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Synthesis of Purine Nucleosides of D-Galactose and D-Galacturonic Acid Derivatives

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Synthesis of Purine Nucleosides of D-Galactose and D-Galacturonic Acid Derivatives This dissertation has been 65-13,266 microfilmed exactly as received PAGNUCCO, Rinaldc Gene, 1938- SYNTHESIS OF PURINE NUCLEOSIDES OF D-GALACTOSE AND D#.GALACTURONIC ACID DERIVATIVES. The Ohio State University, Ph.D., 1965 Chemistry, organic University Microfilms, Inc., Ann Arbor, Michigan SYNTHESIS OF PURINE NUCLEOSIDES OF D-GALACTOSE AND D-GALACTURONIC ACID DERIVATIVES DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University Rinaldo Gene Pagnucco, B.S, The Ohio State University 1965 Approved by Adviser Department of Chemistry ACKNOWLEDGMENT I would like to dedicate this dissertation to my mother. I am grateful to Professor M. L. Wolfrom for suggesting the problems and for the advice given throughout the research period. I would like to acknowledge the helpful advice and encourage­ ment received from all of the members of Sugar Alley and in particular that from Percy McWain. The financial assistance provided by the National Science Foundation and the National Institutes of Health through Professor Wolfrom is gratefully acknowledged. ii \riTA Il Rinaldo Gene Pagnucco» son of Valentino and Regina Pagnucco» was b o m on July 19* 1938» in Alliance» Ohio. After graduating from Alliance High School in 1958» I entered Mount Union College in Alli­ ance» Ohio» from which I graduated, cum laude» in June 1960» with a Bachelor of Science Degree. From June to September I960» I worked as a junior chemist for the Pittsburgh Plate Glass Company» Chemical Division» Barberton, Ohio. In September I96O, I entered Tjie Ohio State University Graduate School, having received from Professor M. L. Wolfrom a research fellowship sponsored by the National Science Foundation. In October I963» I was granted» from Professor M. L. Wolfrom» a research assistantship under the sponsorship of the Depart­ ment of Health» Education» and Welfare» Public Health Service» National Institutes of Health. I have accepted a research assistant­ ship from Professor 0. Th. Schmidt at the Chemical Institute of the University of Heidelberg, Heidelberg, Germany. iii CONTENTS Page ACKNOWLEDGMENT..................................... ii VITA ....................................... iii ILLUSTRATIONS..................................... v i ü INTRODUCTION ...................................... 1 STATEMENT OF OBJECTIVES ............................ 7 HISTORICAL ........................................ 8 lo Nucleosides as Natural Products . ......... 8 Nucleosides as components of nucleic acids . 11 Antibiotics1 nucleosides . ................. 15 Nucleosides of the coenzyme nucleotides ....... 17 Other natural sources of nucleosides ........ 21 II. Synthesis of Nucleosides ..... ............ 21 The Fischer-Helferich method . ............ 22 The Hilbert-Johnson method .......... 23 The Davoll-Lowy (mercuri) m e t h o d ........ 25 Fusion method ............................ 39 Ethyl polyphosphate condensation method ....... 43 Method of fusion of sugar derivatives with trimethylsilyl substituted purines or pyrimidines ..... ........ 44 9y condensation of poly-O-acetyl-glycosyl halide with a nitrogen heterocycle ........ 46 Methods involving cyclization of the aglycon of glycosyl derivatives.................. 47 Other m e t h o d s ................................ 55 iv CONTENTS (Contd.) Page DISCUSSION OF RESULTS............. 57 Synthesis of 2,6-Diacetaraido-9-tetra-0-acetyl- P-D-galactofuranosyl)purine (III) ......... 57 Synthesis of 2-acetamido-9-P-D-galacto- fnranosyladenine ( I V ) .......... 59 Synthesis of 2,6-Diamino-9-P-D-galacto« furanosylpurine (V)......... ......... ... 59 Synthesis of 9-P-D-Galactofuranosyiadenine (Dimorphous) (VI) .................. 6o Synthesis of Penta-0-aoetyl-l-^-benzyl-l- deoxy-l-ethylthio-D-galactose Aldehydrol ( X ) ............. ................... 62 Synthesis of Penta-O-acetyl-l-O-benzyl-1- bromo-l-deoxy-D-galactose Aldehydrol (XI) ...... 64- Synthesis of Penta-0-acetyl-l-(9-adenyl picrate)- 1-0-benzyl-l-deoxy-D-galactose Aldehydrol (XII) . 64- Synthesis of Penta-0-aoetyl-l-(9-adenyl)-1- 0-benzyl-l-deoxy-D-galactose Aldehydrol (XIII) ...................... 65 Synthesis of Ir^Jldenyl)-1-0-benzyl-l- deoxy-D-galactose Aldehydrol (XIV) . .......... 65 Hydrogenolysis of l-(9-Adenyl)-1-0-benzyl- 1-deoxy-D-galactose Aldehydrol (XIV) .......... , 67 Reaction of l-(9-Ader\yl)-1-0-benzyl-1- deoxy-D-galactose Aldehydrol (XIV) with Sodium in Liquid Ammonia .......... ..... 67 Synthesis of 9-(Methyl Tri-g-aoetyl-p-D- galactopyranosyluronate)adenine Picrate (XIX) , , , ........... 68 Synthesis of 9-(Methyl Tri-O-aoetyl-P-D- galactopyranosyluronate)adenine (XX) ........... 69 CONTENTS (Contd.) Page EXPERIMENTAL........................................ ?1 Preparation of penta-O-acetyl-P-D- galactofuranose ( i j ........................... 71 Preparation of tetra-O-acetyl-P-D- galactofuranosyl,chloride (II) . ............ 72 Synthesis of 2 ,6-diacetamido-9-(tetra-0- acetyl-P-D-galactofuranosyl)- purine (III) ................................ 73 Synthesis of 2-acetamido-9-P-D-galacto- furanosyladenine (IV) .............. 74 Synthesis of 2;6-diamino-9-P-D-galacto- furanosylpurine (V)........................... 75 Synthesis of 9-P-D-galactofuranosyladenine (dimorphous) (VI)............................. 7& Preparation of D-galactose diethyl dithioacetal ( V I I ) ........ 78 / Preparation of penta-O-acetyl-D-galactose diethyl dithioacetal (VIII) ................... 79 Preparation of penta-O-acetyl-l-bromo-1*1- dideoxy-l-ethylthio-D-galactose aldehydrol (IX) . ........................... 79 Synthesis of penta-O-acetyl-l-O-benzyl-1- deoxy-1-ethyIthio-D-galactose aldehydrol ( X ) .............................. 80 Synthesis of pehta-Q-acetyl-l-O-benzyl-1- bromo-l-deoxy-D-galactose aldehydrol ( X I ).............................. 81 Synthesis of penta-0-acetyl-l-(9-adenyl picrate)-1-0-benzyl-l-deoxy-D- galactose aldehydrol (XII) ................ 81 Synthesis of penta-0-acetyl-l-(9-adenyl)-l- 0-benzyl-l-deoxy-D-galactose aldehydrol ( X I H ) ............................. 83 vi CONTENTS (Contd.) Page Synthesis of l-(9-adenyl)-1-0-benzyl-l- deoxy-D-galactose aldehydrol (XIV) 83 Hydrogenolysis of l-(9-adenyl)-1-0-benzyl-l- deoxy-D-galactose aldehydrol (XIV) ............. 85 Reaction of 1-(9-adenyl)-1-0-benzyl-I- deoxy-D-galactose aldehydrol (XIV) with sodium in liquid ammonia..... ............ 85 Preparation of a-D-galacturonic acid monohydrate (XV)...................... 86 Preparation of methyl o-D-galacto- uronate (XVI) ................................ 87 Preparation of methyl tetra-O-acetyl- a-D-galactopyranuronate (XVII).................... 88 Preparation of methyl tri-O-acetyl-cu D-galactopyranosyluronate bromide (XVIII)................................ 89 Synthesis of 9-(methyl tri-O-acetyl-P-D- galactopyranosylurona te)adenine picrate (XIX)............................. 89 Synthesis of 9-(methyl t ri-O-acetyl-P-D- galactopyranosyIuronate)adenine (XX) ............... 90 SUMMARY............................................. 92 BIBLIOGRAPHY................................................. 95 vii ILLUSTRATIONS Figure Page 1 Inosinic A c i d ..................................... 10 2 Nucleosides in Ribonucleic Acid ..... ............ 12 3 Nucleosides in Deoxyribonucleic Acid ........ • • • 13 4 Puroinycin....................................... l6 5 Adenosine 5 '-Triphosphate ......................... 18 6 Uridine Diphosphate Glucose ..... 20 7 Synthesis of 2,8-Dic)t’iloro-9-P-D-glucopyranosyladenine . 22 8 Lactam-Lactim Tautomers . .......................... 23 9 Formation of C-1 — C-2-trans Nucleosides.......... » 28 10 Synthesis of 9-(P-D-Glucopyranuronamide)adenine ....... 30 11 Formation and Rearrangement of an 0-Glycoside to the Corresponding Nucleoside ............ 38 12 Synthesis of an Unsaturated Sugar Nucleoside 8y a Modified Fusion Technique..... ...... ........ 42 13 Trimethylsilyl Derivatives of some Purines and I^rimidines..................................... 4-3 14 Adenine Nucleoside from a D-Mannosylamine Derivative . 4-9 15 3-Cyanouracil Nucleoside from a Glycosylamine ...... 50 16 6-Amino-l-P-D-glucopyranosyluracil from Tetra-O-acetyl- D-glucopyranosylurea............. T ......... 52 17 Synthesis of a Thymine Nucleoside from a Glycosylurea ...... ........................ 53 18 9-P-D-XylopyranosylJcanthine from 4-»5-Dimethoxycarbonyl- l-(tri-0-acetyl-D-xylopyranosyl)imidazole 54- Vlll ILLUSTRATIONS (Contd.) Figure Page 19 Synthesis of 2,6-Diamino-9-P-D-galactofuranosyl- purine ( V ) ..................................... 6o 20 Synthesis of 9-P-D-Galactofuranosyladenine (VI) ..... ^2 21 Synthesis of 1-(9-Adenyl)-1-0-benzyl-l-deoxy- D-galactose Aldehydrol (XIV) ...................... 66 22 Synthesis of 9-(Methyl tri-O-acetyl-P-D- galactopyranosyluronate)adenine (XX) ............... yo TABLE Table 1 Hexofuranosyl Nucleosides Prepared by the Mercuri Method ............................ 32 IX INTRODUCTION The term nucleoside» as first proposed by Levene and Jacobs (1)» (1) P. A, Levene and W. A. Jacobs» Ber.» kZt 2474 (1909)* was used to describe the carbohydrate derivatives of purines and pyrimidines obtained on nucleic acid hydrolysis. In recent times it has been expanded to include all glycosyl derivatives of purines and pyrimidines. Interest in the synthesis of nucleosides began with the discovery of the purine nucleoside guanosine in I885 by Schultze(2). Interest (2) E, Schultze and E, Bossard» Z, Physiol, Ghem,» 2» 420 (1885). in nucleosides was further kindled
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