<p>Direct carbon&mdashcarbon bond formation via soft enolization and in situ enolate formation provides a straightforward approach to certain key transformations of synthetic organic chemistry. Reactions are generally operationally simple and proceed under mild conditions using untreated, reagent&ndashgrade solvent open to the air. Using this direct approach as a basis, we have developed methods for the synthesis of β&ndashhydroxy thioesters, β&ndashketo thioesters, and 1,3&ndashdiketones, which are key intermediates for the synthesis of natural products, pharmaceuticals, and other biologically relevant compounds. In particular, we describe: 1) a direct aldol addition of simple thioesters, 2) a direct synthesis of 1,3&ndashdiketone compounds, 3) a direct crossed&ndashClaisen reaction, and 4) an <italic>anti<italic>&ndashselective four&ndashcomponent direct aldol cascade reaction.</p><p>Progress toward the total synthesis of apratoxin D is described. The key steps of the synthesis involve the asymmetric alkylation via chiral <italic>N<italic>&ndashamino cyclic carbamate (ACC) hydrazones, a new technology recently developed in our group.</p> / Dissertation

<p>Modern patterning and fabrication techniques provide powerful opportunities for the preparation of micro- and nanostructured objects with applications in fields ranging from drug delivery and bioimaging to organic based electronic devices and real time biochemical sensors. In this thesis we report a systematic study focused on the development of new unconventional patterning and fabrication techniques with applications in the preparation of functional micro- and nanostructured devices.</p><p>Catalytic microcontact printing is a powerful technique that offers a simple and effective methodology for patterning chemically-functionalized surfaces with sub-100 nm accuracy. By avoiding diffusive mechanisms of pattern replication it effectively obviates the most significant limitation of traditional microcontact printing - lateral molecular ink diffusion. Moreover, catalytic microcontact printing significantly expands the diversity of patternable surfaces by using prefunctionalized substrates and gives rapid facile access to chemically discriminated surfaces that can be further functionalized with organic and biological molecules. We have developed several catalytic microcontact printing techniques that transfer pattern from an elastomeric stamp bearing an immobilized catalyst to a preformed functionalized self-assembled monolayer. By avoiding diffusive pattern transfer we were able to replicate features with sub-50 nm edge resolution. We also demonstrated that catalytic printing can be expanded to technologically important substrates not accessible through conventional soft lithography, by patterning reactive organic monolayers grafted to chemically passivated silicon.</p><p>The non-symmetric structure of Janus particles produces novel physical properties and unusual aggregation behavior that makes these materials attractive candidates for drug delivery and as nano-sensors and nano-probes, SERS and PEF imaging agents, small molecules carriers, and switchable devices. We have developed a new protocol for preparation of non-spherical inorganic Janus particles comprising metallic and semiconductor layers. The method allows for precise control over the composition, shape and size and permits fabrication of non-symmetrical particles, the opposite sides of which can be orthogonally functionalized using well-established organosilane and thiol chemistries.</p> / Dissertation

<p>The dissertation focuses on three main projects which complement the studies towards the total syntheses of biologically active natural products as well as the development of stereoselective synthesis of 2,6-disubstituted piperidines. </p> <p>The first project introduced the first total synthesis of largazole, which is a marine natural product isolated from cyanobacterium of genus Symploca sp. in 2008. It consists of an unusual 16-membered macrocycle incorporating a 4-methylthiazoline linearly fused to a thiazole and an ester of 3-hydroxy-7-mercaptohept-4-enoic acid unit, part of which has been identified to be essential for the potent histone deacetylase (HDAC) inhibitory and consequently antiproliferative activities. Structure-activity relationship (SAR) studies suggest that thiol group generated by hydrolysis of the thioester moiety is the warhead and is critical for its HDAC inhibitory and antiproliferative activity. The biological evaluation of the analogues focusing on macrocycle and linker chain between sulfur atom and macrocycle suggests that the four-atom linker between the macrocycle and the octanoyl group in the side chain and the (S)-configuration at C17-position are critical to potent HDAC inhibitory activity of largazole. In contrast, the valine residue in the macrocycle can be replaced with alanine without compromising activity to a large extent. These SAR results would provide insights into structural requirements for HDAC inhibitory activity including the observed HDAC selectivity of largazole and help in the design of isoform-specific HDAC inhibitors based on largazole.</p> <p>The second project involved the synthesis of cytotoxic mycobactin-like siderophore-brasilibactin A and its unnatural diastereomers, which are then identified to unambiguously confirm that brasilibactin A possesses the 17S, 18R absolute stereochemistry at &#946;-hydroxy acid fragment. The convergent synthetic strategy has been applied to the synthesis of a more water-soluble analogue-Bbtan, iron-binding studies of which suggest brasilibactin A may play an important role in the iron-uptake mechanism in mycobacteria and related organisms. </p> <p>The third project elucidated a convergent stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through a reagent-controlled organocatalytic aza-Michael reaction promoted by the gem-disubstituent effect introduced by 1,3-dithiane. The reaction was applicable to a broad range of substrates and proceeded with good stereoselectivities (up to 20:1 dr) and yields. The 1,3-dithiane group allowed for rapid access to substrates, promoted the intramolecular aza-Michael reaction via the gem-disubstituent effect, and improved the yield of the reaction. This synthetic method should be broadly applicable to the efficient synthesis of a diverse set of bioactive natural products with 2,6-disubstituted piperidines.</p> / Dissertation

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.