Laboratory of Joseph M. Ready
Department of Biochemistry
University of Texas Southwestern Medical Center
Dallas, Texas

The Ready group is engaged in the discovery and application of new chemical reactions and the total synthesis of complex molecules.

The combined effect of three recent developments has created an enormous challenge and a fantastic opportunity for synthetic chemistry. First, the sequencing of the human genome has revealed a huge number of genes associated with human diseases, and the corresponding proteins represent potential drug targets. Second, the development of high-throughput screening methods has given scientists the ability to evaluate large collections of small molecules quickly and accurately. Finally, solid phase synthesis has been revolutionized by new techniques and equipment such that it is now possible to synthesize large libraries of defined molecules in usable quantities. Taken together, the situation facing pharmaceutical companies and academic researchers alike is that we have a platform to access many molecules, and means to test their effect on specific, relevant cellular targets. The great challenge now facing chemistry and, I believe, all of biomedical science, is the need for chemical reactions and protocols that are reliable, predictable and efficient. It is only through the development of such reactions that we can create the molecular diversity required to combat human diseases. Currently, only a limited number of reactions proceed selectively and quantitatively with a broad range of substrates. Thus the preparation of new compounds continues to be one of the slowest steps in drug discovery.

My research program seeks to address the need for new, reliable and general chemical reactions. We are interested in all areas of reaction development, including discovery, application and mechanistic study. Our research is focused on two primary areas of inquiry: the discovery of new reactions and target-oriented synthesis. In the context of reaction discovery, we are studying problems in organometallics, asymmetric catalysis and the chemistry of carbenes. Current research is directed toward the discovery of a catalytic system for enolate alkylation and the development of cycloadditions for the enantioselective synthesis of five-membered rings. Simultaneously, synthetic studies on natural products are guided by an interest in novel approaches to polycyclic skeletons. Target selection is influenced equally by issues of molecular complexity and biological activity. We anticipate that the combination of these efforts will greatly expand the power of organic chemistry and enable the rapid and efficient synthesis of valuable complex molecules.

More information regarding research projects is given below.

Methods Development

Synthesis of a-branched carbonyl compounds

No general catalyst exists for the alkylation of ketones.
No general procedure exists for the enantioselective synthesis of a-branched ketones.

We have initiated a project to develop an asymmetric, catalytic synthesis of a-branched ketones. Initial efforts toward this objective have led to the discovery of a stereospecific cross-coupling of a-chloro carbonyl compounds with alkyl zinc halides:

Regio- and Stereoselective carbometalation reactions

Carbometalation reactions represent a fundemental approach to C-C bond formation. We are interested in carbometalation of alkynes and olefins. In these studies the principle concerns relate to control over stereochemistry and regiochemistry. Our exploration has led to the discovery of a tandem carbometalation/oxygenation of terminal alkynes. The intermediate enolate can be trapped in various ways to give useful products:

Complex Molecule Synthesis

We are interested in developing stereocontrolled syntheses of complex, biologically active molecules. Synthetic studies provide a platform for the development and evaluation of new synthetic methods. Targets are chosen based on consideration of structural elements including quaternary stereocenters, multiply-substituted rings and reactive functional groups. The biological activity of synthetic products will be explored in collaboration with other groups in the biochemistry department. We have recently completed the synthesis of several nigellamine alkaloids. These diterpene natural products show potent lipid metabolism-promoting activity. Our synthetic approach featured an asymmetric intramolecular allylic alkylation, a Cr-mediated macrocyclization and the use of a chiral non-racemic catalyst to effect site and stereoselective epoxidation.

Our curretn efforts are aimed at understanding the biological activity of the nigellamine alkaloids. To this end we are collaborating with the Horton and Russell Groups at UTSW.