THE SYNTHESIS OF ERGOLINE ETHERS by Brian L. Thompson A dissertation submitted to the faculty of The University of Utah in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Medicinal Chemistry The University of Utah December 1978 THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a dissertation submitted by Brian L. Thompson I have read this dissertation and have found it to be of satisfactory quality for a doctoral degree. ') c ( J Dare/ ,:) H. Richard Shough Chairman. Supervisor\ Commitlee I have read this dissertation and have I' / d it to be of satisfactory quality for a doctoral degree. /0-/;·,7[/ e:;/tt1/l-��- ,r/(�· Dare Robert C. �1ason Member. Supervisory Commitree I have read this dissertation and have found it to be of satisfactory quality for a doctoral degree. -!�-71{ Oak fD William K. Nichols \;lember. SupervisorY Commitrce Member. Supervisory Commitree � t� _Cl, have read this dissertation and have found it t. e of satisfactory quality _ · ..·· - --:- .. ··-- -· : , doctoral degree. ' 1 --- (L �-41Cc'((ii� Ie 113/'7\ tb�::�, Dare I Ie . Oa 1 e Pou 1 ter Member. Supervisory Committee THE U\,[VERSITY' OF UTAH GRADUATE SCHOOL FINAL READI0iG APPROVAL To the Graduate Council of The University of Utah: an [have read the thesis of Sri L. Thompson in its fiml form and have found that (I) its format. citations. and bibliographic style are consistent and acceptable; (2) its illustrative materials including figures. tables. and charts are in place: and (3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Graduate School, Da!� Approved for the Major Department Chairman Dean Approvcd for the Graduate Council James L. Clayton . t1 Ilt:<lr. "f The Gradll<l!� SChlH)1 ABSTRACT The photoaddition of water to the ergot clavine alkaloid, lyser­ gene, has been reported by Shough and Taylor. The product of this reaction, 10-hydroxyagroclavine, was found to rearrange in aqueous acid to give the 8-hydroxy derivative setoclavine. A second photo­ addition of water then gave the 8,10-dihydroxy derivative, lumi­ setoclavine. It was suggested that this same series of reactions could be run in alcohols to give the analogous 10-alkoxy, 8-alkoxy, and 8,10-dia1koxy ergoline ethers. Ergolene ethers of this type and c1avine alkaloids, in general, are of current interest due to the recently described prolactin inhibition of certain c1avine alkaloids and the potent a-adrenergic b10ckage of the ergo1ine ether, nicer­ goline. The main objective of this study, then, was to attempt the synthesis of ergolene ethers by various methods including the photo­ addition of alcohols to lysergene. It was also anticipated that cer­ tain of these ergolene ethers could be useful as intermediates in a new synthesis of lysergic acid amides starting from the clavine alka­ lid elymoc1avine. The photoaddition of methanol to 1ysergene was accomplished to give 10 a-methoxyagroc1av;ne. This photoaddition reaction was not successful in higher alcohols, however. The 10 a-methoxyagroc1avine was, therefore, used to obtain the 8-methoxy, 8-ethoxy, 8-n-propoxy, 8-isopropoxy and 8-~-butoxy derivatives by acid catalyzed equilibration in the appropriate alcohol. An attempt to synthesize the 8,10- dialkoxy derivatives by a second photoaddition of alcohols was, again, unsuccessful. The failure of this second photoreaction seems to indi­ cate that the photoaddition of alcohols across the 9,10 double bond of ergot alkaloids to form the limi-derivatives is not as general a reac­ tion as had previously been supposed. Two nonphotochemical methods were also investigated in an attempt to synthesize ergoline ethers. The solvomercuration-demercuration procedure of Brown was attempted with lysergene, lysergine, agro­ clavine, elymoclavine, and lysergol. This procedure was unsuccessful in our hands, however, as the starting materials were recovered un- changed. The oxidation of agroclavine with manganese dioxide in methanol was also attempted. The expected 10-methoxyagroclavine ap­ peared to be the product along with some lysergene. The yield was poor, however, and the product could not be isolated. When this reac­ tion was run in i-butanol, lysergene was isolated in about 20 percent yield. Earlier, in this lab, we synthesized the 10 a-methoxy-~8,9- 1ysergaldehyde from elymoc1av;ne. In the present study this aldehyde was reduced with sodium borohydride to form the 10 a-methoxyelymocla­ vine which was then rearranged in acidic methanol to give the 8-methoxy- 6-methYl-~9,10-8-hydroxymethYlergoline. Also, in this lab, Choong was able to synthesize the lysergic acid methyl ester by a cyanide catalyzed, manganese dioxide oxidation of the 10 a-methOxy-~8,9_lysergaldehyde. A modification of this v procedure was used in this study to synthesize a series of lysergic and isolysergic acid amides. The cyanide catalyzed, manganese dioxide oxidation was run in the presence of the appropriate amine to give 10 ~-methoxy-~8,9_lysergic acid amide, 10 a-methoxy-~8,9_lysergic acid piperidine amide, and 10 a-methOxY-68,9-lysergic acid L-2-amino-l­ propanol amide. The 10-methoxy group was then reduced with zinc and acetic acid to give isomeric lysergic acid amides. This represented the first synthesis of lysergic acid amides from the clavine alkaloid elymoclavine. vi ACKNOWLEDGMENTS The author would like to thank the University of Utah College of Pharmacy Graduate Program Committee for the financial support which he received. A special expression of deep love and appreciation is due to the author1s wife, Joia, for the hard work and sacrifice which she has endured to help make this dissertation possible. The author is indebted to his parents, Mr. and Mrs. Eugene Wright, for their encouragement, support, financial aid, and profound love and understanding. The author is grateful to Dr. James A. McCloskey and his staff for obtaining mass spectra; to Dr. A. Srinivasan for NMR data; to Jeanne Branson for her assistance and support; and to Dr. H. Richard Shou~h for his assistance throughout this study. Special thanks are due to the author1s father, Mr. Leland G. Thompson, Dr. and Mrs. Charles Robert Sokol, Mr. and Mrs. Clinton Bond, Mr. and Mrs. Earl D. Thompson, Mr. and Mrs. Charles Richard Sokol, Miss Carol Sokol, and the author1s two dear little children, Brian Robert and Megan Gayle Thompson. No acknowledgment would be complete without an expression of appreciation for our Heavenly Father upon whose eternal laws science is predicated. For science is indeed watching God work. TABLE OF CONTENTS Page ABSTRACT. iv ACKNOWLEDGMENTS vi; LIST OF TABLES ix LIST OF FIGURES x LIST OF SCHEMES xi CHAPTERS I. INTRODUCTION The Ergot Alkaloids 1 Obj ect; ves . 6 II. BACKGROUND ...... 11 Photochemistry of the Ergot Alkaloids 11 Synthesis of 10-Alkoxyergo1ines 19 Structure-Activity Relationships of the Ergot Alkaloids 28 Production of Lysergic Acid Derivatives 32 III. RESULTS AND DISCUSSION ............ 39 Photochemical Synthesis of 8-Methy1ergoline . 39 Nonphotochemical Synthesis of 8-Methy1ergoline Ethers 52 Synthesis of 8-Hydroxymethylergo1ine Ethers . .. 55 Synthesis of Lysergic Acid Amides from Elymoc1avine (55) 57 Summa ry of Resu 1ts . .. 65 IV. EXPERIMENTAL .......... 69 General Procedures . .. 69 Preparation of Starting Material and Manganese Dioxide. 71 Synthesis of Erog1ine Ethers. 73 Synthesis of Lysergic Acid ami des 80 REFERENCES . 85 VITA .... 91 LIST OF TABLES Table Page 1. Ergot Alkaloids in Current Clinical Use. .. 2 2. Configuration and Chemical Shift Data for Alkoxy Ergolines 25 3. Prolactin Inhibitory Activity .... 31 4. Proton Magnetic Resonance and Mass Spectral Data for 8- Alkoxy Derivatives . 49 LIST OF FIGURES Figure Page 1. Classification of the Ergot Alkaloids. 3 2. Conformations of l-Alkoxyergolines 26 3. Photoreaction of Lysergene in Alcohols 41 LIST OF SCHEMES Scheme Page 1 . 12 2. 12 3. 15 4. 16 5. 18 6. .... 19 7 • •.•. 20 8. 21 9. 23 10. 24 11 . 27 12. 34 13. 35 14. 37 15. 38 16. 43 17 . ..... 46 18 " 47 19. 54 20. 56 21. 58 Scheme Page 22. 59 23. 61 24. 63 25. 67 xii CHAPTER I INTRODUCTION The Ergot Alkaloids Ergot is the name originally given to the sclerotium which de­ velops on cereals and grasses infected by the parasitic fungus, Clavi­ ceps Purpurea (Fries) Tulasne. Today "ergot" applies to approximately 30 species of the genus Claviceps and alkaloids which they produce. During the middle ages, consumption of ergot infected rye was respon­ sible for epidemics of gangrene and convulsions known as liSt. Anthony's fire. 1I1 Today, the toxic effects of ergot are still sometimes seen in grazing cattle which have eaten ergot infected grasses. 2 The medicinal value of ergot was first recorded in Germany in 1582 where it was used by midwives to induce labor. The crude drug was officially introduced into the United States in the early nine­ teenth century.2 The first crystalline ergot alkaloid was isolated in 1875 and since then the pure natural alkaloids and their semi- synthetic derivatives have been shown to possess a wide variety of pharmacological properties. 3 The major exploitable, pharmacological effects of the ergot alkaloids along with some clinically useful alka­ loids which exhibit these effects are given in Table 1. Besides these effects, the ergot alkaloids also exhibit a complex array of effects on the central nervous system. Among these are vasodilator, hypoten­ sive and bradycardic effects, stimulation of the vomiting center, and 2 TABLE 1 Ergot Alkaloids in Current Clinical Use Actions and Effects Use Alkaloid Uterine Prevention of post- Ergonovine, contraction partum hemorrhage Methylergonovine Vasoconstriction Treatment of migraine Ergotamine, Dihydroergotamine Serotonin Migraine prophylaxis Methysergide antagonism a-Adrenergic Anti-hypertensive and Dihydroergotoxine, blockade treatment of peri ph- Niceragolinea eral vascular disease Prolactin Terminate lactation 2-Bromo-a-ergo- inhibition kryptinea aCurrently undergoing clinical evaluation. 8,38 most notably, the hallucinogenic effect of certain lysergic acid amides.