Yes / Chemical manipulation of the cycloadduct of citraconic anhydride and cyclopentadiene enables a new synthetic route to tricyclane sesquiterpenoids. This methodology is applied to the first total synthesis of α-ekasantalic acid. / Spanish Ministry of Education, Culture and Sport for financial support (grant number TME2011-00267 (LL)).

The current increase in antibiotic resistance is of growing concern to the global community. Once easily-treated infections now require last-resort antibiotics with further application only encouraging the eventual buildup of resistance. New drugs are required to fight these infections, specifically with novel mechanisms of action that bacteria have no resistance for. Generally, these drugs will have different scaffolds, contributing to their different mechanisms of action. The literature contains a vast number of antimicrobial metabolites that are understudied but could serve as potential leads for future drugs. One such metabolite is thermorubin, a molecule with a unique scaffold and bacteriostatic mechanism of action. It shows promising sub micromolar activity against both Gram-positive and negative bacteria but suffers from poor oral bioavailability. Difficulties in obtaining this material have led to our development of a total synthetic strategy including a new method for incorporating pyrone moieties into aromatic systems. Based off the Hauser annulation, these conditions were successfully used to insert 15 different pyrones esters and amides into an aromatic system as a dieneophile or a 2-electron component. Modification of the electron-donor, the 4 -electron sulfoxide diene, was also attempted and proved to be somewhat effective. After attempts to use single sulfoxide cycloaddition products failed to propagate, a new donor substrate needed to be created: a symmetrical intermediate already containing both phenyl sulfoxide functionalities. This material was tested and proved successful with further optimization needed to complete the total synthesis of thermorubin. / Doctor of Philosophy / Over the past few decades, the decline in effective ways to treat bacterial infections has become a serious threat to our survival as a species. Easily-treated infections are now becoming impossible to treat, requiring new solutions in the forms of new drugs or drug derivatives. Looking back into the literature, however, potential molecules may have already been discovered but may have been underdeveloped due to having undesirable properties. One such molecule is thermorubin, which shows high selectivity towards bacteria and high activity against a broad range of bacteria. Thermorubin is not water soluble, so part of this work would involve making thermorubin while also making small changes to it to make it more soluble in water. The synthetic construction of thermorubin has never been performed before. The route we would like to use would involve an annulation reaction, a chemical reaction that produces an aromatic ring, with a material that has not been reported in the literature. The structure of this material would also allow for the formation of unwanted side materials. After careful testing, the ideal conditions were developed for product formation, and twenty-one various pyrone esters and amides were applied in the reaction. This optimized reaction was also attempted in the pathway for thermorubin and proved successful, although the product could not be further modified. Due to this inability to be modified, the starting material was altered to already include these modifications before the annulation reaction. Further annulation proved successful, though continued work is required to finish the construction of thermorubin. The synthetic construction of thermorubin has never been performed before. The route we would like to use would involve an annulation reaction, a chemical reaction that produces an aromatic ring, with a material that has not been reported in the literature. The structure of this material would also allow for the formation of unwanted side materials. After careful testing, the ideal conditions were developed for product formation, and twenty-one various pyrone esters and amides were applied in the reaction. This optimized reaction was also attempted in the pathway for thermorubin and proved successful, although the product could not be further modified. Due to this inability to be modified, the starting material was altered to already include these modifications before the annulation reaction. Further annulation proved successful, though continued work is required to finish the construction of thermorubin.

No description available.

The opiate alkaloid (-)-morphine and the Amaryllidaceae alkaloid (-)-galanthamine are well known for their analgesic and anticholinergic properties, respectively. The chemical feature that connects these two molecules is that they are both biosynthesized from an ortho-para phenolic oxidative coupling. Attempts to mimic this aesthetic chemistry in the laboratory for the practical production of these alkaloids have not resulted in good yields of these compounds and there is a lot of scope for improvement. Despite the enormous amount of work devoted to this area, the simple para-alkylation of an appropriately substituted phenol derivative to generate a cross conjugated 2, 5-cyclohexadienone has not been reported. This strategy would avoid the low-yielding phenolic oxidation reaction and the product would merely require a double reductive amination of the aromatic aldehyde and the latent aldehyde (in the acetal) to produce narwedine, the synthetic precursor to (-)-galanthamine. On the other hand, the same intermediate can be elaborated to (±)-morphine via a Henry reaction, followed by reduction and reductive amination. Following the aforementioned methodology, we have successfully completed the synthesis of both these alkaloids via the common intermediate, a 2, 5-cross-conjugated cyclohexadienone. A demonstration of the use of this methodology towards achieving an enantioselective synthesis of these compounds has also been made. The overall yield of the 8 step procedure for galanthamine proceeds in 65% yield, which is approximately five times the yield of the current manufacturing process for this molecule. The synthesis of (±)-morphine, for the first time, allows access to codeine without having to reduce codeinone and, with an overall yield of 20% for the 14 step process, makes this the shortest synthesis of morphine. / text

Merrilactone A (1) was isolated in only 0.004% yield from the methanol extracts of the pericarps of Illicium merrillianum. Structural elucidation of Merrilactone A revealed a compact, cage-like pentacyclic architecture of high molecular complexity, featuring seven stereocentres, five of which as contiguous fully substituted carbon atoms, two γ-lactones and a central oxetane ring. Merrilactone A also exhibits an important neurotrophic activity, significantly promoting neurite outgrowth in the primary cultures of foetal rat cortical neurons at very low concentrations. Structurally, merrilactone A is related to anislactones A and B, a pair of epimeric sesquiterpene dilactones discovered ten years earlier by Kouno and co-workers from the related Illicium anisatum plant. Fukuyama has shown that anislactone B can be converted into merrilactone A using a simple three step sequence, suggesting that the anislactones may be biogenetic precursors to merrilactone A. Described in this thesis are our research efforts directed towards developing a conceptually novel synthetic route enabling regiodivergent total synthesis of both anislactone A / B and merrilactone A. Our synthetic route (around 22 steps) features several key reactions, which include a [2+2] photo-cycloaddition reaction, Tiffeneau-Demjanov ring expansion and titanium(III) mediated radical cyclization.

This thesis is concerned with the development of ring-closing iodoamination and ringexpansion methodology and its subsequent application to the asymmetric syntheses of pyrrolidine and piperidine iminosugars. <strong>Chapter 1</strong> highlights the remarkable biological properties displayed by iminosugars and introduces methods for the formation of the pyrrolidine and piperidine sub-classes. <strong>Chapter 2</strong> describes investigations into the ring-closing iodoamination of bishomoallylic amines which occurs with concomitant <i>N</i>-debenzylation to give an iodomethyl pyrrolidine scaffold. Conversion to the corresponding aziridinium species followed by its regioselective intermolecular ring-opening by H₂O enabled the synthesis of (+)-2,5-dideoxy-2,5-imino-Dglucitol (DGDP). A protocol for the preparation of its 1-deoxy-1-amino analogue (+)-ADGDP was also developed. <strong>Chapter 3</strong> details studies into the ring-expansion of iodomethyl pyrrolidine scaffolds via the trapping of CO₂ (from NaHCO₃) to produce cyclic carbonates as single diastereoisomers. Subsequent deprotection of these piperidines allowed the syntheses of (−)-1-deoxymannojirimycin (DMJ) and (+)-1-deoxyallonojirimycin (DANJ) to be completed. <strong>Chapter 4</strong> delineates investigations into the trapping of alternative “X=C=Y” electrophiles, via the ring-expansion methodology developed in Chapter 3, initially utilising a model system. These studies culminated in the development of the trapping of <i>p</i>-TsNCO and the application of this methodology in the total asymmetric syntheses of (−)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (−)-DMJ and (+)-DANJ, respectively. <strong>Chapter 5</strong> contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

Thesis advisor: Jason Kingsbury / Recent findings have led to the discovery that the Sc-catalyzed addition of substituted diazoalkanes to aldehydes elegantly affords a net carbon insertion into the C-H bond, delivering the requisite ketone in one simple step with no need for a readjustment in oxidation state. This chemistry is much improved over the century old diazomethane chemistry which requires stoichiometric amounts of a promoter and is limited in both application and scope. The new catalytic method has now been utilized as the key step in the synthesis of the pseduosymmetric precursor to the natural product achyrofuran, which has been named “pre-achyrofuran.” Subsequently, a related project was pursued involving the desymmetrization of bicyclic β-diketones by catalytic carbon insertion with trimethylsilyldiazomethane as the reagent. Preliminary developments in this area are disclosed. / Thesis (BS) — Boston College, 2010. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Chemistry Honors Program. / Discipline: Chemistry.

This thesis describes the development of new thermal and oxidative radical cyclization methodologies and their application to the total syntheses of alkaloids, particularly to bridged diketopiperazine (DKP) alkaloids. A practical solvent free approach to diverse DKPs and quinazolines is described. The methodology proceeds by thermal silica gel mediated deprotection of the Boc protecting group and intramolecular condensation of the resulting free dipeptides and tripeptides. It was applied to the total syntheses of alkaloids glyantrypine and ardeemin. A major part of the thesis concerns with the discovery and applications of novel diketopiperazine derived alkoxyamines. Their propensity to undergo facile thermal C-O bond homolysis to generate captodative DKP radicals and persistent TEMPO radical allowed using them as radical surrogates. The methodology takes advantage of the persistent radical effect (PRE). The methodology based on PRE was applied in an asymmetric approach to the alkaloid asperparaline C. An asymmetric synthesis of a very advanced precursor to asperparaline C, 8- oxoasperparaline C, was accomplished in 11 steps and 15% overall yield. The key steps of the synthesis include a direct oxidative cyclization of DKPs, regioselective furan dearomatization with singlet oxygen and a reductive...

Thesis advisor: Marc L. Snapper / A survey of silicon-based reactions and potential for Lewis base catalysis was presented. An efficient site- and enantioselective catalytic silylation of triols is disclosed. The protocol is applied to total syntheses of cleroindicins D, F and C. Catalytic kinetic resolution of &#946;-hydroxyketones is disclosed. A readily available amino acid-based catalyst promotes the kinetic resolution with high efficiency. A presentation of catalytic enantioselective tosylation of syn-1,2-diols is disclosed. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: T. Ross Kelly / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.