Publications

A series of asymmetric N-substituted pyrroles (1−7) has been synthesized from amino acid derivatives and complexed to the pentaammineosmium(II) fragment. Many of these pyrrole complexes (8−14) show a thermodynamic preference for one coordination diastereomer according to their NMR spectra (−5 to −20 °C). This stereoselective coordination results in stereoselective electrophilic addition at the uncoordinated β carbon (C3) when the complexes are treated with trifluoromethanesulfonic acid (HOTf), methyl triflate, or dimethoxymethane. These stereoselective reactions at C3 are a direct result of differentiation of the pyrrole enantiofaces.

The asymmetric π basic metal fragment {TpRe(CO)(MeIm)} (Tp = hydridotris(pyrazolyl)borate, MeIm = 1-methylimidazole) forms thermally stable complexes with ethyl acetate, acetic anhydride, N-methylsuccinimide, N-acetylpyrrole, and N-methylmaleimide in which the metal binds a carbonyl group in a π fashion. In all cases a single diastereomer is observed, indicating that one enantioface of the carbonyl is selectively coordinated. X-ray and NMR data for the compound TpRe(CO)(MeIm)(η²-N-methylsuccinimide) indicate that metal coordination effectively removes the π interaction between the bound carbonyl and the nitrogen of the succinimide ring.

Complexes of the type [TpRe(CO)(L)(η²-furan)], where Tp = hydridotris(pyrazolyl)borate and L = PMe₃ (1) or ^tBuNC (2), undergo dipolar cycloadditions with TCNE (tetracyanoethylene) to afford 7-oxabicycloheptene complexes 3 and 4, respectively. The corresponding 2-methylfuran complexes (5 and 7) for these L ligands give similar methyloxabicycloheptene complexes (6 and 8), with a diastereomer ratio >20:1 for 8. For L = N-methylimidazole (MeIm, 9), TCNE oxidizes the complex, but cycloadditions can be achieved with DMAD (dimethyl acetylenedicarboxylate) as the electrophile. Three complexes are observed:  one in which DMAD undergoes a cycloaddition with the carbonyl ylide form of the complex (10C), and two complexes that are coordination diastereomers where DMAD has undergone a formal [2+2] cycloaddition with the uncoordinated double bond of the 4,5-η²-furan ligand (10B and 10A). With the imidazole complex of 2-methylfuran (11), only the [2+2] products (12B and 12A) are observed. In the case of the 2,5-dimethylfuran complex (L = MeIm, 13), which is formed as a single coordination diastereomer, only one [2+2] product is observed (14), the structure of which was confirmed by X-ray crystallography. Oxidative decomplexation of 14 results in liberation of the free oxabicyclo[3.2.0]heptadiene 15, which can be thermally converted to the corresponding oxepin 16 in 70% yield.

Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M₂ and M₄receptor subtypes, the two G_i/G_o-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M₂ and M₄ mAChRs [M₂/M₄ double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M₂/M₄ double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M₂ receptor single-KO mice, but retained full analgesic activity in M₄ receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M₂ and M₄ receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M₄ than for M₂ receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M₂ and M₄mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.

Conclusion: Using an electron-rich, 16e⁻ metal fragment, aromatic molecules may be coordinated through a single π-bond. Such coordination acts to disrupt the π-system and activates the aromatic toward electrophilic addition reactions. The resulting arenium, allyl, and vinyl cations are stabilized by the metal to the point that nucleophilic addition becomes competitive with electrophilic substitution. In this regard, the chemistry exhibited by the osmium system provides a new method for the activation of unsaturated molecules. This approach is complementary to the more established chemistry of nucleophilic addition to metal-coordinated π-systems. Until recently, this methodology has been limited to the pentaammineosmium(II) system, a reagent which, though remarkably versatile, has practical limitations such as cost and toxicity. On the horizon, however, is the next generation of dearomatization agents of the type {ReTp(CO)(L)}.24., 66. These materials, in addition to being substantially less expensive and more safe than osmium, are chiral at metal, and electronically and sterically tunable. Thus, they can be tailored to optimize a particular reaction sequence.

The π-basic metal fragment {TpRe(CO)(MeIm)} (MeIm = 1-methylimidazole; Tp = hydridotris(pyrazolyl)borate) binds a variety of aromatic molecules, including benzene, 2,6-lutidine, and 1-methylpyrrole, in an η² fashion. Although TpRe(CO)(MeIm)(η²-benzene) as a solid shows no decomposition over several months at 25 °C under a nitrogen atmosphere, the complex has proven to be a valuable precursor to a variety of other aromatic complexes through ligand exchange reactions in solution.

A series of complexes of the type [TpRe(CO)(L_D)(η²-ethylene)] has been synthesized, where L_D is ^tBuNC, PMe₃, pyridine, 1-methylimidazole, or NH₃ (increasing in electron-donating ability of L_D). The rates of the propeller-like rotation of ethylene about the ethylene−rhenium bond have been determined using spin saturation transfer experiments at low temperatures (−85 to −60 °C). It was found that the ΔG^⧧ values correlate with both the C⋮O stretching frequencies and Re(II/I) reduction potentials for these complexes, indicating that the barrier to rotation is primarily electronic in nature.