Chiral metal surfaces may help to manufacture pharmaceuticals

New research shows how metal surfaces that lack mirror symmetry could provide a novel approach towards manufacturing pharmaceuticals.

These ‘intrinsically chiral’ metal surfaces offer potential new ways to control chiral chemistry, pointing to the intriguing possibility of using heterogeneous catalysis in drug synthesis. Such surfaces could also become the basis of new biosensor technologies.

A chiral object, such as your hand, is one that cannot be superposed on its mirror image. Chirality is fundamental in biochemistry. The building blocks of life – amino acids and sugars – are chiral molecules: their molecular structures can exist in either “left-handed” or “right-handed” forms (or “enantiomers”).

A living organism may respond differently to the two enantiomers of a chiral substance. This is crucially important in the case of pharmaceutical drugs, where the therapeutic effect is often tied strongly to just one enantiomer of the drug molecule. Controlling chirality is therefore vital in pharmaceutical synthesis.

Research into controlling chiral synthesis focuses mainly on using homogeneous catalysts, where the catalyst is in the same phase as the reactants and products, such as a liquid added to a liquid-phase reaction. However, this poses significant practical challenges in recovering the valuable catalyst material from the mixture. To avoid this problem, an attractive alternative would be heterogeneous catalysis over a solid surface – the type of catalysis used in catalytic converters in car exhaust systems, as well as in industrial Haber-Bosch synthesis of ammonia and Fischer-Tropsch synthesis of synthetic fuel, for example. The question then is how to achieve enantiomer-specific effects at a surface.

To help answer this question, scientists at the University of Cambridge have been probing the spontaneous self-organization of a simple chiral amino acid, alanine, into regular molecular arrays on copper single-crystal surfaces. Thanks to a powerful scanning tunnelling microscope, capable of resolving individual atoms and molecules, their work is revealing the various manifestations of chirality that occur, giving important clues to how they arise, and how they might be controlled and exploited.

Dr Stephen Driver, of the Department of Chemistry at the University of Cambridge, who led the experimental work, said: “We set out to investigate two distinct scenarios. In one scenario, the surface is non-chiral, so any chirality that we see can only arise from the chirality of the alanine molecule. In the other scenario, we move to a surface that is intrinsically chiral. Now the question becomes: do the two enantiomers of alanine behave differently on this chiral surface?”

On the non-chiral surface, the researchers found that alanine can self-organise into either of two patterns. In one of these, the self-organisation is driven by hydrogen bonding between the molecules, while the chiral centre has no discernable impact on the regular array. In the other structure, a network of long-range chiral boundaries punctuates the array, and the boundary chirality switches with molecular chirality.

Driver explained: “The implication is that the chiral centre is having a direct influence on the packing of two alanine neighbours at the boundary, and that the chirality of this pair propagates to the next pair and the next and so on, so that the chiral boundary is built up over a long range.”

The chiral surface is created simply by choosing a surface orientation that lies away from any of the bulk mirror symmetry planes of the metal crystal. When the researchers added alanine, they found that the surface changes its local orientation, forming nanometre-scale facets. The two enantiomers of alanine self-organise into different chiral patterns: a strong, enantiomer-specific structural effect. This “proof of principle” could potentially be exploited in chiral recognition, in chiral synthesis (forming a chiral product from non-chiral reactants), and in chiral separations.

Driver added: “It looks like alanine can shape a comfortable, chiral bonding site for itself. The copper surface has the flexibility to adapt itself to the shape of the alanine molecule, and this shape is different for the two different molecular enantiomers.”

The results imply that certain surface orientations will form stable, ordered structures with one molecular enantiomer but not the other: exactly the right conditions to promote chiral chemical effects.

Professor Sir David King, former Chief Scientific Advisor to the UK Government and current Director of the Smith School of Enterprise and the Environment at Oxford, brought together the team carrying out this research. “These results are very exciting,” said King. “Tailoring the right surface to the right molecule should lead to strong enantiospecific effects. We see a real basis here for a breakthrough technology in the pharmaceuticals sector. It’s something that pharma companies should be taking a close interest in.”

The Cambridge team’s findings are published in Topics in Catalysis.

More information: Image credit: Steve Driver

Provided by University of Cambridge (news : web)

Chiral metal surfaces may help to manufacture pharmaceuticals; Novel approach could be used in pharmaceutical drug synthesis

New research shows how metal surfaces that lack mirror symmetry could provide a novel approach towards manufacturing pharmaceuticals.

These 'intrinsically chiral' metal surfaces offer potential new ways to control chiral chemistry, pointing to the intriguing possibility of using heterogeneous catalysis in drug synthesis. Such surfaces could also become the basis of new biosensor technologies.

A chiral object, such as your hand, is one that cannot be superposed on its mirror image. Chirality is fundamental in biochemistry. The building blocks of life -- amino acids and sugars -- are chiral molecules: their molecular structures can exist in either "left-handed" or "right-handed" forms (or "enantiomers").

A living organism may respond differently to the two enantiomers of a chiral substance. This is crucially important in the case of pharmaceutical drugs, where the therapeutic effect is often tied strongly to just one enantiomer of the drug molecule. Controlling chirality is therefore vital in pharmaceutical synthesis.

Research into controlling chiral synthesis focuses mainly on using homogeneous catalysts, where the catalyst is in the same phase as the reactants and products, such as a liquid added to a liquid-phase reaction. However, this poses significant practical challenges in recovering the valuable catalyst material from the mixture. To avoid this problem, an attractive alternative would be heterogeneous catalysis over a solid surface -- the type of catalysis used in catalytic converters in car exhaust systems, as well as in industrial Haber-Bosch synthesis of ammonia and Fischer-Tropsch synthesis of synthetic fuel, for example. The question then is how to achieve enantiomer-specific effects at a surface.

To help answer this question, scientists at the University of Cambridge have been probing the spontaneous self-organization of a simple chiral amino acid, alanine, into regular molecular arrays on copper single-crystal surfaces. Thanks to a powerful scanning tunnelling microscope, capable of resolving individual atoms and molecules, their work is revealing the various manifestations of chirality that occur, giving important clues to how they arise, and how they might be controlled and exploited.

Dr Stephen Driver, of the Department of Chemistry at the University of Cambridge, who led the experimental work, said: "We set out to investigate two distinct scenarios. In one scenario, the surface is non-chiral, so any chirality that we see can only arise from the chirality of the alanine molecule. In the other scenario, we move to a surface that is intrinsically chiral. Now the question becomes: do the two enantiomers of alanine behave differently on this chiral surface?"

On the non-chiral surface, the researchers found that alanine can self-organise into either of two patterns. In one of these, the self-organisation is driven by hydrogen bonding between the molecules, while the chiral centre has no discernable impact on the regular array. In the other structure, a network of long-range chiral boundaries punctuates the array, and the boundary chirality switches with molecular chirality.

Driver explained: "The implication is that the chiral centre is having a direct influence on the packing of two alanine neighbours at the boundary, and that the chirality of this pair propagates to the next pair and the next and so on, so that the chiral boundary is built up over a long range."

The chiral surface is created simply by choosing a surface orientation that lies away from any of the bulk mirror symmetry planes of the metal crystal. When the researchers added alanine, they found that the surface changes its local orientation, forming nanometre-scale facets. The two enantiomers of alanine self-organise into different chiral patterns: a strong, enantiomer-specific structural effect. This "proof of principle" could potentially be exploited in chiral recognition, in chiral synthesis (forming a chiral product from non-chiral reactants), and in chiral separations.

Driver added: "It looks like alanine can shape a comfortable, chiral bonding site for itself. The copper surface has the flexibility to adapt itself to the shape of the alanine molecule, and this shape is different for the two different molecular enantiomers."

The results imply that certain surface orientations will form stable, ordered structures with one molecular enantiomer but not the other: exactly the right conditions to promote chiral chemical effects.

Professor Sir David King, former Chief Scientific Advisor to the UK Government and current Director of the Smith School of Enterprise and the Environment at Oxford, brought together the team carrying out this research. "These results are very exciting," said King. "Tailoring the right surface to the right molecule should lead to strong enantiospecific effects. We see a real basis here for a breakthrough technology in the pharmaceuticals sector. It's something that pharma companies should be taking a close interest in."

The Cambridge team's findings are published in Topics in Catalysis.

Story Source:

The above story is reprinted from materials provided by University of Cambridge. The original story is licensed under a Creative Commons license.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Marian L. Clegg, Leonardo Morales de la Garza, Sofia Karakatsani, David A. King, Stephen M. Driver. Chirality in Amino Acid Overlayers on Cu Surfaces. Topics in Catalysis, 2011; DOI: 10.1007/s11244-011-9758-y

Scientists find easier, cheaper way to make a sought-after chemical modification to pharmaceuticals

Scientists at The Scripps Research Institute have devised a much easier technique for performing a chemical modification used widely in the synthesis of drugs and other products.

Known as "trifluoromethylation," the modification adds a CF3 molecule to the original compound, often making it more stable -- and, for a drug, keeping it in the body longer. With the new technique, chemists can perform this feat using a relatively simple, safe, room-temperature procedure and can even select the site of the modification on the target compound.

"I've been presenting this methodology at several pharma companies, and there's a lot of interest -- so much so that their chemists are starting to use it," said Scripps Research Professor Phil S. Baran, senior author of the new study, scheduled for publication the week of August 15, 2011, in an advance online edition of the Proceedings of the National Academy of Sciences.

Standard procedures for trifluoromethylation involve gases and associated hardware, high heat, metal catalysts, and oxidants. "The procedures are often prohibitively complicated, and medicinal chemists often don't have the time or the resources to get into it," said Baran.

Inspired by frequent consulting visits to pharmaceutical companies, Baran and his lab began to look for simpler ways to perform trifluoromethylation. After running more than 500 different reaction setups on a test compound, they found just one that delivered significant quantities of the desired reaction product. It was a simple setup that used a reagent known as sodium trifluoromethanesulfinate, an inexpensive chemical that is stable at room temperature.

Chemists had long believed that this reagent was unsuitable for trifluoromethylating a broad class of molecules frequently found in drug compounds, and also that the reagent required the use of catalyzing metal salts. But in this initial screening, the reagent, known as Langlois's reagent for its discoverer, the French chemist Bernard R. Langlois, seemed to work even without such constraints.

Baran and his team began collaborating with fellow Scripps Research chemistry Professor Donna Blackmond and members of her laboratory to study how Langlois's reagent works and to optimize its use, including the selection of trifluoromethylation sites on target compounds using certain solvents. With the optimized technique, they showed that they could directly and easily trifluoromethylate a variety of test compounds, including the natural malaria drug quinine and the synthetic anti-smoking drug varenicline (Chantix).

"The collaboration with Donna Blackmond and her lab was crucial in enabling us to improve the procedure and to understand why certain modifications led to those improvements," said Baran.

The new technique in principle makes it more feasible for pharmaceutical companies to modify and improve specific drug compounds of interest. It also means that these companies can expand the existing compound libraries they use for drug-discovery screening by making trifluoromethylated versions of these compounds quickly and easily.

"In one instance, a chemist at Pfizer told me that the trifluoromethylated compound we made in one step with our technique would have taken at least eight steps using standard techniques," said Baran.

The Baran and Blackmond labs are now working on new reagents that may be used in this reaction and ways to enable fine control of trifluoromethylation sites. "The interplay of the two labs at the nexus of synthesis and mechanistic analysis is driving this project forward in new and exciting directions," Baran said.

The two first authors of the paper, "Innate C-H Trifluoromethylation of Heterocycles," are Yining Ji and Tobias Brueckl of the Scripps Research Baran lab. Others who contributed are Ryan D. Baxter of the Scripps Research Blackmond lab and Yuta Fujiwara, Ian B. Seiple, and Shun Su of the Baran lab.

The work was supported in part by a grant from the National Institute of General Medical Sciences, part of the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by The Scripps Research Institute.

Journal Reference:

Yining Ji, Tobias Brueckl, Ryan D. Baxter, Yuta Fujiwara, Ian B. Seiple, Shun Su, Donna G. Blackmond, Phil S. Baran. Innate C-H trifluoromethylation of heterocycles. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1109059108