The recent upsurge of degenerative diseases believed to be the result of oxidative stress has sparked an increased interest in utilizing the fundamental principles of physical organic chemistry to understand biological problems. Enzyme pathways can pose several experimental complications due to their complexity, therefore the small molecule probe approach can be utilized in an attempt understand the more complex enzyme mechanisms. The work described in this dissertation focuses on the use of N-cyclopropyl amines that have been used as probes to study the mechanism of monoamine oxidase (MAO) and cytochrome P-450 (cP-450). A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and two of its derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is presented in Chapter 2. The barrier for ring opening of aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) is expected to be low. Reactions of 3BP with all three compounds are very similar. The results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. The chemistry of N-cyclopropyl amines has been used to study the mechanism of amine oxidations by cP-450. Until recently, the rate constant for these ring opening reactions has not been reported. Direct electrochemical examinations of N-cyclopropyl-N-methylaniline showed that the radical cation undergoes a unimolecular rearrangement consistent with a cyclopropyl ring opening reaction. Examination of both the direct and indirect electrochemical data showed that the oxidation potential N-cyclopropyl-N-methylaniline to be +0.528 V (0.1 M Ag⁺/Ag), and rate constant for ring opening of 4.1 x 10⁴ s⁻¹. These results are best explained by two phenomena: (i) a resonance effect in which the spin and charge of the radical cation in the ring closed form is delocalized into the benzene ring hindering the overall rate of the ring opening reaction, and/or (ii) the lowest energy conformation of the molecule does not meet the stereoelectronic requirements for a ring opening pathway. Therefore a new series of spiro cyclopropanes were designed to lock the cyclopropyl group into the appropriate bisected conformation. The electrochemical results reported herein show that the rate constant for ring opening of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] are 3.5 x 10² s⁻¹ and 4.1 x 10² s⁻¹ with redox potentials of 0.3 V and 0.366 V respectively. In order to examine a potential resonance effect a derivative of N-methyl-N-cyclopropylaniline was synthesized to provide a driving force for the ring opening reaction thereby accelerating the overall rate of the ring opening pathway. The electrochemical results show that the rate constant for ring opening of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline to be 1.7 x 10⁸ s⁻¹ . The formal oxidation potential (E°OX) of this substrate was determined to be 0.53 V. The lowered redox potentials of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] can be directly attributed to the electron donating character of the ortho alkyl group of the quinoline base structure of these spiro derivatives, and therefore the relative energy of the ring closed radical cations directly affects the rate of ring opening reactions. The relief of ring strain coupled with the formation of the highly resonance stabilized benzylic radical explains the rate increase for the ring opening reaction of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline. / Ph. D.

Cyclopropanes are strained molecules and undergo reactions, for example, through ring opening and rearrangements. Preparative methods and reactivities of cyclopropanes are known widely in organic synthesis. The high reactivities inherent in cyclopropanes allow them to be valuable building blocks in organic synthesis. The combination of cyclopropanes and carbohydrates has been explored in recent years. Carbohydrates, the naturally-occurring members of chiral pool, are attractive platforms for asymmetric synthesis. Cyclopropanation of, for example, unsaturated sugars affords [4.1.0] bicyclic systems, thereby combining the high reactivities of cyclopropanes together with optical purities of sugars. Chapter 1 of the Thesis describes (i) various types of cyclopropane ring opening reactions in general and (ii) known reactions of cyclopropanes in carbohydrates relevant to the work presented in the Thesis. Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known sugar homologues. Synthesis of septanoses arise interest, due to their configurational and conformational features and the attendant possibilities to explore their chemical, physical and biological properties. In a programme, it was desired to identify a new methodology for synthesis of septanosides. It was envisaged that 2-hydroxy glycals, namely, oxyglycals, would form as suitable substrates for ring expansion, leading to the formation of septanoside derivatives that are retained with hydroxyl groups in each carbon of the septanoside. In the event, a new methodology was identified. A carbene insertion of an oxyglycal substrate, nucleophilic ring opening of the cyclopropyl moiety, oxidation and reduction reactions were identified to expand the six membered pyranoses to seven membered septanosides (Scheme 1). The methodology was established through preparation of two configurationally different septanosides, namely, the methyl α-D-glycero-D-talo-septanoside and methyl α-D-glycero-L-altro-septanoside from D-glucose and D-galactose, respectively. Chapter 2 presents details of the methodology and the preparation of septanosides from precursors oxyglucal and oxygalactal. Scheme 1 Continuing the efforts to extend the methodology, preparation of a variety of septanosides, using phenoxides, sugars and azide were undertaken. It was found that ring opening with sugars were highly stereoselective, leading to an exclusive formation of the -anomer of sugar oxepines, whereas, the phenoxides and azide led to a mixture of anomers of the corresponding oxepines, in a ~1:1 ratio (Scheme 2). Scheme 2 An important observation was -anomer of the oxepine derived intermediates, having diketo-functionalities, underwent NaBH4 mediated conversion to diols with higher diastereoselectivities at the newly generated stereo-centers, whereas the -anomers lacked to retain the diastereoselectivities, in the case of aryl septanosides. This part of work consolidated further the generality of the oxyglycal ring-expansion method to prepare septanosides, possessing different substituents at their reducing ends. Chapter 3 describes the details of syntheses and characterization of various aryl septanosides, septanoside disaccharides and azido-septanoside derivatives. It was planned further to synthesize septanoside containing di-and trisaccharides from naturally-occurring disaccharides, through the oxyglycal route. Oxyglycals, derived from lactose and maltose, were expanded to septanoside-containing trisaccharides through a ring expansion method. Thus septanosides incorporated disaccharides and trisaccharides, with 6-7, 6-7-5 and 6-7-6 ring sizes, were prepared through the ring expansion method. The reaction not only led to a ring expansion, but also, to a concomitant glycoside formation, in a stereoselective manner (Scheme 3). Scheme 3 A conformational analysis of the galacto-septano-glucopyrano-configured 6-7-6 trisaccharide was undertaken with aid of NMR spectroscopy and computational methods. Spatial distances from NMR experiments were utilized while performing molecular dynamics with AMBER* force field and further optimizations using B3LYP/6-31+G* level. The study showed that septanoside ring in the trisaccharide adopted twist-chair conformation O,1TC5,6, as shown in Figure 1. Chapter 4 describes synthesis of septanoside containing di-and trisaccharides and conformational analysis of a 6-7-6 trisaccharide, through solution phase and computational methods. An effort was pursued to prepare septanoside-based amphiphiles with varying alkyl chain lengths, using our newly established methodology and to study their amphiphilicities. A series of septanoside amphiphiles, having C10 to C18 alkyl groups, were prepared as their -anomers as shown in Figure 2. The amphiphilic behavior of the alkyl septanosides was assessed through studies of their liquid crystalline (LC) properties. The LC properties were evaluated using polarizing optical microscopy, differential scanning calorimetry and powder X-ray diffraction methods. All the septanoside amphiphiles exhibited a smectic A phase in general. DSC thermograms showed crystal-crystal and crystal-mesophase phase transitions. Powder X-ray diffraction studies allowed to identify the lamellar structuring of the smectic A phase. Further, two distinct two layer spacings were observed. Such an observation is un-usual in carbohydrate liquid crystals. Chapter 5 details of synthesis and studies of the mesomorphic behavior of septanoside amphiphiles. In summary, the Thesis establishes a new route to synthesize septanoside derivatives, from oxyglycal sugar derivatives. Ring expansion of a pyranoside to a septanoside was achieved through key reactions of a cyclopropanation, ring opening, oxidation and reduction. Methyl α-D-glycero-septanoside derivatives were synthesized, from the corresponding oxyglycals. Cyclopropane ring opening ability of various nucleophiles were studied, it was found that ring-opening reactions with phenols, sugars, and azides are effective, which facilitated the synthesis of various aryl, glycosyl and azido-substituted septanosides. Synthesis of septanosides incorporated with di-and trisaccharides were accomplished. The detailed conformational analysis studies showed that the septanoside adopted twist-chair conformation in a trisaccharide molecule. Preparation and studies of septanoside based amphiphiles and their mesophase behavior were also accomplished. Overall, the studies presented in the Thesis provide a new insight to ring expanded sugars. The salient features of the present method are that the intermediates such as the seven membered vinyl halides, vinyl ethers, the diketones and the diols are potential sites for many other functionalizations. These features can be explored further in functionalizing the newly formed septanosides. (For structural formula pl see the pdf file)

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal