methoxyisopropylamine at a scale of several
thousand metric tons per year, Althoefer says. Production is based
on enzymatic acylation of a racemic amine by a proprietary ester.
Only one enantiomer is acylated to an amide, which can be readily
separated from the unreacted amine. The same principle is used
to make BASF's ChiPros chiral amines in Ludwigshafen. Usually,
Althoefer points out, the unwanted enantiomers are reracemized
and fed back into the process.
uses biocatalytic resolution using a lipase to prepare enantiomerically
pure ß-amino acids. Its lipase technology was developed
in the late 1990s at Chirotech Technology Ltd., Cambridge, England,
which is now a subsidiary of Dow Chemical.
Karen E. Holt, technology leader for biocatalysis at Dowpharma,
says that in previous resolutions of racemic ß-amino acids
the amine is protected--that is, the substrate is derivatized
both at the carboxyl group (as an ester) and the amino group (as
an amide). She and others showed that protecting the amino group
is unnecessary and that the resolution can be achieved in fewer
steps than had been tried before [Tetrahedron Lett.,
41, 2679 (2000)]. This route to 99% enantiopure
ß-phenylalanines has been performed at metric-ton scale
at Dowpharma, she says.
Ian C. Lennon, technology leader for chemocatalysis at Dowpharma,
points out that Chirotech chemists examined producing ß-amino
acids by catalytic asymmetric hydrogenation of carbon-carbon double
bonds in unsaturated substrates. But given the state of that technology
in the late 1990s, they concluded that such a route would be more
complex, with more stages and steps, and would produce more waste
even though the key step is asymmetric.
The complexity is due partly to the mixture of E and Z isomers
produced in the synthesis of the required substrates. Most catalysts
effectively hydrogenate the E isomer in high enantiomeric excess,
and not the Z isomer. But the Z isomer is formed in greater amounts
because it is more thermodynamically stable. In this scenario,
the overall yield of enantioselective hydrogenation would be inferior
compared with biocatalytic resolution.
Chiral Quest recently has offered one solution to this problem
in the form of the rhodium-TangPhos catalyst. According to Xumu
Zhang, a chemistry professor at Pennsylvania
State University and the company's founder and chief technology
officer, this catalyst is indifferent to the geometric-isomer
form of the substrate. In reactions run at mild enough conditions,
rhodium-TangPhos hydrogenates E and Z isomers in 9899% enantiomeric
excess. Because of the high electron-donating ability of TangPhos,
turnovers of up to 10,000 can be achieved, he claims. The company
is now scaling up production of the catalyst to kilogram quantities
in anticipation of demand.
ß-Amino acids are so important--and the lipase route
to them so general--that many companies are trying to commercialize
the chemistry. ß-Amino acids are intermediates for various
drugs being developed, and demand ranges from several hundred
kilograms to a few metric tons per compound, according to Karlheinz
Drauz, Degussa's vice president for technology and R&D management.
Like Dowpharma's, Degussa's route begins with racemic ß-amino
acids prepared through one-pot synthesis. The amino acids are
then esterified with a Degussa proprietary ester. A commercially
available lipase selectively hydrolyzes only the (S)-esters, releasing
(S)-ß-amino acids. The free acid precipitates directly from
the reaction in greater than 99.5% enantiomeric excess and a chemical
purity of 99%. Drauz says Degussa has conducted several multi-hundred-kilogram
campaigns for various ß-amino acids, such as ß-phenylalanines,
and is preparing for even larger campaigns for the near future.
Befor adopting the biocatalytic route to ß-amino acids,
Degussa also tried catalytic enantioselective hydrogenation of
eneamides, but it proved inferior. With Degussa's rhodium-MalPhos
catalyst, only 95% enantiopurity could be achieved. At least one
recrystallization would be needed to raise the enantiopurity to
that required for pharmaceutical applications. Furthermore, the
route yields a derivatized ß-amino acid. Releasing the amino
acid requires another chemical step and additional workup. "An
enzyme that gives greater than 99.5% enantiomeric excess in one
step directly from the solution is hard to beat," Drauz says.
is developing methods to reracemize the undesired enantiomers
while also seeking potential uses for them. It turns out that
(R)-ß-amino acid esters are excellent resolution agents.
According to Drauz, in late March, Degussa revealed that it has
successfully used ethyl (R)-3-amino-3-phenylpropionate in a process
to resolve racemic tert-leucine for kilogram-scale production
of D-tert-leucine. This compound previously could not
be accessed through biocatalytic means, he says. Now a chemical
resolution is available.
"D-tert-Leucine is a missing link in the chiral map,"
Drauz says. Many asymmetric ligands, catalysts, and chiral auxiliaries
are based on tert-leucine, but only those incorporating
L-tert-leucine could be made easily. Now the complementary
compounds based on D-tert-leucine can be prepared "on
a roughly similar cost basis," he explains. "This is a great result
for all asymmetric reactions based on tert-leucine."
Furthermore, a demand exists for D-tert-leucine as a
building block for new drug candidates. It also is needed in the
synthesis of the enantiomers of drug candidates containing L-tert-leucine,
which must also be evaluated during drug development.
Biocatalysis also has been successfully applied to commercial
production of single-enantiomer 3-hydroxybutyrates from prochiral
ketones. One particular compound, ethyl (S)-4-chloro-3-hydroxybutyrate
(ECHB), is an intermediate in the synthesis of cholesterol-lowering
drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin).
Sales of Lipitor alone reached $10.3 billion in 2003. Many companies
are vying to supply the chiral side-chains in these compounds.
At Daicel Chemical Industries, Tokyo, production capability
for ECHB is more than 100 metric tons per year by whole-cell biocatalysis.
Significant improvements to the process have been made since C&EN
reported on it five years ago (C&EN,
July 19, 1999, page 65).
The key step is asymmetric hydrogenation of the carbonyl group
of ethyl 4-chloroacetoacetate (ECAA) by a biocatalyst. That catalyst
is a carbonyl reductase originally isolated from Kluyveromyces
aestuarii and then expressed in Escherichia coli.
ECAA is prepared chemically from diketene, a core raw material
The hydrogen source is reduced nicotinamide adenine dinucleotide
(NADH). Previously it was regenerated through a glucose dehydrogenase
system that converts glucose to gluconic acid. Because of environmental
concerns regarding the large amount of gluconic acid formed in
the waste stream, Daicel switched to a formate dehydrogenase system,
which converts formic acid to carbon dioxide, according to John
R. Peterson, chief executive officer of Thesis
Chemistry LLC, Mentor, Ohio, which is the marketing representative
of Daicel in North America.
A stable and active formate dehydrogenase was isolated from
Mycobacterium vaccae, and its productivity was improved
by site-specific mutation. The variant now in commercial use furnishes
ECHB with greater than 99% enantiopurity at a rate of 49.9 g/L,
much more productive than the wild-type enzyme (19.0 g/L) and
even better than the optimized glucose dehydrogenase (45.6 g/L).
Other targeted, site-specific mutations of the formate dehydrogenase
have led to two other benefits: increased tolerance to ECAA and
better performance in an organic solvent. According to Peterson,
ECAA is toxic to whole cells bearing the wild-type enzyme, which
is usually shut down by organic solvents as well. In this case,
fewer cells are dying from ECAA, and the enzyme actually works
better in organic solvents.
Competition to come up with better ways to make ECHB is intense.
Dowpharma teamed up with the San Diego-based biocatalysis company
Diversa to develop a route
that is likely based on nitrilases (C&EN,
Feb. 18, 2002, page 86; Oct.
7, 2002, page 8). "The team is not in a position to comment
at this time," a Dowpharma spokesperson says in response to C&EN's
request for an update on the project's status.
Chiral Quest has joined in with its ruthenium-C3-TunePhos
catalyst for asymmetric hydrogenation of ECAA. Zhang estimates
that as little as 1 kg of this catalyst can produce up to 9 metric
tons of 98 to 99% enantiopure ECHB from ECAA. And according to
Brandt, Chiral Quest is supplying kilogram amounts of the catalyst
to a client for commercial production of ECHB.
Wacker Specialties, Munich,
Germany, is also targeting single-enantiomer 3-hydroxybutyrates
as part of its mission to be "the number one chiral alcohol producer
based on ketones," according to Hans Pommerening, director for
organic fine chemicals. The company is a major producer of diketene,
from which prochiral acetoacetates are readily made.
To compare the economics of various options for making 3-hydroxybutyrates,
Wacker analyzed two routes it operates to make (R)-3-hydroxybutyrate
esters: biocatalytic reduction with an isolated enzyme and catalytic
asymmetric hydrogenation with ruthenium and a proprietary diphosphine
ligand. On the basis of published literature, the company concluded
that biocatalytic reduction by whole-cell fermentation is an inferior
route, according to Pommerening.
Wacker's isolated-enzyme biocatalytic route is based on an
alcohol dehydrogenase from Lactobacillus brevis. The
commercial application of this enzyme was developed by and is
proprietary to Jülich
Fine Chemicals (JFC). This company, based in Jülich,
Germany, is one of Wacker's collaborators in developing enzymatic
processes for fine chemicals. Wacker claims that the process yields
100% enantiopure product in 97% yield. It has been run at hundreds-of-kilograms
scale. Wacker estimates that this route can produce commercial
quantities of (R)-3-hydroxybutyrates at less than $100 per kg.
By comparison, the chemocatalytic route using Wacker's proprietary
ligand yields 98% enantiopure product in up to 95% yield. This
route also has been run at hundreds-of-kilograms scale. Wacker
estimates that the cost to produce (R)-3-hydroxybutyrates from
this route will be 10 to 15% lower than by biocatalysis.
use standard equipment. The biocatalytic route has
an edge with regard to safety and health issues. It runs at ambient
pressure and temperature, whereas the chemocatalytic route requires
100 °C temperatures and means for handling hydrogen, as well
as a toxic solvent, methanol. On the other hand, the chemocatalytic
route produces less than 100 g of organic waste per kg of product,
compared with 2 L of waste per kg of product for the biocatalytic
BIGGEST DIFFERENCE is that throughput for the chemocatalytic
route is three to four times higher than for biocatalysis. To
achieve the high enantiomeric excess of the biocatalytic route,
the process must run with dilute solutions. That means lower throughput
rates, Pommerening explains. Both routes are poised for operation
at multiton scale, he adds. The customer's requirement for purity
and price will dictate which route to take.
The biocatalytic route yields chiral alcohols of exceptionally
high quality, says Thomas Maier, senior marketing manager at Wacker.
For this reason, he says, Wacker is collaborating with JFC, as
well as Prokaria, a Reykjavik
company that discovers enzymes from Iceland's biodiversity pool,
to develop processes for other specific chiral alcohols.
At Bayer Chemicals, 3-hydroxyesters, including 3-hydroxybutyrates,
are produced with enantiopurities of more than 99% in ton quantities
per year by way of catalytic asymmetric hydrogenation of 3-ketoesters
through Bayer's ruthenium-ClMeOBIPHEP catalyst, according to Ulrich
Scholz, laboratory head for catalysis. At the request of a customer,
Bayer has used the chemistry to prepare enantiopure (S,S)-pentan-2,4-diol
from acetylacetone. Bayer prepared several kilograms of the enantiomer
with greater than 99% enantiomeric excess and greater than 98%
diastereomeric excess. Interestingly, the customer specializes
in biocatalysis and has a biocatalytic route to the R,R enantiomer,
Scholz says. "They were looking for a way to have both enantiomers
in their portfolio."
Pharma Solutions, the best chiral chemistry success so far
is hydrolytic kinetic resolution (HKR) of racemic terminal epoxides,
according to Spagnol. The technology was invented by Harvard University
chemistry professor Eric
N. Jacobsen and is licensed exclusively to Rhodia. The process
produces tens of tons of single enantiomers of epichlorohydrin
per year. An extremely versatile building block, epichlorohydrin
provides access to a diverse range of intermediates of interest
to the pharmaceutical industry.
Rhodia also applies HKR to racemic propylene oxide, a commodity
chemical, to prepare single-enantiomer propylene glycol. (R)-Propylene
glycol is easily converted to (R)-propylene carbonate, an intermediate
in the synthesis of the AIDS drug tenoforvir (Viread), from Gilead
Sciences. This intermediate, produced in multiton quantities
per year, is Rhodia's second largest product based on HKR technology,
Using a cobalt-salen catalyst, the Jacobsen hydrolytic kinetic
resolution hydrolyzes only one enantiomer of a racemic epoxide
to the corresponding diol. Because the diol and the unreacted
epoxide differ greatly in their physical properties, they are
readily separated. The process typically yields single-enantiomer
epoxides in greater than 99% enantiomeric excess.
That HKR consistently achieves excellent enantioselectivities
was a major factor in its adoption by Rhodia, Spagnol says. With
improvements on the original invention, including development
of a second-generation catalyst, the process now uses less than
1 kg of catalyst to make 1 metric ton of product, Spagnol claims.
The technology is so commanding that Rhodia is now the largest
producer of single-enantiomer epichlorohydrins and (R)-propylene
carbonate, he adds.
Hard work and luck both contributed to Rhodia's success with
HKR. According to Spagnol, from the time of licensing, it took
at least four years of intense effort and investment to develop
the technology to its current state. Meanwhile, demand for products
derived from HKR has been increasing. With customers insisting
on high-quality but low-cost supplies, the process had to be made
AN ALTERNATIVE ROUTE to single-enantiomer chiral epoxides
is asymmetric epoxidation of olefins. At DSM, hopes are high for
the reaction developed by chemistry professor Yian
Shi at Colorado State University, Fort Collins. Called the
Shi epoxidation, the reaction is catalyzed by a fructose-derived
ketone and transforms trans alkenes that do not have to bear an
allylic group to single-enantiomer epoxides with enantiomeric
excesses usually greater than 95%.
Pharmaceutical applications of the reaction have been licensed
exclusively to DSM. According to DSM's Ager, DSM has used the
original methodology, in which the oxidant is potassium peroxomonosulfate
(Oxone), to make around 100 kg of a custom-synthesis product for
a pharmaceutical customer.
The substrate scope is broad, including trisubstituted olefins
and olefins bearing a wide range of functional groups. But until
recently, the Shi epoxidation was ineffective for cis olefins
and terminal olefins. In 2002, the reaction was extended to these
substrates through a catalyst that is a glucose-derived nitrogen
analog of the fructose-derived ketone in the original invention.
The Shi epoxidation complements the chemistry developed by
chemistry Nobel Laureate K.
Barry Sharpless. The Sharpless epoxidation, which has been
licensed to PPG
Fine Chemicals, is catalyzed by a titanium-tartrate complex
and requires allylic alcohol substrates. "In many cases, newer
technologies have proven to be more cost-effective than the Sharpless
epoxidation," according to PPG's website.
At Bayer Chemicals, meanwhile, Arne Gerlach, laboratory head
for specialty chemicals, has spent part of the past three years
developing the asymmetric epoxidation reaction called the Juliá-Colonna
oxidation. Here the substrate is an enone; the product is a chiral
epoxy ketone; the oxidant is hydrogen peroxide; and the chiral
catalyst is poly-l-leucine, which can be recycled.
Gerlach says the substrate scope of this reaction is limited
to substituted enones. On the other hand, the reaction is atom
economical and requires mild reaction conditions, an inexpensive
oxidant, and a recyclable catalyst. These advantages were attractive
enough to invest in its development, Gerlach says.
According to Gerlach, the original reaction was not practical.
Throughput was low, and workup was complicated. An industrially
viable process now patented by Bayer Chemicals involves a simpler
workup and a phase-transfer cocatalyst, which was not part of
the original invention. A reliable synthesis of poly-l-leucine
also has been established.
In the Bayer process, the enone substrate is dissolved in an
organic phase, such as toluene. Hydrogen peroxide and an inorganic
base, to generate peroxide anion, are in an aqueous phase. Poly-l-leucine,
which is not soluble in water or organic solvent, constitutes
a third phase. The phase-transfer cocatalyst--tetrabutylammonium
bromide--escorts the peroxide to the organic phase. This innovation
cut the reaction time from more than 90 minutes to seven minutes
in experiments with 75 mg of a chalcone substrate.
In the organic phase, the peroxide delivers an oxygen atom
to the substrate. It is believed that the substrate is bound to
poly-l-leucine through the carbonyl of the enone so that only
one face of the olefin double bond is available to accept it.
The mixture is stirred at 700800 rpm to ensure efficient
mixing of the three phases. After the reaction, the catalyst is
filtered out, the liquid phases are separated, and the product
is concentrated from the organic phase.
Practiced on 100 g of the same chalcone substrate, Bayer's
epoxidation protocol converts 75% of the starting material to
an epoxy ketone with 95.5% enantiopurity. Recrystallization raises
the enantiopurity to more than 99%. "We have now set the stage
to produce multikilogram quantities with this technology," Gerlach
a capacity of more than 10,000 tons per year, the largest-scale
enantioselective catalysis at present produces the penultimate
intermediate in the synthetic route to (S)-metolachlor. This compound
is the active ingredient of Dual Gold, a broad-spectrum herbicide
against grass weeds. The predecessor of Dual Gold is Dual, with
racemic metolachlor as the active ingredient. Dual came to the
market in 1976.
Metolachlor has two elements of chirality: a chiral axis and
a stereogenic center. The active ingredient in Dual therefore
consists of four stereoisomers. In 1982, it was established that
the biological activity resides only in the two S diastereomers.
That knowledge spurred the search for a commercially viable chiral
The chiral switch is based on catalytic enantioselective hydrogenation
of an imine. The reaction was developed in what was then the central
research laboratories of Ciba-Geigy,
in Basel, by chemists led by Blaser, Hans-Peter Jalett, Benoit
Pugin, and Felix Spindler. One key to the success is the catalyst
discovered as the work progressed--iridium complexed to a ferrocenyl
diphosphine ligand now well known as Josiphos.
The iridium-Josiphos catalyst delivers both satisfactory enantiomeric
excess and an amazing turnover number of more than 1 million.
That and the relatively mild reaction conditions--hydrogen pressure
of 80 bar and a reaction temperature of 50 °C--yield a highly
efficient, cost-competitive process.
The story of (S)-metolachlor has been told, most recently in
a chapter of the book "Asymmetric Catalysis on Industrial Scale:
Challenges, Approaches, and Solutions," edited by Blaser and Elke
Schmidt (Wiley, 2004). This account gives the impression that
development proceeded as if according to a well-planned blueprint.
"It's never the whole story in publications," says Blaser. "It's
so much more complex."
Earlier, in a much more nuanced report [Adv. Synth. Catal.,
344, 17 (2002)], Blaser aptly called the 13-year
(198194) effort an odyssey and compared the quest for the
right catalyst with navigating a labyrinth. When the search began,
almost nothing was known about enantioselective reduction of imines,
catalytic asymmetric hydrogenations that could provide guidance
were few, and the number of ligands to choose from was limited.
But even now, with more ligands, more screening capabilities,
and more people with hands-on experience, finding the right catalyst
is still the key, Blaser says. Optimizing and scaling up are routine
Lack of rapid analytical techniques was also a handicap at
the early stages. Enantiomeric excesses were measured from optical
rotations or by nuclear magnetic resonance spectrometry. Chromatographic
methods were not developed until later. "Good analytics are crucial
with any project," Blaser says. "If they are not reliable or are
slower than the throughput of screening systems, they are useless."
Initially, progress was slow as hypotheses about routes and
catalysts failed. Nevertheless, the research continued because
Blaser and his team were trusted by and had the strong backing
of the company. At one point, management suspended the project
as it considered whether another compound altogether should be
developed to replace metolachlor. When finally it was decided
to stick with the chiral switch, the project sped up with the
full force of Ciba-Geigy's organizational expertise and institutional
know-how. "You must have somebody who says, 'This problem is important,
and we want to solve it,'" Blaser tells C&EN. "That was the
situation at Ciba-Geigy's agrochemical division. It was their
most important product, it eventually came off patent, and they
needed a replacement."
Having a champion and years of development time are rare in
the current climate in which speed to market is everything. The
window of opportunity is narrow, and success will be elusive without
certain elements in place, Blaser says. These elements include
a suitable library of ligands, auxiliaries, and metal precursors;
access to rapid screening of catalytic systems; access to very
good analytical equipment; and highly experienced specialists.
The last is especially key, given that so many catalysts are being
invented but their inventors do not always have experience with
process development. Licensed catalysts are not worth much until
somebody applies them to scale, he adds.
The full potential of enantioselective catalysis is far from
realized. As process chemists acquire more experience with catalytic
systems, as researchers gain better understanding of enantioselective
reactions and mechanisms, and as optically pure products progress
through pipelines and eventually to markets, so will the promise
of the catalytic chiral technology incrementally be fulfilled.
Events Of Interest
- June 18, Tetrahedron Symposium 2004. New
York City. Information at http://www.tetrahedron-symposium.elsevier.com/index.htm.
- June 2025, Gordon Research Conference on Stereochemistry.
Newport, R.I. Information at http://www.grc.uri.edu/programs/2004/stereo.htm.
- June 2324, ChemSpec Europe 2004. Amsterdam,
the Netherlands. Information at http://www.dmgworldmedia.com.
- July 1114, 16th International Symposium on Chirality.
New York City. Contact Janet Cunningham, phone (301) 668-6001;
fax (301) 668-4312; e-mail: email@example.com.
- July 1116, Gordon Research Conference on Biocatalysis.
Meriden, N.H. Information at http://www.grc.uri.edu/programs/2004/biocat.htm.
- July 1216, 10th Belgian Organic Synthesis Symposium.
Louvain-La-Neuve, Belgium. Information at http://www.boss10.be.
- July 1316, 10th International Conference on
Organic Process Research & Development. Vancouver,
Columbia. Contact Scientific Update, 011 44 14 3587 3062; e-mail:
- July 1823, Gordon Research Conference on Organic
Reactions & Processes. Bristol, R.I. Information
- July 2530, Gordon Research Conference on Natural
Products. Tilton, N.H. Information at http://www.grc.uri.edu/programs/2004/natprod.htm.
- Sept. 2324, 7th International Symposium on Laboratory
Automation in Process Development. Contact Scientific
- Oct. 45, Chiral USA 2004. Boston. Contact
- Oct. 67, Outsource USA 2004. Boston.
Contact Scientific Update.
- Oct. 1720, SPICA 2004, International Symposium
on Preparative & Industrial Chromatography & Allied Techniques.
Aachen, Germany. Information at http://events.dechema.de/spica.html.
- Nov. 14, 6th International Conference on the
Scale-up of Chemical Processes 2004. Dublin. Contact
- Dec. 79, CPhI Worldwide 2004. Brussels.
Information at http://www.cphi.com.
- Jan. 1720, 2005, Informex 2005. Las
Vegas. Information at http://www.informex.org.