Functionalization of Benzene and its Derivatives by Coordination to a Tungsten Dearomatization Agent

Wilson, Katy, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Harman, W. Dean, Department of Chemistry, University of Virginia

As the efficiency of identifying promising pharmaceutical leads has increased with the use of high throughput bioassays and small-molecule libraries, innovative synthetic methods are sought to keep up with the synthetic challenges of medicinal chemistry and facilitate the stereocontrolled synthesis of novel molecular scaffolds. Traditionally, these types of high throughput bioassays have focused on maximizing the quantity of compounds tested, with less focus on the topological diversity of the library. With the emphasis on the quantity of small molecules, those that make up medicinal chemistry libraries tend to be compounds that are relatively easy to access by traditional synthetic methods.1 Among these methods include C-C coupling reactions between aromatic molecules, as well as SNAr reactions, with the result that overall, the types of compounds tested are predominantly “flat” molecules. This is in contrast to the structural complexity observed in biologically active natural products, which often contain many stereocenters and have long been the targets of synthetic chemists.
In a recent report, Brown et. al. attributed the deficiency in the structural diversity of many medicinal chemistry libraries to the scarcity of new synthetic methods, citing that none of the most used methods were discovered in the last 20 years.1 To this end, new synthetic methods are sought to rapidly access novel molecular scaffolds and address the increasing demand for synthetic innovation in drug discovery chemistry.
Dearomatization provides a powerful synthetic methodology that facilitates the rapid and atom efficient transformation of planar aromatic compounds into more complex alicyclic systems. Aromatics are attractive starting materials for synthetic chemists due to their abundance, low cost, and cyclic structure with multiple sites of unsaturation available for functionalization. However, the inherent stability of aromatic systems renders this class of compounds unreactive towards addition reactions under most conditions. This aromatic stability can be overcome through coordination to an electron-rich metal complex, which coordinates the aromatic through just two of the carbons (η2-coordination). This type of coordination has facilitated novel synthetic transformations with aromatics by breaking the aromaticity and unlocking the latent alkene functionality within the cyclic systems.
The dearomatization chemistry afforded by the potent π-basic {TpW(NO)(PMe3)} fragment has enabled the synthesis of a range of novel alicyclic small molecules starting from simple aromatic precursors such as aniline, phenol, anisole, pyridines, naphthalene, furan, and pyrroles. Recently, we demonstrated the synthesis of a diverse range of chiral functionalized cyclohexenes, starting from simple benzene and its derivatives with a high degree of regio- and stereocontrol. This chemistry could find synthetic use as a means of accessing desymmetrized compounds with absolute stereochemistry defined, to be used as important precursors for further organic elaborations. But in addition to this function, our chemistry provides a unique opportunity to access novel molecular frameworks. We have demonstrated a diverse range of metal-facilitated cyclization reactions, leading to novel lactams, tetrahydrobenzimidazoles, isoquinolines, and other nitrogen heterocycles. Furthermore, we have demonstrated the ability to coordinate aromatic nitrogen heterocycles and transform them into more complex alicyclic systems.
Within the last few years, the enantioenrichment of the tungsten fragment was reported, utilizing a chiral acid to form diastereomers of the dimethoxybenzene complex, which were separated based on disparate solubilities. This enrichment method was optimized to allow access to both enantiomers of the tungsten complex starting from the racemic η2-1,3-dimethoxybenzene complex. Furthermore, we have demonstrated the stereocontrolled synthesis of chiral cyclohexenes originating from benzene and α,α,α-trifluorotoluene with ee’s ranging from 86-99% using this enrichment procedure.

1. Brown, D. G.; Boström, J. Journal of Medicinal Chemistry 2016, 59, 4443.

PHD (Doctor of Philosophy)
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