Lian, Yajing (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/t435gd67c?locale=en


Donor-acceptor carbenoids can undergo many highly asymmetric transformations catalyzed by chiral dirhodium carboxylate catalysts. The use of vinyldiazoacetates as donor-acceptor carbenoid precursors is particularly interesting because vinyl groups in such diazoacetates participate in reactions, leading to unusual transformations.

The first chapter is devoted to exploring the cyclopropanation/Cope rearrangement reaction between siloxyvinyldiazoacetate and various acyclic dienes. The combination of siloxyvinyldiazoacetate with enantiomerically pure Rh2(PTAD)4 is very effective not only in achieving high asymmetric induction, but also in accomplishing an excellent enantiodivergent approaches with racemic dienes. Synthetic applications of this methodology have been demonstrated in the synthesis of 5-epi-vibsanin E, (+)-barekoxide and (-)-barekol.

The second chapter describes the reaction between vinylcarbenoids and N-heterocycles through rhodium-bound ylide intermediates. A novel Rh2(S-DOSP)4-catalyzed asymmetric cyclopentannulation of indolyl rings through the C2-C3 double bond with vinylcarbenoids was developed in a highly diastereo- and enantioselective fashion. The reactive site of indoles was shown to not be restricted to the C3 position, but also is effective at the C2 site, leading to cycloadducts in either the exo- or the endo- configuration. The second part describes the novel vinylogous reactivity of substituted vinylcarbenoids. (Z)-vinylcarbenoids were discovered to have a greater tendency than (E)-vinylcarbenoids for reactions occurring at the vinylogous position. Rh2(S-biTISP)2-catalyzed asymmetric vinylogous alkylations between N-heterocycles and trans-alkylvinyldiazoacetates was successfully developed in a highly enantioselective fashion.

The third part focuses on the stereocontrol of the combined C-H functionalization/Cope rearrangement (CHCR). Guided by a recent computational analysis of the CHCR reaction, an effective CHCR reaction with cyclopentenyl derivatives proceeding through a boat transition state is developed with high asymmetric induction. The CHCR products generated the opposite series of diastereomers to what had been reported earlier. Vinyl ethers undergo the CHCR reaction effectively. The reaction generated products of defined stereochemistry that might typically be generated through the vinylogous Mukaiyama aldol reaction.

The last chapter covers some miscellaneous reactions of vinylcarbenoids. Most of these reactions proceed through rhodium-bound ylide intermediates. Both carbenoid and vinylogous reactivities are possible and lead to different types of products with high selectivity.

Table of Contents

Table of Contents

Chapter I General Introduction to Donor-Acceptor Carbenoids...1

1.1 Introduction...1
1.2 Cyclopropanation of Olefins...7
1.3 Direct C-H Functionalization...8
1.4 Si-H Insertion...12
1.5 O-H Insertion Followed by [2,3]-Sigmatropic Rearrangement...14

Chapter II Asymmetric Cyclopropanation/Cope Rearrangement and its Application in Total Syntheses...15

2.1 Introduction...15

2.1.1 Asymmetric Transformation by Using Chiral Auxiliaries...16
2.1.2 Catalytic Asymmetric Transformation...23
2.1.3 Intramolecular CPCR Reaction...25
2.1.4 CPCR Reaction with Benzofuranyldiazoacetates...28
2.1.5 Double Stereodifferentiation...29
2.1.6 Reaction of Siloxyvinyldiazoacetate with Rh2(PTAD)4...32

2.2 Results and Discussion...34

2.2.1 Asymmetric [4 + 3] Cycloaddition with Acyclis Dienes...34
2.2.2 Enantiodifferentiation in the [4 + 3] Cycloaddition...39

2.3 Conclusion...50

Chapter III Intermolecular Reactions of Electron-rich Heterocycles with Rhodium-stabilized Carbenoids...51

3.1 Introduction...51

3.1.1 Reaction with Pyrroles...52
3.1.2 Reaction with Furans...55
3.1.3 Reaction with Benzofurans and Indoles...56

3.2 Results and Discussion...60

3.2.1 Asymmetric [3+2] Annulation between Indoles and Vinyldiazoacetates...60
3.2.2 Introduction of 4-Substituted (Z)-Pent-2-enoates into Sterically Encumbered Pyrroles and Indoles...70
3.2.3 Asymmetric Vinylogous Alkylation of N-Heterocycles...78

Chapter IV Stereocontrol of the Combined C-H Functionalization/Cope Rearrangement...89

4.1 Introduction...89

4.1.1 Discovery...91
4.1.2 Substrate Scope in the CHCR Reaction...92
4.1.3 Proposed Predictive Mechanism of the CHCR Reaction...95
4.1.4 CHCR Reaction Followed by a Retro-Cope Rearrangement...96
4.1.5 CHCR Reaction Followed by Elimination...99
4.1.6 Enantiodifferentiation and Application in the Syntheses of Complex Molecules...101
4.1.7 Computational Modeling of the CHCR Reaction...106

4.2 Results and Discussion...109

4.2.1 Substrate Designed to Access Other Transition States...109
4.2.2 CHCR Reaction with Cyclopentyl Derivatives...112
4.2.3 CHCR Reaction with Vinyl Ethers...130
4.2.4 Discovery of An Elaborate Cascade Sequence...141

Chapter V Miscellaneous Reactions with Vinylcarbenoids...147

5.1 Introduction...147
5.2 Results and Discussion...148

5.2.1 Facial Approach to Alkynoates by Vinylogous Reactivity of Vinylcarbenoids...148
5.2.2 A Novel [4 + 3] Cycloaddition between Siloxyvinyldiazoacetate and Furans...160
5.2.3 The [3 + 2] Cycloaddition between Vinylcarbenoids and Electron-rich Olefins...163
5.2.4 Vinylogous Reactivity of Vinylcarbenoids in the Formation of 4-Substituted (Z)-Pent-2-enoates...169


Experimental Section...188

General Methods...188
Experiment for Chapter II: Asymmetric Cyclopropanation/Cope Rearrangement and its Application in Total Synthesis...189
Experiment for Chapter III: Intermolecular Reactions of Electron Rich Heterocycles with Rhodium-stabilized Carbenoids...219
Experiment for Chapter IV: Stereocontrol of the Combined C-H Functionalization/ Cope Rearrangement...272
Experiment for Chapter V: Miscellaneous Reactions with Vinylcarbenoids...315

Appendix: X-Ray Crystallographic Data...356

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