ABSTRACT TOTAL SYNTHESIS OF THE BIDENSYNEOSIDES; REMARKABLE PROTECTING GROUP EFFECTS IN GLYCOSYLATION AND SYNTHETIC EFFORTS TOWARDS THE TOTAL SYNTHESIS OF A PENTAACETYLENIC GLUCOSIDE By: Ryan Michael Fox This document describes the work towards the synthesis of polyacetylene glucosides isolated from nature. Theses syntheses represent the first total synthesis of the bidensyneosides (1-5) isolated from Bidens parviflora. Biological assays have shown that the bidensyneosides effectively regulate histamine release and nitric oxide production. Additionally, a remarkable protecting group effect was observed during glycosylations, effectively showing that the nature of the protecting group can lead to a differentiation between the orthoester and anomeric product. Furthermore, an attempt to assemble a pentaacetylenic glucoside 34 isolated from Microglossa pyrifolia was undertaken. The assembly consists of a glycosylation followed by a triply convergent unsymmetrical cross coupling to give a pentaacetylene. To this end, the establishment of conditions capable of producing a pentaacetylene without subsequent addition of base to the electrophilic pentaacetylene side chain has been unsuccessful. Further studies of these conditions should lead to the desired product, which after deprotection would give the natural product. TOTAL SYNTHESIS OF THE BIDENSYNEOSIDES; REMARKABLE PROTECTING GROUP EFFECTS IN GLYCOSYLATION AND SYNTHETIC EFFORTS TOWARDS THE TOTAL SYNTHESIS OF A PENTAACETYLENIC GLUCOSIDE A Thesis Submitted to the Faculty of Miami University in partial fulfillment of the Requirements in the degree of Masters of Science Department of Chemistry and Biochemistry By Ryan Fox Miami University Oxford, Ohio 2004 Advisor ____________________________ Dr. Benjamin W. Gung Reader ____________________________ Dr. Michael W. Crowder Reader ____________________________ Dr. Richard T. Taylor Reader ____________________________ Dr. Christopher A. Makaroff Table of contents Page List of Abbreviations iv List of Figures v List of Schemes vi List of Tables vii List of Structures viii Acknowledgments xix Introduction: The importance of natural product isolation and synthesis 1 Chapter 1: Total Synthesis of Bidensyneoside A2, C, and 3-deoxybidensyneoside C,: Remarkable Protecting Group Effects in Glycosylation 1.1 Introduction 6 1.2 Results and Discussion 10 1.2.1 Preparation of 3-Deoxybidensyneoside C 10 1.2.2 Synthesis of Bidensyneoside C 12 1.2.3 Synthesis of Bidensyneoside A2 21 1.3 Conclusion 23 1.4 Experimental 24 Chapter 2: Total Synthesis of Bidensyneoside A1 and Bidensyneoside B 46 2.1 Introduction 47 2.2 Results and discussion 48 2.2.1 Synthesis of Bidensyneoside B 48 2.2.2 Synthesis of Bidensyneoside A1 49 2.3 Conclusion 51 2.4 Experimental 52 Chapter 3: The Attempted Total synthesis of a pentacetylenic glucoside isolated 58 from Microglossa pyrifolia 3.1 Introduction 59 3.2 Results and discussion 62 3.3 Conclusion 73 3.4 Experimental 74 ii Chapter 4: References 86 Chapter 5: Spectra for select compounds 90 iii List of Abbreviations Ac Acetyl Ac2O Acetic anhydride Bz Benzoyl DMAP 4-Dimethylaminopyridine DMF Dimethylformamide ee Enantiomeric Excess DMTST dimethyl(methylthio) sulfonium triflate Et Ethyl Me Methyl NBS N-Bromosuccinimide PPTS Pyridinium p-Toluenesulfonate Pyr Pyridine TBAF Tetra-n-butylammonium fluoride TBDMS t-Butyldimethylsilyl TEA Triethylamine Tf Triflate THF Tetrahydrofuran THP Tetrahydropyran COSY Correlation Spectroscopy EI/MS Electron Impact Mass Spectroscopy HRMS High resolution Mass spectroscopy IR Infrared Spectroscopy UV Ultraviolet spectroscopy iv List of Figures page Figure 1 Structures of Callypentayne and 2-Deoxydiplyne D sulfate 2 Figure 2 Bioactive sucrose esters from bidens parviflora 3 Figure 3 An Antimalarial compound isolated from Bidens pilosa 3 Figure 4 Triterpeoids from the roots of Microglossa pyrifolia 5 Figure 5 Pentaacetylenic glucoside from Microglossa pyrifolia 5 Figure 1.1 Structures of the bidensyneosides from Bidens parviflora 8 Figure 3.1 Polyacetylenic glucosides from Microglossa pyrifolia 59 Figure 3.2 Polyacetylenic aglucones 60 v List of Schemes page Scheme 1.1 retrosynthetic analysis of the bidensyneosides 9 Scheme 1.2 Synthesis of 3-deoxybidensyneoside C 10 Scheme 1.3 Synthesis of Alcohol 12 12 Scheme 1.4 TBS protection of thioglycoside 15 Scheme 1.5 Acylation of thioglycosides 16 Scheme 1.6 Orthoester formation 17 Scheme 1.7 Methoxy orthoester 18 Scheme 1.8 Synthesis of Bidensyneoside C 19 Scheme 1.9 Synthesis of C3 inverted Bidensyneoside C 21 Scheme 1.10 Synthesis of Bidensyneoside A2 22 Scheme 2.1 Synthesis of Bidensyneoside B 49 Scheme 2.2 Synthesis of E-3-pentene-1-yn 50 Scheme 2.3 Synthesis of Bidensyneoside A1 50 Scheme 3.1 Retrosynthetic analysis of 34 61 Scheme 3.2 Glycosylation model for bromoglucoside 62 Scheme 3.3 Selective protection of primary alcohols; compounds 38 and 39 62 Scheme 3.4 Benzoylation of compounds 13 and 14 63 Scheme 3.5 Glycosylations forming compounds 43-46 64 Scheme 3.6 Formation enamine 47 and 49 66 Scheme 3.7 Symmetric alkynes 50 and 51 67 Scheme 3.8 Synthesis of 52 and 53 69 Scheme 3.9 Kinetic model compounds 70 Scheme 3.10 Kinetic study, compounds 54, 55, 56, 57 73 Scheme 3.11 Kinetic study, compounds 58, 59, 60 74 vi List of Tables page Table 3.1 Product distribution in three component Cadiot-Chodkiewicz 68 Conditions with a variation of ethylamine concentration vii List of Structures No. Structure OH HO O HO O OH HO 1 Bidensyneoside A1 OH HO O HO O OH HO 2 Bidensyneoside A2 OH HO O HO O OH HO 3 Bidensyneoside B OH OH HO O HO O OH HO 4 Bidensyneoside C OH OH HO O HO O OH 5 3-Deoxybidensyneoside C viii OAc AcO O AcO O OAc 6 4-Pentynyl tetra-acetyl-β-D-glucopyranoside Br OTBS 7 Silane, (1,1-dimethylethyl)dimethyl[5-bromo-(2E)-2-penten-4-ynyloxy] OH OTBS HO O HO O OH 8 [10-tert-Butyldimethylsilyloxy-8-decen-4,6-diynyl]-β-D-glucopyranoside OH TBSO 9 (+)-3R-5-tert-butyldimethylsilyloxy-1-pentyn-3-ol O Ph O OMe TBSO 10 O-Methyl mandelate ester of 9 OAc TBSO 11 (+)-3R-3-Acetoxy-1-tert-butyldimethylsilyl-4-pentyn-1-ol OAc HO 12 (+)-3(R)-3-Acetoxy-4-pentyn-1-ol ix OTBS HO O HO STol OH 13 p-Tolyl 6-O-(tert-butyldimethylsilyl)-1-thio-β-D-glucopyranoside OTBS HO O TBSO STol OH 14 p-Tolyl 3,6-O-bis(tert-butyldimethylsilyl)-1-thio-β-D-glucopyranoside OTBS TBSO O HO STol OH 15 p-Tolyl4,6-O-bis(tert-butyldimethylsilyl)-1-thio-β-D-glucopyranoside OTBS HO O HO STol OTBS 16 p-Tolyl 2,6-O-bis(tert-butyldimethylsilyl)-1-thio-β-D-glucopyranoside OTBS HO O TBSO STol OTBS 17 p-Tolyl 2,3,6-O-tris(tert-butyldimethylsilyl)-1-thio-β-D-glucopyranoside OTBS AcO O AcO STol OAc 18 p-Tolyl 2,3,4-O-tris(acetyl)-6-O-(tert-butyldimethylsilyl)-1-thio-β-D- glucopyranoside x OTBS AcO O TBSO STol OAc 19 p-Tolyl 2,4-O-bis(acetyl)-3,6-O-bis(tert-butyldimethylsilyl)-1-thio-β-D- glucopyranoside AcO H1 TBSO O H H 2 OAc 4 O H 3 O OAc O 20 (S)-Orthoester AcO H1 TBSO O H H 2 OAc 4 O H 3 O OAc O 21 (R)-Orthoester OTBS AcO O AcO O OAc OAc 22 (3S)-3-Acetoxy-4-pentynyl 2',3’,4'-O-tris(acetyl)-6'-O-(tert-butyldimethylsilyl)- β-D-glucopyranoside HO TBSO O O O O OH 23 Methoxy Orthoester OTBS AcO O TBSO O OAc AcO xi 24 (3R)-3-Acetoxy-4-pentynyl 2',4'-O-bis(acetyl)-3',6'-O-bis(tert- butyldimethylsilyl)-β-D-glucopyranoside Br OH 25 5-Bromo-2-penten-4-yn-1-ol OTBS OH AcO O TBSO O OAc HO 26 (3R)-3',6'-O-Bis(tert-butyldimethylsilyl)-2',4'-O-bis(acetyl) bidensyneoside C OTBS AcO O TBSO O OAc AcO 27 (3S)-3-Acetoxy-4-pentynyl 2',4'-O-bis(acetyl)-3',6'-O-bis(tert- butyldimethylsilyl)- β-D-glucopyranoside OTBS OH AcO O TBSO O OAc HO 28 (3S)-3',6'-O-bis(tert-butyldimethylsilyl)-2',4'-O-bis(acetyl) bidensyneoside C OH OH HO O HO O OH HO 29 3-(S)-bidensyneoside C xii OTBS AcO O TBSO O OAc Br AcO 30 (3R)-3’-Acetoxy-5’-bromo-4’-pentynyl 2,4-O-bis(acetyl) 3,6-O-bis(tert-butyldimethylsilyl)-β-D-glucopyranoside OTBS AcO O TBSO O OAc HO 31 (8Z)-(3’R)-3’,Hydroxy-8’-decen-4’,6’-diynyl 3,6-O-bis(tert-butyldimethylsilyl)- 2,4-O-bis(acetyl)-β-D-glucopyranoside OTBS AcO O TBSO O OAc HO 32 (3’R)-3’,Hydroxy-4’,6’,8’-triynyl 3,6-O-bis(tert-butyldimethylsilyl) -2,4-O-bis(acetyl)-β-D-glucopyranoside OTBS AcO O TBSO O OAc HO 33 (8E)-(3’R)-3’,Hydroxy-8’-decen-4’,6’-diynyl 3,6-O-bis(tert-butyldimethylsilyl) -2,4-O-bis(acetyl)-β-D-glucopyranoside OH HO O HO O OH OH 34 xiii 2-β-D-Glucopyranosyloxy-1-hydroxy-trideca-3,5,7,9,11-pentayne HO HO 35 1,2-dihyrdoxy-trideca-3,5,7,9,11-pentayne E/Z HO HO 36 1,2-dihydroxy-3(E/Z)-tridecene-5,7,9,11-tetrayne HO OH 37 1,3-dihydroxy-6(E)-tetradecene-8,10,12-triyne OH TBSO Br 38 Silane, (1,1-dimethylethyl)dimethyl[4-bromo-2-S-hydroxy-3-pentyne] OH BzO Br 39 1-bromo-4-benzyol-3(R)-1-butyne-3-ol OTBS BzO O BzO STol OBz 40 p-Tolyl 2,3,4-O-tris(benzoyl)-6-O-(tert-butyldimethylsilyl)- 1-thio-β-D-glucopyranoside xiv OTBS BzO O TBSO STol OBz 41 p-Tolyl 2,4-O-bis(benzoyl)-3,6-O-bis(tert-butyldimethylsilyl)- 1-thio-β-D-glucopyranoside OBz BzO O TBSO STol OBz 42 p-Tolyl 2,4,6-O-tris(benzoyl)-3-O-(tert-butyldimethylsilyl)- 1-thio-β-D-glucopyranoside OTBS BzO O BzO O OBz Br OTBS 43 6-O-(tert-butyldimethylsilyl)-2,3,4-O-tris(benzoyl)-2-β-D-Glucopyranosyloxy-4- bromo-1-tert-butyldimethylsilyl-2(S)-3-butyne OTBS BzO O BzO O OBz Br OBz 44 6-O-(tert-butyldimethylsilyl)-2,3,4-O-tris(benzoyl)-2-β-D-Glucopyranosyloxy- 4-bromo-1-benzoyl-2(S)-3-butyne OTBS BzO O TBSO O OBz Br OTBS xv 45 3,6-O-Di(tert-butyldimethylsilyl)-2,4-O-bis(benzoyl)-2-β-D-Glucopyranosyloxy- 4-bromo-1- tert-butyldimethylsilyl -2(S)-3-butyne OTBS AcO O TBSO O OAc Br OTBS 46 3,6-O-bis(tert-butyldimethylsilyl)-2,4-O-bis(acetyl)-2-β-D-Glucopyranosyloxy-