Guzman, Pablo Elohim (2013)

Permanent URL:


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

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
  • English
Research Field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files