The development of a new pharmaceutical agent often requires screening thousands of compounds. Such compounds are typically derived from high-throughput syntheses, which tend to focus on simple transformations. For this reason, so called ?flat? compounds, made from aromatic rings coupled together, predominate medchem libraries. However, molecules in these libraries stand in contrast to most naturally occurring, biologically active compounds, which have well-defined three-dimensional structures, rich in carbon stereocenters, adapted for specific and selective interactions with receptors. Since more complex molecules are better able to optimally fill space in their binding sites, molecular complexity strongly correlates with clinical success. Thus, a limited scope of synthetic methods used in discovery chemistry has led to an overpopulation of certain types of molecular shapes and properties to the exclusion of others. The challenge is to generate new classes of compounds with both diversity and complexity in a manner that is accessible to medicinal chemists. Such methodologies would open new, more prolific chemical space for exploration in both traditional SAR studies and the generation of fragment libraries. This proposal describes an approach to building cyclohexanes with multiple stereocenters derived from simple benzene precursors. The otherwise inert benzene scaffold is chemically enabled through its dihapto-coordination to a tungsten complexing agent. In the proposed study, we will assess the ability of {WTp(NO)(PMe3)} to activate electrophilic addition and nucleophilic addition reactions with a high degree of regio- and stereochemical control.
Aim 1 focuses on the conversion of the ?2-benzene complex to chiral ?2-1,3-cyclohexadiene complexes.
Aim 2 explores the conversion of these ?2-1,3-cyclohexadienes to highly functionalized ?2-cyclohexene complexes.
Aim 3 is concerned with elaboration of these cyclohexene complexes into a wide variety of cyclohexanes, decorated with amine, alcohol, and carboxylate functionalities.
Aim 4 evaluates the effects of a single substituent on an ?2-benzene substrate. And finally, whereas the first four sections of this proposal explore the potential of creating molecular diversity using nucleophiles, Aim 5 focuses on the strategic use of carbon electrophiles. This dearomatization methodology will open more fertile chemical space-- fragment libraries that feature a diverse range of complex three-dimensional architectures with many of the functional groups common to proven pharmaceuticals. This approach not only increases the chances for finding new lead-like compounds for pharmaceutical development with increased affinity for a targeted binding site, but more importantly, increased specificity for that site.
The goal of the proposed research plan is to develop new classes of chemical compounds to be screened for efficacy against various diseases. The synthetic approach, which involves a tungsten-activated benzene substrate, is fundamentally unique and allows access to new compounds with widely diverse shapes that are rich in amines, alcohols, and carboxylates- groups that are ubiquitous in pharmaceutical agents. Access to such compounds improves the chances for the discovery and development of new medicines to improve public health.
