Publications

Prior work with the dearomatization agent [WTp(NO)(PMe₃)] (Tp = trispyrazolylborate) has demonstrated the ability to synthesize cis, cis−3,4,6 trisubstituted cyclohexenes from phenyl sulfones. Herein, the compatibility of these methods with sulfur nucleophiles was investigated for the synthesis of sp³-enriched thioether- and thioacetate-functionalized cyclohexenes. Protonation of the WTp(NO)(PMe₃)(η²-PhSO₂Me) complex followed by addition of a sulfur nucleophile was only successful for a thioacetate salt. However, when the first nucleophile was an ester enolate, subsequent protonation and nucleophilic addition successfully yielded a range of cyclohexene complexes with thioacetate, thiol, and sulfonyl substituents. Oxidative decomplexation of these complexes liberated the corresponding cyclohexene products. This strategy was then applied to the synthesis of a thioglycolate ester functionalized tetrahydrophenanthridinone.

Heteropolycyclic frameworks are widely represented in biologically and pharmaceutically relevant compounds; however, methods to synthesize these frameworks often result in heterocycles containing predominantly sp²-hybridized carbons. Herein we describe a heteroannulation scheme featuring a double protonation of a tungsten η²-anisole complex. The resulting dicationic intermediate reacts with activated arenes through an electrophilic aromatic substitution reaction to form an oxocarbenium complex, which can be reduced to an allylic ether complex. Subsequent acidolysis results in a π-allyl complex that can react with alcohol or amine substituents of the activated arene reagent to form the desired heteropolycyclic core.

Despite advances in reactions such as hydrogen isotope exchange (HIE) and reductive deuteration, achieving controlled and selective deuteration remains challenging. Moreover, the difficulty of developing successful deuteration platforms is compounded by a lack of means to assess the stereoisotopic purity of deuterated products. We previously reported a highly regio- and stereoselective approach for generating semideuterated cyclohexenes via tandem protonation (H⁺/D⁺) and reduction (H^–/D^–) sequences of a dihapto-coordinate tungsten-benzene complex. While NMR and HRMS analyses suggested successful deuterium incorporation, molecular rotational resonance (MRR) spectroscopy identified numerous over-, under-, and mis-deuteration impurities. At the time of publication, these impurities were attributed to H/D scrambling that could occur during thermolysis of the tungsten-bound cyclohexene ligand prior to MRR analysis. In this work, we describe the analysis of semideuterated cyclohexenes using MRR spectroscopy with an improved thermolysis apparatus that eliminates deuterium scrambling during analysis. Quantitative analysis of both racemic and enantiopure samples enables the optimization of deuteration conditions by providing multiple mechanistic insights into the formation of impurities.

cis-Tetrahydro-2-oxindoles are valuable scaffolds in medicinal chemistry. Herein, we report a transition-metal-mediated dearomatization strategy to access these compounds. The process begins with the coordination of a phenyl sulfone by a tungsten complex designed to bind two carbons of the phenyl ring, rendering it dearomatized. This is followed by protonation of the η²-bound arene followed by the addition of an ester nucleophile. The resulting η²-diene complex then undergoes a second protonation in the ring, and a primary amine is introduced. Dihydro-2-oxindole complexes form spontaneously through the construction of a γ-lactam and the elimination of a sulfinic acid. Dihydro-2-oxindoles are practically unknown─presumably owing to their ability to form indolines─but coordination to tungsten stabilizes these intermediates. The terminal position of the coordinated diene (C4 of the 2-oxindole core) can then be protonated to generate an η²-allyl complex, which undergoes nucleophilic addition with C-, N-, or S-type nucleophiles to form the corresponding tetrahydro-2-oxindole complexes. Finally, the organic ligand is obtained through the oxidative decomplexation of the metal. This methodology provides a modular approach for accessing 1,2,5-functionalized cis-2-oxindole compounds.

The emerging field of dearomatization capitalizes on the synthetic potential of aromatic molecules. By using a transition metal to bind to two carbons of a benzene ring, the remaining four carbons are left available for the attachment of various chemical fragments. If these fragments are connected, this process could be a blueprint for synthesizing polycyclic architectures. The objective of this study is to develop a modular approach for creating classes of saturated polycyclic compounds that are currently underrepresented in the landscape of druggable chemical space. Herein, the phenyl group of methylphenylsulfone is coordinated to the tungsten complex {WTp(NO)(PMe₃)}, largely interrupting its aromatic stabilization because of strong metal-to-ligand backbonding. Through the combination of ester enolate and amine addition reactions to the arene carbons, a wide array of chemically diverse polyheterocyclic systems is prepared. The tungsten stereogenic center influences the configurations of 3-5 stereocenters derived from the phenyl carbons.

The Zincke reaction combines a pyridinium salt bearing an N-withdrawing group and a primary aliphatic amine to form an alkylated pyridinium salt through a ring-opening/ring-closing sequence. Herein, we explore the analogous reaction sequence for a pyridinium salt η²-bound to a transition metal. We find that the N-sulfonylated pyridinium ligand (pyR¹, where R¹ = mesyl or tosyl) of [WTp(NO)(PMe₃)(η²-pyR¹)]OTf selectively reacts with a primary amine, and the resulting 2-aminodihydropyridine complex then undergoes a tungsten-stabilized ring-scission to form the corresponding η²-azatriene complex. Subsequent ring-closure between the newly installed amine and the sulfonylated imine results in a new aminodihydropyridinium species. This dihydropyridinium resists rearomatization due to a stabilizing influence of the tungsten fragment. Subsequent displacement of the sulfonamide by pendent heteroatoms leads to the formation of new heterocyclic frameworks. Herein the syntheses of 30 heterocyclic complexes are described (3 characterized by SC-XRD) including 7 examples of multicyclic systems.

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 (η²) benzenes with alkynes. The resulting η²-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.