George A. Kraus
Organic Synthesis, Bioagricultural Chemistry, Toxicology
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Research Interests
Our approach to total synthesis involves first the creation of generally-useful methodology for natural product subunits (such as quinones or lactones) which are common to a variety of natural products. This methodology is then applied to those compounds for which it is most appropriate. The development of methods for quinone synthesis has led to highly efficient and regioselective syntheses of pyranonaphthoquinones. The development of reactive bridgehead intermediates has led to direct syntheses of lycopodine and modhephene. The study of the stereoselectivity of the Norrish type II photocyclization has led to an expedient synthesis of paulownin, a biologically-active lignan. The more recent studies on the chemistry-virology interface have led to an interesting chemotherapeutic approach termed the "molecular flashlight".
Hydrogen Abstraction Reactions (see publications 92, 93, 104, 113, 117, 160, 193).
A major drawback of the photochemical hydrogen atom abstraction-cyclization reaction is the lack of stereoselectivity in the cyclization of the biradical. By appending the reaction centers onto a rigid ring system, we have been able to achieve excellent stereoselectivity in the closure to a bicyclic ring system. This concept has been employed in a direct total synthesis of the biologically active lignan paulownin. We also employed the type II photocyclization reaction in a direct synthesis of podophyllotoxin and in a clever approach to the pleurotin ring system.
Hydrogen atom abstraction reactions proceeding via many-atom transition states have been developed by Breslow and others. However, hydrogen atom abstraction reactions which proceed by medium-ring transition states are comparatively rare. In the course of examining photochemical strategies for the initiation of radical cyclizations, we discovered several novel 1,9-hydrogen atom abstraction reactions. Their working hypothesis is that the more stable syn conformation of the ester is the key control element which favors 1,9-hydrogen atom abstraction which leads to the synthesis of an eight-membered ring lactone. The hydroxy lactones produced in this reaction are attractive intermediates for the preparation of natural products with the oxocene ring system.
Pollution Prevention via Photochemistry (see publications 135, 140, 151, 169, 173, 181).
Pollution prevention requires a careful rethinking of the ways in which chemists and engineers design organic reactions. Almost all of the reactions and processes in use industrially have the potential to be made more benign. Of particular importance are the subset of reactions that employ toxic reagents, catalysts, or solvents. In order to replace existing processes, the benign alternatives must be efficient, inexpensive and amenable to scale up. Among the candidates as reagents for benign chemistry are 1. enzymes, 2. recyclable catalysts such as molecular sieves, 3. electricity, and 4. sunlight.
The goal of our research program is to develop photochemical alternatives to reactions that produce pollutants. The use of visible light has the advantage that excess reagent is dissipated as thermal energy. Photochemistry has been used on an industrial scale for years. We have focussed initially on benign alternatives to the Friedel-Crafts acylation reaction. The Friedel-Crafts acylation reaction is presently utilized industrially for the synthesis of a number of important chemicals, including pharmaceuticals such as the benzodiazepines.
This reaction is one for which a benign alternative would have significant impact on pollution prevention. In most cases one component is an acid chloride or anhydride. These compounds are corrosive and air sensitive. Exposure of acid chlorides to water produces HCl gas. Many of the Lewis acids used to mediate the reaction (e.g. aluminum chloride, stannic chloride and boron trifluoride) are also corrosive and react vigorously with water. Typical solvents for the Friedel-Crafts reaction include aromatic hydrocarbons, nitrobenzene, carbon disulfide and methylene chloride. Each of the aforementioned solvents presents concerns related to safe handling and disposal.
The subset of Friedel-Crafts reactions for which our photochemical alternative will be most directly applicable is depicted below. The typical Friedel-Crafts reaction used today is also shown. The photochemical alternative has the advantage of atom economy as well as the advantage of using reagents that are stable to air and water. In principle, the benzoquinone might someday be produced using the benign technology recently developed by Frost and coworkers.
The advantages of the photochemical alternative include atom economy, convenient and stable starting materials, and generality with regard to the aldehyde component. A major facet that needs attention if this reaction can truly be considered benign is the solvent. Presently, hydrocarbon solvents or acetonitrile are employed. The reaction fails in water, probably a consequence of the insolubility of the starting materials.
An alternative would be to conduct the reaction in a supercritical solvent such as supercritical carbon dioxide. This possibility has clear advantages in terms of the ease of product isolation. The photochemical reactions described above have been shown to occur in supercritical carbon dioxide. This work is being done in collaboration with Professor James Tanko at the Virginia Polytechnical Institute.
Novel Control of Regioselectivity in Cycloaddition Reactions (see publications 54, 127, 128, 132, 141)
As part of a program to evaluate the directing effects of functional groups not directly attached to the atoms involved in the cycloaddition reaction, we discovered the highly regioselective Diels-Alder reaction shown below. The allylic ester moiety on the diene appears to control the
excellent regioselectivity, since the corresponding alcohol or methyl ether furnished essentially a 1:1 mixture of regioisomeric adducts.
We recently reported that remote substituents on a dienophile can also confer excellent regioselectivity in Diels-Alder reactions. This work has led to the first synthesis of frenolicin B.
In order to better understand the role of the ring substituents on the regioselectivity of the Diels-Alder reaction discussed above, the molecular geometries were optimized without symmetry constraints at the AM1 level of theory. The RHF/6-31G(d) wavefunctions were then used to calculate molecular electrostatic potential contour map which identifies relative positively and negatively charged regions of the molecule. All calculations were performed in collaboration with Professor Mark Gordon. The contour map indicates that the incoming diene should prefer to react from below the plane of the ring with the OTMS substituent away from the butyrolactone ring. This provides a rationale for the observed regioselectivity.We have reecently shown that molecular electrostatic potential maps can be used to predict the effects of remote substituents on electrophilic additions to alkenes.
A Molecular Flashlight (publications 101, 102, 109, 136, 150, 151, 162, 163, 185)
Hypericin is a naturally occurring polycyclic quinone which has been shown to exhibit potent activity against enveloped viruses and certain cancers, reducing the infectivity of cell-free stocks of virus by 99.99% . Our group in collaboration with Dr. Carpenter, a microbiologist, was the first to report that light was required for the antiviral activity of hypericin. The requirement for light activation will permit the development of a drug which will target only virus-infected cells. An expedient choice for the light source is luciferin. The reaction of luciferin with the enzyme luciferase and molecular oxygen produces light in the 520-680 nm region with a quantum efficiency of about unity. Hypericin absorbs light strongly in this range. In vitro experiments have shown that energy transfer between the product of the chemiluminescent reaction and hypericin results in significant antiviral activity.
Our finding that hypericin can be activated by chemiluminescent reactions has important implications for the development of novel methods for the treatment of disease. In vivo generation of luciferase could be accomplished using gene therapy approaches that employ luciferase as a susceptibility gene. Expression of the luciferase gene could be regulated if placed under the control of a tumor-specific promoter, limiting photoactivation of hypericin to cancer cells (or virus-infected cells). This would result in a "molecular flashlight" in which light is turned on or off, depending on the presence of the transacting viral protein. In order to avoid the problems inherent in requiring three separate units to come together in the virus-infected cell, we covalently connected hypericin and luciferin. This tethered molecule, when added to virus-infected cells that contain the luciferase gene, has recently been shown to be highly effective in reducing viral infectivity.
