Thesis advisor: Marc L. Snapper / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / Chapter 1: The design of a novel first aid smart fabric that is linked to a biologically active molecule through an event specific cleavable linker is described. Successful functionalization of a cellulose filter paper fabric mimic and the synthesis of a linker which is potentially selectively cleavable in the presence of blood have been achieved. Chapter 2: Synthetic studies towards the total synthesis of Torilin, a sesquiterpene guaiane natural product with interesting biological activities are described. The synthesis of the hydroazulene core of Torilin is accomplished through a cyclopropanation/ Lewis acid mediated fragmentation of a highly functionalized polycyclic system which is rapidly accessed through the intramolecular cycloaddition of cyclobutadiene. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / Intramolecular cycloadditions of cyclobutadiene provide rapid access to rigid polycyclic systems with high strain energies and unique molecular geometries. Further functionalization of these systems followed by strain-release fragmentation provides great opportunities to construct fused-medium-ring architecture, which are very common in natural products but challenging to achieve efficiently. An intermolecular cyclopropanation/acid-mediated rearrangement strategy has been previously developed to access the 5-7 bicyclic ring systems in a highly stereospecific manner. The application of this strategy is being studied for the synthesis of a biologically interesting guaiane natural product: torilin. In a complementary fashion, an intramolecular cyclopropanation/thermal rearrangement sequence is developed to access two different molecular frameworks of 5-7-5 tricyclic ring systems. A library of functionalized 5-7-5 tricyclic ring systems can be systematically built up from the same starting material for potential future use in high-throughput screening. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / Cyclobutadiene cycloadditions provide rapid access to rigid polycyclic systems with high strain energy and unusual molecular geometries. Further functionalization of these systems allows entry into unexplored chemical space. A tricarbonylcyclobutadiene iron complex on solid support enables exploration of these cycloadditions in a parallel format amenable to diversity oriented synthesis. Modeling of the cycloaddition transition states with density functional calculations provides a theoretical basis for analysis of the regioselectivity observed in generation of these substituted bicyclo[2.2.0]hexene derivatives. The high strain energy accessible in cyclobutadiene cycloadducts and their derivatives renders them useful synthons for access to medium-ring natural products through ring expansion. Torilin, a guaiane sesquiterpene isolated from extracts of the fruits of <italic>Torilis japonica</italic>, exhibits a range of biological activities including testosterone 5&alpha;-reductase inhibition, hKv1.5 channel blocking, hepatoprotective, anti-inflammatory and anti-cancer effects. These activities are reviewed and analyzed from the perspective of a common biochemical target. Tandem oxidation and acid-catalyzed rearrangement of a highly strained tetracyclo[5.3.0.0<super>1,5</super>.0<super>2,4</super>]decane in the presence of tetrapropylammonium perruthenate provides the bicyclo[5.3.0]decane core of this natural product with complete control of relevant stereochemistry. The complex precursor required for this rearrangement is rapidly accessed by cyclopropanation of an intramolecular cyclobutadiene cycloadduct. Synthetic studies are reported which provide preliminary access to 8-deoxytorilolone. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis describes the efforts towards the synthesis of the guaiane-6,12-olide skeleton, which characterises the guaianolide family of bioactive natural compounds. Two approaches have been investigated: the intramolecular hetero Diels Alder (IMHDA) reaction and the intramolecular carbonyl ene reaction. This thesis has been divided in three sections: the first part gives a general background about the guaianolides, the second section describes the synthetic approaches we investigated and, finally, the third section reports the experimental details. The first section gives a brief overview about the biosynthesis, the biological activities of the guaianolides, and the most interesting synthetic approaches to obtain them. The second section describes the two different approaches we investigated and gives a theoretical background about the main chemical transformations used. At first, the IMHDA reaction approach is described: a brief overview of palladium catalysis and Diels Alder reaction is given, and it is followed by the results and discussion of our study. Similarly, a theoretical background of the Alder ene reaction is given, before the results and discussion of the intramolecular carbonyl ene reaction approach are described: particular importance is given to the reasoning that led to the assignment of the relative configuration of the cycloadducts obtained, and to the rationalisation of this stereochemical outcome. Finally, the third section gives a complete description of the experimental procedures followed, and of the experimental data for the synthetic studies performed in the previous chapter.

One area of natural product synthesis which has been heavily investigated in the last eight decades is the total synthesis of terpenoids. Among terpenoids, the presence of a great deal of stereochemical complexity in combination with a variety of functionalities makes sesquiterpenes challenging targets to the synthetic chemists. As a result synthetic activity in this area continues to flourish. The thesis entitled “Enantiospecific Synthesis of Guaianes and Tricyclic Ring Systems of Elisabethins and Dumsins’’ describes the studies directed towards the synthesis of the guaiane sesquiterpenes and exploratory studies towards elisabethins and dumsin diterpenoids. For convenience, the results are presented in two chapters; viz (1) Enantiospecific Total Synthesis of Guaiane Sesquiterpenes; and (2) Enantiospecific Synthesis of ABC Ring System of the Diterpenoids Elisabethins and Tetranortriterpenoids Dumsins. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. Clavukerin A, the first member of the trisnorguaianes, was simultaneously isolated in 1983 by the research groups of Kitagawa from the Okinawan soft coral Clavularia koellikeri (stolonifer), and Bowden from the Australian soft coral Cespituloria sp. In 1992, Kakisawa and his research group reported the isolation of isoclavukerin A from the Okinawan soft coral Clavularia sp. In the present thesis, formal total syntheses of clavukerin A and isoclavukerin A have been described in the first part of the first chapter. To begin with, (R)-limonene has been transformed into 1-[5-isopropenyl-2-methylcyclopent-1-en-1-yl]pent-4-en-1-one via the 5-isopropenyl-2-methyl-cyclopent-1-en-1-carboxaldehyde. RCM reaction of the enone produced 6,10-dimethylbicyclo[5.3.0]deca-1(10),5-dien-2-one, which on epoxidation generated 1-[(1S,2S,5R) and (1R,2S,5S)-2-isopropenyl-5-methyl-6-oxabicyclo[3.1.0]hex-1yl]pent-4-en-1-ones. These epoxy ketones were then transformed into (6S,7S) and (6R,7S)6,10-dimethylbicyclo[5.3.0]dec-1(10)-en-2-ones, thus completing the formal total synthesis of clavukerin A and isoclavukerin A. In the subsequent parts of the first chapter, enantiospecific total syntheses of the guaiane sesquiterpenes, aciphyllenes A and B, isocalamusenone and 6-epiisocalamusenones, and (6S)- and (6R)-11-hydroxyguaiadienes have been described. Aciphyllene A was isolated in 1983 by Kubota and co-workers from the essential oil of the roots of Lindera glauca. Aciphyllene B was isolated by Konig et al. in 1998 from the liverwort D. hirusta. In 1979, Rohr and co-workers reported the isolation of isocalamusenone from the plant Acorus calamus L, In 2000, Nkunya and colleagues isolated (6R)-11-hydroxyguaiadiene from the root bark of Lettowianthus stellatus, whereas (6S)-11-hydroxyguaiadiene was isolated in 1977 by Bohlmann et al. from the roots of Parthenium hysterophorus. The 5isopropenyl-2-methyl-cyclopent-1-en-1-carboxaldehyde derived from (R)-limonene has been converted into the (3R,4S,6S,7S)- and (3R,4S,6R,7S)-3-acetyl-6,10 dimethylbicyclo[5.3.0]dec1(10)-en-4-ols employing a type II carbonyl ene reaction and Wilkinson’s hydrogenation as the key steps, which have been further converted into aciphyllenes A and B along with their C-6 epimers, (+)-isocalamusenone, 6-epi-isocalamusenone, and (6S)- and (6R)-11-hydroxyguaiadienes. In the second chapter of the thesis, enantiospecific synthesis of the ABC-ring systems of elisabethin group of diterpenoids and tetranortriterpenoids dumsins have been described, starting from the readily available monoterpene (R)-carvone. To begin with, (R)-carvone has been transformed into 1,6,6-triallylcarveol, which on two simultaneous RCM reactions generated the ABC-ring system of the elisabethin group of diterpenoids. An alternative synthetic strategy was also developed for the same compound. Thus, first (R)-carvone has been transformed into 6-allyl-10-isopropenyl-7-methylspiro[4.5]deca-2,7-dien-6-ol, which on ROM-RCM reaction generated the requisite tricyclic alcohol, which on oxidation generated 4,8-dimethyltricyclo[7.4.0.01,5]trideca-3,8,11-trien-7-one, which represents the ABC ring system of elisabethins. Introduction of the second allyl group at the C-7 position of 6-allyl-10isopropenyl-7-methylspiro[4.5]deca-2,6-dien-8-one followed by RCM reaction resulted in the formation of the tricyclic ketones (1S,4S,6R) and (1R,4S,6R)-4-isopropenyl-1-methylbicyclo[4.4.0]decanespiro[5,1']-cyclopenta-3',8-diene-2-ones, which represents the ABC ring system of tetranortriterpenoids dumsins.