Download Organic synthesis and methodology related to the malaria drug artemisinin

FLORIDA STATE UNIVERSITY
COLLEGE OF ARTS AND SCIENCES
ORGANIC SYNTHESIS AND METHODOLOGY RELATED TO THE
MALARIA DRUG ARTEMISININ
By
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.
ii
This manuscript is dedicated to my family and friends who have supported me
through out my life.
iii
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.
iv
TABLE OF CONTENTS
List of Tables ................................................................................
List of Figures ...............................................................................
Abstract
....................................................................................
v
vi
x
1. Total Synthesis of (+)-Dihydro-epi-deoxyarteannuin B and
Related Studies ........................................................................
001
Chapter 1: History of Malaria .....................................................
Chapter 2: Artemisinin: The Last Line of Defense Against
Malaria ....................................................................
Chapter 3: Synthesis of (+)-Dihydro-epi-deoxyarteannuin B
and ()-Dihydroartemisinic Acid……………………..
Chapter 4: Experimental: (+)-Dihydro-epi-deoxyarteannuin B...
001
2. The MeyerSchuster Reaction and Beyond ..............................
094
Chapter 5: Evolution of the MeyerSchuster Reaction ..............
Chapter 6: Lewis Acid-Catalyzed MeyerSchuster Reactions:
Methodology for the Olefination of Aldehydes and
Ketones ..................................................................
Chapter 7: MeyerSchuster Experimental………………………
094
REFERENCES .............................................................................
224
BIOGRAPHICAL SKETCH .............................................................
241
v
011
020
038
114
144
LIST OF TABLES
Table 1: Allylation of Menthone and Silyloxymenthone 43 ........................ 028
Table 2: Mo-Au Combo Catalysis for Rearrangement of E into
α,β-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
vi
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,β-Enones via
Functinalization of the Propargyl Alcohol ................................. 103
Figure 48: Preparation of β-Monosubstituted (E)-α,β-Unsaturated
Ketones ................................................................................... 104
Figure 49: Preparation of β,β-Disubstituted α,β-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,β-Unsaturated Amide Formation ........................................... 110
Figure 57: Proposed Mechanism for the Ru-Catalyzed Isomerization of
Propargyl Alcohols into α,β-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
ix
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
x
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,β-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,β-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.
xi
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
o
C 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 percapita 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
2
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
4
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
6
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
7
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).
H
H3C
O
O
O
HO
CH3
H
H3C
H
CH3
CH3
O
O
O
HO
9a R = H, Dihydroartemisinin
9b R = Me, Artemether
H
CH3
O
OR
artemisinin
A
9c R = Et, Arteether
10 R = CO(CH2)2COONa,
Artesunate
Figure 7: The Structure of Artemisinin and its Derivatives
8
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
9
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.
10
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.
H
Me
H
H3C
H
O O
CH3
O
O
O
HO
H
H
H
O
CH3
O
O
O
()-arteannuin B
Me
artemisinin 1
(+)-dihydro-epi-deoxyarteannuin B
H
H
H3C
O
O
O
HO
CH3
H
H3C
H
CH3
OCH3
9
O
O
O
HO
CH3
H3C
O
O
O
HO
H
CH3
OCOCH2COOH
10
H
CH3
N
O
S
11
Figure 9: Artemisinin and Related Compounds
11
CH3
O
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 TseTsung 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
of
solvents
have
low
vapor
pressure,
and
the
generation
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.
These include extraction with EtOH,32 supercritical CO2,33,34 hydrofluorocarbons,31 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
13
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
14
Figure 1139: Schematic Representation of the Engineered Artemisinic Acid Biosynthetic
Pathway in S. cerevisiae
15
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 rearrangement 46,47,50,53 of ketone 12 or an ozone/acid
rearrangement48,49,51 of vinyl silane 13 to install the endoperoxide functionality (Figure 12).
O
O
O21, 78 oC
MeOH, hv
Path A
H
MeO
NaO2C
methylene
blue
HOO
MeO
MeO
HO2C
12a
12
O
O
O
O3/O2
78 oC
Path B
Me3Si
HO2C
0 oC,
H3C
24 h, 30%
H2SO4
H2O
HOO
O
CH2Cl2;
SiO2
HCO2H
CH2Cl2
35%
H
O
O
O
HO
CH3
H
CH3
O
artemisinin 1
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.
16
5 steps
1. LDA, THF, 0 oC
HO
O
H
H
85% yield
14
Me3Si
O
2. 16
62% 6:1 mix of diasteromers
PhCH2O 15
H
H
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).
17
10 equiv.
Me3Si
Li
H
MeO
THF, -78 oC
89%, 8:1 d.r.
O
Me3Si
1. Li, NH3
2. PCC, CH2Cl2
HO
MeO
H
H
Me3Si
3. m-CPBA, CH2Cl2
4. TFA, CH2Cl2
54% over 4 steps
PhCH2O 18
H
MeO
Me3Si
O
O
O
H
19
H
1. O2, methylene blue
methanol, hv, -78 oC
Bu4NF, THF, r.t., 2 h
95% yield
H
H
MeO
HO2C
2. formic acid, CH2Cl2,
0 oC, 24 hr, 30% yield
H3C
O
O
O
HO
CH3
H
CH3
O
20
artemisinin 1
Figure 14: Schmid and Hofheinz End Game Strategy
17
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.
H
1. O2, hv, CH2Cl2
78 oC, methylene blue
H
H
HO2C
2. CH2Cl2 replaced with
petroleum ether, 4 days
17%
21
H3C
O
O
O
HO
CH3
H
CH3
O
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.
18
H
O3
CH2Cl2;
H
O
O
then
Lewis
acid
O O
O
O
O O
O
O
O
23
22
LA
H
O O
O
H3C
O
LA
O
O
O
O
HO
O
24
CH3
H
CH3
O
25
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.
19
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
H
H
H3C
O
H
H
O
O
O
HO
H
CH3
O
O
(+)-dihydro-epi-deoxyarteannuin B 22
CH3
()-artemisinin 1
H
HO2C
H
H
()-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).
20
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
O
25-30%
3:2 mix of epimers
26
27
OH
28
H
H
benzene, 170 oC
Eq (2)
H
O
sealed tube,
2 days, 95%
2:1 mix of epimers
OH
H
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
O
L-proline, MeOH
O
TIPSO
H
H
43%
O
TIPSO
H
H
31
30
Figure 19: Avery and Co-Workers’ Strategy to Avoid Epimerization
21
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
Eq (4)
O
4e, 4HD
(78-95%)
O
32
HO
HO
MeO2C
33
H
CO2Me
Eq (5)
O
SmI2,
THF/MeOH
0 oC (>95%)
34
HO
35
CO2Me
H
CH2Br
CO2C2H5
Eq (6)
O
Zn(Cu)
THF
O
36
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 oxyCope/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
MeO
O
Eq (7)
H
RVC anode
carbon cathode
0.1 M LiClO4
O
20% MeOH/CH2Cl2
2,6-lutadiene
8 mA/ 2.4 F/mole
undivided cell
R
38a. R = H
38b. R = Me
H
MeO
R
39a. R = H, 70%
39b. R = Me, 70%
H
H
o
DBU, toluene, 220 C
Eq (8)
O
HO
HO O
55-60%
40
OH
41
ODPS
HO
H
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).
23
O
H
H
H
O
O
O
(+)-dihydro-epi-deoxyarteannuin B 22
45
O
OTIPS
H
43
OH
OTIPS
H
O
44
OH
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.
Me
Me3Si
I
16
Figure 23: The StorkJung Vinylsilane
24
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 twostep 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;
TMSCl
SiMe3
LiAlH4,
NaOMe; I2
90%
OH
46
Me
SiMe3
SiMe3
CuI, MeLi
68%
96%
OH
48
OH
47
Ph3P,
CCl4
I
SiMe3
Me
60%
NaI
butanone
Me
SiMe3
80%
OH
Cl
I
49
50
16
Figure 24: The Original Synthesis of the StorkJung Vinylsilane75 16
25
SiMe3
Eq (9)
HO
1) LiAlH4
NaOMe
H
2) I2
HO
47
Eq (10)
n-Bu
SiMe3
Stork and Jung75
I
48
SiMe3
1) i-Bu2AlH
Et2O
n-Bu
Zweifel and Lewis80
2) I2
51
SiMe3
H
I
52
Eq (11)
n-Bu
HO
53
1) 2 equiv
i
BuMgCl
HO
(5-C5H5)2TiCl2
n-Bu
H
Sato and co-workers76,77
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 titaniumcatalyzed 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
that 2.3 equivalents of iBuMgCl and 5 mol% of Cp2TiCl2 in diethyl ether at 60 oC 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
5 mol% Cp2TiCl2, 
HO
Me
55
4.6 equiv HMPA, Et2O
3.0 equiv TMSCl, 
70-76%
SiMe3
HO
Me
49
1.1 equiv Ph3P
1.1 equiv NIS
CH2Cl2
0 oC to rt
82-94%
SiMe3
I
Me
16
Figure 26: Dudley Lab Succint Method for Preparation of StorkJung Vinylsilane 16
26
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
OH
B2H6, THF;
H2O2, 94%
95:5 d.r.
(ref 82)
ca. 3:1 dr
B2H6, THF;
H2O2, 57%
OH
OH
H
H
pure crystals
(our work)
56
14
OH
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).
DMSO, (COCl)2
TIPSCl, NEt3
OH
OH
H
H
56
DMAP, CH2Cl2
86%
OH
OTIPS
H
H
NEt3, CH2Cl2
86%
57
O
OTIPS
H
H
43
Figure 28: Conversion of Diol 56 to Ketone 43
27
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
O
Z
H
H
RX
OLi
Z
H
H
THF
B
C
D
Enolate conformations:
(preferred)
CH3
CH3
H3C
O
MLn
Z
O
Z
H
H
additive(s)
LnM O
H3C
Z
A1,2 interaction
Entry
Z
1
H
2
RX
Additive(s)
58
allyl bromide
none
60
1782
OBn
15
16
none
61
5346
3
H
58
allyl iodide
HMPA
60
53
4
H
58
allyl iodide
HMPA, Et2Zn
60
~80a
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
Substrate
Product
Estimated by 1H NMR spectroscopy.
SiMe3
SiMe3
I
16
59 O
(i-Pr)3SiO
28
Yield (%)
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 protocol 87 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).
SiMe3
SiMe3
O
OTIPS
H
H
59
1.Li
(i-Pr)3SiO
59
O
conformation in which the ketone
is the least hindered
vinylMgBr
CeCl3
THF
up to 91%
SiMe3
OH
OTIPS
H
H
63
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 methylenation 97 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).
O
SiMe3
OH
OTIPS
H
H
SiMe3
1. HCl
MeOH
2. TPAP
NMO
>95% overall
63
SiMe3
m-CPBA;
H
O
CF3CO2H
>95%
O 64
O
H
O 65
O
H
PH3P=CH2
H
O
ca.
30-40%
RCM attempts
H
O 66
O
O 45
Grubbs' cat
H
O
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%
H
H
2.RCM
37%
O
TPAP
NMO
62%
OH
OH
67
O 45
H
Ph3P
I
H
68
relay
RCM
O
68, BuLi
H
O
17-37%
(40% brsm)
O 22
Grubbs' cat.
74-90%
O
H
O
69
O 66
O
Figure 31: Ring Closing Metathesis (RCM) Strategies
In summary, we have successfully completed the total synthesis of (+)-dihydro-epideoxyarteannuin B 22 from bulk isopulegol 14.91 We were able to develop an efficient
alkylation strategy based on Noyori’s protocol 87 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,β-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
H
H
43
O
2.Et2Zn, HMPA
OTIPS allyl iodide
80%
O
OTIPS
71
olefination
O
OTIPS
H
H
H
H
62
MeLi, CuCN
DIBAL, THF
OTIPS
70
H
1.TiCl4, PbCl2
Zn, CH2Br2
COCH3
H
H+
H
72
H
CO2H
H
H
CO2H
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
50-85%
58
60
O
60
(OEt)2P(O)CH2P(O)OEt
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,β-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
O
O
Meyer-Schuster
OH
R
n-BuLi
R
60
73
OH
Eq (15)
R3
R1
74
strong acid
E
R3
"Meyer-Schuster"
R1
R2
O
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,β34
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
n-BuLi
O
OH
-78 oCr.t.
12 h, 80%
R
O
CH2Cl2, rt, 5 min
98%
R
74
73
60
5 mol% AuCl3
5.0 equiv. EtOH
R = OEt
Figure 35: Implementation of Our Olefination Strategy Towards Dihydroartemisinic Acid 21
35
36
37
CHAPTER 4
EXPERIMENTAL: (+)-DIHYDRO-EPI-DEOXYARTEANNUIN B
GENERAL EXPERIMENTAL PROCEDURES:
1
H NMR and
13
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
the residual CHCl3 peak (7.26 ppm for 1H NMR and 77.0 ppm for
13
C NMR for all compounds
except for 22, which was referenced to 7.27 ppm for 1H NMR and 77.2 ppm for
13
C 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.
38
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%):
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
1
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,
13
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.
39
40
41
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:
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),
1
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
13
(neat) 2954, 1604, 1437, 1247, 1143, 835 cm-1. MS m/z 254.2 [12, M]+.
42
43
44
1. BH3 THF
2. H2O2, NaOH
OH
Isopulegol 14
3. NEt3, TIPSCl
DMAP, CH2Cl2
4. DMSO, (COCl)2,
NEt3, CH2Cl2
O
OTIPS
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.
H 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,
1
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).
1
H NMR spectra for intermediates are given.
45
46
47
48
SiMe3
O
OTIPS
59
(2S, 3R, 6S)-3-Methyl-6-(1-methyl-2-triisopropylsilanyloxy-ethyl)-2-((E)-3-trimethylsilanylbut-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%).
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
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
(m, 2H), 3.65 (d, J = 4.8 Hz, 2H), 5.64 (tq, J = 6.5, 1.7 Hz, 1 H);
13
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.
49
50
51
O
60
(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 NH 4Cl
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%).
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
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.
52
53
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 NH 4Cl 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%).
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-
1
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
Hz, 1H)
13
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.
54
55
56
SiMe3
OH
OTIPS
63
(1S,2S,3R,6S)-3-Methyl-6-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-2-((E)-3trimethylsilanyl-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 MgSO 4, 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
57
= 20/1) to give a clear colorless oil (0.316 g), tentatively assigned as the propargyl alcohol
SiMe3
corresponding to acetylide addition of ketone 59;
OH
OTIPS
93%. A 15-mL round-
bottomed flask was then charged with 5% Pd on BaSO 4 (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%).
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
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);
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,
13
51.5, 52.5, 65.6, 77.6, 114.1, 132.8, 142.3, 145.7; IR (neat) 3390, 2950, 2868, 1614, 1462,
1246, 1056, 835 cm-1; HRMS (FAB) Calcd for C28H56O2Si2 (M + Na+) 503.3717. Found
503.3711. [α]546 = –7.92° (c 0.001, CHCl3).
58
59
60
SiMe3
O
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
crystalline solid (0.076 g, 0.234 mmol). 1H 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
(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,
13
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)
3306, 2953, 1614, 1456, 1246, 835 cm-1. HRMS (EI) Calcd for C19H36O2Si (M+) 324.2485.
Found 324.2484. [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
(0.075 g, 100%). 1H 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);
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,
13
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+) 320.2172. Found 320.2168. [α]546 = –14.58° (c 0.0024,
CHCl3); mp 7476°C.
61
62
63
64
65
O
O
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%).
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,
1
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);
13
C 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+) 265.1804. Found 265.1791. [α]546 = –11.90° (c 0.0016, CHCl3);
mp 6466 °C.
66
67
68
O
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.
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,
1
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,
1.5 Hz, 2H), 5.66 (dd, J = 17.3, 10.8 Hz, 1H);
13
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)
3072, 2933, 1778, 1646, 1179, 945 cm-1; HRMS (CI) Calcd for C16H26O2 (M + H+) 263.2011.
Found 263.2005.
69
70
71
I
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.
H NMR (300 MHz, CDCl3) 1.52-1.80 (m, 4H), 2.02 (apparent q, J = 6.9 Hz), 3.52-3.62 (m,
1
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);
13
C 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.
72
73
74
O
69
O
(3R, 3aS, 6R, 7S, 7aS)-3,6-dimethyl-7-((Z)-3-methyl-nona-3,8-dienyl)-7a-vinyl-hexahydrobenzofuran-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.
H NMR (300 MHz, CDCl3, Diagnostic Peaks)  0.98 (d, J = 6.5 Hz, 3H), 1.08 (d, J = 7.0 Hz,
1
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.
75
76
O
O
22
(+)-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 1dram 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.
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,
1
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,
3H), 3.15 (apparent quint., J = 6.9 Hz, 1H), 5.65 (q, J = 1.5 Hz, 1H); 13C 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)
2929, 1764, 1449, 1162, 909 cm-1; 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.
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
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,β-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,β-unsaturated carbonyl 74 was needed.
O
olefination
O
H
H
R
HO2C
60
dihydroartemisinic acid 21
74
Figure 36: Strategy Towards Dihydroartemisinic Acid 21
α,β-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,β-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
O
R1
R2
[2 +2]
annulation
Y
R3
R3
Y
R2
ring-opening
1
R
G
R2
O
4  electrocyclic
O
R1
Y
R3
H
(b) nucleophilic 1,2-addition / rearrangement
acetylide
addition
O
R1
R3
R2
Y
R2
R1
G
R3
OH
R
I
R3
R2
3
O
elimination
R2
R1
3
rearrangement R
R1
H
E
Rupe
rearrangement105
R2
O
MeyerSchuster
R1
F
redox
isomerization
Ir106 Pd107,108 Rh109,110 Ru111,112
R2=H
O
R1
R3
K
J
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,β-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,β-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
R1
R2
•
1
R
R2
3
R
E
R3
OH
L
O
R1
R3
H
F
Figure 38: 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
96
H
H
R2
R1
O
H
H
R3
R2
R2
+ H2O
R1
R1
M
R2
N
R3
O
R1
R3
R3
I
O
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,β-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,β-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 HoffmannLa Roche in a variety of terpenoid syntheses (Figure 40).121-123
OH
CHO
4 mol % tri[triphenylsilyl] vanadate
3 mol % triphenylsilanol
O
75
cat. benzoic acid
xylene, 140 oC, 3 h
79%, mix of E/Z
O
76
Figure 40: Hoffmann-La Roche Inc. Application of Vanadate Catalyst 121
97
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,β-enone F (Figure 41).
R1
H
R2
O
R3
OR
OR
V
O
E
OR
P
transEsterification
ROH
O
Q
R3
R3
R2
[3,3]-sigmatropic
OR
V OR
rearrangement
O
R2
O
tautomerization
•
R1
•
R1
R2
R
R3
transEsterification
R1
OH
R3
L
O
O
V
OR
OR
R1
R2
F
126
Figure 41: Proposed Orthovanadate Mechanism
Attempting to expand the scope of this potentially useful reaction, Chabardes and coworkers 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
98
E
R3
(+)
X
•
R1
R2
R
O
O
N
O
X
V
O
N
OR
OR
R3
R4
R4
OR
V
OR
R2
R3
R3
X
N
H
R4
R2
R1 S
R1 T
Aldol-type product
H+
O
O
R2
R1
MeyerSchuster
rearrangement
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)/ptoluenesulfonic 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,β-unsaturated acylsilanes
(Figure 43) in addition to α,β-enones.
O
OH
10 mol% Bu4NReO4
77
Si
10 mol% p-TsOH H2O
CH2Cl2, r.t. 2 hrs, 75%
Si
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 coworkers 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%
d.r. 6:1
OH (6S)-79
O
(S)--ionone
95% ee
80
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,β-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,β-unsaturated Ketones F
R1
R2
MoO2(acac)2
AuCl(PPh3)-Ag(OTf)
(1 mol% each)
OH
E1-6
R3
R1
O
R2
toluene, rt, 2 h
R3
F1-6
Substrate E
Entry
Product F
R1
R2
R3
Time
(h)
Isolated Yield
(%)
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 transesterification 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
R2
non-bonded electons
on oxygen:
1
hard Lewis base R
R3
OH
-bonded electron
of alkyne:
soft Lewis base
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,βunsaturated carbonyl compounds.138,139 These processes typically involve hydration of the
alkyne, followed by β-elimination of the ether alkoxide to generate the α,β-unsaturated
carbonyl. Although the end result is the same, the reactions are not strictly MeyerSchuster
rearrangements, and they involve distinct synthetic challenges.
[M]
R1
R2
O
R3
[M]
R3
O
[3,3]-sigmatropic
rearrangement
U
•
R1
R2
O
O
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 1,2migration147-150 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.
R2
R1
R3
R3
2
1R
R
propargyl acetate
preparation
OH
"catalyst"
rearrangement/
hydrolysis
O
O
U
E
R2
O
R1
R3
H
F
Eq (16) Standard Two-Step Conversion with Isolation of U
R1
2
R
OH
E
R3
cat. Ag+
CO2, DBU
RT
R3
R2
R1
R1
O
O
W
R2
rearrangement
O-
Eq (17) Yamada Lab's Single Operation Conversion
O C O
O
R3
H
F
151
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,β-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(PPh 3)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
3
81
Me
Au(PPh3)NTf2 (2 mol%)
2-butanone, r.t., 92% yield
E only
Me
3
82
Me
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
(5 mol%, 0.05 M in acetone)
OAc
O
n-Bu
83
acetonitrile/H2O (80/1)
0 oC, 30 min; then r.t. 16 h
97% yield
n-Bu
84
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 αylidene-β-diketones,155 cyclopentenones,156 indoline-fused cyclobutanes,157 α-ylidene-β-keto
and –malonate esters,158 indenes,159 aromatic ketones,160 and α-haloenones161,162 (Figure 50).
104
R4
R4
R1
O
O Au catalyst
R1
O
R4
O
R
R2
Y
R2
R2
U
R3
X
O
1
R3
[Au]
O
R4
O
O
R3
•
R1
[Au]-
R2
R3
[Au] V
O
2
R
O
X+ = H+
hydrolysis/protiodeauration
R3
F
Meyer-Schuster Product
O
R1
4
R
-
[Au]
X+ R1
OH
R4
O
R3
X+ = E+
various
functional
products
R2 Z
Figure 50: Proposed Mechanism for Au(PPh3)NTf2-Catalyzed Rearrangement152
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,β-unsaturated carbonyl counterparts.163
The optimal conditions were determined to be 2 mol % of both (ItBu)AuCl and AgSbF6, in a
10:1 THF/H2O solvent system at 60 oC 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
Table 3: Selected Examples of [(ItBu)AuCl]/AgSbF6 Catalyzed Rearrangement[a]
OAc
THF/H2O, 60 oC, 8 h
2
R
R3
U7-14
Entry
R1
[ltBu)AuCl]/AgSbF6 (2 mol%)
R1
O
N
R3
R2
ltBu
F7-14
Propargyl Acetate
U
Enone
OAc
N
F
Yield [%]
F7
91
F8
90
F9
89
F10
90
F11
nr
F12
nr
O
Bu
1
Bu
F
U7
F
OAc
O
Bu
2
[b]
Bu
F
U8
F
OAc
O
Bu
3
Bu
MeO
U9
MeO
OAc
O
H
4
H
U10
OAc
O
Si
5
Si
U11
OAc
O
U12
6
OAc
O
82
U13
7
F13
(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),
H2O (1 mL). [b] performed in a microwave at 80 oC, 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
experimentally and computationally.163 Based on their findings, they suggested a SN2’ 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
O
N
N
N
O
O
H
Au
O
86
85
Au
•
O
OH
O
87
Figure 51: SN2’ Type Addition of Au Catalyst
N
N
Au
OH
H2O
88
86
163
Nolan and co-workers later extended this method to the preparation of α,β-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,β-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)
R3
• •
AA
R1
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 coworkers 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
OAc
89
O
cat. Hg(OTf)2
H2O
90
OAc
91
O
O
O
Hg
93
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,β-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 avoided 166
(Figure 54).
OAc
C7H15
O
Hg(OTf)2 5 mol %
1.5 equiv H2O, CH3CN, 0.1 h
C7H15
94
95 (67%)
C7H15
96 (13%)
Figure 54: Optimized Hg(OTf)2 Rearrangement166
In 2007, Nishizawa and co-workers further extended the method to include the
formation of α,β-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,β-unsaturated esters after
rearrangement, are the most common, other heteroatoms 168 have been utilized. α,βunsaturated thioesters have been synthesized by the lab of Kataoka and Yoshimatsu. 169 They
were able to convert γ-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
O
OAc
Hg(OTf)2 1 mol %
Ph
1 equiv. H2O, CH2Cl2, 2 h
OAc
1 equiv. H2O, CH2Cl2, 40 min
OEt
99
Eq (18)
O
Hg(OTf)2 1 mol %
Ph
OEt
98 (89%) E/Z 100:0
OEt
97
Ph
Ph
Eq (19)
OEt
100 (77%) E/Z 50:50
Figure 55: Hg(OTf)2-Catalyzed Hydration of Ethoxypropargyl Acetates167
Very recently, the first example of a MeyerSchuster rearrangement to form an α,βunsaturated 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
n-C6H13
101
N
Bn
Ts
MoO2(acac)2
AuCl(PPh3)-AgTOf
(1 mol% each)
toluene, rt, 2 h
O
n-C6H13
102 (80%) E only
N
Bn
Ts
Figure 56: α,β-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
R1
O
GG
R2
R1
H+
H2O
CC
R2
OH
BB
Ph
O
O
[LnRu]
R2
HO R1
R1
FF
R2
OH
CC
[LnRu]
H+
LnRu
Ph
O
O
H
LnRu C C R1
R2
HO
DD
H
R2
HO R1
O
EE
HO
Ph
103
Figure 57: Proposed Mechanism for the Ru-Catalyzed Isomerization of Propargyl Alcohols into
α,β-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 β-lactam. They found that they could chemoselectively add lithio tertbutylacetylide to the -lactam, which set the stage for the rearrangement. Standard
MeyerSchuster conditions (i.e. acid) gave the α,β-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
Br
N
N
Br
Br
N
H
N
chartelline A 104
O
O
N PMP
91%
N
H
106
TFA, 0 oC
CH2Cl2
O
O
N PMP
N
Boc
105
OH
N PMP
n-Bu4NReO4
p-TsOH
CH2Cl2, rt
100%
N
Boc O
107
Figure 58: Application of the MeyerSchuster Reaction in Total Synthesis 178
In conclusion, the MeyerSchuster reaction has evolved, from a simple acid-catalyzed
rearrangement of tertiary propargyl alcohols to α,β-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,β-unsaturated ketones and
aldehydes, recent advances have made access to α,β-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,β-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,β-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
addition
O
R1
R2
G
R3
Y
R2
R1
R3
OH
MeyerSchuster
R2
O
3
rearrangement R
R1
H
E
F
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 oxophilic 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 rearrangement 182
(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
CrO3
O
O
H
O
109
Cr
Cr
O
108
O
O
O
O
O
OH
111
110
112
Eq (20): Cr(VI) Oxidation of Tertiary Allylic Alcohols
R1
O
O
HO
R1
R2
3
R
E
CrO3
Cr
O
R1
R2
R2
O
•
R3
O
O
II
Eq (21): Our Proposed Cr(VI) Rearrangement of Propargyl Alcohols
Figure 60: Cr(VI) Rearrangements
115
O
Cr
R3
HH
R1
H+
O
R2
O
R3
F
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
Eq (22)
O
78 oC to rt
96 %
58
O
"catalyst"
OH
n-Bu
n-Bu
113
114
4.0 equiv PCC
Eq (23)
Complex Mixture
113
CH2Cl2, reflux
Eq (24)
Eq (25)
113
113
5.0 equiv MnO2
benzene, reflux
S
C
N N
N
N
No Reaction
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
HO
n-BuLi, THF
Eq (26)
78 oC to rt
quantitative
117
116
115
4.0 equiv PCC
Eq (27)
Complex Mixture
117
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,β-unsaturated ketone 122 was obtained (Eq 29, Figure 63).
5.0 equiv. Ethanol
1 mol% NaAuCl4, 2H2O
OH
Eq (28)183 Ph
O
Ph
C5H11 DCM, rt, 24 h
Ph
Ph
OH
10 mol% AuCl3, DCM
Ph
Ph
C5H11
119 60%
118
Eq (29)
OEt
2.5 equiv. Ethanol
rt, 24 h
117
Ph
Ph
117
120 40%
OEt
Ph
Ph
O
Ph
Ph
121 40%
Figure 63: Initial Gold(III) Experiment
C5H11
122 60%
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
Ph
Ph
OH
Ph
AuCl3, H2O
Ph
Solvent
Ph
Ph
122
117
Entry Substrate
Mol %
Solvent
AuCl3
a
O
Equiv.
H2O
Temperature
Time
%
C
h
Conversiona
0
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%
% 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,βunsaturated 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 AuCl 3 (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
o
C for 24 hours (entries 12 and 13).
Although complete conversion of propargyl alcohol 117 could be achieved with 5 mol %
of AuCl3 in acetonitrile at 60 oC 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
Ph
Ph
OH
Ph
117
Ph
5 mol% AuCl3
O
Ph
MeCN, 60 oC
24 h
Ph
122
By-Product
123
Entry
Substrate
Equivalents of H2O
Ratio of 122 to 123a
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 % AuCl3,
3.0 equiv. H2O
OH
Ph
Ph
Ph
Ph
Ph
MeCN, 2 h
Entry
1
2
3
4
5
6
a
Substrate
117
117
117
117
117
117
Ph
122
117
o
Mol % AuCl3
1
5
10
10
20
50
% Conversion determined by 1H NMR
Temperature C
60
60
60
25
60
60
b
O
By-Product
123
% Conversiona
< 10
50
100
50
100
100
Amount of 123b
N.D.
High
High
High
Low
Low
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
water in CH3CN at 60 oC as our standard conditions. The triphenyl tertiary propargyl alcohol
117 rearranged cleanly to afford α,β-unsaturated ketone 122 in 90 % yield (Eq 30, Figure 64).
Switching to the secondary propargyl alcohol 124 proved to be detrimental. The expected α,βunsaturated 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.
Eq (30)
20 mol % AuCl3
3.0 equiv. H2O
OH
Ph
Ph
Ph
117
MeCN, 60 oC
18 hr
20 mol % AuCl3
3.0 equiv. H2O
OH
Eq (31)
Bu
a
124
OH
Ph
Eq (32)
c
126
MeCN, 60 oC
18 hr
20 mol % AuCl3
3.0 equiv. H2O
MeCN, 60
18 hr
Ph
Ph
O
Ph
122 90%
O
Bu
125b 16%
Ph
oC
127 79%
a
124 was prepared from 1-hexyne addition to benzaldehyde in an 84% yield
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
b
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.
20 mol % AuCl3
3.0 equiv. EtOH
OH
Ph
Ph
Eq (33)
Ph
117
Ph
Ph
CH2Cl2, rt
18 hr
Ph
122 87%
20 mol % AuCl3
3.0 equiv. EtOH
OH
Eq (34)
O
O
Bu
Bu
124
OH
Ph
Eq (35)
126
a
CH2Cl2, rt,
18 hr
125a 44%
20 mol % AuCl3
3.0 equiv. EtOH
Ph
O
Ph
CH2Cl2, rt
18 hr
127 57%
128 31%
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
O
Eq (36)
OEt
Ph
n-BuLi, THF
78 oC to rt
Ph
115
H
131
a
Ph
OEt
129 99%
OH
O
Eq (37)
20 mol % AuCl3
5.0 equiv. EtOH
Ph OH
OEt
132 92%
O
OEt
Ph
130 99%
20 mol % AuCl3
5.0 equiv. EtOH
OEt
n-BuLi, THF
78 oC to rt
CH2Cl2, rt
< 5 min
Ph
CH2Cl2, rt
< 5 min
O
OEt
133a 86%
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 AuCl 3-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
R2
20 mol % AuCl3
5.0 equiv. EtOH
OH
R2
R1
3
E
R
2
R3
R1
CH2Cl2, rt
3
O
F
Entry
1
R
R
R
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
OEt
136
< 5 min
137
> 95
OEt
138
< 5 min
139
86
cyclohexyl
6
adamantyl
7
t-Bu
Me
a
CH3CN was used as the solvent and the reaction was heated to 60 oC b Isolated yield of pure product,
unless otherwise indicated
Table 8: Catalyst Loading and Optimizationa
R2
OH
R1
JJ
Entry
1
2
3
4
5
6
7
8
R1
adamantyl
adamantyl
adamantyl
adamantyl
adamantyl
Ph
t-Bu
n-Bu
R2
AuCl3, rt, 5 min
OEt
R2
Ph
Me
n-Bu
5 equiv EtOH, CH2Cl2
Substrate
136
136
136
136
136
129
138
140
a
OEt
R1
AuCl3
20 mol %
10 mol %
5 mol %
1 mol %
0.1 mol %
5 mol %
5 mol %
5 mol %
O
KK
Product
137
137
137
137
137
130
139
141
Conversion (%)
> 95
> 95
> 95
ca. 50b
< 5b
> 95
> 95
> 95
Typical procedure: Gold(III)chloride added to a solution of propargyl alcohol (1 equiv), EtOH
(5 equiv), and CH2Cl2 in an open flask at room temperature. See Chapter 7 for details. b After 24 h.
124
With the rearrangement under control, attention was switched to streamlining the twostep 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,βunsaturated 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
R1
1. BuLi, H
O
G
Entry
2. AuCl3 (5 mol %)
EtOH (5 equiv), CH2Cl2
Substrate
Ph
R3
R1
KK
Yield (%)
Ph
O 115
Ph
O
2
3
O
Product
Ph
1
R2
OEt, THF
CO2Et
CO2Et
O 143
O
137
99
139
99b
96c
144
CO2Et
145
68%
(84%)c,d
5
146
O
6
CO2Et 147
O
CO2Et
148
149
a
d
91
CO2Et
142
4
130
73
(85)d
See Chapter 7 for details. bCa. 4:3 ratio of olefin isomers. c Ca. 2:1 ratio of olefin isomers.
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
AuCl3 (5 mol %)
EtOH (5 equiv),
OH
OEt
O
CH2Cl2
OEt
138
Entry
1
2
3
4c
5
139
o
Time
5 min
5 min
24 h
20 min
17 h
Temperature C
25
0
25
78
78 to 30
E/Z Ratiob
3:4
2:3
2:3
2:1
2:1
Yield (%)
93
99
99
84
99
a
Typical procedure: Gold(III) chloride added to a solution of propargyl alcohol 138 (1 equiv), EtOH
(5 equiv), and CH2Cl2 at the indicated temperature. b Determined by 1H NMR c 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.
catalyst (10 mol%)
additive (10 equiv)
OH
150
OEt
O
OEt
solvent, r.t
151
P.AuCl
catalyst: AuCl AgSbF6 > AuCl3, AuCl, Ph3
>> 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
5 mol% AuCl/AgSbF6
10 equiv EtOH
OH
O
R
LL
Entry
1aa
R
THFCH2Cl2 (1:1)
rt, 3060 min
OEt
Substrate
OEt
MM
Yield (%, E/Z)
Product
OH
O
1bb
91 (97:3)
OEt
93 (E only)
OEt
150
151
a
O
OH
2a
2bb
OEt
OEt
O
OH
b
3b
5
90 (86:14)
155
154
4aa
91 (63:37)
OEt
5
OEt
82 (99:1)
153
152
3aa
80 (94:6)
O
OH
4bb
75 (57:43)
OEt
OEt
157
156
128
78 (70:30)
Table 11: Continued
5 mol% AuCl/AgSbF6
10 equiv EtOH
OH
R
LL
OEt
THFCH2Cl2 (1:1)
rt, 3060 min
Entry
Substrate
5aa
OH
O
R
OEt
MM
O
72 (40:60)
OEt
b
5b
OEt
70 (40:60)
159
158
6aa
Yield (%, E/Z)
Product
O
OH
6bb
90 (47:53)
OEt
OEt
92 (91:9)
133
132
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
Eq (38)
139
TsOH (20 mol %)
EtOH (5 equiv),
138
CH2Cl2
Eq (39)
138
138 +
70%
1 equiv. AcOH
139
15%
no reaction
THF:CH2Cl2 1:1
50 mol% HCl
Eq (40)
138
THF:CH2Cl2 1:1
1h
138
33%
+
139
67%
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 βhydroxy 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,β-unsaturated ester 151.
130
OH
O
[Au+], EtOH
OEt
OEt
151
150
[Au+]
H
EtOH
O
Au
Au+
+ EtOH
 H2O
•
OEt
160
OEt
OEt
161
OH
OEt
OEt
H2O
[Au+]
H
162
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,β-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,β-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 transesterification. Therefore, n-propanol incorporation must occur before product formation, which
is consistent with our mechanistic hypothesis.
OH
5 mol % AuCl/AgSbF6
10 equiv n-PrOH
OEt
150
THFCH2Cl2 (1:1)
r.t. 30 min
O
O
151
50%
Figure 70: Incorporation of External Alcohol Additive
131
OPr
OEt
163
50%
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 HfCl 4 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, HfCl 4 was competitive
with the aforementioned catalysts in terms of cost.
132
Table 12: Screening of Alternative Catalysts
OH
1 mol% catalyst
C5H11
154
OEt
CH2Cl2/EtOH
CO2Et
C5H11
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.
8
Cu(C5H4F3O2)b
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
14
Pd(OAc)2
24
<100%c
63:37
15
Sc(OTf)3
1.2
100%
90:10
16
PtCl4
24
Trace
17
AuCl3
24
a
As observed by 1H NMR. b Copper(II) trifluoroacetylacetonate
detected by TLC analysis but not by 1H NMR after workup.
n.d
c
<100%
c
>20:1
Ethoxyacetylene 197 could be
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-4methylpyridine (DTBMP), and 1.0 equivalent magnesium oxide (MgO).
133
The effect of the
additives on the reaction rate (qualitatively) and the stereoselectivity (quantitatively) of the
reaction are summarized in Table 13.
Table 13: Effect of Additives
1 mol% catalyst
<additive>
OH
C5H11
154
OEt
CO2Et
C5H11
CH2Cl2/EtOH
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
10
Cu(OTf)2
MgO
1.0 equiv
24b
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
15
Sc(OTf)3
MgO
1.0 equiv
24c
n.d.
a
As observed by 1H NMR
b
Conversion (60%)
134
c
Conversion (30%)
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
R1
R2
G
a
H
OEt
n-BuLi, THF
78 oC to rt
R1
R2
OH
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
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 cosolvent 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 tri135
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
R1
R2
OH
OEt
Entry
Substrate
1a
2a
R1
CO2Et
R1
CH2Cl2/EtOH (4:1)
R2
Product
Cu(OTf)2
154
Sc(OTf)2
n-Heptyl
155
H
Yield (%)b
E/Z Ratioc
53
91:9
63
E only
3
Cu(OTf)2
64
97:3
4
Sc(OTf)2
70
E only
71
E only
75
E only
94
E only
97
E only
86
57:43
89
58:42
90
76:24
93
77:23
5
156
6
7
9
150
12
Cyclohexyl
157
H
Cu(OTf)2
tert-Butyl
151
H
Sc(OTf)2
138
10
11
Cu(OTf)2
Sc(OTf)2
8
a
Catalyst
R2
1 mol% catalyst
Cu(OTf)2
tert-Butyl
139
Me
Sc(OTf)2
132
Cu(OTf)2
Phenyl
133
H
Sc(OTf)2
EtOH (5.0 equiv) in CH2Cl2
b
Isolated yield
c
1
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.
OH
CO2Et
OEt
Boc
H
N
156
1 mol% Sc(OTf)3, 1 h
O
rt, CH2Cl2/EtOH (4:1)
OMe
157, 75% yield
Boc
H
N
OR
O
OMe
OTBS
R = H: 167
R = TBS: 168
168, 99% recovery
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
HornerWadsworthEmmons reaction (refer to Chapter 3).
137
the use of the
Table 16: Two-Stage Olefination of Ketones and Aldehydes
O
R1
1.Li
R2
R2
OEt
2.MeyerSchustera
G
Entry
Substrate
1
()-menthone 58
CO2Et
R1
KK
Product
CO2Et
Yield (%)b
E/Z Ratioc
98
n.d.e
97
58:42
99
_
96
_
60
_
78
_
93
39:61
80
E only
169
2
verbenone 144
CO2Et
3
145
benzophenone 115
CO2Et
4
adamantanone 142
130
CO2Et
137
CO2Et
5
4-tert-butyl cyclohexanone
170
171
CO2Et
6
cycloheptanone 172
7
acetophenone 174
173
CO2Et
175
8
CO2Et
pivaldehyde 166
151
138
Table 16: Continued
O
R1
1.Li
R2
R2
OEt
2.MeyerSchustera
G
Entry
CO2Et
R1
KK
Substrate
Product
Yield (%)b
E/Z Ratioc
94
89:11
94
89:11
97
36:61d
80
E only
CO2Et
9
()-perillaldehyde 176
177
CO2Et
10
4-methoxybenzaldehyde 178
11
2-furaldehyde 180
179
O
O
CO2Et
181
F
12
pentafluorobenzaldehyde
182
F
CO2Et
F
183
F
F
a
b
1 mol % Sc(OTf)3, CH2Cl2/EtOH (4:1) Isolated yield c Determined by 1H 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 812). 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).
1 mol% Sc(OTf)3
5 equiv n-PrOH
OH
Eq (38)
CH2Cl2
OEt
O
O
OEt
OPr
151
150
163
25 : 75 ratio!
O
OEt
Eq (39)
1 mol% Sc(OTf)3
5 equiv n-PrOH
151
CH2Cl2, 24 h
O
OPr
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 β-hydroxy ester byproducts, 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,β-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
LL
CO2Et
R
CH2Cl2/EtOH
OEt
MM
EtOH
H2O
R
NN
•
EtOH
EtOH
OEt
OEt
R
OEt
OEt
OEt
OO
OH
OEt
OEt
H2O
EtOH
R
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,β-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,β-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
1 mol% Sc(OTf)3
<n-propanol>
OH
150
a
CO2R
CH2Cl2
OEt
R = Et, 151
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
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
H-NMR and
13
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
the residual CHCl3 peak (7.26 ppm for 1H NMR, 77.0 ppm for
13
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
chromatography using silica gel F-254 (230-499 mesh particle size).
144
perfomed
by
flash
OH
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 MgSO 4,
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-methylcyclohexanol (113) in 96 % yield (0.45 g) as a clear colorless oil.
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
1
(dt, J = 13.6, 3.7 Hz, 1H), 2.20 (t, J = 7.2 Hz, 2H), 2.35-2.45 (m, 1H);
13
C 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
HO
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 MgSO 4,
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.
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,
1
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
OH
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.
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
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
OH
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 MgSO 4,
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).
light yellow oil; 1H 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 AuCl 3, 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 2neck, 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
1,3,3-triphenyl-propenone [122]: yellow oil; 1H NMR (300 MHz, CDCl3)  7.12 (s, 1H), 7.167.21 (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]
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,
1
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]
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
1
(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 AuCl 3 (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-3methyl-3-tert-butyl-1-propyn-3-ol (138) in 83 % yield (0.34g).
Ph
Ph
OH
129
OEt
3-ethoxy-1,1-diphenyl-prop-2-yn-1-ol (129): yellow oil; 1H 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);
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)
13
3543, 3444, 3060, 2982, 2263, 1450, 1170, 1004, 640 cm-1; HRMS (EI) Calcd for C17H16O2
(M+) 252.1150. Found 252.1153.
159
OH
132
OEt
3-Ethoxy-1-phenyl-prop-2-yn-1-ol [132]
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
1
Hz, 2H), 5.51 (d, J = 6.0 Hz, 1H), 7.31-7.40 (m, 3H), 7.48-7.59 (m, 2H);
13
C 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,
1718, 1450 cm-1; 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.
OH
OEt
134
4-tert-butyl-1-ethoxyethynyl-cyclohexanol [134]: white solid; 1H 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);
13
C
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.
OH
OEt
136
2-ethoxyethynyl-adamantan-2-ol [136]: clear, colorless oil; 1H 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,
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,
13
35.9, 38.0, 39.8, 43.2, 72.7, 74.6, 93.9; IR (neat) 3426, 2902, 2854, 2666, 2259, 1712, 1450,
1247, 1010, 916, 866 cm-1; HRMS (CI) Calcd for C14H20O2 (M+H+) 221.1542. Found 221.1538.
160
OH
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,
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,
13
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.
OH
OEt
150
1-Ethoxy-4,4-dimethyl-pent-1-yn-3-ol [150]: 1H NMR (300 MHz, CDCl3)  0.97 (s, 9H), 1.38
(t, J = 7.1 Hz, 3H), 4.03 (d, J = 6.0 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H); 13C 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.
OH
OEt
152
1-Ethoxy-5-phenyl-pent-1-yn-3-ol [152]: 1H 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,
2H), 4.41 (ap. q, J = 5.3 Hz, 1H), 7.16-7.31 (m, 5H);
13
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,
2862, 2262, 1722, 1603, 1496 cm-1; HRMS (EI) calcd for C13H16O2 (M+) 204.1145. Found
204.1150.
161
OH
OEt
154
1-Ethoxy-dec-1-yn-3-ol [154]: 1H 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,
1H);
13
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,
74.4, 93.5; IR (neat) 3381, 2927, 2263, 1722, 1467 cm-1; HRMS (CI) calcd for C12H22O2
(M+H+) 199.1698. Found 199.1692.
OH
OEt
156
1-Cyclohexyl-3-ethoxy-prop-2-yn-1-ol [156]: 1H 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);
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
13
(neat) 3411, 2980, 2460, 1719, 1450 cm-1; HRMS (CI) calcd for C11H18O2 (M+H+) 183.1385.
Found 183.1390.
OH
OEt
158
1-Cyclohex-1-enyl-3-ethoxy-prop-2-yn-1-ol [158]: 1H 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);
13
C 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.
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
Typical procedure for preparation of α,β-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
Ethyl 3,3-diphenylpropenoate [130]: yellow oil; 1H 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.
O
OEt
133
Ethyl cinnamate [133]: yellow oil; 1H 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,
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,
13
59.4, 112.7, 163.5, 166.9; IR (neat) 3412, 2948, 2867, 1716, 1648, 1478, 1365, 1247, 1143,
1041, 862 cm-1; 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.
O
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
(q, J = 7.1 Hz, 2H), 5.74 (q, J = 1.1 Hz, 1H); 1H 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 =
1.3 Hz, 1H); 13C 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,
1719, 1634, 1466, 1372, 1262, 1182, 1123, 1054, 868 cm-1; HRMS (EI) Calcd for C10H18O2
(M+) 170.1307. Found 170.1306.
183
O
OEt
141
3-butyl-hept-2-enoic acid ethyl ester [141]: clear, colorless oil: 1H 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
(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
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,
2872, 1716, 1642, 1466, 1378, 1190, 1147, 1039, 862 cm-1; HRMS (CI) Calcd for C13H24O2
(M+H+) 213.1855. Found 213.1857.
184
185
186
187
188
189
190
191
192
193
Typical two-step procedure for preparation of α,β-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 CH 2Cl2, 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,
2H), 5.32 (s, 1H), 7.13 (s, 1H); 1H 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),
2.53-2.63 (m, 2H), 4.08-4.20 (m, 2H), 5.46 (s, 1H), 5.77 (s, 1H); 13C 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,
colorless oil; 1H NMR (300 MHz, CDCl3) diagnostic resonance signals for E and Z isomers
appeared at  5.58 (br t, J = 2.3 Hz, 1H), 5.64 (br t, J = 2.0 hz, 1H);
13
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
cm-1; 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
(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,
13
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,
1646, 1461, 1376, 1229, 1154, 1043, 862 cm-1; HRMS (EI) Calcd for C14H24O2 (M+) 224.1776.
Found 224.1771.
195
196
197
198
199
200
201
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 SiO 2 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)
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), 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 CH 2Cl2–THF (5 mL) was then added
dropwise. After 40 min, the reaction mixture was filtered through a plug of SiO 2 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 %).
O
OEt
151
Ethyl (E)-4,4-dimethyl-pent-2-enoate [151]
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),
1
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
O
OEt
153
Ethyl 5-phenyl-pent-2-enoate [153]
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 =
1
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.
O
OEt
155
(E)-Dec-2-enoic acid ethyl ester [155];
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
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.
O
OEt
157
(E/Z)-3-Cyclohexyl-acrylic acid ethyl ester [157]:
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
1
(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), 3.233.34 (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
O
OEt
159
(E/Z)-3-(1-Cyclohexen-1-yl)-2-propenoic acid ethyl ester [159]:
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
1
(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), 2.172.2 (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.
204
205
206
207
208
209
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]:
H NMR (300 MHz, CDCl3, E/Z-mixture, diagnostic peaks)  2.55 (ddd, J = 12.9, 5.5, 1.5 Hz),
1
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);
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,
13
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.
O
OEt
173
Cycloheptyliden-acetic acid ethyl ester [173]:
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),
1
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.
O
O
175
(E/Z)-Ethyl-β-methyl cinnamate [175]:
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
1
(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
O
O
177
(E/Z)-3-(4-Isopropenyl-cyclohex-1-enyl)-acrylic acid ethyl ester [177]:
Diagnostic peaks 1H 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
O
179
O
(E/Z)-Ethyl-3-(4-methoxyphenyl)-2-propenoate [179]:
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,
1
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]:
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,
1
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]:
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
1
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.
213
214
215
216
217
218
219
220
221
222
223
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240
BIOGRAPHICAL SKETCH
Birth Place
Waukesha, Wisconsin
• February 24, 1982
Educational Background
Florida State University, Tallahassee, FL
• August 2004 to August 2009
• Ph.D. in Organic Chemistry (anticipated completion in August 2009)
• Research Advisor: Professor Gregory B. Dudley
Georgia Southern University, Statesboro, GA
• August 2000 to May 2004
• 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, 2009–present
• serving Florida’s emerging biotech industry with premium organic synthesis on demand
• http://www.flsynth.com
Honors and Awards
• MDS Fellowship, 2004–present
• Florida State University Fellowship, 2005-2006, 2007-2008
• American Institute of Chemists Foundation Outstanding Senior Award, 2004
• Georgia Southern Physical Chemistry Award, 2003
• Georgia Southern Organic Chemistry Award, 2002
• Bovey Foundation Scholarship, 2000
• Bird Scholarship, 2000
• Governors Scholarship, 2000
Teaching
• Teacher’s Assistant for Organic Chemistry I, CHM 2210
241
• 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, 235 th 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, 231 st 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.
242