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A Tale Of Two Catalysts

Years of effort reveal the mechanisms of two catalytic asymmetric allylic substitution reactions

by Stuart A. Borman
June 15, 2009 | A version of this story appeared in Volume 87, Issue 24

Floppy Catalyst
It was proposed that in the catalyst formed by TML and Pd, phenyl rings act like flaps and walls to control stereoselectivity (L = allyl substrate).
It was proposed that in the catalyst formed by TML and Pd, phenyl rings act like flaps and walls to control stereoselectivity (L = allyl substrate).

The inner workings of asymmetric organometallic catalyst systems are not revealed to chemists every day, every week, or even necessarily every year. Studies to understand the detailed mechanisms of such systems typically take years of effort. The key to success is hard work—many days and nights of research by students and the ingenuity, dedication, and vision of principal investigators.

It's therefore rare for the mechanisms of two related asymmetric organometallic catalysts to be revealed almost simultaneously. But that's exactly what happened recently, when two independent research groups reported, at about the same time, characterizing the intermediates and mechanisms of two complementary chiral allylic substitution reactions. In such reactions, a group adjacent to a double bond is replaced by another in a highly stereoselective manner.

The studies show that organometallic catalytic complexes are indeed tractable, even if they sometimes might seem all but impossible to decipher. They can be analyzed structurally, and how they accelerate reactions can be figured out, albeit with a lot of effort.

Guy C. Lloyd-Jones of the University of Bristol, in England; Per-Ola Norrby of the University of Gothenburg, in Sweden; and coworkers carried out one of the two studies, on palladium-based asymmetric catalysis (J. Am. Chem. Soc., DOI:10.1021/ja8099757). John F. Hartwig and coworkers of the University of Illinois, Urbana-Champaign (UIUC), did the other, which was on iridium-based chiral catalysis (J. Am. Chem. Soc., DOI: 10.1021/ja902609g). Both studies took years, and it's extraordinary that they were published only a day apart last month.

"There aren't very many catalytic reactions for which people have been able to isolate intermediates and determine the reactivity of the intermediates," Hartwig says. "There are even fewer catalytic asymmetric reactions for which this is true. Many people think of these reactions as a black box. What Guy and I have been trying to do with experiments, and Per-Ola with computational methods, is remove the black box so you can see the inner workings of catalytic systems. These are unusual cases in which structural information has been determined by nuclear magnetic resonance spectroscopy or crystallography on intermediates in a catalytic system, and detailed information obtained on how asymmetry is transferred from the intermediates to reaction products."

Asymmetric catalysis specialist Andreas Pfaltz of the University of Basel, in Switzerland, says the papers "lead to a better understanding of two highly useful, widely used enantioselective catalytic reactions and provide a basis for further catalyst development."

Patrick J. Walsh of the University of Pennsylvania, whose research focus includes asymmetric catalysis, notes that allylic substitution reactions are synthetically very useful but that "our understanding of the transmission of asymmetry from catalyst to substrate in these important reactions has lagged." The new studies "represent significant advances toward demystifying this chemistry," he adds.

And Brian M. Stoltz of California Institute of Technology, who specializes in the synthesis of structurally complex bioactive molecules, says, "These are beautiful studies of mechanism, attempting to understand the very subtle and intricate details of two types of allylic reactions." The mechanisms proposed in the studies "ultimately will allow one to build new hypotheses that move the field further," Stoltz continues.

In the Pd study, mechanistic organometallic chemist Lloyd-Jones—with coworkers Craig P. Butts, Emane Filali, David A. Sale, and York Schramm—and Norrby, a specialist in catalyst mechanisms, collaborated closely to obtain structural and mechanistic information on Trost modular ligands (TMLs). Developed by synthetic organic chemist Barry M. Trost of Stanford University, TMLs combine with Pd to form catalysts.

"Trost introduced these catalysts in 1992, and we started working on their mechanism in 1996, so we've been at this for about 13 years," Lloyd-Jones says. Norrby and coworkers have been investigating the mechanism computationally for about the same amount of time.

High Stereoselectivity
The R,R form of a TML-Pd catalyst converts a racemic substrate to a predominantly S product (X = leaving group, Nu = nucleophile).
The R,R form of a TML-Pd catalyst converts a racemic substrate to a predominantly S product (X = leaving group, Nu = nucleophile).

TML-Pd catalysts have been successfully deployed in hundreds of allylic substitution reactions to help synthesize a wide range of compounds for academic research, drug discovery, and industrial synthesis.

A common structural feature of TML-Pd catalysts is the presence of two triphenylphosphine units linked to each other through Pd on one side and through a chiral scaffold on the other. A TML containing the chiral scaffold cyclohexyldiamine, called the Trost standard ligand, is widely used. With the R,R enantiomer of this ligand, the Pd-catalyzed reaction predominantly yields the S product.

Trost has proposed a mechanism that accurately predicts the catalyst's stereoselectivity based on the hypothesis that in the reaction intermediate, four of the phosphorus-linked phenyl rings control the nucleophile's attack on the substrate, which is linked to Pd.

Deactivating Wall
It was originally proposed that a phenyl wall tends to block attack at one carbon position, and a phenyl flap generally allows it to occur at the other.
It was originally proposed that a phenyl wall tends to block attack at one carbon position, and a phenyl flap generally allows it to occur at the other.

The first step in a TML-Pd-catalyzed allylic substitution reaction is the removal of the substrate's leaving group. With a substrate that's asymmetric at the allylic position, detaching the leaving group from either enantiomer yields the same intermediate, with one pro-R and one pro-S carbon. Nucleophilic attack on the pro-S carbon in the next step creates an S substitution product, and a pro-R attack yields the R enantiomer.

Whether the nucleophile attacks primarily a pro-R or pro-S carbon is controlled by four of the phosphorus-linked phenyl rings on the ligand, according to Trost's proposal. Two of these are oriented equatorially and are like bent-out flaps, and the other two are axially oriented and point straight down, like walls. One wall tends to block the nucleophile from attacking the pro-R carbon, and because of the blockage, the R product isn't formed very often. On the other side, a flap leaves the pro-S carbon open for reaction, which forms an S product, the result obtained most of the time.

Trost's mechanism is a deactivation model in that it proposes that stereoselectivity is controlled by the tendency of one of the walls to block the disfavored R pathway. But "based on experience in my lab and reports from a lot of people who had used the ligand that it was exceptionally reactive, we suspected it was accelerating attack on one carbon instead of blocking attack on the other," Lloyd-Jones says. He believed it might be an activating ligand rather than a deactivating one and that the ligand is not just controlling the reaction's stereoselectivity but is also making it go faster.

The conventional view of the geometry of the reaction complex formed with the Trost standard ligand is that the substrate is appended below Pd and between the four wall and flap phenyl rings. That view suggests that the substrate is located far from the cyclohexyldiamine chiral scaffold and its two amide groups.

But "there's been no structural evidence to support that" view, Lloyd-Jones says. "The majority of our effort for the past 13 years has been trying to determine the structure of the complex and therefore identify where the substrate is located in relation to the ligand."

Plan of Attack
Experimentally determined structure of reaction intermediate suggests that H-bonding between the nucleophile and the chiral scaffold's amide group actually controls stereoselectivity (X = counterion to Pd; M+ = counterion to nucleophile, Nu; curved black arrow = pro-S nucleophilic attack).
Experimentally determined structure of reaction intermediate suggests that H-bonding between the nucleophile and the chiral scaffold's amide group actually controls stereoselectivity (X = counterion to Pd; M+ = counterion to nucleophile, Nu; curved black arrow = pro-S nucleophilic attack).

In the new study, Lloyd-Jones, Norrby, and coworkers demonstrate that the substrate is not between those four phenyl rings; instead, it is twisted up on one side of Pd, bringing it close to one of the chiral scaffold's two amide groups. "We've spent a long time using NMR methods to prove that," Lloyd-Jones says.

From this hard-won structural information, the team derived an alternative mechanism of the catalytic process. "It took Guy and me sitting down together for a very intense week last year to finally make sense of this and come up with a working selectivity model," Norrby says.

Frozen Complex
Researchers believe the phenylethyl group in this Ir complex dictates enantioselectivity by orienting the allyl group (Ph = phenyl, R = allylic substituent).
Researchers believe the phenylethyl group in this Ir complex dictates enantioselectivity by orienting the allyl group (Ph = phenyl, R = allylic substituent).

They propose that the amide group that's close to the substrate forms a hydrogen bond with the incoming nucleophile and thereby controls the stereoselectivity of nucleophilic attack. The other amide group projects back onto the other face of the chiral scaffold and is thus remote from the nucleophile. The team believes the H-bonding acts like a targeting system to set up the nucleophile to attack the pro-S carbon. Pro-S attack to make the S product predominates experimentally with the R,R form of the Trost standard ligand.

"Our explanation predicts the same stereoselectivity as the Trost hypothesis but shows how the ligand can be much more active because that H-bond switches things on," Lloyd-Jones says. First, the ligand helps pull away the substrate's leaving group to generate the intermediate, he explains, and then it "helps bring in a nucleophile via H-bonding, lowering the barrier to nucleophilic attack." The TML-Pd catalyst "is very efficient because it assists in both steps," he adds.

"This is an intriguing, almost enzymelike mechanism," the University of Basel's Pfaltz says. "The Pd atom holds the allyl system in place, and the functional groups present in the chiral ligand guide the nucleophile in the right direction."

Why did it take Lloyd-Jones's group 13 years to obtain the structure of the TML-Pd-substrate complex? That's because most chelating ligands for asymmetric catalysis form complexes with 5-, 6-, or 7-membered rings, whereas the TML-Pd-substrate complex has a 13-membered ring.

"This ring is very flexible, which is key to its success, making it possible to put the Pd near the chiral scaffold," Lloyd-Jones says. "But this flexibility also causes the ligand to form oligomers, and in solution the oligomeric form is favored. That's made study of the monomer extremely difficult because it's such a vanishingly small component in the mixture. And yet it's that vanishingly small component that's the active catalyst. So to deduce its structure by NMR, we've had to use special techniques—such as deuterium labeling and special counterions to control oligomer-monomer ratios—and that's taken us a long time."

The effort was worth it, though, he says. With the new model, researchers can rationalize not only the ligand's enantioselectivity but also an important effect of counterions on selectivity.

"It's been known for a long time that as you change the M+ counterion of the nucleophile, the enantioselectivity changes a lot," Lloyd-Jones says. "People have never been able to satisfactorily explain that. Our model explains it because the more dissociating you make M+—as you go from Li+ to Na+ to K+ to Cs+—the better the nucleophile can H-bond and therefore the higher the enantioselectivity. That's exactly what's observed experimentally. It means you can now rationally optimize conditions to improve selectivity, rather than doing it via empirical screening."

The new mechanism is important because "there are cases where the ligand is not ideal, and it helps to see why that is so," Lloyd-Jones adds. "It shows you how to get the best from that ligand."

In the second study, transition-metal-catalyst specialist Hartwig and UIUC coworkers Sherzod T. Madrahimov and Dean Markovic structurally characterized and analyzed Ir-based, allylic substitution catalysts, which accelerate the formation of products with atomic connectivity complementary to that formed by Pd systems.

Hartwig's group began developing this class of catalysts in 2002. Ir catalysts, together with the Pd ones, allow researchers to dial in the product they will get with allylic substitution. With monosubstituted allylic ester substrates, Ir catalysts promote substitution reactions that produce branched products, and Pd-catalyzed substitutions give linear products.

According to Pfaltz, "Iridium-catalyzed allylation is still a relatively young reaction, but it has become a very powerful method for C–C and C-heteroatom bond formation. What makes it so useful is that it leads to branched chiral substitution products. But compared with Pd-catalyzed allylation, the mechanism was much less understood. Elucidation of the three-dimensional structure of the crucial allyl intermediate represents a breakthrough that gives important insights into the mechanism of this reaction and will allow a more rational approach to catalyst development."

Hartwig says he and his coworkers recently worked out a synthesis that will make the Ir catalysts "more widely available to the research community and to industry groups, but we have not yet scaled it up." Johnson Matthey Catalysts has licensed the Ir catalysts.

Now, after years of effort, Hartwig and coworkers have identified the intermediate that forms in Ir-catalyzed reactions. In addition, they have structurally analyzed it and have proposed a catalytic mechanism.


They generally use allylic esters as substrates in Ir-catalyzed reactions, which convert them into substitution products. To identify the intermediate and obtain its structure, they had to find a way to capture a nonreactive version of the catalyst-substrate complex.

By using allylic chlorides instead of allylic esters as substrates and then removing the chloride from the system, they were able to freeze the catalyst-substrate complex in the absence of any nucleophile, and this enabled them to successfully crystallize the complex. "That was by no means easy to do," Hartwig says. "It took a lot of experimental skill to figure out the right reagents and conditions that would allow the system to crystallize. Dean worked out the conditions to form the intermediate, and Sherzod obtained single crystals."

When they obtained the crystal structure, they were able to see the structure of the whole complex for the first time in the seven years they had been working on it. "We had no idea how the chirality of the ligand would transfer to the chirality of the product," Hartwig says. "This structure gave us a way to view how that transfer process occurs."

The catalyst complex consists of a five-membered ring that includes Ir, a chiral binaphthyl group, a cyclooctadiene, and the bound allyl substrate. Hartwig and coworkers find that a stereocenter in the five-membered ring controls the absolute stereochemistry of the product by causing the neighboring nitrogen-linked phenylethyl group to point toward the allyl substrate in the complex. They believe the phenylethyl group forces the allyl group to orient itself with its substituent toward the outside of the catalyst to avoid a steric clash.

"That controls the orientation at which the allyl group is bound and the catalyst's enantioselectivity," Hartwig says. "The nucleophile adds to the carbon that has the substituent, on the side of the molecule far from the controlling elements of the ligand.

"It's pretty intricate how the catalyst's asymmetry gets transferred from one point to another," Hartwig continues. "Without a structure, there would be no way to envision how that could happen. There are certainly limitations in reaction scope that we would like to overcome, and by knowing how the atoms are interacting in the structure—where there are steric clashes—we are hoping we'll be able to make changes to the structure to allow us to do the reaction with substrates that so far we haven't had success with."

Hartwig adds that "people often throw up their hands and say catalysis is too complicated, that you never know what the active species is, and that asymmetric catalysis is another level less decipherable" than achiral catalysis. "But I think the collaborative work by Guy and Per-Ola and by our group, among others, shows this is not true. We can figure out how these systems work and can learn from the information gained."


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