New strategies for the total synthesis of aza-propellane natural products

The propellane alkaloids comprise a large class of natural products that possess varying degrees of structural complexity and biological activity. The earliest of these to be isolated was acutumine, a chlorinated alkaloid that has been shown to exhibit selective T-cell cytotoxicity and antiamnesic properties. Alternatively, the hasubanan family of natural products has garnered considerable attention from the synthetic community in part due to its structural similarities to morphine. While these alkaloids have been the subject of numerous synthetic studies over the last forty years, very few enantioselective total syntheses have been reported to date.

As part of a research program directed towards the synthesis of various alkaloid natural products, we have developed a unified strategy for the preparation of the hasubanan and acutumine alkaloids. Specifically, a highly diastereoselective 1,2-addition of organometallic reagents to benzoquinone-derived tert-butanesulfinimines was established, which provides access to enantioenriched 4-aminocyclohexadienone products. This methodology enabled the enantioselective construction of functionalized dihydroindolones, which were found to undergo intramolecular Friedel-Crafts conjugate additions to furnish the propellane cores of several hasubanan alkaloids. As a result of these studies, the first enantioselective total syntheses of 8-demethoxyrunanine and cepharatines A, C, and D were accomplished in 9-11 steps from commercially available starting materials.

More recent efforts have focused on applying the sulfinimine methodology to the synthesis of a more structurally complex propellane alkaloid, acutumine. Extensive studies have determined that a properly functionalized dihydroindolone undergoes a photochemical [2+2] cycloaddition followed by a lactone fragmentation/Dieckmann cyclization to establish the carbocyclic framework of the natural product. The preparation of more appropriately oxidized propellane intermediates is currently under investigation, and is anticipated to facilitate our synthetic endeavors toward acutumine.

A multi-scale approach to shaping carbon nanotube structures for hollow microneedles

The concept of a carbon nanotube microneedle array is explored in this thesis from multiple perspectives including microneedle fabrication, physical aspects of transdermal delivery, and in vivo transdermal drug delivery experiments. Starting with standard techniques in carbon nanotube (CNT) fabrication, including catalyst patterning and chemical vapor deposition, vertically-aligned carbon nanotubes are utilized as a scaffold to define the shape of the hollow microneedle. Passive, scalable techniques based on capillary action and unique photolithographic methods are utilized to produce a CNT-polymer composite microneedle. Specific examples of CNT-polyimide and CNT-epoxy microneedles are investigated. Further analysis of the transport properties of polymer resins reveals general requirements for applying arbitrary polymers to the fabrication process.

The bottom-up fabrication approach embodied by vertically-aligned carbon nanotubes allows for more direct construction of complex high-aspect ratio features than standard top-down fabrication approaches, making microneedles an ideal application for CNTs. However, current vertically-aligned CNT fabrication techniques only allow for the production of extruded geometries with a constant cross-sectional area, such as cylinders. To rectify this limitation, isotropic oxygen etching is introduced as a novel fabrication technique to create true 3D CNT geometry. Oxygen etching is utilized to create a conical geometry from a cylindrical CNT structure as well as create complex shape transformations in other CNT geometries.

CNT-polymer composite microneedles are anchored onto a common polymer base less than 50 µm thick, which allows for the microneedles to be incorporated into multiple drug delivery platforms, including modified hypodermic syringes and silicone skin patches. Cylindrical microneedles are fabricated with 100 µm outer diameter and height of 200-250 µm with a central cavity, or lumen, diameter of 30 µm to facilitate liquid drug flow. In vitro delivery experiments in swine skin demonstrate the ability of the microneedles to successfully penetrate the skin and deliver aqueous solutions.

An in vivo study was performed to assess the ability of the CNT-polymer microneedles to deliver drugs transdermally. CNT-polymer microneedles are attached to a hand actuated silicone skin patch that holds a liquid reservoir of drugs. Fentanyl, a potent analgesic, was administered to New Zealand White Rabbits through 3 routes of delivery: topical patch, CNT-polymer microneedles, and subcutaneous hypodermic injection. Results demonstrate that the CNT-polymer microneedles have a similar onset of action as the topical patch. CNT-polymer microneedles were also vetted as a painless delivery approach compared to hypodermic injection. Comparative analysis with contemporary microneedle designs demonstrates that the delivery achieved through CNT-polymer microneedles is akin to current hollow microneedle architectures. The inherent advantage of applying a bottom-up fabrication approach alongside similar delivery performance to contemporary microneedle designs demonstrates that the CNT-polymer composite microneedle is a viable architecture in the emerging field of painless transdermal delivery.