Triptycene Derivatives: From Their Synthesis to Their Unique Properties

Since the first preparation of triptycene, great progress has been made with respect to its synthesis and the understanding of its properties. Interest in triptycene-based systems is intense; in recent years, advances in the synthetic methodology and properties of new triptycenes have been reported by researchers from various fields of science. Here, an account of these new developments is given and placed in reference to earlier pivotal works that underpin the field. First, we discuss new approaches to the synthesis of new triptycenes. Progress in the regioselective synthesis of sterically demanding systems is discussed. The application of triptycenes in catalysis is also presented. Next, progress in the understanding of the relations between triptycene structures and their properties is discussed. The unique properties of triptycenes in the liquid and solid states are elaborated. Unique interactions, which involve triptycene molecular scaffolds, are presented. Molecular interactions within a triptycene unit, as well as between triptycenes or triptycenes and other molecules, are also evaluated. In particular, the summary of the synthesis and useful features will be helpful to researchers who are using triptycenes as building blocks in the chemical and materials sciences.

Methodology development for the synthesis of iminosugars

<p>This thesis investigated the development and application of methodology for the synthesis of iminosugars. The first portion of this thesis (Chapters 2 and 3) explored the scope of previously established protecting-group-free Vasella-reductive-amination and I2-mediated carbamate annulation methodology initially developed within the Stocker-Timmer group for the synthesis of pyrrolidines and piperidines from aldose sugars. In this thesis, the Vasella-reductive-amination methodology was extended to include the use of ketose sugars as starting materials, thereby allowing for the synthesis of primary amines directly from in situ formed ketones under protecting-group-free conditions. The scope of the carbamate annulation was then explored, whereby it was determined that both steric and electronic effects appear to affect transition state energies during the annulation reaction. Here, formation of pyrrolidines with the 2,5-trans and 3,4-cis relationships are favoured, however, in circumstances were conflicting electronic- and steric-effects are present, steric-effects dominate thereby favouring the formation of the 2,5-trans product. Using a combination of this Vasella-reductive-amination and carbamate annulation methodology, 2,5-dideoxy-2,5-imino-L-iditol was thus synthesised in 6 steps and 18% overall yield from D-fructose. Next, the same methodology was applied to the synthesis of the promising molecular chaperone 2,5-dideoxy-2,5-imino-D-altritol. Thus, 2,5-dideoxy-2,5-imino-D-altritol was synthesised over 7 steps and in 22% yield from D-tagatose, which is the most efficient synthesis of this iminosugar to date. The second part of this thesis (Chapters 4 and 5) focused on the optimisation and development of synthetic methodology that would allow for the highly efficient synthesis of a variety of iminosugars including piperidines and azepanes. To this end, modifications to existing synthetic methodology allowed for the rapid synthesis of a variety of iodoglycosides, which are important synthons. Next, reductive amination/cyclisation methodology that allowed for the direct transformation of methyl iodoglycosides or isopropylidene-protected iodoglycosides into iminosugars was developed. As such, the piperidines 1-Deoxynojirimycin, 1-Deoxymannojirimycin (DMJ), L-1-Deoxygalactojirimycin (L-DGJ), and (3R,4r,5S)-piperidine-3,4,5-triol were prepared in 4 steps and good overall yields (44%, 62%, 67%, and 53%, respectively). In the case of DMJ and (3R,4r,5S)-piperidine-3,4,5-triol, these are the most efficient syntheses of these materials to date. Factors influencing the stereochemical outcome of the reductive amination reaction were also explored, and evidence suggests that the reduction occurs from the least sterically hindered face of an intermediate cyclic imine, whereby the preferred conformation of the imine is the one which places the largest number of substituents in the pseudo-equatorial position. Using analogous methodology, the azepane (3S,4R,5S,6R)-azepane-3,4,5,6-tetraol was also prepared in 4 steps and good yield (53%).</p>

Methodology development for the synthesis of iminosugars

<p>This thesis investigated the development and application of methodology for the synthesis of iminosugars. The first portion of this thesis (Chapters 2 and 3) explored the scope of previously established protecting-group-free Vasella-reductive-amination and I2-mediated carbamate annulation methodology initially developed within the Stocker-Timmer group for the synthesis of pyrrolidines and piperidines from aldose sugars. In this thesis, the Vasella-reductive-amination methodology was extended to include the use of ketose sugars as starting materials, thereby allowing for the synthesis of primary amines directly from in situ formed ketones under protecting-group-free conditions. The scope of the carbamate annulation was then explored, whereby it was determined that both steric and electronic effects appear to affect transition state energies during the annulation reaction. Here, formation of pyrrolidines with the 2,5-trans and 3,4-cis relationships are favoured, however, in circumstances were conflicting electronic- and steric-effects are present, steric-effects dominate thereby favouring the formation of the 2,5-trans product. Using a combination of this Vasella-reductive-amination and carbamate annulation methodology, 2,5-dideoxy-2,5-imino-L-iditol was thus synthesised in 6 steps and 18% overall yield from D-fructose. Next, the same methodology was applied to the synthesis of the promising molecular chaperone 2,5-dideoxy-2,5-imino-D-altritol. Thus, 2,5-dideoxy-2,5-imino-D-altritol was synthesised over 7 steps and in 22% yield from D-tagatose, which is the most efficient synthesis of this iminosugar to date. The second part of this thesis (Chapters 4 and 5) focused on the optimisation and development of synthetic methodology that would allow for the highly efficient synthesis of a variety of iminosugars including piperidines and azepanes. To this end, modifications to existing synthetic methodology allowed for the rapid synthesis of a variety of iodoglycosides, which are important synthons. Next, reductive amination/cyclisation methodology that allowed for the direct transformation of methyl iodoglycosides or isopropylidene-protected iodoglycosides into iminosugars was developed. As such, the piperidines 1-Deoxynojirimycin, 1-Deoxymannojirimycin (DMJ), L-1-Deoxygalactojirimycin (L-DGJ), and (3R,4r,5S)-piperidine-3,4,5-triol were prepared in 4 steps and good overall yields (44%, 62%, 67%, and 53%, respectively). In the case of DMJ and (3R,4r,5S)-piperidine-3,4,5-triol, these are the most efficient syntheses of these materials to date. Factors influencing the stereochemical outcome of the reductive amination reaction were also explored, and evidence suggests that the reduction occurs from the least sterically hindered face of an intermediate cyclic imine, whereby the preferred conformation of the imine is the one which places the largest number of substituents in the pseudo-equatorial position. Using analogous methodology, the azepane (3S,4R,5S,6R)-azepane-3,4,5,6-tetraol was also prepared in 4 steps and good yield (53%).</p>

New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues

Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).

Heteroelement Analogues of Benzoxaborole and Related Ring Expanded Systems

The review covers the chemistry of organoboron heterocycles structurally related to benzoxaboroles where one of the carbon atoms in a boracycle or a fused benzene ring is replaced by a heteroelement such as boron, silicon, tin, nitrogen, phosphorus, or iodine. Related ring expanded systems including those based on naphthalene and biphenyl cores are also described. The information on synthetic methodology as well as the basic structural and physicochemical characteristics of these emerging heterocycles is complemented by a presentation of their potential applications in organic synthesis and medicinal chemistry, the latter aspect being mostly focused on the promising antimicrobial activity of selected compounds.

A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines HEK293 (human embryonic kidney), MCF7 (human breast adenocarcinoma), HTB81 (human prostate carcinoma), HeLa (human epithelioid cervix carcinoma), RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma), and A549 (carcinomic human alveolar basal epithelial cell). Given the possibilities in the diversity of the substituents that offer the multicomponent synthetic methodology, an extensive structure-activity profile is presented. In addition, both enantiomers of phosphonate-derived γ-lactam have been synthesized and isolated and a study of the cytotoxic activity of the racemic substrate vs. its two enantiomers is also presented. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.