May 6, 2014

DTRA's JSTO in the News highlighted Professor Ken Houk and colleagues' work on the publication, "Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad."

Defense Threat Reduction Agency's (DTRA) Chemical and Biological Technologies Department Courtesy Story
 
FORT BELVOIR, Va. - Knowledge of quantum mechanics and the practical application of designs at the sub-atomic level could soon provide a new class of rationally designed, synthetic catalysts that would protect warfighters against chemical and biological threats quicker and more efficiently. 
 
A DTRA CB/JSTO-funded research effort, managed by Dr. Ilya Elashvili, DTRA CB, and carried out by Drs. Christian Schafmeister of Temple University and Kendall Houk of the University of California, Los Angeles, has accomplished a series of catalytic reactions using small, non-natural, shape-programmable scaffolds called “spiroligomers.” This opens up the way to address a much larger issue: How to develop catalysts for chem-bio defense, such as nerve agent degradation. 
 
The transition state model of the aromatic Claisen rearrangement was inspired by the active site of the enzyme Ketosteroid Isomerase (KSI). (A) The model, which was optimized using quantum mechanics calculations to
accelerate the Claisen rearrangement reaction, by presenting a carboxylic acid and a phenol group to simultaneously donate two hydrogen bonds and stabilize the negative charge that transiently builds up on the oxygen (labeled ∂-, the oxyanion). (B) The superposition of the most active spiroligomer based catalyst (compound 1, gold) onto the active site of KSI (in green). Similar to the model, KSI presents a carboxylic acid and a phenol to stabilize the negatively charged enolate oxyanion (∂-) that forms during the catalyzed isomerization of “3-oxo-Δ5-steroid.” (Courtesy by Drs. Christian Schafmeister, Temple University and American Chemical Society)
 
In a recent Journal of American Chemical Society (JACS) article, “Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad,” the scientists reported the development of a catalyst that accelerates an important carbon-carbon bond forming reaction called the aromatic Claisen rearrangement. Ever since its discovery more than 100 years ago, the aromatic Claisen rearrangement reaction has served as a model reaction towards the understanding of how enzymes work because enzymes accelerate this unimolecular reaction with a relatively simple, single transition state. 
 
The aromatic Claisen rearrangement breaks a carbon-oxygen (C-O) bond while simultaneously forming a carbon-carbon (C-C) bond (Figure 1A). As the C-O bond breaks and the C-C bond forms, a negative charge transiently builds up on the oxygen, labeled ∂-. The isolated negatively charged oxygen is a high-energy species and the primary reason why the reaction is slow. 
 
The catalyst was developed by the Schafmeister/Houk groups to accelerate this reaction. They used the active site of the enzyme Ketosteroid Isomerase (KSI) as a starting point for the design based on its ability to stabilize a similar transient negative charge on an oxygen atom (Figure 1B). From this structure, the Houk group designed an optimal model of the catalyst using quantum mechanical calculations. The Schafmeister group constructed a series of molecules based on their spiroligomer chemistry that mimicked the presentation of the carboxylic acid and the phenol as hydrogen bond donors to stabilize the oxyanion. They then demonstrated that the synthetic catalysts that best mimicked the designed model generated the largest accelerations of the reaction. 
 
This work demonstrated that the essential catalytic activity of the active site of a large enzyme could be mimicked by the proper presentation of just a few active site residues on a small, pre-organized spiroligomer scaffold that is forty times smaller than the enzyme. 
 
The Claisen catalyst that the Schafmeister/Houk group developed is the first synthetic Claisen catalyst that uses O-H (oxygen-hydrogen) hydrogen bond donors to stabilize oxyanions similar to natural enzymes. 
 
These efforts started five years ago after the Schafmeister group showed a method that synthesizes shape-programmable spiroligomer macromolecules. Since then, the team reported DTRA CB-funded successful work that introduced functional groups at predetermined sites into the scaffold and the ways to create larger and more elaborate structures, enabling the design of two catalysts: a proline-based aldol catalyst (see the JACS article, “Hydrophobic Substituent Effects on Proline Catalysis of Aldol Reactions in Water”) and a transesterification catalyst (see the JACS article, “Spiroligozymes for Transesterifications: Design and Relationship of Structure to Activity”). 
 
This latest effort will be the third DTRA CB-funded catalyst for the aromatic Claisen rearrangement. 
 
Going forward, the Schafmeister and Houk groups plan to construct much larger spiroligomer scaffolds within which more complex active sites can be displayed based on the ideas developed in these earlier works.
 
For more articles from this edition of JSTO in the News, click here: http://www.dvidshub.net/publication/issues/15634