Total synthesis of Dothideopyrone E and Dothideopyrone F
June 2021
Master's thesis
Master's thesis
David Liwara
2021David Liwara NTNU Norwegian University of Science and Technology Faculty of Natural Sciences Department of Chemistry
Total synthesis of Dothideopyrone E and Dothideopyrone F
David Liwara
Master's thesis in Chemistry Submission date: June 2021
Supervisor: Eirik Johansson Solum
Norwegian University of Science and Technology Department of Chemistry
Abstract
The present work relates to the synthesis of two natural molecules, having an optical activity, dothideopyrone E and F. Different pathways have been tried to get these molecules. In the first tests, a Carreira-alkynylation was carried out to obtain the good stereoisomers, but because of some difficulties met in the following steps, another synthesis using an enantioselective and organocatalytic α-oxyamination to get the right stereoisomers was used. To get the two targeted compounds, some steps left but according tests that has been done, they should be synthetized.
Sammendrag
Dette arbeidet er relatert til syntesen av to naturprodukter, dothideopyrone E og F. Ulike veier har blitt prøvd for å syntetisere disse molekylene. I de første testene ble en Carreira- alkynylering utført for å oppnå gode stereoisomerer, men på grunn av noen vanskeligheter som ble møtt i de følgende trinnene, ble en annen syntesevei brukt. Blanty annet ble det brukt en enantioselektiv og organokatalytisk α-oksyaminering for å få de rette stereoisomerer. For å få de to målrettede forbindelsene, noen trinn igjen, men i henhold til tester som er gjort, bør de syntetiseres.
Acknowledgements
The work described in this thesis report has been performed at the Department of Chemistry, Norwegian University of Science and Technology (NTNU), Trondheim, from to May 15, 2021.
I would like to express my gratitude to my supervisor , Professor Eirik Johansson Solum, for his help and support during my work and for being all the time to my disposition when I needed. Thanks to him, I learnt a lot during this project
I want to thank Victor, a french friend who worked on a similar project for his support and sharing his good humor for this year
I want to thank Petros, Karoline and the other students of my supervisor, for the discussions we had and for creating a good working environemnet
Thanks to Jon Erik Aaseng and other group members for help and sharing their knowledges the different training they gave me
My lab colleagues, Sondre, Benedicte and Helgi are acknowledged too.
Finally, I would like to thank my family, who have always given me help and support in my choices.
Trondheim, May 30 , 2021
David Jérémy Liwara
Table of Contents
List of Figures ... 8
List of Schemes ... 13
List of Tables ... 14
List of Abbreviations (or Symbols) ... 15
I - Introduction ... 17
II - Theory ... 20
1. Synthetic routes ... 20
1.1. Retrosynthesis and synthesis path from a commercial pyrone ... 20
1.2. Retrosynthesis and synthesis path by building the pyrone ring ... 22
2. Reactions ... 24
2.1. Methylation ... 24
2.2. Oxidation ... 25
2.3. Carreira alkynylation ... 29
2.4. Hydrogenation ... 30
2.5. Epoxide opening ... 31
2.6 Zipper reaction ... 33
2.7 Alcohol and enol protection ... 34
2.8 Formylation ... 37
2.9 Reduction ... 38
2.10. Enantioselective and organocatalytic-oxidation of aldehydes ... 40
2.11. Vinylogous Mukaiyama aldol addition ... 40
2.12. Knoevenagel and thiol-ene reactions ... 41
2.12.1. Knoevenagel reaction ... 42
2.12.2 Thiol-ene reaction ... 43
2.13. Ring closing ... 44
2.14. Pummerer rearrangement and obtention of the primary alcohol ... 45
2.15. Alcohol deprotection ... 47
III - Results and discussion ... 48
1. Synthesis 1 using a commercial pyrone ring ... 48
1.1 Synthesis of compound 8 ... 48
1.2 Synthesis of compound 9 ... 48
1.3 Synthesis of compound 10 ... 49
1.4 Synthesis of compound 11 ... 50
1.5 Synthesis of compound 12 ... 50
1.6. Attempt to add the primary alcohol to the pyrone ring of compound 12 ... 50
2. Reorganization of the synthesis... 53
2.1 Synthesis of compound 55 ... 53
2.2. Synthesis of compound 56 ... 53
2.3. Synthesis of compound 57 ... 53
2.4. Synthesis of compound 58 ... 54
2.5. Synthesis of compound 59 ... 54
2.6. Synthesis of compound 24 ... 55
2.7. Synthesis of compound 25 ... 55
2.8. Attempted oxidation ... 55
3. Synthesis 2: by building the ring ... 56
3.1. Synthesis of compound 41 ... 56
3.2. Synthesis of compound 42 ... 56
3.3. Synthesis of compound 43 ... 57
3.4. Synthesis of compounds 28 and 44 ... 57
3.5. Synthesis of compounds 29 and 45 ... 57
3.6. Synthesis of compounds 30 and 46 ... 59
3.7. Synthesis of compounds 31 and 47 ... 59
3.8. Synthesis of compounds 32 and 48 ... 60
3.9. Synthesis of compounds 33 ... 60
3.9. Synthesis of compounds 34 and 49 ... 61
3.10. Synthesis of compounds 35 and 50 ... 62
3.11. Try to get 36 ... 63
4. Overview ... 64
IV - Conclusion and Perspective ... 66
V - Experimental part ... 67
References ... 84
Appendices ... 88
List of Figures
Figure 1: Chemical structure of dothideopyrone E (1) and F (2). ... 17
Figure 2: Structure and isolation of the target molecule. ... 17
Figure 3: Chemical structure of dothideopyrones A-D (3-6). ... 18
Figure 4: Classic reactions on a 2-pyrone ring and common pyrone used as a starting material. ... 18
Figure 5: One way to get pyrone ring with a polyketide chain and a base. ... 19
Figure 6: Retrosynthesis of the dothideopyrone F (2). ... 20
Figure 7: Retrosynthesis of the alkyne. ... 21
Figure 8: Retrosynthesis to build the pyrone ring. ... 22
Figure 9: Alcohol methylation by methyl p-toluenesulfonate. ... 25
Figure 10: Mechanism of alcohol methylation by methyl p-toluenesulfonate. ... 25
Figure 11: Allylic oxidation of alkene to alcohol. ... 25
Figure 12: Mechanism of the Riley oxidation. ... 26
Figure 13: Alcohol oxidation with Dess-Martin periodianane (DMP). ... 26
Figure 14: Mechanism of alcohol oxidation by Dess-Martin periodinane. ... 27
Figure 15: Oxidation of sulfide to sulfoxide. ... 27
Figure 16: Oxidation mechanism of sulfide to sulfoxide. ... 28
Figure 17: Cleavage of the C-C bond by ozone. ... 28
Figure 18: Mesomeric forms of ozone. ... 28
Figure 19: Ozonolysis mechanism. ... 29
Figure 20: Creation of propargylic alcohol from aldehyde and terminal alkyne. ... 29
Figure 21: Carreira alkynylation mechanism. ... 30
Figure 22: Hydrogenation of an alkyne to an alkane. ... 30
Figure 23: Hydrogenation of a double bond. ... 31
Figure 24: Opening of an epoxide by a nucleophile. ... 31
Figure 25: Formation of an organolithium compound. ... 31
Figure 26: Opening of an epoxide by an organolithium compound. ... 32
Figure 27: Reagents that improve the reactivity of organolithium compounds. ... 32
Figure 28: Mechanism of epoxide opening by a Grignard reagent. ... 33
Figure 29: Alkyne Zipper reaction. ... 33
Figure 30: Mechanism of the alkyne Zipper reaction. ... 34
Figure 31: Alcohol protection to silyl ether. ... 35
Figure 32: Mechanism of alcohol protection into a silyl ether. ... 35
Figure 33: Silyl enol ether protection. ... 35
Figure 34: Silyl enol ether formation. ... 36
Figure 35: Alcohol protection with pivaloyl chloride. ... 36
Figure 36: Mechanism of alcohol protection into pivalate ether catalized with DMAP. .... 37
Figure 37: Formylation of the pyrone ring. ... 37
Figure 38: Mechanism of formylation on a pyrone ring. ... 38
Figure 39: Reduction of aldehyde to alcohol with NaBH4. ... 38
Figure 40: Mechanism of aldehyde reduction to alcohol by NaBH4. ... 39
Figure 41: Reduction of esters to alcohols by DIBAL-H. ... 39
Figure 42: Mechanism of ester reduction to alcohol by DIBAL-H. ... 39
Figure 43: Enantioselective and organocatalytic α-oxyamination. ... 40
Figure 44: Action of nitrozobenzene and d-proline on the aldehyde. ... 40
Figure 45: Reduction of the intermediate to get the diol. ... 40
Figure 46: Vinylogous Mukaiyama aldol addition. ... 41
Figure 47: Coupling between aldehyde and enolate. ... 41
Figure 48: Mechanism of the coupling between the compound 39 and an aldehyde. ... 41
Figure 49: Knoevenagel reaction followed by a thiol-ene reaction on a pyrone ring. ... 41
Figure 50: Knoevenagel reaction. ... 42
Figure 51: Knoevenagel reaction mechanism on the pyrone ring. ... 43
Figure 52 : Base catalyzed mechanism of the Michael addition. ... 43
Figure 53: Mechanism of the Michael addition to afford the new pyrone ring. ... 44
Figure 54: Cyclization to get the pyrone ring. ... 44
Figure 55: Ring closing mechanism. ... 45
Figure 56: Pummerer rearrangement. ... 45
Figure 57: Path to obtain the primary alcohol. ... 45
Figure 58: Formation of the sulfonium intermediate. ... 46
Figure 59: Two possibilities to get the final alcohol. ... 47
Figure 60: Silyl ether deprotection. ... 47
Figure 61: Mechanism of silyl ether deprotection. ... 47
Figure 62: Reasoning forms of deprotonated compound 3. ... 51
Figure 63: 1H-NMR spectrum of the product obtained after formylation of 8 ... 51
Figure 64: New retrosynthesis from starting material 7... 52
Figure 65: Side product got for the protection of diol 28 ... 58
Figure 66: 1H-NMR spectrum after workup with no signs of cyclic product. ... 62
Figure 67: 1H-NMR spectrum of the product got after column chromatography. ... 63
Figure 68: Unexpected product obtained after the reaction with thiophenol and paraformaldehyde. ... 64
Figure 69: Overview of the molecules synthesized in the project. ... 65
Figure 70: 1H-NMR spectrum of 4-methoxy-6-methyl-2H-pyran-2-one (8). ... 90
Figure 71: 13C-NMR spectrum of 4-methoxy-6-methyl-2H-pyran-2-one (8). ... 91
Figure 72: IR spectrum of 4-methoxy-6-methyl-2H-pyran-2-one (8). ... 91
Figure 73: 1H-NMR spectrum of 4-methoxy-2-oxo-2H-pyran-6-carbaldehyde (9). ... 92
Figure 74: 13C-NMR spectrum of 4-methoxy-2-oxo-2H-pyran-6-carbaldehyde (9). ... 93
Figure 75: IR spectrum of 4-methoxy-2-oxo-2H-pyran-6-carbaldehyde (9). ... 93
Figure 76: 1H-NMR spectrum of (S)-6-(1-hydroxynon-2-yn-1-yl)-4-methoxy-2H-pyran-2- one (10). ... 94
Figure 77: 13C-NMR spectrum of (S)-6-(1-hydroxynon-2-yn-1-yl)-4-methoxy-2H-pyran-2- one (10). ... 95
Figure 78: IR spectrum of (S)-6-(1-hydroxynon-2-yn-1-yl)-4-methoxy-2H-pyran-2-one (10). ... 95
Figure 79: 1H-NMR spectrum of (S)-6-(1-hydroxynonyl)-4-methoxy-2H-pyran-2-one (11). ... 96
Figure 80: 13C-NMR spectrum of (S)-6-(1-hydroxynonyl)-4-methoxy-2H-pyran-2-one (11). ... 97
Figure 81: IR spectrum of (S)-6-(1-hydroxynonyl)-4-methoxy-2H-pyran-2-one (11). ... 97
Figure 82: 1H-NMR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6- methyl-2H-pyran-2-one (12). ... 98
Figure 83: 13C-NMR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6- methyl-2H-pyran-2-one (12). ... 99
Figure 84: IR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6-methyl- 2H-pyran-2-one (12). ... 99
Figure 85: 1H-NMR spectrum of 4-hydroxy-6-methyl-3-((phenylthio)methyl)-2H-pyran-2- one (55). ... 100
Figure 86: 13C-NMR spectrum of 4-hydroxy-6-methyl-3-((phenylthio)methyl)-2H-pyran-
2-one (55) ... 101
Figure 87: IR spectrum of 4-hydroxy-6-methyl-3-((phenylthio)methyl)-2H-pyran-2-one (55). ... 101
Figure 88: 1H-NMR spectrum of 4-methoxy-6-methyl-3-((phenylthio)methyl)-2H-pyran- 2-one (56). ... 102
Figure 89: 13C-NMR spectrum of 4-methoxy-6-methyl-3-((phenylthio)methyl)-2H-pyran- 2-one (56). ... 103
Figure 90: IR spectrum of 4-methoxy-6-methyl-3-((phenylthio)methyl)-2H-pyran-2-one (56). ... 103
Figure 91: 1H-NMR spectrum of 4-methoxy-6-methyl-3-((phenylsulfinyl)methyl)-2H- pyran-2-one (57). ... 104
Figure 92: 13C-NMR spectrum of 4-methoxy-6-methyl-3-((phenylsulfinyl)methyl)-2H- pyran-2-one (57). ... 105
Figure 93: IR spectrum of 4-methoxy-6-methyl-3-((phenylsulfinyl)methyl)-2H-pyran-2- one (57). ... 105
Figure 94: 1H-NMR spectrum of 3-(hydroxymethyl)-4-methoxy-6-methyl-2H-pyran-2-one (58). ... 106
Figure 95: 13C-NMR spectrum of 3-(hydroxymethyl)-4-methoxy-6-methyl-2H-pyran-2- one (58). ... 107
Figure 96: IR spectrum of 3-(hydroxymethyl)-4-methoxy-6-methyl-2H-pyran-2-one (58). ... 107
Figure 97: 1H-NMR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6- methyl-2H-pyran-2-one (59). ... 108
Figure 98: 13C-NMR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6- methyl-2H-pyran-2-one (59). ... 109
Figure 99: IR spectrum of 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6-methyl- 2H-pyran-2-one (59) ... 109
Figure 100: 1H-NMR spectrum of (R)-oct-4-yn-2-ol (23). ... 110
Figure 101: 13C-NMR spectrum of (R)-oct-4-yn-2-ol (23). ... 111
Figure 102: IR spectrum of (R)-oct-4-yn-2-ol (23). ... 111
Figure 103: 1H-NMR spectrum of (R)-tert-butyldimethyl(oct-4-yn-2-yloxy)silane (24).112 Figure 104: 13C-NMR spectrum of (R)-tert-butyldimethyl(oct-4-yn-2-yloxy)silane (24). ... 113
Figure 105: IR spectrum of (R)-tert-butyldimethyl(oct-4-yn-2-yloxy)silane (24). ... 113
Figure 106: 1H-NMR spectrum of (S)-decane-1,2-diol (28). ... 114
Figure 107: IR spectrum of (S)-decane-1,2-diol (28). ... 115
Figure 108: 1H-NMR spectrum of (S)-2-hydroxydecyl pivalate (29). ... 116
Figure 109: 13C-NMR spectrum of (S)-2-hydroxydecyl pivalate (29). ... 117
Figure 110: IR spectrum of (S)-2-hydroxydecyl pivalate (29). ... 117
Figure 111: 1H-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decyl pivalate (30). ... 118
Figure 112: 13C-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decyl pivalate (30). ... 119
Figure 113: IR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decyl pivalate (30). ... 119
Figure 114: 1H-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decan-1-ol (31). 120 Figure 115: 13C-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decan-1-ol (31). 121 Figure 116: IR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decan-1-ol (31). ... 121
Figure 117: 1H-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decanal (32). .... 122
Figure 118: 13C-NMR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decanal (32). ... 123
Figure 119: IR spectrum of (S)-2-((tert-butyldimethylsilyl)oxy)decanal (32). ... 123
Figure 120: 1H-NMR spectrum of ((2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy) trimethylsilane (33) with 2,2,6-trimethyl-4h-1,3- dioxin-4-one (26). ... 124
Figure 121: 1H-NMR spectrum of (S)-6-(3-((tert-butyldimethylsilyl)oxy)-2-oxoundecyl)- 2,2-dimethyl-4H-1,3-dioxin-4-one (34). ... 125
Figure 122: 13C-NMR spectrum of (S)-6-(3-((tert-butyldimethylsilyl)oxy)-2-oxoundecyl)- 2,2-dimethyl-4H-1,3-dioxin-4-one (34). ... 126
Figure 123:: IR spectrum of (S)-6-(3-((tert-butyldimethylsilyl)oxy)-2-oxoundecyl)-2,2- dimethyl-4H-1,3-dioxin-4-one (34). ... 126
Figure 124: 1H-NMR spectrum of (S)-6-(1-((tert-butyldimethylsilyl)oxy)nonyl)-4- hydroxy-2H-pyran-2-one (35). ... 127
Figure 125: 13C-NMR spectrum of (S)-6-(1-((tert-butyldimethylsilyl)oxy)nonyl)-4- hydroxy-2H-pyran-2-one (35). ... 128
Figure 126: IR spectrum of (S)-6-(1-((tert-butyldimethylsilyl)oxy)nonyl)-4-hydroxy-2H- pyran-2-one (35). ... 128
Figure 127: 1H-NMR spectrum of (R)-undec-10-en-2-ol (41). ... 129
Figure 128: 1C-NMR spectrum of (R)-undec-10-en-2-ol (41). ... 130
Figure 129: IR spectrum of (R)-undec-10-en-2-ol (41). ... 130
Figure 130: 1H-NMR spectrum of (R)-tert-butyldimethyl(undec-10-en-2-yloxy)silane (42). ... 131
Figure 131: 13C-NMR spectrum of (R)-tert-butyldimethyl(undec-10-en-2-yloxy)silane (42). ... 132
Figure 132:: IR spectrum of (R)-tert-butyldimethyl(undec-10-en-2-yloxy)silane (42). 132 Figure 133: 1H-NMR spectrum of (R)-9-((tert-butyldimethylsilyl)oxy)decanal (43). .... 133
Figure 134: 13C-NMR spectrum of (R)-9-((tert-butyldimethylsilyl)oxy)decanal (43). .. 134
Figure 135: IR spectrum of (R)-9-((tert-butyldimethylsilyl)oxy)decanal (43). ... 134
Figure 136: 1H-NMR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)decane-1,2-diol (44) ... 135
Figure 137: 13C-NMR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)decane-1,2- diol (44). ... 136
Figure 138: IR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)decane-1,2-diol (44). ... 136
Figure 139: 1H-NMR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)-2- hydroxydecyl pivalate (45). ... 137
Figure 140: 13C-NMR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)-2- hydroxydecyl pivalate (45). ... 138
Figure 141: IR spectrum of (2S, 9R)-9-((tert-butyldimethylsilyl)oxy)-2-hydroxydecyl pivalate (45). ... 138
Figure 142: 1H-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decyl pivalate (46). ... 139
Figure 143: 13C-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decyl pivalate (46). ... 140
Figure 144: IR spectrum of of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decyl pivalate (46). ... 140
Figure 145: 1H-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decan-1- ol (47). ... 141
Figure 146: 13C-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decan-1- ol (47). ... 142
Figure 147: IR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decan-1-ol (47). ... 142
Figure 148: 1H-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decanal (48). ... 143 Figure 149: 13C-NMR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decanal (48). ... 144 Figure 150: IR spectrum of (2S, 9R)-2,9-bis((tert-butyldimethylsilyl)oxy)decanal (48).
... 144 Figure 151: 1H-NMR spectrum of 6-(3S, 10R)-3,10-bis((tert-butyldimethylsilyl)oxy)-2- oxoundecyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (49). ... 145 Figure 152: 13C-NMR spectrum of 6-(3S, 10R)-3,10-bis((tert-butyldimethylsilyl)oxy)-2- oxoundecyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (49). ... 146 Figure 153: IR spectrum of 6-(3S, 10R)-3,10-bis((tert-butyldimethylsilyl)oxy)-2-
oxoundecyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (49). ... 146 Figure 154: 1H-NMR spectrum of 4-hydroxy-6-((5S, 12R)-2,2,3,3,12,14,14,15,15-
nonamethyl-4,13-dioxa-3,14-disilahexadecan-5-yl)-2H-pyran-2-one (50). ... 147 Figure 155: 13C-NMR spectrum of 4-hydroxy-6-((5S, 12R)-2,2,3,3,12,14,14,15,15- nonamethyl-4,13-dioxa-3,14-disilahexadecan-5-yl)-2H-pyran-2-one (50). ... 148 Figure 156: IR spectrum of 4-hydroxy-6-((5S, 12R)-2,2,3,3,12,14,14,15,15-nonamethyl- 4,13-dioxa-3,14-disilahexadecan-5-yl)-2H-pyran-2-one (50). ... 148
List of Schemes
Scheme 1: Overview of the planned synthetic route of dothideopyrone E (1) and
dothideopyrone F (2). ... 22 Scheme 2: Synthetic route of dothideopyrone F (2). ... 23 Scheme 3: Synthetic route of dothideopyrone E (1). ... 24 Scheme 4: Synthesis route with less steps starting by adding the primary alcohol at C-3 position. ... 52 Scheme 5: Other possible route for getting the primary alcohol at C-3 position. ... 52
List of Tables
Table 1: Modification of equivalent of zinc triflate, triethylamine, (-)-NME and 1-octyne in the Carreira-alkynylation. ... 49 Table 2: Use of different cosolvent in the epoxide opening reaction. ... 55
List of Abbreviations (or Symbols)
AcOH Acetic acid
BF3*OEt2 Boron trifluoride etherate
CDCl3 Deuterated chloroform
CHCl3 Chloroform
CH2Cl2 Dichloromethane
δ Chemical shift
DCM Dichloromethane
DIBAL-H Diisobutylaluminium hydride
DIPA Diisopropilamine
DMAP 4-dimethylaminopyridine
DMF Dimethylformamide
DMI 1,3-dimethyl-2-imidazolidinone
DMP Dess-Martin periodinane
DMPU 1,3-dimethyl-1,3-diazinan-2-one
DMSO Dimethylsulfoxide
EtOH Ethanol
HMPA Hexamethylphosphoramide
H2 Hydrogen
IR Infrared spectroscopy
J Coupling constant
K2CO3 Potassium carbonate
LDA Lithium diisopropylamide
LiAlH4 Lithium aluminium hydride
MCPBA Meta-chloroperoxybenzoic acid
MeOH Methanol
MeOTs Methyl p-toluenesulfonate
MgSO4 Magnesium Sulphate
MHz Megahertz
n-BuLi n-butyllithium
NaBH4 Sodium borohydride
NaHCO3 Sodium hydrogen carbonate
Na2SO4 Sodium Sulphate
Na2S2O3 Sodium thiosulfate
NH4Cl Ammonium chloride
(-)-NME (-)-N-methylephedrine
NMR Nuclear magnetic resonance spectroscopy
NTNU The Norwegian University of Science and Technology
Pd/C Palladium on carbon
PhNO Nitrosobenzene
PivCl Pivaloyl chloride
ppm Parts per million
SeO2 Selenium dioxide
TBSCl Tert-butyldimethylsilyl chloride
TMSCl Trimethylsilyl chloride
TFAA Trifluoroacetic anhydride
THF Tetrahydrofuran
TLC Thin layer chromatography
TMEDA Tetramethylethylenediamine
Zn Zinc
Zn(OTf)2 Zinc triflate
I - Introduction
Molecules from natural sources are widely used to design new drugs. Traditionally natural products have been mainstays of antibiotic drug development. However, the focus in drug development has over the time shifted into using synthetic compounds. The result is a lack of antibiotic drug discovery and consequently few new drug candidates reaching the clinic.
In this perspective, the aim of this master's degree was to synthesize the natural product dothideopyrone E (1) and dothideopyrone F (2) which both have showed signs of antibiotic properties [1].
Figure 1: Chemical structure of dothideopyrone E (1) and F (2).
Compound 1 and 2 were isolated from a culture of the endolichenic fungus Dothideomycetes sp. EL003334 and reported in 2018 [1]. The strain was provided by the Korean Lichen & Allied Bioresource Center (KoLABIC) at Sunchon National University, Republic of Korea [1]. A small amount of these compounds was isolated, and to our knowledge there are no reported chemical synthesis of these two molecules.
Figure 2: Structure and isolation of the target molecule.
To this date in total six dothideopyrones have been isolated. The related dothideopyrones A−D (3-6) were isolated from a Thai medicinal plant in 2009 [2]. Dothideopyrones A−C were pharmacologically inactive, however dothideopyrone D showed weak activity against cancer cell lines. Dothideopyrone E (1) has not been evaluated for its biological effects yet, but initial testing of another similar α-pyrone derivative, dothideopyrone F (2) has indicated antioxidant activity [1]. Dothideopyrone E (1) and F (2) have not been evaluated for their ability to inhibit bacterial growth, however several other related α-pyrone derivatives have been showed to have this property [3].
Figure 3: Chemical structure of dothideopyrones A-D (3-6).
The core structure of the target molecules is the 2-pyrones ring, also known as α-pyrone.
2-pyrone is a heterocyclic ring with an oxygen and five sp2-hybridized carbons. One of these carbons is a carbonyl group, see figure 4 [4]. Alpha pyrones can give rise to electrophilic and nucleohpilic substitution reactions. The C-3 and C-5 positions in pyran-2- one are most favorable to electrophilic substitution because of their higher electron density.
Pyran-2-one have also three electrophilic centres namely C-2, C-4 and C-6 which are the main cites for nucleophilic substitution reactions. Due to this reactivity, there are often substituent on the carbons C-4 and C-6 positions, the positions that can stabilize the intermediate species via resonance [4]. One of the most common examples of a substituent is 4-hydroxy-6-methyl-2-pyrone (7) also known as triacetic acid which is a good starting reagent because of the OH group and the possibility of electrophilic substitution at the C- 3 and C-6 position [3].
Figure 4: Classic reactions on a 2-pyrone ring and common pyrone used as a starting material.
Pyrone ring is a motif often see in many types of natural product like plants or bacteria and has shown biological effects especially in the fight against external organisms [3]. For
example, it is possible to see this ring in molecules like solanapyrones E, pyrophen, corallopyronin A or myxopyronin B [5-7].
Different synthetic paths have been developed in order to get the 2-pyrone motif. 4- Hydroxy-6-alkyl-2-pyrones are mainly obtained via a biomimetic synthesis using a polyketide chain. Treatment of the appropriately substituted 3,5-diketo ester with a base generates the desired 2-pyrone [8]. But other ways to get this pyrone ring also exist.
Figure 5: One way to get pyrone ring with a polyketide chain and a base.
Looking at these two target molecules, two synthetic strategies have been considered:
1. A strategy where a commercial available alpha pyrone is functionalized to obtain the desired molecules.
2. A strategy to make the pyrone ring.
The advantage of the first strategy is that it is shorter. However, the presence of the pyrone can limit the reactions to functionalized the ring easily. The second, longer, offers more actions for an enantioselective total synthesis.
This report describes the different synthesis that were considered in order to obtain these two molecules. The first part describes the various synthetic strategies and reactions considered. Then in the second part, the results obtained in the laboratory are presented and the problems encountered. All the protocols used are described at the end of the report and all data proving them are included in the appendix part.
II - Theory
This part presents the different syntheses and reactions investigated to obtain the two compounds, dothideopyrone E (1) and F (2).
1. Synthetic routes
1.1. Retrosynthesis and synthesis path from a commercial pyrone
The initial strategy to obtain the two target compounds was based on functionalizing the pyrone scaffold. Hence, the synthesis can either start by adding the carbon chain in position C-6 or start by adding the primary alcohol in position C-3. We decided to start with the addition of the aliphatic chain to position C-6, as the formation of the stereocenter was considered more delicate. Molecule 2 being the simplest, it served as models to build the synthesis, molecule 1 being quite similar.
In order to control the stereoselectivity of the secondary alcohol, we aim to introduce this group asymmetrically by a Carreira-alkynylation, and subsequently hydrogenation of the resulting alkene. Then introduction of primary alcohol in position C-3.
Figure 6: Retrosynthesis of the dothideopyrone F (2).
An overview of the complete synthesis can be found in scheme 1. The first step is an O- methylation of compound 7 to get the compound 8 [9]. Then the objective was to functionalize the pyrone by adding the carbon chain while having an alcohol with the right stereochemistry beside the ring. Researches in the literature revealed that it was possible to oxidize methyl to aldehyde by a Riley oxidation. [10] With the aldehyde in our hands, a Carreira-alkynylation was employed to achieve the chiral secondary alcohol. The addition of a chiral agent makes it possible to obtain preferentially one of the two enantiomers [11].
So, compound 8 can be oxidized with selenium dioxide in a Riley oxidation to obtain the desired aldehyde 9. Compound 10 then reacts with 1-octyne to obtain a propargylic alcohol Which subsequently can be hydrogenated to obtain the desired carbon chain of the final product 11.
For the addition of primary alcohol at position C-3, two methods are described in the literature. The first one is done by the addition of thiophenol and paraformaldehyde with a thiol-ene reaction followed by oxidation and a Pummerer rearrangement [12-14]. The second is via formylation followed by reduction of aldehyde [9]. The first is done in 3 steps, the second in two but the first solution has been favored because it allows to have better
performance on some pyrones according to the literature [5]. These two possibilities are preceded by a step of protecting alcohol.
Based on the described synthesis of dothideopyrone F (2), the idea was to obtain 1 via a similar path. Hence, a terminal alkyne having the donation alcohol with the right stereochemistry was needed. This can be achieved by an epoxide opening with a terminal alkyne. Then the alkyne in the middle of carbon chain can be isomerized to a terminal alkyne via an alkyne Zipper reaction [15-17].
Figure 7: Retrosynthesis of the alkyne.
After a silyl protection of the resulting alcohol, the rest of the synthesis is similar to dothideopyrone F (2). Thus, the first possibility of synthesis was obtained, see scheme 1.
This synthetic path comprises 9 steps to obtain dothideopyrone F (2), 9 to obtain the dothideopyone E (1), so a total of 18 steps.
Scheme 1: Overview of the planned synthetic route of dothideopyrone E (1) and dothideopyrone F (2).
1.2. Retrosynthesis and synthesis path by building the pyrone ring
An alternative way was to build the pyrone ring. A method for doing that consisted of the coupling between an aldehyde comprising the different asymmetric carbons and a ketene acetal, the ring being obtained then by simple thermolysis of the acetal. This sequence has been widely employed in literature, see figure 8 [9, 18].
Figure 8: Retrosynthesis to build the pyrone ring.
The ketene acetal can be obtained in a single step from 2,2,6-trimethyl-4H-1,3-dioxin-4- one (26). To get the aldehyde, several approaches were considered, especially how to obtain the right asymmetric carbon. An enantioselective α-oxyamination of the decanal (27) to obtain a diol with correct stereochemistry of the secondary alcohol was employed.
The right enantiomer is got predominantly thanks to the use of d-Proline that play the role of organocatalist. Indeed, in this reaction, the nitrogen basicity might divide the addition to get the desired O-addition. This reaction will further discussed in the next part [19-20].
Then, the aldehyde used for the formation of the ring is inspired by the method described in the synthesis of lipoxin A4 using selective alcohol protections followed by an alcohol oxidation [21-22]. Once the aldehyde is obtained, it can be coupled with ketene acetal via an aldol reaction and then cyclized, see scheme 2 [6]. It includes 12 steps.
Scheme 2: Synthetic route of dothideopyrone F (2).
For compound 2 the same process is used with 3 initial steps starting from 8-bromo-1- octene (40). Turned into a Grignard reagent, this one can easily open an epoxide then the alcohol can be protected and the intermediate ozonolyzed to create the analogue of decanal with the TBS group at position C-9 on the carbon chain [23-24]. The diagram below describes the various steps to synthesize the second target compound 1. It includes 15 steps.
Scheme 3: Synthetic route of dothideopyrone E (1).
2. Reactions
The following part details the different reactions involved in the different syntheses as well as their mechanisms. The mechanisms are either carried out with general molecules or with the different intermediates found in the different synthetic routes.
2.1. Methylation
There are different ways to methylate an alcohol. In the literature, dimethyl sulfate in the presence of a base such as K2CO3 has been used for methylated alcohol present on the pyrone ring 7 [12]. However, as dimethyl sulfate is quite toxic, the use of methyl p- toluenesulfonate was preferred to methylate the different molecules in this project. This method has been described in the synthesis of solanapyrone A [9].
Figure 9: Alcohol methylation by methyl p-toluenesulfonate.
The mechanism for the methylation is shown below. It rationalizes the formation of compounds 8, 37 and 51 in this work. First the alcohol is deprotonated by the base. The alcoholate formed can then react with methyl p-toluenesulfonate. The reaction is favored by the departure of the tosylate group stabilized by electronic stabilization.
Figure 10: Mechanism of alcohol methylation by methyl p-toluenesulfonate.
There is also a greener method using dimethyl carbonate but it was not considered here because it requires a high temperature and could possibly degrade the molecules [25].
2.2. Oxidation
An oxidation reaction transforms a chemical function to a more highly oxidized derivative by removal of hydrogen and/or addition of oxygen. This part describes different oxidations used in this work.
2.2.1. Riley oxidation
This reaction uses selenium dioxide for allylic oxidation of alkenes. The starting material can include enones, allylic alcohols, or allylic esters, depending on the reaction conditions.
The allylic alcohols that are the initial oxidation products can be further oxidized to carbonyl groups by SeO2 and the conjugated carbonyl compound is usually isolated
.
Figure 11: Allylic oxidation of alkene to alcohol.
The mechanism consists of three essential steps, see figure 12:
- first, there is an electrophilic-ene reaction with SeO2,
- then followed by a [2,3]-sigmatropic rearrangement that restores the original location of the double bond,
- finally, a solvolysis of the resulting selenium ester. [26]
.
The mechanism is shown below. It rationalizes the formation of compound 8 in this work.
Figure 12: Mechanism of the Riley oxidation.
2.2.2. DMP oxidation
There are many ways of oxidizing a primary or secondary alcohol to aldehyde, for example by using compounds based on:
- chromium such as PCC, - on manganese with MnO2,
- or even based on dimethyl sulfoxide [27].
Methods involve the reagent of Dess-Martin, a hypervalent iodine (V) compound, is widely used and oxidizes the alcohols quickly.
Figure 13: Alcohol oxidation with Dess-Martin periodianane (DMP).
In the mechanism, an acetate group of DMP is replaced by alcohol and then deprotonation occurs. The mechanism is shown below. It rationalizes the formation of compounds 32, 34, 48 and 49 in this work.
Figure 14: Mechanism of alcohol oxidation by Dess-Martin periodinane.
2.2.3. Oxidation of sulfur compound
A sulfide compound is primarily oxidized to a sulfoxide compound.
Figure 15: Oxidation of sulfide to sulfoxide.
A peracid such as hydrogen peroxide or meta-Chloroperoxybenzoic acid (MCPBA) can oxidize sulfides to sulfoxides. MCPBA is an oxidant with strong electrophilicity. It is a peracid, which is widely used in organic chemistry especially to oxidize a compound such as for example an alkene to epoxide [28]. It can oxidize sulphides at low temperature in the presence of dichloromethane. This reaction also forms a side product, meta- chlorobenzoic acid [29].
The mechanism is shown below. It rationalizes the formation of compounds 14, 20, 38, and 63 in this work.
Figure 16: Oxidation mechanism of sulfide to sulfoxide.
2.2.4. Ozonolysis
Ozonlysis are an oxidizing cleavage of the C-C double bond. It involves an alkene which reacts at very low temperature with ozone.
Figure 17: Cleavage of the C-C bond by ozone.
It is not possible to describe the ozone molecule by a single Lewis formula. This molecule has different mesomeric forms.
Figure 18: Mesomeric forms of ozone.
The first intermediate formed is 1,2,3-trixolane. This intermediate is formed via a 1,3- dipolar cycloaddition. This intermediate then fragments and then recombines to give 1,2,4-trioxolane or ozonide. Ozonides are explosive compounds due to the fragility of the peroxo bond. The reaction should be carried out at low temperature. The aldehyde being in an oxidizing medium, because there is formation of hydrogen peroxide, it is
transformed into carboxylic acid. To avoid this reaction, a reducing agent such as powdered zinc or dimethyl sulfide is added to the medium which is then oxidized.
Different reducing agents can be used such as zinc, dimethyl sulfide or triphenylphosphine [30].
The mechanism is shown below. It rationalizes the formation of compound 43 in this work.
Figure 19: Ozonolysis mechanism.
2.3. Carreira alkynylation
This reaction makes it possible to obtain a propargyl alcohol from the reaction between an aldehyde and a terminal alkyne. Additionally, adding chiral additives such as (-) – N- methylephedrine ((-)-NME) or (+)-NME makes this reaction enantioselective. In addition, this reaction creates C-C bonds, using compounds that are readily available and which do not need any special preparation. Indeed, alkynilide used in this kind of reaction are usually prepared via strong base like organolithium compound. However, these strong bases are incompatible with carbonyl group and side reactions can appeared, that is why the alkynilide has to be prepared separately. Under standard conditions, the use of 1.1 equivalent of zinc triflate (Zn(OTf)2), 1.2 equivalent of (+) or (-)-NME and 1.2 equivalent of triethylamine for 1 equivalent of aldehyde and alkyne are necessary and the reaction can last from a few hours to one or two days [11].
Figure 20: Creation of propargylic alcohol from aldehyde and terminal alkyne.
This reaction is mostly carried out in anhydrous toluene but other solvents such as dichloromethane or THF can be used [11]. This reaction was carried out by Carreira's team in the synthesis of Leucascandrolide A [31]. He describes the following mechanism to
explain enantioselectivity by involving two metal centers in the transition state. In this state, aldehyde and alkyne are activited by the zinc complexe. The zinc alkynilide is prepared in situ before adding the aldehyde and (+) or (-)-NME plays the role of chiral ligand for Zn(II). Another advantage of NME is it can be remove from the crude product by acid wash. The chiral ligand/ metal assembly allows the attack on one particular face of the aldehyde. The figure 21 rationalizes the formation of 10 and 16.
Figure 21: Carreira alkynylation mechanism.
2.4. Hydrogenation
Hydrogenation of an alkyne in the presence of a catalyst results in the alkane via an alkene.
The hydrogenation reaction is diastereospecific and the stereochemistry of addition is syn.
Figure 22: Hydrogenation of an alkyne to an alkane.
In heterogeneous catalysis, hydrogenation takes place using a transition metal. It can be nickel, platinum or palladium. In this synthesis, palladium on charcoal was used
The following figure shows the hydrogenation of an alkene by hydrogene [32]. The hydrogen is adsorbed to the surface of the catalyst in atomic form, then the alkene is coordinated to the metal by its p (π) electron pair. The alkene reacts with the hydrogen and is desorbed [32]. In this synthesis, hydrognene first reduces the alkyne to the alkene and then to the corresponding alkane. The mechanism is shown below. It rationalizes the formation of compounds 11 and 17.
Figure 23: Hydrogenation of a double bond.
2.5. Epoxide opening
An epoxide is a cyclic ether with a three-atom ring. Epoxides are electrophilic compounds because of the difference in electronegativity between carbon atoms and the oxygen atom.
It can thus be opened by attacking a nucleophile on one of the two carbon atoms according to a bimolecular nucleophilic substitution. If so, the opening is regioselective, the nucleophile attacks the less hindered carbon.
Figure 24: Opening of an epoxide by a nucleophile.
In this project, the different epoxides involved were opened either by an organolithium compound or by an organomagnesium compound. This makes it possible to lengthen the carbon chain and obtain an alcohol. According to the stereochemistry of epoxide, it is possible to obtain a compound with a particular asymmetric carbon instead of having a mixture.
2.5.1. Opening by an organolithium compounds
A common way of preparing an alkynyllithium reagent is lithiation, that is to say an hydrogen-metal exchange.
Figure 25: Formation of an organolithium compound.
The organolithium is formed by deprotonation of the alkyne. Indeed, n-buthyllithium (n- Buli) is a strong base with a pka of about 50, and the terminal H-atom of the alkyne is acidic due to carbon sp-hybridization. [33]. The organolithium acts as a nucleophile and opens the epoxide on the less hindered side. The mechanism is shown below. It rationalizes the formation of compound 23.
Figure 26: Opening of an epoxide by an organolithium compound.
As the alkyllithium reagents exist in the form of aggregates, the use of chelating ligands is necessary to break down these aggregates and thus have monomers. A chelating ligand used for this is, for example, tetramethylethylenediamine (TMEDA). Other reagents like hexamethylphosphorotriamide (HMPA) and N,N-dimethylpropyleneurea (DMPU) can dissociate these aggregates and make the reagent organolithiums more reactive [33].
Figure 27: Reagents that improve the reactivity of organolithium compounds.
2.5.2. Organomagnesium compounds
Alkyl and aryl halides react with magnesium metal to give organomagnesium compounds.
Their reactivity is based on the polarization of the C-Mg bond. The carbon atom behaves like a "pseudo-carbanion", it has basic and nucleophilic properties. This is why these compounds are very useful synthetic reagents. The reaction takes place in an aprotic solvent. This solvent must also be a Lewis base, it must have one or more free doublets.
The most used solvents are either diethyl ether or anhydrous THF and the most widely used alkyl halides are the alkyl bromides [34]
After the formation of the Grignard reagent. there is a nucleophilic addition of the latter on the less hindered side of the epoxide. The last step is a hydrolysis of the magnesian alcoholate to obtain the alcohol. The mechanism is shown below. It rationalizes the formation of compound 41.
Figure 28: Mechanism of epoxide opening by a Grignard reagent.
2.6 Zipper reaction
The alkyne Zipper reaction is an isomerization of an internal alkyne into a terminal alkyne.
Figure 29: Alkyne Zipper reaction.
On exposure to strong base, an alkyne can migrate to the end of an alkyl chain. The migration is accelerated by 1,3-diaminopropane. The mechanism is a series of alkyne / allene interconversions, all of which are equilibria [35]. Potassium hydride transforms one amine into amide ion, which is a strong base [36-37].
The mechanism is shown below. It rationalizes the formation of 25.
Figure 30: Mechanism of the alkyne Zipper reaction.
2.7 Alcohol and enol protection
The purpose of protection is to preserve an intact function. The function thus protected is no longer the original function, so it no longer reacts in the same way to the different reagents. It is then possible to protect a reactive function so as to carry out numerous functional development steps on other parts of the molecule. Then, during a final deprotection step, the previously protected function is recovered. It then appears that the protection and deprotection steps are steps which must be carried out with yields close to 100%. Alcohols are a functional group that is found very often in organic chemistry and it can react with many compounds. This is why protection is often necessary. There are many ways to protect alcohols. This part describes the methods that have been used in this project.
2.7.1 Silyl ether protection
An alcohol can be protected as silyl ether. There are different compounds for this based on silicon such as TBSCl (tert-butyldimethylsilyl chloride), trimethylsilyl chloride (TMSCl)., or even tert butyldimethylsilyl trifluoromethanesulfonate (TBSOTf). Usually a base is needed to promote the reaction.
Figure 31: Alcohol protection to silyl ether.
An advantage of this protection is that it is more or less selective depending on the size of the silicon. In addition, the deprotection is facilitated because it is possible to selectively deprotonate this group for example by using reagents having a fluoride since by silicon has a great affinity with fluorine.
This is a nucleophilic substitution. The mechanism is shown below. It rationalizes the formation of compounds 12, 18, 24, 30 and 46.
Figure 32: Mechanism of alcohol protection into a silyl ether.
2.7.2 Silyl enol ether
Silyl enol ethers are intermediates which have acquired great importance in modern organic reactions. The enolate, obtained by reaction between the carbonyl compound and a strong base such as lithium diisopropilamide (LDA), could be trapped in the form of enol ether by reaction with TMSCl for example. In this project, the starting compound is 2,2,6- trimethyl-4H-1,3-dioxin-4-one (26).
Figure 33: Silyl enol ether protection.
The first step in this reaction is an acid-base reaction between n-butyllithium and diisopropylamine (DIPA) to form LDA. This strong base reacts with 26 to give an ionic intermediate which will then react with TMSCl via nucleophilic substitution to give the silyl enol ether. The mechanism is shown below. It rationalizes the formation of 33.
Figure 34: Silyl enol ether formation.
2.7.3 Pivalic acid ester
Pivaloyl chloride can be used to protect an alcohol as an ester. The benefit of this compound is that it will selectively protect a primary alcohol, which can be useful when a compound has multiple alcohol functionalties.
Figure 35: Alcohol protection with pivaloyl chloride.
The reaction can be done with or without 4-dimethylaminopyridine (DMAP). DMAP reacts with chloride to give a more reactive intermediate which in the next step will react better with alcohol. It plays the role of catalyst. Via an addition elimination mechanism, the intermediate from pivaloyl chloride and DMAP is formed and then in the same way, the ester is formed. The mechanism is shown below. It rationalizes the formation of compounds 45 and 29.
Figure 36: Mechanism of alcohol protection into pivalate ether catalized with DMAP.
2.8 Formylation
There are not many ways to perform formylation on the pyrone ring. Poulton and coworkers have already tried different reagents [38]. According to these results the Vilsmeier Haack reaction does not give a reaction and it seems that the best way to do this type of reaction is based on the action of titatium chloride (TiCl4) and dichloromethyl ether. However, the observed yields were quite low, around 40% [38].
Figure 37: Formylation of the pyrone ring.
Later, this way was improved to give superior yields especially by modifying the work-up.
The reaction takes place in dichloromethane and 10 equivalents of TiCl4 and dichloromethyl ether are required [9].
The pyrone ring reacts with an electron deficient intermediate. Here this electrophile is done by the action of TiCl4 on dichloromethyl ether. Alkoxypyrone chloride is the intermediate product before hydrolysis [39]. The mechanism is shown below.
Figure 38: Mechanism of formylation on a pyrone ring.
2.9 Reduction
2.9.1 NaBH
4reduction
Sodium boronhydride (NaBH4) allows aldehyde and ketones to be reduced to primary or secondary alcohol.
Figure 39: Reduction of aldehyde to alcohol with NaBH4.
The reaction involves attacking a nucleophile, here a hydride on the carbonyl compound.
It takes place in either methanol or ethanol and is usually done at low temperature. The mechanism is shown below. It rationalizes the formation of compound 28 and 44.
Figure 40: Mechanism of aldehyde reduction to alcohol by NaBH4.
2.9.2 DIBAL-H reduction
Esters can be reduced by reagents stronger than NaBH4. These reagents are often based on aluminum, for example lithium aluminum hydride (LiAlH4) or diisobutylaluminium hydride (DIBAL-H). LiAlH4 is a stronger reductive agent and is more likely to react with other functional groups than DIBAL-H which is why DIBAL-H has been retained.
Figure 41: Reduction of esters to alcohols by DIBAL-H.
First, the DIBAL-H reduces the ester to aldehyde function and then the latter is further reduced to obtain the alcohol. The mechanism is shown below. It rationalizes the formation of compounds 31 and 47.
Figure 42: Mechanism of ester reduction to alcohol by DIBAL-H.
2.10. Enantioselective and organocatalytic-oxidation of aldehydes
This step is based on the protocol described in the work of MacMillan and which was used in the synthesis of resolvin E4 [20, 40]. It makes it possible to switch from an aldehyde to a diol enantioselective via the action of d-Proline.
Figure 43: Enantioselective and organocatalytic α-oxyamination.
For this protocol, good enantiomeric excesses have been obtained using different solvents, but the use of chloroform minimizes the aldolization reaction and allows a better yield [40].
The mechanism is shown below. It rationalizes the formation of compounds 28 and 44.
Starting from aldehyde, d-proline and nitrobenzene provide the following intermediate.
Figure 44: Action of nitrozobenzene and d-proline on the aldehyde.
The aldehyde is then reduced with NaBH4. The mechanism of this step is presented in the section devoted to the reactions of reductions. Then, the N-O bonds are cleaved by zinc in the presence of acetic acid.
Figure 45: Reduction of the intermediate to get the diol.
2.11. Vinylogous Mukaiyama aldol addition
This reaction is a type of aldol reaction. This step involves an aldehyde and a silyl enol ether. Lewis acid is used to deprotect the enolate. Lewis acids such as TiCl4 can be used.
[41].
Figure 46: Vinylogous Mukaiyama aldol addition.
This reaction leads to the creation of a C-C bond. In this project, the Lewis acid used is boron trifluoride etherate. This reaction makes it possible to couple the aldehydes 32 and 48 with the ketene acetal in order to be able to build the pyrone ring.
Figure 47: Coupling between aldehyde and enolate.
This reaction takes place in two steps. First, BF3*OEt2 deprotects the enolate of compound 33 [42]. The intermediate then reacts with the aldehyde to form the alcohol. The mechanism is shown below. It rationalizes the formation of intermediates 34 and 49.
Figure 48: Mechanism of the coupling between the compound 39 and an aldehyde.
2.12. Knoevenagel and thiol-ene reactions
The action of paraformaldehyde, thiophenol and piperidine on the pyrone ring gives the following reaction.
Figure 49: Knoevenagel reaction followed by a thiol-ene reaction on a pyrone ring.
This is a Knoevenagel reaction followed by a thiol-ene reaction. This method was developed by Moreno Manas and coworkers [13-14]. It constitutes an effective method in the addition of a primary alcohol in position C-3 of the pyrone ring, method which was developed in the work of Hagiwara’s team [12].
The mechanism is shown below. First, he describes the Knoevenagel reaction and then the thiol reaction. It rationalizes the formation of intermediates 13, 19, 36 and 51.
2.12.1. Knoevenagel reaction
Knoevenagel reaction looks like a malonic synthesis. It makes it possible to form an α, β- unsaturated carbonyl compound or a related compound.
Figure 50: Knoevenagel reaction.
The X group is an electron withdrawing group such as a carbonyl group, a group which is present on the pyrone ring. A base is needed in order to deprotonate the carbon in the alpha position of the electron-withdrawing groups. One often used base is piperidine. It also acts on the aldehyde to give a more reactive iminium ion. [43] It therefore plays the role of organocatalyst in this reaction.
Figure 51: Knoevenagel reaction mechanism on the pyrone ring.
2.12.2 Thiol-ene reaction
The next reaction is a thiol reaction. It leads to the formation of a thioether by the action of a thiol on an alkene. The mechanism envisaged is a Michael-type-addition. The Michael addition pathway can either be catalysed by a base or a nucleophile. In the base catalysis mechanism, the base used is in general an amine, here the base used is a secondary amine, piperidine. The acidic proton of the thiol is abstracted by the base to give the thiolate anion [44-45].
Figure 52 : Base catalyzed mechanism of the Michael addition.
The thiolate anion is a strong nucleophile which can act on electron deficient alkene. As the intermediate formed is basic, it reacts again with the thiol to regenerate the thiolate anion.
Figure 53: Mechanism of the Michael addition to afford the new pyrone ring.
2.13. Ring closing
During this step, the pyrone ring is formed. This reaction takes place in toluene heated to reflux. This is a retro Diels alder / cyclization cascade.
Figure 54: Cyclization to get the pyrone ring.
The mechanism of this reaction has been studied and reported by Sato [46]. This synthetic strategy was then used on numerous occasions in the formation of the pyrone ring, for example in the synthesis of pyrophen or chatancin [6, 47].
Keto dioxinone is transformed into a highly reactive intermediate by thermolysis. This can be balanced in two ways. The formation of the cycle through A is difficult. Indeed, the reaction is considered as an n-exo-trig closure reaction. In these reactions, the OH group has to be in the right configuration to allow to good trajectory of the nucleophile because of the planarity caused by the C-O and C-C double bonds. Hence, the most probable route is through the intermediate B. The mechanism is shown below. It rationalizes the formation of compounds 35 and 50.
Figure 55: Ring closing mechanism.
2.14. Pummerer rearrangement and obtention of the primary alcohol
This step involves forming the primary alcohol at the C-3 position of the pyrone ring via Pummerer rearrangement. This rearrangement is an alkyl sulfoxide transformation to an α-acyloxy – thioether in the presence of acetic anhydride or by a similar reagent such as trifluoroacetic anhydride TFAA.
Figure 56: Pummerer rearrangement.
In this project, this rearrangement is followed by hydrolysis to lead to the desired alcohol.
Figure 57: Path to obtain the primary alcohol.
The mechanism is shown below. It rationalizes the formation of compounds 15, 21, 39 and 54 in this work. The first steps consist of the formation of a sulfonium ion A by the action of TFAA on the starting compound.
Figure 58: Formation of the sulfonium intermediate.
Then there are two possibilities that explain the formation of alcohol. First, an SN2 substitution. Sulphonium ion A is substituted by a trifluoroacetoxy ion. Alternatively, the phenylsulfenyl group of the starting compound is acylated to sulphonium ion A via SN1 and then elimination leads to intermediate B. Addition of a trifluoroacetoxy ion then leads to intermediate C. This latter intermediate is hydrolyzed to give alcohol [12].
Figure 59: Two possibilities to get the final alcohol.
2.15. Alcohol deprotection
A conventional method of removing a tbs group to obtain the corresponding alcohol is to use tetra-n-butylammoniumfluoride (TBAF) or another source of fluoride.
Figure 60: Silyl ether deprotection.
Nucleophilic attack of the small fluoride anion leads to a pentavalent silicon center which is permitted due to hybridization with the vacant d-orbitals of silicon. In addition, the formation of the strong Si-F bond is the driving force for a fast cleavage. The mechanism is shown below. It rationalizes the formation of 1 and 2.
Figure 61: Mechanism of silyl ether deprotection.
III - Results and discussion
This part describes the results obtained in laboratories for the different paths considered.
It also describes the problems that were encountered.
1. Synthesis 1 using a commercial pyrone ring
1.1 Synthesis of compound 8
The first step is the methylation of the starting product 7. The synthesis took place in DMF, using potassium carbonate and methyl p-toluenesulfonate and the product is obtained by a nucleophilic substitution preceded by an acid-base reaction. The formation of product is rationalized by the mechanism shown on page 25.
The reaction was followed by TLC. After the reaction, numerous washes with water and brine as well as a long evaporation are necessary to remove the DMF. Column chromatography (50% ethyl acetate in n-pentane) makes it possible to obtain the desired product. The yield obtained was 76% quite close to that obtained in the literature [9].
The proton NMR spectrum shows an additional peak compared to the starting product integrating for 3 H, a sign that the methylation worked.
4-methoxy-6-methyl-2H-pyran-2-one (8) was characterized by 1H-NMR, 13C-NMR, Rf, melting point and IR. See experimental section and Appendix 1.
1.2 Synthesis of compound 9
The second step is Riley oxidation. It makes it possible to obtain an aldehyde on the methyl in position C-6 of the pyrone ring of compound 8. The oxidation is done through the use of selenium dioxide and the solvent used was dioxane anhydride. The formation of product is rationalized by the mechanism shown on page 26.
First, this reaction was carried out under nitrogen pressure and heated to reflux for 10 h.
The yield obtained was 30%, far from the 90% obtained in the literature [10]. The use of a sealed tube is crucial for obtaining good yields. After 4 hours of reaction at 160 ° C, the yield obtained was 84%.
The proton NMR spectrum shows a peak around 10 ppm indicating the presence of an aldehyde.
4-methoxy-2-oxo-2H-pyran-6-carbaldehyde (9) was characterized by 1H-NMR, 13C- NMR, Rf, melting point and IR. See experimental section and Appendix 2.
1.3 Synthesis of compound 10
In the literature, this reaction can be done with a non-anhydrous solvent, but most protocols use an anhydrous solvent. The solvent used to carry out this reaction is generally anhydrous toluene. However, compound 9 is not soluble in this solvent, which is why anhydrous dichloromethane was chosen [11]. The formation of product is rationalized by the mechanism shown on page 30.
Carreira gives the precise equivalents to be able to carry out this reaction, namely 1.1 equivalent of Zn(OTf)2, 1.2 equivalent of (-) - NME, 1.2 equivalent of Et3N, 1 equivalent of aldehyde and 1-octyne but these quantities gave low yields, at around 10%, even after 40 hours of reactions [11]. Different tests were performed with different equivalents for zinc triflate, (-) - NME, 1-octyne and triethylamine.
Entry Zinc triflate (-)-NME Et3N 1-octyne Yields
1 1.9 2 2 1.2 18%
2 2.9 3 3 1.2 12%
3 1.1 1.2 1.2 1 10%
4 1.9 2 1.2 1.2 25-42%
Table 1: Modification of equivalent of zinc triflate, triethylamine, (-)-NME and 1-octyne in the Carreira-alkynylation.
The best combination was entry 4. The alkyne was pre-diluted in anhydrous dichloromethane before being added all at once. The reaction was left to stir at room temperature for about 20 h.
Since this reaction is sensitive to air and water, the zinc triflate and (-) - NME were previously dried under vacuum for about ten hours before being used. Under an inert atmosphere, the solvent then 30 minutes later, the triethylamine is added all at once.
The very slow addition of the aldehyde dissolved in the dichloromethane did not increase the yield, a yield of 10% having been obtained. Dilution of the alkyne in the solvent has been found to be necessary in order to have a slightly higher yield.
Concerning purification, TLC reveals numerous spots with disappearance of the starting compound after washings and extractions. The desired product being very close to another spots, two columns were sometimes necessary to be able to recover all the product.
The best yield obtained was 42% but most of the time the yield was around 25-30%. One reason that could explain this low yield is that the starting compound 9 is base sensitive.
[10] Another reason is that this reaction gives lower yields with unsaturated aldehydes.
The use of dimethyl zinc with a chiral ligand and without a base might be a solution to increase the yield and the enantiomeric excess but this route has not been explored [48].
The compound obtained has optical activity. A specific rotational power was found. In view of the low efficiency and the value of the specific rotational power measured, the
enantiomeric excess does not seem high. The enantiomeric mixture was used in the following reactions.
(S)-6-(1-hydroxynon-2-yn-1-yl)-4-methoxy-2H-pyran-2-one (10) was characterized by 1H-NMR, 13C-NMR, Rf, IR and polarimetry. See experimental section and Appendix 3.
1.4 Synthesis of compound 11
This is a hydrogenation of the triple bond of compound 10. The formation of product is rationalized by the mechanism shown on page 30.
The reaction was followed by TLC. It took about 16 h to be able to reduce the triple bond to single bond.
The best yield obtained is around 70%. The proton NMR shows a peak change of less than 2 ppm, a sign of a change in the carbon chain and the disappearance of the triple bond.
The spectrum also does not reveal the presence of peaks suggesting an alkene.
(S)-6-(1-hydroxynonyl)-4-methoxy-2H-pyran-2-one (11) was characterized by 1H- NMR, 13C-NMR, Rf, melting point, IR and polarimetry. See experimental section and Appendix 4.
1.5 Synthesis of compound 12
The compound 11 alcohol is protected by a TBS group via nucleophilic substitution. The formation of product is rationalized by the mechanism shown on page 35.
The yield obtained was about 50% after 12 hours of stirring at room temperature. Better yields could otherwise be obtained by using another source for the tbs group or by using other protecting groups.
The proton NMR spectrum shows the appearance of two integrating peaks at 6 and 9 H, a sign of the presence of the TBS group.
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-methoxy-6-methyl-2H-pyran-2-one (12) was characterized by 1H-NMR, 13C-NMR, Rf, IR and polarimetry. See experimental section and Appendix 5.
1.6. Attempt to add the primary alcohol to the pyrone ring of compound 12
Addition of thiophenol and paraformaldehyde did not give anything on compound 12 and on compound 8. Almost the same amount of product introduced was recovered after work- up. It seems that the problem comes from the method group on the C4 carbon of the
pyrone ring. The mesomeric donor effect appears to be too weak. If we look at the deprotonated form of the pyrone cycle, a negative carbon appears on the C-3 carbon of the ring [14].
Figure 62: Reasoning forms of deprotonated compound 3.
Formylation attempts have been tried on compound 12 but no results could be obtained.
Only compound 8 was able to give rise to formylation but with yields less than 10% and with many failures when trying different protocols.
Figure 63: 1H-NMR spectrum of the product obtained after formylation of 8
Being unable to add the primary alcohol in position 3 of the pyrone ring, the decision was made to start from the starting product 7 by first adding the primary alcohol and then carrying out the riley oxidation followed by the Carreira-alkynylation.
Figure 64: New retrosynthesis from starting material 7.
Another advantage of this close is the length of the synthesis. Indeed, the first 5 stages become common unlike two stages in the first synthesis. Which leads to a total of 15 steps.
Scheme 4: Synthesis route with less steps starting by adding the primary alcohol at C-3 position.
Another method was also thought to get the alcohol in position C-3 from dehydroacetic acid sodium salt 64 like the start of the synthesis of solanapyrone A [49]. But this path was quickly discarded because it has more steps.
Scheme 5: Other possible route for getting the primary alcohol at C-3 position.
