Strategies and Tactics in Organic Synthesis

 
 
Elsevier Science Ltd (Verlag)
  • 1. Auflage
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  • erschienen am 20. August 2015
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  • 442 Seiten
 
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978-0-08-100046-5 (ISBN)
 

Strategies and Tactics in Organic Synthesis provides a forum for investigators to discuss their approach to the science and art of organic synthesis. Rather than a simple presentation of data or a secondhand analysis, this classic provides stories that vividly demonstrate the power of the human endeavor known as organic synthesis and the creativity and tenacity of its practitioners.

Firsthand accounts of each project tell of the excitement of conception, the frustration of failure, and the joy experienced when either rational thought or good fortune gives rise to the successful completion of a project. This book series shows how synthesis is really done. Readers will be educated, challenged, and inspired by these accounts, which portray the idea that triumphs do not come without challenges.

This innovative approach also helps illustrate how challenges to further advance the science and art of organic synthesis can be overcome, driving the field forward to meet the demands of society by discovering new reactions, creating new designs, and building molecules with atom and step economies that provide functional solutions to create a better world.


  • Presents state-of-the-art developments in organic synthesis
  • Provides insight and offers new perspective to problem-solving
  • Written by leading experts in the field
  • Uses firsthand narrative accounts to illustrate vividly the challenges and joys involved in advancing the science of organic synthesis
1874-6004
  • Englisch
  • London
Elsevier Science & Technology
  • Für Beruf und Forschung
  • 17,13 MB
978-0-08-100046-5 (9780081000465)
0081000464 (0081000464)
weitere Ausgaben werden ermittelt
  • Front Cover
  • Strategies and Tactics in Organic Synthesis
  • Copyright
  • Dedication
  • Contents
  • Contributors
  • Preface
  • Chapter 1: Acortatarin A: Spiroketalization Methods and Synthesis
  • 1. Introduction
  • 2. Evolution of Au- and Pd-Catalyzed Spiroketalization Methods
  • 2.1. Au-Catalyzed Allylic Substitution
  • 2.2. Au-Catalyzed Spiroketalization of Propargylic Triols and Acetonides
  • 2.3. Pd-Catalyzed Spiroketalization: An Interrupted Allylic Substitution
  • 3. Acortatarin A and Related Natural Products
  • 3.1. Introduction
  • 3.2. Biological Activity
  • 3.3. Structural Analysis
  • 3.4. First Synthesis of Acortatarins A and B
  • 3.4.1. Retrosynthesis
  • 3.4.2. Initial Synthetic Work
  • 3.5. Acid-Catalyzed Spiroketalization
  • 3.5.1. Brimble's Synthesis of Acortatarin A
  • 3.5.2. Kuwahara's Synthesis of Acortatarin A
  • 3.6. Stereoselective Glycal Cyclization
  • 3.6.1. Retrosynthesis
  • 4. Synthetic Efforts via Pd-Catalyzed Spiroketalization
  • 4.1. Retrosynthesis
  • 4.2. Synthesis of Key Intermediates
  • 4.3. Spiroketalization and Completion of the Synthesis of Acortatarin A
  • 5. Conclusion
  • Acknowledgments
  • References
  • Chapter 2: Devising New Syntheses of the Alkaloid Galanthamine, a Potent and Clinically Deployed Inhibitor of Acetylcholin ...
  • 1. Introduction
  • 2. Studies on the Synthesis of Galanthamine-A Potted History
  • 3. A First-Generation Chemoenzymatic Synthesis of (+)-Galanthamine
  • 4. Total Syntheses of Members of the Ribisin Class of Neurologically Active Natural Product Inspire a Second-Generation Ch ...
  • 4.1. The Ribisins
  • 4.2. A Second-Generation Chemoenzymatic Approach to the Synthesis of (+)-Galanthamine
  • 5. An Abortive, Radical-Based Approach to (±)-Galanthamine
  • 6. Doing Things the Hard Way-De Novo Construction of the Aromatic C-Ring as a Focal Point
  • 7. Conclusions
  • Acknowledgments
  • References
  • Chapter 3: Discodermolide: Total Synthesis of Natural Product and Analogues
  • 1. Introduction
  • 2. Synthetic Approach and Synthetic Methods Development
  • 2.1. Reactivity of an a-Oxygenated Crotyltitanium
  • 2.2. Reactivity of a Z-O-Enecarbamate Group
  • 2.3. 1,2-Dyotropic Rearrangement of Dihydrofuran
  • 3. Total Synthesis of (+)-DDM
  • 3.1. Strategic Considerations
  • 3.2. Preparation of C8-C14 Subunit B
  • 3.3. Preparation of C15-C24 Subunit A
  • 3.4. Preparation of C1-C7 Subunit C
  • 3.5. Completion of Total Synthesis of DDM
  • 4. Conception, Synthesis, and Biological Evaluation of DDM Analogues
  • 4.1. Conformation of DDM and Conception of Analogues
  • 4.2. Modification of Terminal Diene C15-C24 Part
  • 4.3. Modification of the Trisubstituted C13-C14 Double Bond
  • 4.4. Modification of C1-C5 Lactone Part
  • 4.5. Biological Evaluation of Synthetic Analogues
  • 5. Conclusion
  • Acknowledgments
  • References
  • Chapter 4: A Walk Across Africa with Captain Grant: Exploring Mycobacterium ulcerans Infection with Mycolactone Analogs
  • 1. Introduction
  • 2. Synthetic Strategy of the Mycolactone A/B Analogs
  • 2.1. Retrosynthetic Analysis
  • 2.2. Synthesis of the C1-C20 Fragment
  • 2.3. Synthesis of the C1-C16 Fragment
  • 2.4. Completion of the Synthesis and Overview of the Panel of Analogs
  • 3. Exploration of the Biology Induced by Mycolactone A/B Analogs
  • 4. Conclusions and Future Prospects
  • Acknowledgments
  • References
  • Chapter 5: Total Synthesis of the Fungal Metabolite Virgatolide B
  • 1. Introduction
  • 2. First Synthetic Strategy
  • 2.1. First-Generation Retrosynthetic Analysis
  • 2.2. Suzuki Cross-Coupling
  • 2.3. Diastereoselective Aldol Reaction
  • 2.4. Attempted Spiroketalization
  • 3. Second Synthetic Strategy
  • 3.1. Second-Generation Retrosynthetic Analysis
  • 3.2. Suzuki Cross-Coupling
  • 3.3. Aldol Reaction
  • 3.4. Spiroketalization
  • 4. Total Synthesis of Virgatolide B
  • 4.1. Final Retrosynthetic Analysis
  • 4.2. Asymmetric Dihydroxylation and Iodination
  • 4.3. Carboalkoxylation
  • 4.4. Final Elaboration to Virgatolide B
  • 5. Conclusion
  • Acknowledgments
  • References
  • Chapter 6: The Role of Design, Serendipity, and Scientific Competition in the Development of Oxidative Coupling Reactions
  • 1. Introduction
  • 2. Synthesis of Biaryls via Oxidative Cross-Coupling
  • 2.1. Initial Attempts at Oxidative Amination: Scooped Before We Even Started
  • 2.2. Serendipitous Discovery
  • 2.3. Lead Development and Optimization
  • 2.4. Scooped Again
  • 3. Controlling Regioselectivity for Indole Substrates
  • 3.1. Oxidant-Controlled Regioselectivity
  • 3.2. ``pH´´ Adjusted Conditions for N-Alkylindoles
  • 3.3. Application to the Synthesis of a Botulinum Neurotoxin Inhibitor
  • 4. Mechanism of C-H Palladation in Oxidative Coupling Reactions
  • 4.1. CMD Pathways for Both C-H Palladations
  • 4.2. Pd(II)/Pd(IV) for Reactions Oxidized by H4PMo11VO40/O2
  • 5. Returning to Oxidative Amination
  • 5.1. Design of a I(III)-Mediated C-H Amination and the Continuing Role of Serendipity
  • 5.2. Competition and Differing Mechanistic Interpretations
  • 5.3. Second-Generation Oxidative Aminations: Regioselectivity as a Function of Mechanism
  • 6. Conclusion
  • Acknowledgements
  • References
  • Chapter 7: Overcoming Electronics with Strategy: Development of an Efficient Synthesis of the HIV Attachment Inhibitor Pro ...
  • 1. Introduction
  • 1.1. Original Route
  • 1.2. Endgame Modification
  • 2. Route Selection
  • 2.1. Assembly of 6-Azaindole Core
  • 2.1.1. Starting from a Pyridine
  • 2.1.1.1. Attempted Sonogashira-Larock/Heck Approach
  • 2.1.1.2. Attempted Bartoli Approach
  • 2.1.1.3. Overall Analysis
  • 2.1.2. Starting from a Pyrrole
  • 2.1.2.1. C2-C3 Cyclization
  • 2.1.2.2. C3-C2 Cyclization
  • 2.2. Installation of the Triazole: Overcoming Reactivity and Regioselectivity Issues
  • 2.2.1. Nucleophilic Aromatic Substitution
  • 2.2.2. Stepwise Approach
  • 2.2.2.1. Nucleophilic Addition of Hydrazines
  • 2.2.2.2. Functionalization of Unsubstituted Triazole
  • 2.2.2.3. Multicomponent Synthesis
  • 2.2.3. Reissert Approach
  • 2.2.4. C7-Bromination and Cu-Mediated Couplings
  • 2.3. Introduction of the C3 Side Chain
  • 2.3.1. Attempts to Improve the Original Route
  • 2.3.2. Other Attempted Oxalate Analogues
  • 2.3.3. The Knochel Approach
  • 2.3.4. The Friedel-Crafts Approach (Final)
  • 2.4. Assessment
  • 2.5. Endgame: Isolation of 2 and Prodrug Installation
  • 2.5.1. Isolation of 2
  • 2.5.2. Late-Stage Ullmann
  • 2.5.3. Revisiting 19 and Prodrug Installation
  • 3. Lessons Discovered During Process Development
  • 3.1. Azaindole Core: Aromatization and Methoxylation
  • 3.1.1. Mechanistic Considerations and the Impact of Oxygen
  • 3.1.2. Alternative Radical Initiators
  • 3.2. C7 Bromination: PyBrop and Reissert
  • 3.2.1. Optimization of PyBroP Bromination
  • 3.2.1.1. Screening of Solvent and Base
  • 3.2.1.2. First Attempt of Implementation on Scale
  • 3.2.1.3. Mechanistic Investigation
  • 3.2.1.4. Enabling Base-Free, Anhydrous Conditions
  • 3.2.1.5. An Alternative to PyBrop
  • 3.3. Triazole Incorporation: Ullmann Coupling
  • 3.3.1. Optimization of the Ullmann Process
  • 3.3.1.1. Screening of Ligand, Solvent, and Base
  • 3.3.1.2. Reaction Parameters
  • 3.3.1.3. Copper Removal
  • 3.3.1.4. Final Process
  • 4. Conclusion
  • Acknowledgments
  • References
  • Chapter 8: Synthesis of Alkaloids Containing a Quinolizidine Core by Means of Strategies Based on a Hydroformylation Reaction
  • 1. Introduction
  • 2. Aza-Sakurai-Hosomi Reaction Associated with Hydroformylation
  • 3. Hydroformylation Reaction as Trigger of Domino Reaction
  • 3.1. Synthesis Strategy
  • 3.2. Synthesis of Indolo- and Benzoquinolizidinones
  • 3.3. Synthesis of (±)-Epilupinine
  • 4. Hydroformylation of Bis-Homoallylazides
  • 4.1. Development of the Synthesis Strategy
  • 4.2. Synthesis of (+)-Lupinine and (+)-Epiquinamide
  • 5. Conclusion
  • Acknowledgments
  • References
  • Chapter 9: Total Synthesis of Sorbicillactone A: An Inspiration for Methodology and Catalyst Development
  • 1. Introduction
  • 2. Background
  • 2.1. The Sorbicillinoids
  • 2.2. Synthetic Plan
  • 3. Model Studies
  • 3.1. Initial Attempts at Lactonization Through Conjugate Addition
  • 3.2. A Successful Lactonization
  • 3.3. Sidebar 1: Cyclization of Malonate-Tethered Cyclohexadienones
  • 3.4. Installation of Amide Side Chain
  • 4. Synthesis of Sorbicillactone A and 9-epi-Sorbicillactone A
  • 4.1. Synthesis of the Sorbicillactone Phenol
  • 4.2. Synthesis of the Bicyclic Lactone
  • 4.3. Installation of the Sorbyl Side Chain
  • 4.3.1. Initial Studies with Lithium Enolates
  • 4.3.2. Boron Enolates
  • 4.3.3. One-Pot Trapping Experiments
  • 4.3.4. An Unexpected Product During a Reformatsky Pathway
  • 4.3.5. A Return to Lithium Enolates
  • 4.4. Reexamining the Configuration of C9
  • 4.5. Sidebar 2: Diastereoselective Alkylations of Bicyclic Lactones
  • 4.6. Other Attempts at Altering the Diastereomeric Ratio
  • 4.6.1. Asymmetric Phase-Transfer Catalysis
  • 4.6.2. Epimerization via Retro-Michael
  • 4.6.3. Cyclization of a Methylmalonyl Substrate
  • 4.7. Synthesis of 9-epi-Sorbicillactone A
  • 4.8. Synthesis of Sorbicillactone A
  • 5. Conclusion
  • Acknowledgements
  • References
  • Chapter 10: Total Synthesis of (-)-7-Deoxyloganin Exploiting N-Heterocyclic Carbene Catalysis with a,ß-Unsaturated Enol Esters
  • 1. Background
  • 2. Iridoid Glycoside Natural Products
  • 2.1. Background
  • 2.2. Biosynthesis of Iridoids
  • 2.3. Selected Studies on Iridoid Total Synthesis
  • 2.4. Tietze's Total Synthesis of (-)-7-Deoxyloganin
  • 3. Total Synthesis of (-)-7-Deoxyloganin
  • 3.1. Proposed Synthesis
  • 3.2. Synthesis of a,ß-Unsaturated Enol Esters 51
  • 3.3. NHC-Catalyzed Rearrangement
  • 3.4. Chemoselective Reduction of Pyranone Core
  • 3.5. Glycosylation and Completion of Synthesis
  • 4. An Improved Strategy
  • 4.1. Analysis of Original Synthesis
  • 4.2. Improved Synthesis of Acyl Chloride 54
  • 4.3. Improved Sequence to Access Methyl Enol Ester 51a
  • 5. Conclusions
  • Acknowledgments
  • References
  • Chapter 11: The Realization of an Oxidative Dearomatization-Intramolecular Diels-Alder Route to Vinigrol
  • 1. Introduction
  • 2. Wessely Oxidation Studies
  • 2.1. Retrosynthesis
  • 2.2. Intermolecular Wessely Oxidations
  • 2.3. Intramolecular Wessely Oxidations
  • 2.4. Intramolecular Wessely Oxidations Using Rigidified Substrate
  • 3. Adler-Becker Oxidation Attempts
  • 3.1. Retrosynthesis
  • 3.2. Acyclic and Pyran-Fused Adler-Becker Oxidation Substrates
  • 3.3. Furan-Fused Adler-Becker Oxidation Substrates
  • 4. Pyrogallol Dearomatizations (Part 1)
  • 4.1. Retrosynthesis
  • 4.2. Pb(IV)-Mediated Oxidative Dearomatization Studies
  • 4.3. Radical Cyclizations
  • 4.4. Hypervalent Iodide Reagents to the Rescue! Synthesis of the Tetracyclic Core
  • 5. Pyrogallol Dearomatizations (Part 2)
  • 5.1. Retrosynthesis
  • 5.2. Dream Cyclization-Fragmentation Cascade
  • 5.3. Power of the Tetracyclic Cage (Radical/Palladium)
  • 5.4. Radical Trouble
  • 5.5. Stepwise Cage Construction
  • 5.6. More Radical Trouble
  • 6. Pyrogallol Dearomatizations (Part 3)
  • 6.1. Retrosynthesis (Palladium)
  • 6.2. Synthesis of Palladium Cyclization Substrate
  • 6.3. Palladium Cyclization-Cross-Coupling Cascade Studies
  • 6.4. Installation of the C8-Methyl Group
  • 6.5. Synthesis of the Prefragmentation Tetracyclic Cage
  • 7. Pyrogallol Dearomatizations (Part 4)
  • 7.1. Synthesis of Dearomatization Substrate
  • 7.2. Palladium Cyclization Cascade Success
  • 7.3. Installation of the C8-Methyl Group
  • 7.4. C4-Hydroxyl Installation Attempts
  • 8. Fragmentations
  • 8.1. Fragmentation Scenarios
  • 8.2. Samarium Diiodide-Mediated Carbanion Fragmentation Studies
  • 8.3. Baeyer-Villiger to the Rescue-Grob Fragmentation Success
  • 9. Installing the C-14 Isopropyl and C-4 Hydroxyl Groups
  • 9.1. Possible Scenarios for Installing the C-14 Isopropyl Group
  • 9.2. Cerium Addition-Dehydration Approach
  • 9.3. Selenium All the Way! Installation of the C4-Hydroxyl Group
  • 10. Endgame-Deprotection of a New Protecting Group
  • 10.1. Anion-Centered Deprotection Scenarios
  • 10.2. Early Results
  • 10.3. Success at Last-Total Synthesis of Vinigrol
  • 11. Conclusion
  • Acknowledgments
  • References
  • Chapter 12: Total Synthesis of Communesin F and Perophoramidine
  • 1. Introduction
  • 2. Early Methodology Studies for the Construction of the Common Pentacyclic Framework of Communesins and Perophoramidine V ...
  • 2.1. Retrosynthetic Analysis
  • 2.2. Stepwise CRI Reaction for the Construction of the Pentacyclic Ring System
  • 2.2.1. Preparation of Diazo Substrate
  • 2.2.2. CRI Reaction of Diazo Compound 17a
  • 2.2.3. CRI Reaction of Diazo Substrate 17b
  • 2.2.4. CRI Reaction of Diazo Substrate 29
  • 3. Total Synthesis of (±)-Communesin F
  • 3.1. Retrosynthetic Analysis
  • 3.2. Installation of the C8 Quaternary Center
  • 3.3. A-Ring Formation
  • 3.4. Coincident Retro-Diels-Alder Reaction
  • 3.5. Total Synthesis of (±)-Communesin F
  • 4. Asymmetric Total Synthesis of (+)-Perophoramidine
  • 4.1. Initial Studies of the Diels-Alder Strategy
  • 4.1.1. Synthesis of Benzodiene Precursor
  • 4.2. Preparation of the Pentacyclic Skeleton of Perophoramidine and Determination of the Absolute Stereochemistry
  • 4.3. Asymmetric Total Synthesis of (+)-Perophoramidine
  • 5. Conclusions
  • Acknowledgments
  • References
  • Index
Chapter 1

Acortatarin A


Spiroketalization Methods and Synthesis


Barry B. Butler, Jr.; Aaron Aponick1    Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida, USA
1 Corresponding author: email address: aponick@chem.ufl.edu

Abstract


This chapter is a review of the literature on a small family of natural products named the acortatarins. Our interest in these compounds is largely due to their unique structure, which is a pyrrole-fused morpholine spiroketal. The isolation, structural assignment and later correction, biological activity, and syntheses of these molecules are presented. Although the compounds are not extremely complex, two structures were nevertheless incorrectly assigned (as well as correctly assigned in a less well-cited isolation paper!). With all the modern analytical tools at our disposal, incorrect assignments can and do still occur, and, this is a modern example of how synthetic chemistry was used to identify the errors and make the correct assignments. The progression of our research program toward the development of metal-catalyzed spiroketalization methods and our work on acortatarin A is described.

Keywords

Palladium

Gold

Catalysis

Claisen

Rearrangement

Natural product

Synthesis

Acortatarin

Pollenopyranoside

Spiroketalization

Pyrrole

Morpholine

Reactive oxygen species

1 Introduction


In 2006, I began my independent career at the University of Florida and had to make some strategic choices about the direction I wanted to take my research program. Unfortunately, I arrived to find that my labs were not ready for occupancy. This detail drastically shaped my first (nearly) 10 years of work by influencing what we were able to do at a time when we were able to handle evolving projects in an extremely fluid manner. To set the stage, this was July in Florida and, having moved from California, the humidity was palpable both indoors and out. Without a place for the proper equipment such as a glovebox, my "organometallicy" research plans would have had to either be put on hold or modified. At the time, I viewed the situation as grim but we needed to get a good start and, with an enthusiastic first group of students, we initiated work on several different ideas that would not require glovebox chemistry.

Bearing these limitations in mind, we decided to study a metal-catalyzed alkyne hydroalkoxylation reaction to generate a substrate for Claisen rearrangement that would hopefully proceed under mild conditions (Scheme 1). This would involve addition of an allylic alcohol 2 to an alkyne 1 to form the allyl vinyl ether (or metal-analogue) 3 that was primed for either a thermal or catalyzed Claisen rearrangement to form 4. We felt that the appeal of this reaction would be that, instead of adding H2O across the triple bond, we would instead be adding C, H, and O, forming a new CC bond and therefore increasing the complexity more than was traditionally observed. Catalyst selection here would be key, but a wide variety of different metals were known to catalyze alkyne hydration and it seemed likely that we would be able to find a catalyst for this reaction that fit our needs.1

Scheme 1 Initially proposed hydroalkoxylation/Claisen rearrangement sequence.

At the time, the beginning of the homogeneous gold-catalysis boom had begun2 and numerous examples purported Au-complexes to be air and moisture stable-possibly perfect Florida catalysts. Additionally, Au-catalyzed alkyne hydration was known,3 but more importantly, a report by Teles and coworkers was intriguing to us because they described observation of an enol ether in one of their hydration reactions, essentially an incomplete reaction in their system, but exactly the desired reactivity here.4 Furthermore, a report by He and coworkers described a tandem Au-catalyzed aryl Claisen rearrangement/alkene hydroalkoxylation, whereby both Au(III) and Au(I) salts were ostensibly able to catalyze the reaction.5 Armed with this combination of facts, we set about to test the hydroalkoxylation/Claisen hypothesis. Unfortunately, this idea fell flat and seemed untenable, but through the work of observant and dedicated graduate students that I often witnessed standing shoulder-to-shoulder, four wide at our lone 5-ft fume hood, an understanding of why this reaction was not working was developed.

At the time what we did not know, and probably could not have anticipated, was that the allylic alcohol itself was reactive under the conditions. Instead of acting exclusively as nucleophiles, it was found that allylic alcohols could also act as electrophiles. This became evident when what proved to be a volatile byproduct was identified as diallyl ether 8 under a myriad of Au-catalysis conditions employing both Au(I) and Au(III) salts (Scheme 2).6 Although it took until 2012 before the paper finally appeared, we were able to get the hydroalkoxylation/Claisen sequence to work quite well7 and others followed suit.8 This was an arduous endeavor that ultimately would not have been successful without what came next-scope studies and mechanistic investigation of this unexpected reactivity.

Scheme 2 Unexpected ether formation.

2 Evolution of Au- and Pd-Catalyzed Spiroketalization Methods


While trying to use allylic alcohols as nucleophiles in Au-catalyzed reactions, electrophilic reactivity was unexpectedly observed and the potential for a variety of mechanistic pathways responsible for this reactivity was intriguing. Au-complexes are typically reported as soft, carbophilic p-acids,9 but for the observed reaction, it seemed more reasonable that a cationic mechanism whereby the Au-complex functioned as a more traditional oxophilic Lewis acid10 was operative. This piqued our interest, and we decided to change the goals of the project to see where it would take us. Fortunately, pursuing these Au-catalyzed dehydrative transformations developed from a single observation into a research program (vide infra).

2.1 Au-Catalyzed Allylic Substitution


The intermolecular Au-catalyzed reaction to form diallyl ether 8 was mechanistically interesting but not synthetically useful, as the yield was always low and the catalyst loading high. Attempts to optimize the reaction were ultimately unsuccessful, but fortunately it was found that the intramolecular cyclization worked extremely well and could even be categorized as a spot-to-spot reaction. As seen in Scheme 3, with substrates bearing a nucleophilic hydroxyl group tethered to an allylic alcohol, high yields and diastereoselectivities are observed for the tetrahydropyran products.11 The reaction conditions are mild, employing 1 mol% Ph3PAuCl/AgOTf in methylene chloride at room temperature, and the range of substrates tolerated was broad. Both the catalyst loadings and temperature could be reduced, and it is particularly noteworthy that water is the only byproduct.

Scheme 3 Au-catalyzed diol cyclization.

Allylic substitution is well known12 and other metal-based complexes have been reported to catalyze reactions with hydroxyl leaving groups.13 Indeed, with homogeneous Au-catalysis, a variety of reactions that proceed via cationic pathways have been reported.14 While discussion is beyond the scope of this chapter, it is worth noting that the mechanism for this reaction has been extensively studied and does not appear to proceed via an allylic cation.15 Further developments in this area have been reported by a variety of groups and now involve the use of nitrogen nucleophiles, carbon nucleophiles, and intermolecular reactions as well as enantioselective variants.16 While many of those reports came from our laboratory, our interests took us in a different direction and we became keen on using modified substrates to develop spiroketalization methods for applications in synthetic schemes.

2.2 Au-Catalyzed Spiroketalization of Propargylic Triols and Acetonides


Spiroketals are quite common in natural products, displaying a wide range of impressive biological activities.17 This importance has prompted investigations into their syntheses, but the most common method used is still the classical acid-catalyzed dehydration of ketodiols.18 A variety of other strategies based on transition metal catalysis have been developed and this work has recently been reviewed.19 These methods feature a variety of advantages, but most importantly they can be used to employ different substrate classes (nonketodiols) with mild conditions, facilitating new synthetic strategies.

To effect spiroketalization, our goal was to employ a propargyl substrate such as 11 (Scheme 4). The central hypothesis was that if propargyl systems behaved similarly to allylic systems, then by analogy the allene 12 should be formed. This substrate should be reactive toward Au-catalysts, and if the R-substituent contained a second nucleophile, the spiroketal 13 should be directly formed under the reactions conditions. The advantages would be that the necessary...

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