Reducing levels of toxic RNA with small molecules.

Myotonic dystrophy (DM) is one of the most common forms of muscular dystrophy. DM is an autosomal dominant disease caused by a toxic gain of function RNA. The toxic RNA is produced from expanded noncoding CTG/CCTG repeats, and these CUG/CCUG repeats sequester the Muscleblind-like (MBNL) family of RNA binding proteins. The MBNL proteins are regulators of alternative splicing, and their sequestration has been linked with mis-splicing events in DM. A previously reported screen for small molecules found that pentamidine was able to improve splicing defects associated with DM. Biochemical experiments and cell and mouse model studies of the disease indicate that pentamidine and related compounds may work through binding the CTG*CAG repeat DNA to inhibit transcription. Analysis of a series of methylene linker analogues of pentamidine revealed that heptamidine reverses splicing defects and rescues myotonia in a DM1 mouse model.

A triphenylene-based triptycene with large free volume synthesized by zirconium-mediated biphenylation.

Biphenylation using (Li(THF)(4))(2) x Zr(biphe)(3) of hexabromotriptycenes bearing H (1-H) or Bu (1-Bu) at the bridgeheads gave triptycenes with triphenylene blades. The blades extend both perpendicular and parallel to the 3-fold axis and generate a large intramolecular free volume (IMFV) (1-H, AM1, 710 A(3); cf. triptycene, AM1 71 A(3)). Crystals of 1-H could not be obtained. Triptycene 1-Bu, in which the Bu groups fill the voids near the bridgehead, was crystalline. X-ray diffraction analysis revealed crystal packing with alternating, interlocked corrugated and distorted hexagonal layers.

18,18'-Dihexyl[9,9']biphenanthro[9,10-b]triphenylene: construction and consequences of a profoundly hindered aryl-aryl single bond.

The title compound, 1-Hex, was synthesized by the Zr-mediated biphenylation of 4,4'-dihexyloctabromobiphenyl using (Li(THF)4)2 x Zr(biphe)3, where biphe is the 2,2'-biphenyldiyl ligand, in 5% isolated yield. Two independent X-ray diffraction analyses revealed that arene 1-Hex possesses a highly strained and hindered aryl-aryl single bond. This bond causes the phenanthro[9,10-b]triphenylene (PTP) moieties to twist (anthracene subunit dihedral, 69 degrees); the interlocked, helical, homochiral PTP moieties give rise to effective D2 symmetry. The calculated adiabatic homolytic bond dissociation energy of this strained bond is only 67 kcal/mol, but nonetheless the bond exhibits a surprisingly normal length (1.49 A); the reason is elongation only slowly releases strain. Variable temperature NMR revealed two dynamic processes: hexyl rotation (12.0 +/- 0.4 kcal/mol) and inversion of chirality (15.2 +/- 0.6 kcal/mol). DFT calculations provide rate-determining transitions states, whose energies agree with measured values, and provide insight to the mechanism of these processes. Rotation about the central bond is not involved in either observed process. Calculations demonstrate that rotation does not involve a simple torsion of the equilibrium structure, but rather a complex movement with a barrier of 49 kcal/mol from a slipped-parallel, C(2h) intermediate.

Controlling the Scholl reaction.

Guidelines for the application of the Scholl reaction were developed. Labeling experiments demonstrate that the Scholl reaction fails in small, unsubstituted oligophenylenes (e.g., o-terphenyl) due to oligomerization of the products (e.g., triphenylene). Incorporation of suitably placed blocking groups (e.g., t-butyl) suppresses oligomerization. The well-established directing group effects in electrophilic aromatic substitution predict the outcome of Scholl reactions of substituted substrates. Activating o,p-directing groups (e.g., MeO) direct bond formation o,p, either intramolecularly or intermolecularly. Deactivating o,p-directing groups (e.g., Br) also direct bond formation o,p but yields are lower. Deactivating m-directors (e.g., NO2) suppress reaction. MoCl5 and PhI(OOCCF3)2/BF3.Et2O are general and effective reagents for the Scholl oxidation. Calculations (B3LYP/6-31G(d)) predict the Scholl reaction in alkoxyarenes to proceed via arenium cations, not radical cations. Suzuki-Miyaura couplings were used to generate 12 substituted o-terphenyl derivatives.

Uncatalyzed zirconium-mediated biphenylation of o-dihalobenzenes to form triphenylenes.

The reaction of [Zr(biphe)3][(Li.(THF)4)2], where biphe is 2,2'-biphenyldiyl, with an o-dihaloarene produces a triphenylene. Two new bonds are created in this rare example of an uncatalyzed, Zr-mediated aryl-aryl bond formation. Multiple biphe fragments can be incorporated to give larger triphenylene-containing polycyclic aromatic hydrocarbons. This reaction can introduce significant strain and was demonstrated to tolerate alkyl and methoxy substituents.