Intramolecular hydroamination represents a potentially general, simple strategy to access various nitrogen heterocycles. While important progress has been accomplished in recent years, six-membered ring formation via alkene hydroamination is typically difficult and limited to terminal alkenes, suggesting that only 2-methylpiperidines can be accessed reliably with current methods. As part of the Beauchemin group efforts on metal-free concerted hydroamination methods, the first part of this thesis describes the development of a Cope-type hydroamination-Meisenheimer rearrangement (CHMR) sequence that is applicable in inter- and intramolecular reactions. Data acquired from optimization on a difficult substrate (coniine) and the successful application of the CHMR sequence to the syntheses of N-norreticuline and 10-desbromoarborescidine are reported. The amination of alkenes is surprisingly scarcely used in the synthesis of complex alkaloids despite its potential for the construction of structurally challenging molecules while avoiding functional group interconversions. Hence, the second part of this thesis describes the studies on a novel amination sequence, consisting of an intermolecular Diels-Alder followed by an intramolecular hydroamination reaction, in the efforts towards the synthesis of biologically active and structurally complex Manzamine A. As such, the synthesis of the model substrates, including the development of a novel family of aminodienes, as well as the assessment of their reactivity towards [4+2] cycloadditions is reported.

This is a thesis in two parts. Part A examines two potential routes towards the synthesis of the communesin family of alkaloids, as well as an overview of some of the successful synthetic routes to date. Our first proposed route involves the gold catalyzed isomerization of an o-amino aryallene to a vinyl imine and subsequent (formal) cycloaddition with an indole. This would have allowed quick access to the pentacyclic core of the communesins; however, the unexpected 5-endo-dig product was exclusively obtained in good to excellent yields. The second route involves the use of a Meerwein- Eschenmoser Claisen rearrangement. This route was successful in affording the C, D, E and F rings of the communesin alkaloids, however future work is required for completion of the synthesis. Also discussed in these sections is an alternative endgame approach involving a novel Pictet-Spangler reaction to afford the G ring, and the possibility of an asymmetric variation to the proposed route. Part B examines the use of alkyl aluminum sesquichlorides in the catalysis of Diels-Alder cycloadditions of sterically hindered systems, a current obstacle in organic chemistry. Previously developed methods are discussed and preliminary results are presented. Ethyl aluminum sesquichloride is compared to other alkyl aluminum catalyst, and the effects of temperature, catalysts loading, choice of solvent, the use of additives, and the use of chiral oxazolidinones are reported and what these result can tell us about the mechanism of catalysis are discussed.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling. / text

A novel application of the Moore rearrangement was successfully developed and applied to the synthesis of 1,4-dioxygenated xanthones that would have been difficult to obtain otherwise. The 1,4-dioxygenated xanthone moiety is found in several naturally occurring, biologically active compounds. Several methods by which to obtain the 1,4-dioxygenated xanthone core have been reported; however, high step counts, low yields, and harsh reaction conditions preclude the use of these methods to complex xanthone natural products. Using the Moore rearrangement as a key step in the synthetic sequence has allowed us to prepare several xanthone natural products quickly and more efficiently than what is possible with the prior art. Using the Martin group’s prior experience with the application of ring closing metathesis (RCM) to the field of alkaloid natural product synthesis, the preparation of lundurine B was undertaken. Key features of the proposed synthesis to lundurine B include the formation of a cyclopropane ring by the formation pyrazoline intermediate via [3+2] dipolar cycloaddition followed by dinitrogen extrusion. A second key step in the proposed sequence to lundurine B is a double RCM to form a five- and eight-membered ring in a single operation. While double RCM strategies have been applied to several elegant natural product syntheses, the formation of a five- and eight-membered ring in a single sequence has not been reported. Should the double RCM strategy prove successful for lundurine B, the conditions could in principle be applied to other structurally related natural products. / text

Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, two protocols of iterative chain elongation of 1,3-diols to furnish 1,3-polyols were developed. First, one-directional chain elongation employing mono-protected 1,3-diols as starting materials was achieved. In all cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Then, double asymmetric allylation of 1,n-glycols to deliver C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Iterative two-directional elongation of 1,3-diols to furnish 1,3-polyols with high level of catalyst-directed diastereoselectivity was then achieved. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of a known bryostatin A-ring fragment and the total synthesis of bryostatin 7. / text

This dissertation is devoted to our synthetic studies towards the total synthesis of the natural product Nakadomarin A, and Manzamine A using the Pauson-Khand reaction as the key step. Chapter 1 reviews past work using Pauson-Khand technology. Chapter 2 reviews the N-alkyl piperidine family of natural products. Chapter 3 reviews published total syntheses of Manzamine A and Nakadomarin A. Chapter 4 explores our work using the Pauson-Khand reaction to form the ABC rings of Nakadomarin A and subsequent B ring expansion to form the ABC ring core of Manzamine A. Chapter 5 explores our approaches to the furan portion, as well as, our approaches to the macrocyclic F ring. Finally Chapter 6 contains the description of the experiments performed along with relevant analytical data. / text

Callophycolide A is a meroditerpene isolated from Callophycus serratus, a Fijian red macroalgae. Callophycolide A has been shown to inhibit bacterial growth, and it exhibits moderate cytotoxicity against multiple human cancer cell lines. Most importantly, it exhibits moderate activity against Plasmodium falciparum, the dead- liest malaria-causing parasite to humans. Due to its antimalarial action and the need for antimalarial drugs on the pharmaceutical market, efforts toward a modular approach to the total synthesis of callophycolide A are presented that incorporate inexpensive, commercially available starting materials, offer gram-level scalability, and utilize known chemistry, including copper-mediated aryl allylation, hydrolytic kinetic resolution, base-promoted epoxide ring-opening, and the Steglich esterification. Once completed, this synthetic pathway can be used as a template for the total synthesis of other related marine natural products, such as the callophycols, callophycoic acids, and the bromophycolides. Callophycoic acids, also isolated from C. serratus, are the first examples of diterpene- benzoic acids observed in macroalgae. In addition, these acids, particularly callophycoic acids G and H, exhibit modest antibacterial activity. Although they are not strongly potent against malaria, they share a trans-decalin core identical to callophycols A and B, which are halogenated diterpene-phenols isolated from C. serratus that do exhibit modest antimalarial activity. Due to their identical core and their simpler structure (i.e., trisubstituted olefin tail), if a divergent total synthesis of callophycoic acids G and H can be established, it can serve as a template for synthesizing natural products that have been identified to be more potent against malaria, such as the callophycols, which are more complex in structure. Herein, a total synthesis of callophycoic acids G and H is investigated, which consists of a Wittig reaction, nucleophilic addition, and a bromonium-induced cation-pi cascade cyclization, and the progress toward the target molecules in the current study will be disclosed. To access chiral intermediates for the aforementioned metabolites, catalytic methods were sought. Hydrolytic kinetic resolution (HKR) resolves racemic epoxides using water as the nucleophile and is most often catalyzed by chiral Co(III)-salens. Previous studies have shown that the counter-ion of the Co(III)-salen has a direct effect on the rate of the HKR; when catalyzed by a 50:50 mix of (R,R)-Co(III)-salen-OH and (R,R)-Co(III)-salen-SbF6, the fastest HKR rates occurred. It has further been shown that the enantioselectivity is primarily associated with the reaction of (R,R)-Co(III)-salen-OH on the activated epoxide. Based on the aforementioned origin of selectivity, a catalyst containing a 50:50 mix of (R,R)-Co(III)-salen-OH and (±)-trans-Co(III)-salen-SbF6 could, in principle, give high activities and enantioselectivities for HKR comparable to a mixed counter-ion system containing both (R,R)-Co(III)-salens. In this dissertation, a series of experiments are described that demonstrate that highly selective catalysis is only achieved using 100% enantiopure ligand and that mixtures of (R,R)-Co(III)-salen and (±)-trans-Co(III)-salen yield lower activity and selectivity. Control experiments demonstrate that this is due to rapid counter-ion scrambling under the reaction conditions, precluding the possibility of effectively co-utilizing enantiopure (expensive) and racemic (inexpensive) catalysts with differing counter-ions. The mechanistic investigations resolving the counter-ion scrambling are consistent with the currently accepted mechanism for catalysis, involving cooperative activity of the two Co(III)-salen species that activate the epoxide and water in the reaction. Moreover, the application of HKR in the progress toward the total synthesis of callo- phycolide A will be highlighted and discussed.

The syntheses of aflastatin A and its C3-C48 degradation fragment are described. The syntheses feature several complex diastereoselective fragment couplings, including a C35-C36 anti-Felkin-selective boron-mediated oxygenated aldol reaction, a C15-C16 Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, and a C26-C27 chelate-controlled aldol reaction involving soft enolization with magnesium. Careful comparison of the spectroscopic data for the synthetic aflastatin A C3–C48 degradation fragment (2) to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. The cause of the mismatch was initially believed to be stereochemical in origin. Ultimately, the data reported for the naturally derived aflastatin A C3–C48 degradation lactol (2, R = H) was attributed to its derivative lactol trideuteriomethyl ether \((R = CD_3)\). Further, the absolute configurations of six stereogenic centers (C8, C9 and C28–C31) in aflastatin A (1) were formally revised by the isolation group prior to completion of its total synthesis. The synthesis of the aflastatin A C3–C48 lactol trideuteriomethyl ether and its spectroscopic match to the naturally derived C3–C48 degradation fragment confirm the stereochemical revision. The synthesis of a degradation product containing the tetramic acid and two overlapping stereocenters (C4 and C6) was also achieved. Its spectroscopic match to the corresponding naturally derived degradation fragment verified the absolute configuration of the aflastatin A C5' stereocenter. When combined with previous degradation fragment syntheses, and eventually the total synthesis of aflastatin A, the revised stereochemical assignment of aflastatin A was fully affirmed. / Chemistry and Chemical Biology