Energetic but insensitive spiro-tetrahydrotetrazines based on oxetane-3-one

Energetic oxetanes were first described in the 1970s, such as 3,3-bis(azidomethyl)oxetanes (BAMO) and 3-(nitratomethyl)-3-(methyl)oxetanes (NIMMO). Over the past few years, oxetanes were hardly available only as special-purpose chemicals for the pharmaceutical industry. Oxetan-3-one is condensed with energetic compounds with a hydrazino function such as amino-nitroguanidine and picryl hydrazine to form energetic Schiff bases. Hydrazinolysis of the guanidine derivatives lead to energetic spiro-tetrahydrotetrazines which are quite rare in literature. All products were characterized by their crystal structure using single-crystal X-ray diffraction. Furthermore, the new compounds were analyzed using IR, EA, DTA, and multinuclear NMR spectroscopy (H-1 and C-13). The sensitivities towards external stimuli such as friction and impact were determined according to BAM standards and the energetic performances were calculated using the EXPLO5 code

3-(Nitromethylene)oxetane: a very versatile and promising building block for energetic oxetane based monomers

In the field of energetic materials, older developments (e.g., RDX, ONC, CL20) are increasingly replaced by more environmentally benign, less expensive and likewise or more powerful compounds. This is mainly achieved through nitrogen-rich motifs like tetrazoles. However, such materials are mostly used as formulations containing polymeric energetic binders. Unfortunately, prior art binders show very poor performances and therefore reduce the overall performance. To address this problem, new monomers with enhanced performance are a prerequisite. Since the majority of energetic binders is oxetane-based, we chose 3-(nitromethylene)oxetane as a promising building block. It exhibits an explosophoric group, has recently become commercially available and provides suitable monomers by elegant and cost-efficient one-pot syntheses via conjugate addition. Herein, we report derivatives based on 1H-tetrazole, 1H-tetrazole-5-amine and the rather exotic but extremely powerful primary explosives 5-azido-1H-tetrazole (5AzT) and 5-nitro-2H-tetrazole (5NT). The sensitivities toward external stimuli like impact, friction, and electrostatic discharge were assessed by BAM standard procedures. As all molecular structures were elucidated by X-ray diffraction, Hirshfeld analysis was applied to explain the surprisingly low sensitivities found for the 5AzT- and 5NT-derivatives. Further, the compounds were studied by vibrational- and multinuclear NMR spectroscopy (H-1, C-13, N-14), differential scanning calorimetry, and elemental analysis. Their performance was calculated using the EXPLO5 V6.04 thermochemical code. Based on obtained values, the 5AzT- and 5NT-derivatives outperform prior art energetic oxetanes and TNT. Therefore, their performance was additionally demonstrated and evaluated by a small-scale shock reactivity test (SSRT)

Stereoselective synthesis of cyclic ethers via a tandem oxonium ylide formation and rearrangement strategy

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Pushing the Frontiers of Accessible Chemical Space to Unleash Design Creativity and Accelerate Drug Discovery

In highly competitive research environments, the ability to access more complex structural spaces efficiently is a predictor of a company's ability to generate novel IP-protected small molecule candidates with adequate properties, hence filling their development pipelines. SpiroChem is consistently developing new synthetic methodologies and strategies to access complex molecular structure, thereby facilitating and accelerating small molecule drug discovery. Pushing the limits of what are perceived as complex molecular structures allows SpiroChem and its clients to unleash creativity and explore meaningful chemical spaces, which are under-exploited sources of novel active molecules. In this article, we explain how we differentiated ourselves in a globalized R&D environment and we provide several snapshots of how efficient methodologies can generate complex structures, rapidly

Oxetanyl peptides: novel peptidomimetic modules for medicinal chemistry

The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.ISSN:1523-7060ISSN:1523-705

Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry

The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics

Identification Of Key Residues For Interaction Of Vasoactive Intestinal Peptide With Human Vpac(1) And Vpac(2) Receptors And Development Of A Highly Selective Vpac(1) Receptor Agonist - Alanine Scanning And Molecular Modeling Of The Peptide

The widespread neuropeptide vasoactive intestinal peptide (VIP) has two receptors VPAC(1) and VPAC(2). Solid-phase syntheses of VIP analogs in which each amino acid has been changed to alanine (Ala scan) or glycine was achieved and each analog was tested for: (i) three-dimensional structure by ab initio molecular modeling; (ii) ability to inhibit (125)I-VIP binding (K(i)) and to stimulate adenylyl cyclase activity (EC(50)) in membranes from cell clones stably expressing human recombinant VPAC(1) or VPAC(2) receptor. The data show that substituting residues at 14 positions out of 28 in VIP resulted in a >10-fold increase of K(i) or EC(50) at the VPAC(1) receptor. Modeling of the three-dimensional structure of native VIP (central alpha-helice from Val(5) to Asn(24) with random coiled N and C terminus) and analogs shows that substitutions of His(1), Val(5), Arg(14), Lys(15), Lys(21), Leu(23), and Ile(26) decreased biological activity without altering the predicted structure, supporting that those residues directly interact with VPAC(1) receptor. The interaction of the analogs with human VPAC(2) receptor is similar to that observed with VPAC(1) receptor, with three remarkable exceptions: substitution of Thr(11) and Asn(28) by alanine increased K(i) for binding to VPAC(2) receptor; substitution of Tyr(22) by alanine increased EC(50) for stimulating adenylyl cyclase activity through interaction with the VPAC(2) receptor. By combining 3 mutations at positions 11, 22, and 28, we developed the [Ala(11,22,28)]VIP analog which constitutes the first highly selective (>1,000-fold) human VPAC(1) receptor agonist derived from VIP ever described

The Human Vpac(1) Receptor - Three-Dimensional Model And Mutagenesis Of The N-Terminal Domain

peer reviewedThe human VPAC(1) receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide belongs to the class II family of G-protein-coupled receptors with seven transmembrane segments. Like for all class II receptors, the extracellular N-terminal domain of the human VPAC(1) receptor plays a predominant role in peptide ligand recognition. To determine the three-dimensional structure of this N-terminal domain (residues 1-144), the Protein Data Bank (PDB) was screened for a homologous protein. A subdomain of yeast lipase B was found to have 27% sequence identity and 50% sequence homology with the N-terminal domain (8) of the VPAC(1) receptor together with a good alignment of the hydrophobic clusters. A model of the N-terminal domain of VPAC(1) receptor was thus constructed by homology. It indicated the presence of a putative signal sequence in the N-terminal extremity. Moreover, residues (Glu(36), Trp(67), Asp(68), Trp(73), and Gly(109)) which were shown to be crucial for VIP binding are gathered around a groove that is essentially negatively charged. New putatively important residues for VIP binding were suggested from the model analysis. Site-directed mutagenesis and stable transfection of mutants in CHO cells indicated that Pro(74), Pro(87), Phe(90), and Trp(110) are indeed important for VIP binding and activation of adenylyl cyclase activation. Combination of molecular modeling and directed mutagenesis provided the first partial three-dimensional structure of a VIP-binding domain, constituted of an electronegative groove with an outspanning tryptophan shell at one end, in the N-terminal extracellular region of the human VPAC(1) receptor