thesis titled "lnvestigations into the Synthesis of Dendralene Precursors and EPicatechins." submitted for the Degree of Doctor of Philosophy (Ph.D') by Penelope Jane Kerr B.Sc. (Hons.) from the Department of GhemistrY The University of Adelaide ADELAIDE UNIVERSITY AUSTRALIA G;UGE April 2001 Preface Gontents Title page (i) Contents (ii) Abstract (iv) Statement of OriginalitY (vi) Acknowledgments (vii) paft 1 "lnvestigations into the Synthesis of Substituted Dendralene - Precursors" Chapter 1 1.1 lntroduction 1 1 .ll Results and Discussion 1.lll Experimental 1.lv Conclusions 1.V Future Work 1.Vl References Part 2 "lnvestigations into the Synthesis of Epicatechins" Benefits and Chapter 1 "Green Tea Catechins; their lmpoftance, 68 Detection" 1.1 Green Tea Catechins 1 .ll The importance and Benefits of Green Tea Consumption 1 .llt A Novel Radioenzymatic Assay for the Detection of Green Tea Catechins Chapter 2 "Current Extraction and Purification Procedures of Green Tea" 2.1 lntroduction 1-l 2.ll Results and Discussion 2.lll Conclusions ll Preface Chapter 3 "The Manipulation of (+)-Catechin to form Epicatechins" 3.1 lntroduction s1 3.ll Results and Discussion 3.lll Conclusions Chapter 4 "The Formation of Epicatechin and Epicatechin Gallate Precursors" q6 4.1 lntroduction 4,ll Results and Discussion 4.lll Conclusions Ghapter 5 "lnvestigations into the Synthesis of Epicatechins" Section A 5A.l lntroduction 11+ 5A.ll Results and Discussion 5A.lll Conclusions Section B 58.l lntroduction-Route A 117 58.ll Results and Discussion-Route A 58.lll lntroduction-Route B 5B.IV Results and Discussion-Route B 5B.V Conclusions Chapter 6 "Experimental" ßt References 263 Preface Abstract Two heterocyclic chemistry projects were investigated to establish whether new methods for the synthesis of substituted dendralene precursors and green tea catechins were viable. The synthesis of a number of unique, substituted dendralene precursors was achieved in excellent yield using Stille coupling reactions with palladium catalysis between two different substituted vinyl triflates. Some of these precursors were oxidised using either OXONE or OXONE derivatives, to give sulfolene molecules or 'masked dendralenes' in high yields. The extrusion of sulfur dioxide from these unique substituted molecules using many different techniques proved to be extremely difficult compared to simple non-substituted sulfolenes. lt was concluded that the combination of the two particular substituents acted to increase the stability of the sulfolene. The second project investigated potentially new syntheses of the four main green tea catechins. Readily available, natural (+)-catechin (1) was transformed into epicatechin (32) and epicatechin gallate (33) derivatives by oxidation of the alcohol group at position-3 to the corresponding ketone. Of the many oxidising reagents investigated the Dess-Maftin periodinane reagent provided the best yield of 38%. Reduction of the ketone using sodium borohydride and incorporating the use of stereoselective additives such as CeCls afforded the epicatechin derivative (32). Esterification of the alcohol at position-3 of the epicatechin derivative (32) with 3,4,5-trimethoxybenzoic acid and DCC gave the epicatechin gallate derivative (33). Direct synthesis using allylation and acylation reactions were employed in an attempt to synthesise the other required catechin derivatives, epigallocatechin (3) and epigallocatechin gallate (5). lnstead of providing the epicatechin molecules, the allylation reactions afforded a diallylated phloroglucinol species (70). The acylation IV Preface reaction of 1,3,5{rimethoxybenzene and a mixed anhydride formed from trifluoroacetic anhydride and a propiolic acid derivative furnished the novel chalcones such as (95) in one step, via acylation then Michael addition of 1,3,5-trimethoxybenzene to the B-position of the triple bond. The acylation reaction between 1,3,5-tribenzyloxybenzene and a substituted propioloyl chloride catalysed by a Lewis acid gave the aurone (104) in good yield when the Lewis acid was ferric chloride. A number of substituted acetylenic ketones and/or the corresponding hydrogen chloride adducts, were obtained in good yield when the Lewis acid was zinc chloride. The acetylenic ketones and the adducts had one of the benzyl group adjacent to the acyl substitutent removed in situ for which a mechanism is proposed, leaving these products perfectly set up for cyclisation. The cyclisation reactions of both the alkyne and hydrogen chloride-adducts using a broad range of reagents and conditions, gave aurones in excellent yields. In no case was the desired flavone observed indicating that the cyclisation of these species was not as simple as has been suggested in the literature. V Preface Statement of Originality This work contains no material which has been accepted for the award of any other degree of diploma in any university or other tertiary institution and, to the best of knowledge and belief, contains no material previously published or written by another person except where due reference has been made in the text. I give my consent to this copy of my thesis, when deposited in the University Library, being available for loan and photocopying. 3l Penelo Jane lot VI Preface Acknowledgments A thesis of this sort cannot be due solely to the merit and influence of one person. Many people have contributed on many different levels to generate and acquire the four years worth of research presented within this thesis. The people I am indebted to the most are my two superuisors Dr Simon Pyke and Dr David Ward, who gave me the opportunity to research two extremely interesting areas of organic chemistry. Throughout my pHD studies the knowledge, enthusiasm and support I have received from Simon and David has been unsurpassed. Recently their dedication, time and assistance leading to the fruition of this thesis has been outstanding. Within the Chemistry department I would like to thank the academic, research and technical staff who have assisted me on many different matters. There have been many people that have made a remarkable contribution to my research and just as importantly, created a fun and relaxed research environment. ln particular, for both of these reasons I would like to thank Wayne Pearce, Jen Weeks (P&J tours, of which the bus tour was a highlight!), Francine Palmer, Tom Rozek (for his many talents), Steve Blanksby , Suresh Dua (for his many words of wisdom), Martyn Jevric, Jason Geue, Ben Greatrex, Sam Peppe, Nick Head and Gino Farese. Thanks also goes to Dr Edward Tiekink for his contribution in providing the X-ray crystal structures I would especially like to thank Richard and my family, inparticular Jenny, lan and Felicity for their understanding and support at all times. I cannot express enough the encouragement these people have given me, for which I am eternally dedicated. My friends Anja, Yvette, Esther and Nina all require thanks for their understanding and companionship. A special mention goes out to my rabbit Beverage, a companion who passed away during the final days writing this thesis. vil Part 1 Part 1 : lnvestigations into the Synthesis of Substituted Dendralene Precursors. (l) lntroduction Dendralenes are unique acyclic, cyclic or bicyclic cross conjugated molecules.l These trienes are of particular interest since they contain the simplest possible cross-conjugated system,2 represented by 3-dendralene (3-methylene-1,4-pentadiene) (1 ). (1) These novel systems are able to under go two successive Diels-Alder reactions; a reaction process termed the 'diene transmissive Diels-Alder' or'Cascade Diels-Alde/ reaction, as shown in Scheme 1.3 E E R R R E EC=CE EC=CE .....+ Y + Y x Y x E E (2) (3) (4) Scheme 1 1 Part 1, Chapter 1 An initial cycloaddition reaction with a dienophile across one of the diene parts of the triene (2) forms a ring and an endocyclic double bond (3) which then takes part in a second cycloaddition reaction with a dienophile which may be the same or different. A fused cyclic compound (a) is ultimately formed. The different moieties (X, Y and R), may play prominent roles in both activation of dienes and the regioselectivity of reactions,l whilst adding functionality onto the bicyclic product.3 An attractive extension of the diene transmissive Diels-Alder, is a cross type of reaction in which two different dienophiles are used separately in each step.a This may be achieved by carefully controlling the reaction conditions.5 The regioselectivity of Diels-Alder cycloaddition can be controlled in a number of ways. Constraining one diene unit inside a cyclic structure such as in (5), forms a diene unit that is fixed in the transoid configuration and cannot participate in a Diels-Alder reaction.6 Therefore a selective reaction at (a) is achieved. Secondly, regioselectivity may occur by the use of heteroatoms in place of carbon atoms, such as in (6). The heteroatom will usually confer electron deficiency to the diene and react preferentially with electron-rich dienophiles.6 Another option combines inter- and intramolecular cycloadditions. ln molecule (7), the intramolecular cycloaddition would be expected to proceed first regioselectively, because of geometric constraints. This would generate a diene which could then react intermolecularly.6 x -¿ã x=O,NR (s) (6) (71 Regioselectivity of Diels-Alder cycloadditions can also be achieved by use of substituted dendralenes, such as (8). 2 Part 1, Chapter 1 a b \ / oEt T oEt a-diene b-diene (8) The initial Diels-Alder cycloaddition