Part I. the Reactions of 2-Oximino-Cholesta-4, 6-Diene-3

This dissertation has been microfilmed exactly as received ® 7-2401 AHMED, Quazi Anwaruddin, 1938- PART I. THE REACTIONS OF 2-OXIMINO-CHOLESTA-4,6-DIENE-3-ONE. PART n. THE ALKALOIDAL CONSTITUENTS OF TABERNAEMONTANA RIGIDA. The Ohio State University, Ph.D„ 1966 Chemistry, organic University Microfilms, Inc., Ann Arbor, Michigan PART I THE REACTIONS OP 2-0XIMIN0-CH0LESTA-^,6-DIENE-3-0NE PART I I THE ALKALOIDAL CONSTITUENTS OP TABERNAEMONTANA RIGIDA DISSERTATION Presented in Partial Pulfillment of the Requirements for the Degree of Philosophy in the Graduate School of the Ohio S tate U niversity By Quazi Anwaruddin Ahmed, B .Sc..(Honours), M.Sc, ****** The Ohio State U niversity 1966 Approved by Adviser Department of Chemistry ACKNOWLEDGMENTS I wish to express my sincere thanks and appreciation to Professor Michael P. Cava for the guidance and encourage ment received during the course of these problems' and to Dr. G. Praenkel for acting as a temporary adviser. I am indebted to Dr. B. H. Bhat for many helpful dis cussions both in and outside the laboratory. I also thanlc Dr. ,M. J. Mitchell, Dr. K. V. Rao and.Dr. K. Bessho for their helpful suggestions. Lastly, I owe a debt of gratitude to my parents-and most esp ecially to my wife Verena,. l i VITA September 1938 Born - Rajshahi, East Pakistan November, 1958 B. Sc. (Hons.) in Chemistry, Dacca Uni versity, Dacca, East Palcistan November,, 1959 M. Sc. (Thesis Gr.) in Chemistry, Dacca University, Dacca, East Pakistan 1961-1963 . Teaching Assistant, Department of Chemis try , The Ohio S tate U niversity, Columbus, Ohio 1961+-1966 . Research Assistant, Department of Chemis try , The Ohio State U niversity, Columbus, Ohio FIELDS OP STUDY Major Field; Organic Chemistry i l l CONTENTS ■ Pap:e Acknowledgmants ................................. i l V ita ...........................; ......................................... i l l Part I - The Reactions of 2-oximino-choiesta- l+,6-diene-3-one Introduction and Statement of Problem ........................... 1 Historical ............................................................ 5 D isc u ss io n......................................... 38 Experimental ................................................................................... 77 Cholesta-^,6-diene-3-one (CXXII) .................................. 77 2-Oximino-cholesta-^H,6 -diene-3-one (CXXIII) .......... 78 Beckmann rearrangement of 2-oximino-cholesta- . ^-,6-diene-3-one (CXXIII) ............................................... 79 Alkaline degradation of the Beclonann.rearrange ment product CXXIV .......................... 80 Estérification of the acidic degradation product CXXVI ........................................................................ 81 Methyl 2,3-secocholesta-^-,6-diene-2-nitrile- 3-oate (CXXV) ................................. 84 3-Hydroxy-3,3-diphenyl-2,3-secocholesta- 4.6-diene-2-nitrile (CXLVI) ............................ 84 3-Hydroxy-3,3-dimethyl-2,3-secocholesta- 4.6-diene-2-nitrile (CXLVII) ...................................... .86 2,3“Secocholesta-4,6-diene-2-nitrile-3-oic acid-3-amide (CXLV) .......................................................... 87 2,3-Secocholesta-4,6-diene-2-nitrile-3-oic acid-3-N-phenylamide (CXLVIII) ........... 87 Attempted hydrolysis of methyl 2,3-secocholesta- 4 .6 -d io n e -2 -n itrile -3 -o a te (CX:^) ........................... 88 i v CONTENTS (contd.) P a_ge Estérification of 2 , 3-secocholesta-^, 6 -diene- 2.3-dioic acid-2-amide (CXLIX) ........... 90 2 .3-S.ecocholesta-^, 6 -d ien e- 2- n i t r i l e - 3-oio acid (CXXVI) ..................................................................................... 91 Conversion of 2, 3- s e co choie s t a-4-, 6 -d i ene- 2- nitrile-3-oic acid (CXXVI) to 2,3-secocholesta- ^,6-diene-2-nitrile-3-oic acid-3-aiïiide (CXLV).. 91 Attempted isolation of 3-imino-A-homo-cholesta- ^-a,6-diene-^-one-2-methyl ether (CXXIX) .............. 92 2.3-Secocholesta-^,6“diene-2,3-dinitrile (CLII).. 92 Attempted preparation of 2-oximino-3“-phenyl- cholesta— 6 —diene—3^—ol (CXL) ................ 93 Beckmann rearrangement of 2-oximino-3a-phenyl- cholesta-^j6-diene-3i8-ol (CXL) ...................................... 9^- 2- 0ximino-3a-methylcholesta-^, 6 -d ien e- 3;8-o l (CXXXVIII). ....................................................................... 95 Beclcmann rearrangement of 2-oximino-3»-methylcholesta-^,6-diene-3i8-ol (CXXXVIII) .............. 96 2- Diazo- choie s ta-^-, 6-diene-3-one (CLV) ................... • 96 Photolysis of 2-diazo-cholesta-l+,6-diene-3-one (CLV) ......................................................... 97 Attempted lithium and liquid ammonia reduction of 2-oxim ino-cholesta-^,6-diene-3-one (CXXIII) . 99 ; Catalytic hydrogenation of 2-oximino-cholesta- 4 ,6-diene-3-one (CXXIII) ........................................ 100 Catalytic hydrogenation of methyl 2.3-secocholesta-'+,6-diene-2-nitrile-3-oate (CXXV) .... 103 Methyl 2,3“Seco-5®-cholestan-2-nitrile>^3-oate (CLXVIII) ................................................................... 10^- Catalytic hydrogenation of 2,3-secocholesta- lf,6-diene-2,3-dinitrile (CLII) ........................ 10^- V CONTENTS (contd.) Paê 2,3“Seco-5“-cholestan-2~nitrile-3-oic acid- 3-amide (CLXX) ...................... 105 2,3-Seco-5®“Cholest9n-2,3-dlnitrile (CLXIX) .... 106 Part II - Tlie Alkaloidal Constituents of Tabernaemontana' Rigida Intro d u ctio n and Statement ofProblem ............................ 107 Discussion ........................................................ '............................. 120 Experimental ........................ 132 Basic hydrolysis of dl-vincamine (XVIII) to dl-vincaminic acid (XIX) ............................................. 13^ Silver oxide oxidation of dl-vincaminic acid (XIX) to dl-eburnamonine (XX) .......................•............ 135 Dehydration of dl-vincamine (XVIII) to dl-apovincamine (XXI) ................................................ 136 Sodium borohydride reduction of dl-vincamine (XVIII) to dl-vincam inol (XXII) ................................. 137 % Attempted preparation of the quarternary salt XXIII ...................... • 138 Isolation of alkaloids from the crude amorphous tertiary bases B ............................................................. 138 Isolation of alkaloids from P-la .................................... 137 Isolation of alkaloids from F-lb .......................... IÂi- Chromatography of pH 6,6 fraction of F-lb ...... 1,^5 Chromatography of pH 6.0 fraction of F-lb 1^ Chromatography of pH 5.0 fraction of F-lb 1^7 V i CONTENTS (contd.). Appendix Page I. Infrared Spectra ...................... 1^9 II. Ultraviolet Spectra .................... 159 III. Nuclear Magnetic Resonance Spectra ................ 172 v ii Charts P art I I Tentative structure of the dimeric product CXXIV ■.................................................. ^5 P art I I I Alkaloids isolated from Tabernaemontana-... 116 II KnoTOi structures of alkaloids isolated from Tabernaemontana ..................................................' 118 III Plow sheet for the extraction of the total alkaloids ............ 131 v i i i . PART I INTRODUCTION • Steroids are organic molecules ^lÆiich have in common a perhydrocyclopentanophenanthrene nucleus (Fig. 1). Fig. 1 They are so named because they are related to, and in most cases derived from, sterols which are found abundantly in nature, usually in the non-saponifiable fraction of ani mal and plant fats."* The commonest example of a steroid is cholesterol, first isolated from human gallstones, which occurs practically in all animal tissue. It has been found, for example, in beef brain and spinal cord or sheep wool grease. Sitosterol and, "*N. A. Applezweig, "Steroid Drugs," McGraw-Hill Book Co., Inc., New York, N.Y,, 1962, p. 9* 2 stigmasterol, found in vegetable oils, and ergosterol, derived from yeast and other microbiological sources, are all higher alcohols of cyclopentanophenanthrene, having a hydrox yl group at the 3 position"and differing primarily in the side chain at 17. In addition, these naturally occurring ste rols have a double bond between positions 5 and 6. Among other important steroids of natural origin are testosterone, progesterone and estrone. Most of these hormones have a car bonyl group at position 3 and a double bond between positions and 5» There is also a hydroxyl group or side chain at po s itio n 17 and another hydroxyl group or carbonyl group at . position 11 in the case of cortisol-and cortisone respectively. The structure of an insect hormone, ecdysone, has been deter mined and it. was found to be a complex cholesterol derivative. Recently, Kerb and his co-workers^ have synthesized this hormone from a rea d ily av ailab le ste ro id d e riv a tiv e . In recent years, many.authors have reported the prepa ration of modified steroids which have biological activities greater than those of naturally occurring steroids. In these studies, modifications of pharmacological activity resulting from the introduction of halogen atoms, double bonds, hydrox- Û. Kerb, P. Hocks, and R. Wiechert, Tetrahedron L e tte rs, I 387 (1966 ). 3 yl group,3 methyl groups,^.cyano groups,^ thiocyano groups^ as well as combinations of these functions^ have been exam ined. The continuing search for modified steroids with hormonal or antihormonai activity is currently emphasizing structures vri.th hetero atoms such as nitrogen incorporated in the polycyclic nucleus,^ Although some work has been done on the synthesis of aza-steroids

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