Table Of ContentAtropisomeric Diaryl Ethers and other Non-Biaryl
Atropisomers
A thesis submitted to the University of Manchester
for the degree of Doctor of Philosophy
in the Faculty of Engineering and Physical Sciences
2010
Abigail Laura Page
School of Chemistry
2
Contents
List of illustrations 6
List of tables 11
Abstract 13
Declaration 14
Copyright Statement 15
Acknowledgements 15
Abbreviations 16
1. Introduction..................................................................................................................19
1.1 Chirality and the Need for Asymmetric Synthesis...............................................20
1.2 Atropisomers: Discovery and Use........................................................................22
1.3 Non-Biaryl Atropisomers: Tools for Stereoselective Synthesis?.........................26
1.3.1 Amide axis controlled formation of new chial centres...................................26
1.3.2 Utilising conformational interplay to control stereoselectivity......................27
1.3.3 Non-Biaryl Atropisomers as Molecular Machines?.......................................29
1.3.4 Non-biaryl atropisomers in catalysis and synthesis.......................................31
1.4 Asymmetric Synthesis of Atropisomers...............................................................34
1.4.1 Asymmetric coupling methods.......................................................................34
1.4.2 Classic resolution...........................................................................................37
1.4.3 Kinetic resolution methods.............................................................................38
1.4.4 Dynamic Kinetic resolution............................................................................39
1.4.5 Thermodynamic Resolutions..........................................................................40
1.4.6 Dynamic Thermodynamic Resolutions..........................................................44
1.4.7 Aromatic ring construction.............................................................................46
1.4.8 Desymmetrisation methods............................................................................47
1.5 Aims of the Project...............................................................................................51
2. Results and Discussion.................................................................................................53
2.1 Synthesis of Diaryl Ethers....................................................................................53
2.1.1 Diaryl ether synthesis and requirements for chirality....................................53
2.1.2 Synthetic Strategy...........................................................................................56
2.1.3 Chlorination....................................................................................................58
2.1.4 Diaryl ether formation....................................................................................60
2.1.5 DiBAl-H reduction.........................................................................................63
2.1.6 Borohydride reduction....................................................................................64
2.1.7 Routes to the commercially unavailable phenol............................................65
2.2 Biocatalytic Desymmetrisation of Diaryl Ethers.................................................70
2.2.1 Enantioselective acylation and deacylation....................................................70
2.2.2 Kinetic resolution by enantioselective oxidation...........................................72
2.2.3 Desymmetrisation with Ketoreductases.........................................................82
2.2.4 Ongoing and future work: Toward ligand synthesis......................................85
2.3 Enantiopos-Differentiatiation and Stereoselectivity of Laterally Lithiated
Diaryl Ethers ...................................................................................................... 91
2.3.1 Strategy and synthesis of pro-atropisomers...................................................93
2.3.2 Lateral lithiation of meso-dimethoxy analogues............................................94
2.3.3 Lateral lithiation of meso-dimethyl analogues...............................................96
2.3.4 Synthesis and lateral lithiation of meso-carbamate analogues.......................97
2.3.5 Desymmetrisiation and stereoselectivity of laterally lithiated diaryl-ethers100
2.3.6 Configurational stability and stereoselectivity in the reaction and
synthesis of laterally lithiated diaryl ethers ............................................... 104
2.4 Other Stereoselective and Conformational Studies of Non-Biaryl
Atropisomers ....................................................................................................122
2.4.1 Stereoselective reductions of a diaryl ether..................................................122
2.4.2 Stereoselective additions to diaryl sulfides..................................................127
2.4.3 Conformational study of a diaryl amide in solution.....................................131
3. Conclusions and Future Work..................................................................................138
4. Appendices..................................................................................................................144
I. Calculation of barriers to rotation using VT NMR.............................................144
II. Synthesis of diaryl sulfoxides.............................................................................148
III. Examples of HPLC traces...................................................................................151
IV. Selected NMR Spectra.......................................................................................154
5. Experimental Section.................................................................................................159
5.1 General Procedures............................................................................................159
5.2 Experimental Data..............................................................................................165
5.3 Biocatalysis Procedures......................................................................................221
5.4 X-Ray Crystal Data............................................................................................224
6. References...................................................................................................................231
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Total Word Count: 52 627
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List of Illustrations
Figure 1: Chiral structures of Naproxen 1, DOPA 2 and Thalidomide 3 20
Figure 2: 6,6’-dinitro-2,2’-diphenic acid 22
Figure 3: Barriers to atropisomerism 22
Figure 4: Atropisomeric ligands 23
Figure 5: Atropisomeric features in some natural products and 24
pharmaceuticals
Figure 6: Non-Biaryl Atropisomers 25
Figure 7: Predferred conformation of (–)-ephedrine adjacent to an amide axis 28
Figure 8: Conformational preference of Xanthene 29
Figure 9: Diarylether based ligands 31
Figure 10: Atropisomeric organocatalyst NOBIN 32
Figure 11: Structure of Vancomycin aglycon 42
Figure 12: Conformational preference in sulfinyl ethers 45
Figure 13: ABTS peroxidase assay to measure activity of GOase towards 73
substrates 119a-d
Figure 14: Activity Screening of diols 119a-d with GOase M 74
3-5
Figure 15: Enantioselective desymmetrisation of 119d using GOase M3-5 76
Figure 16: CD spectra of (+)-P-140: (blue line) observed for the slower 78
reacting enantiomer of 140
Figure 17: Docking model of the faster reacting enantiomer (M)-140 into the 79
active site of GAose M
3-5
Figure 18: Kinetic resolution of (±)-140 using GOase M3-5 variant 80
Figure 19: HPLC trace of monoaldehyde (+)-P-140 (Chiralcel R,R-Whelk 81
column running 97:3 hexane:IPA at 0.5 ml/min)
Figure 20: Examples of P,N-ligands and their use in synthesis115,116 86
Figure 21: HPLC trace of transaminase reaction mixture after 24 h 87
Figure 22: Increase of product over time for the transamination of 118d with 88
TA-113
Figure 23: Stereoisomers of intermediate organolithium and pathways of 104
epimerisation or racemisation
Figure 24: Reaction mechanism of organolithiums – SE2ret or SE2inv 105
Figure 25: Configurationally stable and configurationally labile benzyl lithium 114
complexes
Figure 26: X-ray crystal structure of 245 showing anti-configuration 124
6
Figure 27: Stereoselectivity of Griganard addition to formyl 243 126
Figure 28: Proposed transition state in the syn selective addition of ortho 129
lithiated ureas to aldehydes13
Figure 29: Conformational control in the diaryl-amides 131
Figure 30: X-ray crystal structure of 269b 133
Figure 31: VT NMR and lineshape simulation using gNMR for 272 135
Figure 32: Transition states for rotation about a benzamide axis when R is 136
small
Figure 33: Transition states for rotation about a benzamide axis when R is 137
large
Figure 34: Takaya’s (R,S)-BINAPHOS 139
Figure 35: Other chiral bases for the asymmetric deprotonation of 195 140
Figure 36: Conformation preferences in solution of diaryl amide 272 142
Figure 37: Plot of ln kA vs 1/T to determine ΔH‡ and ΔS‡ for rotation in 272a 146
Figure 38: Plot of ln kA vs 1/T to determine ΔH‡ and ΔS‡ for rotation in 272b 147
Figure 39: Atropisomerism in diaryl sulfoxides 148
Figure 40: Normal phase HPLC for mixture of diol 119d, monoaldehyde 140 151
and dialdehyde 118d
Figure 41: Reverse phase HPLC for mixture of monoaldehyde 140 and 151
dialdehyde 118d
Figure 42: Desymmetrisation of 119d using GOase (ee of 140 = 91%) 152
Figure 43: Kinetic Resolution of racemic 140 using GOase (ee of 140 = 94%) 152
Figure 44: Reduction of dialdehyde 118d using ketoreductase KRED118 153
Figure 45: Reduction of dialdehyde 118d using ketoreductase KRED108 153
Scheme 1: Products from the addition of aldehydes to lithiated 20 27
Scheme 2: Alkylation of amino acid derived diazines via a chiral relay 27
Scheme 3: 1,5-stereocontrol by stereochemical relay from an oxazolidine 28
Scheme 4: 1,23 remote stereocontrol in trisxanthene 30
Scheme 5: First non-biaryl atropisomeric chiral ligand 31
Scheme 6: Non-biaryl atropisomeric organocatalysis 32
Scheme 7: Taguchi’s enentioselective synthesis of a NET inhibitor 33
Scheme 8: Key step in the synthesis of (+)-kotanin35 34
Scheme 9: Meyers’ oxazoline auxiliary in diastereoselective synthesis of 35
binaphthyl38
7
Scheme 10: Diastereoselective Suzuki cross coupling of planar chiral aryl
bromides with boronic acids43
36
Scheme 11: Asymmetric Kumada cross coupling in the enantioselective 36
synthesis of binaphthyls56
Scheme 12: Suzuki coupling in the asymmetric synthesis of biaryls.60 37
Scheme 13: Synthesis of BINAP by Classic Resolution 38
Scheme 14: Asymmetric Synthesis of an Atropisomeric Urea by Kinetic 39
Resolution
Scheme 15: Bringmann’s method for dynamic kinetic resolution 40
Scheme 16: Meyers thermodynamic resolution of o-bromoaryloxazolines 40
Scheme 17: Thermodynamic resolution in the synthesis of ligand 35 41
Scheme 18: Selective ring closing of C-O-D ring system 43
Scheme 19: Selective ring closing of D-O-E ring system 43
Scheme 20: Nicolaou’s Asymmetric synthesis of the C-O-D ring system of 44
Vancomycin
Scheme 21: Synthesis of enantiomerically enriched atropisomeric diaryl ethers 45
by dynamic thermodynamic
Scheme 22: Asymmetric synthesis of a biaryl by construction of an aromatic 47
ring
Scheme 23: Atroposelective formation of anilides by construction of an 47
aromatic ring
Scheme 24: Desymmetrisation via enantioselective dilithiation 48
Scheme 25: Atroposelective reactions of planar chiral complexes 48
Scheme 26: Enantioselective desymmetrisation of ditriflates by Palladium 49
catalysed cross coupling
Scheme 27: Further manipulation to desymmetrised triflate, synthesis of 49
atropisomeric phosphine67
Scheme 28: Enzymatic desymmetrisation of axially chiral biaryl 105 50
Scheme 29: Increasing the barrier to rotation in the diaryl ethers 51
Scheme 30: SNAr facilitated by ortho-electron withdrawing groups 55
Scheme 31: Chlorination of isophthalonitrile as reported by Krizan. 56
Scheme 32: Synthetic route towards potentially atropisomeric diaryl ethers 57
Scheme 33: Possible reaction mechanisms for the formation of impurities 120 61
and 121
Scheme 34: Synthesis of phenol 123 via its diazonium salt 65
Scheme 35: Reportted synthesis of ortho-substituted phenol via Friedel Crafts 66
chemistry90
8
Scheme 36: Attempted synthesis of 129 via Friedel Crafts chemistry 66
Scheme 37: New route to commercially unavailable phenol 12791 66
Scheme 38: Difficulty of ortholithiating in the presence of MEM 67
Scheme 39: Synthetic strategy towards commercially unavailable phenol 67
Scheme 40: Desymmetrisation of an atropisomeric achiral ether 70
Scheme 41: Synthesis of a mono-acylated racemic reference 71
Scheme 42: Acylation with CAL-B and vinyl acetate 72
Scheme 43: Directed evolution of GOase 73
Scheme 44: Synthesis of racemic references for GOase M3-5 enzyme study 74
Scheme 45: Enantioselective oxidation of pro-atropisomeric diarl ethers 76
Scheme 46: Reduction of 118d with ketoreductases (KREDs) 82
Scheme 47: Synthetic strategy towards diketone 150 from aldehyde 118d 83
Scheme 48: Synthesis of diketone 152a and racemic reference 154 from 85
dinitrile 117d
Scheme 49: Synthesis of Sitagliptin phosphate via a transamination 86
Scheme 50: Synthesis of monoaminated diaryl ether 87
Scheme 51: Synthesis of a phosphinophenyl ethers based ligand 88
Scheme 52: Nitration of phenol 168 89
Scheme 53: Synthesis of a potential ligand 89
Scheme 54: Diastereoselective lateral lithiations of amides 91
Scheme 55: Absolute stereocontrol via lateral lithiations of amides 91
Scheme 56: Desymmetrising lateral lithiation of a benzamide 92
Scheme 57: Lateral lithiation of non-symmetrical diaryl ether 182 92
Scheme 58: Lateral lithiation strategy 93
Scheme 59: Lateral lithiation of dimethoxy compound 184 94
Scheme 60: Possible mechanism for mono-aldehyde biproduct formation 192 96
Scheme 61: Lateral lithiation of dimethyl compound 187 96
Scheme 62: Protection of diol 119 with MEM or diisoptopylcarbamate 97
Scheme 63: Conditions for attempted lateral lithiation of carbamate 194 99
Scheme 64: Lateral lithiation and electrophilic quench of carbamate 195 100
Scheme 65: Lateral lithiation of daryl ether 195 in the presence of (–)- 101
sparteine
Scheme 66: Lateral lithiation and quench of daryl ether 195 with SnBu3Cl 102
9
Scheme 67: Proposed reaction mechanism leading to the diastereotopic ratios 103
of 203
Scheme 68: Stereospecificity in the electrophilic substitution of benzylic 106
organolithium 200
Scheme 69: Lateral lithiation and quench of daryl ether 195 with MeI or 106
MeOTf
Scheme 70: Stereospecificity in tin-lithium exchange 107
Scheme 71: Complimentary syntheses of 201 107
Scheme 72: Complimentary synthesese of 199 and 203 108
Scheme 73: Configurational stability study with Sn-Li exchange 109
Scheme 74: Configurational stability study using Sn-Li exchange 110
Scheme 75: Transmetallation of stannanes 219a and 219b 110
Scheme 76: Non-stereospecificity in the transmetalation of 219b and reactions 111
of 220b
Scheme 77: Mechanism of tin-lithium exchange via ate complex 224 112
Scheme 78: Possible invertive and non-stereospecific tin-litium exchange 112
mechanisms
Scheme 79: Possible invertive transmetallation to explain the stereochemical 113
outcome of 199 and 201
Scheme 80: Possible racemisation mechanism of metallated benzylic 114
carbanions 229
Scheme 81: Enantioselective reaction pathways 115
Scheme 82: Asymmetric deprotonation of aromatic amide 233 115
Scheme 83: Asymmetric substitution – dynamic thermodynamic resolution 116
Scheme 84: Asymmetric substitution by dynamic kinetic resolution 116
Scheme 85: Asymmetric substitution by dynamic thermodynamic resolution 117
Scheme 86: Tansmetallation and electrophilic quench of pivaloyl at either -25 118
°C or -78 °C
Scheme 87: Asymmetric substitution by dynamic kinetic resolution 119
Scheme 88: Tin-lithium exchange in the presence of (–)-sparteine 120
Scheme 89: Reaction of racemic organolithium 204 with electrophiles in the 120
presence of (–)-sparteine
Scheme 90: Reaction of 195 with premixed (–)-sparteine 121
Scheme 91: Stereoselective reductions controlled by the diaryl ether axis 122
Scheme 92: Synthesis and stereoselecte reduction of a prochiral ketone 123
Scheme 93: Possible conformations of starting ketone, when R=Me and when 125
R=Ph
10
Description:2.4 Other Stereoselective and Conformational Studies of Non-Biaryl . Scheme 3: 1,5-stereocontrol by stereochemical relay from an oxazolidine. 28.
