A Renaissance in Organocatalysis

Imagine that you have to carry out a catalytic asymmetric transfer hydrogenation, and all you have to do is reach for a bottle of powder, transfer some powder to a flask, and mix it with solvent and substrate. Then, after a few hours at room temperature, you get the desired product in at least 90% enantiomeric excess. A fanciful notion? Not anymore. With small-molecule organic catalysts, or organocatalysts, this dream is coming true.

Organocatalysts are becoming the darlings of the pharmaceutical industry because they eliminate the need for metals. But “used creatively, organocatalysis is much more than a replacement technology for metal catalysis,” according to David W. C. MacMillan, a chemistry professor at California Institute of Technology and a major proponent of organocatalysis. The greater excitement lies in catalysis of reactions that were not even thought possible, he adds.

THE SUBJECT of a special issue of Accounts of Chemical Research that was published last month, organocatalysis is hot—but it’s not new. A modestly enantioselective alkaloid-catalyzed cyanohydrin synthesis has been around since 1912, note the special issue’s editors, Kendall N. Houk, a chemistry professor at the University of California, Los Angeles, and Benjamin List, an associate professor of chemistry at Max Planck Institute for Coal Research, Mülheim, Germany.

Back in the 1970s, when two industrial teams carried out highly enantioselective intramolecular aldol reactions catalyzed by the amino acid proline, people didn’t pay much attention. But in 2000, people took notice when List and his collaborators showed that proline also catalyzes asymmetric intermolecular, or direct, aldol reactions with up to 96% enantiomeric excess.

List carried out that work while he was an assistant professor at Scripps Research Institute, in collaboration with chemistry professors Carlos F. Barbas III and Richard A. Lerner. List says the work has been cited more than 200 times since it was first reported [J. Am. Chem. Soc., 122, 2395 (2000)].

“I was very surprised to read that paper,” says Sh Kobayashi, a chemistry professor at the University of Tokyo. “Others had been trying to synthesize complex metal catalysts to control that reaction, and the paper demonstrated that simple small molecules can do it.”

“The reaction had been a challenge to organic chemists, and then all of a sudden here was a catalyst that represented pretty much the state of the art,” List says. “The catalyst is so simple: an amino acid that you can eat and you can buy in the supermarket. Yet it catalyzes a fascinating transformation through the same mechanism that enzymes have evolved over millions of years.”

THE MECHANISM'S hallmark is an enamine intermediate formed when proline adds to a carbonyl substrate. The chemistry has since been applied to asymmetric Mannich reactions, Michael reactions, -aminations of aldehydes, -alkylations of aldehydes, and more. Recently, MacMillan reported a two-step synthesis of hexoses in which enamine chemistry is key to the first step (C&EN, Aug. 16, page 6).

Before joining Caltech, at the University of California, Berkeley, MacMillan had been developing a different organocatalytic chemistry: iminium catalysis. Iminium catalysis represents a new catalysis concept; that is, a new mode of activating molecules toward many different types of transformations. In the presence of an ,-unsaturated carbonyl compound, an imine is transformed into a highly active ,-unsaturated iminium ion, which can participate in many reaction types.

In 2000, MacMillan announced the first use of iminium catalysis, which was to catalyze an asymmetric Diels-Alder reaction [J. Am. Chem. Soc., 122, 4243 (2000)]. He says his group has now developed more than 20 asymmetric reactions enabled by iminium catalysis, each yielding products that are at least 90% enantiopure. “The versatility of this catalysis concept has taken us by surprise, given that iminium catalysis is unprecedented in chemistry and, to our knowledge, has no counterpart in biology,” he adds.

Organocatalysis was overlooked until recently, partly because of the prominence of transition-metal-catalyzed asymmetric transformations, exemplified by the work of, among others, the winners of the 2001 Nobel Prize in Chemistry, William S. Knowles, Ryoji Noyori, and K. Barry Sharpless. Compared with intricate transition-metal complexes, simple organic molecules “seemed old-fashioned,” List says.

People also assumed that the proline chemistry discovered in 1970 was a one-reaction deal. “No one thought about applying it to any other transformation until List came along and redeveloped it,” MacMillan says.

The catalysts of List and MacMillan—proline and an imidazolidinone, respectively—may have jump-started the renaissance of organocatalysis, but they are just two in a very diverse field. The Accounts special issue, for example, features alkaloids, amino acids, ketones, peptides, sulfur ylides, and derivatives of 4-dimethylaminopyridine, among others. However, even the special issue did not encompass the totality of the field.

Other organocatalysts being examined are pyridine-type N-oxides and BINAP dioxides. Pavel Koovsk, a chemistry professor at the University of Glasgow, in Scotland, has used pyridine N-oxides to enantioselectively add allylic groups to aromatic aldehydes, while Kobayashi has used the BINAP dioxides to prepare a-amino acids by allylation of imino esters. This reaction, Kobayashi says, has not been achieved stereospecifically with metal catalysts.

The fine chemicals industry has embraced organocatalysis. “It’s green technology because you don’t require metals. In principle, you can do beautiful chemistry with simple molecules,” says Paul L. Alsters, a senior scientist at DSM Pharma Chemicals. In fact, he notes, well before the current bandwagon, DSM had already invested in the technology. He refers to the enantioselective epoxidation reaction invented in 1996 by Yian Shi, a chemistry professor at Colorado State University, Fort Collins. The reaction is catalyzed by a fructose- or glucose-derived ketone. Already DSM can run it at pilot scale, he says. “We have several target molecules of commercial interest that are accessible through this chemistry, and we see more applications popping up.”

Meanwhile, Materia, which was founded to commercialize transition-metal olefin-metathesis catalysts, is commercializing MacMillan’s organocatalysts. Richard A. Fisher, vice president for marketing and business development, points out that MacMillan’s asymmetric technology uses olefin substrates, which are easily made by metathesis. Organocatalysis “allows us to do something we couldn’t readily do: to form chiral products from olefins,” he explains. Applying iminium catalysis to indole alkylations, Materia has begun offering chiral indoles for drug discovery.

EVEN THE PAHRMACEUTICAL industry is on board. “Pharma companies don’t like metals because contamination is a very serious issue,” Kobayashi says.

“It is very exciting to visit pharmaceutical companies and to find that they are all using organocatalysis in some form,” MacMillan says.

“Organocatalysis is practical and user friendly,” List adds. “You typically don’t need argon atmospheres, you don’t have to avoid water completely, and you don’t need heating or cooling. The process is simpler because you use nontoxic reagents.”

Nevertheless, organocatalysis has potential drawbacks. One is the need for protection and deprotection of functional groups, notably in certain applications, DSM’s Alsters points out. Such a requirement makes reactions unattractive for process development. Not only does protection-deprotection add to costs, he explains, but sometimes “the chemistry to remove a protecting group is so dirty that it’s impossible to do on a large scale.”

Organocatalysis has other disadvantages. Reactions are often carried out in dilute solution and are not easily convertible to an industrial process. Catalyst loadings usually are high, making separation of catalyst from product difficult. Enantiomeric excesses usually are less than the 99.9% levels achieved with transition-metal complexes.

It is a matter of development, List says. “Metal systems are very sophisticated because they have been intensely developed over decades by several companies and several research groups. We don’t have that long history in organocatalysis.”

Part of the reason for high catalyst loadings is the occurrence of independent background reactions, Koovsk explains. Citing his work on addition of silanes to carbonyls catalyzed by chiral N-oxides, he says the reaction occurs slowly without catalyst. “You have to compete with that background reaction with your chiral catalyst, because only the catalytic process is enantioselective,” he explains. Nevertheless, catalyst loadings are coming down from the usual 20–30-mol-% levels of the earlier work to 1 mol %. Others have reduced catalyst loadings to as low as 0.1 mol %, he adds.

In fact, catalyst loadings are critical only with expensive transition-metal catalysts, MacMillan says. He explains that chemists in industry tell him: “If the catalyst is 17 cents a gram, nobody worries much about turnovers. What becomes more important is the time of reaction. In some cases, because the catalyst is so cheap, they’ll use 50 mol % to speed up the reaction and move things quickly through the process. That’s where they really save money.”

Related to catalyst loading is catalyst recovery and recycling. Kobayashi, for example, is exploring ways to immobilize organocatalysts to ease recovery and recycling. He believes that polymer-supported organocatalysts can be designed that are even more efficient than the versions that are not immobilized.

But according to MacMillan, “If a catalyst is cheap, it is much easier to dispose of it than to recycle.” That’s especially true if the catalyst is used in a process being run at cGMP (current Good Manufacturing Practice) conditions. Very often the recovered catalyst must be restored to cGMP quality before it can be recycled, and that task is exceedingly costly, he explains.

Regarding enantioselectivity, the consensus is that a reaction that gives at least 90% enantiomeric excess is useful. It will be considered by industry because recrystallization can often yield an enantiopure product.

Much work lies ahead. Many reactions remain to be discovered that seemed impossible before. “Organocatalysis is not just a replacement technology,” MacMillan reiterates. “It’s an amazing opportunity to do reactions that have not been previously possible.”

For an example, MacMillan cites the Diels-Alder reaction. “We are taught in college all the reasons why Diels-Alder reactions have to be endo-selective,” he says. But his group has just developed an exo-selective catalyst, something that small-molecule catalysts have not been able to achieve in a general sense. More important, he adds, organocatalysis has opened up the other half of a reaction that is one of the most powerful chemical transformations.

Bench chemists awaiting new methodologies are lucky because the field is extremely competitive, with multiple groups discovering reactions often almost simultaneously. Earlier this year, for example, two Japanese groups reported using chiral Brønsted acids as organocatalysts: Takahiko Akiyama and coworkers at Gakushuin University, Tokyo, published their work in March [Angew. Chem. Int. Ed., 43, 1566 (2004)]; Masahiro Terada and Daisuke Uraguchi, at Tohoku University, Sendai, followed in May [J. Am. Chem. Soc., 126, 5356 (2004)].

The use of Brønsted acids is one of the most exciting recent methodologies, as far as List is concerned. “You would assume that a relatively strong chiral acid would transfer its proton to a substrate, and the substrate undergoes a reaction,” he explains. “But you wouldn’t expect chirality to be transferred to the substrate. But it is, and significantly.” That has profound implications because the proton is probably the best catalyst around, he adds.

“It’s unbelievable” how fast new reactions are emerging, List continues. Right now, he is working on an organocatalytic asymmetric hydrogenation. That powder in a bottle that bench chemists soon could reach for may be the MacMillan version. Stay tuned.