A dipicolinic acid tag for rigid lanthanide tagging of proteins and paramagnetic NMR spectroscopy

A new lanthanide tag was designed for site-specific labeling of proteins with paramagnetic lanthanide ions. The tag, 4-mercaptomethyl-dipicolinic acid, binds lanthanide ions with nanomolar affinity, is readily attached to proteins via a disulfide bond, and avoids the problems of diastereomer formation associated with most of the conventional lanthanide tags. The high lanthanide affinity of the tag opens the possibility to measure residual dipolar couplings in a single sample containing a mixture of paramagnetic and diamagnetic lanthanides. Using the DNA-binding domain of the E. coli arginine repressor as an example, it is demonstrated that the tag allows immobilization of the lanthanide ion in close proximity of the protein by additional coordination of the lanthanide by a carboxyl group of the protein. The close proximity of the lanthanide ion promotes accurate determinations of magnetic susceptibility anisotropy tensors. In addition, the small size of the tag makes it highly suitable for studies of intermolecular interactions.     

Synthesis and Investigation of Advanced Energetic Materials Based on Bispyrazolylmethanes

Herein we present the preparation and characterization of three new bispyrazolyl‐based energetic compounds with great potential as explosive materials. The reaction of sodium 4‐amino‐3,5‐dinitropyrazolate ( 5 ) with dimethyl iodide yielded bis(4‐amino‐3,5‐dinitropyrazolyl)methane ( 6 ), which is a secondary explosive with high heat resistance (T_dec=310 °C). The oxidation of this compound afforded bis(3,4,5‐trinitropyrazolyl)methane ( 7 ), which is a combined nitrogen‐ and oxygen‐rich secondary explosive with very high theoretical and estimated experimental detonation performance (V_det (theor)=9304 m s^?1 versus V_det(exp)=9910 m s^?1) in the range of that of CL‐20. Also, the thermal stability (T_dec=205 °C) and sensitivities of 7 are auspicious. The reaction of 6 with in situ generated nitrous acid yielded the primary explosive bis(4‐diazo‐5‐nitro‐3‐oxopyrazolyl)methane ( 8 ), which showed superior properties to those of currently used diazodinitrophenol (DDNP).     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Synthesis of a new scaffold: the 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione nucleus

This paper describes a modified method of preparation of a number of alpha-aryl-alpha-(pyridazin-3-yl)-acetonitriles via the C-arylation reaction of the corresponding carbanionsof phenylacetonitriles using 3-chloropyridazine derivatives. KOH and DMSO were used inthe deprotonation process, which made the reaction very simple and safe to perform.Nitriles were obtained in the hydrolysis reaction to the corresponding alpha-aryl-alpha-(pyridazin-3-yl)-acetamide derivatives, which were next subjected to cyclization to afford the finalproducts. A number of new derivatives of 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione weresynthesized in the cyclocondensation reaction of respective alpha-aryl-alpha-(pyridazin-3-yl)-acetamides with diethyl carbonate in the presence of EtONa. The structure andcomposition of the new compounds were confirmed by IR, (1)H- and (13)C- NMR analysesand by elemental C, H and N analysis.     

Glycal glycosylation and 2-nitroglycal concatenation, a powerful combination for mucin core structure synthesis

A 3,4-O-unprotected galactal derivative having bulky 6-O-TIPS protection (compound 2) could be regioselectively 3-O-glycosylated with O-(galactopyranosyl) trichloroacetimidates; depending on the protecting group pattern stereoselectively alpha- and beta-linked disaccharides were obtained. With O-(2-azido-2-deoxyglucopyransyl) trichloroacetimidate as donor (compound 10A), glycosylation of 2 and of a 6-O-unprotected galactal derivative led in acetonitrile as solvent exclusively to a beta(1-3)- and a beta(1-6)-linked disaccharide, respectively. Nitration of the galactal moieties of the saccharides followed by Michael-type addition of serine and threonine derivatives (7a,b) installed the alpha-galacto-configuration, thus readily furnishing O-glycosyl amino acid building blocks for the incorporation of core 1, core 2, core 3, core 6, and core 8 structures into glycopeptides. 2-Nitrogalactal and 2-nitroglucal derivatives could be also successfully employed in glycoside bond formation via Michael-type addition in a reiterative manner, affording the corresponding core 5, core 7, and core 6 building blocks. In this approach, highly stereoselective glycoside bond formations were based exclusively on Michael-type addition to the nitro-enol ether moiety of the 2-nitroglycals. Hence, 2-nitroglycals are versatile intermediates for base-catalyzed glycoside bond formation.     

First Order LSFEM for Fluid‐Structure Problems

The Least‐Squares Finite Element Method (LSFEM) is an interesting alternative to the standard variational principles, which are used to solve partial differential equations. Advantages of the LSFEM are its robustness and the resulting symmetric positive definite matrices, which allow the use of robust iterative solvers like the CG method. In this paper we consider the application of the LSFEM for Fluid‐Structure Interaction (FSI) problems. Our model uses the LSFEM for the discretisation of the instationary incompressible Navier‐Stokes equations, which is coupled with a standard Galerkin FEM model for a linear elastic structure. The results for a simple model problem agree well with results obtained by other authors with different numerical schemes. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Neutrale aromatische Tetraepoxyannulene: Tetraepoxy[26]annulene(4.2.2.2) und Tetraepoxy[30]annulene(4.4.4.2) – Systeme mit hoher molekularer Dynamik

Neutral Aromatic Tetraepoxyannulenes: Tetraepoxy[26]annulenes(4.2.2.2) and Tetraepoxy[30]annulenes(4.4.4.2) – Systems with High Molecular Dynamics The twofold cyclizing Wittig reaction of the bis‐aldehyde 6 with the ylide of the bis‐phosphonium salt 7 yields tetraepoxy[26]annulene(4.2.2.2) 4 , which exists in the two isomeric forms 4a (EE,Z,E,Z) and 4b (EE,Z,E,E). Annulene 4a is a highly dynamic system down to −80°. Temperature‐dependent ¹H‐NMR spectra of 4a establish that the (E,E)‐buta‐1,3‐dien‐1,4‐diyl as well as the (E)‐ethen‐1,2‐diyl bridges rotate around the adjacent σ‐bonds in a synchronous manner. Isomer 4b , for steric reasons, is rigid. By Wittig reaction of the bis‐aldehyde 8 with the ylide of the bis‐phosphonium salt 9 , the tetraepoxy[30]annulene(4.4.4.2) 5 is obtained, which exists also in two isomeric forms, 5a and 5b . Only 5a (EE,ZE,EE,Z) can be isolated in pure form. Like 4a , 5a is highly dynamic, the (E,E)‐buta‐1,3‐dien‐1,4‐diyl as well as the opposite (E)‐ethen‐1,2‐diyl bridge being able to rotate down to −80°. The ¹H‐NMR spectrum at −80° indicates that 5a exists in the stable conformation 5a′ . The 26‐ and 30‐membered annulenes belong to the most expanded neutral annulenes known hitherto; their ¹H‐NMR spectra confirm that they still have diatropic, aromatic character.     

Tetraepoxy[32]annulene(4.4.4.4) und `Tetraoxa[30]porphyrin(4.4.4.4)'‐Dikationen

Tetraepoxy[32]annulenes(4.4.4.4) and `Tetraoxa[30]porphyrin(4.4.4.4)' Dications Of the tetraepoxy[32]annulenes as well as the `tetraoxa[30]porphyrin' dications, hithertoo only the (8.0.8.0) and the (6.2.6.2) systems are known to exist in several geometric isomers and to possess antiaromatic and aromatic character, respectively. Here we describe the still missing symmetric member of the [32]annulenes, the tetraepoxy[32]annulene(4.4.4.4) 1 and the corresponding `tetraoxa[30]porphyrin(4.4.4.4)' dication 2 . The cyclizing Wittig reaction of the dialdehyde 3 with the bis‐phosphonium salt 7 at 70° yields the configurational isomers 1a (ZE,EE,EZ,EE), 1b (ZE,EE,EE,EE), and 1c (EZ,EE,EZ,EE). All isomers are antiaromatic; in 1a and 1c , the two (E,E)‐buta‐1,3‐diene‐1,4‐diyl bridges rotate around the adjacent σ‐bonds; the rigidity of 1b with 3 (E,E) bridges prevents any dynamic character. The Wittig reaction of 3 with 7 at 20° only yields the kinetically controlled annulene 1c , and at 120°, an excess of the thermodynamically most stable isomer 1a is formed. The structure of 1 is elucidated mainly by COSY and NOESY experiments, and the dynamic character of 1a and 1c is established by temperature‐dependent <sup>1</sup>H‐NMR spectroscopy. The oxidation of the isomer mixture 1a – c with 4,5‐dichloro‐3,6‐dioxocyclohexa‐1,4‐diene‐1,2‐dicarbonitrile (DDQ) gives two isomeric `tetraoxa[30]porphyrin(4.4.4.4)' dications 2′ and 2″ , which are frozen conformers with the same (EZ,EE,EZ,EE)‐configuration and geometrically related to 1c . Semiempirical calculations of 1 and 2 are in full agreement with the experimental results.