Nuclear Magnetic Resonance Studies of Natural Products and Ribonucleic Acids

Abstract

<p>Nuclear magnetic resonance (NMR) spectroscopy has been applied to a number of problems in natural products chemistry and biochemistry.</p> <p>Natural abundance ¹³C NMR spectra was used to differentiate the relative stereochemistry of several naturally occurring diastereomers in the phthalideisoquinoline, protoberberine and spirobenzylisoquinoline alkaloids. The data acquired from this study aided the structural elucidation of 10-oxocancentrine which is a new compound in the cularine-morphine dimer group of alkaloids.</p> <p>In order to assess the factors which influence the conformation and base stacking of a dinucleotide, an NMR investigation of the diastereomers of 2'-0-tetrahydropyranyluridylyl[3'-phenyl-5'] and [3'-(2,2,2-trichloroethyl)-5']2'-0-tetrahydropyranyluridine was undertaken. The steric effect of large substituents on the ribose 2' oxygen was found to be the dominant factor. In addition there is an indication of a stacking interaction between the phenyl ester group and the 5' uracil ring.</p> <p>Proton nuclear magnetic resonance was utilized to probe the factors which affect the helix-coil transition of several synthetic oligoribonucleotides. The complementary tetranucleotides GpApGpC:GpCpUpC were examined to confirm the correlation between the duplex melting temperature (Tm) obtained by NMR and that from the extrapolation of the UV data. This was also the first ¹H NMR study of a non-self-complementary duplex formed by synthetic tetraribonucleotides. The self-complementary sequences CpApUpG, CpApUpGpU and CpApUpGpA were examined to investigate the effect of unpaired terminal dangling bases on duplex stability. From the Tm of 24 ±1°C for CpApUpG, the dangling U in CpApUpGpU causes an increase of +5.5°C and the dangling A in CpApUpGpA causes an increase of +11°C. A dangling U is similar in effectiveness at stabilizing a short duplex as an internal A U hydrogen bonded base pair, while a dangling A is more effective. This work represents the first attempt to quantify the effect of a dangling base on ribonucleotide double helix formation.</p> <p>Much of the work presented in this thesis has been previously reviewed and appears in the literature under the following references:</p> <p>1. ¹³C magnetic resonance spectra of some isoquinoline alkaloids and related model compounds. D.W. Hughes, H.L. Holland, and D.B. MacLean, Can. J. Chem, 54, 2252 (1976).</p> <p>2. ¹³C nuclear magnetic resonance spectra of the spirobenzyliso-quinoline alkaloids and related model compounds.</p> <p>D.W. Hughes, B.C. Nalliah, H.L. Holland, and D.B. MacLean, Can. J. Chem., 55, 3304 (1977).</p> <p>3. Cancentrine V: The ¹³C magnetic resonance spectra of cancentrine and some derivatives; the structure of 10-oxocancentrine. Can. J. Chem. In press.</p> <p>4. Proton magnetic resonance studies on short duplexes. I. Helix formation in the duplex set GpApGpC:GpCpUpC.</p> <p>D.W. Hughes, R.A. Bell, T.E. England, and T. Neilson, Can. J. Chem., 56, 2243 (1978).</p> <p>5. Proton magnetic resonance studies on short duplexes. II. The self-complementary oligoribonucleotide CpApUpG.</p> <p>P.J. Romaniuk, T. Neilson, D.W. Hughes, and R.A. Bell. Can. J. Chem., 56, 2249 (1978).</p> <p>6. The stabilizing effect of dangling bases on a short RNA double helix as determined by proton nuclear magnetic resonance spectroscopy.</p> <p>P.J. Romaniuk, D.W. Hughes, R.J. Gregoire, T. Neilson, and R.A. Bell, J. Am. Chem. Soc., 100, 3971 (1978).</p>