Ozonolysis of silyl enol ethers Synthesis of 3-silyloxy-12-and PDF

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University of Redlands

InSPIRe @ Redlands Undergraduate Honors Theses

Theses, Dissertations, and Honors Projects

2015

Ozonolysis of silyl enol ethers: Synthesis of 3-silyloxy-1,2-and 3-alkyl-3-silyloxy-1,2-dioxolanes Katrina Wilson

Follow this and additional works at: https://inspire.redlands.edu/cas_honors Part of the Medicinal-Pharmaceutical Chemistry Commons, Organic Chemistry Commons, and the Other Chemistry Commons Recommended Citation Wilson, K. (2015). Ozonolysis of silyl enol ethers: Synthesis of 3-silyloxy-1,2-and 3-alkyl-3-silyloxy-1,2-dioxolanes (Undergraduate honors thesis, University of Redlands). Retrieved from https://inspire.redlands.edu/cas_honors/123

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Ozonolysis of silyl enol ethers: Synthesis of 3-silyloxy-1,2and 3-alkyl-3-silyloxy-1,2-dioxolanes By: Katrina Wilson A thesis submitted to the Faculty of the Department of Chemistry at The University of Redlands in partial fulfillment of the requirements for a Bachelor of Science degree

Department of Chemistry 2015

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ii Abstract

Katrina Wilson (B.S. Chemistry and Biology) Synthesis and Ozonolysis of Silyl Enol Ethers Thesis Directed by Dr. David Soulsby Silyl enol ethers are important synthetic intermediates that are used in a variety of reactions. The ozonolysis of silyl enol ethers to anomalous 1,2-dioxolane products has not yet been fully been explored. Though the synthesis of silyl enol ethers from aldehydes, ketones, and esters is relatively straightforward, the most commonly used methods still require air- or moisture-sensitive conditions and/or the use of toxic solvents. We have shown that silyl enol ethers can be easily synthesized from aldehydes and ketones under mild conditions and with a straightforward workup procedure in good to excellent yields. We ozonolyzed these silyl enol ethers to study their reactivity and found that unsubstituted and 1-substituted silyl enol ethers gave (3-alkyl)-3-silyloxy1,2-dioxolane products in excellent to moderate yields, respectively. However, alkyl substitution at the 2-position led to the formation of polymeric product. Finally, we investigated the reactions of these dioxolane products and found that they can undergo rearrangement to β-hydroxy esters via the addition of acid and diols via hydrogenation.

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iii Acknowledgments The University of Redlands has provided me with a wonderful place to learn and grow as an individual. Throughout my four years here, I have met many people who have contributed to my development as a chemist, and as a person, and I would like to thank them for influencing my life and career path and creating quite an unforgettable experience. First and foremost, I would like to express my deepest appreciation to Dr. David Soulsby for being such an incredible research advisor and mentor, and for pushing me to apply for honors. He has taught me everything I know about organic chemistry and 1H NMR, and has helped me with everything, from teaching me how to do various lab techniques, to editing, reediting, and re-re-editing my thesis. His excitement for this project and patience with me has allowed me to thrive in the lab and as a student. I would also like to thank Dr. Lisa Olson, Dr. Tommi Cahill, and Dr. David Soulsby for being amazing and compassionate academic advisors and professors. Without their guidance and help I would not have been able to complete all three of my majors. I would also like to thank Dr. Teresa Longin, Dr. Sue Blauth, and Dr. Daniel Wacks for being on my honor’s committee, and a special thanks to Dr. Sue Blauth for being such a wonderful mentor and friend during summer research. Additionally I would like to thank Dr. Van Engelen, Dr. Aquaye, Dr. Lyons, Dr. Schrum, and Dr. Aronson for being such wonderful professors and for always answering all my endless questions. I would also like to thank Tavleen Kochar for putting up with me in everything that we did together, and to say thank you to Madison Michaud for teaching me how to be a mentor and making research fun and entertaining, and to all the seniors in the chemistry and biology departments. Finally, I would like to thank my family and friends both back home and in Redlands for always supporting me in everything that I do.

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iv Table of Contents

Abstract........................................................................................................................................... ii Acknowledgements........................................................................................................................iii

1. Introduction.................................................................................................................................1 1.1 Organic Synthesis..........................................................................................................1 1.2 Structures and Synthesis of Silyl Enol Ethers...............................................................2 1.3 Synthesis Applications of Silyl Enol Ethers..................................................................6 1.4 Ozonolysis of Alkenes...................................................................................................7 1.5 Ozonolysis of Enol Ethers.............................................................................................9 1.6 Ozonolysis of Silyl Enol Ethers.....................................................................................7 2. Experimental Design and Data..................................................................................................14 2.1 Optimization of Synthesis of Silyl Enol Ethers from Aldehydes................................14 2.1.1 (Tert-butyldimethylsilyloxy)ethene..............................................................14 2.1.2 (Tert-butyldimethylsilyloxy)ethene..............................................................15 2.1.3 (Triisopropylsilysilyloxy)ethene...................................................................15 2.1.4 (Tert-butyldimethylsilyloxy)propene............................................................16 2.1.5 (Tert-butyldimethylsilyloxy)propene............................................................16 2.1.6 (Tert-butyldimethylsilyloxy)butylene...........................................................17 2.1.7 3-phenyl(tert-butyldimethylsilyloxy)propene...............................................18 2.1.8 3,7-dimethyl-1-(tert-butyldimethylsilyloxy)-1,6-octadiene..........................18 2.1.9 3,7-dimethyl-1-(tert-butyldimethylsilyloxy)-1,6-octadiene..........................19 2.2 Optimization of Synthesis of Silyl Enol Ethers from Ketones....................................19 2.2.1 1-(Tert-butyldimethylsilyloxy)-cyclohexene................................................19 2.2.2 2-(Tert-butyldimethylsilyloxy)-propene.......................................................20 2.2.3 Synthesis of 2-Triisopropylsilyloxypropene.................................................21 2.2.4 1-Triisopropylsilyloxystyrene.......................................................................21 2.2.5 Synthesis of (tert-butyldimethylsilyloxy)-1,3-dicyclohexene......................22 2.3 Ozonolysis of Silyl Enol Ethers..................................................................................23 2.3.1 3-(Tert-butylsilyloxy)-1,2-dioxolane............................................................23 2.3.2 3-Methyl-3-(trimethylsilyloxy)-1,2-dioxolane.............................................23 !

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2.4 Further Reactions of Ozonolyzed Silyl Enol Ether Products..................................................24 2.4.1 Ring Opening of 3-Silyloxy-1,2-dioxolane..................................................24 2.4.2 Hydrogenation of 3-Methyl-3-silyloxy-1,2dioxalane..................................25 3, Results and Discussion..............................................................................................................26 3.1 Synthesis of Silyl Enol Ethers from Aldehydes..........................................................26 3.2 Synthesis of Silyl Enol Ethers from Ketones..............................................................30 3.3 Ozonolysis of Silyl Enol Ethers...................................................................................33 3.4 Further Reactions of 3-Silyloxy-1,2-dioxolane Products............................................37 4. Conclusions................................................................................................................................38 5. Future Work...............................................................................................................................39

References......................................................................................................................................39

Appendix: 1H NMR Spectra .........................................................................................................41

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Table of Figures Figure 1: The Generic Structure of a Silyl Enol Ether (R=alkyl)...................................................2 Figure 2: Kinetic versus Thermodynamic Silyl Enol Ether Formation of 2-methylcyclohexanone Reaction Energy Diagram........................................................................3 Figure 3. Addition of Silylating Agent via SN2 Mechanism, (R=alkyl).........................................4 Figure 4. Synthesis of Silyl Enol Ethers Regiospecifically…........................................................5 Figure 5: Reactions of Silyl Enol Ethers…....................................................................................6 Figure 6. Acid-Catalyzed Diels-Alder Reaction with Silyl Enol Ethers.........................................7 Figure 7: Criegee Mechanism of Ozonolysis.................................................................................8 Figure 8: Ozonolysis Workup of Alkenes......................................................................................8 Figure 9. Ozonolysis of Benzyl Ether, Nitronate Anion, and Vinyl Ether.....................................9 Figure 10: Ozonolysis Reaction of Enol Ether.............................................................................10 Figure 11: Mechanism of Ozonolysis of Enol Ether....................................................................10 Figure 12: Ozonolysis of Silyl Enol Ethers..................................................................................11 Figure 13: Ozonolysis of Silyl Enol Ether Through Intramolecular Cycloaddition.....................12 Figure 14. Proposed Mechanism for the Ozonolysis of Silyl Enol Ethers...................................13 Figure 15. Synthesis of 3,7-dimethyl-1-(tert-butyldimethylsilyloxy)-1,6-octadiene with LDA..27 Figure 16. Use of DBU to Synthesize Silyl Enol Ether 99 from β-keto Ester.............................27 Figure 17: Le Chatelier’s Principle in Synthesis of Silyl Enol Ethers..........................................28 Figure 18. Synthesis of Silyl Enol Ether from Acetone and Cyclohexanone...............................30 Figure 19. Synthesis of (Tert-butyldimethylsilyloxy)-1,3-dicyclohexene....................................30 Figure 20. Acidity of Alpha Hydrogens........................................................................................31 Figure 21. Resonance Structure of Ester Enolate.........................................................................32

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Figure 22. Comparison of Leaving Groups..................................................................................32 Figure 23. A) Ozonolsis and B) NMR Analysis of (Tert-butyldimethylsilyloxy)ethane 64........34 Figure 24. Predicted Products from Ozonolysis of Monosubstituted Silyl Enol Ether................36 Figure 25. Proposed Mechanisms for Polymer Formation during Ozonolysis of Monosubstituted Silyl Enol Ethers. ..........................................................................................................................37 Figure 26. Ozonolysis of 2-triisopropylsilyloxypropene 82 to Produce 3-methyll-3-silyloxy-1,2Dioxolane 89..................................................................................................................................37 Figure 27. Ring-opening of 3-siloxy-1,2-dioxoalne 87 to 3-(Tert-butyldimethylsilyloxy)ester propanol and Methyl-3-hydroxypropanoate 93.............................................................................38 Figure 28. Hydrogenation of 3-silyloxy-1,2-dioxolane 89...........................................................39

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iv Table of Tables

Table 1. Synthesis of 3,7-dimethyl-1-(tert-butyldimethylsilyloxy)-1,6-octadiene in Various Solvents Systems..........................................................................................................................28 Table 2. Comparison of Synthesizing Silyl Enol Ethers from Aldehydes in DMF vs. Pentane Solvent...........................................................................................................................................29 Table 3. Synthesis of Silyl Enol Ethers from Ketones..................................................................33 Table 4. Summary of (Tert-butyldimethylsilyloxy)ethene 64 in Various Ozonolysis Conditions......................................................................................................................................35

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Introduction 1.1 Organic Synthesis The discovery and development of new pharmacologically active drugs depends upon many fields: biology, chemistry, and the field at the interface of these two disciplines, biochemistry. Understanding how to isolate compounds from organisms, synthesize them, and develop the derivatives are all necessary components required to develop new treatments for disease. For example, without scientists, creative thinking, and even serendipity, the development of the first antibacterial molecules would never have occurred. And as the occurrence of drug-resistant bacteria continues to rise,1 and the current arsenal of antibiotics become less effective, new approaches will be required. Synthetic organic chemistry will play a pivotal role in this area by allowing for the possibility of fully synthetic routes to new antibiotic natural product platforms that are not yet accessible in current methodologies. The development of the first new antibacterial class of molecules in decades,1 alongside sources of new structural classes for biological testing and new building blocks for novel materials,2 are due to the power and flexibility of synthetic organic chemistry. Organic synthesis is concerned with the construction of organic molecules, often with specific compounds in mind, using one of two approaches; target oriented synthesis or methods oriented synthesis.3 In target oriented synthesis, also known as total synthesis, complex molecules are retrosynthetically disconnected to simpler starting materials by disconnecting bonds that can be formed using known reactions. However, not all bonds can be disconnected and reformed because the chemistry for those connections simply doesn’t exist. In methods !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 1!Myers, A. G., Wright, P. M., and Seiple, I. B., The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery; Angew. Chem Int. Ed. 2014, 53, 8840-8869 ! 2!Sunjic, V., Parnham, M.J.!Signposts to Chiral Drugs Organic Synthesis in Action; Springer: Basel. 2011. p 1-4.! 3!Nicolaou, K.C., Sorensen, E. J. Classics in Total Synthesis; VCH: Weinheim, 1996. p 1-17. ! !

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oriented synthesis, or synthetic methodology, the focus is on the improvement and development of new synthetic reactions, reagents, and catalysts that can be used to construct new bonds or improve on known process through increased efficiencies (e.g., yield, regio-, enantio-, and diasteroselectivity, etc.). Improvements made in this field can be directly applied towards the synthesis of more complex targets, opening up new pathways and potentially allowing the synthesis of new physiologically important compounds that can cure or treat disease. As such, this study focuses on the method development, specifically explaining the synthesis and ozonolysis of silyl enol ethers. 1.2 Structures and Synthesis of Silyl Enol Ethers Silyl enol ethers are an important class of molecules that have found widespread use in organic synthesis, Figure 1.4

OSiR3 1 Figure 1: The Generic Structure of a Silyl Enol Ether (R=alkyl) They are comprised of an alkene with an oxygen bonded to a silyl group, with the alkene being mono-, di-, or tri-substituted. Silyl enol ethers can be regarded as protected enolates; with the stability of the silyl enol ethers heavily influenced by the alkyl R groups that are bonded to the silicon. Silyl enol ethers with less bulky groups, such as trimethyl, are quite labile and are very sensitive to acid and base. Bulkier groups, such as tert-butyldimethyl or triisopropyl, are significantly more stable to harsh conditions. The most frequently employed method for synthesizing silyl enol ether is to deprotonate an aldehyde or ketone, trapping the resulting enolate ion with a trialkylsilyl chloride.5 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 4!Weber, W. Silicon Reagents for Organic Synthesis; Springer-Verlag: Berlin, 1983. p 206-224. !

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Trialkylsilyl chlorides were developed in the 60’s as protecting groups for acidic hydrogen containing functionalities, e.g., alcohols, amines, etc.2 When a strong bulky base, such as lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LHMDS), is used to irreversibly deprotonate the least hindered αhydrogen atom this is called a kinetic approach (pathway 1, kinetic control, Figure 2).

O-

Pathway 1

Pathway 2 O-

O

OSiMe3

OSiMe3

OSiMe3

99%

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O-

O

O-

Kinetic enolate Intermediate

Thermodynamic enolate Intermediate

78%

3

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6

OSiMe3

2. NaHCO3, H2O

Kinetic enolate Intermediate

3

OPathway 2 1. Me3SiCl, DMF, Et3 N, heat

Pathway 1 1. LDA, DME 2. Me3SiCl

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Figure 2: Kinetic Versus Thermodynamic Silyl Enol Ether Formation of 2-methylcyclohexanone Reaction Energy Diagram !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 5!Colvin, E. Silicon in Organic Synthesis; Butterworths: London, 1981. P 198-205.! !

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Removal of the least hindered hydrogen typically leads to the formation of the least substituted enolate, which is slightly higher in energy than the more substituted enolate. This enolate then reacts with the trialkylsilyl chloride to generate a silyl enol ether. When a weaker base is used, deprotonation is now reversible and an equilibrium is established between both enolates. Given sufficient time, the equilibrium will favor the most stable enolate, leading to the thermodynamic product (pathway 2, thermodynamic control Figure 2). While the rate determining step is de...