Multicomponent reactions involving 2-methyleneaziridines: rapid synthesis of 1,3-disubstituted propanones

Ring opening of 1-alkyl-2-methyleneaziridines 1 or 2 is accomplished with organocopper reagents (R(2)CuLi or RMgX/CuI) in the presence of boron trifluoride diethyl etherate giving 1-substituted propan-2-ones 3-9 in 42-88% yield. Ring opening with RMgCl/CuI in the absence of the Lewis acid allows further alkylation of the metalloenamine (metalated imine) intermediate in a regiocontrolled manner. The sequential formation of two new intermolecular carbon-carbon bonds in this reaction provides a rapid entry into a variety of 1,3-disubstituted propan-2-ones, including 11 and 14-23. The scope and mechanism of this multicomponent reaction (MCR) has been assessed. It is established that this MCR tolerates alkyl, aryl, and benzylic Grignard reagents and a wide range of electrophiles, including alkyl iodides, bromides, and tosylates, as well as epoxides and aldehydes. In addition, gem-dimethyl substitution on the exocyclic double bond of the 2-methyleneaziridine is tolerated. This MCR has been applied to the one-pot synthesis of (Z)-6-heneicosen-11-one, 25, an important sex attractant of the Tussock moth. Using 3-deuterio-1-(1-phenylethyl)-2-methyleneaziridine, 26, we determined that this MCR occurs predominantly by direct ring opening at the sp(3)-hybridized aziridine carbon atom (C-3).     

Prediction of extended aromaticity for a novel C(48)N(12) azafullerene structure

We report the existence of a novel C48N12 molecular structure to the recently reported thin-film formation of nano-onions of carbon and nitrogen with similar composition [Phys. Rev. Lett. 2001, 87, 225503]. An extended local aromaticity of eight all-carbon hexagonal rings is the driving force toward the maximum stability of this molecule, which is found to be 13.1 kcal/mol energetically more stable at the B3LYP/6-31G* level of theory than the recently reported structure [Chem. Phys. Lett. 2001, 340, 227]. The extended region of electron delocalization enhances the stability of this molecule via resonance energy contribution. On the basis of HUMO-LUMO gap of 2.74 eV, the new material is predicted to be an insulator.     

Donor-rich and acceptor-rich pyridine-phosphadiazonium adducts: diversifying the Lewis acceptor chemistry of phosphorus(III)

[Mes*NP(DMAP)2][OTf] represents the first ligand-rich coordination complex of a phosphorus(III) Lewis acceptor, and a three coordinate hypervalent electron-rich (lone pair bearing) center; further diversification is demonstrated by, [(Mes*NP)2(4,4'-BIPY)][OTf]2, representing an acceptor-rich dication.     

Incorporating protein flexibility in structure-based drug discovery: using HIV-1 protease as a test case

We have developed a receptor-based pharmacophore method which utilizes a collection of protein structures to account for inherent protein flexibility in structure-based drug design. Several procedures were systematically evaluated to derive the most general protocol for using multiple protein structures. Most notably, incorporating more protein flexibility improved the performance of the method. The pharmacophore models successfully discriminate known inhibitors from drug-like non-inhibitors. Furthermore, the models correctly identify the bound conformations of some ligands. We used unliganded HIV-1 protease to develop and validate this method. Drug design is always initiated with a protein-ligand structure, and such success with unbound protein structures is remarkable - particularly in the case of HIV-1 protease, which has a large conformational change upon binding. This technique holds the promise of successful computer-based drug design before bound crystal structures are even discovered, which can mean a jump-start of 1-3 years in tackling some medically relevant systems with computational methods.     

Heme cleavage with remarkable ease: paramagnetic intermediates formed by aerobic oxidation of a meso-amino-substituted iron porphyrin

Hemes must be oxidatively stable to carry out their functions as biological oxidants, but introduction of a single amino group at a meso position of octaethylheme renders it extremely sensitive to ring opening by dioxygen. Exposure of a red pyridine (py) solution of diamagnetic (py)(2)Fe(II)(H(2)N-OEP) (1) (H(2)N-OEP is the dianion of meso-amino-octaethylporphyrin) to air results in the immediate formation of a green intermediate which is subsequently converted into a second species that has been crystallized and characterized by X-ray diffraction. This process is distinct from coupled oxidation, a model for biological heme cleavage, because it does not require a sacrificial reducing agent to initiate the process.     

A mechanical model of vocal-fold collision with high spatial and temporal resolution

The tissue mechanics governing vocal-fold closure and collision during phonation are modeled in order to evaluate the role of elastic forces in glottal closure and in the development of stresses that may be a risk factor for pathology development. The model is a nonlinear dynamic contact problem that incorporates a three-dimensional, linear elastic, finite-element representation of a single vocal fold, a rigid midline surface, and quasistatic air pressure boundary conditions. Qualitative behavior of the model agrees with observations of glottal closure during normal voice production. The predicted relationship between subglottal pressure and peak collision force agrees with published experimental measurements. Accurate predictions of tissue dynamics during collision suggest that elastic forces play an important role during glottal closure and are an important determinant of aerodynamic variables that are associated with voice quality. Model predictions of contact force between the vocal folds are directly proportional to compressive stress (r2 = 0.79), vertical shear stress (r2 = 0.69), and Von Mises stress (r2 = 0.83) in the tissue. These results guide the interpretation of experimental measurements by relating them to a quantity that is important in tissue damage.     

Structural polymorphism of DNA-dendrimer complexes

DNA condensation in vivo relies on electrostatic complexation with small cations or large histones. We report a synchrotron x-ray study of the phase behavior of DNA complexed with synthetic cationic dendrimers of intermediate size and charge. We encounter unexpected structural transitions between columnar mesophases with in-plane square and hexagonal symmetries, as well as liquidlike disorder. The isoelectric point is a locus of structural instability. A simple model is proposed based on competing long-range electrostatic interactions and short-range entropic adhesion by counterion release.