Synthesis of azetidines and pyrrolidines: towards medicinal chemistry and organocatalysis applications

Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2- (iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 °C to 50 °C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans- substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivative were probed in a zebrafish embryo developmental assay for capacity to illicit morphological changes. The range of effects across the probed molecules demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly promising effects in the developmental assay

Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes

Seven N,N’-palladium(II) chloride complexes, one N,N’-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N’-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN’ metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal-ligand orientation

Decreased cognition is associated with altered cardiovascular autonomic functions and decreased baroreflex sensitivity in women with premenstrual syndrome

Premenstrual syndrome (PMS) is a clinical entity of concern in women of reproductive age group with its onset during the late luteal phase of the menstrual cycle that typically resolves within a few days after the onset of menstruation. Female reproductive hormones stimulate the gene promotor region of Gonadal steroids, which are modulators of the hypothalamic-pituitary axis, in association with the autonomic nervous system (ANS), form the stress system, which regulates the homeostatic mechanisms of the body. Disruption of this mechanism can lead to sympathovagal imbalance and cognitive deficits. Objectives: This study was aimed to compare the autonomic functions and cognition between PMS and control group. Methodology: This cross-sectional study was conducted as a pilot study with 20 subjects in each group. Autonomic function test and P300 were recorded. Study participants were also asked to answer Montreal cognitive assessment (MOCA) questionnaire. Results: On comparison of the test results between the two groups, individuals in PMS group were found to have increased sympathetic activity and reduced cognition when compared to the no PMS (control) group. Conclusion: The findings from this study proves a detrimental effect of gonadal steroids on autonomic nervous system and cognition

Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis.

A series of single enantiomer, 2,4-cis-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a cis-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn. A preliminary example of the use of a cis-disubstituted azetidine scaffold in thiourea H-bonding catalyst is noted in the supporting information

Self-immolative systems for the disclosure of reactive electrophilic alkylating agents

In this paper we report the design, synthesis and assessment of the first examples of self-immolative systems triggered by non-acidic electrophilic agents such as methyl, allyl or benzylic halides. These systems provide a visual colorimetric disclosure response upon exposure to these electrophilic reagents under mild, basic conditions without the need for the use of analytical instrumentation

A dynamic supramolecular polyurethane network whose mechanical properties are kinetically controlled

We report the synthesis and characterization of a kinetically controlled, thermoreversible supramolecular polyurethane whose mechanical properties depend unusually strongly on the processing history. Materials were prepared by solution casting, quenching and annealing of quenched material, allowing pronounced micro-structural evolution, which leads to rapid increases in modulus as determined by rheological analysis. Tensile tests showed that the quenched material is soft, weak and ductile (shear modulus ~ 5 MPa, elongation ~ 250 %), but after annealing, at 70 °C for one hour, it becomes stiffer, stronger and more brittle (~ 20 MPa, ~ 20 %). FTIR and NMR spectroscopic analysis, coupled with MDSC and SAXS, were performed to investigate the network’s dynamic structural changes. SAXS results suggest the presence of a lamellar structure in the sample when solution cast at high temperature, or annealed. This ordering is unique when compared to structurally-related supramolecular bisurethane and bisurea polymers, and may be the cause of the observed path dependence. These mechanical properties, which can be switched repeatedly by simple thermal treatments, coupled with its adhesion properties as determined from peel and tack tests, make it an excellent candidate as a recyclable material for adhesives and coatings

Effect of temperature and strain rate on the compressive behaviour of supramolecular polyurethane

Supramolecular polyurethanes (SPUs) possess thermoresponsive and thermoreversible properties, and those characteristics are highly desirable in both bulk commodity and value-added applications such as adhesives, shape-memory materials, healable coatings and lightweight, impact-resistant structures (e.g. protection for mobile electronics). A better understanding of the mechanical properties, especially the rate and temperature sensitivity, of these materials are required to assess their suitability for different applications. In this paper, a newly developed SPU with tuneable thermal properties was studied, and the response of this SPU to compressive loading over strain rates from 10−3 to 104 s−1 was presented. Furthermore, the effect of temperature on the mechanical response was also demonstrated. The sample was tested using an Instron mechanical testing machine for quasi-static loading, a home-made hydraulic system for moderate rates and a traditional split Hopkinson pressure bars (SHPBs) for high strain rates. Results showed that the compression stress-strain behaviour was affected significantly by the thermoresponsive nature of SPU, but that, as expected for polymeric materials, the general trends of the temperature and the rate dependence mirror each other. However, this behaviour is more complicated than observed for many other polymeric materials, as a result of the richer range of transitions that influence the behaviour over the range of temperatures and strain rates tested

Poly(Vinyl alcohol)/gelatin scaffolds allow regeneration of nasal tissues

Need for regeneration and repair of nasal tissues occurs as a consequence of several pathologies affecting the nose, including, but not limited to infective diseases, traumas and tumor resections. A platform for nasal tissue regeneration was set up using poly(vinyl alcohol)/gelatin sponges with 20%–30% (w/w) gelatin content to be used as scaffolds, for their intrinsic hydrophilic, cell adhesive and shape recovery properties. We propose mesodermal progenitor cells (MPCs) isolated from the bone marrow as a unique stem cell source for obtaining different connective tissues of the nose, including vascular tissue. Finally, epithelial cell immune response to these scaffolds was assessed in vitro in an environment containing inflammatory molecules. The results showed that mesenchymal stromal cells (MSCs) deriving from MPCs could be used to differentiate into cartilage and fibrous tissue; whereas, in combination with endothelial cells still deriving from MPCs, into pre-vascularized bone. Finally, the scaffold did not significantly alter the epithelial cell response to inflammatory insults derived from interaction with bacterial molecules

Stereoselective synthesis of functionalized pyrrolidines by the diverted NH insertion reaction of metallocarbenes with β-aminoketone derivatives

A highly stereoselective route to functionalized pyrrolidines from the metal catalyzed diverted N-H insertion of a range of diazocarbonyl compounds with β-aminoketone derivatives is described. A number of catalysts (rhodium(II) carboxylate dimers, copper(I) triflate and an iron(III)porphyrin) are shown to promote the process under mild conditions to give a wide range of highly substituted proline derivatives. The reaction starts with a metallocarbene N-H insertion but is diverted by an intermolecular aldol reaction

Property enhancement of healable supramolecular polyurethanes

Low molecular weight additives which can cooperatively self-assemble with supramolecular polyurethanes via complementary hydrogen bonding interactions offer an attractive route to enhancing the properties of addressable polymer networks. Here, we present the design, synthesis, characterisation and mechanical properties of a series of supramolecular polyurethanes with varied loadings of a low molecular weight bis-urea additive. These additives are able to self-assemble with analogous recognition motifs within the supramolecular polyurethanes to form polar ‘hard’ domains, promoting phase separation within the material and, crucially, increasing the strength of the polymer network. In addition, the bis-urea additive is a by-product within the polymerisation and thus can be synthesised in situ, without the need for complex purification or blending. The mechanical properties of these reinforced polymers were enhanced when compared to the pristine supramolecular polyurethane alone, as a result of higher degrees of order within the polymer matrix. Furthermore, a formulation comprising the small molecule blended with the supramolecular polyurethane was produced to examine the effect of material preparation and filler dispersion within the polymer matrix. Interestingly, the mechanical performance of a blended material was diminished as a result of modest dispersion and incorporation within the polymer matrix. These findings thus demonstrate a facile, one-pot, method that does not require purification to produce reinforced supramolecular polyurethanes. This methodology may find use in industrial applications in which enhancements to the physical and mechanical properties can be easily achieved through the in situ synthesis of low molecular weight additives within the polymerisation