Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6402. Adviser: Scott E. Denmark. Includes bibliographical references (leaves 243-256). Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6406. Adviser: David Y. Gin. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-11, Section: B, page: 6410. Adviser: Robert M. Coates. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph. D.)--Syracuse University, 2006. / "Publication number AAT 3241864."

This thesis centers on the asymmetric synthesis of polycyclic amines, focussing on three distinct classes of polycyclic alkaloid natural products. The work aims to use common methodology of lithium amide conjugate additions as the source of asymmetry in all cases, and for each product class a single strategy is used to synthesise a variety compounds. Chapter 1 describes the importance of the synthesis of polycyclic alkaloids, highlighting three classes of compounds and documenting prior synthetic strategies. The classes discussed are: the Hancock alkaloids, hydroxymethyl-substituted azabicycles, and the tetraponerine alkaloids. Chapter 2 describes two separate synthetic strategies towards the Hancock alkaloid (-)-cuspareine, one using a benzyne mediated cyclisation and one a Buchwald-Hartwig cyclisation. The Buchwald-Hartwig methodology was also applied in the synthesis of two more Hancock alkaloids (-)-galipinine and (-)-galipeine; the synthesis of (-)-galipeine led to a reassignment of the structure of the natural product. Chapter 3 describes work in the synthesis of four [x.y.0]-azabicycles with differing in ring sizes (x, y = 3, 4). The strategy employs sequential SN2-like ring-closing reactions to form the bicyclic structures where pyrrolizidine, indolizidine and quinolizidine scaffolds can be accessed. Amongst the products are two natural alkaloids, (-)-lupinine and (+)-isoretronecanol. Chapter 4 describes the synthesis of all eight tetraponerine alkaloids T1-8. Two sequential lithium amide conjugate addition reactions allow for the synthesis of the differing ring-sizes and diastereoisomers displayed by the eight alkaloids. Ring-closing metathesis and diamine condensation with 4-bromobutanal provide the ring-closing steps in the syntheses. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2-4.

The use of small molecule chemical probes is highly attractive in dissecting complex biological processes (i.e. multiple protein-protein interactions and protein complexes-derived signaling networks) because of the probe's ability to induce subtle, and generally reversible, changes in protein dynamics. With the goal of developing new synthesis methods leading to high-throughput generation of natural product-like Indoline derivatives having different architectures, this thesis will highlight a modular, tandem reaction approach in which a key reaction is the use of a tandem Michael or aza-Michael reaction to obtain indoline alkaloid-like polycyclic architectures. An interesting feature is that the choice of an amino acid moiety in the side chain allowed the formation of different fused ring systems. The solution phase synthesis method was then developed on solid phase with an objective of generating few analogs in a high-throughput manner.

The hydroamination of alkenes and alkynes is a highly desirable, yet underdeveloped approach to nitrogen incorporation into molecules. Currently, this approach is predominantly limited to transition metal catalysis and suffers from limitations in substrate scope and functional group compatibility. The focus of thesis is the development of simple, metal-free hydroaminations through a different approach that is concerted in nature: the Cope-type hydroamination (eq. 1). This transformation was applied towards the intermolecular hydroamination of alkynes with hydrazines, and is regioselective for the linear, "anti-Markovnikov" isomer 5 (eq. 2) and is presented in Chapter 2. This methodology has also been applied to intramolecular cyclizations and has been extended towards the synthesis of natural products with a specific focus on the challenging formation of 6-membered rings. The total synthesis of the benzyltetrahydroisoquinoline alkaloid norreticuline 8 through a Cope-type hydroamination key step (eq. 3) is presented in Chapter 3.

Étant une transformation difficile, l'hydroamination d'alcènes et d'alcynes inactives n'a encore aujourd'hui pas été développée à son plein potentiel. Cette thèse se penche donc sur l'exploration de l'hydroamination de type Cope. Cette approche concertée est conceptuellement différente et potentiellement générale, pouvant être appliquée aux alcènes et aux alcynes (équation 1).* De la nouvelle réactivité sur la version intermoléculaire a été decouverte entre des alcynes 4 et de l'hydroxylamine aqueuse et est présentée dans le deuxième chapitre de cette thèse (équation 2). Également pour la première fois, l'importance de l'étape du transfert de proton (t.p.) sur la réactivité d'hydroamination intermoléculaire de type Cope a été observée et etudiée avec des résultats expérimentaux, et a été appuyée par des calculs théoriques (DFT). Dans le troisième chapitre, ces nouvelles connaissances acquises sur la réactivité intermoléculaire ont été extrapolées à la réactivité intramoléculaire. La (+/-)-2-epi-pumiliotoxine C a été synthétisée via une étape cle d'hydroamination intramoléculaire de type Cope sur un alcène (équation 3), sous de nouvelles conditions permettant de faciliter le transfert de proton. C'est le premier exemple difficile d'hydroamination de type Cope qui a été accompli en formant un cycle à six membres à partir d'un alcène substitué en sa position terminale. *Please refer to dissertation for diagrams.

The total synthesis of penostatin F (1) has been a goal in our laboratory for the last 6 years. Our first approach developed by Patrick Ang and Roch Lavigne (Scheme 1) involved a hydroxy-directed Diels-Alder (HDDA) reaction between diene 2 and dienophile 4 through the formation of a magnesium alkoxide 3. The single resulting Diels-Alder adduct 5 is then poised to undergo a Claisen rearrangement upon heating, to rapidly afford the bicyclo[5.3.1]undecenone core of penostatin F. Unfortunately, numerous attempts to employ this strategy to complete the synthesis have failed.* This thesis discusses a new approach towards the total synthesis of penostatin F. The key step involves a 6pi electrocyclization of a triene precursor followed by a Claisen rearrangement, as depicted below. Following a successful key step model study, the syntheses of a functionalized alkoxydienyl boronic ester and an enol triflate dihydropyran as coupling partners are described. Issues surrounding the electrocyclization are discussed and possible solutions are presented.* *Please refer to dissertation for diagrams.

Our laboratory reported a novel method to prepare highly oxygenated and functionalized bicyclo[m.n.l]alkanones from acetals using a Lewis acid mediated Prins-pinacol cationic cascade1. This allows us to access complex bridgehead ketone frameworks encountered in many natural products. Garsubellin A is an example of highly functionalized bicyclo[3.3.1]alkanone that we expect to synthesized using the Prins-pinacol methodology. For instance, we were able to prepare diastereoselectively an advanced intermediate for the total synthesis of garsubellin A using this method. Even if the Lewis acid mediated Prins-pinacol cationic cascade appears to be a powerfull method to access complex bridgehead ketone frameworks, we are presently envisaging a second method for the preparation of the garsubellin A core. This method consists in a gold catalyzed Conia-ene reaction. It was already demonstrated in our laboratory that unsubstituted bicyclo[3.3.1]alkanone can be prepared using the gold catalyzed Conia-ene reaction. We want to apply this new methodology to the total synthesis of garsubellin A.