Publications

The tungsten fragment \WTp(NO)(PMe3)\ (Tp = trispyrazolylborate) is an effective dearomatization agent for benzene and its derivatives. The dihapto-coordination of this system to an arene disrupts its aromatic stability, thereby promoting facile electrophilic additions to the hydrocarbon, which can then be followed by the addition of nucleophiles. This preliminary study endeavors to extend this conceptual approach to other aromatic and antiaromatic carbocycles. Dihapto-coordinated complexes of $η$2-tropylium, $η$2-cyclopentadienyl cation, and $η$2-cyclooctatetraene have been synthesized and characterized using SC-XRD, DFT, CV, and 1H, 31P, and 13C NMR (including COSY, NOESY, HSQC, HMBC). Their fluxional behavior and reactivity toward electrophilic/nucleophilic additions, such as protonation and methylation, are also demonstrated.

The Diels—Alder reaction of benzenes remains a significant synthetic challenge, owing to their highly stabilized aromatic cores. In this work, the dearomatization agent \WTp(NO)(PMe3)\ is used to promote Diels—Alder reactions of dihapto-coordinated ($η$2) benzenes with alkynes. The resulting $η$2-barrelene complexes can be oxidized to liberate intact barrelenes. Alternatively, mild pyrolysis leads to the extraction of the corresponding tungsten-acetylene complex and concomitant formation of new arenes possessing substituents originating from the acetylene dienophiles.

Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d0—d8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H-/D- and H+/D+. The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro-methylphenidate were also prepared.

For nearly a century, chemists have explored how transition-metal complexes can affect the physical and chemical properties of linear conjugated polyenes and heteropolyenes. While much has been written about higher hapticity complexes ($η$4—$η$6), less is known about the chemistry of their $η$2 analogues. Herein, we describe a general method for synthesizing 5,6-$η$2-(1-azatriene) tungsten complexes via a 6$π$-azaelectrocyclic dihydropyridine ring-opening that is promoted by the $π$-basic nature of \WTp(NO)(PMe3)\. This study includes detailed spectroscopic and crystallographic data for the $η$2-dihydropyridine and $η$2-1-azatriene complexes, both of which were prepared as single regio- and stereoisomers.

Medicinal chemists use vast combinatorial molecular libraries to develop leads for new pharmaceuticals. The syntheses of these compounds typically rely on coupling molecular fragments through atoms with planar (sp2) geometry. These so-called flat molecules often lack the protein binding site specificity needed to be an effective drug. Here, we demonstrate a coupling strategy in which a cyclohexene is used as a linker to connect two diverse molecular fragments while forming two new tetrahedral (sp3) stereocenters. These connections are made with the aid of a tungsten complex that activates anisole toward an unusual double protonation, followed by sequential nucleophilic additions. As a result, either cis- or trans-disubstituted cyclohexenes can be prepared with a range of chemical diversity unparalleled by other dearomatization methods. Three sequential nucleophilic additions provide cis and trans cyclohexenes with structural complexity.

Friedel-Crafts Arylation (the Scholl reaction) is the coupling of two aromatic rings with the aid of a strong Lewis or Brønsted acid. This historically significant C–C bond forming reaction normally leads to aromatic products, often as oligomeric mixtures, dictated by the large stabilization gained upon their rearomatization. The coordination of benzene by a tungsten complex disrupts the natural course of this reaction sequence, allowing for Friedel-Crafts Arylation without rearomatization or oligomerization. Subsequent addition of a nucleophile to the coupled intermediate leads to functionalized cyclohexenes. In this work, we show that by coordinating benzene to tungsten through two carbons (dihapto-coordinate), a rarely observed double protonation of the bound benzene is enabled, allowing its subsequent coupling to a second arene without the need of a precious metal or Lewis acid catalyst.

Abstract Reactions are described for complexes of the form WTp(NO)(PMe3)(?2-arene) and various amines, where the arene is benzene or benzene with an electron-withdrawing substituent (CF3, SO2Ph, SO2Me). The arene complex is first protonated to form an ?2-arenium species, which then selectively adds the amine. The resulting ?2-5-amino-1,3-cyclohexadiene complexes can then be subjected to the same sequence with a second nucleophile to form 3-aminocyclohexene complexes, where up to three stereocenters originate from the arene carbons. Alternatively, 1,3-cyclohexadiene complexes containing an ester group at the 5 position (also prepared from an arene) can be treated with acid followed by an amine to form trisubstituted 3-aminocyclohexenes. When the amine is primary, ring closure can occur to form a cis-fused bicyclic ?-lactam. Highly functionalized cyclohexenes can be liberated from the tungsten through oxidative decomplexation. The potential utility of this methodology is demonstrated in the synthesis of the alkaloid ?-lycorane. An enantioenriched synthesis of a lactam precursor to ?-lycorane is also described. This compound is prepared from an enantioenriched version of the tungsten benzene complex. Regio- and stereochemical assignments for the reported compounds are supported by detailed 2D-NMR analysis and 13 molecular structure determinations (SC-XRD).