Synthetic Studies on Molecules Related to the Azinothricin Family and Allopumiliotoxin 339A A Thesis Presented to the University of London in Partial Fulfilment of the Requirements for the Degree of Doctor of Philosophy Amandine Andree Huguette LEFRANC Christopher Ingold Laboratories Department of Chemistry University College London London WC1H OAJ May 2008 UMI Number: U591613 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 complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U591613 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT The Azinothricin family of compounds are based on a cyclodepsipeptide core and were first encountered in the late 1980s. Most of the members exhibit potent antitumour and antibiotic activities. In 1997, the Hale group synthesised A83586C through a chemoselective coupling strategy between an unprotected cyclohexadepsipeptide and a fully elaborated pyran activated ester. In this thesis, the asymmetric synthesis of two cyclodepsipeptides analogues are investigated, the L-proline analogue of GE3 cyclodepsipeptide and the (3S,5S)- 5-hydroxypiperazic acid analogue of A83586C cyclodepsipeptide. The synthesis of analogues may be of value for elucidating the mode of action of these natural products. Furthermore, it might allow the identification of a considerably simplified structure for industrial purposes. In a second project, a new approach to the synthesis of (+)-allopumiliotoxin 339A was studied. The pumiliotoxin and allopumiliotoxin class of amphibian alkaloids displays significant cardiotonic activity. Allopumiliotoxin 339A is one of the most potent compounds of the family; its activity is due to an interaction with a modulatory site on the voltage-dependent sodium channel. Our strategy to (+)-allopumiliotoxin 339A was based on the synthesis of two main fragments, an a-alkoxyaldehyde and a functionalised side chain fragment. Our initial research to the a-alkoxyaldehyde involved a Sharpless Asymmetric Aminohydroxylation reaction. However, this reaction proved not to be feasible on the trisubstituted alkene precursor. Eventually the a- alkoxyaldehyde was successfully prepared using a Trost's opening of an epoxide followed by an asymmetric induction of chiral sulfinimine to access the desired stereochemistry. The synthesis of the side chain segment was achieved via an O-directed hydrostannation strategy developed in the Hale group. This strategy allowed the stereoselective synthesis of the trisubstituted alkene moiety of the side chain. 1 ACKNOWLEDGMENTS First of all, I would like to thank my supervisor, Professor Karl Hale for his supervision and guidance throughout my PhD studies. I am grateful to Novartis for providing me a fully-funded studentship. I would like also to acknowledge my secondary supervisor, Professor Charles Marson, for his valuable advice and his help during the submission process. I am very grateful to Dr. Abil E. Aliev for all the time and patience he accorded me for the run and interpretation of my NMR spectra and to Dr Lisa Harris for performing mass- spectroscopy analysis. I would like to thank Dr. Soraya Manaviazar for her support in the lab and the members of the Hale group, Mathias, Sandrine, Marcus, Pascalis, Jon, Guillaume, Claire, Yi, Mernoosh and Russel for their advice and their help. I am also grateful to my colleague in the Chemistry Department for their support and their friendship, especially Pascal, S6bastien, Sarah, Greg, Sandra, Laure. Many thanks to my friends here and abroad, you have patiently listened to me complain about my work, I look forward spending more time with all of you when I finish this achievement. I wish to thank Julien for helping me get through the difficult times, and for all the emotional support he provided. I cannot end without thanking my family, especially my parents, on whose constant encouragement and love I have relied throughout my time at UCL. 2 ABBREVIATIONS Ac acetyl acac acetylacetonate AIBN azobisisobutyronitrile All allyl Ar aryl B' base BAIB [bis(acetoxy)iodo]benzene Bn benzyl Boc tert-butoxycarbonyl BOM benzyloxymethyl BOP reagent benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate BOPCI A/-A/-bis(2-oxo-3-oxazolidinyl)phosphinic chloride br broad r?-Bu n-butyl f-Bu f-butyl Bz benzoyl Cl chemical ionisation m-CPBA mete-chloroperbenzoic acid CSA camphorsulfonic acid d doublet dd doublet of doublet ddd doublet of doublet of doublet dt doublet of triplet dba dibenzilideneacetone DBAD di-fert-butylazodicarboxylate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC 1-2-dicyclohexylcarbodiimide 3 DCM dichloromethane DDQ dichlorodicyanoquinone DEPC diethylphosphorocyanidate (DHQD)2PHAL 1,4-bis(9-0-dihydroquinidinyl)-phthalazine (DHQ)2PHAL 1,4-bis(9-0-dihydroquininyl)-phthalazine DIEA A/,A/-diisopropylethylamine (HOnig’s base) DIBAL-H diisobutylaluminium hydride DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DMP Dess-Martin periodinane DMPU 1,3-dimethyl-3-4-5-6-tetrahydro-2(1 H)-pyrimidinone DMSO dimethylsulfoxide DNP dinitrophenyl dppf 1,1 '-bis(diphenylphosphino)ferrocene dr diastereoisomeric ratio E+ electrophile ee enantiomeric excess ESI electrospray ionisation eq equivalent Et ethyl FAB fast atomic bombardment Fmoc fluorenylmethyloxycarbonyl h hour HATU A/-[(dimethylamino)-1/-/-1l2,3-triazolo[4l5,b]pyridin-1-ylmethylene]-A/- methylmethanaminium hexafluorophosphate HOBt 1-hydroxybenzotriazole HMBC heteronuclear multiple bond connectivity HMPA hexamethylphosphoramide HMQC heteronuclear multiple quantum coherence HRMS high resolution mass spectroscopy 4 Hz Hertz IR infra red J coupling constant KHMDS potassium hexamethyldisilazide L ligand LDA lithium diisopropylamide LiDBB lithium di-ferf-butylbiphenyl m meta M molar m/z mass to charge ratio m-CPBA mefa-chloroperbenzoic acid Me methyl min minute mM milimolar MOM methoxymethyl Ms methylsulfonyl MS molecular sieves MTPA methoxy(trifluoromethyl)phenylacetyl) NBS A/-bromosuccinimide NEM A/-ethylmorpholine NMO A/-methylmorpholine-A/-oxide NMR nuclear magnetic resonance Nu' nucleophile o ortho ox. oxidation p para PCC pyridinium chlorochromate PG protecting group Ph phenyl Piz piperazic 5 PMB para-methoxybenzyl PPTS pyridinium para-toluenesulfonate i-Pr isopropyl PTX pumiliotoxin pyr pyridine R alkyl RedAI-H sodium bis(2-methoxyethoxy)aluminum hydride rt room temperature s singlet SAA Sharpless Asymmetric Aminohydroxylation SEM [2-(trimethylsilyl)ethoxy]methyl SM starting material t triplet TBAF tetra r?-butylammonium fluoride TBDMS ferf-butyldimethylsilyl TBDPS fe/t-butyldiphenylsilyl TEMPO 2,2,6,6-tetramethylpiperidine-1 -oxyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroacetamide THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMS trimethylsilyl TPAP tetra-n-propylammonium perruthenate Troc trichloroethoxycarbonyl Ts p-toluenesulfonyl Z benzyloxycarbonyl 6 TABLE OF CONTENTS PART A: SYNTHETIC STUDIES ON MOLECULES RELATED TO THE AZINOTHRICIN FAMILY..........................................................................................9 1. T he A zinothricin fam ily of antibiotics ......................................................................9 1.1. Biological introduction.......................................................................................................... 9 1.2. Isolation and Biological Activity of Some Member of the Family ....................................10 2. P r evio us w o r k on the A zinothricin Fa m il y ........................................................... 16 2.1. Past Syntheses of Some Related Natural Products ........................................................17 2.1.1. Total Synthesis of L-152,602 ................................................................................................................. 17 2.1.2. Total Synthesis of A83586C ................................................................................................................... 23 2.1.3. Synthesis of Verucopeptin Cyclodepsipeptide Core ........................................................................34 2.1.4. Synthesis of GE3 Cyclodepsipeptide Core .........................................................................................37 2.2. Previous Syntheses of Analogues of the Azinothricin Family of Antibiotics ................. 39 3. Synth etic Stu d ies T o w ards A nalogues of the A zinothricin Fa m il y ..........43 3.1. Synthesis of an L-proline analogue of GE3 cyclodepsipeptide ..................................... 46 3.2. Toward the synthesis of an (3S, 5S)-5-hydroxypiperazic acid modified mimetic of A83586C..................................................................................................................................... 53 4. Conclusion.........................................................................................................................57 PART B: SYNTHETIC STUDIES TOWARDS THE SYNTHESIS OF (+)- ALLOPUMILIOTOXIN 339A..................................................................................59 5. Introduction