Double Click: Unexpected 1:2 Stoichiometry in a Norbornene–Tetrazine Reaction

We report a new reactivity for the inverse electron demand Diels–Alder (iEDDA) reaction between norbornene and tetrazine. Instead of simple 1:1 condensation between norbornene- and tetrazine-conjugated biomolecules, we observed that dimeric products were preferentially formed. As such, an olefinic intermediate formed after the addition of the first tetrazine unit to norbornene rapidly undergoes a consecutive cycloaddition reaction with a second tetrazine unit to result in a conjugate with a 1:2 stoichiometric ratio. This unexpected dimer formation was consistently observed in the reactions of both small-molecule norbornenes and tetrazines, as well as oligonucleotide conjugates. When norbornene was replaced with bicyclononyne to bypass the formation of this olefinic reaction intermediate, the reactions resulted exclusively in rapid formation of the expected 1:1 stoichiometric conjugates

Influence of Conformational Flexibility on Single-Molecule Conductance in Nano-Electrical Junctions

The temperature dependence of the single-molecule conductance of conformationally flexible alkanedithiol molecular bridges is compared to that of more rigid analogues which contain cyclohexane ring(s). Molecular conductance has been measured with a scanning tunneling microscope (STM) at fixed gap separation by observing the stochastic formation of molecule bridges between a gold STM tip and substrate (the so-called “I(t)” technique). Under these conditions, the junction can be populated by a wide distribution of conformers of alkanedithiol molecular bridges and a strong temperature dependence of the single-molecule conductance is observed. By contrast the rigid analogues that contain cyclohexane ring(s), which cannot form the thermally accessible gauche rich conformers open to the alkanedithiols, show no dependence of the single-molecule conductance on temperature. This comparison demonstrates that it is the conformational flexibility and access to thermally populated higher energy conformers of the linear polymethylene (alkane) bridges which leads to the temperature dependence. By removing this possibility in the cyclohexane ring-containing bridges, this conformational gating is excluded and the temperature dependence is then effectively suppressed

Combining Structural Rugosity and Crystal Packing Comparison: A Route to More Polymorphs?

In this study, we have combined structural comparisons and the rugosity model to investigate experimental and predicted crystal structures from previous results of a crystal structure prediction study on a group of three rigid, planar small molecules, 2-methyl-, 3-methyl-, and 2,3-dimethyl-benzo­[b]­thiophene 1,1-dioxide. The results of the crystal structure comparisons provided some insights into the possibility that pairs of predictions, close in energy, might be related by potential phase transitions. In particular, we observed that for some pairs of predictions, a transformation from one type of crystal packing to the other would require only small shifts between adjacent molecules. This raised the question of whether only a few of these predictions can effectively be experimentally isolated. The calculations of the structural rugosity, a parameter that correlates surface rugosity with ease of crystallization, indicated smooth surfaces only for a few predictions. With the aim to isolate new polymorphs, we performed a small experimental study, limited to a few common solvents and crystallizations from the melt. Crystallizations from the melt selectively produced single crystals of new polymorphs for the 3-methyl- and the 2,3-methyl-benzothiophene derivatives. These showed good correlations with the above calculations, suggesting that the combination of crystal structure analysis and experimental screening might represent a useful approach in polymorphism screenings

Induction of Planar Chirality in Formation of (η⁵:η¹-1-(1-Cyclohexyl-2-(diphenylphosphino)ethyl)indenyl)carbonylrhodium and (η⁵:η¹-1-(2-Phenyl-2- (diphenylphosphino)ethyl)indenyl)carbonylrhodium

The enantiopure bidentate indenyl−phosphine ligands (1S)-[2-(3H-inden-1-yl)-1-phenylethyl]diphenylphosphine (9) and [(2R)-2-cyclohexyl-2-(3H-inden-1-yl)ethyl]diphenylphosphine (18) were synthesized in 20% yield and three steps from (R)-styrene oxide and in 61% yield and four steps from vinylcyclohexane, respectively. In both cases ring opening of a spirocyclopropane-1,1‘-indene with potassium diphenylphosphide was a key step. Addition of the lithium salts of 9 and 18 to [Rh(μ-Cl)(CO)2]2 gave (η5:η1-indenyl-CH2CH(Ph)PPh2)RhCO and (η5:η1-indenyl-CH(Cy)CH2PPh2)RhCO as 75:25 and 78:22 mixtures of diastereoisomers, from which the major complexes were readily obtained by crystallization. The chiral centers in the linking chain β and α to the indenyl ring had thus induced good planar chirality of the complexed indenyl moiety. Both complexes were characterized by X-ray crystallography

Novel Routes to Bidentate Cyclopentadienyl−Alkoxide Complexes of Titanium: Synthesis of (η⁵-σ-C₅R¹₄CHR²CH₂CR³R⁴O)TiCl₂

Reaction of C5R14(SiMe3)CHR2CH2CR3R4OR5 with titanium tetrachloride gives the bidentate η5-σ-cyclopentadienyl−alkoxide complexes of titanium (η5-σ-C5R14CHR2CH2CR3R4O)TiCl2 through elimination of chlorotrimethylsilane and RCl (R = SiMe3, CH2Ph, CMe3). A potentially tridentate system (R1, R2, R3 = H, R4 = −(CH2)2OMe) was synthesized in optically pure form and its structure determined by X-ray diffraction. The pendant ether oxygen does not coordinate to the metal, and hydride transfer reactions catalyzed by the complex gave racemic products. Efficient routes to tetramethylcyclopentadienyl-substituted ligands (R1 = Me) were developed on the basis of the addition of 2-butenylmagnesium bromide to γ-lactones to give the dienyl alcohols [C(CH3)CH(CH3)]2C(OH)CHR2(CH2)2OH, which could be functionalized on the primary alcohol before acid-catalyzed cyclization to afford the 3-alkoxypropyl-substituted tetramethylcyclopentadienes

Induction of Planar Chirality in Formation of (η⁵:η¹-1-(1-Cyclohexyl-2-(diphenylphosphino)ethyl)indenyl)carbonylrhodium and (η⁵:η¹-1-(2-Phenyl-2- (diphenylphosphino)ethyl)indenyl)carbonylrhodium

The enantiopure bidentate indenyl−phosphine ligands (1S)-[2-(3H-inden-1-yl)-1-phenylethyl]diphenylphosphine (9) and [(2R)-2-cyclohexyl-2-(3H-inden-1-yl)ethyl]diphenylphosphine (18) were synthesized in 20% yield and three steps from (R)-styrene oxide and in 61% yield and four steps from vinylcyclohexane, respectively. In both cases ring opening of a spirocyclopropane-1,1‘-indene with potassium diphenylphosphide was a key step. Addition of the lithium salts of 9 and 18 to [Rh(μ-Cl)(CO)2]2 gave (η5:η1-indenyl-CH2CH(Ph)PPh2)RhCO and (η5:η1-indenyl-CH(Cy)CH2PPh2)RhCO as 75:25 and 78:22 mixtures of diastereoisomers, from which the major complexes were readily obtained by crystallization. The chiral centers in the linking chain β and α to the indenyl ring had thus induced good planar chirality of the complexed indenyl moiety. Both complexes were characterized by X-ray crystallography

The Endofullerene HF@C₆₀: Inelastic Neutron Scattering Spectra from Quantum Simulations and Experiment, Validity of the Selection Rule, and Symmetry Breaking

Accurate quantum simulations of the low-temperature inelastic neutron scattering (INS) spectra of HF@C60 are reported for two incident neutron wavelengths. They are distinguished by the rigorous inclusion of symmetry-breaking effects in the treatment and having the spectra computed with HF as the guest, rather than H2 or HD, as in the past work. The results demonstrate that the precedent-setting INS selection rule, originally derived for H2 and HD in near-spherical nanocavities, applies also to HF@C60, despite the large mass asymmetry of HF and the strongly mixed character of its translation–rotation eigenstates. This lends crucial support to the theoretical prediction made earlier that the INS selection rule is valid for any diatomic molecule in near-spherical nanoconfinement. The selection rule remains valid in the presence of symmetry breaking but is modified slightly in an interesting way. Comparison is made with the recently published experimental INS spectrum of HF@C60. The agreement is very good, apart from one peak for which our calculations suggest a reassignment. This reassignment is consistent with the measured INS spectrum presented in this work, which covers an extended energy range

Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1

We report the identification of substituted cis-bicyclo[3.3.0]oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1

Intra- and Intermolecular Alkylation of <i>N</i>,<i>O</i>‑Acetals and π‑Activated Alcohols Catalyzed by in Situ Generated Acid

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally <i>N</i>,<i>O</i>-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take advantage of the ability of this solvent to continuously release small amounts of HCl by thermolytic elimination. A study of the reaction led to several improved protocols such as (1) preheated TCE, (2) microwave-assisted reactions, and (3) flow or sealed-tube conditions, which allow significant reaction rate enhancements and made possible some challenging reactions such as the α-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to the alkylation using proelectrophiles such as π-activated alcohols, which are normally unreactive toward HCl catalysis. This work represents the first successful use of HCl, the simplest strong Brønsted acid, as an efficient alkylation catalyst

Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(<i>E</i>-oct-4-en-4-yl)-1-phenylamino-2-phenyl-<i>cis</i>-bicyclo[3.3.0]oct-2-ene <b>5</b> is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure−activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes