ASYMMETRIC REACTIONS OF DONOR/ACCEPTOR RHODIUM CARBENOIDS: FROM FORMAL CYCLOADDITIONS TO C-H INSERTION Open Access
Guzman, Pablo Elohim (2013)
Published
Abstract
Rhodium(II)-stabilized donor/acceptor carbenoids, derived from donor/acceptor diazo
compounds, have enriched modern organic synthesis and revolutionized our approach
towards complex target synthesis.
The first chapter of this dissertation describes the development of a new formal [4+3]
cycloaddition reaction between siloxyvinyldiazoacetates and dienes. Vinylcarbenoids exhibit
electrophilic character at both the carbenoid carbon and at the vinylogous position. Initiating
reactivity at the electrophilic terminus in the presence of an electron-rich diene allowed us to
formulate the concept of a rhodium-catalyzed inverted [4+3] cycloaddition. This reactivity
leads to the enantio- and diastereoselective synthesis of a series of regiochemically inverted
products thus broadening the synthetic potential of the [4+3] cycloaddition. The combination
of siloxyvinyldiazoacetates with sterically demanding triarylcyclopropanecarboxylate
catalyst, Rh2(S-BTPCP)4, is very effective in achieving high levels of asymmetric induction.
Chapter two discusses a ReactIRTM guided exploratory study in which investigations were
conducted seeking optimum sets of reaction conditions and possible combinations of
donor/acceptor, acceptor, and acceptor/acceptor diazo compounds in attempt to design,
synthesize and modulate the reactivity of bis-diazo systems containing nonequivalent diazo
groups. It was determined that multiple variables such as catalyst loading, chiral dirhodium
catalyst, pyrazole additives as well as sterically demanding esters all directly impact the
decomposition profile of diazo compounds. Conditions in which a donor/acceptor diazo is
selectively decomposed in the presence of an acceptor/acceptor diazo compound were
identified and directed towards the construction of the tetracyclic core of phorbol.
The final chapter of this dissertation focuses on the examination of stereoselective benzylic
C-H insertion reactions. A non-diastereoselective benzylic C-H insertion reaction was
rendered diastereoselective as a result of simple substrate modifications inferred by a recent
predictive C-H insertion model developed in the Davies group. The insertion reactions were
conducted in the presence of phenyldiazoacetate and chiral rhodium tetraprolinate catalysts
Rh2(S-DOSP)4 and Rh2(R-DOSP)4. Insertion onto the activated benzylic position is substrate
controlled while the stereochemistry of the carbenoid carbon is catalyst controlled.
Table of Contents
Table of contents
Chapter I
I Development of the Rhodium-Catalyzed Asymmetric Vinylogous [4+3] Cycloaddition Between Vinyldiazoacetates and Dienes 1
1.1 Introduction 1
1.2Chiral auxiliary-mediated tandem cyclopropanation/Cope rearrangement 9
1.3 Rhodium-catalyzed enantioselective tandem cyclopropanation/Cope Rearrangement 16
1.4 Vinylogous reactivity of vinylcarbenoids 24
1.5 Results and discussion 33
1.6 Conclusion 45
1.7 References 46
1.8 Experimental section 50
1.8.1 General considerations 50
1.8.2 General procedures 52
1.8.3 X-Ray crystallographic data 72
Chapter II
II An Exploratory Study to the Bis-Diazo Approach Towards Phorbol........... 87
2.1 Introduction 87
2.11 Transition-metal catalyzed complexity generating reactions involving mono-diazo compounds 89
2.12 Overview of complexity generating reactions with bis-diazo compounds: photo- and thermal decomposition studies 94
2.13 Overview of transition-metal-mediated decomposition of bis-diazo compounds 98
2.2........... Davies' approach towards differentially substituted bis-diazo systems........... 111
2.3........... Results and discussion........... 116
2.4........... Synthesis of exocyclic 1,3 butadiene 138........... 138
2.5........... Future work........... 139
2.6........... Additional studies with bis-diazo 100 and furan........... 140
2.7........... Conclusion........... 142
2.8........... References........... 143
2.9........... Experimental Procedures and Compound Characterization........... 147
2.9.1........... General procedure........... 147
Chapter III
III Catalyst versus Substrate Control in Asymmetric C-H Insertion Reactions 168
3.1 Introduction 168
3.2 Rhodium carbenoid-mediated intermolecular C-H insertion 173
3.3 Diastereoselective rhodium carbenoid-mediated intermolecular C-H
insertion 203
3.4 Results and discussion 181
3.5 Intermolecular C-H insertion of 7-methoxy-1-tetralol 192
3.6 Conclusion 198
3.7 References 199
3.8 Experimental Section 201
List of figures
Chapter I
Figure 1. 1. Representative examples of natural products and drug
molecules that contain seven-membered rings 1
Figure 1. 2. Wender's [5+2] regiochemical rationale 9
Figure 1. 3.Proposed model for cyclopropanation with
(R)-pantolactone auxiliary 12
Figure 1. 4. Biologically relevant tropanes accessed by CPCR reaction
of N-Boc pyrrole 16
Figure 1. 5. Electrophilic sites of vinylcarbenoids 27
Figure 1. 6. Key nOe correlation studies for compounds 18h and 20b 40
Chapter II
Figure 2. 1. Reaction scope of metallocarbenoids 88
Figure 2. 2. Boger's [4+2]/[3+2] cycloaddition rationale 93
Figure 2. 3. Effect of diazo structure on the relative rate of cyclopropanation
catalyzed by Rh2(S-DOSP)4 111
Figure 2. 4. Desired bis-diazo skeleton 116
Figure 2. 5. Donor/acceptor, acceptor and acceptor/acceptor diazo candidates 117
Figure 2. 6. Proof-of-concept experiment between diazo 94 and 91 119
Figure 2. 7. Decomposition of 91 and 94 with 0.1 mol% Rh2(S-PTAD)4 120
Figure 2.8. Graphical representation of IR plot from Figure 2.7 121
Figure 2.9. Model bis-diazo 96 121
Figure 2.10 Potential bis-diazo candidates 128
Chapter III
Figure 3.1. Catalytic cycle for Hartwig's rhodium-catalyzed functionalization 171
Figure 3.2. Classification of carbenoid intermediates 174
Figure 3.3. Pictorial representations of Davies' chiral dirhodium catalyst
Rh2(S-DOSP)4 175
Figure 3.4. Possible approach angles between the substrate C-H bond vector
and the rhodium carbenoid plane 177
Figure 3.5. C-H insertion predictive model 178
Figure 3.6. Application of the new predictive model to 5-methoxyindane 180
Figure 3.7. 1-D nOe correlations 183
Figure 3.8 . Formation of 8a via the new predictive model 184
Figure 3.9. Formation of 9a via new predictive model 184
Figure 3.10. Formation of 8a 186
Figure 3.11. Formation of 9a product via new predictive model 186
Figure 3.12. Formation of 10a via the new predictive model 187
Figure 3.13. Formation of 17b 194
Figure 3.14. X-ray structure of compound 17b and 18b 195
Figure 3.15. Formation of 18a and 19a products via the new
predictive model 197
List of schemes
Chapter I
Scheme 1.1. Wender's Rh(I)-catalyzed intramolecular [5+2] cycloaddition
of vinylcyclopropanes and alkynes 2
Scheme 1.2. Proposed mechanism for the metal-catalyzed intramolecular
[5+2] cycloaddition of vinylcyclopropanes and alkynes 5
Scheme 1. 3. Representative cycloaddition reactions inspired by Wender's
[5+2] methodology 4
Scheme 1.4. Wender's intermolecular [5+2] cycloaddition 4
Scheme 1.5. Proposed conformations for Wender [5+2] cycloaddition 6
Scheme 1.6. Davies' Cyclopropanation/Cope rearrangement with furan 10
Scheme 1.7. Tandem cyclopropanation/Cope rearrangement 11
Scheme 1.8. Total synthesis of (-)-englerin A and norhalichondron B 14
Scheme 1.9. Rh2(S-TBSP)4 catalyzed decomposition of vinyldiazoacetates in the
presence of various dienes 18
Scheme 1.10. Selected examples for the comparison of Rh2(S-DOSP)4 and
Rh2(S-TBSP)4 20
Scheme 1.11. Total synthesis of 5-epi-vibsanin E, barekoxide and barekol using
the Rh2(S-PTAD)4-catalyzed CPCR reaction between diazo 57 and
dienes 24
Scheme 1.12. Proposed mechanism for the formation of 62 25
Scheme 1.13. Synthesis of various heterocycles via Doyle's vinylogous
methodology 28
Scheme 1.14. Alkynoate synthesis via vinylogous reactivity of
siloxyvinylcarbenoids 29
Scheme 1.15. Mechanistic rational for alkynoate formation 30
Scheme 1.16. Enantioselective synthesis of acylic alkynoates and
Cyclopentenones via vinylogous addition of acyclic silyl enol
ethers 31
Scheme 1.17. Tentative mechanism for the formation of 81 and 84 32
Scheme 1.18. Intermolecular regioselective Diels-Alder cycloaddition 33
Scheme 1.19. Proposed mechanism for the formation of 88 37
Scheme 1.20. X-ray crystallographic structure of 103 43
Scheme 1.21. Proposed mechanism for the vinylogous [4+3] cycloaddition 44
Scheme 1.20. Proposed rational for the disfavored vinylogous [4+3] 45
Chapter II
Scheme 2. 1.Major synthetic routes to diazo compounds 87
Scheme 2.2. First example of intramolecular cyclization-cycloaddition strategy 89
Scheme 2.3. Inter- and intramolecular cyclization-cycloaddition methodology 90
Scheme 2.4. Padwa's approach towards (±)-aspidophytine 91
Scheme 2. 5.Dauben's approach to the tigliane skeleton 91
Scheme 2.6. Boger's [4+2]/[3+2] cycloaddition approach to (-)-vindoline 92
Scheme 2.7. Comparison of Krimse and Trost's rationale for the formation
of 23 95
Scheme 2.8. Chapman's synthesis of acenapthyne 95
Scheme 2.9. Maier's approach to unusual oxides of carbon 96
Scheme 2.10. Tomioka's selective photodecomposition of 34 in an argon
matrix 97
Scheme 2.11. Photodecomposition of 34 in solution 98
Scheme 2.12. Serratosa's synthesis of g-tropolone 99
Scheme 2.13. McKervey's synthesis of cycloalk-2-ene-1,4-diones 100
Scheme 2.14. Doyle's total synthesis of patulolide A and B 101
Scheme 2.15. Che's total synthesis of patulolide B 104
Scheme 2.16. Liu's denitrogen alkene coupling/polymerization 104
Scheme 2.17. Liu's denitrogen alkene polymerization proposed mechanism 105
Scheme 2.18. Muthusamy's three-component approach to bis-spiro-polycyclic
systems 106
Scheme 2.19. Undheim's rhodium(II)-catalyzed double C-H insertion approach 107
Scheme 2.20. Moody's simultaneous O-H insertion attempt 108
Scheme 2.21. Moody's selective Rh(II)-catalyzed diazo decomposition 109
Scheme 2.22. Muthusamy's Rh(II)-catalyzed C-alkylation and cycloaddition
approach 110
Scheme 2.23 Selected core-generating approaches towards phorbol 113
Scheme 2.24. Retrosynthetic analysis to the phorbol core 114
Scheme 2.25. Stereochemical rationale for the formation of 88 115
Scheme 2.26. Doyle's Zn(II)-catalyzed Mukaiyama-Michael reaction 122
Scheme 2.27. Retrosynthetic analysis for the formation of bis-diazo 96 122
Scheme 2.28. Synthesis of Michael-acceptor diazo 104 123
Scheme 2.29. Synthesis of vinylsiloxydiazoacetate 92 124
Scheme 2.30. First-generation synthesis of bis-diazo 100 124
Scheme 2.31. Second-generation synthesis of bis-diazo 100 125
Scheme 2.32 Synthesis of bis-diazo 96 125
Scheme 2.33. Formation of 112 via simultaneous formal [4+3] and [3+2]
cycloadditions 126
Scheme 2.34 Intramolecular C-H insertion attempt with diazo 120a 134
Scheme 2.35. Novikov's intramolecular C-H insertion 135
Scheme 2.36. Retrosynthetic Analysis and key fragment for bis-diazo 125 136
Scheme 2.18. Progress towards the synthesis of bis-diazo 125 137
Scheme 2.38. Rh(II)-catalyzed conversion of a-diazo-b-hydroxyesters to
b-ketoesters 138
Scheme 2.39. Synthesis of exocyclic diene 138 138
Scheme 2.40. End-game sequence to 125 139
Scheme 2.41. Reaction of 100 with various dienes 140
Chapter III
Scheme 3.1. Hoffman's radical C-H activation 169
Scheme 3.2. C-H functionalization strategy via oxidative addition approach 170
Scheme 3.3. Hartwig's rhodium-catalyzed functionalization 170
Scheme 3.4. Intramolecular cyclization of 1,5-dienylpryidine via C-H bond
cleavage 172
Scheme 3.5. Murai's asymmetric intramolecular C-H/olefin coupling 172
Scheme 3.6. Comparison of strategies developed for C-H functionalization 174
Scheme 3.7. Benzylic C-H activation of 5-methoxyindane 179
Scheme 3.8. Preparation of TBS protected enantiomer enriched 6-methoxy-
1-indanol 182
Scheme 3.9. C-H insertion of TBS protected enantiomer enriched 6-methoxy-
1-indanol catalyzed by Rh2(S-DOSP)4 182
Scheme 3.10. C-H insertion of TBS protected (R)-6-methoxy-1-indanol
mediated by Rh2(R-DOSP)4 185
Scheme 3.11. C-H insertion onto racemic TBS protected 6-methoxy-1-indanol
mediated by Rh2(S-DOSP)4 188
Scheme 3.12. C-H insertion of racemic TBS protected 6-methoxy-1-indanol (1 eq)
mediated by Rh2(S-DOSP)4 190
Scheme 3.13. Silicon group steric effects 190
Scheme 3.14. Catalyst effect on diastereoselectivity 191
Scheme 3.15. C-H insertion on 6-methoxy-1,2,3,4-tetrahydronaphthalene 193
Scheme 3.16. Preparation of TBS protected (R)-7-methoxy-1-tetralol 193
Scheme 3.17. C-H insertion of 16 mediated by Rh2(S-DOSP)4 194
Scheme 3.18. C-H insertion of TBS protected (R)-7-methoxy-1-tetralol
mediated by Rh2(R-DOSP)4 196
List of tables
Chapter I
Table 1.1. Cycloadditions of VCP 13 with representative alkynes 6
Table 1.2. Substituent effects on the [5+2] cycloaddition with methyl
propiolate 7
Table 1.3. Asymmetric syntheis of tropanes using (R)-pantolactone as a chiral
auxiliary 15
Table 1.4. Rh2(S-TBSP)4 catalyzed decomposition of vinyldiazoacetates
trapped by cyclopentadiene 17
Table 1.5. CPCR reactions of Rh2(S-DOSP)4 with cyclopentadiene 20
Table 1.6. Reaction of trans-piperylene with diazo 57 and Rh2(S-DOSP)4 21
Table 1.7. Comparison of Rh2(S-PTAD)4 and Rh2(S-DOSP)4 in the CPCR
reaction of N-Boc pyrrole 21
Table 1.8. Rh2(S-PTAD)4-catalyzed CPCR reaction between
siloxyvinyldiazoacetate 57 and various dienes 22
Table 1.9. Effect of catalyst and solvent on the Rh(II)-catalyzed
decomposition of 60 in the presence of cyclopentadiene 24
Table 1.20. Steric effects of ester on vinylogous reactivity 26
Table 1.21. Catalyst and solvent optimization 35
Table 1.22. Reduction of alkynoate formation 37
Table 1.23. Vinylogous [4+3] substrate scope 39
Table 1.24. Diastereoselective vinylogous [4+3] cycloaddition 41
Chapter II
Table 2.1.Che's intramolecular coupling of bis-diazo esters 102
Table 2.2. Che's intramolecular coupling of glycol derived bis-diazo esters 103
Table 2.3. Relative rates of donor/acceptor, acceptor/acceptor and acceptor
diazo compounds 118
Table 2.4. Mukaiyama-Michael approach to diazo 116a and 116b 129
Table 2.5. Effect of diazo decomposition due to pyrazole additives 131
Table 2.6. Rh(II)-catalyzed reaction of 96 with diene 108 and
additive 117 132
Table 2.7. Selected Chemical Shifts in CDCl3 at 600MHz (1H), 100 MHz
(13C) and nOe correlations for cycloadduct 120a 133
Table 2.8. Effect of ester substituent on diazo decomposition 141
Chapter III
Table 3.1. Examples of high asymmetric induction by enantiopure
Rh2(DOSP)4 and donor/acceptor diazo compounds 175
Table 3.2. Examples of diastereoselective C-H insertion reactions with
Rh2(DOSP)4 179
Table 3.3. Comparison of observed and theoretical d.r. and % ee for an
enantiomer divergent process 188
List of abbreviations
Ac Acetyl
p-ABSA 4-Acetamidobenzenesulfonyl azide
Ar Aryl
Boc tert-Butyloxycarbonyl
coe cyclooctene
t-Bu tert-Butyl
DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene
DCM (CH2Cl2) Dichloromethane
2,2-DMB 2,2-Dimethylbutane
DMAD Dimethyl acetylenedicarboxylate
DOSP N-(4-dodecylbenzenesulfonyl)prolinate
dr Diastereomeric ratio
ee Enantiomeric excess
EDG Electron-donating group
ESI Electrospray ionization
Et Ethyl
EWG Electron-withdrawing group
Equiv. Equivalent
FAB-MS Fast atom bombardment mass spectroscopy
HCl Hydrochloric acid
c-Hex Cyclohexyl
OHex Hexanoate
Hz Hertz
HPLC High-performance liquid chromatography
IR Infrared spectroscopy
L Ligand
M Metal
Me Methyl
MeO Methoxy
nOe Nuclear Overhauser effect
OAc Acetate
OEt Ethoxy
OOct Octanoate
Ph Phenyl
(R)-(S)-PPFOMe (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl methyl ether
Ph Phenyl
POCl3 Phosphorous oxychloride
iPr Isopropyl
Rh Rhodium
rt Room temperature
TBS tert-Butyldimethylsilyl
TBSP (4-tert-butylphenyl)sulfonyl-prolinate
TFA Trifluoroacetic acid (trifluoroacetyl)
THF Tetrahydrofuran
TIPS Triisopropylsilyl
TISP 2,4,6-tri-iso-propyl-benzenesulfonyl
TMEDA N,N,N',N',-Tetramethylethylenediamine
TMS Trimethylsilyl
About this Dissertation
| School | |
|---|---|
| Department | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Keyword | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
ASYMMETRIC REACTIONS OF DONOR/ACCEPTOR RHODIUM CARBENOIDS: FROM FORMAL CYCLOADDITIONS TO C-H INSERTION () | 2018-08-28 13:41:05 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|