Faculty of Biology, Chemistry and Geosciences University of Bayreuth Total synthesis of naturally occurring glycosylated tetramic acids Dissertation to obtain the degree Doctor of natural scienes (Dr. rer. nat.) Submitted by Sebastian Loscher Bayreuth 2015 The presented doctoral thesis was prepared at the Faculty of Chemistry, Biology and Geosciences in the Department of Organic Chemistry of the University of Bayreuth in Germany from September 2010 till April 2015. The work was supervised by Prof. Dr. Rainer Schobert. This is a full reprint of the dissertation submitted to obtain the academic degree of Doctor of Natural Sciences (Dr. rer. nat.) and approved by the Faculty of Biology, Chemistry and Geosciences of the University of Bayreuth. Date of submission: 20. May 2015 Date of approval by the commission: 27. May 2015 Date of scientific presentation: 31. July 2015 Prof. Dr. Rhett Kempe Acting Dean Doctoral Comittee Prof. Dr. Rainer Schobert 1st reviewer Prof. Dr. Karl-Heinz Seifert 2nd reviewer Prof. Dr. Andreas Kirschning 3rd reviewer Prof. Dr. Birgit Weber chairman Prof. Dr. Andreas Möglich member of the committee “The biggest problem on being successful is that it looks quite easy.” Prof. Dr. Jean-Jacques Dordain, General Director of the European Space Agency (ESA) in an interview 12.11.2014 concerning the Rosetta mission. TABLE OF CONTENT TABLE OF CONTENT I. ABSTRACT ........................................................................ 1 II. INTRODUCTION .............................................................. 3 II.1. Tetramic acid derivatives and their structural diversity ........ 3 II.1.1. 3-Acyl tetramic acids ................................................................................ 4 II.1.2. 3-Polyenoyl tetramic acids ....................................................................... 5 II.1.3. 3-Decanoyl tetramic acids ........................................................................ 7 II.1.4. Macrocyclic tetramic acids ...................................................................... 8 II.1.5. Additional tetramic acids ........................................................................ 9 II.2. Biological function of tetramic acids ......................................... 9 II.2.1. Cell wall interaction of tetramic acids and quorum sensing .............. 10 II.2.2. Tetramic acids as nucleotide or pyrophosphate mimics .................... 11 II.3. Chemical and structural properties of tetramic acids ........... 12 II.4. Biosynthesis of tetramic acids .................................................. 14 II.5. Chemical synthesis of tetramic acids ....................................... 17 II.5.1. Synthetic methods to form the core pyrrolidine-2,4-dione system .... 17 II.5.2. 3-Acylation of the tetramic acid core ................................................... 20 II.5.3. Aldol reaction for C-5 alkylation .......................................................... 21 II.5.4. Direct synthesis of 3-acyl tetramic acids .............................................. 22 i TABLE OF CONTENT II.6. Glycosylated tetramic acids ...................................................... 23 II.6.1. Ancorinosides .......................................................................................... 23 II.6.2. Epicoccamides......................................................................................... 24 II.6.3. Virgineone ............................................................................................... 25 II.6.4. Streptolydigin ......................................................................................... 27 II.6.5. Aurantosides ........................................................................................... 30 II.6.6. Rubrosides ............................................................................................... 30 III. PROJECT AIMS ............................................................. 32 IV. RESULTS ....................................................................... 33 IV.1. Total synthesis of epicoccamide D .......................................... 33 IV.1.2. Retrosynthesis of epicoccamide D ....................................................... 34 IV.1.3. Total Synthesis ...................................................................................... 35 IV.1.4. Assignment and absolute configuration of synthetic products ........ 47 IV.1.5. Comparison of synthetic products with natural epicoccamide D .... 48 IV.2. Total synthesis of ancorinoside B diglycoside ....................... 49 IV.2.2. Retrosynthesis of ancorinoside B ........................................................ 49 IV.2.3. Disaccharide unit of ancorinoside B via glucuronic acid .................. 51 IV.2.4. Total synthesis of ancorinoside B diglycoside .................................... 54 IV.3. Contribution to virgineone total synthesis ............................ 61 IV.3.2. Retrosynthesis of the virgineone side chain ....................................... 62 IV.3.3. Synthesis of the virgineone side chain ................................................. 63 ii TABLE OF CONTENT IV.4. Contribution to aurantoside G and J total synthesis ............ 66 IV.4.2. Retrosynthesis of aurantoside G and J ............................................... 66 IV.4.3. Direct N-glycosylation trials with tetramic acids ............................... 69 IV.4.4. N-Glycosylated tetramic acids via Fukuyama-Mitsunobu reaction 70 IV.5. Stereoinduction by tetramic acid boron complexes .............. 72 V. CONCLUSION ................................................................ 74 V.1. Total synthesis of epicoccamide D ............................................ 74 V.2. Total synthesis of the ancorinoside B diglycoside .................. 75 V.3. Contribution to virgineone total synthesis .............................. 77 V.4. N-Glycosylation for aurantoside G and J synthesis ............... 79 V.5. Stereoinduction by tetramic acid boron complexes ............... 80 VI. EXPERIMENTAL SECTION ........................................ 82 VI.1. General remarks ....................................................................... 82 VI.2. Epicoccamide D ........................................................................ 83 VI.2.1. Glycosyl donor ....................................................................................... 83 VI.2.2. Synthesis of the C16 alkyl chain ........................................................... 87 VI.2.3. Phosphonate........................................................................................... 88 VI.2.4. Synthesis of alanine derivatives ........................................................... 90 VI.2.5. Synthesis of epicoccamide D and derivatives ..................................... 93 iii TABLE OF CONTENT VI.2.6. Synthesis of model compounds .......................................................... 116 VI.3. Ancorinoside B........................................................................ 122 VI.3.1. Glycosyl donor ..................................................................................... 122 VI.3.2. Synthesis of the C20 alkyl chain ......................................................... 123 VI.3.3. 6-O-PMB protected glycosyl acceptor .............................................. 125 VI.3.4. Total synthesis of ancorinoside B diglycoside .................................. 129 VI.4. Virgineone ............................................................................... 135 VI.4.1. Synthesis of the C20-alkene for Sharpless dihydroxylation ............. 135 VI.4.2. Dihydroxylation and selective protection ......................................... 138 VI.5. Aurantoside G and J .............................................................. 143 VI.5.1. O-Glycosylation ................................................................................... 143 VI.5.2. N-Glycosylation ................................................................................... 144 VI.6. Tetramic acid boron complexes ............................................ 147 VII. ABBREVIATIONS ..................................................... 149 VIII. LITERATURE ........................................................... 152 IX. ACKNOWLEDGEMENTS .......................................... 162 X. ABSTRACT (GERMAN VERSION) ............................ 163 iv TABLE OF SCHEMES TABLE OF SCHEMES II. INTRODUCTION .............................................................. 3 Scheme II.1. Tautomerism of 3-acyl tetramic acids ................................................................. 13 Scheme II.2. First biosynthetic steps to streptolydigin ............................................................. 14 Scheme II.3. Second set of biosynthetic steps to streptolydigin .............................................. 15 Scheme II.4. Third set of biosynthetic steps to streptolydigin .................................................. 16 Scheme II.5. Terminal biosynthetic steps to streptolydigin ...................................................... 16 Scheme II.6. Tetramic acid synthesis via Meldrum’s acid ....................................................... 17 Scheme II.7. Tetramate synthesis with Bestmann’s ylide ........................................................ 18 Scheme II.8. Tetramate synthesis with SmI2 and CH2N2 ......................................................... 18 Scheme II.9. Tetramic acid synthesis via CO2 incorperation ................................................... 19 2+ Scheme