Synthesis of Thiourea and Urea Organocatalysts by Opioids

215 Pages·2017·10.34 MB·English

by  Chloe Chu

Synthesis of Thiourea and Urea
Organocatalysts by Opioids

By Bo Liu (B.Sc.)

Supervisors: Dr. Kieran Nolan
Prof. Nicholas Gathergood
(Tallinn University of Technology, Estonia)

For the award of Master’s Degree by Research in Organic Chemistry

School of Chemical Sciences
Dublin City University

July 2017
Declaration
I hereby certify that this material, which I now submit for assessment on the programme
of study leading to the award of a Master’s degree by research is entirely my own work,
that I have exercised reasonable care to ensure that the work is original, and does not to
the best of my knowledge breach any law of copyright, and has not been taken from the
work of others save and to the extent that such work has been cited and acknowledged
within the text of my work.

Signed: __________________
Bo Liu

(Candidate) ID No.: 12211565

Date: __________________

I
Table of Contents
Declaration ..................................................................................................................... I
Table of Contents .......................................................................................................... II
List of Abbreviations .................................................................................................... V
List of Figures ............................................................................................................... X
List of Schemes ......................................................................................................... XIV
List of Tables .......................................................................................................... XVIII
List of Appendix Figures and Tables ...................................................................... XIX
Acknowledgements ................................................................................................... XXI
Abstract ................................................................................................................... XXII
Chapter 1 Literature Review ....................................................................................... 1
1.1 Chiral compounds .............................................................................................. 2
1.2 Primary sources of chiral compounds ................................................................ 2
1.2.1 Resolution of racemates ........................................................................... 3
1.2.2 Asymmetric synthesis .............................................................................. 5
1.2.3 Chiral pool approach ................................................................................ 6
1.3 Other sources of chiral compounds .................................................................... 9
1.3.1 Transition-metal catalysts ........................................................................ 9
1.3.2 Organocatalysis ...................................................................................... 12
1.3.3 Classification of organocatalysis ............................................................ 13
1.3.3.1 Lewis base catalysis ......................................................................... 13
1.3.3.2 Lewis acid catalysis ......................................................................... 17
1.3.3.3 Brønsted base catalysis .................................................................... 23
1.3.3.4 Brønsted acid catalysis .................................................................... 26
1.3.3.5 Specific (strong) Brønsted acid catalysis ......................................... 27
1.3.3.6 General Brønsted acid catalysis ....................................................... 32
1.4 Bifunctional chiral phosphoric acids ................................................................ 41
1.4.1 Catalysis by acids ................................................................................... 41
1.4.2 Structural features of chiral phosphoric acids ........................................ 43
1.4.3 Catalysis of Mannich reaction by a chiral phosphoric acid ................... 44
1.5 Cinchona alkaloid-based thiourea and urea derivatives ................................... 48
II
1.5.1 The cinchona alkaloids ........................................................................... 48
1.5.2 Cinchona alkaloid-based thiourea, urea and squaramide derivatives .... 50
1.5.3 Catalysis of asymmetric Michael addition reactions by cinchona-derived
urea and thiourea derivatives .......................................................................... 57
1.6 Opium alkaloid-based organocatalysts ............................................................ 59
1.6.1 The morphine alkaloids .......................................................................... 59
1.6.2 The structure of morphine alkaloids ...................................................... 60
1.6.3 Catalysis of reactions by morphine alkaloids......................................... 61
1.7 Conclusion ....................................................................................................... 63
1.8 References ........................................................................................................ 65
Chapter 2 Synthesis and structural characterisation of thiourea and urea opioid
derivatives .................................................................................................................... 83
2.1 Synthesis of opioid derivatives ........................................................................ 84
2.1.1 Synthesis of 6-O-tosylcodeine (1) .......................................................... 86
2.1.2 Synthesis of 8-isothiocyanocodide (2) and 8-azidocodide (3) ............... 88
2.1.3 Synthesis of 8-aminocodide (4) ............................................................. 90
2.1.4 Synthesis of N,N’-disubstituted thiourea (5) and urea (6) derivatives ... 91
2.1.5 Attempted synthesis of chiral phosphoric acid based opioid derivative.93
2.2 Characterization of opioid precursors .............................................................. 96
2.2.1 1H NMR of opioid precursors ................................................................ 96
2.2.2 13C NMR of opioid precursors ............................................................. 100
2.3 Characterization of N,N’-disubstituted thiourea and urea derivatives ........... 103
2.3.1 1H NMR of N,N’-disubstituted thiourea and urea derivatives ............. 104
2.3.2 1H-1H COSY of N,N’-disubstituted thiourea and urea derivatives ...... 108
2.3.3 13C and DEPT-135 of N,N’-disubstituted thiourea and urea derivatives
....................................................................................................................... 111
2.3.4 HMQC of N,N’-disubstituted thiourea and urea derivatives ................ 114
2.3.5 IR spectroscopy of N,N’-disubstituted thiourea and urea derivatives .. 117
2.3.6 MS of N,N’-disubstituted thiourea and urea derivatives ...................... 119
2.3.7 XRD of N,N’-disubstituted thiourea and urea derivatives ................... 122
2.4 Future work .................................................................................................... 129
2.5 References ...................................................................................................... 132
III
Chapter 3 Catalytic study of N,N’-disubstituted thiourea opioid derivative in
Michael addition reactions ....................................................................................... 139
3.1 Introduction .................................................................................................... 140
3.2 Catalysis of Michael addition reaction by Takemoto catalyst........................ 140
3.3 Evaluation of N,N’-disubstituted thiourea derivative in the Michael addition
reaction ................................................................................................................. 146
3.3.1 Evaluation of the effects of selected solvents ...................................... 147
3.3.2 Evaluation of the effects of reagent ratios ............................................ 150
3.3.3 Evaluation of the effects of catalyst loading ........................................ 151
3.4 Discussion ...................................................................................................... 153
3.5 Future work .................................................................................................... 155
3.6 References ...................................................................................................... 157
Chapter 4 Experimental ........................................................................................... 159
4.1 Chemicals and instruments ............................................................................ 160
4.2 Preparation of opioid derivatives ................................................................... 161
4.3 Study of Michael addition reaction ................................................................ 170
4.4 References ...................................................................................................... 172
Appendices ...................................................................................................................... i
Appendix A: NMR spectra ...................................................................................... ii
Appendix B: HPLC chromatograms (Solvent Tests) ............................................ xii
Appendix C: Crystal data and structure refinement for N,N’-disubstituted thiourea
and urea derivatives............................................................................................. xvii

IV
List of Abbreviations
*: stereogenic center

A
Å: Angstrom
[α]: specific rotation
Ac: acetyl
aq.: aqueous
Ar: aryl
atm: atmosphere

B
BINAP: 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl
BINOL: 1,1’-bi-2-naphthol
BINSA: 1,1’-binaphthyl-2,2’-disulfonic acid
Boc: tert-butoxycarbonyl

C
ºC: degrees Celsius
cm-1: wavenumber (s)
COD: 1,5-cyclooctadiene
COSY: correlation spectroscopy
δ: chemical shift in parts per million

D
DABCO: 1,4-diazabicyclo[2.2.2]octane
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM: dichloromethane
DCE: 1,2-dichloroethane
de: diastereomeric excess
DEPT: distortionless enhancement by polarization transfer
DHQ: dihydroquinine
DHQD: dihydroquinidine
DIOP: 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane
V
DiPAMP: ethane-1,2-diylbis[(2-methoxyphenyl)phenylphosphane]
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
DPEN: 1,2-diphenylethane-1,2-diamine
dr: diastereomeric ratio

E
ee: enantiomeric excess
endo: endothermic
eq.: equivalent
er: enantiomeric ratio
ESI: electrospray ionization
Et: ethyl
et al.: and others
exo.: exothermic
Exp.: experiment

F
FGI: Functional Group Interconversion
Fig.: Figure

G
g: gram (s)

H
h: hour (s)
HMQC: heteronuclear multiple quantum correlation
HOMO: highest occupied molecular orbital
HPLC: high-performance liquid chromatography
Hz: Hertz

I
IR: infrared

VI
J
J: coupling constant (in NMR spectrometry)

K
kg: kilogram (s)

L
LC-MS: liquid chromatography-mass spectrometry
ʟ-DOPA: ʟ-3,4-dihydroxyphenylalanine
Lit.: literature
LUMO: lowest unoccupied molecular orbital

M
M+: parent molecular ion
Me: methyl
MeOH: methanol
min: minute (s)
mL: milliliter
mol: mole (s)
mmol: millimole
m.p.: melting point
MS: mass spectrometry
Ms: methanesulfonyl
m/z: mass to charge ratio

N
NMR: nuclear magnetic resonance

O
OTs: tosylate (p-toluenesulfonate)

P
Ph: phenyl

VII
PhSH: thiophenol
PMP: 4-methoxyphenyl
ppm: parts per million
iPr: isopropyl
PPh : triphenylphosphine
3

R
RI: relatively intensity
rt: room temperature

S
S 2: bimolecular nucleophilic substitution
N
S 2’: bimolecular nucleophilic substitution with allylic rearrangement
N
SOMO: singly occupied molecular orbital

T
TADDOL: α,α,α’,α’-tetraaryl-1,3-dioxolane-4,5-dimethanol
TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene
TBS: tert-butyldimethylsilyl
TEA: triethylamine
TEMP.: temperature
THF: tetrahydrofuran
TIPS: triisopropylsilyl
TIPBs: triisopropylbenzenesulfonyl
TLC: thin layer chromatography
TMG: 1,1,3,3-tetramethylguanidine
TMSCN: trimethylsilyl cyanide
TsCl: 4-toluenesulfonyl chloride

V
VANOL: 3,3’-diphenyl-2,2’-bi-1-naphthalol
VAPOL: 2,2’-diphenyl-(4-biphenanthrol)

VIII
X
XRD: X-ray powder diffraction

IX