1. STUDIES RELATED TO THE SYNTHESIS OF ARYLNAPHTHAtRNE LIGNANS A thesis presented by SUSAN MARY MELLOWS in partial fulfilment of the requirements for the degree of DOCTOR OF PHILOSOPHY of the UNIVERSITY OF LONDON Imperial College London S.W.7. October 1970. 2. Abstract This thesis is concerned with the synthesis o cyclolignans and in particular the synthesis of the pharmacologically active cyclolignan, podophyllotoxin. Existing syntheses of cyclolignans are reviewed. Various photochemical synthetic routes to the cyclolignans are proposed. One of these, the photoenolisation of o-benzylbenzaldehydes and subsequent Diels-Alder addition to the dienol of an appropriate dienophile has been investigated. Some general aspects of the photoenolisation reaction are discussed. Irradiation with ultra-violet light of the model compound o-tolualdehyde in the presence of dimethyl- acetylenedicarboxylate gave 2,3-dicarboxymethy1-1,4- -dihydro-l-naphthol. Cis-C1,C2-cis-C2,C3-l-tetralol- -2,3-dicarboxylic anhydride was formed by photoenolisation of o-tolualdehyde in the presence of maleic anhydride. Metal hydride reduction of the maleic anhydride adduct gave a mixture of cis-C1,C2-cis-C2,C3-2-carboxy-3-hydroxy- methyl-l-tetralo1-2,3'--lactone and cis-C1,C2-cis-C2,C3- 3-carboxy-2-hydroxymethyl-l-tetralo1-2',3-6'-lactone. gn acid catalysed rearrangement of the maleic anhydride adduct gave cis-C1,C2-cis-C2,C3-2,3-dicarboxy-l-tetralo1- 4-lactone which was reduced with diborane to cis-C1,C2- -cis-C2,C3-37carboxy-2-hydroxymethyl-l-tetralo1-2' ,3- - 3 • lactone. The synthesis of 6-(3,k,5-trimethoxybenzyl)piperonal is reported. Photoenolisation of this aldehyde in the presence of dimethylacetylenedicarboxylate gave 2,3-dicarboxymethy1-6,7-methylenedioxy-1-(3,4,5- -trimethoxypheny1)-1,4-dihydro-4-naphthol which could be dehydrated to give 2,3-dicarboxymethy1-6,7- -methylenedioxy-l-(3,4,5-trimethoxyphenyl)naphthalene or oxidised to 2,3-dicarboxymethy1-6,7-methylenedioxy- -1-(3,4,5)trimethoxypheny1)-4-naphthol. 4. Acknowledgements I sincerely thank Dr.P.G.Sammes for his guidance and help during the course of this work. I also thank Professor D.H.R.Barton for the privilege of working in his department. The technical assistance of Mr.R.Carter and his colleagues is gratefully acknowledged. Mr.K.I.Jones and his staff are thanked for micro-analyses. Nuclear magnetic resonance spectra were kindly run by Mrs.I.Boston and Mr.P.Jenkins and mass spectra by Mr.J.Bilton and Mrs. Lee. Colleagues, past and present, in the Tilden laboratory, especially Dr.K.W.Blake, Mr.A.E.A.Porter and Mr.F.Ellis are also thanked for their many useful discussions and their congenial company. 'The Road goes ever on and on Down from the door where it began. Now far ahead the Road has gone, And I must follow, if I can Pursuing it with eager feet, Until it joins some larger way Where many paths and errands meet. And whither then? I cannot say.' Bilbo Baggins The Fellowship of the Ring. Index Page Abstract 2 Acknowledgements 4 Review 7 Introduction 8 Interconversion of naturally occurring lignans 12 to other lignans and cyclolignans Synthesis of dehydrocyclolignanolides from 19 p-aroylpropionic acids Synthesis of cyclolignans,cyclolignanolides and 21 their dehydroderivatives via a 1-aryltetralone intermediate Synthesis of dehydrocyclolignanolides from 38 methyleugenol oxide or from safrole oxide Synthesis of dehydrocyclolignanolides and 44 1-arylnaphthalene-2,3-carboxylic acid anhydrides by photolysis of 1,4-diarylbutadiene derivatives Synthesis of dehydrocyclolignanolides and 47 cyclolignanolides by an intra-molecular Diels-Alder reaction Biosynthesis of lignans 58 Results and Discussion 62 Introduction 63 6. Page Synthesis of 6-(3,b,5-trimethoxybenzyl)piperonal 71 General discussion of the photoenolisation 98 reaction Photoenolisation of o-tolualdehyde and of 112 6-(3,4,5-trimethoxybenzyl)piperonal Experimental 139 References 184 7• REVIEW 8. Introduction Lignans are a group of naturally occurring phenols made up of two phenylpropane (c6-c3) units, joined at the 0-carbon atoms of the side chains. Weinges and Spanigl classified the lignans as true lignans, deriveable from structures Ia and Ib, or cyclolignans, derivatives of II (having two less hydrogen atoms than the true lignans). Those lignans having additional structural features were given more specific names ie. lignanolides III, monoepoxylignans IV and bisepoxylignans V. Similarly, those cyclolignans having a )'-lactone function at C2 and C3 were separately classified as cyclolignanolides VIa and VIb. No specific mention was made by these authors of dehydrocyclo- lignans but in view of the isolation' in recent years of a number of arylnaphthalene lignans, two new groups of cyclolignans warrant independent consideration, dehydrocyclolignans VII and dehydrocyclolignanolides Villa and VIIIb. Ar— C— C—C— Ar— C— C--C- Ar C— C— C— • -C—I —C —Ar ' Ia Ib 9. Ar / \ Ar-- C — c — c4Q,......0 c—c—C Ar'— C— C—e-..... C,z— C , Ar4 II III IV ,Ar . .. • .. /C— C—C R R '\o—L ,. `Ai"' V VIa VIb VII VIIIa VIIIb 10. Examples of arylnaphthalene lignans recently isolated from the Western red cedar, Thuja plicata Donn. are plicatinaphthalene and plicatinaphthol (1, R=H and 1, R=OH)2'8, dehydroderivatives of naturally occurring plicatin (2) which had previously been isolated from the same source4. Further examples, isolated from Justicia procumbens L.5'86 are Justicidin C (3, R=R1=0Me), Justicidin D (3, RR=0.CH2.0, RI=OMe) and Justicidin E (3, RR=0.CH2.0, R1=H). A few dihydroarylnaphthalene lignans have also been isolated LE. (dl)-thomasic acid (4, X=CH2OH) and (d1)-thomasidioic acid (4, X=CO2H) from the heartwood of Ulmus thomasii Sarg.8'7 and collinusin (5) from the leaves of Cleistanthus collinus.8 OH Me0 HO 014 OMe HO OMe HO HO 1 2 11. Me0 Me0 Me0 Me0 OH 4 5 The chemistry of lignans is the subject of reviews by Haworth9, Hearon and MacGreggorl°, Erdtman11, Adjangba12, Kato13, and Weinges and Spanigl . Shrecker and Hartwel114 have reviewed the podophyllum lignans. The present review covers syntheses of the cyclolignans, an aspect which has not previously been comprehensively surveyed. The review will deal.mainly with complete syntheses from common laboratory chemicals although a few illustrations of the numerous interconversions of naturally occurring lignans to other lignans and cyclolignans will be briefly discussed. A short synopsis of the biosynthesis of lignans is also included. 12. 1. Interconversion of naturally occurring lignans to other lignans and cyclolignans. Lignans and lignanolides can be converted to dehydrocyclolignans and dehydrocyclalignanolides, respectively. Flr example, the dimethyl ether (6) of naturally occurring (-)-guaiaretic acid which has been isolated from the resin of Guaiacum officinale L. and Guaiacum sanctum L.1° can be oxidised with iodine and mercuric chloride to dimethyldehydroguaiaretic acid (7)42. Cyclisation of the dimethyl ether (8) of natural (-)-matairesinol, obtained from the heartwood of the New Zealand matai, Podocarpus spicatus78 would be expected to occur towards either of the aromatic nuclei. In the event, treatment with lead tetraacetate gave a mixture of dimethyldehydroconidendrin (9) and dimethyldehydroretrodendrin (10)17. Sometimes partial dehydrogenation of lignans is possible. (-)- Arctigenin (11, R=H) occurs in the seeds of burdock, Arctum lappa L.'6 and its acetyl derivative (11, R=Ac) on treatment with lead tetraacetate yields (-)-acetylcyclo- arctigenin (12, R=Ac). Base hydrolysis of 12 (R=Ac) gives (-)-cycloarctigenin (12, R=H) which in turn, on methylation yields a-conidendrin (12, R=Me)18, a cyclolignan which is widely distributed in nature1°. 13. Me0 Me0 6 7 Me0 Me• • • 400 0 Me0 40100 0 40 OMe 0 OMe OMe 8 9 10 Me0 RO OMe OMe 11 12 14. Monoepoxylignans of the 2,5-diaryltetrahydrofuran type, after reduction with sodium and liquid ammonia and subsequent cyclisation in acidic media yield cyclolignans. For example, (-)-galbelgin (13) which has been isolated from Himantandra belgraveana F.v.Mul12°is converted to (-)-galbulin (14)20, a naturally occurring cyclolignan from the same source". These epoxylignans also undergo cyclisation with loss of water to give dehydrocyclolignans in acidic conditions, (-)-galbelgin (13) giving dehydrogalbelgin (15)20. Some 2,5-diaryltetrahydrofuran lignans occur naturally in a reduced form 2.E. (-)-podorhizol (16, 111=R=OMe) has been isolated as the glucoside from Podophyllum emodi resin", and more recently (-)-para- benzlactone (16, 111=H, RR=0.CH2.0-stereochemistry undefined) has been isolated from Parabenzoin trilobum Nakai?6 Acid catalysed cyclisation of these lignans yields the corresponding cyclolignan, eg. (-)-podorhizol gives a mixture of C1 epimers, desoxypodophyllotoxin (17, R1=R=OMe) and isodesoxypodophyllotoxin (18, 111=R=OMe) and (-)-parabenzlactone is transformed to Justicidin E (3, RR= 0.CH2.0, R1=H) after dehydrogenation of the cyclisation product with N-bromosuccinimide. 15. OMe 111 15 16 17 18 Acid treatment of 2-aryl-4-benzyltetrahydrofuran epoxylignans yields the corresponding cyclolignans. Although (+)-cyclo-olivil (20) has now been found in the resin of the Australian olive, Olea cunninghamii21, it was first obtained by acid treatment of (-)-olivil (19)22, which has been 2 24 isolated from the resin of the olive tree, Olea europaea-;n-' The structures given here for (-)-olivil and (+)-cyclo-olivil have only recently been assigned by Ayres et al.25,28 Similarly, (+)-lariciresinol (21) which occurs in the resin of Larix decidua27, gives (+)-cyclolariciresinol(22) in acidic media27. 16. ss.00H Me0 CH2OH ss OH HO H ,,%iCH2OH -...,. OMe .../ OMe OH 19 . 20 OMe MeO HO sCH112 osCH2OH OH OMe OH 21 22 17. Bisepoxylignans may be partially hydrogenated to the corresponding 2-aryl-k-benzyltetrahydrofuran monoepoxylignans which can yield cyclolignans under acidic conditions. For example (+)-eudesmin (23) which has been isolated from the wood of Humbertia madagasca:riensis and from the wood of Araucaria angustifolia28'29, may be converted to (+)- lariciresinol dimethyl ether and thence to (+)-dimethylcyclolariciresino13°.