Part I. Stereoselective Synthesis of Geminal Bromofluoroalkenes by Kinetic Differentiation of Oxaphosphetane Intermediates Part II. Investigation of Stereoselective Alkene Synthesis via 4π-Electrocyclization of Aldazine Derivatives
- Abstract
- Part I: Geminal bromofluoroalkenes are an important subclass of versatile organic interhalides, but the widely applicable stereoselective synthesis remained elusive before our work. In particular, the Wittig-type haloolefination had been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Thus, a thermodynamically controlled stereoselective approach in the Wittig-type interhaloolefination was investigated via the addition of lithium cation to establish an equilibrium between the betaine intermediates. Unfortunately, despite the exhaustive survey of various lithium salts and phosphorus(III) reagents with modulated steric and electronic properties, the reaction suffered from intermediate decomposition and poor reproducibility. Alternatively, high stereoselectivity could be attained via selectively converting one of the oxaphosphetane intermediates. The suitably identified phosphonite and non-polar reaction medium enabled efficient kinetic differentiation. Through our method, the highly diastereoselective synthesis of geminal E-bromofluoroalkenes was accomplished conveniently in one step from a wide range of readily available carbonyl compounds, including ketones and pharmaceutically relevant substrates. Furthermore, upon extensive efforts to expand this newly discovered strategy to other haloolefinations, α-bromoacrylate was successfully afforded with excellent selectivity.
Part II: The stereoselective synthesis of alkenes was explored via 4π-electrocyclization of aldazines and aldazine N-oxides. To promote a conformational change to requisite but less favorable s-cis, N-functionalization and bimetallic complexation were examined. Unfortunately, aldazine derivatives remained unreacted, or a complex mixture was produced. In order to enhance the reactivity of aldazine by polarization of 4π-system, an unsymmetrically functionalized push-pull structure was prepared. However, the desired 4π-electrocyclization did not proceed. Furthermore, investigation of charged N-carbo-functionalized aldazinium formation via oxidation of hydrazone precursors resulted in decomposition of the substrates. Then, sequential 4π-electrocyclic ring opening and cyclization of N-aziridinyl imines as well as the use of macrocyclic ketazines were attempted, but the substrate preparation was unsuccessful.
- Issued Date
- 2025
- Type
- Thesis
- Alternative Author(s)
- Jaeseong Jin
- Department
- 대학원 화학과
- Advisor
- Chung, Won-jin
- Table Of Contents
- Abstract i
List of Contents ii
List of Schemes vii
List of Figures xi
List of Tables xiii
Part I: Stereoselective Synthesis of Geminal Bromofluoroalkenes by Kinetic Differentiation of Oxaphosphetane Intermediates
1. Introduction 2
1.1. Difficulty in stereoselective synthesis of geminal interhaloalkenes 2
1.2. Importance of stereoselective synthesis of geminal bromofluoroalkenes 3
1.3. Previous stereoselective synthesis of geminal bromofluoroalkenes 4
1.4. Our proposal for Li+-promoted thermodynamically controlled stereoselective geminal bromofluoroolefination 5
1.5. Kinetically controlled, E-selective geminal bromofluoroolefination via faster transformation of trans-oxaphosphetane intermediates 6
2. Results and Discussion 8
2.1. Li+-promoted stereoselective geminal bromofluoroolefination via thermodynamic control 8
2.1.1. Identification of suitable P(III) reagents and lithium salts 8
2.1.2. Attempts at attenuation of Arbuzov-type side reactions 11
2.1.3. The use of various phosphonites 15
2.1.4. The use of other geminal bromofluoroolefinating reagents 29
2.1.5. The use of (bromofluoromethyl)triphenylphosphonium bromide 35
2.1.6. The use of non-polar solvents 45
2.2. Kinetically controlled stereoselective synthesis of geminal bromofluoroalkenes 50
2.2.1. Selective conversion of trans-oxaphosphetane in the absence of lithium salt 50
2.2.2. Reaction condition optimization with PhP(Oi-Pr)2 53
2.2.3. Examination of substrate scope 56
2.2.4. Attempts at isolation of cis-oxaphosphetane 66
2.2.5. Computational analysis of reaction mechanism 67
2.2.6. Synthetic application of geminal bromofluoroalkene 70
2.2.7. Attempts at stereoselective synthesis of geminal bromofluoroalkenes from imines 70
2.2.8. Application of kinetically stereocontrolling strategy to other haloalkenes 73
3. Conclusion 84
4. Experimental 86
4.1. General experimental 86
4.2. Experimental procedures 89
4.2.1. Preparation of phosphorus(III) reagents 89
4.2.1.1. Trialkyl phosphites 89
4.2.1.2. Isopropyl diphenylphosphinite 91
4.2.1.3. Unhindered primary and secondary dialkyl phenylphosphonites 92
4.2.1.4. Sterically hindered dialkyl phenylphosphonties 95
4.2.1.5. Bis(3,3,4,4-tetramethylcyclopentyl) phenylphosphonite 98
4.2.1.6. Di(7-norbornyl) phenylphosphonite 100
4.2.1.7. Di(1-norbornyl) phenylphosphonite 102
4.2.2. Synthesis of geminal bromofluoroolefinating reagents 104
4.2.2.1. (Dibromofluoromethyl)triphenylphosphonium bromide 104
4.2.2.2. (Bromofluoromethyl)triphenylphosphonium bromide 105
4.2.2.3. Detection of side products from attempts at (dibromofluoromethyl)phosphonium bromide synthesis using di(7-norbornyl) phenylphosphonite 106
4.2.2.4. Debromination of bromofluoroacetate salts for the synthesis of phosphobetaine 107
4.2.2.5. Diisopropyl bromofluoromethylphosphonate 108
4.2.3. Preparation of non-commercial lithium salts 109
4.2.3.1. Lithium carboxylates 109
4.2.3.2. Lithium pentafluorophenoxide 110
4.2.3.3. Lithium p-methylthiophenolate 110
4.2.4. Preparation of carbonyl substrates 110
4.2.4.1. MIDA (1-oxohexan-2-yl)boronate 111
4.2.4.2. Dimethyl(phenyl)silanecarbaldehyde 113
4.2.5. Investigation of Li+-promoted thermodynamically controlled stereoselective geminal bromofluoroolefination 114
4.2.5.1. The use of dicyclopentyl phenylphosphonite 114
4.2.5.2. Examination of epoxide as a bromide scavenger 117
4.2.5.3. The use of (bromofluoromethyl)triphenylphosphonium bromide as a phosphorus ylide precursor 117
4.2.6. Kinetically controlled stereoselective synthesis of geminal bromofluoroalkenes via selective conversion of oxaphosphetane intermediates 118
4.2.6.1. Preliminary quantitative 19F NMR analysis of the reaction progress 118
4.2.6.2. General procedure 127
4.2.6.3. Expansion of substrate scope 129
4.2.7. Derivatization of geminal bromofluoroalkene 145
4.2.8. Attempts at stereoselective synthesis of geminal bromofluoroalkenes from imines 146
4.2.8.1. Preparation of imines 146
4.2.8.2. Isolation of side products 148
4.2.9. Expansion of newly developed stereocontrolling strategy to other haloalkenes 150
4.2.9.1. Preparation of haloolefinating reagents 150
4.2.9.2. Representative example of geminal bromochloroalkene synthesis 153
4.2.9.3. Isolation of side products generated from the synthesis of α-bromoacrylate 154
4.2.9.4. Stereoselective synthesis of α-bromoacrylate 155
4.2.9.5. Representative example of geminal chloro(trifluoromethyl)alkene synthesis 156
5. References 157
Part II: Investigation of Stereoselective Alkene Synthesis via 4π-Electrocyclization of Aldazine Derivatives
1. Introduction 169
1.1. Importance of stereoselective alkene synthesis 169
1.2. Our approach for development of stereoselective alkene synthesis 170
1.2.1. Stereoselective construction of Δ1-1,2-diazetine via 4π-electrocyclization of aldazine 170
1.2.2. Strategies for aldazine activation 171
1.2.3. 4π-Electrocyclization of cyclic ketazine 174
1.2.4. Sequential pericyclic reactions of N-aziridinyl imines 175
2. Results and Discussion 178
2.1. 4π-Electrocyclization of aldazine derivatives 178
2.1.1. N-Silylation of benzaldazine and benzaldazine N-oxide 178
2.1.2. Synthesis of unsymmetrically functionalized push-pull structure for polarization of 4π-system 179
2.1.3. N-Arylation of aldazines 180
2.1.4. Activation of 4π-system by aldazinium formation 181
2.1.5. Activation of 4π-system by azomethine ylide formation 184
2.1.6. Bimetallic complexation of aldazines 188
2.2. Attempts at preparation of cyclic ketazine 190
2.3. Attempts at preparation of N-aziridinyl imines 191
3. Conclusion 194
4. Experimental 195
4.1. General experimental 195
4.2. Experimental procedures 198
4.2.1. N-Silylation of benzaldazine and benzaldazine N-oxide 198
4.2.2. Synthesis of unsymmetrically functionalized push-pull structure for polarization of 4π-system 198
4.2.3. N-Arylation of aldazines 200
4.2.4. Attempts at aldazinium formation by oxidation of hydrazone 202
4.2.5. Attempts at formation of azomethine ylides 206
4.2.6. Bimetallic complexation of aldazines 209
4.2.7. Attempts at preparation of cyclic ketazine 210
4.2.8. Attempts at preparation of N-aziridinyl imines 213
5. References 220
Appendix: Synthesis of Phosphatidylserine Methyl Ester and Phosphatidylcholine
1. Synthesis of phosphatidylserine methyl ester 227
1.1. Esterification of phosphatidylserine 227
1.2. Multi-step synthesis of phosphatidylserine methyl ester 228
2. Synthesis of phosphatidylcholine-maleimide 229
3. Experimental 233
3.1. General experimental 233
3.2. Experimental procedures 235
3.2.1. Multi-step synthesis of phosphatidylserine methyl ester 235
3.2.1.1. Synthesis of phosphoramidite from L-serine methyl ester 235
3.2.1.2. Synthesis of 1,2-diacylglycerol 237
3.2.1.3. Coupling of phosphoramidite and 1,2-diacylglycerol 238
3.2.2. Synthesis of phosphatidylcholine-maleimide 240
3.2.2.1. Extraction of phosphatidylcholines from soybean lecithin 240
3.2.2.2. Preparation of starting materials 240
3.2.2.3. Acylation of 1-oleoyl-sn-glycero-3-phosphocholine 241
4. References 244
Curriculum Vitae 246
Acknowledgement 248
NMR Spectra 249
- Degree
- Doctor
- Appears in Collections:
- Department of Chemistry > 4. Theses(Ph.D)
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