Synthetic and Structural Studies on Natural Coumarins, THESIS presented to the University of'Glasgow for the degree of Doctor of Philosophy by Rlichael Sutcliffe 1973 ProQuest Number: 11017959 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 11017959 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 Acknowledgments To someone not conversant with the day-to-day atmosphere end work of an Organic Research Laboratory, the successful completion of a Ph.d thesis represents simply three years labour on behalf of its author. Nothing could be further from the truth. The very essence of successful research in Organic Chemistry lies in discussion with one’s neighbours, and also in seeking the help and advice of one’s superiors. In Glasgow, neither of these things is lacking. In particular I should like to thank my supervisor, Dr,R ,D ,H .(Hurray for his guidance, advice and unstinting help over the last three years. His enthusiasm for the subject was the source of much inspiration during my low periods. Outwith the realms of Chemistry his friendship, good humour and ready willingness to listen to any problems will be with me long after the content of this thesis is forgotten. I should also like to thank Dr.P ,H .McCabe for much helpful discussion and advice in bath the theoretical and practical aspects of the subject. I owe the greatest debt of all to two people totally unconnected with the Chemistry Department. The first is my wif9 , Alison, who has suffered uncomplainingly for the whole three years and has helped me more than she knows; the second is my late Grandfather, without whose help and encouragement I would never have taken the road to University. I shall be forever grateful to them both. Technical assistance was freely rendered by Iflrs.F. Laturie and her staff; ITlr. 3 .M .L .Cameron, Miss F.Cowan and their staffs; Mr.A .Ritchie and Miss M. Laing; and Mr.A.Haetzman and Mr.3.Gall. Their help is gratefully acknowledged. Samples were kindly provided by: Dr.T.3.King, Nottingham; Professor M.Nakajima, Kyoto; Professor B.S.3oshi, Bombay and Professor M.Hasegawa, Tokyo. I should also like to thank ths Science Research Council for a maintenance award. September, 1973 Summary. In the f irst part of the thesis, synthetic approaches to a number of natural coumarins are described. Oxi­ dative cyclisation reactions of the prenylated phenolic coumarins osthenol and 7-demethylsuberosin are discussed. It has been found that, by varying the reaction conditions, cyclisation con be specifically directed to give either furanocoumarins or pyranocoumarins. In particular, the natural coumarins («)-marmesin, (-)-columbianstin, (~)« decursinol and («)~Iomati.n have each been synthesised in high yield. The regioselective dehydration of (£)~coiumbianGtin to give the naturally occurring isopropenyldihydrofurano- coumarin, -'raasquin, has been investigated. Conditions for the regioselective dehydration of the linear hydroxyiso- propyldihydrofuranocoumarin, (-)-marmesin, to the previously unknown isopropenyldihydrofuranocoumarin have been deter­ mined. The corresponding reaction with the angular hydroxy- isopropyldihydrofuranocoumarin, (l)-colufnbi£netin, has given synthetic (-)-masquin, which could, not be separated from the isomeric isopropylfurocoumarin. Selenium dioxide oxidation of osthenol acatate has been shown to result in exclusive oxidation of the allylic methyl group. In the second section of the thesis, chemical evidence is presented which unequivocally establishes the ^tructura of tomentin, the major aglycone of the wood of Prunua tomentosa, as 5-hydroxy-5,7-dimethoxycoumarin. Attempts ware made to introduce a 1,1-dimethyla.iiyi group at C-8 of t omen tin u/ith a view to obtaining a direct correlation with nieshoutol, the sternutatory constituent of Ptaeroxylon obliquum. The key synthetic precursor, 0-1,1-dimethyl- allyltomentin, was found to undergo a novel charge-induced ortho-CIaisen rearrangement, at R.T., specifically to C~6. This blocked ertha-dienone failed to undergo a para- Claisen rearrangemsnt on heating, while on reduction followed by aromatisation, 6,7-dimethoxycoumarin was ob­ tained. The complex mixture resulting from 1,1-dimethylpropargy1- ation of tornentin has been separated and structures assigned to all of the principle components. The struc­ tures of two novel, isomeric, blocked ortho-dienones, bach containing an -3.3-dimethylallenyl group, have besn rigorously secured on the basis of spectroscopic evidence and the reduction and aromatis3tion of one of them to the known natural coumarin, alloxanthoxyletin. Synthetic and Structural Studies on Natural Coumarins Page, Introduction to Part 1« Including a Short Review. of the Biogenesis of Furocoumarins..... 1. PART 1 Elaboration of the Coumarins, Osthenol and 7-Demethylsuberosin............. ............... 18. General Experimental and Abbreviations...... ... 42. Experimental......... 46. References ...... 65. PART 11 The Chemistry of the Coumarin, Tomentin ... 7 6. E x p e r i m e n t a l 116. References. .................. 137. Introduction to Part 1, Including a Short Reviaw of th8 BioQQnesis of Furocoumarins. (3) R = H i R = OH i Mj 1 The well— estsblished position of the coumarins as natural products has its origin in 1820, when the 1 2 simplest member, coumarin(l) 9 was isolated by Vogel from Coumarouna odorata tUilld. (Tonka beans)* Since then its derivatives have been found to be widely 3-5 distributed throughout the plant kingdom as u/ell 6 7 as being present in some animals and micro-organisms • In 1963, Dean reported^ that about ninety naturally Q occurring coumarins u/ere knou/n. By 1970 more than twice this number had been isolated, with a current approximate estimate being over three hundred. These large increases represent advances in isolation and separation 3 4 9 techniques • * and in physical methods for structure determination. Thus, recently, the seeds alone of Iflammea americana L^. have been shown^^ to contain at least twenty-eight new coumarins. ffluch interest has centred on the diversity of 3 4 physiological effect 9 which natural coumarins can exhibit; these range from the contraceptive activity of psoralen(2)^ and the well-established^ skin sensitising properties of some f urocoumarins-, through anticoagulant^ and vasodilatory^ activity, to behavior 12 as antitumour agents. The aflatoxins(3), on the other hand, 13 are exceedingly toxic . Whereas the synthesis of the aflatoxins has been the subject of some elegant work by Buchi*4, the synthesis of many natural coumarins still remains the province of the enzyme. To illustrate th® problems facing ths synthetic chemist, the structures of a few coumarins, chosen at random from the literature and as yet unsynthesised, are givenin Scheme 1.1. SCHEME 1■ 1 OCR. r | ° Y ^ Y ° Y HOy V 0' t 0 t o 0 ^ : ° h f 2. » - t o b o * 4. 6. o V ° n J ss/ 0>^0 t m v W <C b j C ° 3 J° 7. R = -5CH, , V 0 a ■.. .... "S' Y y ° y ° o V U / , / “ *3 11. 12. CKjO^^YO-yO mrYj° 13. 14 15*v3H CHO^'Y^H ^Jy^NHCO OCONH2 6h 16. 17 HOYo ^ J y U ° y k / ° Y ° och^ ochJ H o t o ^ 1 OCR, V R = { V T 19. N 20. i 2 Index to Scheme 1,1 Th8 numbering system refers only to Scheme 1.1 and not to that of the text. Trivial Name Reference Trivial Mama Reference l.Hydroxyeriobrucinol.••••••15 ll.Rutaretin,..,*25 2#8-ffiethoxygravelliferone..,16 12#Arnottianin.#.26 3.Sa b a n d i n o n e . .17 13#Chalepensin#..27 4«Pinnaterin*•••••••••••••••18 lA.Brosiprenin*••28 5. - .19 15. - ...29 6. Lasiocephalin. ••••••••••••20 16.\/aginidiol««««30 7.Phloro8eseli n............. 21 17.Novobiocin.. .31 8.Tomentolide A.•••••••••••*22 18#Surangin A....32 9.Benahorin.••••••••••••••••23 19*Halfordinin#..33 10. - ••••••••••....... 24 20.Nieshoutol.•..34 00* (1) (4) (5) Examination of the basic coumarin nucleus (l) reveals that there are six possible sites at which oxygenation can occur, all of which are represented in nature. These oxygen functions can be present as phenols or ethers, as can be seen from Scheme 1.1, or as glycosidic ethers, or esters. The presence of one or more isoprenoid chains of variable length, attached to either carbon or oxygen, or to both, is also common feature. These isoprene units are often further elaborated by oxygenation and cyclisation, as shown in Scheme 1.2, imparting an apparently endless variety to natural coumarins. The most common subdivision in coumarins is based on the oxygenation pattern of the nucleus, those having an oxygen atom at C-7 being by far the most numerous. For this reason, umbelliferone (4) is best regarded as the parent natural compound, rather than the structurally more basic coumarin (l). Almost all known coumarins carrying an isoprene unit on nuclear carbon have this moiety ortho to an oxygen 3—5 function ". This probably reflects the biosynthetic pathway leading to the prenylatsd coumarins, it being thought that the C-5 unit is inserted directly by C-alkylation of a phenolic precursor* with dimethylallyl pyrophosphate as a likely candidate for this purpose. At least one exception, that of no brosiprenin (5) , is known, in which the C-5 prenyl group may well arise by a biogenetic para-Claisen rearrangement. SCHEME 1.2 pOR RO"S 1 X R ' H p Y ' R0 roX x ° R 03 > A c R°Nff ^ ' r o Y O ^ O R RoX k o v A* oX i n “K ' 9 > ~U ~K 9 t ° r A -_^CH2OH ~ k a K*- OR m^fsy o r o j l X c T*' (7) (8) Progressive enzymatic elaboration of the 37 3,3-dimethylallyl unit is the probablB process by which compounds like peucedanol(6) marmesin (7) and more complex systems exemplified by micromelumin (8) are generated.