Thursday, April 3, 2025
4/3/2025
Rapid Synthesis of Topologically Complex Molecules with Tungsten Dearomatization Agents - Project Summary/Abstract The development of a new pharmaceutical agent often requires the screening of millions of compounds. Such compounds are typically derived from high-throughput syntheses, which tend to utilize a relatively small set of reliable reactions. The 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. Research in the Harman group concentrates on the preparation of stereochemically complex alicyclic compounds derived from simple aromatic precursors. While previous studies from our group have included dearomatization of pyridine, furan, and pyrrole heterocycles, this MIRA application describes the preparation of functionalized cyclohexenes from benzene. The otherwise inert benzene ring is chemically enabled through its dihapto-coordination to the tungsten complexing agent {WTp(NO)(PMe3)}. Over the next five years we will explore the full range of nucleophilic and electrophilic fragments that can be added to a benzene core, as enabled by this tungsten complex. Specifically, we describe in this application the development of a general route to the addition of so-called π-nucleophiles , such as phenols, anisoles, furans, thiophenes, and indoles, generating new sp3 stereocenters from the benzene ring carbons. Further, we are targeting the addition of more complex nitrogen-based functional groups including amides, imides, sulfonamides, uracils, carbazoles, and triazoles. Significantly, these nitrogen additions to the benzene ring that create new stereocenters are practically unknown. Another research thrust in the next five years will be to surgically manipulate the regiochemistry and stereochemistry of the cyclohexene targets, developing general routes to 3,4- 3,5- and 3,6- disubstituted cyclohexenes with either cis- or trans- configurations. A third major thrust will be the assembly of polycyclic cores with well-defined stereochemistry. Using the foundations that we have developed, we are pursuing several different approaches to structurally complex and biorelevant tri- and tetracyclic lactams and lactones. The ultimate goal of our program is to provide access to a broad and diverse class of enantioenriched organic cyclohexenes and cyclohexanes, all prepared from a single, logical, and highly modular platform. 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.
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