Organic Synthesis and Methodology Related to the Malaria Drug Artemisinin Douglas Aaron Engel

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2009 Organic Synthesis and Methodology Related to the Malaria Drug Artemisinin Douglas Aaron Engel

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COLLEGE OF ARTS AND SCIENCES

ORGANIC SYNTHESIS AND METHODOLOGY RELATED TO THE

MALARIA DRUG ARTEMISININ

DOUGLAS A. ENGEL

A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

Degree Awarded: Summer Semester, 2009

The members of the committee approve the dissertation of Douglas A. Engel defended on June 30th, 2009.

______Gregory B. Dudley Professor Directing Dissertation

______Thomas Keller Outside Committee Member

______Marie Krafft Committee Member

______Lei Zhu Committee Member

______Geoffery Strouse Committee Member

Approved: ______Joesph Schlenoff, Chair, Department of Chemistry

The Graduate School has verified and approved the above-named committee members.

This manuscript is dedicated to my family and friends who have supported me

through out my life.

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ACKNOWLEDGMENTS

Academically, I could not have achieved what I have without the guidance of Dr. Gregory Dudley. It the early years, he was an invaluable source of information and gave me the opportunity to work on some amazing projects. The reactions course he taught my first year in graduate school was probably the most educational course I have ever taken. In the later years, despite my protests, he has forced me to draw my own conclusions and rarely relinquishes an answer to a question I am capable of determining the answer to. I am truly appreciative of this forced evolution from a graduate student to an independent scientist. On the personal level, I have too many thank yous to include in this short acknowledgements page. So thank you to everyone who has bettered my life over the last 5 years. This includes my family who has always supported me, whether they agreed with me or not, and one of the best group of friends one could ask for. So thank you; Mom, Dad, Tiffany, Sean, Van, Shawn, Sam, and everyone else. Financially, I have to thank my mother once again. Her answer was always ―just put it on the credit card.‖ I am guessing she has her eye on some sweet rewards program prize and is just using me to get ever closer to obtaining the coveted pink American Express embroidered teddy bear. Seriously, I am truly appreciative. I also have to thank the Bovay Foundation and the MDS Research Foundation whose financial support made life on the meek graduation stipend a little more bearable. In addition, the completion of this manuscript would have been impossible without the army of editors that so graciously agreed to proofread this document. They include Dr. Mark Kearley, Sami Tlias, Kerry Gilmore, Mike Rosana, and Cece O’Leary. Special thanks go to my sister Tiffany Harris who agreed to proofread a document in a foreign language, and Dave Jones and Dr. Dudley who edited the entire document.

TABLE OF CONTENTS

List of Tables ...... v List of Figures ...... vi Abstract ...... x

1. Total Synthesis of (+)-Dihydro-epi-deoxyarteannuin B and Related Studies ...... 001

Chapter 1: History of Malaria ...... 001 Chapter 2: Artemisinin: The Last Line of Defense Against Malaria ...... 011 Chapter 3: Synthesis of (+)-Dihydro-epi-deoxyarteannuin B and ()-Dihydroartemisinic Acid…………………….. 020 Chapter 4: Experimental: (+)-Dihydro-epi-deoxyarteannuin B... 038

2. The MeyerSchuster Reaction and Beyond ...... 094

Chapter 5: Evolution of the MeyerSchuster Reaction ...... 094 Chapter 6: Lewis Acid-Catalyzed MeyerSchuster Reactions: Methodology for the Olefination of Aldehydes and Ketones ...... 114 Chapter 7: MeyerSchuster Experimental……………………… 144

REFERENCES ...... 224

BIOGRAPHICAL SKETCH ...... 241

LIST OF TABLES

Table 1: Allylation of Menthone and Silyloxymenthone 43 ...... 028

Table 2: Mo-Au Combo Catalysis for Rearrangement of E into α,-unsaturated Ketones F ...... 101

Table 3: Selected Examples of [(ItBu)AuCl]/AgSbF6 Catalyzed Rearrangement ...... 106

Table 4: Solvent Screening With AuCl3 Catalyst ...... 118

Table 5: Screening of Water Equivalents ...... 119

Table 6: Catalyst Loading ...... 120

Table 7: Initial Screening of Substrates Using Oxygen Activated Alkynes 124

Table 8: Catalyst Loading and Optimization ...... 124

Table 9: Olefination of Hindered Ketones ...... 126

Table 10: Temperature Effect on (E/Z)-Selectivity ...... 127

Table 11: MeyerSchuster Reaction of Ethoxyalkynyl Carbinols ...... 128

Table 12: Screening Alternative Catalysts ...... 133

Table 13: Effect of Additives ...... 134

Table 14: Ethoxy Acetylene Addition ...... 135

Table 15: Scandium and Copper Rearrangements ...... 136

Table 16: Two-Stage Olefination of Ketones and Aldehydes ...... 138

Table 17: Incorporation of External Alcohol Additive ...... 142

LIST OF FIGURES

Figure 1: Estimated Incidence of Malaria per 1000 Population, 2006...... 002

Figure 2: Global Distribution of Per Capita GDP ...... 003

Figure 3: Overview of Antimalarial Drugs ...... 005

Figure 4: Plasmodium falciparum Cycle Within Humans ...... 006

Figure 5: Model For Formation of the Non-Covalent Heme-Chloroquine Complex ...... 007

Figure 6: Global Status of Resistance to Chloroquine and Sulphadoxine/ pyrimethamine, the Two Most Widely Used Antimalarial Drugs. 008

Figure 7: The Structure of Artemisinin and its Derivatives ...... 008

Figure 8: General Reactivity of Artemisinin After Reductive Activation of The Endoperoxide Function ...... 009

Figure 9: Artemisinin and Related Compounds ...... 011

Figure 10: Artemisinin is a Natural Product Extracted from Artemisia annua or Sweet Wormwood ...... 012

Figure 11: Schematic Representation of the Engineered Artemisinic Acid Biosynthetic Pathway in S. cerevisiae ...... 015

Figure 12: Early Approaches Toward Artemisinin ...... 016

Figure 13: Construction of the Schmid and Hofheinz Singlet Oxygen Precursor 17 ...... 017

Figure 14: Schmid and Hofheinz End Game Strategy ...... 017

Figure 15: First Example of Dihydroartemisinic acid 21 being converted into Artemisinin 1 ...... 018

Figure 16: Our Proposal for Generating the Key Endoperoxide ...... 019

Figure 17: Our Synthetic Targets ...... 020

vii

Figure 18: Eq (1) Ravindranathan Intramolecular Diels-Alder, Eq (2) Meinwald Intramolecular Diels-Alder ...... 021

Figure 19: Avery and Co-Workers’ Strategy to Avoid Epimerization...... 021

Figure 20: Electrocyclic Stategies to the Decalin Ring System ...... 022

Figure 21: Other Approaches Towards the Decalin Ring System ...... 023

Figure 22: Our Retro-Synthetic Analysis ...... 024

Figure 23: The StorkJung Vinylsilane ...... 024

Figure 24: The Original Synthesis of the StorkJung Vinylsilane ...... 025

Figure 25: Early Modifications of the StorkJung Synthesis ...... 026

Figure 26: Dudley Lab Succint Method for Preparation of StorkJung Vinylsilane 16 ...... 026

Figure 27: Hydroboration of Bulk Isopulegol vs. Pure Isopulegol ...... 027

Figure 28: Conversion of Diol 56 to Ketone 43 ...... 027

Figure 29: Vinyl Addition to Silyloxymenthone 59 ...... 029

Figure 30: Elaboration to First Metathesis Precursor 6322 ...... 030

Figure 31: Ring Closing Metathesis (RCM) Strategies ...... 031

Figure 32: Proposed Synthesis of Dihydroartemisinic Acid 21 ...... 032

Figure 33: Olefination Attempts on Menthone and Menthone Derivatives . 033

Figure 34: Proposed Olefination Strategy ...... 034

Figure 35: Implementation of Our Olefination Strategy Towards Dihydroartemisinic Acid 21 ...... 035

Figure 36: Strategy Towards Dihydroartemisinic Acid 21 ...... 094

Figure 37: Atom-Economical Carbonyl Olefination Strategies ...... 095

Figure 38: Meyer and Schuster’s Rearrangement...... 096

Figure 39: Competing Rupe Rearrangement ...... 097

viii

Figure 40: Hoffmann-La Roche Inc. Application of Vanadate Catalyst ...... 097

Figure 41: Proposed Orthovanadate Mechanism ...... 098

Figure 42: Trapping of Oxo-Vanadate Allene R ...... 099

Figure 43: Narasaka Lab Perrhenate(VII)/p-Toluenesulfonic Acid System 099

Figure 44: Vidari’s Lab Extension of Toste’s Methodology ...... 100

Figure 45: Lewis Basic Sites on a Propargyl Alcohol ...... 102

Figure 46: ―Soft Lewis Acid Activation ...... 102

Figure 47: Two-Step vs. Single-Step Preparation of α,-Enones via Functinalization of the Propargyl Alcohol ...... 103

Figure 48: Preparation of -Monosubstituted (E)-α,-Unsaturated Ketones ...... 104

Figure 49: Preparation of ,-Disubstituted α,-Unsaturated Ketones ...... 104

Figure 50: Proposed Mechanism for Au(PPh3)NTf2-Catalyzed Rearrangement ...... 105

’ Figure 51: SN2 Type Addition of Au Catalyst ...... 107

Figure 52: Chung’s Proposed Cumulene Intermediate ...... 108

Figure 53: Attempted Regioselective Hydration ...... 108

Figure 54: Optimized Hg(OTf)2 Rearrangement ...... 109

Figure 55: Hg(OTf)2-Catalyzed Hydration of Ethoxypropargyl Acetates .... 110

Figure 56: α,-Unsaturated Amide Formation ...... 110

Figure 57: Proposed Mechanism for the Ru-Catalyzed Isomerization of Propargyl Alcohols into α,-Unsaturated Aldehydes ...... 111

Figure 58: Application of the MeyerSchuster Reaction in Total Synthesis ...... 112

Figure 59: Two-Step Olefination Strategy ...... 114

Figure 60: Cr(VI) Rearrangements...... 115

Figure 61: Initial Oxo-philic Approaches to the MeyerSchuster Rearrangement ...... 116

Figure 62: Switch to Triphenyl Propargyl Alcohol 117 ...... 117

Figure 63: Initial Gold(III) Experiment ...... 117

Figure 64: Initial Substrate Screening with MeCN ...... 121

Figure 65: Initial Substrate Screening with CH2Cl2 ...... 122

Figure 66: Use of Electron-Rich Ethoxyacetylene ...... 123

Figure 67: Qualitative Screening for Optimal Conditions ...... 127

Figure 68: Gold Salts vs. Acid Catalysts ...... 130

Figure 69: Hypothesis on the MeyerSchuster Reaction Pathway ...... 131

Figure 70: Incorporation of External Alcohol Additive ...... 131

Figure 71: Functional Group Compatability ...... 137

Figure 72: Test for trans-Esterification ...... 140

Figure 73: Revised Mechanistic Hypothesis of Scandium(III) Salts ...... 141

ABSTRACT

Malaria is a global epidemic, resulting in the deaths of nearly one million people every year. Part 1 of this dissertation will focus on the history of Malaria and ways to combat this devastating disease. Artemisinin has emerged as the drug of choice for treatment of malaria due to its effectiveness against all strains of the malaria parasite. Access to artemisinin through isolation, bio-engineering, and chemical synthesis will be described. Our attempts to access the artemisinin family of anti-malarials through the total synthesis of dihydro-epi-deoxyarteannuin B and dihydroartemisinic acid will be discussed fully. Key features of the syntheses will include alkylation of menthone derivatives using Noyori’s zincate enolate method and nucleophilic addition to a hindered ketone using either organocerium or acetylide nucleophiles. In addition, two alternative olefin metathesis approaches are described for the final cyclization. Problems associated with the olefination of a key intermediate in our efforts toward dihydroartemisinic acid led us to develop a two-step olefination of ketones and aldehydes. Part II will discuss this olefination strategy which consists of acetylide addition to generate a propargyl alcohol followed by a MeyerSchuster rearrangement to the corresponding α,-enone. A complete history of the MeyerSchuster rearrangement will be presented, highlighting the short comings of the method prior to our work. A complete overview of our research pertaining to the MeyerSchuster reaction will be given. Key topics will include development of a Au(III)-catalyzed rearrangement of propargyl ethynyl ethers into α,-unsaturated esters and its use in the olefination of hindered ketones, efforts to control the (E/Z)-selectivity of the MeyerSchuster rearrangement, and the search for more affordable catalysts.

PART 1: TOTAL SYNTHESIS OF (+)-DIHYDRO-EPI-DEOXYARTEANNUIN B AND

RELATED STUDIES

CHAPTER 1

HISTORY OF MALARIA

Malaria is the most devastating tropical parasitic disease in the world and is ranked in the top three of communicable diseases it terms of deaths.1 The size and the scope of the malaria pandemic are astounding with the World Health Organization (WHO) reporting an estimated 247 million cases in 2006. Of those cases, nearly 1 million resulted in death, mostly in children under the age of 5.2 It is estimated that a child dies from malaria every 40 seconds, resulting in the loss of thousands of adolescents every day.1 Malaria is so deadly that many experts contend it has contributed significantly to the proliferation of the sickle-cell trait. When inherited from both parents the sickle-cell mutation is fatal, yet when inherited from only one parent the trait is protective against malaria. Natural selection would tend to remove the sickle cell trait from the gene pool, but the risk of death from malaria is so severe that the sickle cell trait remains a prominent and needed mutation.3,4 With the staggering number of malaria cases every year, malaria may be perceived as a global problem. In reality, malaria is centered in tropical regions and extends into subtropical regions across five continents putting 3.3 billion people at risk. Currently, 109 countries are considered to have malaria epidemics with nearly half of those countries being located in Africa2 (Figure 1). Unlike tropical areas, temperate regions possess distinct seasons, and their cold winters are a key element in the fight against malaria. The life cycle of the malaria parasite is highly temperature dependant. In order to become infectious to other individuals, the parasite inside the mosquito must undergo a highly specific life cycle change. The amount of time necessary for this transformation is inversely proportional to the ambient temperature. As

1 average temperatures decline, the time necessary for the life cycle change approaches the life span of the mosquito, leaving a much smaller window for transmission. At temperatures of 16 oC and below malaria parasite development ceases completely.1,5,6 Seasonal temperatures have the most pronounced affect on malaria, but other climate factors such as humidity and rainfall must also be considered when assessing transmission rates.1

Figure 12: Estimated Incidence of Malaria per 1000 Population, 2006

The correlation between malaria and poverty may also be responsible for the malaria epidemic in the tropical regions. Areas of the world where malaria is prevalent have lower per- capita gross domestic products (GDP) than areas that are unaffected (Figure 2). From 1965 to 1990, countries with major segments of their populations living in regions at high risk for malarial transmittance had an average growth of per-capita GDP of 1.9 % less than that of countries with little malaria risk.7

Figure 21: Global Distribution of Per Capita GDP.

The correlation between poverty and malaria is undisputable; however, there is debate as to whether malaria causes poverty or poverty results in the proliferation of malaria. Most likely it is a combination of both.1,2 Wealthier nations possess the resources to initiate government control programs such as the draining of swamplands and other breeding grounds, along with large scale spraying of pesticides. General urban development including improved housing significantly reduces individuals’ exposure to mosquitoes and the malaria parasite. These factors combined with personal expenditures on bednets and household insecticides led to the elimination of malaria in wealthier nations with temperate climates by the 1950’s. Although economic development and wealth are important factors in controlling malaria, they are not enough by themselves. Wealthy countries with high year-round temperatures still suffer from malaria and are unable to eliminate the disease.1 Malaria has much broader social and economic impacts than simply causing a lower average growth in GDP in affected countries. Malaria infected regions not only have slower growing economies, but they are also forced to spend a significant amount of their GDP on combating the disease. These costs include personal and private medical costs as well as loss

3 of income due to illness and death. This financial burden is most severe for people in the lowest income brackets. With most of their disposable income going towards prevention and treatment of malaria there is little money for schooling, migration, or savings resulting in serious social costs. The lack of proper education is a major obstacle in combating not only malaria but also sexually transmitted diseases like HIV. Limited female education and low availability of birth control, combined with high infant mortality rates, have led to high fertility rates. In order to assure a certain number of surviving heirs, couples are forced to have large numbers of children. The net result is large population growth in poor malaria stricken countries, causing a magnification of the problem.8-11 Despite the obstacles facing those areas impacted by malaria, modern medicine has afforded ways to combat this disease. Currently, there are three major classes of anti-malarial drugs—the quinoline family, the artemisinin family, and all other antimalarials12 (Figure 3). The need for so many classes of antimalarial drugs originates from the ability of the malaria parasite to develop drug resistance. The two most widely used antimalarial drugs are chloroquine and the antifolate sulphadoxine/pyrimethamine. Chloroquine is a member of the quinoline family of antimalaria drugs. The quinoline family of compounds draws their origin from quinine, a centuries old malaria treatment isolated from the bark of Cinchona.13 While quinine has excellent antimalarial activity, it requires multiple doses per day over 7 days. This long treatment schedule has led to problems associated with toxicity. Structural elucidation of quinine and medicinal chemistry studies led to derivatives including chloroquine and amodiaquine, which only have to be administered over 3 days, reducing the chances of a toxic build-up in the body.13 This short treatment period, combined with the malaria parasite’s low propensity to develop resistance to it, have made chloroquine the drug of choice for many years.14

Figure 312: Overview of Antimalarials Drugs

While there are four different species of the malaria parasite, (Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasomodium falciparum) Plasmodium falciparum is the strain that is responsible for severe malaria that results in death.15 Plasmodium falciparum’s life cycle within the human body consists of several distinct phases. Initially, the parasite takes up residence in hepatocytes, where it quickly develops and causes the release of merozoites. The newly released merozoites then invade erythrocytes. Once inside the erythrocytes the malaria parasite goes through a series of evolutions resulting in the eventual release of more merozoites, which then infect more cells (Figure 4).15 Malaria symptoms manifest during the phase of the Plasmodium’s life cycle in which it inhabits the erythrocyte. The parasites’ survival at this stage is dependent on modifications to the cells metabolic processes. These modifications, while ensuring the parasites’ survival, also allow for drugs to differentiate between infected cells and healthy cells. This makes them

5 susceptible to chemotherapeutic attack. While Plasmodium is present in the host erythrocyte, it degrades up to 80% of the hemoglobin present.16 As a result, large amounts of Fe(II) heme are released and are subsequently oxidized to Fe(III) hematin. The hematin then aggregates to form a pigment called hemozoin.16 Chloroquine’s activity is believed to lie in its ability to prevent hemozoin formation by binding with heme through  stacking of their planar aromatic structures.17 These chloroquine-heme complexes are toxic to the parasite, though the exact source of their toxicity is under debate (Figure 5).18-19

Figure 415: Plasmodium falciparum Cycle Within Humans Heptaocytes: a cell of the main tissue of the liver Erythrocytes: red blood cells Merozoites: a daughter cell of a protozoan parasite

Figure 5: Model For Formation of the Non-Covalent Heme-Chloroquine Complex

While the ability of the malaria parasite to develop resistance to chloroquine is quite low, widespread usage over a long time period has resulted in increased resistance in many areas of the world. The recent globalization of chloroquine resistant malaria parasites has brought to the forefront the need for alternative treatments (Figure 6). Other drugs from the quinoline family can be substituted for chloroquine in many cases, but due to their similar structure and biological activity, resistance to these drugs tends to develop rapidly.14 Since their isolation in the early 1970’s, the artemisinin family of antimalarials have seen unprecedented growth in their frequency of use.2,20,21 This rapid switch from the commonly used quinolines to the artemisnins is due to the aretemisinins’ remarkable ability to combat quinoline resistant strains of the malaria parasite. To date, there have been no examples of any strain of the malaria parasite showing resistance to the artemisinin family of drugs.2,22

Figure 612. Global Status of Resistance to Chloroquine and Sulphadoxine/pyrimethamine, the Two Most Widely Used Antimalarials Drugs. Data are From the World Heatlh Organization

Their high level of activity against all strains of the malaria parasite is attributed to their mode of action. Like the quinoline family of drugs, the artemisinin family of drugs are believed to derive their activity through interaction with Fe(II) heme, but by a drastically different pathway,15 related to the unique endoperoxide bridge of the artemisinins (Figure 7).

CH CH H 3 H 3 9a R = H, Dihydroartemisinin O O H3C O H3C O 9b R = Me, Artemether O O H H H O H O 9c R = Et, Arteether CH3 CH3 O OR 10 R = CO(CH2)2COONa, artemisinin A Artesunate Figure 7: The Structure of Artemisinin and its Derivatives

It is generally accepted that the endoperoxide bridge is the source of artemisinin’s activity. Derivatives lacking the peroxide bridge (deoxyartemisinin) have shown no activity against the malaria parasite.23 There is believed to be an interaction between the peroxidic bond in artemisinin and the Fe(II) heme generated from the parasites degradation of hemoglobin within the erythrocyte. The result is cleavage of the peroxide bridge yielding carbon-centered free radicals15 (Figure 8).

Figure 815. General Reactivity of Artemisinin After Reductive Activation of the Endoperoxide Function

The free radicals rapidly react, causing destruction of anything in the immediate proximity. The artemisinins can also target the malaria parasite in stages of its life cycle outside of the erythrocyte through other mechanisms.15 In addition, the artemisinins pose little threat to uninfected cells. Micromolar concentrations are necessary to induce toxicity to mammalian cells, while only nanomolar concentrations are required to kill the malaria parasite. These low dosage requirements have resulted in very few instances of negative side-effects from treatment.24 The only shortcoming of the artemisinin family of drugs is their relatively short half-lives in the body, on the order of 2-3 hours.25 For this reason, they are usually administered in combination with other antimalarial drugs that have longer half-lifes. The World Health Organization (WHO) now suggests artemisinin combinational therapy as the first-choice to treat malaria.2 In summary, malaria is a global epidemic resulting in nearly 1 million deaths every year.2 Efforts to combat this devastating disease such as government control programs and distribution of bednets have done little to stop its spread. With advances in modern medicine, treatment of malaria through drug therapy is now a reality. The malaria parasite shows resistance to many of the original quinoline family of antimalarial drugs, but it has yet to show resistance to artemisinin and its derivaties. The outstanding biological properties of artemisinin have made it an important target for both isolation and synthetic chemists.

CHAPTER 2

ARTEMISININ: THE LAST LINE OF DEFENSE AGAINST MALARIA

Artemisinin 1, a unique sesquiterpene lactone endoperoxide, is an efficient and universal antimalarial drug. It is also the precursor to a larger family of more potent antimalarials that are derivatized at C(10), which includes artemether 9, artesunate 10, artemisone28 11, and many others26-28 (Figure 9). This class of drugs has received considerable attention due to their effectiveness against all strains of the malaria parasite.2,22,27 Amazingly, despite the fact that artemisinin-based combinational and monotherapies have been in use for over a decade, there have been no reported cases of the malaria parasite showing resistance in humans.22 As a result, the demand for artemisinin has increased significantly.

Me CH3 Me H H H O H3C O O H H O H O O H O CH3 O O O ()-arteannuin B artemisinin 1 (+)-dihydro-epi-deoxyarteannuin B CH H 3

CH3 CH3 H C O H H 3 O O H O O H H3C O H3C O O O O CH3 H H N H O H O CH3 CH3 OCH3 OCOCH2COOH S O O 9 10 11 Figure 9: Artemisinin and Related Compounds

Artemisinin is isolated from the leaves of Artemisia annua, a leafy plant native to China and Vietnam commonly referred to as sweet wormwood (Figure 10). The Chinese have used cold teas made from the leaves of A. annua to treat malaria and other ailments since as early as the 2nd century B.C.29 In spite of its widespread use, it was not until 1972 during a comprehensive investigation into Chinese herbal medicine ordered by Chairman Mao Tse- Tsung that artemisinin was isolated and identified as the active ingredient.23 It took another seven years before the structure was finally elucidated.30 Today, the three main sources of artemisinin are direct isolation from the leaves of Artemisia annua, bioengineering, and chemical synthesis.

Figure 10: Artemisinin is a Natural Product Extracted from Artemisia annua or Sweet Wormwood (Qinghao). cmbi.bjmu.edu.cn/.../200382031.jpg

Direct isolation from the plant is the main source of artemisinin. Artemisinin content in the plant ranges from 0.01 to 1.4 wt % based on dry leaf mass, depending on which species of A. annua is being examined.31 An estimated 120 million courses of artemisinin-based combinational therapies are needed every year to combat the malaria epidemic.2 An average

12 course of treatment comprises 20 tablets, each contain 20 mg of artemether 9, which is obtained from artemisinin in a 60 % chemical yield.28 This information, combined with the average amount of leaf harvested per acre in a given season, predicts that 35,000 acres of A. annua plantations are needed to meet the global need.31 On a global scale this is a relatively small portion of land. However, these calculations assume an isolation efficiency of 100 %, which is far from the actual isolation efficiency of 60 %. The largest processing centers for the extraction of artemisinin from Artemisia annua are located in China and Vietnam. A mixture of hexanes and petroleum ether is used to extract artemisinin from the leaves of the plant. The advantages are the simplicity of the process and the low capital cost necessary for start up and maintenance. The disadvantage is that this technique is very hazardous to both the workers and the environment. These highly flammable solvents have low vapor pressure, and the generation of explosive hydrocarbon/oxygen mixtures is problematic. Emission of greenhouse gases, smog generation, and the entrapment of hexanes in the resulting biomass, which is commonly used as animal feed, also detract from this method. In an attempt to make the extraction process more efficient and environmentally friendly, other extraction techniques have been developed. 32 33,34 31 These include extraction with EtOH, supercritical CO2, hydrofluorocarbons, and ionic liquids.31 These extraction techniques have not yet been fully investigated and have not made it beyond laboratory scale. Even with the advances in isolation techniques, the viability of using only cultured A. annua as the source for artemisinin remains cost prohibitive.35 An alternative to agricultural drug production, which has long production cycles and is highly dependent on weather and climate, is biosynthesis. Biosynthesis is the process in which chemical compounds are created from simpler starting materials with-in a living organism. Biosynthesis has the advantages of being easier to scale, requiring less space, and being more efficient in terms of product produced per kg of starting material.36 All of these factors point to the possibility of using biosynthesis to create an affordable source of artemisinin. Unfortunately, the direct bioconversion of simple starting materials to artemisinin has yet to be achieved.37 Most efforts aim at the bioconversion of simple chemicals into artemisinic acid, another constituent of A. annua, which can then be transformed chemically to artemisinin.38 The biosynthesis of artemisinic acid can be achieved by the use of engineered yeast36,39 or through enzyme manipulation of other heterologous hosts.40,41

The most efficient yeast developed for the production of artemisinic acid is Saccharomyces cerevisiae.36,39 The yeast was engineered by Keasling and co-workers to perform three key transformations. The first was the conversion of simple sugars into farnesyl pyrophosphate (FPP) using a modified biosynthetic pathway. This new pathway produced higher yields of the desired FPP as compared to the naturally occurring, unmodified pathway. The second step was the conversion of farnesyl pyrophosphate into amorphadiene. To achieve this transformation the amorphadiene synthase gene (ADS) from A. annua was isolated and then expressed into the high FPP producer. The third step involved cloning of a new cytochrome P450 which could carry out a three-step oxidation of amorphadiene into artemisinic acid (Figure 11).39 The transgenic yeast produced artemisinic acid at an efficiency of 100 mg/L. To help gauge that number, one needs to look at the natural source of artemisinic acid. Artemisinic acid can be isolated in 1.9 % relative to the biomass of A. annua compared with 4.5 % from the yeast. The yeast is therefore capable of a productivity that is over two times greater than the plant. In addition, the yeast can produce artemisinic acid in 45 days compared to several months for A. annua.39 The efficiency of the process can be greatly improved by moving from laboratory to industrial scale. The use of bioreactors with the same yeast resulted in a 25-fold improvement from 100 mg/L to 2.5 g/L isolated yield.36 There has also been interest in the bioconversion of arteannuin B (refer to Figure 9) to artemisinin. Arteannuin B can also be isolated from Artemisia annua. It occurs at a relative abundance of three times that of artemisinin.42 In addition, there are several synthetic routes to arteannuin B.43,44 Unfortunately, all attempts to convert arteannuin B to artemisinin through enzymatic or microbial transformations have failed.37 An enzyme involved in the bioconversion of arteannuin B to artemisinin in A. annua has been isolated and purified,45 but all attempts to express it into a heterologous host have been unsuccessful.37 The only success has been the in vitro bioconversion of arteannuin B to artemisinin by incubation with an extract from A. annua L.42

Figure 1139: Schematic Representation of the Engineered Artemisinic Acid Biosynthetic Pathway in S. cerevisiae

In addition to extraction and bioengineering efforts, access to artemisinin through total synthesis is being explored.46-53 The reported syntheses all use similar end game strategies, either employing a singlet oxygen/acid rearrangement46,47,50,53 of ketone 12 or an ozone/acid rearrangement48,49,51 of vinyl silane 13 to install the endoperoxide functionality (Figure 12).

O 1 o O O2 , 78 C MeOH, hv HOO HCO H Path A methylene 2 MeO CH Cl CH3 H blue MeO 2 2 H MeO o NaO C HO2C 0 C, O 2 H3C O 12 12a 24 h, 30% O H H O CH3 O H2SO4 O O O /O H O O Path B 3 2 2 78 oC artemisinin 1 HOO 35% Me3Si CH2Cl2; O SiO2 HO2C HO2C 13 13a Figure 12: Early Approaches Toward Artemisinin, Path A was Explored by Hofheinz46 and Later Modified by Yadav,53 Path B was Explored by Avery51

Where the syntheses differ is in their construction of precursors 12 and 13. The first reported total synthesis was completed by Schmid and Hofheinz.46 The synthesis begins with commercially available ()-isopulegol 14, which is converted into ketone 15 through a protection/hydroboration/oxidation sequence in 58 % yield over 5 steps. Ketone 15 was then alkylated with the StorkJung vinylsilane54 16 giving intermediate 17 as a 6:1 mixture of diastereomers in 62 % yield (Figure 13). For a full discussion on the StorkJung vinylsilane refer to chapter 3.

5 steps Me Si 1. LDA, THF, 0 oC 3 HO O O H 2. 16 H 85% yield H H 62% 6:1 mix of diasteromers 14 PhCH2O 15 PhCH2O 17

Me3Si I 16 Figure 13: Construction of the Schmid and Hofheinz Singlet Oxygen Precursor 17

A large excess of lithium methoxy(trimethylsilyl)methylide was added to 17, giving alcohol 18 as a 8:1 mixture of diastereomers. Lactonization followed by unmasking of the ketone from the vinylsilane gave bicyclic intermediate 19. Subsequent desilylation triggered enol ether formation and ring opening to give artemisinin precursor 20. Treatmeant of 20 with molecular oxygen, methylene blue and h followed by addition of formic acid gave artemisinin 1 in 30% yield (Figure 14).

10 equiv. O Me3Si Me Si 1. Li, NH H Li 3 HO 3 H MeO MeO 2. PCC, CH2Cl2 MeO 17 o H O THF, -78 C Me3Si H Me Si H 3. m-CPBA, CH2Cl2 89%, 8:1 d.r. 3 4. TFA, CH2Cl2 18 O PhCH2O 54% over 4 steps 19

CH O H 3 1. O2, methylene blue H C O Bu4NF, THF, r.t., 2 h methanol, hv, -78 oC 3 O O H 95% yield 2. formic acid, CH Cl , H 2 2 H O MeO H 0 oC, 24 hr, 30% yield CH HO C 3 2 O 20 artemisinin 1 Figure 14: Schmid and Hofheinz End Game Strategy

The next three total syntheses of artemisinin completed by the Avery,48,49,51 Zhou,47 and Yadav53 labs all used similar alkylation strategies to obtain their singlet oxygen or ozone rearrangement precursors. The only exception was a formal synthesis completed by Ravindranathan and co-workers, in which an intra-molecular DielsAlder reaction was employed to give access to the singlet oxygen precursor.50 The discovery by Roth and Action in 1989 that dihydroartemisinic acid 21 could be converted directly to artemisinin 1 through exposure to singlet oxygen instantly made dihydroartemisinic acid 21 an important synthetic target (Figure 15).55 The first group to take advantage of this new access point to artemisinin 1 was the Liu lab,52 though other groups soon followed.56 Immediately recognizing the great potential for accessing artemisinin through 21, we also began developing a short and efficient route to dihydroartemisinic acid 21. Our first proposed pathway to 21 will be discussed in chapter 3.

CH H 3 1. O , hv, CH Cl 2 2 2 O 78 oC, methylene blue H3C O O H 2. CH Cl replaced with H 2 2 H O H petroleum ether, 4 days CH3 HO2C 17% O 21 artemisinin 1 Figure 15: First Example of Dihydroartemisinic Acid 21 Being Converted into Artemisinin 1

In addition to accessing artemisinin through artemisinic acid 21, we also hypothesized that it may be possible to convert (+)-dihydro-epi-deoxyarteannuin B 22 into artemisinin 1 through a dyotropic ozonide rearrangement (Figure 16).57-60 Generation of the ozonide 23 followed by treatment with a Lewis acid should cause the lactone to open giving intermediate 24. A 1,2-shift of the ozonide bridge followed by ring closure would generate artemisinin 1.

H O3 O CH2Cl2; O O O then O O H O O Lewis O acid O O O 22 23 LA 24

CH H 3 O O O H3C O O O H O H O CH3 O LA 25 O artemisinin 1 Figure 16: Our Proposal for Generating the Key Endoperoxide

With our end game strategies in place, we turned our attention to the synthesis of both artemisinic acid 21 and (+)-dihydro-epi-deoxyarteannuin B 22. Chemical synthesis of these two molecules would allow us to test our proposed ozonide rearrangement and would also provide general contributions to artemisinin research as a whole.

CHAPTER 3

SYNTHESIS OF (+)-DIHYDRO-EPI-DEOXYARTEANNUIN B AND ()-DIHYDROARTEMISINIC ACID

(+)-Dihydro-epi-deoxyarteannuin B 22, which also occurs naturally in Artemisia annua,61 is a key intermediate in our long term efforts to develop an efficient synthetic route to artemisinin 1. Both artemisinin and 22 derive their origins from dihydroartemisinic acid 21, another extract from A. annua, through a nonenzymatic autooxidation process (Figure 17).62-63 Both 21 and 22 have also been converted chemically into semisynthetic 1.55,64

CH H 3 H H O H3C O O H H H H O O H H CH3 HO2C O O (+)-dihydro-epi-deoxyarteannuin B 22 ()-artemisinin 1 ()-dihydroartemisinic acid 21 Figure 17: Our Synthetic Targets

The common feature in both 21 and 22 is the decalin ring system. An efficient way to establish the decalin ring system is therefore paramount in developing an economical approach to artemisinin 1. Several groups have approached the decalin ring system through the DielsAlder reaction.50,65,66 The Ravindranathan50 and Meinwald65 labs both used intramolecular DielsAlder reactions to establish the decalin system (Figure 18).

Ravindranathan and co-workers further elaborated 27 to complete a formal synthesis of artemisinin 1. However, due to the low yield and poor selectivity in their key DielsAlder step the overall efficiency of the synthesis was quite low.50

H toluene, 210 oC sealed tube, 72 h Eq (1) H 25-30% H O 3:2 mix of epimers O 26 27 H

H benzene, 170 oC Eq (2) OH sealed tube, OH 2 days, 95% H 28 2:1 mix of epimers 29 Figure 18: Eq (1) Ravindranathan Intramolecular Diels-Alder,50 Eq (2) Meinwald Intramolecular Diels-Alder65

Avery and co-workers chose to use an aldol cyclization of ketone 30 to generate bicyclic enone 31 in their pursuit of artemisinin derivatives.67 The aldol condensation proved to be much more difficult than the authors had envisioned. Under normal aldol conditions they saw significant epimerization of the propanol side chain. They were able to combat the epimerization by incorporation of L-proline into the reaction mixture, but yields were still quite low (Figure 19).67

L-proline, MeOH O H 43% O H TIPSO H TIPSO H 30 31 Figure 19: Avery and Co-Workers’ Strategy to Avoid Epimerization

In the course of their investigation into electroreductive cyclizations,68 Schwaebe and Little investigated the electroreductive cyclization of epoxy ketone 32 to give bicycle 33.69 The reaction proceeded in high yield, but there was no control of stereochemistry (Eq 4, Figure 20). Dreiding and co-workers experienced a similar problem in their Zn-Cu cyclization of ketone 36. Dreiding was able to access the tricyclic core of artemisinic acid in a single operation. Unfortunately, none of the stereoisomers obtained were consistent with naturally occurring artemisinic acid (Eq 6, Figure 20).70 Schwaebe and Little were later able to overcome the selectivity problem by using samarium iodide (Eq 5, Figure 20).69

H CO2Me 4e, 4HD Eq (4) O (78-95%) O HO HO 32 33 MeO2C

H SmI2, CO2Me THF/MeOH Eq (5) 0 oC (>95%) O 34 HO 35

CO2Me

CH2Br H Zn(Cu) Eq (6) CO2C2H5 THF O 36 O 37

O Figure 20: Electrocyclic Strategies to the Decalin Ring System

Other methods employed to access the arteannuin ring system include an anodic coupling reaction developed by Wu and Moeller71 (Eq 7, Figure 21) and a tandem oxy- Cope/ene reaction developed by Barriault and Deon72 (Eq 8, Figure 21). While the anodic coupling reaction has the advantage of providing direct access to the tricyclic core of the arteannuins in a single step, preparation of 38, the coupling precursor, is cumbersome.71 The

22 tandem oxy-Cope/ene reaction, on the other hand, proceeds with excellent diastereoselectivity and builds complexity quickly. With this as their key step, Barriault and Deon were able to complete the total synthesis of (+)-arteannuin M 42 in ten steps with an overall yield of 14.1%.72

H MeO RVC anode carbon cathode 0.1 M LiClO4 O Eq (7) O O 20% MeOH/CH2Cl2 R 2,6-lutadiene R MeO 8 mA/ 2.4 F/mole 38a. R = H undivided cell 39a. R = H, 70% 38b. R = Me 39b. R = Me, 70% H H H DBU, toluene, 220 oC Eq (8) 55-60% HO O H OH HO HO 40 ODPS 41 ODPS O (+)-arteannuin M 42 Figure 21: Other Approaches Towards the Decalin Rings System

In our retro synthetic analysis of dihydro-epi-deoxyarteannuin B 22, we planned on constructing the decalin ring system through a ring closing metathesis of diene 45. Diene 45 would be constructed from ketone 44 by olefination followed by oxidation of the primary alcohol to trigger lactonization. Ketone 44 was envisioned to be prepared from silyloxy menthone 43 by alkylation with a methyl vinyl ketone equivalent followed by vinyl Grignard addition. The starting material for our synthesis was isopulegol 14 (Figure 22).

H O

H H OH O O H OTIPS O O (+)-dihydro-epi-deoxyarteannuin B 22 45 44

H O OH OTIPS

43 isopulegol 14 Figure 22: Our Retro-Synthetic Analysis

For the conversion of isopulegol 14 to ketone 43, we planned to modify a known literature procedure and expected few problems.67 Our first anticipated challenge was the alkylation of ketone 43. We needed to prepare a Michael adduct between methyl vinyl ketone (MVK) and an unstabilized cyclohexanone enolate. Unfortunately, methyl vinyl ketone is a poor electrophile for this transformation due to competing polymerization. To circumvent the competing polymerization, a number of MVK equivalents73,74 have been developed for carrying out this transformation. The StorkJung vinylsilane54 16 was identified as the MVK equivalent that best met our needs (Figure 23). The weakness of the StorkJung vinylsilane 16 is its lengthy preparation.75-80 Therefore, we needed to develop a short and efficient route to prepare 16 on large scale.

Me3Si I 16 Figure 23: The StorkJung Vinylsilane

The original synthesis of 16 by Stork and Jung can be seen in Figure 24.75 The synthesis begins with propargyl alcohol 46, which is converted to the trimethylsilyl acetylene 47 before regioselective reduction of the triple bond using lithium aluminum hydride. Subsequent iodination gave the (Z)-iodo silane 48 exclusively. Organocuprate addition followed by a two- step conversion of the primary alcohol to the iodide finished the synthesis. While several slightly modified procedures have been developed,76-80 the StorkJung method remains the most commonly used procedure. There are a couple notable modifications of the original StorkJung procedure.75 The first is a method developed by Zweifel and Lewis that allowed for the preparation of the (E)- iodo silane 52 by use of iso-butylaluminum hydride instead of lithium aluminum hydride as the reducing agent.80 Second, Sato and co-workers showed that (E)-iodo-alcohols 54 could be prepared through a titanium-catalyzed hydromagnesiation of propargyl alcohol 53 followed by trapping with iodine (Figure 25).76,77

H BuLi; SiMe3 LiAlH4, I SiMe3 TMSCl NaOMe; I2 CuI, MeLi 90% 68% 96% OH OH OH 46 47 48

Me SiMe3 Me SiMe Me SiMe Ph3P, 3 NaI 3 CCl4 butanone 60% 80% OH Cl I 49 50 16

Figure 24: The Original Synthesis of the StorkJung Vinylsilane75 16

1) LiAlH4 NaOMe H SiMe3 SiMe3 75 Eq (9) 2) I Stork and Jung HO 2 HO I 47 48

1) i-Bu2AlH Et O n-Bu SiMe3 Eq (10) n-Bu SiMe 2 3 Zweifel and Lewis80 2) I 51 2 H I 52 1) 2 equiv i HO n-Bu n-Bu BuMgCl 76,77 Eq (11) Sato and co-workers 5 HO ( -C5H5)2TiCl2 53 H I 54 2) I2 Figure 25: Early Modifications of the StorkJung Synthesis

Our lab envisioned constructing the StorkJung vinyl silane 16 by the use of a titanium- catalyzed hydromagnesiation of 2-butynol 55 followed by trapping with trimethylsilyl chloride, based on Sato’s protocol.76 The optimized conditions can be seen in Figure 26.81 It was found i o that 2.3 equivalents of BuMgCl and 5 mol% of Cp2TiCl2 in diethyl ether at 60 C gave the cleanest reaction and the highest yield. Trapping with trimethylsilyl chloride could be done with or without the toxic hexamethylphosphoramide (HMPA) additive, however yields decrease by 10-15% without it. Subsequent conversion of the vinyl alcohol to the vinyl iodide by triphenylphosphine and N-iodosuccinimide gave us a convenient two-step protocol for the generation of the StorkJung vinylsilane 16.81

2.3 equiv i-BuMgCl, Et2O SiMe 1.1 equiv Ph3P 3 SiMe3 HO 5 mol% Cp2TiCl2,  1.1 equiv NIS Me HO Me CH Cl 4.6 equiv HMPA, Et2O 2 2 I Me 55 3.0 equiv TMSCl,  49 0 oC to rt 16 70-76% 82-94% Figure 26: Dudley Lab Succint Method for Preparation of StorkJung Vinylsilane 16

With a short and efficient way to prepare the StorkJung vinylsilane 16, we turned our attention to the preparation of the second alkylation partner, ketone 43. The synthesis begins with the hydroboration of isopulegol 14. The first concern was the large price difference between crude ($55 for 1 L, Aldrich) and pure isopulegol ($32 for 1 mL, Aldrich). The diastereoselective hydroboration of refined isopulegol was known to provide a crystalline diol 56.82 This led us to develope a recrystallization procedure which allowed us to start from bulk isopulegol which is over 500 times cheaper than the pure form (Figure 27).

pure ca. 3:1 dr B2H6, THF; B2H6, THF; H2O2, 94% H2O2, 57%

OH 95:5 d.r. H OH pure crystals OH (ref 82) H OH (our work) 14 56 14 Figure 27: Hydroboration of Bulk Isopulegol vs. Pure Isopulegol

Monoprotection of the primary alcohol of 56 with triisopropylsilyl chloride (TIPSCl) followed by Swern oxidation83 gave us silyloxymenthone 43 (Figure 28).

TIPSCl, NEt3 DMSO, (COCl)2 H OH H OH O DMAP, CH Cl NEt3, CH2Cl2 H H OH 2 2 H OTIPS H OTIPS 86% 86% 56 57 43 Figure 28: Conversion of Diol 56 to Ketone 43

Coupling of silyloxymenthone 43 with the StorkJung vinylsilane 16 proved to be more difficult than we had anticipated (Table 1). Initial attempts at alkylation of 43 (Z = OTIPS) under standard conditions yielded 59 in a modest 45% yield (Table 1, Entry 6). Similar alkyations of menthone (58, Z = H) also proved problematic (Table 1, Entries 1 and 3).84-86

Table 1. Allylation of Menthone and Silyloxymenthone 43

R LDA RX O OLi O H THF H additive(s) H H Z H Z H Z B CD Enolate conformations: (preferred)

CH CH3 H C 3 3 O LnM O MLn Z Z H3C A1,2 interaction

Entry Z Substrate RX Additive(s) Product Yield (%) 1 H 58 allyl bromide none 60 1782 2 OBn 15 16 none 61 5346 3 H 58 allyl iodide HMPA 60 53 a 4 H 58 allyl iodide HMPA, Et2Zn 60 ~80

5 OTIPS 43 allyl iodide HMPA, Et2Zn 62 80 6 OTIPS 43 16 HMPA 59 45

7 OTIPS 43 16 HMPA, Et2Zn 59 89 a Estimated by 1H NMR spectroscopy.

SiMe3

I SiMe3 (i-Pr) SiO O 16 3 59

We believe the problem lies in the conformation of enolate C. A1,2 strain forces the enolate C to adopt a conformation in which the adjoining alkyl substitutents must adopt a pseudoaxial orientation, blocking both the top and bottom faces (Table 1). The use of diethylzinc as an additive according to Noyori’s protocol87 provided for substantial improvements (Table 1, cf. Entries 3 and 4; 6 and 7). Optimal conditions were determined to be 1.0 equivalents of ketone 43 plus 1.1 equivalents lithium diisopropylamide, 1.0 equivalents of hexamethyldiphosphoramide (HMPA), 1.0 equivalents of diethylzinc, and 1.5 equivalents of the StorkJung vinylsilane 16 from 78 oC to room temperature for eight hours giving ketone 59 in 89% yield. Addition of vinyl Grignard to the sterically congested ketone 59 failed to give the desired tertiary alcohol. Fortunately, the use of the organocerium reagent88 made from freshly prepared vinylmagnesium bromide and freshly activated CeCl3 cleanly added to give the desired alcohol 63 in up to 91% yield. An additional three-step procedure beginning with the addition of lithium trimethylsilylacetylide, followed by deprotection and reduction also afforded 63 in a 85% percent overall yield. The three step process avoids the need for the careful preparation of the organocerium reagent and can be performed in a shorter amount of time with less technical difficulty (Figure 29).

SiMe SiMe3 3 vinylMgBr SiMe3 CeCl3 O (i-Pr) SiO O H 3 59 H OH H OTIPS THF H OTIPS conformation in which the ketone up to 91% 59 is the least hindered 63

1.Li SiMe3 THF; 2. K2CO3, MeOH; 3. H2 Pd/BaSO4, pyridine, EtOH ca. 85% overall Figure 29: Vinyl Addition to Silyloxymenthone 59

Removal of the silyl ether under acidic conditions followed by oxidation of the resulting diol yielded lactone 64 in excellent yield. The vinylsilane was then selectively epoxidized over

29 the terminal olefin with m-CPBA, presumably due to the shielding effect of the lactone. Subsequent treatment of epoxide 65 with trifluoroacetic acid resulted in formation of ketone 66. Waiting until this point in the synthesis to unmask the ketone allowed us to avoid the need for lengthy protecting group strategies. Wittig methylenation97 of ketone 66 proceeded with moderate yield; however, the most disappointing development was that all attempts at effecting a ring-closing metathesis (RCM)89 reaction on the resulting diene 45 failed (Figure 30).

SiMe3 1. HCl SiMe3 SiMe3 MeOH m-CPBA; H OH O O 2. TPAP H CF3CO2H H H OTIPS NMO >95% O 63 >95% overall 64 O 65

O H

PH3P=CH2 RCM attempts ca. O O Grubbs' cat H H 30-40% H O O 66 O 45 O 22 Figure 30: Elaboration to First Metathesis Precursor 63-22

The failed ring-closing metathesis may be attributed to steric congestion around the vinyl substituent. In addition to steric congestion, the spiro-tricyclic product 22 may be significantly more strained than the diene precursor 45 prohibiting cyclization. Reductive opening of the lactone with lithium aluminum hydride did allow for the ring-closing metathesis to proceed in low yield. Subsequent tetrapropylammonium perruthenate (TPAP) oxidation successfully yielded (+)-dihydro-epi-deoxyarteannuin B 22 (Figure 31). The lower yield associated with the final lactonization step compared with the earlier lactonization step (63 to 64) lends credence to our hypothesis that the failed RCM is partially due to mild strain associated with the spiro-lactonization step. Cross metathesis by-products resulting from the

30 ruthenium catalyst reacting with the mono-substituted alkene but then failing to cyclize led us to consider the possibility of using Hoye’s relay ring closing metathesis90 (RRCM) strategy to force the catalyst onto the disubstituted olefin. Olefination of ketone 66 with phosphonium salt 68 (prepared from 5-hexen-1-ol in two steps) provided the desired RRCM substrate 69, albeit in modest yield. Despite the moderate yield in the olefination step, vast improvements were seen in the subsequent relay ring closing metathesis step (Figure 31).

H 1.LiAlH4 92% TPAP NMO 2.RCM H H O OH 62% 37% OH O 67 45 H

I Ph3P H 68 O

O relay O 22 RCM 68, BuLi Grubbs' cat. 74-90% O 17-37% H H O (40% brsm) 69 O 66 O Figure 31: Ring Closing Metathesis (RCM) Strategies

In summary, we have successfully completed the total synthesis of (+)-dihydro-epi- deoxyarteannuin B 22 from bulk isopulegol 14.91 We were able to develop an efficient alkylation strategy based on Noyori’s protocol87 that allowed us to alkylate menthone derivatives in high yield. These alkylated derivatives can serve as valuable building blocks in the synthesis of a variety of artemisinin related compounds. Two solutions were developed to overcome the initial failure of the late stage ring closing metathesis. These studies will provide

31 valuable information for our future research into the chemical synthesis of members of the artemisinin family of antimalarial compounds. Upon successful completion of (+)-dihydro-epi-deoxyarteannuin B, our next course of action was to approach artemisinin through the known oxidation of dihydroartemisinic acid 21.55 Prior approaches to the decalin ring system of dihydroartemisinic acid 21 were discussed previously in our discussion of (+)-dihydro-epi-deoxyarteannuin B 22.50,65-72 Our proposed synthesis of dihydroartemisinic acid 21 can be seen in Figure 32. We planned to begin with the same silyloxymenthone derivative 43 that we had prepared previously for our synthesis of (+)-dihydro-epi-deoxyarteannuin B 22.91 Alkylation with allyl iodide followed by olefination would give us α,-unsaturated ester 70. We then wanted to complete a one pot methylenation and ring-closing metathesis based on Rainier’s work with the Takai reagent.92 Hydrolysis of the silyl ether followed by an acidic oxidation was intended to give a mixture of carboxylic acids 72 and 21. Carboxylic acid 21 can then be oxidized to artemisinin using singlet oxygen.55

1.LDA, THF olefination MeLi, CuCN COCH 3 DIBAL, THF H O 2.Et2Zn, HMPA H O H H OTIPS allyl iodide H OTIPS H OTIPS 80% 43 62 70

H 1.TiCl4, PbCl2 H O + Zn, CH2Br2 H

H H OTIPS H H CO2H CO H 71 2 72 dihydroartemisinic acid 21 Figure 32: Proposed Synthesis of Dihydroartemisinic Acid 21

With the alkylation conditions for the conversion of 43 to 62 having been worked out previously91 we immediately began investigations into the olefination of ketone 62. We first

32 looked at the olefination of a model system 60, which lacked the triisopropylsilyl moiety. Ketone 60 could be made from ()-menthone 58 by alkylation with allyl iodide (Figure 33). To our surprise, the HornerWadsworthEmmons (HWE)94 olefination failed to give any of the desired product. Believing that the steric hindrance of the ketone may be to blame for the lack of reactivity, we next examined the HWE olefination of ()-menthone 58. Again the HWE olefination provided no reaction (Figure 33). A search of the literature yielded no examples of menthone or similar derivatives being olefinated by the use of stabilized Wittig or HWE reagents.

LDA, Et2Zn HMPA, THF O allyl iodide O 50-85%

58 60

(OEt)2P(O)CH2P(O)OEt 60 No Reaction NaH

(OEt)2P(O)CH2P(O)OEt 58 No Reaction NaH Figure 33: Olefination Attempts on Menthone and Menthone Derivatives

The neighboring alkyl groups of these ketones (58 and 60) screen against nucleophilic attack. Thus, we found ourselves in need of an efficient way to olefinate hindered ketones. This led us to develop an alternative olefination strategy sequence, which began with acetylide addition followed by MeyerSchuster rearrangement—a formal 1,3 hydroxy shift of a propargyl alcohol to the corresponding enone (Figure 34).116-117 Acetylide additions are relatively insensitive to steric congestion, and it was believed that acetylide addition to ketone 60 should proceed smoothly (Figure 34). Rearrangement of

33 the resulting propargyl alcohol to the α,-unsaturated enone via the MeyerSchuster rearrangement would complete our desired olefination. Unfortunately, the traditional MeyerSchuster reaction is limited in scope and often requires harsh reaction conditions.117-130 We therefore need to develop mild and general reaction conditions to effect this transformation.

R Meyer-Schuster O OH O n-BuLi R R 60 73 74

OH 3 "Meyer-Schuster" R O 3 Eq (15) R 1 2 R1 strong acid R R E R2 F Figure 34: Proposed Olefination Strategy

In summary, we designed a concise route to dihydroartemisinic acid 21. In order to test the feasibility of this route, we first have to develop a method for the olefination of hindered ketones. We proposed a two-step olefination consisting of acetylide addition followed by MeyerSchuster rearrangement. The scope of the original MeyerSchuster rearrangement is limited due to harsh reaction conditions. Our efforts into developing mild reaction conditions for this powerful transformation will be discussed fully in Part II.

Addendum:

We have successfully implemented the two-step olefination strategy outlined above. Ethoxyacetylene cleanly added to ketone 60 with the use of n-BuLi in THF to give propargyl alcohol 73. Treatment of propargyl alcohol 73 with 5 mol % AuCl3 and 5.0 equivalents of ethanol in methylenechloride at room temperature gave what appears to be the desired α,-

34 unsaturated ester 74 (Figure 35). These are preliminary results and are based on analysis of only the 1H NMR (spectra immediately follow). However, these initial findings support the feasibility of the approach.

R 5 mol% AuCl3 O n-BuLi OH 5.0 equiv. EtOH o O -78 Cr.t. CH2Cl2, rt, 5 min R 12 h, 80% R 98% 60 73 74 R = OEt

Figure 35: Implementation of Our Olefination Strategy Towards Dihydroartemisinic Acid 21

CHAPTER 4

EXPERIMENTAL: (+)-DIHYDRO-EPI-DEOXYARTEANNUIN B

GENERAL EXPERIMENTAL PROCEDURES: 1 13 H NMR and C NMR spectra were recorded on a 300 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) relative to 1 13 the residual CHCl3 peak (7.26 ppm for H NMR and 77.0 ppm for C NMR for all compounds except for 22, which was referenced to 7.27 ppm for 1H NMR and 77.2 ppm for 13C NMR). The coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on an FTIR spectrometer on NaCl discs. Mass spectra were recorded using chemical ionization (CI), electron ionization (EI), fast atom bombardment (FAB), or electrospray ionization (ESI). Yields refer to isolated material judged to be ≥95 % pure by 1H NMR spectroscopy following silica gel chromatography. All chemical were used as received unless otherwise stated.

Tetrahydrofuran (THF) and diethyl ether (Et2O) were purified by passing through a column of activated alumina. The n-BuLi solutions were titrated against a known amount menthol dissolved in tetrahydrofuran using 1,10-phenanthroline as the indicator. The purifications were performed by flash chromatography using silica gel F-254 (230-499 mesh particle size). HMPA was distilled under reduced pressure over CaH2, and stored under an inert atmosphere.

Diisopropylamine was distilled over CaH2, under an inert atmosphere, and used fresh.

SiMe3

HO Me 49 (E)-3-Trimethylsilanylbut-2-en-1-ol [49] To an oven-dried, three-necked, round-bottom flask equipped with a pressure-equalizing dropping funnel, reflux condenser, and septum was added isobutylmagnesium chloride in diethyl ether (46.0 mL, 92.0 mmol) under argon. To the Grignard solution was added bis(cyclopentadienyl)titanium dichloride (0.50 g, 2.0 mmol) at 0 oC. The reaction was held at 0 oC for 30 min then 2-butyn-1-ol (3.0 mL, 40.0 mmol) was added dropwise as a solution in diethyl ether (100 mL). The reaction was then heated to reflux and held for 16 hr. The reaction was then allowed to cool to room temperature and hexamethylphosphoramide (19.0 mL, 109 mmol) was added dropwise as a solution of THF (125 mL) followed by chlorotrimethylsilane (14.0 mL, 109 mmol). The reaction was heated to reflux and held for 16 hr, then allowed to cool to room temperature. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1-5/1) to give 49 as a pale yellow oil (4.38 g, 76%): 1 H NMR (300 MHz, CDCl3)  0.07 (s, 9H), 1.71 (dt, J = 1.7, 0.8 Hz, 3H), 4.27 (dd, J = 6.0, 0.8 13 Hz, 2H), 5.88 (tq, J = 5.8, 1.7 Hz, 1H). C NMR (75 MHz, CDCl3)  -2.4, 14.6, 59.5, 137.5, 139.2. IR (neat) 3324, 2954, 1621, 1440, 1359, 1247 cm-1; MS m/z 143.1 [65, M – H]+. CH:

Calcd for C7H16OSi: C, 58.27; H, 11.18. Found: C, 58.04; H, 10.88.

SiMe3

I Me 16

((E)-3-Iodo-1-methylpropenyl)trimethylsilane [16] (E)-3-Trimethylsilanylbut-2-en-1-ol (49, 0.20 g, 1.4 mmol, 1.0 equiv) and triphenylphosphine (0.40 g, 1.5 mmol, 1.1 equiv) were weighed into an oven-dried, two-necked, round-bottomed flask equipped with an argon inlet and septum. Methylenechloride (3.5 mL) was added via syringe followed by the addition of N-iodosuccinimide (0.34 g, 1.5 mmol, 1.1 equiv, freshly recrystallized from dioxane/carbontetrachloride). The flask was wrapped in aluminum foil and the reaction mixture was stirred for 1 h in an ice bath and then 3 h at room temperature. When the reaction was complete (as determined by TLC), 5 mL of hexanes were added and the mixture was immediately filtered through 4 g of silica gel with the aid of 200 mL of hexanes. The filtrate was concentrated in vacuo give a thick yellow oil. (Note: Material at this stage was judged to be >95% pure by 1H NMR and was suitable for use.) Subsequent filtration through 2 g of neutral alumina with 100-150 mL of hexanes and concentration in vacuo afforded 0.29 g (82%) of 1 as a pale yellow liquid: 1 H NMR (300 MHz, CDCl3)  0.06 (s, 9H), 1.71 (d, J = 1.8 Hz, 3H), 3.93 (d, J = 8.4 Hz, 2H), 13 6.02 (tq, J = 8.4, 1.8 Hz, 1H); C NMR (75 MHz, CDCl3)  -2.5, 1.2, 13.7, 134.2, 143.2; IR (neat) 2954, 1604, 1437, 1247, 1143, 835 cm-1. MS m/z 254.2 [12, M]+.

1. BH3 THF 2. H2O2, NaOH

OH 3. NEt3, TIPSCl O DMAP, CH2Cl2 4. DMSO, (COCl)2, OTIPS NEt3, CH2Cl2 Isopulegol 14 43 (2S,5R)-5-Methyl-2-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-cyclohexanone [43] For detailed procedures and characterization data in support of the conversion of a crude mixture of isopulegol diastereomers to analytically pure 43 refer to Avery, M. A.; Fan, P.; Karle, J. M.; Bonk, J. D.; Miller, R.; Goins, D. K. J. Med. Chem. 1996, 39, 18851897. 1H NMR: 3.68 (dd, J = 5.1, 9.6 Hz, 1H), 3.61 (dd, J = 5.6, 9.6 Hz, 1H), 2.33 (m, 1H), 2.30 (m, 1H), 2.12 (ddd, J = 3.0, 6.0, 9.0 Hz, 1H), 1.95-2.04 (m, 2H), 1.75-1.92 (m, 2H), 1.29-1.51 (m, 2H), 1.04 (m, 21H), 0.99 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H). 1H NMR spectra for intermediates are given.

SiMe3

O OTIPS 59 (2S, 3R, 6S)-3-Methyl-6-(1-methyl-2-triisopropylsilanyloxy-ethyl)-2-((E)-3-trimethylsilanyl- but-2-enyl)-cyclohexanone [59] To a THF solution (6 mL) of n-BuLi (1.44 mL, 3.38 mmol, 2.35 M) was added diisopropylamine (0.52 mL, 3.68 mmol) at –78 °C under an argon atmosphere. The reaction mixture was held at –78 °C for 15 min. then allowed to warm to room temperature and keep there for 30 min before being recooled to –78 °C. Next, 43 (1.00 g, 3.07 mmol) was added dropwise as a solution in THF (2.0 mL). The reaction was held at –78 °C for 40 min. before being allowed to warm to 0 °C and held for 30 min., after which the reaction was recooled to –78 °C. Hexamethylphosphoramide (0.53 mL, 3.07 mmol) was added, the reaction mixture was stirred for 5 min, and then diethyl zinc (0.31 mL, 3.07 mmol) was added. A solution of 16 (1.19 g, 4.6 mmol) in 2 mL of THF was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give 59 as a clear colorless oil (1.24 g, 89%). 1 H NMR (300 MHz, CDCl3) 0.00 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H), 1.03-1.06 (m, 21H), 1.33- 1.49 (m, 2H), 1.55 (s, 3H), 1.64-1.68 (m, 3H), 1.82-1.99 (m, 3H), 2.05-2.26 (m, 3H), 2.34-2.48 13 (m, 2H), 3.65 (d, J = 4.8 Hz, 2H), 5.64 (tq, J = 6.5, 1.7 Hz, 1 H); C NMR (75 MHz, CDCl3) - 2.1, 12.0, 14.4, 15.7, 18.0, 20.7, 25.4, 31.1, 35.1, 41.3, 53.3, 58.4, 65.7, 136.0, 137.9, 213.0; IR (neat) 2953, 2866, 1712, 1617, 1463, 1246, 1098, 836 cm-1; HRMS (ESI) Calcd for + C26H52O2Si2 (M + Na ) 475.3404. Found 475.3388.

(2S, 3R, 6R)-2-Allyl-6-isopropyl-3-methyl-cyclohexanone [60] To a THF solution (4 mL) of n-BuLi (2.31 mL, 4.27 mmol, 1.85 M) was added diisopropylamine (0.65 mL, 4.66 mmol) at –78 °C under an argon atmosphere. The reaction mixture was held at –78 °C for 15 min. then allowed to warm to room temperature and keep there for 30 min before being recooled to –78 °C. Next, ()-menthone (0.67 mL, 3.88 mmol) was added dropwise as a solution in THF (2.0 mL). The reaction was held at –78 °C for 40 min. before being allowed to warm to 0 °C and held for 30 min., after which the reaction was recooled to –78 °C. Hexamethylphosphoramide (0.68 mL, 3.88 mmol) was added, the reaction mixture was stirred for 5 min, and then diethyl zinc (5.62 mL, 3.88 mmol, 0.69 M) was added. A solution of allyl iodide (1.07 mL, 11.67 mmol) in 2 mL of THF was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine.

The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give 60 as a clear colorless oil (0.64 g, 85%). 1 H NMR (300 MHz, CDCl3) 0.87 (dd, J = 13.3, 6.5 Hz, 6H), 1.05 (d, J = 6.2 Hz, 2H), 1.21- 1.67 (m, 4H), 1.87 (dq, J = 8.7, 2.7 Hz, 1H), 1.99-2.16 (m, 4H), 2.27-2.38 (m, 2H), 4.91-5.05 (m, 2H), 5.84 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H). For full characterization refer to: Nakashima, K.; Imoto, M.; Sono, M.; Tori, M.; Nagashima, F.; Asakawa, Y. Molecules 2002, 7(7), 517527.

O OTIPS

62 (2S,3R,6R)-2-Allyl-3-methyl-6-(R-1-methyl-2-triisopropylsilyoxyethyl)-cyclohexanone [62] To a THF solution (6 mL) of n-BuLi (1.54 mL, 3.23 mmol, 2.1 M) was added diisopropylamine (0.49 mL, 3.52 mmol) at –78 °C under an argon atmosphere. The reaction mixture was held at –78 °C for 15 min. then allowed to warm to room temperature and keep there for 30 min before being recooled to –78 °C. Next, 43 (0.96 g, 2.94 mmol) was added dropwise as a solution in THF (2.0 mL). The reaction was held at –78 °C for 40 min. before being allowed to warm to 0 °C and held for 30 min., after which the reaction was recooled to –78 °C. Hexamethylphosphoramide (0.61 mL, 3.52 mmol) was added, the reaction mixture was stirred for 5 min, and then diethyl zinc (0.36 mL, 3.52 mmol) was added. A solution of allyl iodide (1.0 mL, 10.95 mmol) in 2 mL of THF was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give 62 as a clear colorless oil (0.86 g, 80%). 1 H NMR (300 MHz, CDCl3)  0.91-1.14 (m, 21H), 1.20-1.68 (m, 7H), 1.80-2.02 (m, 4H), 2.20- 2.49 (m, 5H), 3.66 (dd, J = 4.9, 1.8 Hz, 2H), 4.89-5.06 (m, 2H), 5.84 (ddt, J = 17.1, 10.1, 6.8 13 Hz, 1H) C NMR (75 MHz, CDCl3)  5.3, 11.5, 15.6, 18.0, 20.5, 29.7, 30.5, 35.0, 40.4, 53.1, 57.7, 62.5, 65.6, 115.3, 137.3, 212.9.

SiMe3

OH OTIPS

(1S,2S,3R,6S)-3-Methyl-6-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-2-((E)-3- trimethylsilanyl-but-2-enyl-1-vinyl-cyclohexanol [63]

Procedure 1: A flask containing CeCl3 (0.066 g, 0.27 mmol) was heated to 140 °C under vacuum for 3 hr then cooled to 0 °C and placed under an argon atmosphere. THF (0.9 mL) was added and the mixture was allowed to stir for 2 hr. The resulting slurry was then cooled to –78 °C and vinylmagnesium bromide (2.5 mL, 0.94 mmol, 0.37 M) in THF was added. After 30 min, a solution of 59 (0.06 g, 0.13 mmol) in 0.5 mL of THF was added dropwise by syringe. The reaction mixture was held at –78 °C for 1 h and then allowed to warm to –15 °C and held for 1 h. Cold saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give 63 as clear colorless oil (0.56 g, 87%). Procedure 2: To a THF solution (6 mL) of trimethylsilylacetylene (0.20 mL, 1.4 mmol) was added n-BuLi (0.51 mL, 1.1 mmol, 2.1 M) dropwise at –78 °C under an argon atmosphere. The excess dry ice was removed and the reaction was allowed to slowly warm to 0 °C over 1.5 hr, then recooled to –78 °C. Next, 59 (0.324 g, 0.72 mmol) was added dropwise as a solution in THF (2.0 mL) and the reaction was allowed to slowly warm to room temperature. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude mixture was then added to a methanol solution saturated with potassium carbonate (7.0 mL) and left overnight. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium bicarbonate and brine. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate

= 20/1) to give a clear colorless oil (0.316 g), tentatively assigned as the propargyl alcohol

SiMe3

OH corresponding to acetylide addition of ketone 59; OTIPS 93%. A 15-mL roundbottomed flask was then charged with 5% Pd on BaSO4 (31 mg, 0.014 mmol) under an atmosphere of hydrogen. The palladium turned a dark black color. Methanol (4.0 mL) and pyridine (0.07 mL, 0.87 mmol) were then added and the solution was allowed to mix for 15 min. The propargyl alcohol (0.295 g, 0.62 mmol) obtained earlier was then added as a solution in methanol (2.0 mL). After 18 hr the reaction mixture was filtered through a plug of Celite (hexanes/ethyl acetate = 20/1) and was then purified using silica gel column chromatography (hexanes/ethyl acetate = 100/1) to give 63 as clear colorless oil (0.274 g, 93%). 1 H NMR (300 MHz, CDCl3)  0.00 (s, 9H), 0.77 (d, J = 7.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 1.03-1.13 (m, 21H), 1.32 (dd, J = 13.0, 3.3 Hz, 1H), 1.44 (dq, J = 12.5, 3.3 Hz, 1H), 1.55-1.79 (m, 8H), 1.96-2.05 (m, 1H), 2.16-2.23 (m, 1H), 2.32-2.40 (m, 1H), 3.35 (dd, J = 10.1, 4.0 Hz, 1H), 3.46 (dd, J = 10.3, 10.3 Hz, 1H), 4.37 (d, J = 1.3 Hz, 1H), 5.18 (dd, J = 10.5, 2.4 Hz, 1H), 5.32 (dd, J = 17.2, 10.5 Hz, 1H), 5.62 (dd, J = 17.2, 10.5 Hz, 1H), 5.73 (tq, J = 6.4, 1.6 Hz, 1H); 13 C NMR (75 MHz, CDCl3) -2.1, 11.9, 14.5, 18.0, 18.6, 20.6, 20.8, 28.6, 33.3, 34.5, 36.3, 51.5, 52.5, 65.6, 77.6, 114.1, 132.8, 142.3, 145.7; IR (neat) 3390, 2950, 2868, 1614, 1462, -1 + 1246, 1056, 835 cm ; HRMS (FAB) Calcd for C28H56O2Si2 (M + Na ) 503.3717. Found

50γ.γ711. [α]546 = –7.92° (c 0.001, CHCl3).

SiMe3

64 O (3R, 3aS, 6R, 7S, 7aS)-3,6-Dimethyl-7-((E)-3-trimethylsilanyl-but-2-enyl)-7a-vinyl- hexahydro-benzofuran-2-one [64] To a methanol solution (8.5 mL) of 63 (0.113 g, 0.234 mmol) was added conc. HCl (88 μL, 2.87 mmol) at 0 °C under an argon atmosphere. After 2 hr the reaction was quenched with aqueous sodium bicarbonate and extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 10/1-5/1) to give a diol intermediate as a white 1 crystalline solid (0.076 g, 0.234 mmol). H NMR (300 MHz, CDCl3) 0.03 (s, 9H), 0.78 (d, J = 7.3 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H), 1.04-1.14 (m, 1H), 1.18-1.30 (m, 3H), 1.48-1.60 (m, 3H), 1.64 (t, J = 1.5 Hz, 3H), 1.82-1.88 (m, 2H), 2.15-2.24 (m, 2H), 2.33-2.42 (m, 1H), 3.26 (dd, J = 11.0, 3.5 Hz, 1H), 3.39 (dd, J = 10.6, 10.6 Hz, 1H), 5.25 (ddd, J = 18.8, 14.1, 1.5 Hz, 2H), 5.66 13 (dd, J = 17.3, 10.8 Hz, 1H), 5.82-5.86 (m, 1H); C NMR (75 MHz, CDCl3)  -2.2, 14.9, 18.6, 20.3, 20.5, 27.4, 31.5, 34.4, 36.0, 50.9, 52.2, 64.0, 79.3, 114.4, 137.4, 138.4, 144.3; IR (neat) -1 + 3306, 2953, 1614, 1456, 1246, 835 cm . HRMS (EI) Calcd for C19H36O2Si (M ) 324.2485.

Found γβ4.β484. [α]546 = –9.80° (0.0012, CHCl3); mp 6567 °C. To a mixture of the diol (0.076 g, 0.234 mmol), 4 Å molecular sieves (0.10 g), and N-methylmorpholine oxide (0.082 g, 0.7 mmol) in CH2Cl2 (2.0 mL) was added tetra-n-propylammonium perruthenate (0.008 g, 0.023 mmol) under an argon atmosphere. After 2.5 hr the reaction mixture was flushed through a plug of SiO2 (hexanes/ethyl acetate = 10/1) to give lactone 64 as a white crystalline solid 1 (0.075 g, 100%). H NMR (300 MHz, CDCl3)  0.01 (s, 9H), 0.92 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.20-1.26 (m, 2H), 1.39-1.43 (m, 1H), 1.55-1.74 (m, 6H), 2.08-2.18 (m, 2H), 2.40-2.48 (m, 1H), 2.94 (apparent quint., J = 6.9 Hz, 1H), 5.22-5.32 (m, 2H), 5.63-5.72 (m, 2H); 13 C NMR (75 MHz, CDCl3) -2.2, 9.1, 14.5, 20.7, 24.1, 28.1, 32.9, 33.7, 39.1, 43.4, 49.3, 87.5, 115.4, 134.7, 140.3, 140.4, 179.8; IR (neat) 2952, 1778, 1615, 1455, 1246, 1178, 835 cm-1; + HRMS (EI) Calcd for C19H32O2Si (M ) γβ0.β17β. Found γβ0.β168. [α]546 = –14.58° (c 0.0024,

CHCl3); mp 7476°C.

66 O (3R, 3aS, 6R, 7S, 7aS)-3,6-Dimethyl-7-(3-oxo-butyl)-7a-vinyl-hexahydro-benzofuran-2-one [66]

To a CH2Cl2 solution (5.0 mL) of 64 (0.075 g, 0.234 mmol) was added m-CPBA (0.064 g, 0.281 mmol) at 0 °C under an argon atmosphere. After 2 hr the reaction was quenched with aqueous sodium bicarbonate and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The resulting residue was dissolved in CH2Cl2 (3.0 mL) and trifluoroacetic acid (60 μL, 0.8 mmol) was added. After 1 h the reaction was quenched with aqueous sodium bicarbonate and extracted with CH2Cl2. The organic layer was dried over

MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 8/1) to give 66 as a white crystalline solid (0.062 g, 100%). 1 H NMR (300 MHz, CDCl3)  0.94 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.19-1.25 (m, 2H), 1.39-1.51 (m, 1H), 1.59-1.94 (m, 6H), 2.11 (s, 3H), 2.30-2.41 (m, 1H), 2.63-2.74 (m, 1H), 2.90 (apparent quint., J = 6.9 Hz, 1H), 5.29 (m, 2H), 5.66 (dd, J = 17.3, 10.7 Hz); 13C NMR (75

MHz, CDCl3) 9.0, 20.1, 21.1, 24.0, 29.9, 30.5, 32.7, 38.7, 41.1, 43.5, 46.9, 87.6, 115.5, 140.1, 179.7, 209.1; IR (neat) 2929, 2359, 1771, 1714, 1448, 1177, 947 cm-1; HRMS (CI) + Calcd for C16H24O3 (M + H ) β65.1804. Found β65.1791. [α]546 = –11.90° (c 0.0016, CHCl3); mp 6466 °C.

45 O (3R, 3aS, 6R, 7S, 7aS)-3,6-Dimethyl-7-(3-methyl-but-3-enyl)-7a-vinyl-hexahydro- benzofuran-2-one [45] To a THF solution (1.0 mL) of methyltriphenylphosphonium bromide (0.073 g, 0.2 mmol) was added n-BuLi (0.13 mL, 0.18 mmol, 1.4 M) at –40 °C under an argon atmosphere. The solution turned a bright yellow. The mixture was allowed to warm to 0 °C over 1 h then 66 (0.027 g, 0.10 mmol) was added as a solution in THF (1.0 mL). The mixture was then allowed to warm to room temperature and left overnight. The reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1) to give 45 (0.008 g, 31%) as a clear colorless oil. 1 H NMR (300 MHz, CDCl3)  0.98 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.01-1.13 (m, 3H), 1.16-1.31 (m, 1H), 1.40-1.50 (m, 2H), 1.67-1.80 (m, 6H), 1.87-1.97 (m, 1H), 2.05-2.16 (m, 2H), 2.93 (apparent quint., J = 6.9 Hz, 1H), 4.63 (d, J = 7.1 Hz, 1H), 5.29 (ddd, J = 18.8, 14.1, 13 1.5 Hz, 2H), 5.66 (dd, J = 17.3, 10.8 Hz, 1H); C NMR (75 MHz, CDCl3) 9.1, 20.4, 22.4, 24.1, 26.5, 32.4, 32.9, 37.6, 39.2, 43.4, 48.0, 87.7, 109.5, 115.3, 140.2, 146.3, 179.8; IR (neat) -1 + 3072, 2933, 1778, 1646, 1179, 945 cm ; HRMS (CI) Calcd for C16H26O2 (M + H ) 263.2011. Found 263.2005.

PPh3 68 Hex-5-enyl-triphenyl-phosphonium iodide [68] To a nitromethane solution (35 mL) of 6-iodo-1-hexene (3.1 g, 14.75 mmol) was added triphenylphosphine (3.9 g, 14.75 mmol). The mixture was heated to 50 °C for 18 hr then cooled to room temperature. The mixture was then diluted with diethyl ether (50 mL) and a white solid crashed out. The precipitate was gravity filtered and rinsed with diethyl ether (30 mL) to give 68 (4.7 g, 67 %) as a white crystalline solid. 1 H NMR (300 MHz, CDCl3) 1.52-1.80 (m, 4H), 2.02 (apparent q, J = 6.9 Hz), 3.52-3.62 (m, 2H), 4.81-4.91 (m, 2H), 5.62 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 7.63-7.79 (m, 15H); 13C NMR

(75 MHz, CDCl3)  21.5, 21.6, 22.4, 23.1, 28.9, 29.1, 32.7, 115.2, 117.3, 118.4, 130.3, 130.5, 133.4, 133.5, 135.0, 137.4; mp 166168 °C.

69 O (3R, 3aS, 6R, 7S, 7aS)-3,6-dimethyl-7-((Z)-3-methyl-nona-3,8-dienyl)-7a-vinyl-hexahydro- benzofuran-2-one [69] To a diethyl ether solution (2.0 mL) of hex-5-enyl-triphenyl-phosphonium iodide 68 (0.137 g, 0.29 mmol) was added n-BuLi (0.124 mL, 0.248 mmol, 2.0 M) at –78 °C under an argon atmosphere. The mixture was then allowed to warm to room temperature and then recooled to –78 °C. Next, 66 (7.6 mg, 0.029 mmol) was added as a solution in diethyl ether (1.0 mL) and allowed to warm to room temperature. After 4 hr the reaction was quenched with water and extracted with diethyl ether. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1) to give 69 (3.5 mg, 37%) as a white crystalline solid. 1 H NMR (300 MHz, CDCl3, Diagnostic Peaks)  0.98 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 2.93 (apparent quint., J = 6.9 Hz, 1H), 4.92-5.09 (m, 3H), 5.24-5.36 (m, 2H), 5.60-5.69 (m, + 1H), 5.71-5.88 (m, 1H); HRMS (ESI) Calcd for C22H34O2 (M + Na ) 353.2457. Found 353.2460.

22 O (+)-Dihydro-epi-deoxyarteannuin B [22]

To a CH2Cl2 (1.5 mL) solution of 69 (8.0 mg, 0.024 mmol) under an argon atmosphere in a 1- dram vial was added Grubbs 2nd generation catalyst (2.0 mg, 0.0024 mmol). The sealed vial was heated to 40 °C for 4 hr then cooled to room temperature and flushed through a plug of

SiO2. The resulting eluent was concentrated and purified using silica gel column chromatography (hexanes/ethyl acetate = 10/1) to give 22 (4.4 mg, 77%) as a white crystalline solid. 1 H NMR (300 MHz, CDCl3) 0.95 (d, J = 6.5 Hz, 3H), 0.97-1.09 (m, 1H), 1.16 (d, J = 7.1 Hz, 3H), 1.17-1.25 (m, 2H), 1.37-1.48 (m, 1H), 1.62-1.76 (m, 6H), 1.85-1.93 (m, 1H), 2.02-2.13 (m, 13 3H), 3.15 (apparent quint., J = 6.9 Hz, 1H), 5.65 (q, J = 1.5 Hz, 1H); C NMR (75 MHz, CDCl3)  9.5, 19.9, 23.7, 24.0, 29.9, 31.1, 32.7, 39.9, 43.0, 46.9, 83.4, 122.0, 142.5, 179.5; IR (neat) -1 + 2929, 1764, 1449, 1162, 909 cm ; HRMS (ESI) Calcd for C15H22O2 (M + Na ) 257.1518.

Found 257.1518. [α]546 = 14.2° (c 0.00056, CHCl3); mp 6870 °C. Copies of NMR spectra that support our structural and stereochemical assignments are provided on pages 7893.

PART II: THE MEYER-SCHUSTER REACTION AND BEYOND

CHAPTER 5:

EVOLUTION OF THE MEYER-SCHUSTER REACTION

In the course of our investigation into the total synthesis of dihydroartemisinic acid 21, we encountered the need to convert ketone 60 into α,-unsaturated enone 74 (Figure 36). Initial attempts at olefination of 60 by the HornerWadsworthEmmons reaction proved unsuccessful, with starting material being recovered in all cases. The lack of reactivity was attributed to the steric hinderance around the ketone. Therefore, an alternative method to access α,-unsaturated carbonyl 74 was needed.

olefination O O R H H HO2C 60 74 dihydroartemisinic acid 21

Figure 36: Strategy Towards Dihydroartemisinic Acid 21

α,-Unsaturated carbonyl compounds are common building blocks in organic synthesis.95 Their construction is most commonly achieved by the homologation of aldehydes and ketones through aldol condensations,96 Wittig olefinations,97 HornerWadsworthEmmons (HWE) olefinations,97 or other olefination methods.98 The aldol condensation is the most atom economical99 of these approaches, producing only water as a by-product. While the aldol

94 condensation avoids the need for the use of toxic stoichiometric phosphines, phosphine oxides, and phosphonates associated with the Wittig and HWE reactions, it often provides inferior yields. In addition, all of the aforementioned olefination methods are sensitive to steric congestion around the carbonyl. As a consequence, they often fail to olefinate hindered carbonyl compounds, as illustrated in our failed olefination attempts of 60. Therefore, alternative and atom-economical means of converting carbonyls into their homologated α,-unsaturated carbonyl analogs was desirable. One potential method would be an addition/rearrangement sequence between a carbonyl and an acetylenic -bond (Figure 37).

(a) stepwise annulation / electrocylic ring-opening Y [2 +2] O R2 O annulation O 4  electrocyclic R2 1 1 3 3 ring-opening Y R R R2 R Y R 1 R R3 G H

(b) nucleophilic 1,2-addition / rearrangement acetylide 2 O R2 O addition R MeyerSchuster 1 R3 1 R3 Y R R3 R1 R R2 OH rearrangement H G E F redox Rupe isomerization rearrangement105 elimination Ir106 Pd107,108 Rh109,110 Ru111,112 R2=H 2 R1 R O R3 3 2 R1 R3 R R R1 I O J K Figure 37: Atom-Economical Carbonyl Olefination Strategies

The nature of the alkyne utilized dictates which reaction pathway will be followed. Highly electron-rich alkynes (i.e., ynolates,100 ynamine,101,102 or ynamides,103,104 Figure 37a) undergo a formal [2+2] cycloaddition with the carbonyl to produce an oxatene intermediate, which then

95 undergoes electrocyclic ring opening to provide the homologated enoate/enamide H. The use of terminal alkynes opens the door to an alternative pathway. The acetylide can add to ketone G via a 1,2-nucleophilic addition to give propargyl alcohol E. The resulting propargyl alcohol E is capable of undergoing a variety of reactions,105-112 including the desired MeyerSchuster rearrangement to give α,-unsaturated carbonyl compound F (Figure 37b). To a certain extent, control over which pathway the propargyl alcohol follows can be achieved by careful selection of the reaction conditions. However, development of precise reaction conditions allowing for only the desired MeyerSchuster reaction to take place is paramount to the success of the proposed two-stage olefination method. A full understanding of the MeyerSchuster reaction is a prerequisite to the development of new reaction conditions. The MeyerSchuster reaction is a powerful rearrangement that converts propargyl alcohols into α,-enones. The process formally involves a 1,3-shift of the hydroxyl moiety followed by tautomerization of the presumed allenol intermediate L (Figure 38).113-115

R2 OH R2 O 1 1 R • R R3 R1 R3 R2 3 R OH H EL F

Figure γ8: Meyer and Schuster’s Rearrangement

The reaction was first reported by Meyer and Schuster in 1922, and it was conducted in acidic media at elevated temperatures.116 The requirements of strong acid and high temperatures severely limited the scope of the MeyerSchuster reaction.117 Substrates were confined to propargyl alcohols that lacked -hydrogens. The presence of -protons allowed for the Rupe rearrangement105 (Figure 39), which generally took precedence over the MeyerSchuster reaction.117

H 2 H 2 2 R R2 R R 3 + H O R 1 2 1 3 R1 1 R R R O R H H 3 R3 R O M N OI Figure 39: Competing Rupe Rearrangement

Initial attempts to increase the efficiency and the scope of the MeyerSchuster reaction focused on activation of the hydroxyl moiety by transition metal catalysts. Vanadium was the first transition metal to show promise. Chabardes and co-workers demonstrated that trialkyl orthovanadates could be used to prepare aliphatic α,-unsaturated aldehydes from propargyl alcohols with a terminal alkyne.118 While avoiding the need for strong acid, temperatures in excess of 140 oC were still necessary to promote rearrangement. At these high temperatures catalyst degradation was problematic. Catalyst decomposition was partially addressed by Pauling and co-workers, who developed more stable tris[triarylsilyl] vanadates.119 The tris[triarylsilyl] vanadate catalysts were also limited to the preparation of α,-unsaturated aldehydes.120 Catalyst stability was advanced further by the Vol’pin lab with the development of a polymeric silyl vanadate catalyst.124 The polymeric catalyst showed much greater stability than its monomeric counterpart. The new catalyst allowed for lower catalyst loadings, but it did nothing to address the high temperature requirements. Despite its shortcomings, this novel vanadate chemistry was used by Hoffmann- La Roche in a variety of terpenoid syntheses (Figure 40).121-123

OH CHO 4 mol % tri[triphenylsilyl] vanadate 3 mol % triphenylsilanol cat. benzoic acid o O xylene, 140 C, 3 h O 75 79%, mix of E/Z 76 Figure 40: Hoffmann-La Roche Inc. Application of Vanadate Catalyst121

The orthovanadate-catalyzed rearrangement is thought to proceed by formation of an intermediate vanadate ester Q, which can then undergo a [3,3]-sigmatropic rearrangement to give allene ester R. Allene R then undergoes trans-esterification or hydrolysis to give allenol L, which tautormerizes to the α,-enone F (Figure 41).

R3 R3 R3 2 OR 2 1 R 1 R R OR trans- R [3,3]-sigmatropic 1 • O V OR R OR O O OR Esterification O rearrangement H V OR 2 V ROH R O OR E P QR O R3 O R1 trans- tautomerization OH 3 2 Esterification R1 • R R R2 L F Figure 41: Proposed Orthovanadate Mechanism126

Attempting to expand the scope of this potentially useful reaction, Chabardes and co- workers performed a comprehensive study on the use of a variety of oxo-derivatives of vanadium, molybdenum,125 rhenium, and tungsten to catalyze the rearrangement.126 Ultimately, low transformation rates, even under high dilution, and harsh reaction conditions limited the utility of the reaction.126 The early oxovanadium work saw little use outside of industrial application, until it was resurrected by Chung and Trost in 2006. They found that in the presence of suitable electrophiles (initial work focused on imines), the vanadium allene intermediate R could be trapped to yield aldol-type products T, instead of undergoing hydrolysis to the MeyerSchuster products (Figure 42).127

O 3 4 (+) R R E N X V X H X O N OR O N OR 1 • O R OR R3 R4 R3 R4 2 V R O OR 2 1 2 1 R R R S R R T Aldol-type product H+

O R2 MeyerSchuster rearrangement R3 R1 product F Figure 42: Trapping of Oxo-Vanadate Allene R

Other early catalyst systems that were explored to activate the propargyl alcohol included a Ti/Cu system128 (which activated both the propargyl alcohol and the alkyne) and a vanadium-pillared montmorillonite system.129 Both catalyst systems improved the yield and lowered the reaction time of the rearrangement, but neither addressed the high temperature requirements. It was not until the development of a tetrabutylammonium perrhenate(VII)/p- toluenesulfonic acid catalyst system, in the early 1990’s by the Narasaka Lab, that the rearrangement could be carried out at room temperature without sacrificing yield.130 An attractive feature of this catalyst system is its ability to generate α,-unsaturated acylsilanes (Figure 43) in addition to α,-enones.

OH O 10 mol% Bu4NReO4 Si 10 mol% p-TsOH H O Si 2 CH Cl , r.t. 2 hrs, 75% 77 2 2 78

Figure 43: Narasaka Lab’s Perrhenate(VII)/p-Toluenesulfonic Acid System130

Recently, there has been a reemergence in the use of high oxidation-state metal-oxo complexes to catalyze the MeyerSchuster rearrangement. In their investigation into the

99 rhenium(V)-catalyzed nucleophilic substitution of propargyl alcohols, the Toste Lab noticed the formation of MeyerSchuster by-products.131 Using this as a starting point, Vidari and co- workers developed an efficient rhenium(V)-oxo catalyst to effect the MeyerSchuster rearrangement of both alkyl and aryl substituted alkynols132 (Figure 44).

[ReOCl3(OPPh3)(SMe2)] (5 mol%) DME, 80 oC, 36 h, yield 91% OH (6S)-79 O d.r. 6:1 (S)--ionone 80 95% ee

Figure 44: Vidari’s Lab Extenstion of Toste’s Methodology132

The rhenium-catalyzed reactions proceeded with high (E)-selectivity, which can be attributed to the isomerization of the (Z)-isomer to the more stable (E)-isomer under the reaction conditions.133 Terminal alkynes leading to the corresponding α,-unsaturated enals were also supported by this catalyst system. Due to the high oxo-philicity of the rhenium catalyst, these reactions were performed under strictly anhydrous conditions. The ability of the rhenium catalyst to be recycled multiple times, without loss of catalytic efficiency, added to the appeal of the method.132 Primary propargyl alcohols have proven to be very difficult substrates for the MeyerSchuster reaction.117 To address this shortcoming in MeyerSchuster methodology,

Akai and co-workers developed a multi-catalyst system consisting of MoO2(acac)2, AuCl(PPh3) and AgOTf, which allowed for the MeyerSchuster rearrangement to proceed smoothly under mild conditions.134 Selected examples can be seen in Table 2.

100

Table 2: Mo-Au Combo Catalysis for Rearrangement of E into α,-unsaturated Ketones F

MoO2(acac)2 1 OH R1 O R AuCl(PPh3)-Ag(OTf) 2 R (1 mol% each) R2 R3 3 E1-6 R toluene, rt, 2 h F1-6 Substrate E Product F

Time Isolated Yield Entry R1 R2 R3 (h) (%)

1 E1 H H (CH2)2Ph 0.5 F1 93

2 E2 H H n-C7H15 0.5 F2 84 3 E3 H H Ph 1 F3 61

4 E4 H Me n-C6H13 0.25 F4 97 (E/Z 93:7) 5 E5 Me Me Ph 2.5 F5 90

6 E6 Me Ph(CH2)2 n-C4H9 2 F6 94 (E/Z 67:33)

Primary (entries 1-3), secondary (entry 4), and tertiary (entries 5-6) propargyl alcohols all rearrange smoothly and in high yield. The low reaction times, typically less than an hour, and the ability of the rearrangement to proceed at room temperature can be attributed to the double activation of the propargyl alcohol. The Au and Ag catalysts activate the alkyne - system, while the Mo catalyst activates the alcohol.125,126,135-137 The catalytic activity of all the transition metal catalysts discussed thus far originates from formation of a propargyl metal ester, which then undergoes rearrangement and trans- esterification to give the formal MeyerSchuster rearrangement product (refer back to Figure 41). The transition metal oxo-catalysts are acting as ―hard‖ Lewis acids, preferring to coordinate to the more Lewis basic lone pair of the oxygen than the ―soft‖ -system of the alkyne (Figure 45).

101

2 non-bonded electons R -bonded electron on oxygen: 3 of alkyne: 1 R hard Lewis base R soft Lewis base OH

Figure 45: Lewis Basic Sites on a Propargyl Alcohol

The drawback to these ―hard‖ Lewis acid catalysts is they generally require harsh reaction conditions to carry out the catalytic cycle. An alternative approach would be first to functionalize the propargyl alcohol as an ether or ester. Ideally, this pre-functionalization would allow for the rearrangement to proceed under mild reaction conditions, through activation of the alkyne -system by a ―soft‖ Lewis acid (Figure 46). There are several examples of propargyl ethers being successfully converted into α,- unsaturated carbonyl compounds.138,139 These processes typically involve hydration of the alkyne, followed by -elimination of the ether alkoxide to generate the α,-unsaturated carbonyl. Although the end result is the same, the reactions are not strictly MeyerSchuster rearrangements, and they involve distinct synthetic challenges.

[M] [M] R3 R3 R2 [3,3]-sigmatropic 1 O R R1 • rearrangement O 2 O R O U V Figure 46: ―Soft‖ Lewis Acid Activation

In contrast, propargyl acetates can undergo a 1,3-migration140-146 of the acetate, yielding formal MeyerSchuster products after hydrolysis (Figure 47, Eq. 16), or a 1,2- migration147-150 leading to metal carbenes, which have their own unique chemistry.

102

The Yamada lab has shown that covalent activation of the propargyl alcohol as a carbonate and the rearrangement/hydrolysis sequence can be merged into a single operation using high-pressure carbon dioxide, base, and a silver catalyst (Figure 47, Eq 17).151 However, functionalization of the propargyl alcohol in a separate step is much more common.

3 R3 2 R 2 R R2 O 1 R R1 R propargyl acetate "catalyst" 1 3 O R R OH preparation O rearrangement/ hydrolysis H E U F Eq (16) Standard Two-Step Conversion with Isolation of U

3 R3 2 R R2 2 R + 1 R O R1 cat. Ag R rearrangement 1 3 CO , DBU O R R OH 2 O RT H E W O- OC O F Eq (17) Yamada Lab's Single Operation Conversion151 Figure 47: Two-Step vs. Single-Step Preparation of -Enones via Functionalization of the Propargyl Alcohol

Cationic gold catalysts have received attention for their exceptional ability to activate carbon-carbon triple bonds.135-137 Zhang and co-workers exploited the affinity of gold salts towards acetylenic -bonds to efficiently convert propargylic esters to α,-unsaturated carbonyl derivatives at room temperature.152 In the initial examination of the reaction, Zhang et al. focused on optimization of the rearrangement of propargyl esters derived from aldehydes, because they were less likely to undergo elimination to form enynes than propargyl esters derived from ketones. A variety of Au(I) and Au(III) catalysts were screened. Au(PPh3)NTf2 provided the best results, and all further studies were conducted with this catalyst. Optimization allowed for catalyst loading to be lowered to 2 mol %, without sacrificing yield or selectivity; in almost all cases complete (E)-selectivity was achieved (Figure 48).152

103

OAc O Me Au(PPh3)NTf2 (2 mol%) Me 2-butanone, r.t., 92% yield 3 Me Me 3 81 E only 82

Figure 48: Preparation of -Monosubstituted (E)-,-Unsaturated Ketones

Simple extension of these optimized reaction conditions to substrates derived from ketones was not practical, with elimination to form enynes and other side reactions being substantial. Diligent optimization was required before the method was extended to the preparation of -disubstituted -unsaturated ketones. Catalyst loading had to be increased to 5 mol % and solvent conditions had to be carefully controlled (Figure 49).153 The limitation in Zhang’s methodology is that it does not work for terminal alkynes, which readily undergo Markovinkov hydration under the reaction conditions.

Au(PPh3)NTf2 OAc (5 mol%, 0.05 M in acetone) O n-Bu acetonitrile/H2O (80/1) n-Bu 0 oC, 30 min; then r.t. 16 h 83 84 97% yield Figure 49: Preparation of -Disubstituted -Unsaturated Ketones

The reaction is believed to proceed through a Au-catalyzed [3,3]-rearrangement140-146 of the propargylic ester U, followed by Au activation of the intermediate allene V giving rise to intermediate Z. Intermediate Z can then under-go hydrolysis/protiodeauration to give MeyerSchuster products F. With a suitable electrophile present, intermediate Z could be trapped to yield a wide range of products including alkenyl enol esters/carbonates,154 α- ylidene--diketones,155 cyclopentenones,156 indoline-fused cyclobutanes,157 α-ylidene--keto and –malonate esters,158 indenes,159 aromatic ketones,160 and α-haloenones161,162 (Figure 50).

104

4 R4 R R4 O O O O R4 1 O O Au catalyst R1 OO R R1 2 R2 2 R3 R3 R R R1 • 3 - U R3 X R Y [Au] [Au] V [Au] R2

4 X+ = H+ O R 2 various R O hydrolysis/protiodeauration -[Au] X+ = E+ R3 functional 3 products R1 R O + X R1 R F 4 2 Z Meyer-Schuster Product R OH 152 Figure 50: Proposed Mechanism for Au(PPh3)NTf2-Catalyzed Rearrangement

At the same time as Zhang’s work, another gold-based catalyst system was being developed in the lab of Nolan. During their investigation of a Au(I)/Ag(I) catalyst system designed to achieve a tandem [3,3]-sigmatropic rearrangement/intramolecular hydroarylation of phenylpropargyl acetates yielding indenes,159 Nolan and co-workers noticed MeyerSchuster by-products when water was present in the reaction. Wishing to capitalize on this observation, the Nolan and Maseras labs modified the original Au(I)/Ag(I) catalyst system to convert a variety of propargyl acetates to their α,-unsaturated carbonyl counterparts.163

The optimal conditions were determined to be 2 mol % of both (ItBu)AuCl and AgSbF6, in a o 10:1 THF/H2O solvent system at 60 C for 8 hr (Table 3). Nolan et al. found that these long reaction times could be avoided by the use of a microwave. Microwave irradiation at 80 oC allowed for the reaction to proceed in 12 minutes, without any negative effect on yield or selectivity (entry 2). A variety of substituents at the propargylic position were tolerated, including electron-rich (entry 3) and electron-deficient (entry 1) aryl groups, as well as simple alkyl groups (entry 7). Alkyl and aryl substituents on the alkyne were also tolerated. Terminal alkynes (entry 4), which have proved to be poor substrates for other methods, could also be used. However, the use of sterically bulky substituents, such as trimethylsilyl (TMS) and tert-butyl (entries 5 and 6), resulted in no reaction. In most cases, excellent (E)-selectivity was observed (e.g. entry 7).163

105

[a] Table 3: Selected Examples of [(ItBu)AuCl]/AgSbF6 Catalyzed Rearrangement

OAc 1 [ltBu)AuCl]/AgSbF6 (2 mol%) R O R1 N N 2 o 3 R THF/H2O, 60 C, 8 h R2 R 3 ltBu U7-14 R F7-14 Entry Propargyl Acetate U Enone F Yield [%]

OAc O Bu Bu 1 F U7 F F7 91 OAc O Bu [b] Bu 2 F U8 F F8 90 OAc O Bu Bu 3 MeO U9 MeO F9 89 OAc O H 4 H U10 F10 90 OAc O Si Si U11 F11 5 nr OAc O U12 F12 6 nr OAc O 82 U13 F13 7 (E:Z, 12:1)

OAc O

8 Bu U14 Bu F14 94

[a] Reaction conditions: alkyne U (1 mmol), [(ItBu)AuCl]/AgSbF6 (2 mol%), THF (10 mL), o H2O (1 mL). [b] performed in a microwave at 80 C, reaction time 12 min.

While Nolan and co-workers’ method proved to be fairly general, perhaps the most interesting aspect of their study was their proposed mechanism. In an attempt to understand

106 better the reaction mechanism, Nolan and Maseras investigated the reaction both 163 experimentally and computationally. Based on their findings, they suggested a SNβ’ type mechanism, instead of the more commonly accepted 1,3 shift of the propargyl acetate.140-146 The gold-catalyst was believed to activate water, instead of the -system of the alkyne, to generate [(NHC)AuOH]. The AuOH complex acted as the the active catalyst (Figure 51).163

N N O N N NN O Au O H Au Au • H O O 86 O O 2 OH

85 OH 87 88 86 163 Figure 51: SNβ’ Type Addition of Au Catalyst

Nolan and co-workers later extended this method to the preparation of α,-unsaturated carbonyls from propargyl alcohols, eliminating the functionalization step, using a similar catalyst system.164 High conversions were achieved for a variety of substrates; however, rearrangement of primary alcohols and terminal alkynes proved unsuccessful.164 The Chung lab also found success in converting propargyl alcohols into α,-unsaturated ketones using a Au(I) catalyst system. Chung et al. screened a variety of Lewis acids including

FeCl3, InCl3, GaCl3, PtCl2, Ag(OTf) and AuCl3 before selecting [Au(PPh3)](OTf). The only catalyst that gave complete conversion was [Au(PPh3)](OTf), generated from AuCl(PPh3) and Ag(OTf).165 Yields were generally moderate, and side reactions such as the Rupe rearrangement105 and enyne formation were problematic. Chung suggested a new mechanism for his Au(I) catalyst system featuring a cumulene intermediate, although it was purely speculative (Figure 52).

107

Au(1) R1 • R3 • AA R2 Figure 52: Chung’s Proposed Cumulene Intermediate165

Although cationic gold is the most commonly used ―soft‖ Lewis acid catalyst to achieve the MeyerSchuster rearrangement, many other ―soft‖ Lewis acids are also capable of catalyzing the rearrangement of propargyl acetates. During their investigation into the regioselective hydration of internal alkynes using a Hg(OTf)2 catalyst, Nishizawa and co- workers attempted to influence the reaction site by using neighboring group participation.166 They hypothesized that by placing an acetate group in the propargylic position, directed hydration could be achieved through a coordination between the mercury catalyst and the acetate functionality. To test this hypothesis, they examined the reaction of propargyl acetate

89, in water with a catalytic amount of Hg(OTf)2. Instead of obtaining the expected hydration products 91 and 92, the major product was vinyl ketone 90. Trace amounts of the dialkylated mercuric product 93 were also present (Figure 53).166

O OAc cat. Hg(OTf)2

H2O OAc 89 90 91 O O O

93 Hg OAc 92

O Figure 53: Attempted Regioselective Hydration166

108

Based on the initial findings, the Nishizawa lab chose to optimize the reaction for the formation of α,-enones. A screening process revealed the optimal conditions to be 5 mol %

Hg(OTf)2 with 1.5 equivalents of water in acetonitrile, at room temperature for 4 hours. Despite optimization, yields were generally moderate and side reactions could not be avoided166 (Figure 54).

O OAc Hg(OTf)2 5 mol % C H C7H15 1.5 equiv H2O, CH3CN, 0.1 h 7 15 C7H15 94 95 (67%) 96 (13%) 166 Figure 54: Optimized Hg(OTf)2 Rearrangement

In 2007, Nishizawa and co-workers further extended the method to include the formation of α,-unsaturated esters from secondary-ethoxyalkynyl acetates.167 The switch from aliphatic alkynes to the more electron rich ethoxy alkyne allowed for the reaction to proceed with only 1 mol % catalyst loading, compared with the 5 mol % required for aliphatic alkynes. Yields were generally high, and excellent (E)-selectivity was achieved for substrates containing alkyl substituents in the propargyl postion (Eq 18, Figure 55). However, a mixture of (E/Z)- isomers were obtained when aryl substituents were introduced at the propargyl position (Eq 19, Figure 55).167 While oxygen activated alkynes, which result in α,-unsaturated esters after rearrangement, are the most common, other heteroatoms168 have been utilized. α,- unsaturated thioesters have been synthesized by the lab of Kataoka and Yoshimatsu.169 They were able to convert -sulfur substituted propargyl alcohols to the MeyerSchuster products using polyphosphoric acid trimethylsilyl ester, albeit in low yield with significant elimination to form enynes.

109

OAc O Hg(OTf)2 1 mol % Ph OEt Eq (18) Ph 1 equiv. H2O, CH2Cl2, 2 h 97 OEt 98 (89%) E/Z 100:0

OAc O Hg(OTf) 1 mol % 2 Eq (19) Ph Ph OEt 1 equiv. H2O, CH2Cl2, 40 min OEt 99 100 (77%) E/Z 50:50

167 Figure 55: Hg(OTf)2-Catalyzed Hydration of Ethoxypropargyl Acetates

Very recently, the first example of a MeyerSchuster rearrangement to form an α,- unsaturated amide was realized by the Akai lab, using their aforementioned Mo/Au/Ag catalyst system (Figure 56).134 To the best of our knowledge, these two reports are the only examples of non-oxygen heteroatom activation of alkynes towards the MeyerSchuster rearrangement.

OH MoO2(acac)2 AuCl(PPh3)-AgTOf O n-C H (1 mol% each) 6 13 Ts Ts N toluene, rt, 2 h n-C6H13 N Bn Bn 101 102 (80%) E only

Figure 56: α,-Unsaturated Amide Formation134

In addition to strong acid, oxo-philic transition metals, and Lewis acid catalysis, the MeyerSchuster reaction can also be catalyzed by ruthenium complexes.170-174 The ruthenium catalysts are limited to the conversion of propargyl alcohols with a terminal acetylene. The requirement for terminal alkynes can be explained by the proposed mechanism. The reaction is a two-step process. In the first step, a carboxylic acid is added to the alkyne, presumably through a Ru-allenylidene intermediate DD, which can only be formed from a terminal alkyne.

110

The resulting enol esters FF can be isolated or cleaved with strong acid to give MeyerSchuster products GG (Figure 57).

H O R1 GG 2 R R1 R2 H+ OH CC H2O BB [L Ru] Ph O R2 n 1 1 HO R R 2 O R FF OH CC [LnRu]

H+ H 1 LnRu C C R R2 LnRu H HO DD Ph O R2 HO R1 O O EE HO Ph 103 Figure 57: Proposed Mechanism for the Ru-Catalyzed Isomerization of Propargyl Alcohols into α,-Unsaturated Aldehydes170

With the variety of methods now available for the mild execution of the MeyerSchuster rearrangement, it has begun to be applied to the total synthesis of complex molecules.175-178 A representative example can be found in the Weinreb lab’s efforts towards the total synthesis of the marine alkaloid chartelline A 104.178 They needed to olefinate a -lactam chemoselectively

111 in the presence of a -lactam. They found that they could chemoselectively add lithio tert- butylacetylide to the -lactam, which set the stage for the rearrangement. Standard MeyerSchuster conditions (i.e. acid) gave the α,-unsaturated ketone 106; however, the acidic conditions resulted in removal of the Boc protecting group. Gratifyingly, use of the milder tetrabutyl-ammonium perrhenate/p-toluenesulfonic acid catalyst system developed by the Narasaka130 lab allowed for the rearrangement to take place in quantitative yield without loss of the Boc group (Figure 58).178 Undoubtedly, the application of the MeyerSchuster reaction to other total synthesis will be soon to follow.

O Cl Br N N Br Br N Br N H

chartelline A 104

O O O

TFA, 0 oC N PMP N PMP n-Bu4NReO4 N PMP CH2Cl2 p-TsOH OH N 91% N CH2Cl2, rt N O 100% O H Boc Boc 106 105 107 Figure 58: Application of the MeyerSchuster Reaction in Total Synthesis178

In conclusion, the MeyerSchuster reaction has evolved, from a simple acid-catalyzed rearrangement of tertiary propargyl alcohols to α,-enals, into an elegant reaction whose reactivity can be precisely controlled by activation of the alcohol and alkynyl moieties independently or in tandem. Once limited only to the formation of α,-unsaturated ketones and aldehydes, recent advances have made access to α,-unsaturated esters,167,179 amides,134 thioesters,169 and acylsilanes130 a reality. A vast array of metals have been used to achieve

112 this transformation, including Au, Ag, Cu, Ti, Re, V, Mo, W, and Ru. The use of the MeyerSchuster reaction has not been confined to method development; it has also found use in a variety of total synthesis.175-178 The variety of methods now available to execute the MeyerSchuster rearrangement will undoubtedly lead to an increase in the use of this powerful reaction. In the next chapter, our contributions to MeyerSchuster methodology will be discussed. Key topics will include development of a Au(III)-catalyzed rearrangement of propargyl ethynyl ethers into α,-unsaturated esters and its use in the olefination of hindered ketones,179 efforts to control the (E/Z)-selectivity of the MeyerSchuster rearrangement,180 and the search for more affordable catalysts.181 It is important to note that our work pre-dates (and may have played a role in stimulating) much of the chemistry discussed above in Chapter 5.

113

CHAPTER 6

LEWIS ACID-CATALYZED MEYER-SCHUSTER REACTIONS: METHODOLOGY FOR THE OLEFINATION OF ALDEHYDES AND KETONES

Our interest in the MeyerSchuster reaction stemmed from the desire to develop an efficient, atom-economical means to olefinate hindered ketones. As discussed in the previous chapter, classic olefination techniques such as the Wittig olefination, the HornerWadsworthEmmons (HWE) olefination, and the aldol condensation are sensitive to steric congestion around ketones. The phosphorus-based reagents used in the HornerWadsworthEmmons and HornerWittig olefinations are particularly sensitive to steric congestion and often fail to work on hindered substrates. An alternative approach would be to use a two-step olefination process, consisting of acetylide addition followed by rearrangement to the α,-unsaturated carbonyl (Figure 59). Acetylide addition is relatively insensitive to steric congestion and is expected to proceed smoothly. Therefore, the limiting factor in the two-step olefination is the rearrangement.

acetylide 2 O R2 O addition R MeyerSchuster 1 R3 1 R3 Y R R3 R1 R R2 OH rearrangement H F G E Figure 59: Two-Step Olefination Strategy

An obvious choice for this rearrangement is the MeyerSchuster reaction. The original MeyerSchuster reaction was conducted in acidic media at elevated temperatures. Metal oxide

114 and transition metal catalysts have also been employed to carry out the MeyerSchuster reaction, but limited scope, harsh reaction conditions, and a prevalence of side reactions have detracted from the usefulness of these methods. For a more detailed explanation of our proposed olefination strategy and a complete history of the MeyerSchuster reaction, refer to Chapter 5. Note that our initial studies and publication pre-date much of the work described in Chapter 5. In order for the two-step olefination strategy to succeed, we needed to develop mild conditions for promoting the MeyerSchuster rearrangement. Our initial approach towards the MeyerSchuster reaction derived its origins from a combination of (1) early oxo-vanadium chemistry, which showed the feasibility of using oxo- philic reagents to effect the MeyerSchuster rearrangement (refer to chapter 5), and (2) the observation that Cr(VI) salts can oxidize tertiary allylic alcohols through a 1,3 rearrangement182 (Eq 20, Figure 60). We hypothesized that these same Cr(VI) salts would be able to undergo a similar rearrangement with propargyl alcohols, to give chromate ester-allene II. Subsequent hydrolysis would yield the MeyerSchuster product F (Eq 21, Figure 60).

O OH O Cr O O O CrO O 3 H O Cr O Cr O O O OH 108 109 110 111 112 Eq (20): Cr(VI) Oxidation of Tertiary Allylic Alcohols

O R1 O 2 R 1 HO CrO Cr O + R O 1 3 3 H R R O • O O 2 R2 R3 R R1 R3 R3 Cr R2 E O O F HH II Eq (21): Our Proposed Cr(VI) Rearrangement of Propargyl Alcohols Figure 60: Cr(VI) Rearrangements

115

Our ultimate goal was to develop an efficient means to olefinate hindered ketones, so we decided to use the propargyl alcohol 113, derived from 1-hexyne addition to (-menthone 58, as our model substrate (Eq 22, Figure 61). The first chromium reagent screened was pyridinium chlorochromate (PCC) (Eq 23, Figure 61). The starting propargyl alcohol 113 was completely consumed within 24 hours, but there was no evidence of the desired product. Other catalyst systems that were capable of undergoing 1,3-rearrangements were also tested, including MnO2 and 1,1’-thiocarbonyl diimidazole (Eqs 23 and 24, Figure 61); even with elevated temperatures and extended reaction times, no reaction was observed.

n-Bu n-BuLi, THF "catalyst" O Eq (22) OH O 78 oC to rt n-Bu 96 % n-Bu 58 113 114

4.0 equiv PCC Eq (23) 113 Complex Mixture CH2Cl2, reflux

5.0 equiv MnO2 Eq (24) 113 No Reaction benzene, reflux S C N N N N Eq (25) 113 No Reaction DCE, reflux Figure 61: Initial Oxo-philic Approaches to the Meyer-Schuster Rearrangement

In an attempt to limit the potential side reactions and to make 1H NMR interpretation more facile, propargyl alcohol 113 was replaced with 117 in further studies. Propargyl alcohol 117 was readily prepared from phenylacetylene addition to diphenyl ketone 115 (Eq 26, Figure 62). Disappointingly, treatment of 117 with PCC again resulted in a complex mixture of products (Eq 27, Figure 62).

116

O n-BuLi, THF HO Eq (26) 78 oC to rt quantitative 115 116 117

4.0 equiv PCC Eq (27) 117 Complex Mixture CH2Cl2, reflux Figure 62: Switch to Triphenyl Propargyl Alcohol 117

A concurrent report in the literature led us to consider an alternative approach. Campagne and co-workers observed MeyerSchuster by-products when attempting a gold(III)- catalyzed nucleophilic substitution of propargyl alcohol 118 with ethanol (Eq 28, Figure 63).183 Based on these findings, similar conditions were applied to triphenyl propargyl alcohol 117.

Propargyl alcohol 117 was treated with 10 mol % AuCl3 and 2.5 equivalents of ethanol in dichloromethane at room temperature. After 24 hrs, a 2:3 mixture of ethyl ether 121 and the desired α,-unsaturated ketone 122 was obtained (Eq 29, Figure 63).

OH 5.0 equiv. Ethanol OEt O 1 mol% NaAuCl4, 2H2O Eq (28)183 Ph Ph Ph C5H11 DCM, rt, 24 h C5H11 C5H11 118 119 60% 120 40%

OH OEt Ph O Ph 10 mol% AuCl3, DCM Ph Eq (29) Ph 2.5 equiv. Ethanol Ph Ph Ph Ph rt, 24 h Ph 117 121 40% 122 60% Figure 63: Initial Gold(III) Experiment

117

Based on this initial hit, a series of experiments was conducted to determine the optimal conditions for this transformation. A quick screening of common organic solvents with 5 mol % of gold(III) chloride was performed (Table 4).

Table 4: Solvent Screening With AuCl3 Catalyst OH Ph O Ph AuCl3, H2O Ph Solvent Ph Ph Ph 117 122 Entry Substrate Mol % Solvent Equiv. Temperature Time % 0 a AuCl3 H2O C h Conversion

1 117 5 CH2Cl2 6.0 25 24 0

2 117 5 H2O N.A. 25 24 0

3 117 5 H2O N.A. Reflux 24 0 4 117 5 DMF 4.0 25 24 0 5 117 5 DMF 4.0 100 24 0

6 117 8 Et2O 4.0 25 24 < 5% 7 117 15 Ethanol 0 25 24 100b 8 117 3 THF 4.0 25 24 0 9 117 3 1,4-dioxane 4.0 25 24 0 10 117 3 1,4-dioxane 4.0 60 24 0

11 117 5 CH3CN 0 25 24 < 5%

12 117 5 CH3CN 4.0 25 24 10 %

13 117 5 CH3CN 4.0 60 24 100% a % conversion based on 1H NMR. b gave exclusively the ethyl ether 121

118

Surprisingly, the only two solvents that provided any conversion to the desired α,- unsaturated ketone 122 were diethyl ether (entry 6) and acetonitrile (entry 11). The lack of reactivity in dichloromethane with 6 equivalents of water and 5 mol% of AuCl3 (entry 1) was most likely due to the lower catalyst loading; however, the switch from ethanol to water cannot be ruled out as the problem. Not wishing to increase the catalyst loading, we chose to optimize the reaction with acetonitrile as the solvent. The addition of water as an additive increased the conversion to 10%, and complete conversion could be achieved by heating the mixture to 60 oC for 24 hours (entries 12 and 13). Although complete conversion of propargyl alcohol 117 could be achieved with 5 mol % o of AuCl3 in acetonitrile at 60 C in 24 h, the reaction was not clean. There was a significant amount of an unidentified by-product present. The number of equivalents of water present in the reaction mixture was found to influence by-product formation (Table 5).

Table 5: Screening of Water Equivalents OH Ph O Ph 5 mol% AuCl3 Ph By-Product MeCN, 60 oC Ph Ph Ph 24 h 117 122 123 a Entry Substrate Equivalents of H2O Ratio of 122 to 123 1 117 1.0 1 : 0.66 2 117 2.0 1 : 0.62 3 117 3.0 1 : 0.29 4 117 4.0 1 : 0.40 5 117 5.0 1 : 0.46 a Ratios based on integration of 1H NMR spectra for comparative purposes. Numbers do not necessarily reflect the mole fraction of the unknown product.

Three equivalents of water were found to be optimal for suppression of by-product formation. Unfortunately, the by-product could not be suppressed completely. It was thought

119 that perhaps the long reaction times (24 h) were contributing to by-product formation by allowing AuCl3 to react with the solvent. The reactions were limited to 2 hours and catalyst loading was increased to achieve complete conversion (Table 6). A 10 mol % catalyst loading resulted in complete conversion, but there was still significant by-product formation (entry 3). Decreasing the temperature resulted in incomplete conversion and appeared to have little effect on by-product formation (entry 4). A catalyst loading of 20 mol % was found to allow the reaction to go to completion with little by-product formation (entry 5). Based on these results, reaction time seemed to be less important than catalyst loading in prevention of by-product formation.

Table 6: Catalyst Loading X mol % AuCl , OH 3 Ph O Ph 3.0 equiv. H2O Ph By-Product MeCN, 2 h Ph Ph Ph 117 122 123 o a b Entry Substrate Mol % AuCl3 Temperature C % Conversion Amount of 123 1 117 1 60 < 10 N.D. 2 117 5 60 50 High 3 117 10 60 100 High 4 117 10 25 50 High 5 117 20 60 100 Low 6 117 50 60 100 Low a % Conversion determined by 1H NMR b Amount of 123 present determined qualitatively by 1H NMR

We next examined the scope of the reaction using 20 mol % AuCl3, 3.0 equivalents of o water in CH3CN at 60 C as our standard conditions. The triphenyl tertiary propargyl alcohol 117 rearranged cleanly to afford α,-unsaturated ketone 122 in 90 % yield (Eq 30, Figure 64). Switching to the secondary propargyl alcohol 124 proved to be detrimental. The expected α,- unsaturated ketone 125 was obtained in only a 16 % yield. The other 84 % comprised of a complex mixture of unidentified by-products (Eq 31, Figure 64). The tertiary propargyl alcohol

120

126 also proved to be a poor substrate, giving only the elimination product 127 in a 79 % yield (Eq 32, Figure 64). Even at room temperature, only the elimination product 127 was observed.

OH 20 mol % AuCl3 Ph O Ph 3.0 equiv. H2O Eq (30) Ph Ph Ph o Ph MeCN, 60 C 117 18 hr 122 90%

OH 20 mol % AuCl3 O 3.0 equiv. H2O Eq (31) Bu o Bu MeCN, 60 C 18 hr 124a 125b 16%

20 mol % AuCl OH 3 Ph 3.0 equiv. H2O Ph Eq (32) MeCN, 60 oC 126c 18 hr 127 79% a 124 was prepared from 1-hexyne addition to benzaldehyde in an 84% yield b only the (E)-isomer was observed based on 1H NMR c 126 was prepared from phenyl acetylene addition to 3-pentanone in an 98% yield Figure 64: Initial Substrate Screening with MeCN

These initial results suggested that the conditions were unsuitable for substrates other than tertiary propargyl alcohols, which are incapable of undergoing elimination. In addition, the unidentified by-product was still present in all cases. Previously, we avoided the use of CH2Cl2 as a solvent, due to the lack of reactivity exhibited when 5 mol % gold catalyst loading was employed. Now using 20 mol % of AuCl3 in our reactions, CH2Cl2 was re-examined (Figure

65). Gratifyingly, the use of 20 mol % of AuCl3, in CH2Cl2, allowed for the conversion of propargyl alcohol 117 into 122 in an 87 % yield. The use of methylenechloride also increased the conversion of 124 to 125 from 16 % (in CH3CN) to 44 %. Under the new conditions, formation of 128 from 126 was also possible, although elimination to 127 was still the major

121 product. Other advantages of the CH2Cl2 system were the reaction could be carried out at room temperature, and there was no sign of any by-product formation.

OH 20 mol % AuCl3 Ph O Ph 3.0 equiv. EtOH Eq (33) Ph Ph Ph Ph CH2Cl2, rt 18 hr 117 122 87%

OH 20 mol % AuCl3 O 3.0 equiv. EtOH Eq (34) Bu Bu CH2Cl2, rt, 18 hr 124 125a 44%

20 mol % AuCl3 OH O Ph 3.0 equiv. EtOH Ph Eq (35) Ph CH2Cl2, rt 126 18 hr 127 57% 128 31%

a only the (E)-isomer was observed based on 1H NMR

Figure 65: Initial Substrate Screening with CH2Cl2

Although the switch from acetonitrile to methylenechloride eliminated by-product formation and led to higher yields, the overall efficiency of the reactions was still quite low. The gold(III) salt is presumed to catalyze the reaction through an initial activation of the -system of the alkyne.135-137 Increasing the electron density of the -system may aid the transformation by increasing gold’s affinity towards the -system. To test this theory, the ethynyl ether versions of 117 and 124 were prepared from lithium ethoxyacetylide addition to the necessary ketone. These analogs were then subjected to the reaction conditions (Figure 66). The tertiary propargyl alcohol 129 rearranged cleanly to give the α,β-unsaturated ester 130 in a 99 % yield in less than 5 minutes (Eq 36, Figure 66). Rearrangement of secondary ethoxy propargyl alcohol 132 also proceeded smoothly; however, the increased yield and lower reaction time came at the sacrifice of selectivity (Eq 37, Figure 66).

122

20 mol % AuCl Ph O O Ph OH 3 OEt 5.0 equiv. EtOH Eq (36) OEt Ph n-BuLi, THF Ph Ph Ph CH Cl , rt o OEt 2 2 78 C to rt < 5 min 115 129 99% 130 99%

O OH 20 mol % AuCl3 O OEt 5.0 equiv. EtOH Eq (37) H OEt n-BuLi, THF OEt CH2Cl2, rt o < 5 min a 131 78 C to rt 132 92% 133 86%

a Obtained as a 1:1 mixture of the (E) and (Z)-isomers Figure 66: Use of Electron-Rich Ethoxyacetylene

The use of oxygen-activated alkynes expanded the scope of the reaction to a wider range of substitution patterns (Table 7). Preparation of both di- and tri-substituted olefins is supported (entries 3 and 4-7), and yields are generally excellent. Entries 1-3 highlight the evolution of the conditions. An attractive feature of these AuCl3-catalyzed rearrangements is that they can be performed open to air with wet solvents, without sacrificing yield. The use of oxygen-activated alkynes allowed for lowering of the catalyst loading. Table 8 recounts our efforts to determine the minimum catalyst loading needed to achieve the MeyerSchuster rearrangement of ethoxyalkynyl carbinol 136. Below 5 mol % (entries 4 and 5), complete conversion is not achieved. Based on qualitative thin-layer chromatography (TLC) monitoring of the experiments, the reactions appear to proceed rapidly and then stall at a certain point. Why the reactions stall is not yet understood. Thus, 5 mol % catalyst loading was the minimum that allowed for complete conversion. The 5 mol % catalyst loading could be extended to a variety of substrates including aliphatic, aromatic, hindered, and unhindered propargyl alcohols (entries 6-8).

123

Table 7: Initial Screening of Substrates Using Oxygen Activated Alkynes 2 2 OH 20 mol % AuCl3 R O R 5.0 equiv. EtOH 3 R1 R1 R E R3 CH2Cl2, rt F Entry R1 R2 R3 Substrate Time Product Yield (%)b 1a Ph H Bu 124 18 h 125 16 2 Ph H Bu 124 18 h 125 44 3 Ph H OEt 132 < 5 min 133 86 4 Ph Ph OEt 129 < 5 min 130 > 95 5 4-t-Bu- OEt 134 < 5 min 135 82 cyclohexyl 6 adamantyl OEt 136 < 5 min 137 > 95 7 t-Bu Me OEt 138 < 5 min 139 86 a o b CH3CN was used as the solvent and the reaction was heated to 60 C Isolated yield of pure product, unless otherwise indicated

Table 8: Catalyst Loading and Optimizationa

OH 2 R2 R O AuCl3, rt, 5 min R1 1 OEt 5 equiv EtOH, CH2Cl2 R JJ OEt KK

1 2 Entry R R Substrate AuCl3 Product Conversion (%) 1 adamantyl 136 20 mol % 137 > 95 2 adamantyl 136 10 mol % 137 > 95 3 adamantyl 136 5 mol % 137 > 95 4 adamantyl 136 1 mol % 137 ca. 50b 5 adamantyl 136 0.1 mol % 137 < 5b 6 Ph Ph 129 5 mol % 130 > 95 7 t-Bu Me 138 5 mol % 139 > 95 8 n-Bu n-Bu 140 5 mol % 141 > 95

a Typical procedure: Gold(III)chloride added to a solution of propargyl alcohol (1 equiv), EtOH b (5 equiv), and CH2Cl2 in an open flask at room temperature. See Chapter 7 for details. After 24 h.

124

With the rearrangement under control, attention was switched to streamlining the two- step addition/rearrangement process. It was found that the two-stage olefination could proceed without purification of the intermediate propargyl alcohol. The advantages of carrying out the rearrangement on the crude alcohol were three-fold. The time necessary to complete the overall olefination of the carbonyl was significantly reduced, the high costs associated with silica gel and solvents were reduced, and the risk of losing material in the intermediate purification process was eliminated. The new streamlined two-stage olefination process was applied to a diverse group of hindered ketones (Table 9). Benzophenone 115, adamantanone 142, and pinacolone 143 produced alkenes 130, 137, and 139 in excellent yields (entries 1-3). Dienonate 145 was obtained from verbenone 144 in nearly quantitative yield (entry 4). The ethoxyacetylide addition to camphor 146 and 3,3,5,5-tetramethylcyclohexanone 147 failed to go to completion resulting in slightly lower yields for alkenoates 148 and 149. However, the yields were still quite reasonable (entries 5 and 6). As illustrated in Table 9, we developed an atom-economical olefination strategy. The limitation in the method is the (E/Z)-selectivity (entries 3-6). The effects of the reaction temperature on the (E/Z)-selectivity of the rearrangement of ethoxyacetylene 138 can be seen in Table 10. The selectivity shifted from favoring the (Z)-isomer to favoring the (E)-isomer by lowering the reaction temperature to 78 oC (entries 4 and 5). The effect of the temperature was found to be independent of reaction time (entries 3 and 5). While temperature could be used to influence the formation of the major isomer, all attempts to obtain a single isomer by varying the temperature were unsuccessful. Exposure of the purified (E/Z)-mixture of α,- unsaturated ester 139 to the normal reaction conditions resulted in no observable change in the (E/Z)-ratio. This suggests that isomerization under the reaction conditions is not a contributing factor to the (E/Z)-selectivity. Ultimately, temperature control alone was insufficient to control selectivity.

125

Table 9: Olefination of Hindered Ketonesa

R2 1. BuLi, H OEt, THF R2 O

1 3 R O 2. AuCl3 (5 mol %) R1 R G EtOH (5 equiv), CH2Cl2 KK Entry Substrate Product Yield (%)

Ph Ph CO2Et 1 Ph O 115 Ph 130 91

O CO2Et

2 137 99 142

CO2Et O 143 139 b 3 99

4 96c O 144 CO Et 2 145

5 68% (84%)c,d O 146 CO2Et 147

6 O CO2Et 73 148 149 (85)d a See Chapter 7 for details. bCa. 4:3 ratio of olefin isomers. c Ca. 2:1 ratio of olefin isomers. d 10 mol % of AuCl3 employed. Value in parentheses is the calculated yield based on recovered ketone

126

Table 10: Temperature Effect on (E/Z)-Selectivitya

OH AuCl3 (5 mol %) EtOH (5 equiv), O CH Cl OEt 2 2 OEt 138 139 Entry Time Temperature oC E/Z Ratiob Yield (%) 1 5 min 25 3:4 93 2 5 min 0 2:3 99 3 24 h 25 2:3 99 4c 20 min 78 2:1 84 5 17 h 78 to 30 2:1 99 a Typical procedure: Gold(III) chloride added to a solution of propargyl alcohol 138 (1 equiv), EtOH b 1 c (5 equiv), and CH2Cl2 at the indicated temperature. Determined by H NMR 20 mol % of AuCl3 was used

To identify conditions that afford the enoate products stereoselectively, we examined the rearrangement of secondary propargyl alcohols (prepared by addition of lithium ethoxyacetylide to the corresponding aldehydes). The dampened reactivity of secondary propargyl alcohols, compared to that of the tertiary alcohols which ionize more easily, along with the greater steric distinction between the aliphatic substituent and the hydrogen were hoped to make stereocontrol more facile. A qualitative screening of gold catalysts, additives, and solvents was conducted, and the results can be seen in Figure 67.

OH catalyst (10 mol%) O additive (10 equiv) OEt OEt solvent, r.t 150 151 . catalyst: AuCl AgSbF6 > AuCl3, AuCl, Ph3P AuCl >> AgSbF6 additive: EtOH >> CF3CH2OH, AcOH, PhOH, morpholine, none solvent: THFCH2Cl2 > THF, CH2Cl2, EtOH, H2O Figure 67: Qualitative Screening for Optimal Conditions

127

Of the protic additives screened, which were believed to assist in the formal 1,3-hydroxy migration, ethanol was the most effective. A mixed solvent system of 1:1 THF and CH2Cl2 proved superior to the use of either solvent independently. Although all of the gold catalysts screened performed well, a mixed AuCl/AgSbF6 system provided the best results. Similar to previous results, a 5 mol % catalyst loading was found to be optimal. The new rearrangement conditions were then tested on a series of representative secondary alcohols (Table 11). Neopentyl alcohol 150 yielded the non-enolizable enoate 151 with almost complete selectivity (entry 1a). Alkyl-substituted alcohols 152, 154, and 156 gave enoates 153, 155, and 157 (entries 2a-4a) without any elimination to the enynes. Addition of camphorsulfonic acid (CSA) to the reaction mixture improved the selectivity of most reactions (entries 1b-6b).

Table 11: Meyer-Schuster Reaction of Ethoxyalkynyl Carbinolsa

OH 5 mol% AuCl/AgSbF6 O 10 equiv EtOH R R OEt OEt THFCH2Cl2 (1:1) LL rt, 3060 min MM Entry Substrate Product Yield (%, E/Z)

1aa OH O 91 (97:3) 1bb OEt 93 (E only) OEt 150 151 2aa OH O 80 (94:6) 2bb OEt 82 (99:1) OEt 152 153 3aa OH O 91 (63:37) b 3b 5 5 OEt 90 (86:14) OEt 154 155 4aa OH O 75 (57:43) 4bb OEt 78 (70:30) OEt 156 157

128

Table 11: Continued

OH 5 mol% AuCl/AgSbF6 O 10 equiv EtOH R R OEt THFCH2Cl2 (1:1) LL OEt MM rt, 3060 min Entry Substrate Product Yield (%, E/Z)

5aa OH O 72 (40:60) 5bb OEt 70 (40:60) OEt 158 159 6aa OH O 90 (47:53) 6bb OEt 92 (91:9) OEt 132 133 a Solutions of AgSbF6 (5 mol %) and AuCl (5 mol %) in 1:1 THFCH2Cl2 added sequentially to ethoxyalkynl carbinol (1.0 equiv) and EtOH (10 equiv) in 1:1 THFCH2Cl2. No camphorsulfonic acid (CSA) was included unless otherwise indicated. b 1.0 Equiv CSA.

The addition of camphorsulfonic acid (CSA) not only improved the selectivity of the reaction but also accelerated the reaction, while addition of 2,6-di-tert-butyl)-4-methylpyridine (DTBMP, an acid scavenger) inhibited the reaction. These results suggest that exchangeable protons play a significant role in the gold-catalyzed rearrangement. To test whether the gold catalyst has an active role in the reaction mechanism, or if the reaction is simply catalyzed by acid generated under the reaction conditions, a series of control experiments were conducted. Propargyl alcohol 138 was exposed to a variety of acidic conditions (Figure 68).

Use of 20 mol % of TsOH·H2O in place of the gold catalyst resulted in a 70:15 mole ratio of 138 and 139, along with unidentified product, after 18 hours (Eq 38). Aqueous acidic conditions were also tested. The use of 1 equivalent of AcOH in a 1:1 THFH2O mixture resulted in no reaction, while the use of 50 mol % HCl resulted in incomplete conversion after 1 hour. The use of strong acids like HCl is much more likely to promote undesired side reactions and can only be used with acid-stable compounds. Therefore, although acid may be generated under the reaction conditions, there seems to be an important role for the gold catalyst.

129

OH O "acid" OEt OEt 138 139

TsOH (20 mol %) EtOH (5 equiv), Eq (38) 138 138 + 139 CH2Cl2 70% 15%

Eq (39) 138 1 equiv. AcOH no reaction THF:CH2Cl2 1:1

50 mol% HCl Eq (40) 138 138 + 139 THF:CH2Cl2 1:1 33% 67% 1 h Figure 68: Gold Salts vs. Acid Catalysts

The exact role of the gold catalyst in the reaction mechanism is still unknown. One possible mechanistic sequence for the MeyerSchuster rearrangement of 150 to 151 can be seen in Figure 69. Coordination between the cationic gold catalyst and the electron-rich - system of the alkyne allows for -addition of ethanol to generate 1,1-diethoxyallene 161, after immediate expulsion of water. The formation of allene 161 is consistent with the lack of - hydroxy ester byproducts in any of the reactions, which is in sharp contrast to the acidic hydrolysis of ethoxyalkynyl carbinols.176,177 The gold catalyst may or may not promote subsequent reincorporation of water to produce 162. The stereoselectivity of the reaction is presumably set in this step. Control experiments have shown that there is no isomerization of the (Z)-enoates to the (E)-enoates under the reaction conditions. Therefore, we believe that the non-thermodynamic product distribution is the result of kinetic control. Collapse of 162 yields α,-unsaturated ester 151.

130

OH O + [Au ], EtOH OEt OEt 151 150 [Au+] EtOH

H O Au + OH + EtOH Au OEt H2O  H O • + OEt 2 OEt [Au ] OEt H OEt 162 160 161 Figure 69: Hypothesis on the MeyerSchuster Reaction Pathway

The mechanism depicted in Figure 69 suggests that there is incorporation of an external alcohol into the α,-unsaturated ester, based on competitive collapse of tetrahedral intermediate 162. Alcohol 150 was subjected to the standard reaction conditions with replacement of ethanol with n-propanol, following the assumption that ethanol and n-propanol would be ejected from the tetrahedral intermediate at a similar rate. α,-Unsaturated ethyl (151) and n-propyl (163) esters were obtained in an approximately 1:1 ratio (Figure 70). Exposure of enoate ester 151 to the same reaction conditions yielded no evidence of trans- esterification. Therefore, n-propanol incorporation must occur before product formation, which is consistent with our mechanistic hypothesis.

O OH 5 mol % AuCl/AgSbF6 O 10 equiv n-PrOH OEt OPr THFCH Cl (1:1) OEt 2 2 163 r.t. 30 min 151 150 50% 50%

Figure 70: Incorporation of External Alcohol Additive

131

Our research to this point has mainly focused on the use of cationic gold catalysts to achieve the MeyerSchuster reaction. The use of cationic gold and other precious metal catalysts offer many advantages in synthesis.184 The ability of these catalyst to engage in redox chemistry, through facile interconversion between oxidation states, has contributed to their use in a variety of applications. However, when selectively using these catalysts for their -Lewis acidity, their ability to engage in redox chemistry is unnecessary and often makes interpretation of the reaction mechanism difficult. Another limitation of the precious metal catalysts, which is often ignored or confined to a footnote, is their high cost. This makes low catalyst loading and high turnover essential for developing a cost effective method. Working under the hypothesis that the MeyerSchuster rearrangement of ethoxyalkynyl carbinols by late transition metal-catalysts stems from simple Lewis acid/base interactions, we became interested in identifying other Lewis acids that could provide similar or superior activity. Table 12 provides a summary of our catalyst screenings, which focused primarily (though not exclusively) on soft transition metal salts. In an open reaction vessel, ethoxyacetylene 154 was dissolved in methylenechloride and treated with reagent-grade ethanol (ca. 510 equiv) and 1 mol % of various Lewis acid catalysts (and one protic acid, camphorsulfonic acid, entry 1) at room temperature. Reactions were allowed to proceed for up to 24 hours or until TLC analysis showed consumption of starting material. The lone protic acid (CSA) is listed first; the rest of the table is arranged by the typical cost of the catalysts (per mole), from lowest to highest. From this general screening emerged three top choices: copper(II) triflate, indium(III) chloride, and scandium(III) triflate, and all further studies were conducted with these catalysts. Of these, indium(III) chloride was the least reactive; the copper and scandium triflates were comparable in reactivity. All three are air-stable powders and are convenient to handle and use.

It should be noted that many of the catalysts (most notably HfCl4 and PtCl4) that provided trace conversion with 1 mol % catalyst loading could achieve complete conversion with increased catalyst loading. Even with the higher catalyst loading, HfCl4 was competitive with the aforementioned catalysts in terms of cost.

132

Table 12: Screening of Alternative Catalysts OH 1 mol% catalyst CO2Et C5H11 C5H11 CH2Cl2/EtOH OEt 154 155 Entry Catalyst Time (h) Conversion E/Z Ratioa 1 CSA 24 0 _

2 NiCl2·xH2O 24 0 _ 3 CuI 24 0 _

4 Cu(OAc)2 24 Trace n.d.

5 CeCl3·7H2O 24 0 _

6 HfCl4 24 Trace n.d.

7 ZrCl4 24 Trace n.d. b 8 Cu(C5H4F3O2) 24 0 _

9 Hg(CF3CO2)2 24 Trace n.d.

10 NaReO4 24 0 _

11 Cu(OTf)2 1.5 100% 89:11

12 InCl3 24 100% 84:16

13 Ag(OTf)2 0.3 100% 43:57 c 14 Pd(OAc)2 24 <100% 63:37

15 Sc(OTf)3 1.2 100% 90:10

16 PtCl4 24 Trace n.d c 17 AuCl3 24 <100% >20:1 a As observed by 1H NMR. b Copper(II) trifluoroacetylacetonate c Ethoxyacetylene 197 could be detected by TLC analysis but not by 1H NMR after workup.

In an attempt to gain more insight on these Lewis acid-catalyzed MeyerSchuster reactions, the effects of various additives were explored. Two acidic and two basic additives were chosen: 1 mol % CSA, 1.0 equivalent acetic acid (AcOH), 1 mol % 2,6-di-tert-butyl-4- methylpyridine (DTBMP), and 1.0 equivalent magnesium oxide (MgO). The effect of the

133 additives on the reaction rate (qualitatively) and the stereoselectivity (quantitatively) of the reaction are summarized in Table 13.

Table 13: Effect of Additives

OH 1 mol% catalyst CO2Et C5H11 C5H11 CH2Cl2/EtOH OEt 154 155 Entry Catalyst Additive Amount Time (h) E/Z Ratioa

1 InCl3 None _ 24 84:16

2 InCl3 CSA 1 mol % 6 67:33

3 InCl3 DTBMP 1 mol % 24 75:25

4 InCl3 AcOH 1.0 equiv 24 91:9

5 InCl3 MgO 1.0 equiv 24 78:22

6 Cu(OTf)2 None _ 1.5 89:11

7 Cu(OTf)2 CSA 1 mol % 1.5 86:14

8 Cu(OTf)2 DTBMP 1 mol % 24 76:24

9 Cu(OTf)2 AcOH 1.0 equiv < 1 89:11 b 10 Cu(OTf)2 MgO 1.0 equiv 24 76:24

11 Sc(OTf)3 None _ 1.2 90:10

12 Sc(OTf)3 CSA 1 mol % < 1 92:8

13 Sc(OTf)3 DTBMP 1 mol % 4 91:9

14 Sc(OTf)3 AcOH 1.0 equiv < 1 92:8 c 15 Sc(OTf)3 MgO 1.0 equiv 24 n.d. a As observed by 1H NMR b Conversion (60%) c Conversion (30%)

134

Lewis acid and protic acids catalyze the MeyerSchuster reaction, so one would expect acidic additives to accelerate the reaction and basic additives to quench or retard the reaction. This hypothesis is supported by the results presented in Table 13. However, the fact that basic additives retard but do not quench the reaction suggests that protic acid, though helpful, is not required for catalytic activity. Therefore, one can choose between a short reaction time (e.g., entries 9 or 14) and reaction conditions that are presumably free of protic acid (e.g., entry 5).

Since the Sc(OTf)3 and Cu(OTf)2 were more reactive and gave better (E)-selectivity than the InCl3 catalyst in the absence of additives, they were used in the two-step olefination of aldehydes and ketones. As expected, ethoxyacetylene addition to both ketones and aldehydes proceeded smoothly and with high isolated yields (Table 14).

Table 14:Ethoxy Acetylene Addition

O OH H OEt R1 2 R1 R2 n-BuLi, THF R G78 oC to rt JJ OEt Entry Substrate R1 R2 Yield (%)a

1 164 n-C7H15 H > 99 2 165 Cyclohexyl H 76 3 166 t-Bu H 97 4 143 t-Bu Me 83 5 131 Ph H 92 a Isolated yield

The resulting secondary and tertiary propargyl alcohols were treated with either 1 mol % of Cu(OTf)2 or Sc(OTf)3 to complete the two-step olefination (Table 15). Use of EtOH as a co- solvent instead of an additive provided superior selectivity (entries 1-4). Aliphatic substitution at the propargyl position was universally tolerated. In the case of aliphatic di-substituted alkenes, (E)-selectivity increased as branching increased (entries 1-8). Stereoselection eroded when tri-

135 substituted alkenes were formed, or an aromatic group was introduced at the propargyl position (entries 9-12). The two catalyst systems gave similar results; however, scandium (III) triflate performed slightly better. Scandium(III) triflate also has the advantage of being recoverable and reusable after aqueous work upwithout loss of activity.185

Table 15: Scandium and Copper Rearrangements

OH R2 R1 1 mol% catalyst 2 1 CO2Et R CH2Cl2/EtOH (4:1) R OEt Entry Substrate Catalyst R1 R2 Product Yield (%)b E/Z Ratioc a 1 Cu(OTf)2 53 91:9 a 2 154 Sc(OTf)2 n-Heptyl H 155 63 E only

3 Cu(OTf)2 64 97:3

4 Sc(OTf)2 70 E only

5 156 Cu(OTf)2 Cyclohexyl H 157 71 E only

6 Sc(OTf)2 75 E only

7 150 Cu(OTf)2 tert-Butyl H 151 94 E only

8 Sc(OTf)2 97 E only

9 138 Cu(OTf)2 tert-Butyl Me 139 86 57:43

10 Sc(OTf)2 89 58:42

11 132 Cu(OTf)2 Phenyl H 133 90 76:24

12 Sc(OTf)2 93 77:23 a b c 1 EtOH (5.0 equiv) in CH2Cl2 Isolated yield As observed by H NMR

Up until this point, our substrates had been limited to those containing aliphatic and aryl substituents. To test the functional group compatibility of this method, N-Boc-serine methyl ester 167 was converted to into the tert-butyldimethylsilyl (TBS) ether 168. It was then included

136 in the reaction mixture during the conversion of 156 to 157 (Figure 71). Ester 157 was isolated in 75 % yield, and the TBS protected N-Boc-serine methyl ester was recovered in near quantitative yield. The high recovery of 168 indicates that our current MeyerSchuster conditions are compatible with typical alkyl esters, amine carbamates, and silyl ethers.

CO2Et OEt 156 157, 75% yield 1 mol% Sc(OTf)3, 1 h H O rt, CH2Cl2/EtOH (4:1) H O N N Boc OMe Boc OMe

OR OTBS R = H: 167 168, 99% recovery R = TBS: 168 Figure 71: Functional Group Compatability

In our earlier gold(III) chloride catalyst work, we developed a two-stage olefination method that avoided the need to purify the propargyl alcohol intermediate. The use of the crude propargyl alcohol allowed for higher yields over the two steps and greatly reduced the time needed to complete the overall olefination. The use of 1 mol % scandium(III) triflate in place of 5 mol % of the more expensive gold(III) chloride had no negative effect and yields were generally excellent (Table 16). A series of trisubstituted olefins were prepared (entries 1-7) in good to excellent yield, although control of stereochemistry was limited (entries 1-2, 7). Entries 1-4 illustrate the ability of this method to olefinate hindered ketones in excellent yields. Preparation of 169 is of particular interest since we were unable to prepare it through the use of the HornerWadsworthEmmons reaction (refer to Chapter 3).

137

Table 16: Two-Stage Olefination of Ketones and Aldehydes O 1.Li OEt R2 a CO Et R1 R2 2.MeyerSchuster R1 2 G KK Entry Substrate Product Yield (%)b E/Z Ratioc

1 ()-menthone 58 98 n.d.e CO2Et

169

2 verbenone 144 97 58:42 CO Et 2 145

3 benzophenone 115 99 _

CO2Et 130

4 adamantanone 142 CO2Et 96 _

137

CO2Et 60 _ 5 4-tert-butyl cyclohexanone 170 171 CO2Et 6 cycloheptanone 172 78 _ 173

CO2Et 7 acetophenone 174 93 39:61 175

8 pivaldehyde 166 CO2Et 80 E only 151

138

Table 16: Continued O 1.Li OEt R2 a CO Et R1 R2 2.MeyerSchuster R1 2 G KK Entry Substrate Product Yield (%)b E/Z Ratioc

CO2Et

9 ()-perillaldehyde 176 177 94 89:11

CO2Et

10 4-methoxybenzaldehyde 178 O 179 94 89:11

11 2-furaldehyde 180 O 97 36:61d CO2Et 181 F F CO2Et 12 pentafluorobenzaldehyde 80 E only 182 F F 183 F a b c 1 1 mol % Sc(OTf)3, CH2Cl2/EtOH (4:1) Isolated yield Determined by H NMR unless otherwise stated d E and Z isomers were isolated separately e Unable to determine the E/Z ratio by 1H NMR

The method also proved efficient for the preparation of disubstituted olefins (entries 8- 12). Excellent (E)-selectivity was achieved for aliphatic substituents (entry 8); however, selectivity diminished when aryl (entries 10-12) or vinyl (entry 9) substituents were introduced (exception is entry 12). Both electron-rich (entries 10 and 11) and electron-deficient (entry 12) aryl substituents at the propargyl position were tolerated. In our earlier studies using gold and silver salts to catalyze the MeyerSchuster reaction, we suggested a mechanism in which the alcoholic additive becomes incorporated into 50 % of the product via an intermediate 1,1-diethoxy-allene 161 (refer to Figure 69). This hypothesis was supported by the observation that the ethyl and propyl esters were obtained in a roughly 1:1 ratio when n-propanol was used as the additive. This experiment was repeated

139 with the use of the scandium(III) triflate catalyst. Instead of obtaining the expected 1:1 ratio of ethyl and propyl esters, we obtained a ratio of 25:75 (as estimated by 1H NMR, Eq 38 Figure 72). In other words, there was only a 25 % retention of the original ethoxy group. Based on our previous mechanism, the ethoxy group should be retained in at least 50 % of the product, even in the presence of excess n-propanol. The possibility of trans-esterification was eliminated by a control experiment in which pure ethyl ester 151 was subjected to the reaction conditions. There was no evidence of the propyl ester product, even after extended reaction times (Eq 39, Figure 72).

OH 1 mol% Sc(OTf)3 O O 5 equiv n-PrOH Eq (38) OEt OPr CH2Cl2 OEt 151 150 163 25 : 75 ratio!

O 1 mol% Sc(OTf)3 O 5 equiv n-PrOH Eq (39) OEt OPr CH Cl , 24 h 151 2 2 163 not observed Figure 72: Test for trans-Esterification

These observations led us to suggest a slightly modified mechanism for the scandium(III) triflate catalyst (Figure 73). Based on the consistent lack of -hydroxy ester by- products, the scandium(III) triflate-catalyzed MeyerSchuster reaction most likely also proceeds via intermediate 1,1-diethoxy-allene NN. Subsequent addition of a second equivalent of ethanol would give rise to tetrahedral intermediate OO, which can hydrolyze via intermediate PP to reach the α,-unsaturated ester MM. Invoking ortho-ester intermediate OO can account for up to a 67 % incorporation of the alcohol additive; however, we observed a 75 % incorporation. One possible explanation would be dynamic alcohol exchange reactions of ortho-ester OO.

140

OH 1 mol % Sc(OTf)3 R CO2Et CH Cl /EtOH R OEt 2 2 LL MM

EtOH EtOH H2O

OEt H O OH R • EtOH OEt 2 OEt OEt EtOH OEt R OEt R OEt NN OO PP Figure 73: Revised Mechanistic Hypothesis for Scandium(III)Salts

A series of experiments were conducted with varying amounts of n-PrOH. In every case, there was almost complete statistical incorporation of the n-propanol additive (Table 17). These results provide support for a hemi-labile intermediate OO, that can undergo partial equilibrium before proceeding irreversibly to the α,-unsaturated ester MM. The equilibrium can also account for the high (E)-selectivity observed in the case of disubstituted olefins with the scandium catalyst, by allowing for the thermodynamic establishment of the olefin geometry at the stage of the ortho-ester. We have developed an efficient, two-step, atom-economical method for the olefination of aldehydes and ketones. The first step was acetylide addition to a carbonyl substrate. Acetylide addition is relatively insensitive to steric congestion, which allowed for the use of hindered ketones as substrates. The second step was the conversion of the resulting propargyl alcohol to the desired α,-enone by the use of MeyerSchuster reaction. The MeyerSchuster reaction was found to proceed more readily and with lower catalyst loading when the propargyl alcohol contained an oxygen-activated alkyne.

141

Table 17: Incorporation of External Alcohol Additive

OH 1 mol% Sc(OTf)3 CO2R CH Cl OEt 2 2 R = Et, 151 150 R = nPr, 163 Entry PrOH (equiv) 150:PrOH 151:163a 1 1 50:50 55:45 2 2 33:67 42:58 3 3 25:75 38:62 4 5 17:83 25:75 5 10 9:91 22:78 6 100 1:99 16:84 a As observed by 1H NMR

Gold(III) chloride was the first catalyst to provide consistent results. The relatively expensive gold catalyst required a 5 mol % catalyst loading and showed little stereochemical control. The lack of stereochemical control was partially addressed by the use of a Au(I)/Ag(I) catalyst system. Inclusion of 1.0 equivalent of CSA allowed for the preparation of a variety of disubstituted olefins with high (E)-selectivity. A screening of various Lewis acids revealed that the less expensive Sc(OTf)3 could be substituted for the precious metal catalysts without sacrificing yield. Not only did the use of Sc(OTf)3 allow for the catalyst loading to be lowered to 1 mol %, it also proved significantly more adept in controlling the stereochemistry of the rearrangement. Future plans are to test scandium(III) triflate’s ability to catalyze the MeyerSchuster rearrangement of propargyl alcohols derived from aliphatic alkynes, which have proven to be poor substrates for the gold catalysts. We would also like to determine whether the electronic nature of the alkyne effects the (E/Z)-selectivity of the reaction, for both the gold and scandium-based catalysts. Finally, further mechanistic experiments will be conducted to identify the exact role of gold and scandium salts in the reaction mechanism.

142

In conclusion, we outlined and discussed a strategy for the olefination of aldehydes and ketones using the MeyerSchuster rearrangement of ethoxyalkynyl carbinols. The method appears to be limited only by the ability to access the requisite propargyl alcohols via ethoxyacetylide addition to carbonyls. This method is likely to find widespread application in organic synthesis, particularly for its unique ability to complete the olefination of hindered ketones in excellent yield.

143

CHAPTER 7

EXPERIMENTAL: MEYERSCHUSTER

GENERAL EXPERIMENTAL PROCEDURES:

1 13 H-NMR and C-NMR spectra were recorded on 300 MHz spectrometer using CDCl3 as the deuterated solvent. The chemical shifts () are reported in parts per million (ppm) relative to 1 13 the residual CHCl3 peak (7.26 ppm for H NMR, 77.0 ppm for C NMR). The coupling constants (J) were reported in Hertz (Hz). IR spectra were recorded on an FTIR spectrometer on NaCl discs. Mass spectra were recorded using chemical ionization (CI) or electron ionization (EI) techniques. Yields refer to isolated material judged to be ≥95 % pure by 1H NMR spectroscopy following silica gel chromatography. All chemicals were used as received unless otherwise stated. Tetrahydrofuran (THF) was purified by passing through a column of activated alumina. The n-BuLi solutions were titrated with menthol dissolved in tetrahydrofuran using 1,10-phenanthroline as the indicator. The purifications were perfomed by flash chromatography using silica gel F-254 (230-499 mesh particle size).

144

113 (2S, 5R)-1-Hex-1-ynyl-2-isopropyl-5-methyl-cyclohexanol [113] To a THF solution (5 mL) of 1-hexyne (0.44 mL, 3.94 mmol) was added n-BuLi (1.29 mL, 2.96 mmol, 2.29 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 h and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and ()-menthone (0.34 mL, 1.97 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 h and held at room temperature for an additional 3 h. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1 – 10/1) to give (2S, 5R-1-hex-1-ynyl-2-isopropyl-5-methyl- cyclohexanol (113) in 96 % yield (0.45 g) as a clear colorless oil. 1 H NMR (300 MHz, CDCl3):  0.83-0.96 (m, 12H), 1.23-1.57 (m, 10H), 1.65-1.78 (m, 2H), 1.92 (dt, J = 13.6, 3.7 Hz, 1H), 2.20 (t, J = 7.2 Hz, 2H), 2.35-2.45 (m, 1H); 13C NMR (75 MHz,

CDCl3):  13.5, 18.3, 18.6, 20.5, 21.8, 21.9, 23.9, 27.3, 28.2, 30.9, 34.9, 50.5, 50.9, 71.8, 83.7, 85.0 For full characterization refer to Spino, C.; Beaulieu, C. J. Am. Chem. Soc. 1998, 120(45), 1183211833.

145

146

147

117 1,1,3-Triphenyl-2-propyne-1-ol [117] To a THF solution (6 mL) of phenylacetylene (0.85 mL, 7.69 mmol) was added n-BuLi (3.3 mL, 6.59 mmol, 2.0 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 hr and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and benzophenone (1.0 g, 5.52 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 h and held at room temperature for an additional 3 hr. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1 – 10/1) to give 1,1,3-triphenyl-2-propyne-1-ol (117) in 100 % yield (1.57 g) as a white crystalline solid. 1 H NMR (300 MHz, CDCl3):  2.85 (s, 1H), 7.28-7.42 (m, 9H), 7.48-7.53 (m, 2H), 7.64-7.73 (m, 3H); For full characterization refer to Sanz, R.; Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J. Org. Chem. 2006, 6, 13831386.

148

149

118

1-Phenyl-hept-2-yn-1-ol [118] To a THF solution (6 mL) of 1-hexyne (0.76 mL, 6.59 mmol) was added n-BuLi (2.47 mL, 5.65 mmol, 2.29 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 h and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and benzaldehyde (0.48 mL, 4.71 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 hr and held at room temperature for an additional 3 hr. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1 – 10/1) to give 1-phenyl-hept-2-yn-1-ol (118) in 84 % yield (0.75 g) as a clear yellow oil. 1 H NMR (300 MHz, CDCl3):  0.92 (t, J = 7.2 Hz, 3H), 1.32-1.61 (m, 4H), 2.08 (dd, J = 6.1, 3.1 Hz, 1H), 2.28 (td, J = 6.9, 1.9 Hz, 2H), 5.46 (d, J = 6.0 Hz, 1H), 7.29-7.46 (m, 3H), 7.55 (d, J = 7.2 Hz, 2H); For full characterization refer to Fuerstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118(49), 1234912357.

150

151

126

3-Ethyl-1-phenyl-1-pentyn-3-ol [126] To a THF solution (6 mL) of phenylacetylene (1.55 mL, 14.1 mmol) was added n-BuLi (4.6 mL, 10.6 mmol, 2.29 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 hr and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and 3-pentanone (0.75 mL, 7.1 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 hr and held at room temperature for an additional 3 hr. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1 – 10/1) to give 3-ethyl-1-phenyl-1-pentyn-3-ol (126) in 100 % yield (1.33 g). 1 light yellow oil; H NMR (300 MHz, CDCl3) 1.11 (t, J = 7.4 Hz, 6H), 1.77 (q d, J = 7.4, 4.5 Hz, 4H), 1.94 (br s, 1H), 7.28-7.33 (m, 3H), 7.40-7.44 (m, 2H). For full characterization refer to Galli, C. et al. J. Org. Chem. 1994, 59, 67866795.

152

153

Typical procedure for solvent screening with AuCl3, Table 4

To a MeCN solution (1 mL) of 1,1,3-triphenyl-2-propyne-1-ol 117 (23.3 mg, 0.82 mmol) in a 1 dram vial under Ar was added AuCl3 (1.2 mg, 0.004 mmol) at room temperature. After 24 hr, the reaction mixture was filtered through a plug of SiO2 with the aid of an ethyl acetate/hexane mixture (1/7). The filtrate was concentrated and resulting residue was subjected to 1H NMR. Conversion to 122 was 5 %. Typical procedure for screening of water equivalence, Table 5 To a MeCN solution (1 mL) of 1,1,3-triphenyl-2-propyne-1-ol 117 (23.3 mg, 0.82 mmol) in a 1 dram vial under Ar was added water (44 L, 2.46 mmol) followed by AuCl3 (1.2 mg, 0.004 mmol). Reaction mixture was heated to 60 oC in an oil bath for 24 hr, then allowed to cool to room temperature. Reaction mixture was concentrated and the resulting residue was subjected to 1H NMR. Qualitative ratio of 122 to the unidentified by-product was determined.

Typical procedure for AuCl3 catalyst loading in CH3CN, Table 6 To a MeCN solution (1 mL) of of 1,1,3-triphenyl-2-propyne-1-ol 117 (23.3 mg, 0.82 mmol) in a

1 dram vial under Ar was added water (44 L, 2.46 mmol) followed by AuCl3 (2.4 mg, 0.008 mmol). Reaction mixture was heated to 60 oC in an oil bath for 2 hr, then allowed to cool to room temperature. Reaction mixture was concentrated and the resulting residue was subjected to 1H NMR. Qualitative ratio of 122 to the unidentified by-product was determined. Typical procedure for preparation of α,β-unsaturated ketones 122 and 125 and enyne 127 in MeCN, Figure 63 To a MeCN solution (8 mL) of 1,1,3-triphenyl-2-propyne-1-ol 117 (102 mg, 0.36 mmol) in a 2- neck, 25 mL round bottom flask was added water (19 L, 1.08 mmol) followed by AuCl3 (22 mg, 0.073 mmol). Reaction was heated to 60 oC for 18 hr, then allowed to cool to room temperature. Reaction mixture was concentrated and the resulting residue was purified by flash chromatography (hexanes/ethyl acetate = 100/1) to give 122 in 90 % yield (92 mg).

154

Ph O

Ph Ph 122 1 1,3,3-triphenyl-propenone [122]: yellow oil; H NMR (300 MHz, CDCl3)  7.12 (s, 1H), 7.16- 7.21 (m, 2H), 7.25-7.28 (m, 3H), 7.35-7.4 (m, 7H), 7.46-7.51 (m, 1H), 7.91 (d, J = 7.1 Hz, 2H); For full characterization refer to Gurdeep et al. J. Chem. Soc. Perkin Trans. I. 1985, 12891294. O

125 (E)-1-Phenyl-hept-1-en-3-one [125] 1 H NMR (300 MHz, CDCl3)  0.77-1.02 (m, 3H), 1.20-1.47 (m, 2H), 1.57-1.78 (m, 2H), 2.67 (t, J = 7.4 Hz, 2H), 6.75 (d, J = 16.2 Hz, 1H), 7.35-7.47 (m, 3H), 7.49-7.66 (m, 3H); For full characterization refer to Concellon, J.; Rodriguez-Solla, H.; Mejica, C. Tetrahedron 2006, 62(14), 32923300.

127 3-Ethyl-pent-3-en-1-ynyl benzene [127] 1 H NMR (300 MHz, CDCl3)  1.14 (t, J = 7.5 Hz, 3H), 1.91 (dt, J = 6.8, 1.1 Hz, 3H), 2.18-2.27 (m, 2H), 5.81 (qt, J = 6.8, 1.2 Hz, 1H), 7.27-7.39 (m, 3H), 7.40-7.50 (m, 2H); For full characterization refer to Mayr, H.; Halberstadt-Kausch, I. Chem. Ber. 1982, 115(11), 34793515.

155

156

157

158

Typical procedure for the preparation of α,β-unsaturated ketones 122, 125, and 128 in

CH2Cl2, Figure 64

To a CH2Cl2 solution (8 mL) of 3-ethyl-1-phenyl-1-pentyn-3-ol 126 (0.10 g, 0.54 mmol) in an open flask was added 95 % ethanol (0.15 mL, 2.7 mmol) followed by AuCl3 (33 mg, 0.11 mmol). After 18 hr the reaction mixture was diluted with diethyl ether (10 mL) and concentrated. The resulting residue was purified by flash chromatography (hexanes/ethyl acetate = 100/1) to give 3-ethyl-1-phenyl-pent-2-en-1-one 128 in 31 % yield (31.8 mg).

Typical procedure for the preparation of ethoxy propargylic alcohols 129, 132, 134, 136, 138, 150, 152, 154, 156, 158 To a THF solution (7 mL) of ethyl ethynyl ether (0.7 g, ca. 40% by weight in hexanes, ca. 9 mmol was added n-BuLi (1.5 mL, 3.4 mmol, 2.3 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 hr and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and pinacolone (0.30 mL, 2.4 mmol) was added in one portion. The solution was allowed to warm to room temperature over

1 hr and held at room temperature for an additional 3 hr. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (hexanes/ethyl acetate = 20/1 – 7/1) to give 1-ethoxy-3- methyl-3-tert-butyl-1-propyn-3-ol (138) in 83 % yield (0.34g).

OH Ph Ph 129 OEt 1 3-ethoxy-1,1-diphenyl-prop-2-yn-1-ol (129): yellow oil; H NMR (300 MHz, CDCl3)  1.41 (t, J = 7.1 Hz, 3H), 2.64 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 7.21-7.34 (m, 6H), 7.60-7.63 (m, 4H); 13 C NMR (75 MHz, CDCl3)  14.4, 42.2, 74.4, 74.8, 95.9, 125.9, 127.2, 128.0, 146.1; IR (neat) -1 3543, 3444, 3060, 2982, 2263, 1450, 1170, 1004, 640 cm ; HRMS (EI) Calcd for C17H16O2 (M+) 252.1150. Found 252.1153.

159

OEt 132 3-Ethoxy-1-phenyl-prop-2-yn-1-ol [132] 1 H NMR (300 MHz, CDCl3)  1.39 (t, J = 7.1 Hz, 3H), 2.04 (d, J = 5.9 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 5.51 (d, J = 6.0 Hz, 1H), 7.31-7.40 (m, 3H), 7.48-7.59 (m, 2H); 13C NMR (75 MHz,

CDCl3)  14.4, 38.8, 64.6, 74.8, 95.4, 126.5, 128.0, 128.5, 129.2; IR (neat) 3401, 2981, 2226, -1 + 1718, 1450 cm ; HRMS (EI) calcd for C11H12O2 (M ) 176.0834. Found 176.0837. Consistent with data from Raucher, S.; Bray, B. J. Org. Chem. 1987, 52(11), 23322333.

OEt

134 1 4-tert-butyl-1-ethoxyethynyl-cyclohexanol [134]: white solid; H NMR (300 MHz, CDCl3)  0.87 (s, 9H), 0.98 (t t, J = 11.9, 3.5 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.26-1.55 (m, 4H), 1.71 (br d, J = 12.8 Hz, 2H), 1.89 (s, 1H), 1.94 (br d, J = 10.6 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H); 13C

NMR (75 MHz, CDCl3)  14.3, 25.0, 27.6, 32.2, 41.1, 41.3, 47.1, 69.6, 74.4, 94.0; IR (neat) 3390, 2944, 2865, 2257, 1479, 1444, 1393, 1365, 1178, 1059, 900, 834 cm-1; HRMS (CI) + Calcd for C14H24O2 (M+H ) 225.1855. Found 225.1856.

OEt

136 1 2-ethoxyethynyl-adamantan-2-ol [136]: clear, colorless oil; H NMR (300 MHz, CDCl3) 1.37 (t, J = 7.1 Hz, 3H), 1.53 (br s, 1H), 1.57 (br s, 1H), 1.68-1.80 (m, 7H), 1.88 (br s, 2H), 2.14 (br t, 13 J = 12.6 Hz, 4H), 4.09 (q, J = 7.1 Hz, 2H); C NMR (75 MHz, CDCl3)  14.6, 27.1, 27.3, 32.0, 35.9, 38.0, 39.8, 43.2, 72.7, 74.6, 93.9; IR (neat) 3426, 2902, 2854, 2666, 2259, 1712, 1450, -1 + 1247, 1010, 916, 866 cm ; HRMS (CI) Calcd for C14H20O2 (M+H ) 221.1542. Found 221.1538.

160

OEt 138 1-ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol [138]: clear, colorless oil; 1H NMR (300 MHz,

CDCl3)  1.03 (s, 9H), 1.37 (t, J = 7.1 Hz, 3H), 1.41 (s, 3H), 1.71 (s, 1H), 4.08 (q, J = 7.1 Hz, 13 2H); C NMR (75 MHz, CDCl3)  14.3, 25.2, 25.6, 38.4, 41.9, 73.9, 74.2, 92.8; IR (neat) 3479, 2971, 2873, 2261, 1481, 1392, 1369, 1219, 1094, 1007, 908, 878 cm-1; HRMS (CI) Calcd for + C10H19O2 ([M+H] ) 171.1385. Found 171.1390.

OEt 150 1 1-Ethoxy-4,4-dimethyl-pent-1-yn-3-ol [150]: H NMR (300 MHz, CDCl3)  0.97 (s, 9H), 1.38 13 (t, J = 7.1 Hz, 3H), 4.03 (d, J = 6.0 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H); C NMR (75 MHz, CDCl3)  14.2, 25.2, 35.8, 38.0, 71.0, 74.3, 94.0; IR (neat) 3431, 2956, 2714, 2264, 1629 cm-1; HRMS + (EI) calcd for C9H16O2 (M ) 156.1150. Found 156.1103.

OEt 152 1 1-Ethoxy-5-phenyl-pent-1-yn-3-ol [152]: H NMR (300 MHz, CDCl3)  1.38 (t, J = 7.1 Hz, 3H), 1.66 (d, J = 5.3 Hz, 1H), 1.97-2.03 (m, 2H), 2.78 (t, J = 7.9 Hz, 2H), 4.11 (q, J = 7.1 Hz, 13 2H), 4.41 (ap. q, J = 5.3 Hz, 1H), 7.16-7.31 (m, 5H); C NMR (75 MHz, CDCl3)  14.3, 31.6, 38.8, 40.1, 61.7, 74.6, 94.0, 125.8, 128.3, 128.4, 141.6; IR (neat) 3400, 3084, 3061, 2931, -1 + 2862, 2262, 1722, 1603, 1496 cm ; HRMS (EI) calcd for C13H16O2 (M ) 204.1145. Found 204.1150.

161

154 OEt 1 1-Ethoxy-dec-1-yn-3-ol [154]: H NMR (300 MHz, CDCl3)  0.86-0.90 (m, 3H), 1.21-1.46 (m, 10H), 1.37 (t, J = 7.1 Hz, 3H), 1.56-1.70 (m, 3H), 4.09 (q, J = 7.1 Hz, 2H), 4.39 (q, J = 6.3 Hz, 13 1H); C NMR (75 MHz, CDCl3)  14.0, 14.2, 22.5, 25.3, 29.2, 29.2, 31.7, 38.6, 39.6, 62.3, -1 74.4, 93.5; IR (neat) 3381, 2927, 2263, 1722, 1467 cm ; HRMS (CI) calcd for C12H22O2 (M+H+) 199.1698. Found 199.1692.

OEt 156 1 1-Cyclohexyl-3-ethoxy-prop-2-yn-1-ol [156]: H NMR (300 MHz, CDCl3)  0.83-1.3 (m, 6H), 1.38 (t, J = 7.1 Hz, 3H), 1.57-1.84 (m, 6H), 4.10 (q, J = 7.1 Hz, 2H), 4.18 (t, J = 5.7 Hz, 1H); 13 C NMR (75 MHz, CDCl3)  14.3, 25.9, 25.9, 26.4, 28.1, 28.6, 38.3, 44.6, 67.0, 74.5, 94.3; IR -1 + (neat) 3411, 2980, 2460, 1719, 1450 cm ; HRMS (CI) calcd for C11H18O2 (M+H ) 183.1385. Found 183.1390.

OEt 158 1 1-Cyclohex-1-enyl-3-ethoxy-prop-2-yn-1-ol [158]: H NMR (300 MHz, CDCl3)  1.38 (t, J = 7.1 Hz, 3H), 1.55-1.65 (m, 8H), 2.07 (br s, 1H), 4.12 (q, J =7.1 Hz, 2H), 4.77 (d, J = 5.5 Hz, 1H), 5.85 (s, 1H); 13C NMR  14.3, 22.3, 22.5, 24.0, 24.9, 38.0, 66.7, 74.6, 94.6, 123.8, 138.0, 143.8; IR (neat) 3392, 2980, 2929, 2858, 2837, 2658, 2837, 2659, 2455, 2263, 1716 cm-1; + HRMS (EI) calcd for C11H16O2 (M ) 180.1151. Found 180.1150.

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Typical procedure for preparation of α,-unsaturated esters 130, 133, 135, 137, 139, 141 using AuCl3 (Table 7 and Table 8)

To a CH2Cl2 solution (8 mL) of 1-ethoxy-3-methyl-3-tert-butyl-1-propyn-3-ol (138) in an open flask was added 95 % ethanol (0.16 mL, 2.9 mmol) followed by AuCl3 (35 mg, 0.12 mmol, fine powder). After 5 min, the reaction mixture was filtered through a plug of SiO2 with the aid of an ethyl acetate/hexane mixture (1/7). The filtrate was concentrated and purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give 3,4,4-trimethyl-pent-2-enoic acid ethyl ester (139) in 86% yield (85 mg).

Ph O

Ph OEt 130 1 Ethyl 3,3-diphenylpropenoate [130]: yellow oil; H NMR (300 MHz, CDCl3)  2.01 (t, J = 7.1 Hz, 3H), 4.95 (q, J = 7.1 Hz, 2H), 8.09-8.12 (m, 2H), 8.18-8.30 (m, 8H); For full characterization refer toLe Tadic-Biadatti et al. J. Org. Chem. 1997, 62, 559563 and Rathke, M. et al. Synth. Commun. 1990, 20, 869875.

OEt

133 1 Ethyl cinnamate [133]: yellow oil; H NMR (300 MHz, CDCl3, E-Isomer)  1.33 (t, J = 7.1 Hz, 3H), 4.26 (q, J = 7.1 Hz, 2H), 6.44 (d, J = 16.0 Hz, 1H), 7.35-7.53 (m, 5H), 7.69 (d, J = 16.0 Hz, 1H); Z-Isomer  1.24 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 5.95 (d, J = 12.6 Hz, 1H), 6.95 (d, J = 12.6 Hz, 1H), 7.33-7.38 (m, 3H), 7.57-7.59 (m, 2H); For full characterization refer to Wadsworth, E. J. Am. Chem. Soc. 1961, 83, 1733.

182

OEt

O 135 4-tert-butylcyclohexylidene-acetic acid ethyl ester [135]: clear, colorless oil; 1H NMR (300

MHz, CDCl3)  0.84 (s, 9H), 1.04-1.28 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.76-1.95 (m, 3H), 2.14 (t d, J = 13.5, 3.9 Hz, 1H), 2.27-2.32 (m, 1H), 3.86 (d q, J = 13.7, 2.7, 1H), 4.12 (q, J = 7.1 Hz, 13 2H), 5.58 (s, 1H); C NMR (75 MHz, CDCl3)  14.3, 27.5, 28.4, 29.2, 29.5, 32.4, 37.9, 47.8, 59.4, 112.7, 163.5, 166.9; IR (neat) 3412, 2948, 2867, 1716, 1648, 1478, 1365, 1247, 1143, -1 + 1041, 862 cm ; HRMS (CI) Calcd for C14H24O2 (M+H ) 225.1855. Found 225.1849.

OEt

O 137 adamantan-2-ylidene-acetic acid ethyl ester [137]: clear, colorless oil: 1H NMR (300 MHz,

CDCl3)  1.27 (t, J = 7.1 Hz, 3H), 1.86 (br s, 6H), 1.93-1.96 (m, 6H), 2.43 (br s, 1H), 4.07 (br s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 5.58 (s, 1H); For full characterization refer to L. Griaud et al. Tetrahedron, 1998, 54, 1189911906.

OEt 139 (E/Z)-3,4,4-trimethyl-pent-2-enoic acid ethyl ester [139]: clear, colorless oil: 1H NMR (300

MHz, CDCl3, E-isomer)  1.10 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 2.16 (br d, J = 1.1 Hz, 3H), 4.14 1 (q, J = 7.1 Hz, 2H), 5.74 (q, J = 1.1 Hz, 1H); H NMR (300 MHz, CDCl3, Z-isomer)  1.20 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H), 1.84 (br d, J = 1.3 Hz, 3H), 4.14 (q, J = 7.1 Hz, 2H), 5.63 (q, J = 13 1.3 Hz, 1H); C NMR (75 MHz, CDCl3, (E/Z)-mixture) 14.1, 14.3, 15.1, 23.9, 28.5, 29.0, 36.4, 37.9, 59.4, 60.0, 112.9, 116.6, 158.5, 167.2, 167.5, 167.9; IR (neat, (E/Z)-mixture) 2970, 2873, -1 1719, 1634, 1466, 1372, 1262, 1182, 1123, 1054, 868 cm ; HRMS (EI) Calcd for C10H18O2 (M+) 170.1307. Found 170.1306.

183

OEt 141 1 3-butyl-hept-2-enoic acid ethyl ester [141]: clear, colorless oil: H NMR (300 MHz, CDCl3)  0.89-0.94 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H), 1.28-1.47 (m, 8H), 2.13 (br t, J = 7.6 Hz, 2H), 2.59 13 (br t, J = 7.6 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 5.61 (s, 1H); C NMR (75 MHz, CDCl3)  13.88, 13.92, 14.3, 22.4, 23.0, 29.8, 30.8, 31.9, 38.1, 59.3, 115.0, 164.8, 166.6; IR (neat) 2958, 2931, -1 2872, 1716, 1642, 1466, 1378, 1190, 1147, 1039, 862 cm ; HRMS (CI) Calcd for C13H24O2 (M+H+) 213.1855. Found 213.1857.

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Typical two-step procedure for preparation of α,-unsaturated esters 130, 137, 139, 145,

147, 149 using AuCl3 (Table 9) To a THF solution (2.6 mL) of ethyl ethynyl ether (0.13g, ca. 40 % by weight in hexanes, ca. 2 mmol) was added n-BuLi (0.40 mL, 0.75 mmol, 2.0 M) dropwise over 5 min at –78 °C under argon atmosphere. The solution was allowed to warm to 0 °C over 1 hr and held at 0 °C for an additional 30 min. The solution was then recooled to –78 °C and 2-adamantanone (75 mg, 0.5 mmol) was added in one portion. The solution was allowed to warm to room temperature over

1 hr and held at room temperature for an additional 3 hr. Saturated aqueous NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. To the concentrated mixture in an open flask was added 6 mL of CH2Cl2, followed by 95 % ethanol (0.14 mL, 2.5 mmol) and

AuCl3 (7.6 mg, .025 mmol, fine powder). [NOTE: 15.2 mg, 0.05 mmol of AuCl3 was used for the preparation of 147 and 149.] After 30 min, the reaction mixture was filtered through a plug of SiO2 with the aid of an ethyl acetate/hexane mixture (1/7). The filtrate was concentrated and purified using silica gel column chromatography (hexanes/ethyl acetate = 50/1) to give adamantan-2- ylidene-acetic acid ethyl ester (137) in 99 % yield (109 mg) over two steps.

CO2Et 145 (4,6,6-trimethyl-bicyclo[3.1.1]hept-3-en-(2E/Z)-ylidene)-acetic acid ester [145]: clear oil; 1H

NMR (300 MHz, CDCl3, E-isomer)  0.86 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.40 (s, 3H), 1.68 (d, J = 7.9 Hz, 1H), 1.90 (d, J = 1.5 Hz, 3H), 2.20-2.45 (m, 1H), 2.53-2.63 (m, 2H), 4.08-4.20 (m, 1 2H), 5.32 (s, 1H), 7.13 (s, 1H); H NMR (300 MHz, CDCl3, Z-isomer)  0.84 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.44 (s, 3H), 1.58 (d, J = 8.8 Hz, 1H), 1.86 (d, J = 1.4, 3H), 2.20-2.45 (m, 1H), 13 2.53-2.63 (m, 2H), 4.08-4.20 (m, 2H), 5.46 (s, 1H), 5.77 (s, 1H); C NMR (75 MHz, CDCl3, E/Z mixture)  14.3, 14.4, 21.7, 21.8, 23.2, 23.6, 26.4, 26.5, 37.5, 38.1, 45.3, 47.8, 48.2, 49.0, 49.1, 53.1, 59.2, 59.3, 107.6, 110.0, 117.6, 121.6, 156.9, 158.0, 159.6, 161.2, 166.8, 167.4; IR (neat)

194

2979, 2930, 2870, 1708, 1622, 1466, 1443, 1380, 1370, 1226, 1164, 1040, 874, 705 cm-1; + HRMS (EI) Calcd for C14H20O2 (M ) 220.1463. Found 220.1462.

CO2Et 147 (1,7,7-trimethyl-bicyclo[2.2.1]hept-(2E/Z)-ylidene)-acetic acid ethyl ester [147]: clear, 1 colorless oil; H NMR (300 MHz, CDCl3) diagnostic resonance signals for E and Z isomers 13 appeared at  5.58 (br t, J = 2.3 Hz, 1H), 5.64 (br t, J = 2.0 hz, 1H); C NMR (75 MHz, CDCl3, E/Z mixture)  12.7, 13.2, 14.5, 14.6, 19.0, 19.1, 19.8, 20.2, 27.5, 27.8, 34.0, 34.4, 38.6, 40.6, 44.0, 44.6, 48.2, 50.0, 53.9, 54.0, 59.6, 60.0, 108.2, 112.2, 166.9, 167.6, 175.6; IR (neat, E/Z mixture) 2955, 2874, 1714, 1652, 1450, 1368, 1306, 1288, 1200, 1177, 1097, 1048, 873, 850 -1 + cm ; HRMS (CI) Calcd for C14H22O2 (M+H ) 223.1698. Found 223.1695.

CO2Et

149 (3,3,5,5-tetramethyl-cyclohexylidene)-acetic acid ethyl ester [149]: clear, colorless oil; 1H

NMR (300 MHz, CDCl3)  0.95 (s, 6H), 0.97 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H), 1.33 (s, 2H), 1.95 13 (s, 2H), 2.61 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 5.69 (s, 1H); C NMR (75 MHz, CDCl3)  14.3, 30.8, 30.9, 34.8, 34.9, 42.2, 51.1, 52.5, 59.4, 115.8, 160.4, 166.6; IR (neat) 2953, 2896, 1716, -1 + 1646, 1461, 1376, 1229, 1154, 1043, 862 cm ; HRMS (EI) Calcd for C14H24O2 (M ) 224.1776. Found 224.1771.

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Typical Procedure for the Gold-Catalyzed Meyer–Schuster Rearrangement of Ethoxyalkynyl Carbinols, 133, 151, 153, 155, 157, 159 (Table 11).

A mixture of AuCl (7.4 mg, 0.032 mmol) in 1:1 CH2Cl2–THF (5 mL) was prepared and allowed to stir for 20 min to give a homogeneous solution with an insoluble residue. A separate 25 mL roundbottomed flask under argon was charged with 150 (100 mg, 0.64 mmol), EtOH (95 %,

0.36 mL, 6.4 mmol) and a solution of AgSbF6 (11 mg, 0.032 mmol) in 1:1 CH2Cl2–THF (5 mL).

The mixture of AuCl in 1:1 CH2Cl2–THF (5 mL) was then added dropwise. After 40 min, the reaction mixture was filtered through a plug of SiO2 with the aid of 1:7 Et2O–hexane. The filtrate was concentrated and purified using silica gel column chromatography (Et2O–hexane, 1:50) to give ethyl 4,4-dimethylpent-2-enoate (151); yield 0.091 g (91 %, 97:3 E/Z ratio).

Typical Procedure for the Gold-Catalyzed Meyer–Schuster Rearrangement of Ethoxyalkynyl Carbinols in the Presence of Camphorsulfonic Acid (CSA) (Table 11)

0.36 mL, 6.4 mmol), CSA (0.15 g, 0.64 mmol) and a solution of AgSbF6 (11 mg, 0.032 mmol) in 1:1 CH2Cl2–THF (5 mL). The mixture of AuCl in 1:1 CH2Cl2–THF (5 mL) was then added dropwise. After 40 min, the reaction mixture was filtered through a plug of SiO2 with the aid of

1:7 Et2O–hexane. The filtrate was concentrated and purified using silica gel column chromatography (Et2O–hexane, 1:50) to give ethyl (E)-4,4-dimethylpent-2- enoate (151); yield 0.093 g (93 %).

OEt 151 Ethyl (E)-4,4-dimethyl-pent-2-enoate [151] 1 H NMR (300 MHz, CDCl3)  1.08 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 4.19 (q, J = 7.1 Hz, 2H), 5.73 (d, J = 15.9 Hz, 1H), 6.97 (d, J = 15.9 Hz, 1H); For full characterization refer to Comasseto, J. et. al. Tetrahedron 2005, 61, 23192326.

202

OEt 153 Ethyl 5-phenyl-pent-2-enoate [153] 1 H NMR (300 MHz, CDCl3) E-isomer  1.21 (t, J = 7.1 Hz, 3H), 2.38-2.50 (m, 2H), 2.70 (t, J = 7.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 5.77 (d, J = 15.6 Hz, 1H), 6.93 (dt, J = 15.6, 6.8 Hz, 1H), 7.06-7.27 (m, 5H); Z isomer  1.28 (t, J = 7.1 Hz, 3H), 2.77 (t, J = 7.1 Hz, 2H), 2.94-3.03 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 5.78 (d, J = 11.2, 1H), 6.23 (dt, J =11.2, 7.3 Hz, 1H), 7.15-7.33 (m, 5H); For full characterization refer to Yamada, T. et. al. J. Am. Chem. Soc. 129, 129(43), 1290212903.

OEt 155 (E)-Dec-2-enoic acid ethyl ester [155]; 1 H NMR (300 MHz, CDCl3)  0.86-0.90 (m, 3H), 1.26-1.31 (m, 8H), 1.28 (t, J = 7.1 Hz, 3H), 1.42-1.47 (m, 2H), 2.19 (ddd, J = 14.6, 7.1, 1.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 5.80 (br d, J = 15.6 Hz, 1H), 6.96 (dt, J = 15.6, 7.0 Hz, 1H); For full characterization refer to Concellón, J. M.; Concellón, C.; Méjica, C. J. Org. Chem. 2005, 70, 61116113.

OEt 157 (E/Z)-3-Cyclohexyl-acrylic acid ethyl ester [157]: 1 H NMR (300 MHz, CDCl3) E-Isomer  1.12-1.31 (m, 5H), 1.29 (t, J = 7.1 Hz, 3H), 1.64-1.77 (m, 5H), 2.04-2.17 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 5.76 (dd, J = 15.8, 1.4 Hz, 1H), 6.91 (dd, J = 15.8, 6.8 Hz); Z-Isomer 1.12-1.31 (m, 5H), 1.29 (t, J =7.1 Hz, 3H), 1.64-1.77 (m, 5H), 3.23- 3.34 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 5.65 (dd, J = 11.5, 1.0 Hz, 1H), 6.02 (dd, J = 11.5, 9.8 Hz, 1H). For full characterization refer to Concellón, J. M.; Concellón, C.; Méjica, C. J. Org. Chem. 2005, 70, 61116113.

203

OEt 159 (E/Z)-3-(1-Cyclohexen-1-yl)-2-propenoic acid ethyl ester [159]: 1 H NMR (300 MHz, CDCl3) E-Isomer  1.29 (t, J = 7.1 Hz, 3H), 1.65-1.73 (m, 4H), 2.11-2.16 (m, 2H), 2.20-2.25 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 5.76 (d, J = 16.4 Hz, 1H), 6.16 (t, J = 4.1 Hz, 1H), 7.28 (d, J = 15.7 Hz, 1H); Z-Isomer  1.28 (t, J = 7.1 Hz, 3H), 1.57-1.63 (m, 4H), 2.17- 2.2 (m, 2H), 2.24-2.26 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 5.58 (d, J = 12.7 Hz, 1H), 6.00 (t, J = 3.8 Hz, 1H), 6.31 (dd, J =12.7, 0.9 Hz, 1H); For full characterization refer to Stille, J. K. et. al. J. Am. Chem. Soc. 1987, 109, 813817.

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Typical procedure for the preparation of -unsaturated esters 133, 139, 151, 155, 157 using Sc(OTf)3, Table 15.

To a 4:1 v/v CH2Cl2/ethanol solution (10 mL) of 1-ethoxydec-1-yn-3-ol (154, 0.10 g, 0.51 mmol) in an open flask was added Sc(OTf)3 (2.5 mg, 0.005 mmol). Progress of the reaction was monitored by TLC analysis. After 1 hr, the reaction mixture was concentrated under reduced pressure and purified using silica gel column chromatography (hexanes/ethyl acetate, 50:1) to give ethyl (E)-dec-2-enoate (155) in 70 % yield (70 mg).

Typical two-step procedure for the preparation of -unsaturated esters 130, 137, 145,

151, 169, 171, 173, 175, 177, 179, 181, 183 using Sc(OTf)3, Table 16. To a THF solution (2.6 mL) of ethyl ethynyl ether (0.13 g, ca. 40 % by weight in hexanes, ca. 2 mmol) was added n-BuLi (0.40 mL, 0.75 mmol, 2.0 M) dropwise over 5 min at 78 oC under argon atmosphere. The solution was allowed to warm to 0 oC over 1 hr and held at 0 oC for an additional 30 min. The solution was then recooled to 78 oC and 2-adamantanone (142, 75 mg, 0.50 mmol) was added in one portion. The solution was allowed to warm to room temperature over 1 hr and held at room temperature for an additional 3 hr. Saturated aqueous

NH4Cl solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. To the concentrated mixture in an open flask were added CH2Cl2 (8 mL), absolute ethanol (2 mL), and Sc(OTf)3 (2.5 mg, 0.005 mmol). After 6 hr, the reaction mixture was concentrated under reduced pressure and purified using silica gel column chromatography (hexanes/ethyl acetate, 50:1) to give adamantan-2-ylidene-acetic acid ethyl ester (137) in 96 % yield over two steps (106 mg).

210

CO2Et

169 (2-Isopropyl-5-methyl-cyclohexylidiene)-acetic acid ethyl ester [169]: 1 H NMR (300 MHz, CDCl3, E/Z-mixture, diagnostic peaks)  2.55 (ddd, J = 12.9, 5.5, 1.5 Hz), 3.14 (dd, J = 12.9, 4.3 Hz), 3.48-3.52 (m), 4.13 (q, J = 7.1 Hz), 4.14 (q, J = 7.1 Hz), 5.63 (br s); 13 C NMR (75 MHz, CDCl3, E/Z-mixture)  14.3, 18.1, 19.5, 20.5, 20.8, 21.8, 23.4, 26.1, 26.8, 27.0, 27.6, 30.4, 31.6, 33.6, 33.9, 35.4, 36.1, 40.0, 43.5, 50.8, 52.6, 55.9, 59.3, 59.4, 113.3, 116.3, 164.8, 167.1.

OEt 173 Cycloheptyliden-acetic acid ethyl ester [173]: 1 H NMR (300 MHz, CDCl3)  1.27 (t, J = 7.1 Hz, 3H), 1.51-1.56 (m, 4H), 1.60-1.69 (m, 4H), 2.37 (dt, J = 1.3 Hz, 2H), 2.87 (dt, J = 1.3 Hz, 2H), 4.13 (q, J =7.1 Hz, 2H), 5.66 (quint, J = 1.2 Hz, 1H); For full characterization refer to Friese, A. et al. J. Med. Chem. 2002, 45, 15351542.

175 (E/Z)-Ethyl-β-methyl cinnamate [175]: 1 H NMR (300 MHz, CDCl3) E-Isomer  1.32 (t, J = 7.1 Hz, 3H), 2.58 (d, J = 1.2 Hz, 3H), 4.22 (q, J = 7.1 Hz, 2H), 6.14 (q, J = 1.3 Hz, 1H), 7.1-7.5 (m, 5H); Z-Isomer  1.08 (t, J = 7.1 Hz, 3H), 2.18 (d, J = 1.4 Hz, 3H), 4.00 (q, J = 7.1 Hz, 2H), 5.91 (q, J =1.4 Hz, 1H), 7.1-7.5 (m, 5H); For full characterization refer to Tsuda, T. et. al. J. Org. Chem. 1988, 53, 607610.

211

177

(E/Z)-3-(4-Isopropenyl-cyclohex-1-enyl)-acrylic acid ethyl ester [177]: 1 Diagnostic peaks H NMR (300 MHz, CDCl3) E-Isomer  5.77 (d, J = 15.8 Hz, 1H), 6.18 (br s, 1H), 7.30 (d, J = 15.8 Hz, 1H); Z-Isomer  5.61 (d, J = 12.6 Hz, 1H), 6.02 (br s, 1H), 6.33 (d, J = 12.6 Hz, 1H).

O 179 (E/Z)-Ethyl-3-(4-methoxyphenyl)-2-propenoate [179]: 1 H NMR (300 MHz, CDCl3) E-Isomer  1.33 (t, J =7.1 Hz, 3H), 3.84 (s, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.31 (d, J = 16.0 Hz, 1H), 6.90 (d, J =8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H); For full characterization refer to Aggarwal, V. et. al. J. Am. Chem. Soc. 2003, 125, 60346035. Z-Isomer  1.28 (t, J = 7.1 Hz, 3H), 3.82 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H), 5.83 (d, J =12.7, 1H), 6.84 (d, J =12.7, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H); For full characterization refer to Mueller, A. et . al. Org. Lett. 2007, 9, 53275329.

O CO2Et

181 (E/Z)-Ethyl-3-(2-furyl)-propenoate [181]: 1 H NMR (300 MHz, CDCl3) E-Isomer  1.32 (t, J = 7.1 Hz, 3H), 4.24 (t, J = 7.1 Hz, 2H), 6.31 (d, J = 15.8 Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 6.60 (d, J = 3.4 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.46 (d, J =6.5 Hz, 1H); For full characterization refer to Cristau, H. J. et. al. Tetrahedron 1998, 54, 15071522. Z-Isomer  1.32 (t, J = 7.1 Hz, 3H), 4.22 (q, J = 7.1 Hz, 2H), 5.74 (d, J = 12.9 Hz, 1H), 6.50 (dd, J = 3.5, 1.7 Hz, 1H), 6.79 (d, J =12.9 Hz, 1H), 7.47 (d, J =1.6 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H); For full characterization refer to Reetz, M. T. et. al. Eur. J. Org. Chem. 2003, 34853496.

212

F O F O

F F 183 F (E)-3-Pentafluorophenyl-acrylic acid ethyl ester [183]: 1 H NMR (300 MHz, CDCl3)  1.35 (t, J = 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 6.74 (d, J = 16.5 Hz, 1H), 7.64 (d, J = 16.5 Hz, 1H); For full characterization refer to Shen, Y. et. al. Syn. Comm. 1991, 21, 14031408.

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BIOGRAPHICAL SKETCH

Birth Place Waukesha, Wisconsin • February 24, 1982 Educational Background Florida State University, Tallahassee, FL • August β004 to August 2009 • Ph.D. in Organic Chemistry (anticipated completion in August β009) • Research Advisor: Professor Gregory B. Dudley Georgia Southern University, Statesboro, GA • August β000 to May β004 • B.A. degree in Chemistry, with Honors - summa cum laude • Research Advisor: Professor James M. LoBue Gordon Central High School, Calhoun, GA • August 1996 to June 2000 • Valedictorian

Professional Experience Florida Custom Synthesis, Inc., Tallahassee, FL • CEO, β009–present • serving Florida’s emerging biotech industry with premium organic synthesis on demand • http://www.flsynth.com

Honors and Awards • MDS Fellowship, β004–present • Florida State University Fellowship, β005-2006, 2007-2008 • American Institute of Chemists Foundation Outstanding Senior Award, β004 • Georgia Southern Physical Chemistry Award, 2003 • Georgia Southern Organic Chemistry Award, β00β • Bovey Foundation Scholarship, β000 • Bird Scholarship, β000 • Governors Scholarship, β000

Teaching • Teacher’s Assistant for Organic Chemistry I, CHM ββ10

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• Teacher’s Assistant for Organic Chemistry II, CHM 2211 Research Talks: (2) ―Synthetic approaches to Artemisinin-related natural products, Didesmethylartemisinin and dihydro-epi-Deoxyarteannuin B.‖ Engel, Douglas A. Abstract of Papers, βγ5th ACS National Meeting, New Orleans, LA, April 6-10, 2008, ORGN-504. (1) ―Synthetic approaches to Artemisinin-related natural products, Dihydroartemisinic Acid and Arteannuin M.‖ Engel, Douglas A. Abstract of Papers, βγ1st ACS National Meeting, Atlanta, GA, March 26-30, 2006, ORGN-477. Publications: (4) Engel, D. A.; Lopez, S. S. Lewis acid-catalyzed Meyer–Schuster reactions: methodology for the olefination of aldehydes and ketones. Tetrahedron 2008, 64, 6988–6996. (invited contribution to Symposium in Print special issue) (3) Dudley, G. B.; Engel, D. A.; Ghiviriga, I.; Lam, H.; Poon, K. W. C.; Singletary, J. A. Synthesis of dihydro-epi-deoxyarteannuin B. Org. Lett. 2007, 9, 2839–2842. (2) Lopez, S. S.; Engel, D. A.; Dudley, G. B. The Meyer–Schuster rearrangement of ethoxyalkynyl carbinols. Synlett 2007, 949–953. (1) Engel, D. A.; Dudley, G. B. Olefination of ketones using a gold(III)-catalyzed Meyer–Schuster rearrangement. Org. Lett. 2006, 8, 4027–4029.

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