INVESTIGATIONS OF RING–OPENING REACTIONS OF CYCLOPROPANATED CARBOHYDRATES: TOWARDS THE SYNTHESIS OF THE NATURAL PRODUCT (−)-TAN-2483B by Russell James Hewitt A thesis submitted to Victoria University of Wellington in fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Victoria University of Wellington 2010 Abstract Cyclopropanes and carbohydrates are materials of great interest to chemists. Ring opening reactions of cyclopropanated carbohydrates have excellent potential for syn- thesis, due to the many diverse structures that may be obtained. The work described in this thesis explores the scope of such ring opening reactions, and extends to the synthesis and reactions of several novel cyclopropanated carbohydrates, in which synthesis of a natural product was also investigated. Several bicyclic gem-dihalocyclopropanes, including 97, were synthesised. Base– mediated cyclopropane ring opening of 97 in the presence of nucleophiles afforded a series of 2-C -branched glycosides 389 and 390 (Chapter 2), whereas silver–promoted ring expansion provided access to seven–membered rings (255 and 256) (Chapter 3). Studies on the mechanisms of the ring opening processes were also carried out. H OR O OR O BnO O BnO BnO Br Br BnO Br BnO BnO H OBn Br OBn BnO 389, 390 97 255, 256 Ring–opening reactions of carbohydrate–derived gem-dihalocyclopropanes were also applied to the exploration of possible routes to the natural product (−)-TAN-2483B (154). Attempts to convert d-galactose and d-xylose into the dihydropyran 193 are the subject of Chapter 4, while the transformation of d-mannose into 193 and subsequent efforts to prepare the natural product 154 are discussed in Chapter 5. R' R O OH H H O O PGO OH HO OH O OH PGO X HO O 193 154 ′ R = H, CH2OH R = H, CH2OPG (−)-TAN-2483B PG = protecting group ii To my Grandmother, Rev. Joan M. Pascoe iii Acknowledgements Gandalf : “I am looking for someone to share in an adventure that I am arranging. ” Bilbo : “...I have no use for adventures. Nasty disturbing uncomfortable things! Make you late for dinner!” J. R. R. Tolkien The Hobbit First and foremost, thanks to Dr Joanne Harvey, it has been an absolute pleasure working for you. Your enthusiasm (for cyclopropanes especially) and knowledge of chemistry has been so beneficial. Whenever I hit a brick wall, you were always able to provide me with alternative ways around problems. No matter how small my research updates may have been, I was guaranteed of your interest, especially if I had another unusual set of spectra to show you. Thanks also to the other organic synthesis academics, Dr Brendan Burkett and Dr Paul Teesdale–Spittle. You both had so many useful questions or comments at group meeting, which often helped me think about my chemistry from a different point of view. I’m very grateful to my thesis editors, Joanne, Brendan, Lynton and Mark. Not only was your hard work of immense value, your kind comments helped my confidence in my storytelling immensely. I have had a great bunch of labmates over the years. From the earlier days, thanks to Lynton (whose calm efficiency I could never emulate), Emma T, Rhys, Shivali, Emma D, and my labmates in 208 - Robert, Catherine, Ashna, Shi and Jim. For those more recent labmates who put up with a slightly odd “senior lab guy”, thanks to Anita, Febly, Sam (best person to share a fumehood with), Thomas, Hemi, Jack, Mark, Peter M (my prot´eg´e), Peter C and Xuyu. iv Thanks to Assoc. Prof. Peter Northcote, Dr Mattie Timmer and Prof. John Spencer, and of course their students. Helpful advice, in addition to great commu- nication between the labs was of great benefit. The general staff at SCPS make postgraduate study so much easier. A big thanks to Lisa and Sally, who saw a lot more of me than most, and always had an answer for my numerous queries. Darren, Grant, Helen, Alan, Manu and John Ryan have all been very helpful in solving all sorts of problems that arose over the years. Thanks also to the lab technicians Rhys, Teresa, Jackie and Jaime–Anne, who frequently let me use or borrow their equipment. And of course, the gradroom camaraderie has been another bonus, thanks to Anna, Azeem, Benjamin, Carla, Ramprasad and Srikanth. A special thanks to Ashna, who has been a great friend, and it was great to be able to share the latest lab results with Jacqui, one of the few people whose enthusiasm for research could match mine. Thanks to Mina and John Ryan for providing very helpful LATEX templates, and for all the others who recommended I change from Word! Finally, I must thank those outside of SCPS. Thanks to my friends and numerous flatmates, especially to Chao and Jo, and Nancy (a wonderful neighbour) who could always help me take my mind off chemistry. A final thanks to my family. Mum and Terry, Dad and Helen, and my sister Re- becca, you have always been there for me, and have made study so much easier with your support, despite the distances that separate us. v Table of Contents Abstract ii Acknowledgments iv Table of Contents vi List of Figures ix List of Schemes x List of Tables xiv Glossary xv Compound Numbering xvii Publication xviii 1 Introduction 1 1.1 Cyclopropanes............................... 1 1.1.1 SynthesisofCyclopropanes. 1 1.1.2 Ring Expansion of gem-Dihalocyclopropanes . 2 1.2 CyclopropanatedCarbohydrates . 3 1.2.1 Synthesis of Cyclopropanated Carbohydrates . ... 4 1.2.2 Reactions of Cyclopropanated Carbohydrates . .. 10 1.3 Oxepanes,OxepinesandSeptanoses. 19 1.4 Furo[3,4-b]pyran-5-ones.......................... 21 1.4.1 Syntheses of Furo[3,4-b]pyran-5-ones . 21 1.4.2 Furo[3,4-b]pyran–basedNaturalProducts . 23 1.4.3 Syntheses of Furo[3,4-b]pyran–Based Natural Products . 26 1.5 ResearchObjectives. 30 1.5.1 Ring–ExpansionStudies . 30 1.5.2 Synthesis of (−)-TAN-2483B................... 32 vi 2 Base–MediatedRing–OpeningReactions 35 2.1 Introduction................................ 35 2.2 Synthesis of Cyclopropanes 97 and 190 ................. 36 2.3 Base–Mediated Methanolysis of Cyclopropanes 97 and 190 ...... 39 2.4 MechanisticStudies. 43 2.5 Base–Mediated Ring Opening with Alternative Nucleophiles ..... 48 2.6 Palladium–Catalysed Coupling Reactions . .... 49 2.7 Reactions of Galactose and Xylose Derivatives . .... 50 2.8 SummaryofChapter2 .......................... 53 3 Silver–Mediated and Thermal Ring–Opening Reactions 54 3.1 Introduction................................ 54 3.2 Silver–Mediated Ring–Expansion Reactions in Acetic Acid ...... 55 3.3 Ring–Expansions of Cyclopropane 97 with Alternative Nucleophiles . 57 3.4 ScopeofOxepineSynthesis . 60 3.5 Oxepines Derived from Galactose and Xylose. .. 62 3.6 OxepineDerivatisationReactions . .. 63 3.7 SynthesisofFuranosylSugars . 64 3.8 SummaryofChapter3 .......................... 69 4 Galactose and Xylose–Based Approaches to (−)-TAN-2483B 70 4.1 Introduction................................ 70 4.2 Synthesis and Cyclopropanations of 2,3-Unsaturated Sugar 290 ... 72 4.3 Synthesis of Alternative 2,3-Unsaturated Carbohydrates ........ 74 4.4 p-Methoxybenzyl–Protected Xylal Route to (−)-TAN-2483B . 76 4.5 Benzyl–Protected Xylal Route to (−)-TAN-2483B . 79 4.6 SummaryofChapter4 .......................... 81 5 Approaches to (−)-TAN-2483BfromMannose 82 5.1 Introduction................................ 82 5.2 Synthesis of Mannose–Based Glycal 209 ................ 84 5.3 Synthesis of the Pyran Ring of (−)-TAN-2483B . 85 5.3.1 Cyclopropanation of Glycal 209 ................. 86 5.3.2 Ring Expansion of Mannose–Derived Cyclopropane 340 .... 87 5.4 Functionalisation of the Pyran Ring of (−)-TAN-2483B . 89 5.4.1 EthylideneWittig–BasedRoute . 89 5.4.2 MethylideneWittig–DerivedRoute . 91 5.4.3 Stabilised Wittig–Based Route to (−)-TAN-2483B . 93 5.4.4 HWE/Ramberg–B¨acklund Route to (−)-TAN-2483B . 94 5.5 Approaches to the furo[3,4-b]pyran-5-one skeleton of (−)-TAN-2483B 99 5.6 SummaryofChapter5 . .102 vii 6 Future Work 103 6.1 RingOpeningStudies. .103 6.2 NaturalProductSynthesis . .104 7 Experimental 106 7.1 GeneralExperimentalDetails . 106 7.2 ChapterTwoExperimental . .107 7.3 ChapterThreeExperimental. .127 7.4 ChapterFourExperimental . .145 7.5 ChapterFiveExperimental . .155 Spectra 180 References 193 viii List of Figures 1.1 Simmons–Smithderivedcyclopropanes . .. 6 1.2 Formation of septanoside–based trisaccharides via cyclopropanes . 18 1.3 Seven–memberedringnaturalproducts . .. 19 1.4 Seven–memberedoxacycles. 19 1.5 Examplesofseptanosecarbohydrates . .. 20 1.6 Furo[3,4-b]pyran-5-one .......................... 21 1.7 Selected examples of furo[3,4-b]pyran–based natural products . 23 1.8 FusidilactonesA–E ............................ 24 1.9 MassarilactonesA-D ........................... 25 1.10 TAN-2483naturalproducts . 25 1.11 Initial and revised structures of waol A and B . .... 26 2.1 1H-NMR spectra of 213 and 214 .................... 40 2.2 Selected NMR correlations of 213 and 214 ............... 40 2.3 Selected methylene and halomethylene compounds . ..... 41 4.1 (R,R)-Jacobsen’scatalyst . 78 5.1 Cyclopropanes 290 and 243 ....................... 82 ix List of Schemes 1.1 Commoncyclopropanationmethodologies . .. 2 1.2 gem-Dihalocyclopropaneringopening . 2 1.3 Conversion of gem-dihalocyclopropane 7 intoanallylic acetate . 2 1.4 Ring expansion of cyclopropanated pyran 10 .............. 3 1.5 Exemplification of DePuy’s “cis-in, trans-out”rule .......... 3 1.6 Exocyclic carbanion–mediated cyclopropanation . ....... 5 1.7 Silver–mediated synthesis of 4,5-cyclopropanated carbohydrate 20 .. 5 1.8 Ring–contractioncyclopropanation . ... 5 1.9 Simmons–Smith cyclopropanation of 2,3-unsaturated sugar 25 .... 6 1.10 Ethyl diazoacetate–mediated cyclopropanation . ........ 7 1.11 Preparation of a cyclopropyl–linked fullerene–sugar conjugate . 7 1.12 HWE–typecyclopropanation. 8 1.13 A cyclopropane synthesised from an S-ylide .............. 8 1.14 The first reported cyclopropanated carbohydrate (39)......... 9 1.15 Formation of spirocyclopropane sugars . .... 9 1.16 Cyclopropanations reported by Nagarajan . ... 9 1.17 Stereoselective cyclopropanations of 4,5-unsaturatedsugars .