gold- and copper-catalyzed activation of...
TRANSCRIPT
GOLD- AND COPPER-CATALYZED ACTIVATION OF ALKYNES
By
LINDSEY GRAHAM DERATT
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2017
© 2017 Lindsey Graham DeRatt
To my family, friends and teachers
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ACKNOWLEDGMENTS
I cannot even begin to think where I would be without those who helped shape
me into the person and professional I am today. I would like to begin with
acknowledging those who have supported me throughout my life endeavors.
I would like to thank my parents for their unwavering support and for always
putting their children’s needs before their own. They spent so much of their time
attending all school and athletic events for both me and my sisters. They instilled in me
the confidence, work ethic and determination to be successful in all that I do. I also want
to thank my sisters, Barbara and Jamie, for being an invaluable support system. I know
I can always count on them to give advice, whether I ask for it or not, and add in a few
laughs during trying times. This probably should be much more emotional, but that’s not
the DeRatt way.
I greatly appreciate all that Nick Paci has done for me over the last several years.
He has been a constant source of support whenever things got difficult and has been
endlessly encouraging throughout my time in graduate school.
I do not have the words to express my gratitude to my advisor, Professor Aaron
Aponick, for all that he has taught me over the last 5 years. His patience in teaching
chemistry concepts to his students is something that I greatly admire and hope to be
able to imitate in the future. He has really created a great atmosphere for learning and I
am thankful to have had the privilege of learning from such a creative and hard-working
individual.
I could not have imagined a better learning environment than that of the Aponick
Lab. I have had the privilege of working alongside and learning from some very
talented, creative and genuinely good people. I have enjoyed all of our chemistry
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discussions and appreciate the time you all have taken to proofread documents and
brainstorm ideas throughout the years. I will miss the time spent with you all both in and
out of the lab.
I also need to thank Dr. Jeremy Morgan for introducing me to synthetic organic
chemistry research. The training I received from both him and Katie Scholl set the
foundation that has aided me throughout graduate school. Their enthusiasm for
chemistry inspired me and showed me that I wanted to do organic chemistry research
for my career.
Lastly, I need to express my appreciation to my committee members, Professors
Alexander Grenning, Ronald Castellano, Leslie Murray and Yousong Ding for all of their
help during my doctoral studies. They have provided invaluable suggestions and
guidance throughout this process.
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TABLE OF CONTENTS page
ACKNOWLEDGMENTS .................................................................................................. 4
LIST OF FIGURES .......................................................................................................... 8
LIST OF ABBREVIATIONS ........................................................................................... 13
ABSTRACT ................................................................................................................... 18
CHAPTER
1 LATE TRANSITION METAL-CATALYZED ACTIVATION OF ALKYNES ............... 20
Introduction ............................................................................................................. 20
-Bonded Activation of Alkynes .............................................................................. 22
1,2-Addition ...................................................................................................... 22 1,4-Addition ...................................................................................................... 28
Allylic Systems ................................................................................................. 30 Cross-Coupling ................................................................................................. 31
Azide-Alkyne Cycloadditions ............................................................................ 33 Propargylations ................................................................................................ 34
-Bonded Activation of Alkynes .............................................................................. 35
Addition of Heteroatoms ................................................................................... 35 Addition of Metals ............................................................................................. 43
Cycloisomerizations/Cycloadditions ................................................................. 48
Carbonylations ................................................................................................. 51 Reductions ....................................................................................................... 53 Oxidations ........................................................................................................ 54
Miscellaneous Reactions ........................................................................................ 56
Dissertation Overview ............................................................................................. 58
2 APPLICATION OF A TANDEM GOLD-CATALYZED CYCLIZATION/DIELS-ALDER REACTION IN A SIMPLE APPROACH TO INDOLOCARBAZOLES ......... 60
Indolocarbazole Background and Significance ....................................................... 60 Approaches to Indolocarbazole Core ...................................................................... 63
Formation of C then B, D Rings ........................................................................ 64 Formation of C Ring from Indole Substrates .................................................... 65
Formation of C, B, D Rings in Single Step ........................................................ 67 Sequential Formation of C then B then D Ring ................................................. 68
Development of the Tandem Gold-Catalyzed Cyclization/Diels-Alder Sequence ... 69 Our Synthetic Approach to Indolocarbazoles .......................................................... 72 Conclusions and Outlook ........................................................................................ 81
3 COPPER-CATALYZED ASYMMETRIC ALKYNYLATION OF CHROMONES ....... 83
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Chromanone Prevalence ........................................................................................ 83
Enantioselective Synthesis of Chromanones and Flavanones ............................... 84
Activation of Chromone........................................................................................... 88 Asymmetric Alkynylation of Chromones .................................................................. 90
Reaction Optimization and Scope .................................................................... 93 Determination of Absolute Stereochemistry ..................................................... 98 Versatility of Products ..................................................................................... 100
Conclusion ............................................................................................................ 102
4 DESIGN AND SYNTHESIS OF METHYLASE INHIBITORS ................................ 103
Histone Methylation: Metnase ............................................................................... 103 Design, Synthesis, and Biological Activity of Inhibitors ......................................... 104
Inhibitors with Lactam Scaffold ....................................................................... 105
Inhibitors with Tertiary Amine Scaffold ........................................................... 108
Conclusions and Outlook ...................................................................................... 116
5 EXPERIMENTAL SECTION ................................................................................. 118
General Considerations ........................................................................................ 118
Preparation of Indolocarbazoles ........................................................................... 119 Preparation of Alkynes .......................................................................................... 128
Preparation of Chromones .................................................................................... 131 Asymmetric Alkynylation of Chromones ................................................................ 134 Determination of Stereochemistry ......................................................................... 157
Preparation of Methylase Inhibitors ...................................................................... 159
LIST OF REFERENCES ............................................................................................. 178
BIOGRAPHICAL SKETCH .......................................................................................... 192
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LIST OF FIGURES
Figure page 1-1 Example of end-on bonding orbital interactions .................................................. 21
1-2 Example of side-on bonding orbital interactions ................................................. 22
1-3 General transition metal-catalyzed 1,2-addition.................................................. 23
1-4 Watson’s copper-catalyzed alkynylation of isochroman ketals ........................... 23
1-5 Megger’s alkynylation of trifluoromethylketones ................................................. 24
1-6 Li’s cross-dehydrogenative alkyne coupling with tetrahydroisoquinolines .......... 25
1-7 Shibasaki’s copper-catalyzed alkynylation of imines .......................................... 26
1-8 Coupling of diazo compounds with alkynes ........................................................ 26
1-9 Wang’s coupling of N-tosylhydrazones with alkynes .......................................... 27
1-10 Wang’s coupling of diazo compounds with alkynes to form chiral allenes .......... 27
1-11 General conjugate alkynylation reaction ............................................................. 28
1-12 Aponick’s asymmetric alkynylation of Meldrum’s acid acceptors ........................ 29
1-13 Pedro and Glay’s asymmetric addition to β-trifluoromethylenones ..................... 29
1-14 Alkyne addition to allylic systems ....................................................................... 30
1-15 Linear-selective alkynylation of Morita-Baylis-Hillman adducts........................... 30
1-16 Asymmetric alkynylation of primary allylic phosphates ....................................... 31
1-17 General mechanism for cross-coupling reaction with alkynes ............................ 32
1-18 Hu’s Sonogashira coupling with alkyl halides at room temperature .................... 32
1-19 Shi’s cross-dehydrogenative alkyne coupling ..................................................... 33
1-20 Copper-catalyzed azide-alkyne cycloaddition (CuAAC) ..................................... 34
1-21 Catalytic propargylic substitution reactions ......................................................... 34
1-22 Guo’s asymmetric addition of enamines to propargyl acetates........................... 35
1-23 General transition metal-catalyzed additions to alkynes ..................................... 36
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1-24 Nolan’s gold-catalyzed hydroalkoxylation of internal alkynes ............................. 37
1-25 Ferreira’s vicinal bis-heterocyclizations of alkynes ............................................. 38
1-26 Li’s copper-catalyzed cascade reaction .............................................................. 39
1-27 Love’s transition metal-catalyzed hydrothiolation in total synthesis .................... 40
1-28 Cui’s double hydrophosphination of alkynes ...................................................... 42
1-29 Vadola’s gold-catalyzed hydroarylation of N-arylalkynamides ............................ 42
1-30 Mechanism of metal addition across alkynes ..................................................... 44
1-31 Petit’s hydrosilylation of alkynes ......................................................................... 45
1-32 Yun’s hydroboration of alkynes........................................................................... 46
1-33 Buchwald’s hydroamination of alkynes using CuH catalyst ................................ 47
1-34 Gillaizeau’s carbozincation of ynamides catalyzed by cobalt ............................. 48
1-35 General cycloisomerization of 1,n-enynes .......................................................... 49
1-36 Gagne’s enantioselective gold-catalyzed cycloisomerization ............................. 50
1-37 Michelet’s synthesis of 2-aminopyridines ........................................................... 50
1-38 Transition metal-catalyzed carbonylation of alkynes mechanism ....................... 52
1-39 Alper’s conditions for the carbonylation of alkynes ............................................. 52
1-40 Lindhardt’s trans-selective reduction of alkynes ................................................. 54
1-41 Proposed mechanism for the oxidation of alkynes with transition metals ........... 55
1-42 Li’s oxidation of internal alkynes ......................................................................... 55
1-43 Zhang’s synthesis of cyclopentanones ............................................................... 56
1-44 Enyne metathesis ............................................................................................... 57
1-45 Enyne metathesis to form cyclic homoallylic alcohols ........................................ 57
1-46 Enantioselective Pauson-Khand ......................................................................... 58
2-1 Structural arrangements of indolocarbazoles ..................................................... 61
2-2 Diversity in indolo[2,3-a]carbazole natural products ........................................... 62
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2-3 Summary of access to indolo[2,3-a]carbazole core ............................................ 63
2-4 Raphael’s approach to arcyriaflavin core ............................................................ 64
2-5 Bergman’s approach to arcyriaflavin core .......................................................... 65
2-6 Wallace’s approach to arcyriaflavin core ............................................................ 66
2-7 Uang’s approach to arcyriaflavin core ................................................................ 66
2-8 Zhu’s approach to arcyriarubin core ................................................................... 67
2-9 Saulnier’s approach to arcyriaflavin core ............................................................ 68
2-10 Tomé’s approach to unsymmetrical arcyriaflavin core ........................................ 69
2-11 General strategies towards vinyldihydropyrans .................................................. 70
2-12 Gold-catalyzed diene synthesis .......................................................................... 71
2-13 Substrate scope of tandem reaction ................................................................... 72
2-14 Retrosynthetic strategy ....................................................................................... 73
2-15 Synthesis of requisite propargyl alcohols and gold-catalyzed dehydrative cyclization ........................................................................................................... 74
2-16 Optimization of Diels-Alder reaction ................................................................... 75
2-17 Reductive cyclization attempts using trivalent organophosphorous reagents ..... 76
2-18 Reductive cyclization attempts using Grignard reagents .................................... 77
2-19 C–H amination attempts ..................................................................................... 78
2-20 Mechanism of the formation of carbazoles using MoO2Cl2(dmf)2 ....................... 79
2-21 Reductive cyclization with oxotransfer catalyst ................................................... 80
2-22 Overall synthetic route to unsymmetrical arcyriaflavin A .................................... 81
3-1 Select members of the flavonoid family of natural products ............................... 83
3-2 Chromanone prevalence in natural products and analogues ............................. 84
3-3 Intramolecular versus intermolecular conjugate additions to access 2-substituted chromanones ................................................................................... 85
3-4 Diastereoselective conjugate addition approach to chromones .......................... 86
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3-5 Liao’s conjugate addition of sodium tetraarylborates to chromones ................... 86
3-6 Hoveyda’s conjugate addition of dialkylzinc reagents to chromone .................... 87
3-7 Feringa’s conjugate addition of Grignard reagents to chromones ...................... 88
3-8 Activation of chromone ....................................................................................... 89
3-9 Mattson’s asymmetric functionalization of chromones ........................................ 89
3-10 General strategy for the asymmetric alkynylation of chromones ........................ 90
3-11 Atropisomeric P,N-ligands .................................................................................. 91
3-12 Ground state stabilization of StackPhos ............................................................. 92
3-13 General synthesis of StackPhos ligands ............................................................ 92
3-14 Enantioselective StackPhos-enabled alkynylation reactions .............................. 93
3-15 Optimization of reaction conditions ..................................................................... 95
3-16 Alkyne Scope...................................................................................................... 96
3-17 Chromone Scope ................................................................................................ 97
3-18 Incompatible chromones and pyrones ................................................................ 98
3-19 Determination of absolute stereochemistry ........................................................ 98
3-20 Proposed stereochemical model ........................................................................ 99
3-21 Versatility of the scaffold ................................................................................... 101
4-1 SET and MAR domains of Metnase ................................................................. 104
4-2 Lead compound CH7126443 ............................................................................ 105
4-3 Synthesis of 4-4 ................................................................................................ 106
4-4 Synthesis of 4-9 ................................................................................................ 106
4-5 Synthesis of 4-11 .............................................................................................. 107
4-6 Epoxide opening with benzyl amines ................................................................ 107
4-7 Protein-ligand interactions and docking images of SAM and 4-18.................... 109
4-8 Synthesis of 4-21 .............................................................................................. 109
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4-9 Synthesis of 4-18 .............................................................................................. 110
4-10 Protein-ligand interactions and docking image of 4-25 ..................................... 110
4-11 Synthesis of 4-25 .............................................................................................. 111
4-12 Protein-ligand interactions and docking image of 4-30 ..................................... 111
4-13 Synthesis and Metnase methylase inhibitory activity of 4-30 ............................ 112
4-14 Protein-ligand interactions and docking image of 4-36 ..................................... 113
4-15 Synthesis and Metnase methylase inhibitory activity of 4-36 ............................ 114
4-16 Protein-ligand interactions and docking image of 4-42 ..................................... 115
4-17 Synthesis and Metnase methylase inhibitory activity of 4-42 ............................ 116
5-1 General preparation of aromatic alkynes .......................................................... 128
5-2 Synthesis of isoflavone ..................................................................................... 131
5-3 General procedure for the alkynylation of chromones ...................................... 134
5-4 Preparation of 4-4 ............................................................................................. 159
5-5 Preparation of 4-13 ........................................................................................... 163
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LIST OF ABBREVIATIONS
Å Angstrom(s)
Ac Acetyl
aq Aqueous
Ar Aryl
atm atmosphere
Bn Benzyl
Boc Tert-butyloxycarbonyl
BPE 1,2-bis(phospholano)ethane
Bz Benzoyl
C Celsius or centigrade
Cat Catalyst
cm Centimeter
Cp cyclopentadienyl
Cy Cyclohexyl
d Doublet
DABCO 1,4-diazabicyclo[2.2.2]octane
DCM Dichloromethane
DCC N,N-dicyclohexylcarbodiimide
de Diastereomeric excess
DIPEA N,N-diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMDO Dimethyldioxirane
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
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dppf 1,1’-bis(diphenylphosphino)ferrocene
dppp 1,3-bis(diphenylphosphino)propane
dr Diastereomeric ratio
dtbbpy di-tert-butyl-2,2’-bypyridyl
DTBM (3,5-di-tert-butyl-4-methoxyphenyl)phosphine
dtbpmb 1,2-Bis(di-tert-butylphophinomethyl)benzene
EDG Electron donating group
ee Enantiomeric excess
equiv. Equivalent
Et Ethyl
EWG Electron withdrawing group
g Gram
h Hour
HPLC High performance liquid chromatography
HRMS High-resolution mass spectra
Hz Hertz
IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene
iPr isopropyl
IR Infrared
JohnPhos (2-biphenyl)di-tert-butylphosphine
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
m Multiplet
M Metal
m/z Mass-to-charge ratio
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Me Methyl
Mes Mesityl
mg Milligram
MHz Megahertz
min Minute
mL Milliliter
mM Millimolar
mmol Milimol
MP Melting point
MS Molecular sieves
MTBD 7-methyl-1,5,7,triazabicyclo[4.4.0]dec-5-ene
MW Microwave
NBS N-Bromosuccinimide
nBu Normal (primary) butyl
NHC Nitrogen heterocyclic carbene
NMP N-methyl-2-pyrrolidone
NMR Nuclear magnetic resonance
Nuc Nucleophile
p Pentet
PDC Pyridinium dichromate
Pg Protecting group
Ph Phenyl
phen phenanthroline
PIFA [Bis(trifluoroacetoxy)iodo]benzene
ppm Part(s) per million
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PPSE Trimethylsilyl polyphosphate
PPTS Pyridinium para-toluenesulfonate
ppy 2,2’-phenylpyridyl
q Quartet
R Alkyl or aryl
rac Racemic
Rf Retention factor
rt Room temperature
s Second or singlet
t Triplet
TBAF Tetrabutylammonium fluoride
TBDPS Tert-butyldiphenylsilyl
TBS Tert-butyldimethylsilyl
tBu Tert-butyl
TC Thiophene carboxylate
TES Triethylsilyl
Tf Trifluoromethanesulfonyl
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
THF Tetrahydrofuran
THP Tetrahydropyran
TIPS Triisopropylsilyl
TLC Thin-layer chromatography
TMS Trimethylsilyl
TOF Time-of-flight mass analyzer
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tr Retention time
Ts Para-toluenesulfonyl (tosyl)
UV Ultraviolet
W Watts
α Observed optical rotation in degrees
Δ Delta or heat
G Gibbs free energy change
H Enthalpy change
S Entropy change
δ Chemical shift in parts per million downfield from tetramethylsilane
L Microliter
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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
GOLD- AND COPPER-CATALYZED ACTIVATION OF ALKYNES
By
Lindsey Graham DeRatt
August 2017
Chair: Aaron Aponick Major: Chemistry
The use of various transition metal complexes to catalyze organic
transformations of alkynes forms the basis for many well-known methods for carbon-
carbon and carbon-heteroatom bond formation. In Chapter 1, a review of the modes of
activation that are achieved upon metal complexation to alkynes and the inherent
reactivity that alkyne complexes possess based on these modes of activation is
covered. Recent examples from the literature which demonstrate advances in this field
are also presented.
In the context of activation of alkynes toward electrophilic attack, in Chapter 2 we
report a tandem gold-catalyzed dehydrative cyclization/Diels-Alder reaction. This
methodology was then used in a strategic approach towards the arcyriaflavin A
skeleton, an indolocarbazole natural product. The convergent design allows for the
synthesis of unsymmetrical cores with the potential for various substitution around the
aromatic rings. Additionally, the synthetic plan allows for indole nitrogen differentiation
for regioselective functionalization.
In terms of using alkynes as nucleophiles, we have recently reported numerous
enantioselective alkynylation reactions employing a novel P,N-ligand, namely
19
StackPhos, developed in our lab. Using this ligand, in Chapter 3 we report a copper-
catalyzed synthesis of enantioenriched 2-alkynylchromanones. The reaction tolerates a
broad scope with respect to both the alkynes and chromones employed. In addition, we
demonstrate the versatility of these products with various elaborations to biologically
relevant substructures.
The use of small molecules to inhibit or promote protein functions is a growing
field in medicinal chemistry and chemical biology. In Chapter 4, we report the first small
molecule methylase inhibitors of Metnase. Metnase is a novel protein recently isolated
and characterized by the Hromas lab. In this collaboration, we docked potential targets
using the Schrodinger Glide program and compounds with high docking scores were
then synthesized and the in vitro inhibitory activity was tested. Thus far, these
compounds have exhibited the best inhibitory activity (µM) for this target to date.
20
CHAPTER 1 LATE TRANSITION METAL-CATALYZED ACTIVATION OF ALKYNES
Introduction
Alkynes are extremely versatile reagents used throughout all areas of chemistry.
In particular, recent developments in the transition metal-catalyzed reactions of alkynes
have enabled the synthesis of diverse products.1 The popularity of alkynes in catalytic
transformations is partially due to the two distinct modes of bonding the alkyne can
achieve with transition metal complexes. Investigations of the chemistry of both
andbonded metal-alkyne complexes have led to the development of new catalytic
pathways. This chapter will highlight how late transition metal catalysts activate alkynes
for the formation of carbon-carbon and carbon-heteroatom bonds.
In the end-on binding mode, terminal alkynes and transition metals form a -
bond when a base is present to intercept the alkyne’s acidic hydrogen or via a cross-
dehydrogenative pathway. Because acetylide and carbon-monoxide are isoelectronic,
this type of bonding can be compared to well-studied metal-carbonyl complexes. 2 The
dominant bonding model considers the metal-alkyne bond in terms of overlap of a) an
sp orbital of the acetylide with an empty metal orbital and b) an occupied d orbital of the
metal with an empty -orbital of the acetylide (Figure 1-1).The relative contributions of
-donation and -backbonding3 as well as which orbitals are involved in bonding can
vary depending on the specific metal complex. In general, this end-on bonding mode
generates a nucleophilic metal acetylide which can undergo various transformations,
such as 1,2- and 1,4-additions, cycloadditions and cross-coupling reactions.
21
Figure 1-1. Example of end-on bonding orbital interactions
In catalysis, a widely proposed interaction of alkynes with transition metals is the
side-on bonding mode. The transition metal can function as a -acid, which can
coordinate to the -system of the alkyne altering the nature in an opposite manner than
discussed above, generating an electrophilic species (Figure 1-2). The -bonding
between transition metal complexes and alkynes is typically explained in terms of the
Dewar-Chatt-Duncanson model which dictates that four principle components contribute
to the metal-alkyne bonding.4 The -system of the alkyne donates electrons to an empty
metal d orbital resulting in a -donation component. Additionally, a filled metal d orbital
can donate electrons back to the ligand *-orbital resulting in a -backbonding
component. The orthogonal, out-of-plane -orbitals of the alkyne can engage in ligand
to metal -donation while the empty out-of-plane *-orbital can mix with an occupied d
orbital for an additional component of metal to ligand backbonding. The latter two
interactions result in significantly weaker overlap; thus, the metal-alkyne bonding of
interest can predominately be discussed in terms of the initial two components for the
complexes of interest to this review.5 This electrophilic metal-alkyne complex can
undergo a separate set of transformations including electrophilic additions by
heteroatoms, alkenylations, cycloisomerizations, cycloadditions, etc.
22
Figure 1-2. Example of side-on bonding orbital interactions
While most reactions fall under these two subsets, there are other transition
metal-catalyzed reactions with alkynes that do not easily fall into these groups and
examples of these reactions will be discussed separately. This chapter is not intended
to be a comprehensive review of transition metal-catalyzed reactions of alkynes, but
aims to display the differing reactivity of alkynes based on their binding mode with
transition metals and use select recent literature examples to demonstrate the directions
this field is heading.
-Bonded Activation of Alkynes
Transition metal-alkynyl complexes have been used extensively throughout
organic synthesis as a catalytic source of carbanions as well as transmetalation
reagents. As such, the typical reactions of -complexed metal-alkynes include
nucleophilic additions to various electrophiles and as partners in cross-coupling
reactions. This section will discuss recent examples of these reactions as well as the
use of metal-alkynyl complexes in click and propargylation reactions. In all cases, the
metal acetylide species is generated from the terminal alkyne catalytically in situ.
1,2-Addition
The in situ generation of metal acetylides enables an efficient method for
catalytic carbon-carbon and carbon-heteroatom bond formation. The propargyl scaffolds
23
generated are important building blocks for natural product synthesis, pharmaceuticals
and pesticides.6 Focusing on 1,2-addition reactions, the most common substrates are
carbonyls, oxocarbenium ions, imines and iminium ions (Figure 1-3).7
Figure 1-3. General transition metal-catalyzed 1,2-addition
The addition of alkynes to carbon-oxygen double bonds is an efficient method to
form propargyl alcohols. Mary Watson has been a pioneer in the copper-catalyzed
alkynylation of cyclic oxocarbenium ions.8 Her strategy involves the installation of a
leaving group alpha to the oxygen and the use of a Lewis acid to generate the
oxocarbenium in situ. In the latest report, the formation of tetrasubstituted stereocenters
by the addition of terminal alkynes to isochroman ketals 1-4 was achieved using a chiral
PyBox ligand 1-6 (Figure 1-4).9 High yields and selectivities were observed for an array
of isochroman ketals as well as alkynes.
Figure 1-4. Watson’s copper-catalyzed alkynylation of isochroman ketals
24
The asymmetric addition of alkynes to aldehydes has also been reported with
primarily copper10 and zinc11 transition metal catalysts. Ketones are more challenging
substrates due to their lower electrophilicity. Recently, Meggers and coworkers
developed a chiral-only-at-metal ruthenium catalyst 1-7 for a highly selective
alkynylation of trifluoromethylketones 1-8 (Figure 1-5).12 They were able to achieve low
catalyst loadings (0.5 mol %) for the efficient and highly enantioselective formation of
chiral tertiary alcohols.
Figure 1-5. Megger’s alkynylation of trifluoromethylketones
The addition to carbon-nitrogen double bonds has been well developed over the
years, generating biologically important racemic and -chiral amines.13 The addition of
alkynes to iminiums and imines is one of the most reported alkynylation reactions due to
the ease of generating these groups in situ.14 For this reason, couplings of aldehydes,
alkynes and amines (A3 coupling); and ketones, alkynes and amines (KA2 coupling) are
the most prevalent transformations for the generation of propargyl amines. Furthermore,
imines and iminiums can be generated from the corresponding enamine under the
reaction conditions allowing for alkynylation starting from these substrates as well.15
25
Additional reported reactions include the activation of basic nitrogen heterocycles with
acylating agents to promote the alkynylation.16
In terms of iminiums, both aldiminiums17 and ketiminiums18 have been
demonstrated to undergo nucleophilic attack by terminal alkynes to give trisubstituted
and tetrasubstituted stereocenters, respectively. In a recent example, Li and coworkers
merged photoredox catalysis for the generation of the iminium ion of
tetrahydroisoquinolines 1-10 with copper catalysis to yield optically active 1-alkynyl
tetrahydroisoquinolines 1-11 (Figure 1-6).19 Good yields and high enantioselectivities
were achieved at low temperatures and low catalyst loadings. The absolute
stereochemistry was not determined in the products.
Figure 1-6. Li’s cross-dehydrogenative alkyne coupling with tetrahydroisoquinolines
The alkynylation of imines is much more challenging than iminiums due to their
lower reactivity. Furthermore, the susceptibility of ketimines to nucleophilic attack is
significantly lower than aldimines. A recent report by Shibasaki and coworkers describe
the direct catalytic asymmetric alkynylation of ketimines 1-12 (Figure 1-7).20 Their
strategy included incorporation of a thiophosphinyl group on the nitrogen which
undergoes activation by the catalyst. Using copper catalysis with a chiral bisphosphine
26
ligand (S,S)-Ph-BPE, they achieved moderate selectivities in the propargyl amine
products 1-13. They further used this methodology in an enantioselective synthesis of a
potent antimalarial agent, KAE609.21
Figure 1-7. Shibasaki’s copper-catalyzed alkynylation of imines
It is well-known that the reactions of metal carbenes with alkynes typically
provide the cyclopropene products,22 however under certain conditions an alternative
reaction may occur (Figure 1-8). The direct coupling of diazo compounds with terminal
alkynes is an attractive method to construct C(sp)-C(sp3) bonds from readily available
fragments.23 These coupling reactions are proposed to follow a common reaction
pathway involving migratory insertion of the alkyne in the carbenoid species 1-15 to
form 1-16. Depending on the site of protonation, the allene 1-1724 or the alkynylation
product 1-1825 is obtained.
Figure 1-8. Coupling of diazo compounds with alkynes
27
Wang and coworkers have developed the use of N-tosylhydrazones as coupling
partners in metal-catalyzed reactions, forming the diazo compound in situ.26 In 2012,
they discovered that the use of N-tosylhydrazones 1-19 as reaction partners with
trialkylsilylacetylenes 1-20 provided the alkynylation product 1-21 (Figure 1-9).27 The
use of other alkynes provided the allene product.
Figure 1-9. Wang’s coupling of N-tosylhydrazones with alkynes
Within the past year, the Wang group also demonstrated the enantioselective
synthesis of trisubstituted allenes starting with the disubstituted diazo compound 1-22
directly, presumably to avoid high temperature conditions (Figure 1-10).28 The
transformation generated the chiral trisubstituted allenes 1-23 in high yields and
selectivities under copper(I) conditions with a chiral bisoxazoline ligand 1-24.
Figure 1-10. Wang’s coupling of diazo compounds with alkynes to form chiral allenes
28
1,4-Addition
The transition metal-catalyzed conjugate addition reaction of carbon nucleophiles
to Michael acceptors is a powerful method for the construction of carbon-carbon bonds
(Figure 1-11).29 A number of different metals have been used to accomplish this
transformation such as rhodium,30 copper,31 zinc,32 ruthenium33 or cobalt34 with a range
of different Michael acceptors. Recent advances in this field focus on the development
of enantioselective conjugate additions for the synthesis of optically active building
blocks.
Figure 1-11. General conjugate alkynylation reaction
After Carreira’s seminal report, Meldrum’s acid acceptors emerged as ideal
substrates for conjugate additions as the adducts are versatile in subsequent synthetic
transformations. .35 A recent report from our group demonstrated the alkyne addition to
Meldrum’s acid acceptors 1-27 using copper catalysis (Figure 1-12).36 Enabled by a
newly developed class of ligands, namely StackPhos, the reaction tolerates a wide
range of alkynes yielding the products 1-28 in high yields and selectivities. Additionally,
the enantioselective synthesis of preclinical agent OPC 51803 1-29, was achieved using
this methodology.
29
Figure 1-12. Aponick’s asymmetric alkynylation of Meldrum’s acid acceptors
Pedro and Glay have shown the conjugate alkynylation of less electrophilic
enones, specifically β-trifluoromethylenones 1-30 (Figure 1-13).37 Using copper
conditions with a diphosphine ligand, (R,R)-taniaphos 1-31, furnished the corresponding
β-alkynylcarbonyl compounds 1-32 in moderate to high yields and selectivities but under
extended reaction times.
Figure 1-13. Pedro and Glay’s asymmetric addition to β-trifluoromethylenones
30
Allylic Systems
The Tsuji-Trost reaction, a palladium-catalyzed allylation of carbon nucleophiles,
represents an important reaction in organic synthesis and has been widely developed.38
However, the alkynylation of allylic systems can be a challenging feat as the 1,4-dienes
may be formed as potential side-products.39 Thus, examples of the addition of terminal
alkynes to allylic systems is extremely limited and have only been reported within the
past few years. The alkynylation can occur at either end of the allylic system providing
the linear 1,4-enyne 1-34 or a chiral branched 1,4-enyne 1-35 (Figure 1-14).
Figure 1-14. Alkyne addition to allylic systems
In 2015, Liu and coworkers reported a palladium-catalyzed allylic alkynylation of
Morita-Baylis-Hillman adducts 1-37 with (triisopropyl)acetylene in water (Figure 1-15).40
The corresponding linear 1,4-enynes 1-38 were obtained in moderate to high yields.
Figure 1-15. Linear-selective alkynylation of Morita-Baylis-Hillman adducts
The enantioselective allylic alkynylations of alkynes has been reported with
iridium and copper catalysts using stoichiometric amounts of metal acetylides.41
However, the first example of using a terminal alkyne directly in an enantioselective
allylic alkynylation was only recently reported by Sawamura and coworkers (Figure 1-
31
16).42 They achieved a copper-catalyzed allylic alkynylation with primary allylic
phosphates 1-40 with excellent branch selectivity and high enantioselectivity.
Figure 1-16. Asymmetric alkynylation of primary allylic phosphates
Cross-Coupling
The earliest examples of alkyne cross-coupling reactions include the
Sonogashira43 and Glaser-Hay reactions.44 These reactions are powerful methods in
both academia and industry for the formation of internal alkynes (Figure 1-17). The
mechanism of cross-coupling reactions generally proceeds through oxidative addition of
an organic halide 1-43, followed by transmetalation with the metal acetylide 1-45. After
cis/trans-isomerization, the reductive elimination step yields the coupled alkyne product
1-48. In comparison to the coupling of terminal alkynes with aryl or alkenyl halides,45 the
coupling of alkyl halides continues to remain a challenge. This is primarily due to the
difficulty of alkyl halides to undergo oxidative addition and the low propensity of
reductive elimination of an sp3 carbon-metal species to occur.46
32
Figure 1-17. General mechanism for cross-coupling reaction with alkynes
The Hu group recently reported a new catalyst for the directly alkylation of
terminal alkynes at room temperature (Figure 1-18).47 In this work, they designed a
nickel pincer complex 1-51 that enabled the transformation with good substrate scope
and high functional group tolerance. They also provided some insight to the mechanism
of this transformation which suggests the pincer ligand is hemilabile, and the
dissociation of the amine donor is the turnover-determining step. They were able to
isolate and characterize the metal-alkyne complex, and proposed that a second
equivalent of the alkyne coordinates to promote the dissociation of one of the amine
donors of the ligand.
Figure 1-18. Hu’s Sonogashira coupling with alkyl halides at room temperature
33
Alternatively, instead of oxidative addition, the reaction pathway can initiate with
a C–H activation step. This avoids the need for a prefunctionalized or organic halide
coupling partner and is formally called a cross-dehydrogenative coupling.48 Though the
generation of a strong acid is avoided by this method, elevated temperature is a
common requirement for these reactions to proceed. Most of the recent work has
focused on the C–H activation of unactivated sp3 carbons. A very recent example was
reported by Shi and coworkers using nickel and copper catalysis for the construction of
C(sp3)-C(sp) bonds.49 The amide functionality in 1-52 was needed as a directing group
to provide the β-alkynylamides 1-53 in moderate yields.
Figure 1-19. Shi’s cross-dehydrogenative alkyne coupling
Azide-Alkyne Cycloadditions
Using a metal catalyst to enable cycloaddition of terminal alkynes with azides
allows for a reliable and regiospecific method for the synthesis of important 1,2,3-
triazoles 1-56 (Figure 1-20).50 In the majority of these reactions, copper is employed as
the transition metal catalyst so that this transformation is formally named the copper-
catalyzed azide-alkyne cycloaddition reaction (CuAAC). Click chemistry has been used
extensively in drug discovery, bioconjugation, polymer, and supramolecular chemistry.51
34
Recently developed methods in this class of reactions rely on the transmetalation or
reaction with electrophilic reagents of the cuprate-triazole 1-55 with other reagents to
form fully substituted triazoles.52
Figure 1-20. Copper-catalyzed azide-alkyne cycloaddition (CuAAC)
Propargylations
Thus far, the metal acetylide formed is nucleophilic in nature, however, if a
terminal propargyl alkyne is employed, an electrophilic metal allenylidene intermediate
1-58 is formed, enabling functionalization at the -carbon (Figure 1-21). 53 A variety of
heteroatom- and carbon-centered nucleophiles such as alcohols, amines, amides,
thiols, phosphine oxides, β-diketones, and silyl enol ethers can be introduced at the
propargylic position by this method. Furthermore, if a chiral metal complex is utilized,
products 1-59 can be obtained enantioselectively.54
Figure 1-21. Catalytic propargylic substitution reactions
Propargyl acetates are the most common electrophiles used in these
transformations and copper being the most popular choice in metal. An asymmetric
variant reported by Guo and coworkers involved the addition of enamines 1-60 to
propargyl acetates 1-61 using copper catalysis (Figure 1-22).55 The final product
generated is highly enantioenriched -substituted carbonyl compounds 1-62.
35
Figure 1-22. Guo’s asymmetric addition of enamines to propargyl acetates
-Bonded Activation of Alkynes
Achieving chemical transformations by taking advantage of the activation of
unsaturated systems is one of the most successful concepts in transition metal
catalysis. The coordination of a -bond to a metal center generates an electrophilic
species facilitating the functionalization of unsaturated systems. In particular, a plethora
of transformations have been developed which include alkyne activation by
complexation of a transition metal.
Addition of Heteroatoms
One of the most widely used reactions of unsaturated carbon-carbon bonds is
the nucleophilic addition by heteroatoms.56 These reactions have green chemistry
features because there is no waste formation and can, in principle, be performed with
complete atom economy. This method is extremely powerful to introduce carbon,
nitrogen, oxygen, sulfur, and phosphorous atoms across alkynes to form valuable
alkenyl organic compounds.45 Furthermore, the intramolecular hydrofunctionalization
establishes a means to access heterocycles in a straightforward manner. The use of
36
transition metal catalysts allows for the electrophilic addition of alkynes to proceed
under mild conditions and with the capability to achieve high regio- and
stereoselectivities, a challenge that is commonly encountered with addition to
unsymmetrical alkynes, based on catalyst design.
In general, most late transition metal-catalyzed nucleophilic additions to alkynes
go through the same steps (Figure 1-23a). First, coordination of the alkyne to the metal
complex occurs followed by an anti-nucleophilic attack to produce a trans-alkenyl metal
intermediate 1-65. Although beyond the scope of this review, the vinyl metal
intermediate formed can react further with other electrophiles or undergo
protodemetalation to afford the product 1-66 and regenerate the catalyst. Alternatively,
with some nucleophiles, an inner sphere mechanism is proposed (Figure 1-23b). In this
case, the (E)-isomer 1-70 is the observed product arising from syn-addition.
Figure 1-23. General transition metal-catalyzed additions to alkynes a) Outer sphere mechanism b) Inner sphere mechanism
Oxygen: The addition of alcohols to alkynes is a direct pathway for the synthesis
of enol ethers, carbonyl compounds and oxygen-containing heterocycles. Avoiding the
use of harsh reaction conditions and the need for strong bases, many transition metals
37
have been demonstrated to be effective catalysts for this transformation. The textbook
example for alkyne hydration uses mercury(II),57 however both gold58 and palladium59
catalysts have been the most predominate in recent years. As mentioned above, the
intermolecular addition of water or alcohols to alkynes can suffer from regioselectivity
issues, especially in the case of unsymmetrical internal alkynes.60 Strategies focusing
on catalyst design or through substrate directing groups have been developed to
circumvent this issue.61
Recently, Nolan and coworkers reported a solvent-free intermolecular
hydroalkoxylation of symmetrical and unsymmetrical internal alkynes 1-48 using primary
1-71 and secondary alcohols 1-72 to form enol ethers while avoiding the formation of
typically seen by-products 1-75 and 1-76 (Figure 1-24).62 Using gold N-heterocyclic
carbene (NHC) catalysts, a broad range of (Z)-vinyl ethers were obtained in high
selectivity. In the case of unsymmetrical alkynes, a mixture of regioisomers was
obtained with substrate electronics dictating the preferred site of nucleophilic attack.
Figure 1-24. Nolan’s gold-catalyzed hydroalkoxylation of internal alkynes
38
As previously mentioned, intramolecular hydroalkoxylation of alkynes yields
interesting oxygen-containing heterocycles such as furan, pyran and benzofuran
derivatives. Our group has found success in developing these types of transformations
with gold and palladium.63 Taking advantage of this reactivity, Ferreira and coworkers
recently reported a novel platinum-catalyzed double heterocyclization of propargylic
ethers 1-77 (Figure 1-25).64 Upon the first 5-endo-dig cyclization, the second pendant
alcohol is proposed to intercept an ,-unsaturated carbene intermediate 1-78. This
report demonstrates the synthesis of vicinal bis-heterocyclic compounds 1-79 under
mild conditions. Interestingly, compared to the platinum catalyst, both gold and
palladium catalysts gave different reactivity with these substrates.
Figure 1-25. Ferreira’s vicinal bis-heterocyclizations of alkynes
Nitrogen: The addition of nitrogen nucleophiles across carbon-carbon triple
bonds is analogous to the previously discussed hydroalkoxylation reactions with both
inter- and intramolecular variants being known. In turn, hydroamination of alkynes
39
provides valuable nitrogen-containing compounds such as imines, enamines and N-
heterocyclic systems. Indoles are prevalent heterocycles synthesized by this method.65
This class of hydrofunctionalization of alkynes has been well developed over the
years and most reports of hydroalkoxylations also include examples of the
hydroamination equivalent. Thus, a recent report using a hydroamination cyclization as
a step in a tandem sequence will be presented as an example (Figure 1-26). In 2016, Li
and coworkers reported a copper-catalyzed cascade reaction that initiated with a 5-
endo-dig cyclization of a homopropargylic amine 1-80, followed by an intermolecular
Povarov reaction with imines 1-81.66 This method provides access to hexahydro-1H-
pyrrolo[3,2-c]quinoline derivatives 1-82, a unique motif found in natural product alkaloids
of Martinella iquitosensis.
Figure 1-26. Li’s copper-catalyzed cascade reaction
Sulfur: Though vinyl sulfides are of great synthetic utility67 and sulfur-containing
compounds are frequently found in natural products exhibiting biological activity,68 the
40
transition metal-catalyzed addition of thiols to alkynes is often less explored compared
to its oxygen and nitrogen equivalents.69 Consequently, both inter- and intramolecular
reactions are known but with much more limited examples. This is partially due to the
widespread belief that organosulfur compounds strongly bind to the catalyst and poison
the reaction.70 The intermolecular reactions are predominately performed on terminal
alkynes with palladium catalysts, providing primarily branched Markovnikov products.71
A few palladium72 and rhodium73 catalysts allow access to the anti-Markovnikov
products. The intramolecular hydrothiolation allows access to thiophenes under
relatively mild conditions.74 Mechanistically, based off the olefin product geometry, the
transformation is generally proposed to proceed through an inner sphere pathway.
In 2016, Love and coworkers reported the first use of transition metal-catalyzed
alkyne hydrothiolation in total synthesis in their approach to K777 1-86, a potent
cysteine protease inhibitor (Figure 1-27).75 Using Wilkinson’s catalyst, they were able to
achieve the formation of vinyl sulfide 1-85 in high yields and anti-Markovnikov selectivity
towards the (E)-linear isomer. The observed stereochemistry suggests that a syn-
addition mechanism is operative.
Figure 1-27. Love’s transition metal-catalyzed hydrothiolation in total synthesis
Phosphorous: Organophosphines serve as important reagents in synthetic
organic chemistry.76 Hydrophosphination of alkynes is a direct approach for the
41
synthesis of organophosphorous compounds, however this transformation can be
complicated by many issues.77 The chelating effects of phosphine promotes
substrate/product coordination to the metal and can result in catalyst poisoning during
the reaction. If a primary phosphine is used as the reactive partner, both single and
double activation can occur generating a mixture of products. For these reasons, the
area of transition metal-catalyzed hydrophosphinations of alkynes has significant room
for growth and development.78 As with hydrothiolations, terminal alkynes are the primary
substrates and an inner sphere mechanism is typically proposed, whereby the
phosphorous nucleophile is coordinated to the metal center before attack to give the
syn-addition product. Additionally, P(V) nucleophiles are known to add to alkynes to
provide hydrophosphinylation79 and hydrophosphorylation80 products. Rhodium,
palladium, and nickel catalysts are popular choices for the addition of phosphorous
nucleophiles across unsaturated bonds.
The addition of two phosphines across an alkyne using primary phosphines is
extremely challenging and has only been reported within the last five years.81 Cui and
coworkers very recently reported the catalytic double phosphination of terminal alkynes
1-2 using diphenylphosphine 1-87 and a copper-NHC system (Figure 1-28).82 The
double hydrophosphination of alkynes generates valuable 1,2-bis(phosphino)ethanes 1-
88.
42
Figure 1-28. Cui’s double hydrophosphination of alkynes
Carbon: Transition metal-promoted hydroarylation provides an approach to the
preparation of styrene, stilbene, chalcone and olefinic derivatives.83 Since haloarenes
and other arene electrophiles are not used, this procedure is simpler than those based
on Heck reactions and cross couplings. Additionally, other classes of carbon
nucleophiles, such as enolate derivatives, can be used to form carbocycles and other
scaffolds.84
Recently, Vadola used a gold-catalyzed hydroarylation of N-aryl alkynamides 1-
90 in a novel route to biologically important 2-quinolinones 1-91 (Figure 1-29).85 The
transformation proceeded with high functional group tolerance and yields.
Figure 1-29. Vadola’s gold-catalyzed hydroarylation of N-arylalkynamides
43
Addition of Metals
The addition of metal-carbon or metal-hydrogen bonds to alkynes is an attractive
process for the construction of complex molecules. This method provides a
straightforward way to generate stable or reactive vinylorganometallic species that can
be used in subsequent transformations including cross-coupling, addition and other
reactions. The hydro- or carbometalation of alkynes usually begins with an oxidative
addition or -bond metathesis step to form a transition metal-hydride or transition metal-
metal intermediate which then coordinates to the alkyne to form complex 1-92. Thus,
this class of reactions typically falls under the inner sphere mechanism and
predominately produces syn-addition products. The resulting mechanism is usually
discussed according to the Chalk-Harrod mechanism (Figure 1-30, path a).86 After
insertion of the transition metal-hydrogen/carbon bond (X-[M1]) to form 1-93, then
reductive elimination to form the vinylcarbon-[M2] bond, the vinyl metal product is
generated. Alternatively, a modified Chalk-Harrod mechanism has been proposed,
suggesting that the alkyne inserts in the [M1]-[M2] bond to form a vinyldimetal species 1-
94 (Figure 1-30, path b). Following reductive elimination 1-95 is formed. The
conventional product is the (E)-isomer, however the ligands on the catalyst and solvent
can be tuned to favor the formation of the trans-addition products.87
44
Figure 1-30. Mechanism of metal addition across alkynes
Silicon: Vinylsilanes are attractive platforms in synthesis due to their low cost,
minimal toxicity, ease of handling and compatibility with many organic transformations.
This makes them versatile building blocks which can be employed in further
transformations including oxidation, electrophilic substitutions, cross-couplings
(Hiyama), nucleophilic additions, etc. 88 However, the synthetic utility of the
alkenylsilanes remains dependent on their regio- and stereoselective synthesis.89
Recently cobalt-based90 catalysts have been developed to achieve selective formation
of the desired alkenylsilane, however many other transition metals can be employed. 91
The cost of using platinum and other noble metals to obtain organosilanes has
spurred research efforts to develop nonprecious metal replacements. In this respect,
iron92 and cobalt90,93 catalysts have recently emerged as promising candidates to
replace the more expensive, less abundant noble metals in hydrosilylation reactions.
Petit and coworkers have shown that a low-valent cobalt complex, HCo(PMe3)4, can
catalyze the complete regio- and stereoselective hydrosilylation of unsymmetrical
internal alkynes (Figure 1-31).94 They achieved complete regioselectivity by using
alkynes with an apparent large and small group. Additionally, the reaction is compatible
45
with tertiary and alkoxysilane substrates. Their experimental studies suggest that a
typical Chalk-Harrod mechanism is operable with the (E)-isomer 1-97 predominately
formed in high yields. Complete regioselectivity is observed when there is an obvious
small and large group on the alkyne.
Figure 1-31. Petit’s hydrosilylation of alkynes
Boron: Organoboron reagents are remarkably valuable precursors in organic
synthesis. Their use as carbon nucleophiles allows for their transformation into a wide
range of organic compounds containing diverse functional groups.95 The carbon-carbon
bond forming processes that vinylboranes undergo such as Suzuki-Miyaura coupling96
and Petasis reaction,97 are essential for the synthesis of biologically active molecules
and functional materials. 98 As with alkenylsilanes, alkenyl boranes have advantages
over other alkenylorganometallics with their bench stability and easy-to-handle
properties. In addition, they also have low toxicity and high functional group
compatibility. New synthetic methods allowing for regio- and stereocontrolled synthesis
of these compounds are highly pursued. In this context, extensive work has been
devoted to developing hydroboration reactions of alkynes under transition metal
catalysis conditions, a direct and practical method to access vinylboron compounds.
Typically, products with (E) stereochemistry are observed resulting from anti-
Markovnikov, syn-addition of the B–H bond. However, though the selective formation of
46
the (Z)-isomers is more challenging, new catalysts for this transformation have recently
been developed.99
Yun and coworkers developed two sets of conditions for the hydroboration of
terminal alkynes 1-99 under copper-catalyst conditions (Figure 1-32).100 With a
diphosphine ligand and CuTC as the metal, the (Z)-isomer 1-101 is formed in complete
selectivity. Alternatively, when an NHC-copper complex is used, the formation of the
(E)-isomer 1-102 forms.
Figure 1-32. Yun’s hydroboration of alkynes
Copper: One of the most popular hydrometalation reactions of alkynes is
hydrocupration.101 The electrophilic functionalization of the alkenyl copper intermediate
leads to a variety of functionalized olefins.102 Alternatively, this method can be used to
obtain the partial reduction of alkynes to the corresponding cis-olefins if protonation of
the vinylmetal species occurs.103
Contrary to previously discussed examples in this review, the functionalization of
the alkenyl copper species will be the focus in this example. Buchwald and coworkers
recently reported the direct preparation of enamines in high regio- and stereoselectivity
(Figure 1-33).104 The transformation was accomplished using a silane to reduce the
copper metal to a copper hydride species, which underwent hydrocupration with internal
47
alkynes 1-103. The alkenyl copper species was then quenched with an electrophilic
nitrogen source 1-104, providing the (E)-enamines 1-105. In all examples, less than 5%
of the other regioisomer was observed.
Figure 1-33. Buchwald’s hydroamination of alkynes using CuH catalyst
Magnesium, aluminum, zinc: Carbon-carbon -bonds are generally unreactive
towards nucleophilic metal reagents such as Grignards, organoaluminums, and
organozincs. However, employing transition metal catalysis, carbometalation of alkynes
achieves the formation of valuable, highly reactive alkenyl metal reagents.105 Similar to
the previous discussion of copper-based reagents, due to their high nucleophilicity, the
vinyl metal intermediates generated are typically quenched with an electrophile to
provide multisubstituted alkenes.106
A recent example of carbometalation of alkynes was described by Gillaizeau and
coworkers (Figure 1-34).107 Their work focused on the carbozincation of ynamides 1-
106 under cobalt-catalyzed conditions. The proposed mechanism includes the insertion
of the alkyne into the aryl-cobalt bond. Transmetalation between the alkenyl cobalt
species with the arylzinc reagent 1-107, followed by protonation yields the 3-aryl
48
enamides 1-108 as a single regioisomer. The reaction proceeded in high yields under
mild conditions with good functional group tolerance.
Figure 1-34. Gillaizeau’s carbozincation of ynamides catalyzed by cobalt
Cycloisomerizations/Cycloadditions
The following section will describe the cycloisomerization of alkynes catalyzed by
transition metals. There are many different variations that fall under the broad scope of
cycloisomerization reactions depending on the reactive partners as well as the number
of unsaturated bonds involved. Alkynes can have multiple reaction partners, such as
other alkynes, alkenes, allenes, and carbonyl/imine systems for the cycloisomerization
leading to a variety of different carbocycles and heterocycles.108 If multiple unsaturated
bonds are incorporated in the substrates, extremely complex polycyclic scaffold can be
accessed in a single transformation. Cycloisomerizations are rearrangements of
polyunsaturated systems by which carbon-carbon bonds are formed and one degree of
unsaturation is consumed to make a cyclic product.109 Such rearrangements are an
atom-economical approach to cyclic or bicyclic compounds as no formal loss or gain of
atoms take place. Notably, transition metal catalysts activate polyunsaturated
substrates enabling the formation of carbon-carbon bonds under mild conditions.
49
The cycloisomerization of 1,n-enynes is one of the most well-known
isomerization reactions. These transformations provide access to complex molecules
from readily assembled substrates through an intramolecular process. Many different
mechanisms can arise leading to an array of products. In addition to the expected Alder-
ene product from 1-109, mechanisms involving cyclopropyl metal carbenes 1-110 and
1-111 can be used to explain other observed products (Figure 1-35). These
intermediates, in the absence of a nucleophile, rearrange into 1-112 and 1-113.
Figure 1-35. General cycloisomerization of 1,n-enynes
Recently, chiral catalysts have been employed to render cycloisomerization
reactions asymmetric.110 An example of an enantioselective gold-catalyzed
cycloisomerization of 1,5-enynes 1-114 was reported by Gagné and coworkers (Figure
1-36).111 After the cycloisomerization, a ring-expansion lead to bicyclo[4.2.0]octanes 1-
115, a scaffold found in numerous biologically active natural products. The
transformation proceeded in high yields with moderate selectivities.
50
Figure 1-36. Gagne’s enantioselective gold-catalyzed cycloisomerization
Additionally, alkynes can react with external reactive partners leading to the
corresponding cycloaddition products. As mentioned previously, this reaction class is
extensive and multiple different reaction partners can be used. To focus on a prevalent
reactivity pattern, the [2+2+2] cycloaddition of alkynes is a widely-used method for the
synthesis of aromatic systems. In 2017, Michelet reported an efficient cycloaddition
approach using diynes 1-116 and cyanamides 1-117 for the preparation of 2-
aminopyridines 1-118 catalyzed by a ruthenium complex (Figure 1-37).112 In the cases
of unsymmetrical diyne substrates, high regioselectivities were observed.
Figure 1-37. Michelet’s synthesis of 2-aminopyridines
51
Carbonylations
Carbonylation reactions introduce a C=O moiety across unsaturated substrates
to generate a diverse range of carbonyl compounds.113 The transition metal-catalyzed
carbonylation of alkynes in the presence of nucleophiles constitutes an important type of
three-component reaction to access a range of carboxylic acids, ester, and amides. This
process is generally known as the Reppe carbonylation, and palladium is one of the
most frequently used metals.114 Hydroformylation is a special case of carbonylation of
unsaturated substrates in which hydrogen is the nucleophile and the corresponding
aldehyde is formed.115 The ratio of linear and branched -unsaturated carbonyl
products is largely dependent on the catalytic system, the substrate, and the
nucleophiles. Carbonylation reactions are particularly useful in the industrial setting and
there is an increasing interest in the development of regio- and chemoselective
transition metal catalysts. Furthermore, due to the toxicity and physical properties of
carbon monoxide, surrogates have been applied to achieve these transformations.116
A general mechanism for the transition metal-catalyzed carbonylation of terminal
alkynes can be depicted as shown below (Figure 1-38).117 The catalytic cycle begins
with a metal-hydride species 1-119, which is usually formed by the reaction of the
precatalyst with acid additives. Subsequent coordination then insertion of the alkyne
yields 1-121. Further insertion of carbon monoxide generates an acyl metal complex
which undergoes nucleophilic attack to form the enone 1-123 and regenerate the metal-
hydride.
52
Figure 1-38. Transition metal-catalyzed carbonylation of alkynes mechanism
As mentioned previously, depending on the regiochemistry of the metal-hydride
insertion step, a mixture of linear and branched products can be formed. Recently, Alper
reported two sets of conditions for the aminocarbonylation of alkynes (Figure 1-39).118
By employing different ligands and additives, branched and linear isomers could be
selectively formed. Using boronic acid and 5-chlorosalicylic acid as the additives, the
linear amides 1-125 were formed where the use of p-toluenesulfonic acid monohydrate
as the additive produced the branched isomer 1-126. To demonstrate the application of
this strategy, the natural product avenanthramide A 1-127 was synthesized directly via
the carbonylation of 2-amino-5-hydroxybenzoic acid and 4-ethynylphenol.
Figure 1-39. Alper’s conditions for the carbonylation of alkynes
53
Reductions
Olefins are biologically important structures in pharmaceuticals, natural products,
and industrial chemicals.119 The stereochemistry of the carbon-carbon double bond can
be a decisive factor for the biological activity as it dictates the geometry of the molecule.
The stereoselective catalytic partial hydrogenation of internal alkynes using hydrogen
provides valuable disubstituted alkenes. Heterogeneous catalysts, such as Lindlar’s
catalyst,120 have been widely used to reduce alkynes to the corresponding cis-olefins.
However, the stereocomplementary formation of the trans-olefin is much more
challenging. Dissolving metal reduction conditions have been used to form the trans-
isomer, however the conditions employed limit the functional group tolerance.121 The
recent processes for partial reduction of alkynes that use transition metal catalysts
require high temperatures and/or employ inorganic or organic acids as the hydrogen
source, thus limiting functional group tolerance as well.122 Additionally, two-step
sequences involving hydrometalation/protodemetalation have been reported for the
synthesis of both cis- and trans-isomers.123
Lindhardt and coworkers developed an efficient method for the trans-selective
hydrogenation of alkynes using a commercially available ruthenium(II) catalyst (Figure
1-40).124 The transformation proceeded with a maximum of 10 equivalents of H2 (~3
atm) and low reaction temperatures, thus allowing for a broad substrate scope. The
reaction is carried out in a two-chamber set-up with ex situ generated H2 (using Zn and
HCl) and is highly suitable for deuterium labeling. They also demonstrated the
semireduction of terminal alkynes to access styrene derivatives.
54
Figure 1-40. Lindhardt’s trans-selective reduction of alkynes
Oxidations
In addition to Wacker-type conditions,125 the oxidation of alkynes has been
described using both internal and external oxidizing agents such as pyridine N-oxides,
sulfoxides, nitrones, and epoxides. The oxidation is proposed to proceed through -oxo
metal carbenes, which are highly susceptible to nucleophilic attack (Figure 1-41).126 The
same mechanism discussed for nucleophilic attack by heteroatoms to alkynes is
proposed. Coordination of the metal to alkyne generates an electrophilic complex 1-64
that under goes nucleophilic attack by the oxidizing species in an anti-fashion. The
formed intermediate can eliminate X, to generate species 1-131. This intermediate,
which can be viewed as an -diazo carbonyl surrogate, can undergo further oxidation
with another equivalent of oxidizing agent to form the diketone, or be intercepted by
another nucleophile. As discussed previously, regiochemistry issues can arise for
unsymmetrical internal alkynes. For terminal alkynes, the metal carbene species is
always positioned at the terminal carbon. This method allows for hazardous -diazo
carbonyl compounds to be replaced by readily available and benign alkynes. These
reactions are most frequently seen using gold as the transition metal catalyst.126,127
55
Figure 1-41. Proposed mechanism for the oxidation of alkynes with transition metals
In 2011, Li reported the gold-catalyzed oxidation of diarylacetylenes or ynamides
to 1,2-diarylketones and -ketimides, respectively (Figure 1-42).128 The reaction uses
diphenylsulfoxide 1-134 as an external oxidant, producing the 1,2-dicarbonyl
compounds 1-135 in high yields under mild conditions.
Figure 1-42. Li’s oxidation of internal alkynes
Liming Zhang and his group have studied reactions involving -oxo gold carbene
intermediates generated from alkynes extensively. His methods have trapped the
carbene intermediate with various nucleophiles, both inter- and intramolecularly forming
an array of different products.127 In 2015, his group realized the first intramolecular
insertion into unactivated C(sp3)-H bonds by -diketone--gold carbenes 1-138.129 The
substrate conformation control via the Thorpe-Ingold effect is the key design feature that
enables high efficiency in forming the cyclopentanone products 1-141 and 1-142. With
56
this method, cyclopentanones, including spiro-, bridged and fused bicyclic ones can be
readily accessed.
Figure 1-43. Zhang’s synthesis of cyclopentanones
Miscellaneous Reactions
The addition of a transition metal to a reaction with an alkyne substrate can most
likely guarantee the activation of the alkyne by either the end-on or side-on mode as
discussed above. However, a select few types of reactions with alkynes are reported
that are difficult to classify under these two modes. Two examples which fall under this
category include enyne metathesis reactions and the Pauson-Khand reaction.
Enyne metathesis is a powerful method for the formation of 1,3-dienes (Figure 1-
44).130 This transformation involves the bond reorganization of an alkene and an alkyne,
very similar to the previously discussed enyne cycloisomerization. Though there is most
likely some -activation of the alkyne by the metal species, the reaction mechanism is
by far less understood than the examples discussed in the previous section.
Additionally, the metals that catalyze these reactions are generally metal carbenes,131
such as those developed by Grubbs and Hoveyda. A recent mechanistic report by Diver
and Keister suggests that the Hoveyda complex first reacts with the alkene to generate
57
the corresponding metal carbenoid species 1-147 which further reacts with the
alkyne.132 The resultant metal carbenoid 1-148 then undergoes a reaction with another
equivalent of the alkene to furnish the 1,3-diene product 1-149 and regenerate the
active metal carbenoid species 1-147.
Figure 1-44. Enyne metathesis
Fustero and Barrio recently utilized the enyne metathesis to demonstrate the
versatility of the products generated from their allyl(propargyl)boration of
alkynylbenzaldehydes method (Figure 1-45).133 In turn, the benzofused cyclic
homoallylic alcohols 1-150 were generated retaining the stereochemistry of the starting
material.
Figure 1-45. Enyne metathesis to form cyclic homoallylic alcohols
58
The Pauson-Khand reaction is a formal [2+2+1] cycloaddition involving an
alkyne, an alkene and carbon monoxide leading to cyclopentenone products.134 The
transformation can proceed intramolecularly to form bicyclic ring systems or
intermolecularly. Generally, cobalt, iron and rhodium are used for this transformation
with recent achievements in this field including asymmetric variants.135 Once more,
coordination of the metal to the alkyne is likely involved at some point in the reaction.
Highlights in this field are focused on the catalytic asymmetric version of the
Pauson-Khand reaction. Riera and Verdaguer recently developed the first catalytic
system with useful levels of enantioselectivity (Figure 1-46).136 Using norboradiene 1-
151 as the olefin component, products 1-153 were generated in moderate yields and
selectivities. However, both the alkene and alkyne scope are extremely limited, a
common seen challenge in the Pauson-Khand reaction.
Figure 1-46. Enantioselective Pauson-Khand
Dissertation Overview
The present dissertation covers the versatility of alkynes when paired with a
transition metal catalyst. As described in Chapter 1, new methodologies focusing on
transition metal-activation of alkynes are being developed continuously. We will use the
same primary bonding motifs described herein to develop methods for the synthesis of
biologically relevant compounds and core structures.
59
In Chapter 2, a tandem gold-catalyzed dehydrative cyclization/Diels-Alder
reaction utilizing -activation of propargyl alcohols will be described. An approach to
indolocarbazole alkaloids using this transformation will also be discussed.
In Chapter 3, an asymmetric alkynylation of chromones will be reported. The
versatility of these 2-alknylchromanone scaffolds will be demonstrated with important
synthetic elaborations.
In Chapter 4, we focused on the synthesis of biologically important compounds
upon initial docking studies. We developed the first small molecule inhibitors of a
particular histone-lysine methyltransferase protein.
60
CHAPTER 2 APPLICATION OF A TANDEM GOLD-CATALYZED CYCLIZATION/DIELS-ALDER
REACTION IN A SIMPLE APPROACH TO INDOLOCARBAZOLES
Indolocarbazole Background and Significance
The indolocarbazole family of natural products is a well-known family of
carbazole alkaloids that have been isolated from bacteria, fungi, and marine
invertebrates.137 Staurosporine was the first indolocarbazole isolated by Omura in
1977.138 Since then, these compounds have garnered the attention of both the
synthetic139 and biological communities140 due to the vast range of biological activities
exhibited and the variety of chemical structures observed. Perhaps because of this
elevated interest, several indolocarbazole analogues have advanced to clinical studies
and are being tested as possible therapeutic agents in cancer chemotherapy and
against other diseases.
It has been discovered that indolocarbazoles operate by at least three modes of
action in mammalian cells: intercalative binding to DNA, inhibition of DNA
topoisomerase I, and inhibition of a number of protein kinases.137 A slight modification to
the indolocarbazole structure could potentially shift the preferred mode of action and
thus alter the observed biological activity. Due to these modes of action, antitumor,
antiviral, antifungal, antiviral, and many other biological activities have been observed
for this family of compounds.137
Structurally, the natural products of the indolocarabazole family can be classified
into five groups based on the isomeric ring systems arising from the location of the
indole ring annulation with the carbazole: indolo[2,3-a]carbazole 2-1, indolo[2,3-
b]carbazole 2-2, indolo[2,3-c]carbazole 2-3, indolo[3,2-a]carbazole 2-4, and indolo[3,2-
61
b]carbazole 2-5 (Figure 2-1).137 The indolo[2,3-a]carbazole 2-1 structural unit is by far
the most frequently isolated indolocarbazole from nature.
Figure 2-1. Structural arrangements of indolocarbazoles
The structural diversity of the indolo[2,3-a]carbazoles 2-1 makes this family of
natural products particularly interesting and will be the sole focus of this chapter (Figure
2-2).141 Based on its aglycone, each natural product can be classified into four groups:
1) the parent indolocarbazole compound as in tjipanazol F2 2-6, 2) compounds with a
fused imide as can be found in rebeccamycin 2-7, arcyriaflavin 2-8, and
indocarbazostatin 2-9, 3) a hydroxy lactam functionality which is found in the UCN-
compounds 2-10 and 2-11,142 and 4) compounds with fused lactams such as in
staurosporine 2-12. In each of these groups, various substitution patterns on the
aromatic rings are observed. In addition, these compounds are also diverse in the
connectivity of the aglycone to the carbohydrate via the indole nitrogens.
62
Figure 2-2. Diversity in indolo[2,3-a]carbazole natural products
The most well-known examples in this indolocarbazole family include
rebeccamycin 2-7 and staurosporine 2-12, however other interesting members of this
family are the indocarbazostatins 2-9. These compounds have been found to be
nanomolar inhibitors of nerve growth factor-induced neurite outgrowth.143 Inhibitors of
neurite outgrowth have demonstrated success in epilepsy patients144 and rat models of
Huntington’s disease145 and could be potentially used in the treatment of patients with
other nerve diseases. Structurally, indocarbazostatin contains the arcyriaflavin core 2-8
yet the indolocarbazole core is unsymmetrical with respect to the substitution patterns
on the aromatic rings. Thus, a method to access these compounds in an efficient and
convergent manner which allows for diverse functionalization would be highly desirable.
63
Approaches to Indolocarbazole Core
Several strategies to the indolo[2,3-a]carbazole core have been reported in the
literature which were recently reviewed by Knölker and Reddy, along with the synthesis
of the other isomeric indolocarbazoles.146 These syntheses can primarily be divided into
approaches focused on formation of the B and D indole rings and those which involve
formation of the C ring in a final cyclization step (Figure 2-3). The syntheses that form
the B and D ring systems as the key step have been accomplished through both nitrene
insertions147 and Fischer indolizations.148 The formation of the C ring is generally
achieved by carbene insertion,149 oxidative cyclization (or acid catalyzed cyclization
then aromatization),150 cycloaddition,151 and ring closing metathesis.152
Figure 2-3. Summary of access to indolo[2,3-a]carbazole core
In contrast to the numerous approaches to staurosporine 2-12, the formation of
the arcyriaflavin skeleton 2-8, which consists of the indolocarbazole core fused to a
maleimide ring, has only been reported using a limited number of approaches, with no
new synthetic approaches being reported in the last ten years. The most recent reports
have been limited to enzymatic processes.153 Representative examples to demonstrate
the reported strategies to the arcyriaflavin core 2-8 are presented herein. An ideal
strategy would allow for various substitution patterns on the aromatic rings, providing
access to indocarbazostatin analogues, and differentiation of the indole nitrogens for
64
further functionalization. However, it is evident that previous strategies suffer from being
limited to symmetrical products and/or have no way to regioselectively introduce further
functionality on the indole rings.
Formation of C then B, D Rings
One strategy to the arcyriaflavin skeleton includes the formation of the C ring,
typically via a Diels-Alder reaction, followed by cyclization to form the indole rings. An
early method using this approach was reported in 1990 by Raphael and coworkers
(Figure 2-4).147b Access to the 1,4-diarylbutadiene was achieved through a Wittig
reaction between 2-13 and 2-14. Subsequent Diels-Alder cycloaddition of 2-15 with
maleimide 2-16 then oxidation, yielded 2-17. The double nitrene insertion using
Cadogan conditions154 lead to the arcyriaflavin derivative 2-18. Based on the different
aldehydes and phosphonium bromides used, a variety of different unsymmetrical cores
could potentially be accessed by this method; however, it would be difficult to
differentiate the indoles in further functionalizations.
Figure 2-4. Raphael’s approach to arcyriaflavin core
65
A different approach by Bergman using double Fischer indolization for the
formation of the indole rings was later developed (Figure 2-5).148a First, the Diels-Alder
reaction with diene 2-19 and maleimide 2-16 formed the adduct 2-20, which was then
reacted with arylhydrazines to give intermediate 2-21. Fischer indolization yielded the
final arcyriaflavin core 2-8. Though this is a rapid approach to the core, it is limited to the
synthesis of symmetrical products as it proceeds through a dimeric intermediate.
Figure 2-5. Bergman’s approach to arcyriaflavin core
Formation of C Ring from Indole Substrates
Alternatively, the indolocarbazole core could be approached in an opposite
manner, by forming the C ring in the last step from indole substrates. Like Raphael’s
approach (Figure 2-4), Wallace also employed a Diels-Alder approach as the key step,
however with a bisindole substrate 2-24 (Figure 2-6).151 The yields for the cycloaddition
step with this type of substrate are much lower than with the 1,4-diarylbutadiene.
Additionally, due to the synthetic pathway to the bisindole, only symmetrical products
can be obtained.
66
Figure 2-6. Wallace’s approach to arcyriaflavin core
Numerous methods proceed through a bisindolylmaleimide intermediate 2-27,
using various oxidative conditions to cyclize the C ring. The methods vary in the way to
access the bisindolylmaleimide intermediate, with typical oxidizing agents to effect
cyclization being DDQ,155 Pd(OAc)2 (and other Pd(II) sources),156 or PIFA/BF3·OEt2.157
Uang and coworkers synthesized the bisindolylmaleimides 2-27 from the
indolylmagnesium bromide 2-25 with 3,4-dichloromaleimides 2-26 (Figure 2-7). 158 They
then formed the C ring in high yields using a novel set of oxidative photocyclization
conditions.150e Again, this approach is limited to the synthesis of symmetrical products
as it proceeds through a dimeric substrate and there is no indole nitrogen differentiation.
Figure 2-7. Uang’s approach to arcyriaflavin core
67
To circumvent the limitation of only being able to access a symmetrical product,
Zhu and coworkers accessed the bisindolylmaleimide structure using an alternative
method.150d They utilized readily available indole-3-acetamides 2-29, and reacted them
with methyl indolyl-3-glyoxylates 2-30 under basic conditions to enable condensation
(Figure 2-8). Cyclization was achieved with Uang’s photocyclization conditions or with
DDQ. An additional advantage of this strategy is that it achieves nitrogen differentiation
for further regioselective functionalization of the indoles.
Figure 2-8. Zhu’s approach to arcyriarubin core
Formation of C, B, D Rings in Single Step
To date, there has been only a single report that achieves the formation of the C
ring and both the indole rings of the arcyriaflavin skeleton in a single step. In 1995,
Saulnier reported an approach to the arcyriaflavin core starting from diacetylene 2-32
(Figure 2-9).159 Protection of the anilines formed 2-33, followed by a polyannulation
reaction, yielded the benzyl-protected product 2-35 in 52% yield. This is an extremely
efficient synthesis and the core is accessed in a rapid manner with the last step yielding
four new bonds and three rings in a single step. Unsymmetrical products could be
challenging depending on the synthesis used to form the diacetylene precursor.
68
Figure 2-9. Saulnier’s approach to arcyriaflavin core
Sequential Formation of C then B then D Ring
The last reported method for the synthesis of the arcyriaflavin core utilized a
stepwise strategy for the formation of the necessary rings. In 2005, Tomé and
coworkers described the synthesis of the arcyriaflavin core via Diels-Alder and Fischer
indolization approaches (Figure 2-10).147d Each step of the process was high yielding,
starting with a Wittig reaction of o-nitrobenzaldehyde 2-36 with ylide 2-37. Their strategy
relied first on formation of the C ring through a Diels-Alder reaction to form 2-40. Upon
nitrene insertion, the first indole ring was formed. The second indole ring was then
generated by reaction of 2-41 with (4-methoxyphenyl)hydrazine under acidic reflux
conditions. With this reaction sequence, they were also able to access an
unsymmetrical analogue 2-42 with the potential of nitrogen differentiation if a protection
step was incorporated after the first indole ring formation.
69
Figure 2-10. Tomé’s approach to unsymmetrical arcyriaflavin core
Many of the aforementioned approaches proceeded through a dimeric substrate,
and thus are limited to the synthesis of symmetrical compounds. Additionally, the
strategies that yield unsymmetrical products may not have nitrogen differentiation for
the selective installation of the carbohydrate moiety or for any other functionalization.
Despite these previous synthetic advances, the need for a more adaptable route that
addresses these issues remains.
Development of the Tandem Gold-Catalyzed Cyclization/Diels-Alder Sequence
One of the most well-known electron rich dienes in synthetic organic chemistry is
the Danishefsky diene for Diels-Alder reactions.160 This 1,3-dioxygen-substituted
reagent has found extensive use in natural product synthesis, however the analogous 2-
alkoxy-substituted dienes161 are much less frequently encountered. Despite the reduced
occurrence, many elegant applications that take advantage of this functionality have
been reported.162 In each example, the preparation of the necessary vinyldihydropyran
2-43 or other 2-vinyl oxygen heterocycles used in these syntheses is required. Several
70
groups have developed methodologies to arrive at these intermediates, which typically
focus on enol ethers 2-44, lactones 2-46, or sugar derivatives 2-47 as the starting
material with the introduction of the unsaturation by cross-coupling,163 a vinyl
organometallic addition/dehydration sequence,164 or an oxidation/Wittig olefination
sequence, respectively (Figure 2-11).165
Figure 2-11. General strategies towards vinyldihydropyrans
In 2008, our group reported the gold-catalyzed dehydrative cyclization of
monopropargylic triols 2-48166 and acetonides 2-49167 to form unsaturated spiroketals 2-
50 (Figure 2-12a). Mechanistic investigations using propargyl substrates without a
second pendant alcohol such as 2-51 suggested the intermediacy of allene 2-52, and
the diene 2-53 was observed in these cases (Figure 2-12b).166 Considering the mild
reaction conditions and readily available starting substrates for this transformation, we
envisioned this method being a valuable way to access electron rich dienes 2-53.
Considering the sensitive nature of the enol ether functional group, we postulated that
these dienes would be highly advantageous when coupled with the Diels-Alder reaction
to form adducts 2-55,168 which have been demonstrated to be valuable synthetic
intermediates.162
71
Figure 2-12. Gold-catalyzed diene synthesis
Optimization of the reaction by Dr. Nicholas Borrero revealed the best results
were obtained with a JohnPhos·AuCl/AgOTf catalytic system and benzene as the
solvent. With these conditions, the tandem reaction was studied by in situ trapping of
the reactive diene with dienophiles. After the cyclization was complete, the reaction
mixture was heated to reflux to effect cycloaddition. As expected, highly electron-
deficient dienophiles gave the best results. The broad scope of propargyl alcohols and
dienophiles allowed for a wide range of adducts to be accessed (Figure 2-13). Both 5-
membered and 6-membered dienes were readily formed with oxygen and nitrogen
nucleophiles. Their cycloaddition with dienophiles such as N-methylmaleimide,
tetracyanoethylene, and 4-phenyl-1,2,4-triazoline-3,5-dione provided the Diels-Alder
adducts in good to excellent yields and diastereoselectivities. As this method proved to
be efficient over a broad array of substrates, we postulated that it would be applicable in
a convergent synthesis of indolocarbazoles.
72
Figure 2-13. Substrate scope of tandem reaction
Our Synthetic Approach to Indolocarbazoles
The strategy we proposed focused on the formation of the C–N bond of one of
the indole rings as the last step by a nitrene insertion reaction. We envisioned the other
indole ring and the C ring being easily accessed using the gold-catalyzed dehydrative
cyclization/Diels-Alder methodology discussed in the above section. Retrosynthetically,
the intermediate 2-65, with all atoms necessary for the protected arcyriaflavin core,
would be achieved by the Diels-Alder cycloaddition between maleimide 2-16 and diene
2-66 (Figure 2-14). The key diene intermediate would be obtained from the Au-
catalyzed dehydrative cyclization of monopropargylic alcohol 2-67, which would be
formed by a simple alkynylation step. We felt that this convergent strategy should allow
access to analogues and other natural products in the indolocarbazole family in a rapid
manner by varying substitution on the three different components (2-16, 2-68, 2-69).
73
Additionally, this synthetic design allows for differentiation of the indole nitrogens so that
further functionalization can be performed regioselectively.
Figure 2-14. Retrosynthetic strategy
The synthesis of the key propargyl alcohol intermediate for the gold-catalyzed
diene formation initiated with the known Boc-protected 2-aminobenzyl alcohol 2-70
(Figure 2-15). Conversion to the alkyne 2-73 was achieved by bromide formation,
followed by cross-coupling with tris(trimethylsilylacetylene)indium, then silyl deprotection
with potassium carbonate in methanol. This process was efficient, forming the products
in 91%, 77%, and 85% yields, respectively. Alkyne addition to two different aldehydes
furnished propargyl alcohols 2-74 and 2-75 in 88% and 69% yield, respectively. At the
outset, it was unclear if these substrates would be suitable for the dehydrative
cyclization, but under the optimized conditions, dienes 2-76 and 2-77 were formed in
79% and 58% yield, respectively. It was found to be convenient to isolate and purify the
diene prior to the cycloaddition step due to ease of handling.
74
Figure 2-15. Synthesis of requisite propargyl alcohols and gold-catalyzed dehydrative cyclization
The Diels-Alder reaction required extensive optimization (Figure 2-16). Many
different conditions were employed to promote cycloaddition. Addition of Lewis acids
typically used to catalyze Diels-Alder reactions, such as BF3·OEt2 and SnCl2 did not
promote cyclization (entries 1,2). Altering the temperature between 80 °C to 150 °C for
various reaction times either resulted in trace product formation or decomposition
(entries 3–5). Performing the reaction neat or using microwave irradiation also proved
ineffective (entries 6,7). In an attempt to determine the point of decomposition, the
reaction was run at 100 °C, but was quenched after 2.5 hours with the TLC showing
substantial conversion. By 1H-NMR, a clean 80% conversion was observed. Attempts to
achieve full conversion resulted in significant decomposition. It was found that the best
conditions were heating maleimide 2-16 and 2-76 in toluene at 100 °C with vigorous
75
stirring for 3 hours yielding 90% of the isolated Diels-Alder adduct 2-78 (entry 8). These
conditions proved to be very specific and any minor change in the conditions
dramatically decreased the yield. In these cases, decomposition of the starting material
and/or the product was observed. The optimized conditions were also used to provide
the chlorosubstituted adduct 2-79 in 83% yield (entry 9).
Figure 2-16. Optimization of Diels-Alder reaction
With both Diels-Alder adducts in hand, oxidation with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) afforded 2-80 and 2-81 in 84% and 62% yield, respectively.
To complete the sequence, the final nitrene insertion step remained to form the C–N
bond of the second indole ring. Unfortunately, this was not easily achieved and
numerous conditions were screened with no success. Traditionally, this type of ring
closure is accomplished using the Cadogan reaction.169 However, due to the high
76
temperature needed for initial deoxygenation and difficulty removing the excess
phosphorous reagent, this method was abandoned after numerous attempts (Figure 2-
17). Numerous combinations of conditions varying the organophosphorous reagents,
temperature, reaction time and concentration were studied but to no avail. Either
decomposition occurred or cleavage of the Boc protecting group was observed.
Figure 2-17. Reductive cyclization attempts using trivalent organophosphorous reagents
In addition to the methods examined that included using a variety of trivalent
organophosphorous reagents, other attempts for reductive cyclization using Grignard
reagents were explored (Figure 2-18).170 When the reported conditions were attempted
on our substrate 2-80 (PhMgBr (3.0 equiv.), THF, 0 °C, 15 min), a complex mixture was
77
generated. The hydroxylamine, resulting from nucleophilic addition of the Grignard to
the nitroso intermediate, was the major isolable product. We then theorized that a more
electron withdrawing or sterically demanding Grignard would be less likely to attack the
nitroso intermediates, favoring the second deoxygenation, and thus precluding
formation of the hydroxylamine intermediate. Using o-nitrobiphenyl as a model
substrate, we found that p-CO2EtPhMgCl was best at reducing the generation of the
hydroxylamine (mesityl-, tolyl-, p-fluorophenyl-, and phenylmagnesium halides were
also studied), allowing for a higher yield of the desired carbazole to be isolated.
However, when our system was subjected to these conditions, only partial conversion
and complex mixtures were obtained.
Figure 2-18. Reductive cyclization attempts using Grignard reagents
Alternatively, a variety of catalytic and oxidative C–H amination methods were
attempted on modified substrates (Figure 2-19).171 Reduction of the nitro to the amine
followed by acetyl and benzyl protection yielded derivatives 2-84 and 2-85, respectively.
Conditions attempted with substrate 2-84 involved palladium and high temperature
conditions which cleaved the Boc protecting group in the starting material and inhibited
the reaction from proceeding (entries 1-3). Using a less electron withdrawing benzyl
group as the protecting group was reported using more mild conditions, however when
employed in our system, no product was recovered (entries 4-5).
78
Figure 2-19. C–H amination attempts
Fortunately, it was discovered that this key bond formation has been
accomplished with substituted o-nitrobiphenyls and o-nitrostyrenes to yield carbazoles
and indoles, respectively, using an oxotransfer catalyst, MoO2Cl2(dmf)2,172 with
triphenylphosphine (Figure 2-20). Synthesis of the molybdenum catalyst was simple and
large quantities could be obtained from inexpensive starting materials. Mechanistically,
the reaction is proposed to proceed through the same intermediates as in the Cadogan
cyclization. Initially, the molybdenum catalyst is reduced by triphenyl phosphine to form
triphenylphosphine oxide and MoOCl2(dmf)2. This species or the dinuclear
oxomolybdenum is responsible for the first deoxygenation of the nitroaromatic to form
the corresponding nitroso intermediate. Due to the relative ease of the second
deoxygenation, it is proposed to take place without catalyst participation to form the
79
nitrene which undergoes C-H insertion to generate the carbazole. Alternatively, the
direct cyclization of the nitroso then deoxygenation could also be proposed.
Figure 2-20. Mechanism of the formation of carbazoles using MoO2Cl2(dmf)2
Many combinations of conditions with various trivalent organophosphorous
reagents were examined and it was found that using 25 mol % of the catalyst with
triphenylphoshine in toluene at 90 °C for 16 hours resulted in 60% of the product being
isolated (Figure 2-21). We think that the presence of a carbonyl group at the para
position in relation to the site of nitrene insertion adds difficulty to the reaction.
Unfortunately, under these optimized conditions, substrate 2-81 resulted in the
deprotected product along with other unidentified side products. We believe that the
insolubility of this substrate causes additional reactivity issues and further optimization
will be needed.
80
Figure 2-21. Reductive cyclization with oxotransfer catalyst
With the formation of the last C–N bond, the synthesis of mono-protected
arcyriaflavin A was completed in nine steps (Figure 2-22). This synthesis demonstrated
the applicability of the gold-catalyzed dehydrative cyclization/Diels-Alder methodology
developed in our lab. The Boc protecting group seemed to be difficult to retain in the last
steps of the synthesis as high temperature conditions were typically needed. Other
protecting groups such as benzyl, mesyl and phenylsulfonyl were also tested, however
the initial steps to access the corresponding alkyne were unsuccessful. We were
successful in obtaining indole differentiation throughout the synthesis, allowing for the
possibility of regioselective functionalization of the indole rings. Attempts to access an
unsymmetrical indolocarbazole core with respect to the substitution on the aromatic
rings, were unsuccessful with the specific example we attempted. However, other
unsymmetrical analogues could potentially be accomplished with this strategy.
81
Figure 2-22. Overall synthetic route to unsymmetrical arcyriaflavin A
Conclusions and Outlook
In summary, using a novel methodology developed in our lab, the synthesis of
the unsymmetrical arcyriaflavin A core was accomplished in a convergent manner. We
82
believe this approach will be highly applicable to natural product synthesis and provide
access to highly diverse analogues. The design also allows for differentiation of the
indole nitrogens so that further functionalization could be performed regioselectively.
Future studies include incorporation of the chlorosubstituent on the aniline ring to
determine if the 11-deschloro-rebeccamycin product could be accessed by switching
the substrates. If successful, this strategy would offer a flexibility in the synthesis of
indolocarbazoles not commonly seen.
Additionally, it would be interesting to study the reactivity of the key diene
intermediate further. This 2-vinyl-1H-indole moiety has proved to be extremely valuable
in the synthesis of important heterocyclic compounds.173 In respect to the Diels-Alder
reaction, if 2-vinyl-1H-indole, generated from the alkynylation with formaldehyde, could
be accessed, then subsequent cycloaddition would provide the substituted
tetrahydrocarbazoles174 or carbazoles if oxidation conditions are used .175 An
electrocyclization variant could also be studied if alkenylation at the C3 position of the
indole ring occurred.176 In this context, other functionalization could be performed on the
C3 position for further elaboration to increase molecular complexity from the diene
intermediate.
83
CHAPTER 3 COPPER-CATALYZED ASYMMETRIC ALKYNYLATION OF CHROMONES
Chromanone Prevalence
The ability to easily and rapidly access common core skeletons prevalent among
numerous natural products is a well-recognized motive for method development
research in organic chemistry.177 The flavonoid family of natural products is a class of
plant metabolites that have been credited for diverse functions in plant growth and
development.178 In addition to their biological role in plants, these compounds have
also been studied for potential health benefits in humans demonstrating anticancer,
antibacterial, antioxidant, and other properties.177 In addition to the diverse biological
responses observed, this family of natural products is composed of structurally diverse
compounds (Figure 3-1).The nomenclature varies depending on the oxidation state of
the benzylic position and the type of substitution at C2.
Figure 3-1. Select members of the flavonoid family of natural products
In particular, the common benzopyranone core 3-6 is shared among an array of
natural products that have been shown to have promising biological activities (Figure 3-
2).179 For instance, the blennolides 3-7 are monomer units of the secalonic acids which
are antitumor agents.180 Aposphaerin A 3-8 is an antibacterial fungal metabolite181 and
Lachnone D 3-9 has been shown to mildly inhibit the growth of Mycobacterium
tuberculosis.182 In addition to being present in diverse natural products directly, the
chromanone moiety has also been incorporated into various analogues. Recently, the
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Krische group reported the synthesis and biological activity of a novel chromanone-
based byrostatin analogue, namely WN-3 3-10.183 This analogue and its derivatives
were shown to be potent growth inhibitors of Toledo cells, a common model for tumor
growth. Additionally, as chromanones are precursors to other plant metabolites such as
the chromanols and chromanes, access to this scaffold could allow for the synthesis of
a variety of important pharmacophores.
Figure 3-2. Chromanone prevalence in natural products and analogues
Enantioselective Synthesis of Chromanones and Flavanones
In many of the chromanone-based natural products and analogues such as those
depicted above, there is a stereocenter at the C2 position. Thus, access to various
functionality at this position would greatly enhance the scope of natural product
derivatives and potential therapeutic candidates alike. There are several approaches to
access enantioenriched 2-substituted benzopyranones 3-11 including asymmetric
reduction of the 2-substituted chromone, kinetic resolution, Mitsunobu inversion and
conjugate addition.184 In nature, these valuable scaffolds are synthesized from the
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corresponding 2’-hydroxychalcone derivatives 3-12 using the chalcone isomerase
enzyme with remarkable enantioselectivity for 2S-flavanones (99.998%).185 The acid-
and base-catalyzed biomimetic cyclization of 2’-hydroxychalcones are the most
common synthetic methods to access chromanones and flavanones.186 However, this
method can limit the library of analogues generated since a new substrate must be
synthesized before each cyclization.187 By far, a more convergent approach would be
through an intermolecular conjugate addition with readily available materials, the parent
chromone 3-13 and a nucleophile, but these examples are much more limited (Figure 3-
3). In both approaches, the asymmetric version can be challenging due to the reversible
phenoxide elimination, especially under the basic conditions that are typically used for
these transformations.188
Figure 3-3. Intramolecular versus intermolecular conjugate additions to access 2-substituted chromanones
The retrosynthetic disconnection for intermolecular conjugate addition reactions
can be divided into two groups: a) the introduction of an aromatic moiety to generate
flavanones and b) the introduction of other functionality to form the chromanones. One
approach reported by Wallace and Saengchantara employed an enantioenriched
sulfoxide 3-14 for a diastereoselective conjugate addition of chromones (Figure 3-4).189
Upon nucleophilic addition using stoichiometric amounts of the methyl cuprate, the cis-
isomer 3-15 was isolated after recrystallization. Removal of the sulfoxide, followed by
oxidation yielded enantioenriched (S)-2-methylchroman-4-one 3-16. Solladie and
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coworkers were able to develop modified conditions for the introduction of a phenyl
group.190
Figure 3-4. Diastereoselective conjugate addition approach to chromones
In terms of catalytic asymmetric conjugate addition reactions, boron reagents
have been used to introduce aromatic groups. In 2010, Liao and coworkers reported the
asymmetric 1,4-addition of chromones 3-17 using sodium tetraarylborates 3-18 and a
rhodium catalyst (Figure 3-5).191 This method allowed access to a wide range of
enantioenriched flavanones 3-19. An additional report by Korenaga demonstrated that
arylboronic acids also underwent conjugate addition but required a slightly modified
catalyst system.192
Figure 3-5. Liao’s conjugate addition of sodium tetraarylborates to chromones
Aside from aromatic groups, limited functionality has been incorporated in the C2
position in an enantioselective fashion. The first report of an asymmetric copper
catalyzed alkyl addition to chromone 3-13 came from Hoveyda in 2005 (Figure 3-6).193
Under the reaction conditions, it was necessary to use an enolate trap to avoid
undesired elimination reactions that lead to racemization of the product. After retro-
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aldol, the 2-alkylchromanone products 3-23 and 3-24 were obtained in 92% and 84%
yield respectively, with high enantioselectivity, 98% ee. These were the only two
examples of chromone functionalization reported in this work.
Figure 3-6. Hoveyda’s conjugate addition of dialkylzinc reagents to chromone
As a wide range of dialkyl zinc reagents are not readily available, this can restrict
the substrate scope in the above method. In 2013, Feringa and coworkers reported a
method for the asymmetric addition of alkyl groups to chromones with more readily
available Grignard reagents (Figure 3-7).194 In this work, they reacted various
substituted chromones 3-17 with alkyl Grignard reagents 3-26 under low temperature,
copper-catalyzed conditions. The use of chiral ligand 3-28, enabled the transformation
to be highly enantioselective.
88
Figure 3-7. Feringa’s conjugate addition of Grignard reagents to chromones
In all cases described previously, a stoichiometric amount of a strong nucleophile
is required. Thus, a transformation that is completely catalytic in metal under mild
conditions would be highly desirable. Additionally, because of the diverse range of
functionality at the C2 position, the introduction of a more versatile handle compared to
an alkyl or aromatic group would be extremely valuable in accessing diverse natural
product analogues.
Activation of Chromone
Another challenge with the conjugate addition of nucleophiles to chromones,
aside from the problems with elimination when the enolate forms, is the weak
electrophilicity of the substrate. This requires the use of harsh conditions and/or strong
nucleophiles, making elimination even more likely. In the literature, several groups have
taken advantage of the electrophilicity of the 4-silyloxybenzopyrylium ion 3-35
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generated when the chromone is activated with silyl-based Lewis acids to add various
mild nucleophiles (Figure 3-8).195 After a mild acidic quench, the ultimate product from
this pathway is the conjugate addition product.
Figure 3-8. Activation of chromone
However, only recently has there been an asymmetric addition to the
benzopyrylium species. Mattson and coworkers were the first to report an asymmetric
addition to 4-silyloxybenzopyrylium triflates using silyl enol ether 3-36 (Figure 3-9).196 By
generating a chiral ion pair between the benzopyrylium ion and a newly developed
silane diol catalyst 3-38, the products 3-37 were generated in modest yields and
selectivities. They showed a broad chromone substrate scope but only using the
disubstituted silyl enol ether nucleophile 3-36.
Figure 3-9. Mattson’s asymmetric functionalization of chromones
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Asymmetric Alkynylation of Chromones
Aware of the above examples in the literature, we envisioned an asymmetric
alkynylation of chromones would have significant advantages. The incorporation of such
a functional handle in the C2 position would allow access to a large amount of diversity.
Furthermore, a wide range of alkynes are commercially or readily available so that a
large analogue library could be generated rapidly. Additionally, because the metal
acetylide can be generated in situ, the transformation would be completely catalytic in
the organometallic species. Our strategy would rely on the activation of the chromone to
form the scarcely utilized 4-silyloxybenzopyrylium triflate intermediate 3-39, which in
turn would undergo electrophilic addition by a metal acetylide. The resulting unique
scaffold 3-40 is thus equipped with functional handles in the context of an alkyne and
silyl enol ether for further elaboration (Figure 3-10). The employment of a chiral ligand to
generate a chiral metal acetylide complex would render the transformation
enantioselective.
Figure 3-10. General strategy for the asymmetric alkynylation of chromones
The first aspect to consider is the type of ligand that would be appropriate for this
transformation. In recent years, atropisomeric P,N-ligands have gained increasing
interest for their use in asymmetric catalysis (Figure 3-11).197 More specifically, QUINAP
3-41198 and PINAP 3-42199 have been shown to succeed in various alkynylation
reactions.200 In 2013, our group reported the development of a new ligand, namely
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StackPhos 3-43.201 Interestingly, this ligand is an atropsiomeric imidazole-based P,N-
ligand, in contrast to the typically seen 6,6-biaryl ring system. In general, the barrier to
rotation around the biaryl ring system is too low for 5,6-membered biaryls to be of use in
asymmetric catalysis. This is largely due to the decreased sterics around the biaryl bond
making it configurationally labile.
Figure 3-11. Atropisomeric P,N-ligands
Diverting from the typical approach using steric interactions to restrict bond
rotation by destabilizing the transition state, our group designed a novel strategy to
increase the barrier to rotation of biaryls by stabilization of the ground state through π, π-
stacking interactions (Figure 3-12). The stabilization energy between StackPhos 3-43
and its non-fluorinated derivative 3-45 is 2.2 kcal/mol.201 This allows for the isolation of
either enantiomer of enantiomerically pure StackPhos (3-43 and 3-44), a typical
requirement for use in asymmetric catalysis, whereas when the ligand lacks the π, π-
stacking interaction (3-45 and 3-46), it can only be isolated in 56% ee. This stacking
interaction was observed by X-ray crystallography.
92
Figure 3-12. Ground state stabilization of StackPhos
Additionally, derivatives of the StackPhos ligand are much more accessible as
compared to QUINAP and PINAP. This is due to the ability of 5-membered ring
heterocycles to be formed through simple condensation reactions (Figure 3-13). Thus,
this design offers the opportunity to rapidly generate a library of these ligands that could
address potential reactivity and/or selectivity issues in catalytic asymmetric reactions.
Figure 3-13. General synthesis of StackPhos ligands
Our lab has recently found success using these ligands in a variety of
alkynylation reactions (Figure 3-14). In terms of the addition of alkynes to various
iminiums, we demonstrated that StackPhos succeeded in the A3 coupling
reaction,201,202 as well as in the addition to acyl quinoliniums203 to generate
enantioenriched amino skipped diynes 3-55 and 2-alkynyldihydroquinolines 3-57,
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respectively. The alkynylation of quinolines methodology was then used in an
enantioselective total synthesis of martinella alkaloids.204 Furthermore, we reported that
the methyl derivative of StackPhos (i.e. methyl groups instead of phenyl on the
imidazole ring) enabled the enantioselective conjugate alkynylation of Meldrum’s acid
acceptors to form chiral -alkynyl Meldrum’s acid 3-59 building blocks.36 With
StackPhos excelling in the above asymmetric alkynylation reactions as well as the facile
synthetic access to its various derivatives, we postulated that this class of ligands would
be an ideal choice for use in the asymmetric alkynylation of an oxocarbenium species to
generate products 3-60.7a,8
Figure 3-14. Enantioselective StackPhos-enabled alkynylation reactions
Reaction Optimization and Scope
We surmised that with the appropriate conditions, a highly selective addition to 4-
silyloxybenzopyrylium triflates could be achieved, allowing for the formation of
enantioenriched 2-alkynylchromanones (Figure 3-15). To this end, chromone 3-13 and
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phenylacetylene 3-61, trimethylsilyl trifluoromethanesulfonate, and N,N-
diisopropylethylamine were allowed to react in dichloromethane at -78 °C for 4 hours in
the presence of 5 mol % CuBr and 5.5 mol % (S)-StackPhos. After an acidic quench,
the desired product 3-62 was isolated in 52% yield and 74% ee (entry 1). The
enantioselectivity increased to 88% ee employing THF as the solvent and warming the
reaction to 0 °C, albeit with greatly diminished yield (entry 2). With toluene as the
solvent both moderate yield and selectivity, 62% and 62%, respectively, were achieved
(entry 3). Only trace product and/or enantioselectivity was observed when other copper
sources such as CuOAc, CuTC, or Cu(MeCN)4PF6 were used (entries 4-6). However,
employing CuI as the copper source provided high levels of reactivity and selectivity,
96% yield and 88% ee, respectively (entry 7). Notably, when these same conditions
were employed without the ligand, 73% of the desired product was isolated (entry 8).
This result indicates a significant competing background reaction which results in
racemic product. Use of the methyl derivative of StackPhos, namely Me-StackPhos,
proceeded to give high reactivity but with significantly reduced selectivity (entry 9).
Ultimately, at lower temperatures with StackPhos, the reactivity was retained and the
selectivity increased to provide 3-62 in 89% yield and 94% ee (entry 10). Other
modifications such as varying the base or the silyl triflate provided no further increase in
enantioselectivity.
95
Figure 3-15. Optimization of reaction conditions
With the optimized conditions established, the scope of the reaction was
explored. It was found that this transformation tolerates a variety of different alkynes
(Figure 3-16). In addition to phenylacetylene, both electron withdrawing and electron
donating groups on the aromatic ring of the alkynes produced 3-64 and 3-65 in 94% and
89% ee, respectively. The reaction also tolerated substitution on the aromatic alkynes in
the ortho- and meta-positions as well as heteroaromatic alkynes. Highly versatile
protected propargyl alcohols and amines also worked well under the reaction conditions
forming 3-69, 3-70, 3-71 in 95%, 90% and 92% ee, respectively. Additionally, aliphatic
alkynes and enynes gave moderate selectivities in this transformation. Lastly, the
reaction proceeded smoothly using simple trimethylsilylacetylene, giving the alkynylated
product 3-74 in 73% yield and 95% ee. Other alkynes that were screened such as
methyl propiolate and 2-nitrophenylacetylene, provided lower levels of selectivity, 59%
ee and 81% ee, respectively.
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Figure 3-16. Alkyne Scope
Next, we turned our attention to the scope of the chromone substrate (Figure 3-
17). The reaction proceeded smoothly with incorporation of an electron donating
acetoxy group 3-77, as well as an electron withdrawing fluorine 3-78 in the C6 position,
providing 86% and 89% ee, respectively. The presence of a methoxy group in the C7
position, which is seen in numerous natural products, yielded 3-79 in 78% yield and
97
94% ee. Alkynylation of 7-bromochromone also worked well under the reaction
conditions, which allows for a site for further functionalization of the chromanone
skeleton through cross-coupling reactions. Matching the substitution pattern in the
bryostatin analogue 3-10, a methoxy group can be present at the C8 position, providing
high levels of enantioselectivity in 3-81. Additionally, isoflavone was used to
demonstrate the reaction can be performed with a substituent at C3, which adds an
additional stereocenter that is dictated by the stereocenter set in the alkynylation step.
The product 3-82 was isolated as a diastereomeric mixture, with the cis-diastereomer
predominating.
Figure 3-17. Chromone Scope
Other substrates were also tested in attempts to expand the scope of the
reaction (Figure 3-18). No reaction was observed using chromones 3-83, 3-84, 3-85,
and pyrone 3-86 as the substrate. For chromone 3-87 and pyrone 3-88, the reaction
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resulted in significant amounts of byproducts with the major observed product resulting
from the elimination reaction discussed above.
Figure 3-18. Incompatible chromones and pyrones
Determination of Absolute Stereochemistry
The absolute stereochemistry of the products was determined by comparison to
a known compound.205 Chromanone 3-62 was hydrogenated under 1 atmosphere of H2
with 10% Pd/C for 48 hours to deliver 3-89 in 80% yield (Figure 3-19). The observed
optical rotation was found to be -103.18 (c 1.0, CHCl3) compared to the literature value
for (S)-2-phenethylchromane which is -116.3 (c 1.0, CHCl3). The absolute configuration
for 2-(phenylethynyl)chroman-4-one 3-62 is thus assigned as R. The other chromanone
products were assigned by analogy.
Figure 3-19. Determination of absolute stereochemistry
In a stereochemical model, the bidentate StackPhos ligand creates four sterically
different quadrants around the copper-bound alkyne complex (Figure 3-20a). Using the
model proposed by coworker Dr. Paulo Paioti, the quadrant containing the aromatic ring
on the imidazole is assigned as the most sterically encumbered site. In part, this
hindrance arises from the proximity of the aromatic ring to the reactive metal center.
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The sterics decrease in the quadrants containing the aromatic groups of the
phosphorous, with one being more hindered that the other. The last quadrant has
negligible steric interactions. Including the electrophile in the model, in this case the 4-
silyloxybenzopyrylium ion, and considering the Bürgi-Dunitz trajectory,206 two transition
states arise. In one case, the enol ether is in the most sterically encumbered quadrant
with the aromatic portion in the sterically free quadrant (Figure 3-20b). In the other,
there are no interactions with the most sterically encumbered site but the entire
electrophile is in somewhat sterically hindered quadrants (Figure 3-20c). Even though
there are two steric interactions between the electrophile in the reactive environment,
the former case involving an interaction with the most sterically hindered quadrant must
be significant enough as (R) 3-62 is observed.
Figure 3-20. Proposed stereochemical model
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Versatility of Products
The newly synthesized scaffolds offer many positions for further functionalization.
The versatility and utility of these compounds are demonstrated in Figure 3-21. General
silyl enol ether chemistry can be used in subsequent transformations to increase
molecular complexity and install functionalization at the C3 position. In this context, 3-93
was demonstrated to react under Rubottum oxidation conditions with dimethyldioxirane
(DMDO), to provide the corresponding -hydroxyketone 3-94, like the core of Lachnone
D, as a single diastereomer in 68% yield over the two transformations. (Figure 3-20a).
Additionally, the silyl enol ether can react with other electrophiles, such as aldehydes, to
give the resultant aldol product 3-95 as a single diastereomer. In both cases, the
enantioselectivity is essentially the same as what is observed in the alkynylation
reaction. A preliminary racemic reaction using 3-methylchromone 3-96 as the substrate
provided evidence that a quaternary center can be formed at C3 using the same aldol
conditions, in high diastereoselectivity. We believe this silyl enol ether is extremely
valuable in the functionalization at C3 as basic enolate conditions can have problems
with elimination reactions, destroying the stereochemical integrity. Furthermore, the
incorporation of an alkyne at the C2 position allows for the potential of diverse
functionalization to be incorporated. As an example, 3-98, the deprotected product of 3-
71, was cyclized under gold conditions previously developed in our lab207 to provide the
2-furanylchromanone 3-99 in high yields. These 2-heterocyclic chromanones are used
extensively in pesticides due to their potent antifungal activities.208 In principle, other
heterocycles could be generated depending on the choice of alkyne. Lastly, the
chromanone ring can be contracted to provide the functionalized dihydrobenzofuran 3-
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100, a privileged scaffold in natural products,209 with no loss in enantioselectivity. One
could also envision transformations taking advantage of the carbonyl moiety, such as
reductions, additions and reductive aminations, to access many other types of products.
Figure 3-21. Versatility of the scaffold
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Conclusion
In conclusion, we have disclosed an asymmetric alkynylation of chromones
enabled by a Cu(I)-StackPhos system. This is the first example of the use of StackPhos
in an addition to oxocarbenium ions. The convergent method demonstrates a strategy to
introduce diverse functionality at the C2 position of chromanones, allowing for the
potential of a wide range of natural product analogues to be accessed. A broad scope of
alkynes and chromones are tolerated providing high levels of enantioselectivity in the
chromanone products. This method generates unique, functional scaffolds useful for
further elaborations as demonstrated by several preliminary applications. In addition,
natural products containing the chromanone moiety in various oxidation states, such as
the chromanol and chromanes could, in principle, be accessed from these products.
103
CHAPTER 4 DESIGN AND SYNTHESIS OF METHYLASE INHIBITORS
Histone Methylation: Metnase
Post-translational covalent modifications of histone tails such as acetylation,
phosphorylation and methylation play key roles in the regulation of chromatin and gene
expression.210 In particular, several histone methyltransferases have been isolated and
characterized, with the large majority containing a SET (Su(var)3-9, Enhancer-of-zeste
and Trithorax) domain that is responsible for the methylating function.211 These
methylation events can occur at two sites, either on the lysine or the arginine residues
of the histone tails. The class of lysine histone methyltransferases function by
transferring a methyl group from S-adenosyl-L-methionine (SAM) to the amino group of
the lysine.212
Recently, the Hromas lab in the Department of Medicine at the University of
Florida isolated and characterized a hybrid fusion protein with both a SET domain and a
transposase/nuclease domain termed Metnase (Figure 4-1).213 This protein is found in
anthropoid primates and appears to have emerged only 40-58 million years ago.214
Metnase has numerous documented functions resulting from both domains, with
methylation of lysine residues from the SET domain being one. More specifically, it was
found that Metnase stimulates the dimethylation of histone H3 at lysine 36 (H3K36me2)
and to a lesser extent lysine 4 (H3K4me2). Further assessing the key methylation
events that occur after DNA double-strand breaks (DSB) revealed that H3K36me2 was
the major event and was rapidly induced.215 Subsequent studies indicated that this
event is directly catalyzed by Metnase near DSBs. Additionally, the Hromas group
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reported that Metnase regulates the recruitment of certain DNA repair components to
the region near an induced DSB.
Figure 4-1. SET and MAR domains of Metnase214
From the results of these studies, it was determined that Metnase
overexpression enhances cell survival after exposure to ionization radiation which
generates the DSBs. Thus, it would be extremely beneficial to develop small molecule
inhibitors of Metnase to reduce resistance to common cancer chemotherapies that
utilize this type of treatment.
Design, Synthesis, and Biological Activity of Inhibitors
As described above, Metnase is an ideal target for new therapeutic agents. The
main goal for this work is to target the SET domain and design molecules that inhibit the
methylase function by binding to the methyl donating cofactor, SAM, binding site.
Beneficially, a crystal structure of the SET domain of Metnase with S-adenosyl-
homocysteine in available in the protein data bank (PDB 3BO5). The approach
presented herein will use structural information in combination with computer modeling
and medicinal chemistry to identify potential methylase inhibitors of Metnase. The goal
is to obtain a more negative score with each inhibitor that is docked. After synthesis and
biochemical assay of the docked compounds, we can pinpoint a compound with a score
which demonstrates in vitro methylase inhibition and use this as the baseline score. We
can then do further modifications to this base compound and ultimately find a structure
105
that gives a more negative score and proceed to synthesize the next compound. Ideally,
we would like to identify compounds with the highest inhibitory activity at the lowest
concentration.
Inhibitors with Lactam Scaffold
A high-throughput docking of commercially available ligands from the Molport
database using the Schrödinger Maestro Glide program was performed to identify
potential inhibitors of Metnase. Compounds that had a structural backbone similar to
that of SAM were excluded in an effort to increase specificity for Metnase and decrease
toxicity, as SAM is used in a number of metabolism pathways. This screen revealed 13
compounds that were identified to have substantial interactions with the SAM binding
site. These compounds were then subjected to in vitro biochemical inhibition and one
compound, CH7126443 4-1 was found to block the methylase activity of Metnase at 50
M (Figure 4-2). Interestingly, structural analogues of these compounds are nearly
absent in the literature.
Figure 4-2. Lead compound CH7126443
To probe the potential of this novel scaffold for Metnase methylase inhibition, a
series of potential analogues were designed and submitted to docking studies.
Structurally, these docked compounds consisted of the same central core lactam as in
CH7126443, with various substitution on the benzyl groups on the amide and amine
portion. From these compounds, a few were selected to test the synthetic plan and
inhibitory activity, starting with the simpler analogues. The only difference in the three
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synthesized compounds presented herein is on the benzyl amine portion. The central
lactam moiety was synthesized efficiently from ethyl 2-oxopiperidine-3-carboxylate 4-2
by reduction of the ester to the alcohol 4-3, followed by conversion to the enone 4-4
(Figure 4-3).
Figure 4-3. Synthesis of 4-4
The synthesis of the electrophile for functionalization of the amide initiated with a
monoreduction of isophthalaldehyde 4-5 with sodium borohydride, followed by tosyl
protection to provide 4-7. Addition of a freshly prepared solution of
cyclopropylmagnesium bromide to 4-7, yielded unstable alcohol 4-8 in high yields,
which was immediately deoxygenated to generate 4-9 (Figure 4-4).
Figure 4-4. Synthesis of 4-9
The reaction of 4-4 and 4-9 with sodium hydride yielded the benzylated product
4-10 which was then oxidized with mCPBA to yield the corresponding epoxide 4-11
(Figure 4-5).
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Figure 4-5. Synthesis of 4-11
The epoxide 4-11 was then opened under microwave conditions with benzyl
amines 4-12 and 4-13 (Figure 4-6). The corresponding products 4-14 and 4-15 were
isolated in 28% and 53% yields, respectively. Deprotection of the benzyl group in 4-15
under hydrogenation conditions yielded another target 4-16.
Figure 4-6. Epoxide opening with benzyl amines
Unfortunately, compounds 4-14, 4-15, and 4-16 showed no methylase inhibition
of Metnase when subjected to the biochemical assay at concentrations up 25 µM. The
lack of biological activity combined with the problematic synthesis and purification of
these compounds encouraged us to learn to use the docking software in hopes of
designing a better scaffold in house.
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Inhibitors with Tertiary Amine Scaffold
By assessing the shape of the SAM binding site and the residues surrounding
the pocket, we found that a tertiary amine scaffold with a phthalimide substituent 4-18 fit
well into the binding pocket and had favorable interactions. A comparison of the new
scaffold shows that the phthalimide moiety is positioned in the left pocket where the
adenosyl group of SAM 4-17 binds, while the aromatic group in the scaffold is located in
the right pocket where the amino acid group of SAM binds (Figure 4-7). The amide
group protrudes towards the front of the pocket. The docking images also reveal the
electrostatic potentials at the surface of the protein with positive potentials represented
as blue, negative potentials as red and neutral as grey. The phthalimide group
seemingly played a significant role in the better docking of these types of substrates
with interactions with residues Tyr274 and His210. Interestingly, these are the same
residues that interact with the adenosyl substituent in SAM. Whereas the highest
docking score for the lactam targets that were synthesized was -7.4, this simple amine
already showed a higher docking score of -8.8, suggesting good interaction and thus
potentially higher inhibitory activity. Because the phthalimide portion (4-18, blue)
interacted strongly, we envisioned altering the aromatic portion (4-18, red) to enhance
interactions on that side of the binding pocket. With this promising score, we began
synthesis of this compound and other analogues. The results from the docking studies,
the synthesis, and the in vitro inhibitory activity are presented for each target
synthesized. Aruna Jaiswal in the Hromas lab completed the inhibitory testing for all
compounds synthesized.
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Figure 4-7. Protein-ligand interactions and docking images of a) SAM and b) 4-18
The required reagent to install the phthalimide group was synthesized starting
from 4-methylphthalic anhydride 4-19. After conversion to the phthalimide then Boc
protection, desired product 4-20 was obtained in high yields. The final bromination step
lead to a mixture of brominated products, with the desired product 4-21 being isolated in
47% yield (Figure 4-8).
Figure 4-8. Synthesis of 4-21
In all syntheses, the strategy was to synthesize the 3-(benzylamino)propanamide
portion then alkylate with the phthalimide reagent 4-21. Michael addition of benzylamine
4-12 to acrylamide 4-22 provided 4-23, which was then alkylated with 4-21 to provide 4-
110
24 in high yields over two steps (Figure 4-9). Deprotection of the Boc group yielded
target 4-18 in a 16% yield. Unfortunately, there was no biological activity observed for
this compound up to 25 µM.
Figure 4-9. Synthesis of 4-18
To increase the interactions from the phenyl ring, we then added a chlorine
substituent to fill the pocket and potentially have Van der Waals interactions (Figure 4-
10). This increased the docking score from -8.8 for 4-18 to -9.3 for 4-25.
Figure 4-10. Protein-ligand interactions and docking image of 4-25
The synthesis of 4-25 follows the same steps as 4-18 except the aldehyde 4-26
was first converted to the benzylamine 4-27 (Figure 4-11). Michael addition to
acrylamide followed by alkylation provided 4-29 in 84% over the two steps.
111
Disappointingly, there was no biological activity observed up to 25 µM for this
compound either.
Figure 4-11. Synthesis of 4-25
The presence of residues with the potential for hydrogen bonding in the right side
pocket encouraged us to incorporate a hydroxy group on the aromatic moiety 4-30
(Figure 4-12). Indeed, we observed hydrogen bonding interactions between the
hydroxyl group and Lys135. We were delighted to see that this change resulted in an
increase in docking score to -10.3.
Figure 4-12. Protein-ligand interactions and docking image of 4-30
112
The synthesis of 4-30 began with the corresponding aldehyde. However,
conversion to the benzyl amine was unsuccessful. Thus, after protection of the hydroxyl
group, an overall reductive amination sequence by forming the imine followed by
hydrogenation formed 4-34. Alkylation with 4-21 then global deprotection yielded the
target 4-30. Gratifyingly, this compound yielded good inhibitory activity at 25 µM,
indicated by substantial disappearance of the Histone 3 (lys36) Me2 spot (Figure 4-13).
Figure 4-13. a) Synthesis and b) Metnase methylase inhibitory activity of 4-30
113
Excited by this result, we were interested in finding an analogue that qualitatively
showed inhibitory activity at a lower concentration. By comparing the different
conformations that 4-30 docked in the binding pocket, we observed that the aromatic
ring would rotate and have hydrogen bonding interactions with residues on the bottom
side. We therefore included a second hydroxy group in 4-36 which resulted in a better
docking score of -11.1 (Figure 4-14). Surprisingly, the hydroxyl group no longer had an
interaction with the same amino acid residue as 4-30, but with new residues Trp137 and
Arg206.
Figure 4-14. Protein-ligand interactions and docking image of 4-36
Protection of 3-5-dihydroxybenzoate 4-37 followed by a reduction/oxidation
sequence generated 4-39. The same steps as in the synthesis of 4-30 were then
followed to yield 4-36 in a straightforward manner. The qualitative biological testing of 4-
36 revealed almost complete methylase inhibition at 10 µM, though curiously it seems to
lose some activity at 25 µM (Figure 4-15).
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Figure 4-15. a) Synthesis and b) Metnase methylase inhibitory activity of 4-36
The last compound 4-42 that was synthesized focused on increasing the
flexibility of the compound by adding two more methylene spaces between the aromatic
group and the amine. Our hope was that this would allow for the target to find stronger
interactions. Indeed, this change increased the docking score slightly to -11.9 (Figure 4-
16). Interestingly, unlike the others, many of the poses docked for this compound had
115
the phthalimide and aromatic group in the opposite pocket than what was typically
observed.
Figure 4-16. Protein-ligand interactions and docking image of 4-42
The synthesis of 4-42 was achieved using aldehyde 4-39 in a Horner-
Wadsworth-Emmons reaction with 4-43 to obtain 4-44. Hydrogenation followed by
reduction of the cyano group provided 4-47 which was then alkylated and deprotected
to yield the last target 4-42 (Figure 4-17). Surprisingly, we did not observe the expected
biological activity. There seemed to be inhibition at 5 µM, but at higher concentrations
the inhibitory activity seemed to be diminished and essentially no inhibition by 25 µM. At
this time, we are unsure why it seems to be losing its inhibitory activity as the
concentration is increased. One issue may be stability of the compound in the solution
which will have to be studied further.
116
Figure 4-17. a) Synthesis and b) Metnase methylase inhibitory activity of 4-42
Conclusions and Outlook
In conclusion, we have reported the first small molecule methylase inhibitors of
Metnase. These compounds demonstrate a new class of methylase inhibitors as they
do not incorporate an adenosyl methionine backbone. Of the compounds that were
117
docked by our collaborators, we synthesized three of them that did not demonstrate any
inhibitory activity up to 25 µM. Of the hundreds of compounds that we docked
ourselves, we discovered a tertiary amine scaffold that showed promising docking
scores. A total of 5 of these compounds were synthesized with three having inhibitory
activity. Thus far, 4-36 seems to be the best candidate with almost complete inhibition at
~10 µM. A more qualitative study will have to be performed to determine specific IC50
values. Further studies to find a more potent inhibitor would focus on varying the
aromatic group further as well as altering the propanamide substituent. Additionally,
other scoring functions may be considered, to determine better potential targets before
synthesis.
118
CHAPTER 5 EXPERIMENTAL SECTION
General Considerations
All reactions were carried out under an atmosphere of nitrogen unless otherwise
specified. Anhydrous solvents were transferred via syringe to flame-dried glassware,
which had been cooled under a stream of dry nitrogen. Anhydrous tetrahydrofuran
(THF), acetonitrile, diethyl ether and dichloromethane were dried using an mBraun
solvent purification system. Analytical thin layer chromatography (TLC) was performed
using 250 μm Silica Gel pre-coated plates (Analtech). Flash column chromatography
was performed using 230-400 Mesh 60Å Silica Gel (Aldrich). Proton nuclear magnetic
resonance (1H NMR) spectra were recorded using Varian Unity Inova 500 MHz and
Varian Mercury 300 MHz spectrometers. Chemical shifts (δ) are reported in parts per
million (ppm) downfield relative to tetramethylsilane (TMS, 0.0 ppm) or CDCl3 (7.26
ppm). Coupling constants (J) are reported in Hz. Multiplicities are reported using the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet;
b, broad; Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded
using a Varian Unity Mercury 300 spectrometer at 75 MHz and a Varian Unity Inova 500
MHz at 125 MHz. Chemical shifts are reported in ppm relative to the carbon resonance
of CDCl3 (77.23 ppm). Fluorine-19 (19F NMR) nuclear magnetic resonance spectra were
recorded using Varian Unity Mercury 300 at 281 MHz. Specific Optical rotations were
obtained on a JASCD P - 2000 Series Polarimeter (wavelength = 589 nm). High
resolution mass spectra (HRMS) were obtained by Mass Spectrometry Core Laboratory
of University of Florida, and are reported as m/z (relative ratio). Accurate m/z are
reported for the molecular ion [M+H]+, [M+NH4]+ or [M+Na]+. Enantiomeric ratios were
119
determined by chiral HPLC analysis (Shimadzu) using Chiralcel AD-H and Chiralcel
OD-H columns. Schrödinger Maestro Glide 13 was used for the docking of the small
molecule inhibitors. The grid for docking in the SAM binding site was generated
following the tutorial guides from Schrodinger.216 The ligand preparation product
LigPrep was used to generate variations and optimize the structures. The default
options were used which include minimizing the ligand and generating possible
protonation states within a pH range of 5.0-9.0. All of the minimized ligands were
selected in the workspace and then subjected to glide docking using the same grid for
each inhibitor. The XP (extra precision) docking setting was used along with the set
default parameters.
Preparation of Indolocarbazoles
tert-butyl (2-(hydroxymethyl)phenyl)carbamate (2-70). The desired compound was
synthesized via a reported literature procedure with matching spectroscopic data. 217
tert-butyl (2-(bromomethyl)phenyl)carbamate (2-71). To a solution of
triphenylphosphine (5.45 g, 20.8 mmol) and tert-butyl (2-
(hydroxymethyl)phenyl)carbamate 2-70 (3.87 g, 17.3 mmol) in THF (62 mL) at -20 °C
was added N-bromosuccinimide (3.70 g, 20.8 mmol) portionwise over 5 minutes.
Stirring was continued for 3 hours at the same temperature, and the reaction mixture
120
was filtered over a pad of silica and concentrated. Purification by column
chromatography yielded the product as a white solid (91% yield) which matched
previously reported spectroscopic data.218
tert-butyl (2-(3-(trimethylsilyl)prop-2-yn-1-yl)phenyl)carbamate (2-72). To a
refluxing solution of tert-butyl (2-(bromomethyl)phenyl)carbamate 2-71 (4.35 g, 15.8
mmol) and Pd(dppf)Cl2-dichloromethane adduct (245 mg, 0.3 mmol) in THF (45 mL)
was added (TMS-acetylene)3In (60 mL of a 0.1M solution in THF)219 and the mixture
was stirred for 4 hours at the same temperature. After this time, the reaction was
quenched with MeOH. The crude mixture was concentrated onto silica gel and purified
by flash column chromatography to furnish the title compound as a white solid (77%
yield). Rf = 0.50 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 7.5
Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.17 (bs, 1H), 7.05 (t, J = 7.5
Hz, 1H), 3.57 (s, 2H), 1.56 (s, 9H), 0.21 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 153.1,
136.7, 129.4, 127.9, 123.8, 102.5, 88.5, 80.4, 28.4, 23.8, -0.1; IR (neat): νmax 3270,
2962, 2178, 1680, 1530, 1032, 837; HRMS (ESI) Calculated for C17H25NO2SiNa
[M+Na]+ 326.1547, found 326.1555.
tert-butyl (2-(prop-2-yn-1-yl)phenyl)carbamate (2-73). To a solution of alkyne 2-72
(3.68 g, 12.1 mmol) in MeOH (80 mL) was added K2CO3 (2.0 g, 14.5 mmol). The
121
reaction was allowed to stir for 2 hours at room temperature. The reaction was
quenched with H2O, then extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure. The crude
material was subjected to flash column chromatography to furnish the alkyne as a pale
yellow solid (85% yield). Rf = 0.41 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.74 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5
Hz, 1H), 6.70 (bs, 1H), 3.55 (d, J = 2.4 Hz, 2H), 2.27 (t, J = 2.4 Hz, 1H), 1.55 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 153.3, 136.0, 129.2, 128.0, 124.5, 80.6, 80.6, 71.5, 28.4,
21.9; IR (neat): νmax 3287, 2980, 1713, 1230, 1152, 744; HRMS (ESI) m/z: [M+Na]+
Calculated for C14H17NO2Na 254.1151, found 254.1152.
tert-butyl (2-(4-hydroxy-4-(2-nitrophenyl)but-2-yn-1-yl)phenyl)carbamate (2-74). A
solution of alkyne 2-73 (1.01 g, 4.37 mmol) in THF (25 mL) was cooled in a dry
ice/acetone bath to -78 °C and treated with nBuLi (3.67 mL, 2.5 M solution in hexanes).
The mixture was stirred 1 hour before addition of a solution of 2-nitrobenzaldehyde (792
mg, 5.24 mmol) in THF (2 mL). After an additional 4 hours, the reaction was quenched
with a saturated aqueous NH4Cl solution, and allowed to warm to room temperature.
The resulting mixture was extracted with EtOAc. The organic phase was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure. The crude
material was subjected to flash column chromatography to furnish the title compound as
a viscous yellow syrup (88% yield). Rf = 0.19 (25% EtOAc/hexanes); 1H NMR (500
122
MHz, CDCl3) δ 7.98 (dd, J = 8.2, 1.4 Hz, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.76 – 7.64
(td, J = 7.8, 1.4 Hz, 2H), 7.49 (m, 1H), 7.34 – 7.23 (m, 2H), 7.10 (td, J = 7.5 Hz, 1.3 Hz,
1H), 6.57 (s, 1H), 6.03 (t, J = 2.0 Hz, 1H), 3.61 (d, J = 2.0 Hz, 2H), 3.21 (s, 1H), 1.50 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 153.3, 147.9, 135.9, 135.6, 133.8, 129.3, 129.2,
128.0, 125.0, 124.6, 83.8, 81.2, 80.7, 61.4, 28.3, 22.2; IR (neat): νmax 3385, 3274, 2981,
2901, 2247, 1712, 1527, 1346, 1154, 1018, 731; HRMS (ESI) m/z: [M+Na]+ Calculated
for C21H22N2O5Na 405.1421, found 405.1429.
tert-butyl (2-(4-(3-chloro-2-nitrophenyl)-4-hydroxybut-2-yn-1-yl)phenyl)carbamate
(2-75). A solution of alkyne 2-73 (444 mg, 1.92 mmol) in THF (11 mL) was cooled in a
dry ice/acetone bath to -78 °C and treated with nBuLi (1.61 mL, 2.5 M solution in
hexanes). The mixture was stirred 1 hour before addition of a solution of 3-chloro-2-
nitrobenzaldehyde (426 mg, 2.30 mmol) in THF (2 mL). After an additional hour, the
reaction was quenched with saturated aqueous NH4Cl solution and allowed to reach
room temperature. The resulting mixture was extracted with EtOAc. The organic phase
was washed with brine, dried over Na2SO4, and concentrated under reduced pressure.
The crude material was subjected to flash column chromatography to furnish the title
compound as a viscous yellow syrup (69% yield) of sufficient purity for the following
step. 1H NMR (300 MHz, CDCl3) δ 7.74 – 7.62 (m, 2H), 7.52 – 7.39 (m, 2H), 7.31 – 7.18
(m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.53 (s, 1H), 5.62 (m, 1H), 3.60 (d, J = 1.7 Hz, 2H),
2.94 (s, 1H), 1.50 (s, 9H).
123
tert-butyl (E)-2-(2-nitrostyryl)-1H-indole-1-carboxylate (2-76). In a foil covered round
bottom flask at room temperature were combined Au[P(t-Bu)2(o-biphenyl)]Cl (13.0 mg,
24.0 µmol), AgOTf (6.3 mg, 24.0 µmol), and benzene (1 mL). The solution was stirred
for 10 minutes, after which time a solution of propargyl alcohol 2-74 (466 mg, 1.22
mmol) in benzene (5 mL) was added. After stirring for an additional 25 minutes, the
reaction was filtered over plug of silica, and the plug was washed with 15%
EtOAc/hexanes. The solvent was removed in vacuo, and the residue subjected to flash
column chromatography to afford pure title compound as an orange solid (79% yield). Rf
= 0.53 (25% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 1H),
7.98 (dd, J = 8.1, 1.0 Hz, 1H), 7.87 – 7.75 (m, 2H), 7.68 – 7.50 (m, 3H), 7.43 (t, J = 7.5
Hz, 1H), 7.35 – 7.18 (m, 2H), 6.97 (s, 1H), 1.71 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
150.9, 148.1, 138.8, 137.1, 133.3, 133.0, 129.4, 128.5, 128.2, 126.0, 125.0, 125.0,
124.9, 123.4, 121.0, 116.0, 108.6, 84.6, 28.5; IR (neat): νmax 2981, 2921, 1725, 1512,
1329, 1121, 1085, 951; HRMS (ESI) m/z: [M+Na]+ Calculated for C21H20N2O4Na
387.1315, found 387.1323.
tert-butyl (E)-2-(3-chloro-2-nitrostyryl)-1H-indole-1-carboxylate (2-77). In a foil
covered round bottom flask at room temperature were combined Au[P(t-Bu)2(o-
124
biphenyl)]Cl (14.1 mg, 27.0 µmol), AgOTf (6.8 mg, 27.0 µmol), and benzene (1 mL).
The solution was stirred for 10 minutes, after which time a solution of propargyl alcohol
2-75 (554 mg, 1.33 mmol) in benzene (5 mL) was added. After stirring for an additional
25 minutes, the reaction was filtered over a plug of silica, and the plug was washed with
benzene. The solvent was removed in vacuo and the crude product was purified via
flash column chromatography to afford the title compound as a yellow solid (58% yield).
Rf = 0.51 (25% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.3 Hz, 1H),
7.96 (d, J = 16.0 Hz, 1H), 7.74 (dd, J = 7.7, 1.2 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.46 –
7.38 (m, 2H), 7.33 (td, J = 8.3, 1.2 Hz, 1H), 7.29 – 7.23 (t, J = 7.7 Hz, 1H), 6.91 (s, 1H),
6.85 (d, J = 16.0 Hz, 1H), 1.73 (s, 9H);13C NMR (125 MHz, CDCl3) δ 150.7, 148.5,
138.0, 137.1, 131.5, 130.9, 129.2, 129.1, 127.2, 125.5, 125.2, 124.9, 123.5, 121.1,
121.0, 116.0, 109.0, 84.8, 28.5; IR (neat): νmax 3106. 2976, 1726, 1530, 1328, 1152,
747; HRMS (DART) m/z: [M]+ Calculated for C21H10ClN2O4 398.1033, found 398.1040.
tert-butyl 4-(2-nitrophenyl)-1,3-dioxo-2,3,3a,4,10b,10c-hexahydropyrrolo[3,4-
c]carbazole-6(1H)-carboxylate (2-78). To a flask fitted with a cold finger condenser,
diene 2-76 (600 mg, 1.6 mmol) and maleimide (717 mg, 8.2 mmol) was added. The
flask was evacuated and refilled with nitrogen. Toluene (6.4 mL) was added and the
reaction was vigorously stirred for 3 hours at 100 °C. The crude reaction was loaded
onto silica and purified via flash column chromatography to afford the Diels−Alder
125
adduct (90% yield). Rf = 0.18 (30% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 8.15
(s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (m, 1H), 7.69 – 7.52 (m, 2H), 7.52 – 7.41 (m, 2H),
7.32 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.47 (s, 1H), 4.1 – 3.98 (m, 2H), 3.91 –
3.81 (m, 2H), 1.63 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 176.0, 175.0, 151.2, 149.6,
142.6, 141.6, 134.6, 132.9, 132.5, 128.4, 128.2, 127.6, 125.0 124.5, 123.5, 115.9,
105.1, 83.4, 45.1, 44.1, 41.9, 38.8, 28.3. IR (neat): νmax 3248, 3080, 2979, 2932, 1718,
1525, 1372, 1157, 766. HRMS (ESI) m/z: [M+Na]+ Calculated for C25H23N3O6Na
484.1479, found 484.1477.
tert-butyl 4-(3-chloro-2-nitrophenyl)-1,3-dioxo-2,3,3a,4,10b,10c-
hexahydropyrrolo[3,4-c]carbazole-6(1H)-carboxylate (2-79). To a flask fitted with a
cold finger condenser, diene 2-77 (100 mg, 0.25 mmol) and maleimide (109 mg,
1.25mmol) was added. The flask was evacuated and refilled with nitrogen. Toluene (1
mL) was added and the reaction was vigorously stirred for 3 hours at 100 °C. The crude
reaction was loaded onto silica and purified via flash column chromatography to afford
the Diels−Alder adduct (83% yield). Rf = 0.22 (30% EtOAc/hexanes); 1H NMR (300
MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.49 (m, 4H), 7.33 (t, J = 8.0 Hz,
1H), 7.19 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 4.01 (m, 1H), 3.81 (t, J = 7.8 Hz, 1H), 3.61 (t,
J = 7.8 Hz, 1H), 3.45 (m, 1H), 1.65 (s, 9H). 13C NMR data was not obtained due to low
solubility of the substrate.
126
tert-butyl 4-(2-nitrophenyl)-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazole-6(1H)-
carboxylate (2-80). To 2,3-dichloro-5,6-dicyano-p-benzoquinone (85 mg, 0.375 mmol),
a solution of 2-78 (70 mg, 0.15 mmol) in toluene (3 mL) was added. The reaction was
allowed to stir for 4 hours at 65 °C then quenched with saturated aqueous NaHCO3.
The resulting mixture was extracted with EtOAc and washed multiple times with
NaHCO3. The crude product was purified by recrystallization from MeOH (84% yield.) Rf
= 0.40 (25% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 9.18 (d, J = 8.0 Hz, 1H),
8.74 (s, 1H), 8.35 – 8.20 (m, 2H), 7.81 – 7.69 (m, 2H), 7.6 (t, J = 8.0 Hz, 2H), 7.52 (t, J =
7.6 Hz, 2H), 1.77 (s, 9H). 13C NMR (125 MHz, DMSO) δ 169.5, 169.3, 150.2, 148.6,
142.5, 139.9, 134.4, 134.0, 133.1, 132.7, 130.4, 130.3, 126.7, 125.6, 124.9, 124.6
124.6, 122.5, 121.9, 121.6, 116.3, 86.2, 28.1. IR (neat): νmax 3193, 3071, 2979, 1718,
1525, 1349, 1147, 746. HRMS (ESI) m/z: [M+Na]+ Calculated for C25H19N3O6Na
480.1166, found 480.1141.
tert-butyl 4-(3-chloro-2-nitrophenyl)-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazole-
6(1H)-carboxylate (2-81). To 2,3-dichloro-5,6-dicyano-p-benzoquinone (29 mg, 0.12
127
mmol), a solution of 2-79 (25 mg, 0.05 mmol) in toluene (1 mL) was added. The reaction
was allowed to stir for 24 hours at 65 °C then quenched with saturated aqueous
NaHCO3. The resulting mixture was extracted with EtOAc and washed multiple times
with NaHCO3. The crude product was purified by recrystallization from MeOH (62%
yield). Rf = 0.43 (30% EtOAc/hexanes); 1H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H),
9.10 (d, J = 7.8 Hz, 1H), 8.50 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H),
7.81 – 7.69 (m, 3H), 7.58 (t, J = 7.8 Hz, 1H), 1.71 (s, 9H). 13C NMR was not obtained
due to low solubility of the substrate.
tert-butyl 5,7-dioxo-5,6,7,13-tetrahydro-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-
12-carboxylate (2-82). Substrate 2-80 (10 mg, 0.02 mmol), MoO2Cl2(dmf)234
(1.7 mg,
0.004 mmol), and PPh3 (16 mg, 0.06 mmol) were added to a flask. Freshly distilled
toluene (0.4 mL) was then added and the mixture was allowed to stir for 24 hours at 90
°C. The reaction mixture was absorbed onto silica and purified by flash column
chromatography (5% THF/toluene). The title compound was obtained as a bright yellow
solid (60% yield). Rf = 0.5 (25% EtOAc/hexanes); 1H NMR (500 MHz, DMSO) δ 11.35
(s, 1H), 11.20 (s, 1H), 9.21 (d, J = 8.0 Hz, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0
Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.44
(t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 1.75 (s, 9H). 13C NMR (125 MHz, DMSO) δ
171.3, 171.1, 151.7, 140.8, 139.2, 131.4, 129.28, 128.6, 127.3, 125.7, 125.4, 125.1,
128
124.9, 124.8, 121.30, 120.8, 119.5, 119.1, 116.8, 113.3, 87.4, 28.7. IR (neat): νmax
3362, 3194, 3064, 2981, 2922, 1698, 1455, 1313, 1299, 1140, 754. HRMS (ESI) m/z:
[M+Na]+ Calculated for C25H19N3O4Na 448.1268, found 448.1274.
Preparation of Alkynes
Figure 5-1. General preparation of aromatic alkynes
General Procedure: To a solution of the aromatic iodide (1.0 mmol) in THF (1 mL) was
added Et3N (4.0 mmol), CuI (0.05 mmol), PdCl2(PPh3)2 (0.05 mmol), and
trimethylsilylacetylene (1.5 mmol) at room temperature. The reaction was stirred for 16
hours at room temperature then concentrated and purified by flash column
chromatography. The product was then dissolved in MeOH (0.15 M) and K2CO3 (3.0
equiv.) was added. The reaction was stirred for 3 hours at room temperature then
EtOAc and water was added. The organic layer was extracted, dried over MgSO4,
filtered and concentrated. The crude material was purified by flash column
chromatography to furnish the alkyne.
129
1-bromo-3-ethynylbenzene (5-1). Synthesis of alkyne 5-1 was achieved using 1-iodo-
3-bromobenzene following the general procedure above with the obtained
spectroscopic data matching the reported data for this compound. 220
1-ethynyl-4-nitrobenzene (5-2). Synthesis of alkyne 5-2 was achieved using 1-iodo-4-
nitrobenzene following the general procedure above with the obtained spectroscopic
data matching the reported data for this compound. 221
2-ethynylthiophene (5-3). Synthesis of alkyne 5-3 was achieved using 1-iodothiophene
following the literature procedure as above with the obtained spectroscopic data
matching the reported data for this compound. 222
5-ethynylbenzo[d][1,3]dioxole (5-4). The synthesis of alkyne 5-4 was accomplished
through a known literature procedure using a Corey-Fuchs sequence starting with
piperonal providing the alkyne with matching spectroscopic data as compared to
previously reported data. 223
130
((prop-2-yn-1-yloxy)methyl)benzene (5-5). Alkyne 5-5 was synthesized using
propargyl alcohol according to a literature procedure furnishing the alkyne with matching
spectroscopic data as compared to the reported data. 224
N,N-dibenzylprop-2-yn-1-amine (5-6). Akyne 5-6 was synthesized from propargyl
amine according to a literature procedure furnishing the alkyne with matching
spectroscopic data as compared to the reported data.224
but-3-yne-1,2-diyl diacetate (5-7).225 To a solution of crude but-3-yne-1,2-diol226 (200
mg, 2.2 mmol) in CH2Cl2 (1.0 mL) was added acetic anhydride (0.52 mL, 5.5 mmol). The
solution was stirred for 3 hours at room temperature then concentrated. The alkyne was
obtained as a colorless oil after flash column chromatography. Rf = 0.26 (20%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 5.60 (m, 1H), 4.36 (dd, J = 11.8, 3.6 Hz,
1H), 4.24 (dd, J = 11.8, 7.3 Hz, 1H), 2.53 (d, J = 2.2 Hz, 1H), 2.12 (s, 3H), 2.09 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 170.5, 169.7, 77.6, 75.3, 64.5, 61.7, 20.9, 20.8. HRMS
(ESI) m/z: [M+Na]+ Calculated for C8H10O4Na+ 193.0471; found 193.0509.
131
Preparation of Chromones
Figure 5-2. Synthesis of isoflavone
Isoflavone (5-10).227 3-iodochromone 5-9228 was synthesized via a previous literature
procedure starting from 2-hydroxyacetophenone furnishing the product with matching
spectroscopic data. Using a modified literature procedure, the Suzuki couple of 5-9 with
phenylboronic acid provided isoflavone 5-10 with obtained spectroscopic data matching
the previously reported data.
4-oxo-4H-chromen-6-yl acetate (5-11).229,230 To a solution of 6-methoxychromone (50
mg, 0.28 mmol, Indofine Chemical) in acetic acid (1.0 mL) was added 40% HBr (0.5
mL). The solution was heated at 120 °C for 48 hours then cooled to room temperature.
Upon addition of water, a white precipitate formed, which was filtered and washed with
water. The crude product was dissolved in pyridine (0.5 mL) and acetic anhydride (32
µL, 0.34 mmol) was added. The reaction was heated at 80 °C for 8 hours then cooled to
room temperature and concentrated. The desired product was obtained in 56% yield
over two steps after purification by flash column chromatography. Rf = 0.10 (30%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 6.0
132
Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.8 Hz, 1H), 6.33 (d, J = 6.0 Hz, 1H),
2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 177.0, 169.4, 155.6, 154.2, 147.7, 128.2,
125.8, 119.7, 118.0, 112.7, 21.1. HRMS (ESI) m/z: [M+Na]+ Calculated for C11H8O4Na+
227.0315; found 227.0312.
2-hydroxy-N,3-dimethoxy-N-methylbenzamide (5-12). To a solution of methyl 2-
hydroxy-3-methoxybenzoate (500 mg, 2.75 mmol) and N,O-dimethylhydroxylamine
hydrochloride (550 mg, 5.5 mmol) in THF at 0 °C, was added iPrMgCl (7.0 mL, 13.8
mmol, 2.0 M in THF) dropwise. The reaction was allowed to warm to room temperature
and stirred for 16 hours then quenched with saturated aqueous NH4Cl and acidified with
1N HCl. Ethyl acetate was added and the solution was allowed to stir overnight. The
reaction was worked up and the organic layer was dried over MgSO4, filtered and
concentrated. The crude mixture was purified by flash column chromatography to yield
the weinreb amide (45% yield). Rf = 0.30 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 10.46 (s, 1H), 7.45 (dd, J = 8.0, 1.3 Hz, 1H), 6.97 (dd, J = 8.0, 1.3 Hz, 1H),
6.81 (t, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 3.39 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 169.6, 150.0, 148.6, 120.9, 118.4,116.0, 114.5, 61.4, 56.3, 34.2. HRMS (ESI)
m/z: [M+Na]+ Calculated for C10H13NO4Na+ 234.0737; found 234.0739.
133
1-(2-hydroxy-3-methoxyphenyl)ethan-1-one (5-13). To a solution of 5-12 (250 mg,
1.5 mmol) in THF (10 mL) at -78 °C was added MeMgBr (1.7 mL, 5.0 mmol, 3.0 M in
ether). The reaction was quenched after 1 hour with saturated aqueous NH4Cl and
acidified by 1N HCl then extracted with EtOAc. The organic layer was dried over
MgSO4, filtered and concentrated to yield the product in 25% yield with spectroscopic
data that matched previously reported data.231
8-methoxychromone (5-14). To a solution of 5-13 (50 mg, 0.3 mmol) in ethylformate
(0.5 mL) at 0 °C, was added NaH (36 mg, 1.5 mmol) in one portion. The mixture was
allowed to warm slowly to room temperature and stirred for 1 hour. Concentrated HCl
was then added and the reaction was stirred for an additional 2 hours, after which
EtOAc and water was added. The organic layer was collected, dried over MgSO4,
filtered and concentrated. The crude mixture was purified by flash column
chromatography (61% yield). Rf = 0.22 (40% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.92 (dd, J = 6.0, 1.1 Hz, 1H), 7.76 (dt, J = 8.0, 1.1 Hz, 1H), 7.33 (td, J = 8.0,
1.1 Hz, 1H), 7.18 (dt, J = 8.0, 1.1 Hz, 1H), 6.36 (dd, J = 6.0, 1.1 Hz, 1H), 4.00 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 177.6, 155.2, 148.9, 147.1, 126.0, 125.1, 116.8, 114.5,
134
113.2, 56.6. HRMS (ESI) m/z: [M+Na]+ Calculated for C10H8O3Na+ 199.0366; found
199.0374.
Asymmetric Alkynylation of Chromones
Figure 5-3. General procedure for the alkynylation of chromones
General Procedure: Copper iodide (1.3 mg, 0.0068 mmol) was added to a test tube in
the glove box. (S)-StackPhos (5.3 mg, 0.0075 mmol) was then added to the test tube
and dissolved in toluene (0.5 mL). The mixture was stirred at room temperature for 0.5
hours to give a pale yellow solution. Chromone (0.137 mmol, 1.0 equiv.), alkyne (0.178
mmol, 1.3 equiv.), and N,N-diisopropylethylamine (38 µL, 0.219 mmol, 1.6 equiv.) were
then added sequentially. The reagents were rinsed down the test tube with an additional
aliquot of toluene (0.9 mL). The mixture was cooled to -78 °C and TMSOTf (32 µL,
0.178 mmol, 1.3 equiv.) was added. The test tube was then transferred to a -20 °C bath
and allowed to stir for 16-44 hours. The reaction was then quenched with 3N HCl and
allowed to stir until the silyl enol ether was completely hydrolyzed as monitored by TLC.
Saturated aqueous NaHCO3 was added to neutralize the solution then the reaction
mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate,
filtered and concentrated. The crude product was purified by flash column
chromatography using EtOAc/hexanes.
135
The racemic reactions followed the same procedure except were ran at room
temperature with rac-StackPhos.
(R)-2-(phenylethynyl)chroman-4-one (3-62).232 The general procedure described
above was followed to give the chromanone as a white solid (89% yield) which matched
previously reported spectroscopic data. Rf = 0.31 (10% EtOAc/hexane); [α]22D = -99.841
(c 1.0, CHCl3).
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 8.6 min (minor) tr= 10.1 min (major); 94% ee.
(R)-2-((4-nitrophenyl)ethynyl)chroman-4-one (3-64). The general procedure
described above was followed to give the chromanone as a solid (73% yield) after
136
preparatory TLC. Rf = 0.13 (10% EtOAc/hexanes); [α]22D = -78.763 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 8.9 Hz, 2H), 7.92 (d, J = 7.8, 1.3 Hz 1H), 7.54
(m, 3H), 7.08 (m, 2H), 5.55 (X of ABX, 1H), 3.13, 3.07 (AB of ABX, J = 16.8, 8.2, 4.5 Hz,
= 28.9 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.0, 160.1, 147.8, 136.6, 133.0,
128.4, 127.2, 123.8, 122.5, 121.2, 118.4, 89.7, 85.4, 67.9, 43.2. HRMS (ESI) m/z:
[M+Na]+ Calculated for C17H11NO4Na+ 316.0580; found 316.0620.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 22.5 min (minor) tr= 25.6 (major); 94% ee.
(R)-2-(benzo[d][1,3]dioxol-5-ylethynyl)chroman-4-one (3-65). The general procedure
described above was followed to give the chromanone in 70% yield. Rf = 0.20 (10%
EtOAc/hexanes); [α]22D = -79.676 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J
= 7.9 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.06 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 (s,
1H), 6.73 (d, J = 8.0 Hz, 1H), 5.96 (s, 2H), 5.47 (X of ABX, 1H), 3.07, 3.03 (AB of ABX,
137
J = 16.8, 7.8, 5.2 Hz, = 18.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.7, 160.4,
148.7, 147.6, 136.4, 127.1, 122.2, 121.3, 118.4, 114.8, 112.0, 108.6, 101.6, 87.6, 83.1,
68.3, 43.7. HRMS (ESI) m/z: [M+Na]+ Calculated for C18H12O4Na+ 315.0628; found
315.0675.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (5%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 25.6 min (major) tr= 27.8 min (minor); 89% ee.
(R)-2-(o-tolylethynyl)chroman-4-one (3-66). The general procedure described above
was followed to give the chromanone in 95% yield. Rf = 0.42 (20% EtOAc/hexanes);
[α]22D = -110.572 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, J = 8.0, 1.8 Hz,
1H), 7.50 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.21 (td, J = 7.5, 1.4
Hz, 1 H), 7.15 (d, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 – 7.03 (m, 2H), 5.56 (X
of ABX, 1H), 3.13, 3.04 (AB of ABX, J = 16.8, 7.4, 4.6 Hz, = 28.0 Hz, 2H), 2.27 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 190.6, 160.2, 140.9, 136.4, 132.3, 129.7, 129.3,
138
127.1, 125.7, 122.1, 121.5, 121.4, 118.5, 88.7, 86.5, 68.3, 43.8, 20.6. HRMS (ESI) m/z:
[M+Na]+ Calculated for C18H14O2Na+ 285.0886; found 285.0913.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 7.5 min (minor) tr= 9.4 min (major); 89% ee.
(R)-2-((3-bromophenyl)ethynyl)chroman-4-one (3-67). The general procedure
described above was followed to give the chromanone in 89% yield. Rf = 0.29 (10%
EtOAc/hexanes); [α]22D = -76.886 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.92 (dd,
J = 7.8, 1.6 Hz, 1H), 7.60 – 7.40 (m, 3H), 7.34 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz,
1H), 7.10 – 7.02 (m, 2H), 5.50 (X of ABX, 1H), 3.08, 3.04 (AB of ABX, J = 16.8, 8.2, 4.7
Hz, = 19.9 Hz, 2H).13C NMR (126 MHz, CDCl3) δ 190.4, 160.2, 136.5, 134.9, 132.5,
130.7, 130.0, 127.2, 123.6, 122.3, 121.2, 118.4, 86.0, 85.9, 68.0, 43.5. HRMS (ESI)
m/z: [M+Na]+ Calculated for C17H11BrO2Na+ 348.9835; found 348.9882.
139
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 8.1 min (minor) tr= 10.4 min (major); 93% ee
(R)-2-(thiophen-2-ylethynyl)chroman-4-one (3-68). The general procedure described
above was followed to give the chromanone in 78% yield. Rf = 0.52 (10%
EtOAc/hexanes); [α]22D = 81.700 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J
= 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 – 7.21 (m, 2H), 7.10 – 7.01 (m, 2H), 6.96
(m, 1H), 5.51 (m, 1H), 3.06 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 190.5, 160.3 136.5,
133.7, 128.5, 127.2, 127.2, 122.3, 121.4, 121.2, 118.5, 88.6, 81.0, 68.3, 43.4. HRMS
(ESI) m/z: [M+Na]+ Calculated for C15H10O2SNa+ 273.0342; found 273.0342.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 8.7 min (major) tr= 9.5 min (minor); 93% ee.
140
(R)-2-(3-(benzyloxy)prop-1-yn-1-yl)chroman-4-one (3-69). The general procedure
described above was followed to give the chromanone in 85% yield. Rf = 0.31 (20%
EtOAc/hexanes); [α]22D = -66.697 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J
= 7.9 Hz, 1H), 7.52 – 7.40 (t, J = 7.9 Hz, 1H), 7.32 – 7.12 (m, 5H), 6.98 (m, 2H), 5.29 (X
of ABX, 1H), 4.44 (s, 2H), 4.12 (s, 2H), 2.97, 2.90 (AB of ABX, J = 16.8, 8.0, 4.5 Hz,
= 38.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.4, 160.1, 137.2, 136.5, 128.6, 128.4,
128.2, 127.1, 122.2, 121.3, 118.5, 83.9, 82.5, 71.8, 67.7, 57.2, 43.5. HRMS (ESI) m/z:
[M+Na]+ Calculated for C19H16O3Na+ 315.0992; found 315.0992.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (7%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 14.6 min (major) tr= 15.7 min (minor); 95% ee.
141
(R)-2-(3-(dibenzylamino)prop-1-yn-1-yl)chroman-4-one (3-70). The general
procedure, except placing the reaction flask in a -10 °C bath instead of a -20 °C bath,
described above was followed to give the chromanone in 63% yield. Rf = 0.23 (10%
EtOAc/hexanes); [α]22D = -67.777(c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.98 (dd,
J = 8.0, 1.7 Hz, 1H), 7.54 (m, 1H), 7.36 – 7.15 (m, 10H), 7.08 (m, 2H), 5.41 (X of ABX,
1H), 3.47 (s, 4H), 3.19 (s, 2H), 3.14 (AB of ABX, J = 16.7, 6.1, 4.7 Hz, = 93.6 Hz,
2H). 13C NMR (126 MHz, CDCl3) δ 190.7, 160.0, 138.7, 136.4, 129.2, 128.5, 127.3,
127.1, 122.2, 121.8, 118.7, 83.0, 81.8, 68.0, 57.7, 44.1, 41.2. HRMS (ESI) m/z: [M+H]+
Calculated for C26H24NO2+ 382.1802; found 382.1804.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (7%
iPrOH/hexanes, 0.5 mL/min, 254 nm); tr= 17.7 min (minor) tr= 18.5 min (major); 90% ee.
142
(R)-2-(4-bromobut-1-yn-1-yl)chroman-4-one (3-72). The general procedure described
above was followed to give the chromanone as a colorless oil in 71% yield. Rf = 0.29
(10% EtOAc/hexanes); [α]22D = -67.762 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.50 (ddd, J = 8.4, 7.9, 1.7 Hz, 1H), 7.05 (m, 1H), 7.02 (d,
J = 8.4 Hz, 1H), 5.28 (m, 1H), 3.39 (t, J = 7.2 Hz, 2H), 2.99, 2.93 (AB of ABX, J = 16.8,
8.4, 4.4 Hz, 2H), 2.78 (td, J = 7.2, 1.9 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.6,
160.2, 136.4, 127.1, 122.1, 121.2, 118.4, 85.3, 78.3, 67.8, 43.7, 28.9, 23.3. HRMS (ESI)
m/z: [M+Na]+ Calculated for C13H11BrO2Na+ 300.9835; found 300.9881.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 11.0 min (minor) tr= 16.0 min (major); 87% ee.
143
(R)-2-(cyclohex-1-en-1-ylethynyl)chroman-4-one (3-73). The general procedure
described above was followed to give the chromanone as a colorless oil 44% yield. Rf =
0.46 (10% EtOAc/hexanes); [α]22D = -73.197 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.90 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 7.50 (ddd, J = 8.4, 7.8 Hz, 1.7 Hz, 1H), 7.05 (m,
2H), 6.07 – 6.24 (m, 1H), 5.38 (X of ABX, 1H), 2.98, 2.97 (AB of ABX, J = 17.0, 11.1,
2.3 Hz, = 8.8 Hz, 2H), 2.09 (m, 4H), 1.58 (m, 4H). 13C NMR (126 MHz, CDCl3) δ
190.9, 160.5, 137.4, 136.3, 127.1, 122.0, 121.2, 119.6, 118.4, 89.52, 82.0, 68.4, 43.9,
29.0, 3.82, 22.3, 21.5. HRMS (ESI) m/z: [M+Na]+ Calculated for C17H16O2Na+ 275.1043;
found 275.1049.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (1%
iPrOH/hexanes, 0.5 mL/min, 254 nm); tr= 19.3 min (minor) tr= 20.6 min (major); 82% ee
144
(R)-2-((trimethylsilyl)ethynyl)chroman-4-one (3-74). The general procedure
described above, except placing the reaction flask in a -15 °C bath instead of a -20 °C
bath, was followed to give the chromanone as an oil 73% yield. Rf = 0.63 (10%
EtOAc/hexanes); [α]22D = -72.071 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J
= 7.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.07 – 7.00 (m, 2H), 5.16 (m, 1H), 2.99 – 2.93
(m, 2H), 0.16 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 190.6, 160.4, 136.4, 127.1, 122.2,
121.2, 118.4, 100.7, 93.4, 68.1, 43.7, -0.2. HRMS (ESI) m/z: [M+Na]+ Calculated for
C14H16O2SiNa+ 267.0812; found 267.0841.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (0.1%
iPrOH/hexanes, 0.5 mL/min, 254 nm); tr = 20.9 min (minor) tr = 22.2 min (major); 95%
ee.
145
(R)-4-oxo-2-(phenylethynyl)chroman-6-yl acetate (3-77). The general procedure
described above was followed to give the chromanone in 83% yield. Rf = 0.23 (20%
EtOAc/hexanes); [α]22D = -82.736 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.62 (d,
J = 2.9 Hz, 1H), 7.45 – 7.40 (m, 2H), 7.37 – 7.22 (m, 4H), 7.07 (d, J = 8.9 Hz, 1H), 5.50
(X of ABX, 1H), 3.07, 3.05 (AB of ABX, J = 16.9, 7.9, 5.2, = 11.1 Hz, 2H), 2.29 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 189.8, 169.6, 157.9, 145.2, 132.2, 130.0, 129.3,
128.5, 121.5, 121.5, 119.6, 119.3, 87.8, 84.4, 68.4, 43.4, 21.1. HRMS (ESI) m/z:
[M+Na]+ Calculated for C19H14O4Na+ 329.0784; found 329.0796.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 11.0 min (minor) tr= 16.0 (major); 86% ee.
146
(R)-6-fluoro-2-(phenylethynyl)chroman-4-one (3-78). The general procedure
described above was followed to give the chromanone in 84% yield. Rf = 0.43 (10%
EtOAc/hexanes); [α]22D = -87.370 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.57 (dd,
J = 8.2, 3.1 Hz, 1H), 7.46 – 7.16 (m, 6H), 7.04 (dd, J = 8.2, 4.2 Hz, 1H), 5.49 (X of ABX,
1H), 3.09, 3.05 (AB of ABX, J = 17.0, 7.6, 5.1 Hz, = 13.0 Hz, 2H). 19F NMR (282 MHz,
CDCl3) δ -120.5; HRMS (ESI) m/z: [M+Na]+ Calculated for C17H11FO2Na+ 289.0635;
found 289.0654.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 8.4 min (minor) tr= 11.3 min (major); 89% ee.
147
(R)-7-methoxy-2-(phenylethynyl)chroman-4-one (3-79). The general procedure
described above was followed to give the chromanone in 78% yield. Rf = 0.27 (20%
EtOAc/hexanes); [α]22D = 17.354 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J
= 8.8 Hz, 1H), 7.43 (m, 2H), 7.38 – 7.20 (m, 3H), 6.62 (d, J = 8.8, 1H), 6.50 (s, 1H), 5.58
– 5.30 (m, 1H), 3.84 (s, 3H), 3.09 – 2.91 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 189.2,
166.4, 162.4, 132.7, 129.3, 128.9, 128.5, 121.7, 115.1, 110.6, 101.4, 87.4, 84.8, 68.6,
55.9, 43.3. HRMS (ESI) m/z: [M+Na]+ Calculated for C18H14O3Na+ 301.0835; found
301.0835.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 13.4 min (minor) tr= 15.2 min (major); 94% ee.
148
(R)-7-bromo-2-(phenylethynyl)chroman-4-one (3-80). The general procedure
described above was followed to give the chromanone in 52% yield. Rf = 0.33 (10%
EtOAc/hexanes); [α]22D = 18.910 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J
= 8.5 Hz, 1H), 7.41 (m, 2H), 7.32 (m, 3H), 7.26 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 5.52 (X
of ABX, 1H), 3.09, 3.03 (AB of ABX, J = 16.9, 7.8, 4.5 Hz, = 29.7 Hz, 2H). 13C NMR
(126 MHz, CDCl3) δ 189.7, 160.4, 132.2, 130.8, 129.4, 128.6, 128.4, 125.8, 121.7,
121.5, 120.2, 88.0, 84.2, 68.6, 43.5. HRMS (ESI) m/z: [M+Na]+ Calculated for
C17H11BrO2Na+ 348.9835; found 348.9850.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 10.8 min (minor) tr= 12.0 min (major); 94% ee.
12.0
149
(R)-8-methoxy-2-(phenylethynyl)chroman-4-one (3-81). The general procedure
described above was followed to give the chromanone in 81% yield. Rf = 0.37 (30%
EtOAc/hexanes); [α]22D = -61.429 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (dd,
J = 8.0, 1.4 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.35 – 7.25 (m, 3H), 7.09 (dd, J = 8.0, 1.4 Hz,
1H), 7.00 (t, J = 8.0 Hz, 1H), 5.60 (X of ABX, 1H), 3.92 (s, 3H), 3.12, 3.05 (AB of ABX, J
= 16.8, 7.8, 4.5 Hz, = 32.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.6, 150.2,
149.3, 132.2, 129.2, 128.5, 122.0, 121.8, 121.6, 118.2, 117.3, 87.7, 84.6, 68.7, 56.5,
43.5. HRMS (ESI) mz/: [M+Na]+ Calculated for C18H14O3Na+ 301.0835; found 301.0868.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 16.1 min (major) tr= 22.9 min (minor); 91% ee.
150
(2R,3R)-3-phenyl-2-(phenylethynyl)chroman-4-one (3-82). The general procedure
described above was followed to give the chromanone as a 10:1 mixture of
diastereomers in 78% yield. Rf = 0.41 (20% EtOAc/hexanes); [α]22D = -157.083 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 8.2, 1.7 Hz, 1H), 7.54 (m, 1H), 7.42
(dd, J = 8.2, 1.7 Hz, 2H), 7.38 – 7.21 (m, 8H), 7.11 (m, 2H), 5.64 (d, J = 4.4 Hz, 1H),
4.23 (d, J = 4.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 191.0, 156.0, 136.4, 133.4,
132.1, 130.1, 129.2, 128.7, 128.4, 128.3, 127.8, 122.4, 121.7, 121.4, 118.5, 89.3, 83.5,
72.8, 57.0. HRMS (ESI) m/z: [M+Na]+ Calculated for C23H16O2Na+ 347.1043 found
347.1066.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (5%
iPrOH/hexanes, 0.25 mL/min, 254 nm); tr= 54.8 min (minor) tr= 57.1 min (major); 94%
ee.
151
(2S,3S)-3-hydroxy-2-(phenylethynyl)chroman-4-one (3-94). Copper iodide (1.3 mg,
0.0068 mmol) was added to a test tube in the glove box. (S)-StackPhos (5.3 mg, 0.0075
mmol,) was then added to the test tube and dissolved in toluene (0.5 mL). The mixture
was stirred at room temperature for 1 hour to give a pale yellow solution. Chromone (20
mg, 0.137 mmol), alkyne (20 µL, 0.178 mmol), and N,N-diisopropylethylamine (38 µL,
0.219 mmol) were then added sequentially. The reagents were rinsed down the sides of
the test tube with an additional aliquot of toluene (0.9 mL). The mixture was cooled to -
78 °C and TMSOTf (32 µL, 0.178 mmol) was added. The test tube was then transferred
to a -20 °C bath and allowed to stir 16 hours. The reaction mixture was then cooled
down to -78 °C and dimethyldioxirane was added and stirred until reaction was
completed as determined by TLC. A 3N HCl solution was added to quench the reaction
then workup with EtOAc provided the crude product in a diastereomeric ratio of 20:1.
The product was purified by column chromatography to provide the chromanone in 68%
yield. Rf = 0.20 (20% EtOAc/hexanes); [α]22D = -56.823 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3) δ 7.91 (dd, J = 7.8, 1.7 Hz, 1H), 7.57 (m, 3H), 7.43 – 7.30 (m, 3H), 7.16 –
7.06 (m, 2H), 5.12 (d, J = 12.0 Hz, 1H), 4.61 (dd, J = 12.0, 2.0 Hz, 1H), 3.76 (d, J = 2.0
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 193.1, 161.1, 137.3, 132.5, 129.4, 128.5, 127.6,
122.8, 121.7, 118.7, 118.4, 88.7, 83.1, 73.1, 72.9. HRMS (ESI) m/z: [M+Na]+ Calculated
for C17H12O3Na+ 287.0679; found 287.0703.
152
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 18.2 min (minor) tr= 28.9 min (major); 93% ee.
(2R,3S)-3-((S)-hydroxy(phenyl)methyl)-2-((trimethylsilyl)ethynyl)chroman-4-one (3-
95). Copper iodide (1.3 mg, 0.0068 mmol) was added to a test tube in the glove box.
(S)-StackPhos (5.3 mg, 0.0075 mmol) was then added to the test tube and dissolved in
toluene (0.5 mL). The mixture was stirred at room temperature for 1 hour to give a pale
yellow solution. Chromone (20 mg, 0.137 mmol), alkyne (25 µL, 0.178 mmol), and N,N-
diisopropylethylamine (38 µL, 0.219 mmol,) were then added sequentially. The reagents
were rinsed down the sides of the test tube with an additional aliquot of toluene (0.9
mL). The mixture was cooled to -78 °C and TMSOTf (32 µL, 0.178 mmol) was added.
The test tube was then transferred to a -15 °C bath and allowed to stir for 24 hours.
After the reaction was complete, the crude mixture was filtered over a plug of basic
alumina washing with toluene and then concentrated under vacuum. The crude residue
was then dissolved in CH2Cl2 (1.0 mL) and freshly distilled benzaldehyde (18 µL, 0.178
mmol) was added. The mixture was cooled to -78 °C and freshly distilled BF3·OEt2 (25
153
µL, 0.2 mmol) was added. After 15 minutes, the reaction was quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4,
filtered and concentrated. Purification by flash column chromatography provided the
chromanone in 74% yield in a diastereomeric ratio of 20:1. Rf = 0.26 (20%
EtOAc/hexanes); [α]22D = -128.123 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.95
(dd, J = 7.8, 1.7 Hz, 1H), 7.52 (ddd, J = 8.5, 7.8, 1.7 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H),
7.39 (t, J = 7.5 Hz, 2H), 7.36 – 7.30 (m, 1H), 7.08 (m, 1H), 7.01 (d, J = 8.5 Hz, 1H), 5.02
(dd, J = 8.3, 4.4 Hz, 1H), 4.87 (d, J = 3.8 Hz, 1H), 2.99 (dd, J = 8.3, 3.8 Hz, 1H), 2.90 (d,
J = 4.4 Hz, 1H), 0.04 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 192.2, 159.1, 140.8, 136.6,
129.0, 128.7 127.5, 126.8, 122.4, 120.6, 118.5, 100.5 94.1, 72.4, 69.5, 59.2, -0.3.
HRMS (ESI) m/z: [M+Na]+ Calculated for C21H22O3SiNa+ 373.1230; found 373.1235.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (5%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 10.5 min (major) tr= 17.4 min (minor); 94% ee.
154
(±) 3-(hydroxy(phenyl)methyl)-3-methyl-2-((trimethylsilyl)ethynyl)chroman-4-one
(3-97). The same procedure to obtain 3-89, using racemic ligand and 3-
methylchromone 3-90, was used to provide 3-91 in 60% isolated yield as a single
diastereomer. Rf = 0.61 (30% EtOAC, hexanes); 1H NMR (300 MHz, CDCl3) δ 7.88 (dd,
J = 7.9, 1.6 Hz, 1H), 7.48 (ddd, J = 8.3, 7.9, 1.6 Hz, 1H), 7.34 – 7.21 (m, 5H), 7.05 (m,
1H), 6.99 (d, J = 8.3, 1H), 4.90 (m, 2H), 4.50 (s, 1H), 1.54 (s, 3H), 0.21 (s, 9H); 13C
NMR (126 MHz, CDCl3) δ 197.8, 159.8, 140.5, 136.7, 128.5, 128.3, 127.7, 122.4, 120.7,
118.3, 99.0, 95.8, 77.6, 74.0, 53.3, 15.1, -0.2. HRMS (ESI) m/z: [M+H]+ Calculated for
C22H24O3SiH+ 365.1567; found 365.1576.
(2R)-2-(3,4-dihydroxybut-1-yn-1-yl)chroman-4-one (3-98). The general procedure
described above was followed for the alkynylation using but-3-yne-1,2-diyl diacetate as
the alkyne. Instead of the workup describe above, the crude reaction mixture was
concentrated then MeOH (1.0 mL) was added followed by AcCl (19 µL, 0.27 mmol). The
reaction was stirred for 4 hours then concentrated and purified by column
chromatography (55% yield over two steps). The enantiomeric excess was determined
after cyclization to afford 3-93. Rf = 0.15 (50% EtOAc/hexanes);1H NMR (500 MHz,
CDCl3) δ 7.87 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 7.00
155
(d, J = 7.8 Hz, 1H), 5.31 (X of ABX, J = 8.4, 4.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 3.67 (AB
of ABX, J = 11.5 Hz, = 33.4 Hz, 2H), 3.00, 2.93 (AB of ABX, J = 16.8, 8.4, 4.4 Hz,
= 32.9 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.8, 160.1, 136.7, 127.1, 122.3, 121.1,
118.4, 85.8, 81.8, 67.6, 66.2, 63.2, 43.3. HRMS (ESI) m/z: [M+Na]+ Calculated for
C13H12O4Na+ 255.0628; found 255.0628.
(R)-2-(furan-2-yl)chroman-4-one (3-99). Gold chloride (1.6 mg, 0.007 mmol) was
added to a test tube in the glovebox. A solution of 3-92 (16.7 mg, 0.07 mmol) in THF
(1.4 mL) was added and the reaction was allowed to stir for 1 hour then filtered over
silica. The crude mixture was concentrated and purified by column chromatography to
yield the product as an oil (92% yield) that matched previously reported spectroscopic
data.233 Rf = 0.26 (10% EtOAc/hexanes); [α]22D = -96.047 (c 1.0, CHCl3); HRMS (ESI)
m/z: [M+Na]+ Calculated for C13H10O3Na+ 237.0522; found 237.0560.
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (10%
iPrOH/hexanes, 1.0 mL/min, 254 nm); tr= 8.3 min (minor) tr= 9.2 min (major); 92% ee.
156
ethyl (2R,3R)-2-(phenylethynyl)-2,3-dihydrobenzofuran-3-carboxylate (3-100).
Following a similar reported procedure,234 H2SO4 (0.28 mL) was added dropwise to a
solution of 3-62 (50 mg, 0.2 mmol) and PIFA (95 mg, 0.22 mmol) in triethylorthoformate
(8.2 mL) and formic acid (0.82 mL) at 0 °C. The reaction was stirred for 0.5 hours at 0
°C then extracted with EtOAc. The organics were dried over Na2SO4, filtered and
concentrated. The product was obtained as a single diastereomer in 70% yield after
flash column chromatography. Rf = 0.39 (10% EtOAc/hexanes); [α]22D = -134.787 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.42 (m, 2H), 7.38 (d, J = 7.5, 1H), 7.34 –
7.26 (m, 1H), 7.25 – 7.20 (t, J = 7.5 Hz, 1H), 6.93 (td, J = 7.5, 0.9 Hz, 1H), 6.88 (d, J =
8.2 Hz, 1H), 4.49 (d, J = 6.8 Hz, 1H), 4.28 (p, J = 6.7 Hz, 1H), 4.27 (m, 2H), 1.34 (t, J =
7.1 Hz, 2H).13C NMR (126 MHz, CDCl3) δ 170.1, 158.6, 132.1, 130.0, 129.1, 128.5,
125.2, 123.7, 122.1, 121.4, 110.6, 87.4, 86.2, 74.0, 62.1, 55.2, 14.4. HRMS (ESI) m/z:
[M+Na]+ Calculated for C19H16O3Na+ 315.0992 found 315.1002.
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (3%
iPrOH/hexanes, 0.5 mL/min, 254 nm); tr= 14.5 min (minor) tr= 15.3 min (major); 94% ee.
157
Determination of Stereochemistry
(S)-2-phenethylchromane (3-89). To a solution of 3-62 (34 mg, 0.14 mmol, 88% ee) in
EtOAc (0.5 mL) was added 10% Pd/C (10 mg). The reaction was stirred under an
atmosphere of H2 for 48 hours. The crude mixture was filtered over celite and purified
by column chromatography (80% yield). The spectroscopic data matched previously
reported data.205 The observed optical rotation was found to be []22D = -103.180 (c 1.0,
CHCl3) compared to a literature report by Schaus205 which was []23D = -116.3 (c 1.0,
CHCl3, 98% ee) for (S)-2-phenethylchromane. Thus, the stereochemistry of 2-
(phenylethynyl)chroman-4-one 3-62 was assigned as R.
(±)-2-ethynyl-3-((S)-hydroxy(phenyl)methyl)chroman-4-one (5-15). To a solution of
3-89 (15 mg, 0.04 mmol) in MeOH (0.5 mL) was added KF (3.5 mg, 0.06 mmol). The
reaction was stirred for 1 hour at room temperature then water was added. The organics
were extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude
158
mixture was purified by flash column chromatography to give 44% yield of the product.
Rf = 0.13 (EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 7.9, 1.6 Hz, 1H),
7.56 (dt, J = 8.4, 1.7 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.39 –
7.27 (m, 1H), 7.12 (td, J = 7.9 Hz, 0.9 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 8.9
Hz, 1H), 4.88 (t, J = 2.4 Hz, 1H), 2.96 (d, J = 8.9, 2.4 Hz, 0H), 2.40 (d, J = 2.3 Hz,
1H).13C NMR (75 MHz, CDCl3) δ 191.9, 158.8, 140.4, 136.8, 129.1, 128.9, 127.6, 126.9,
122.6, 120.5, 118.4, 79.2, 76.3, 72.4, 68.7, 59.1. HRMS (ESI) m/z: [M+Na]+ Calculated
for C18H14O3Na+ 301.0835; found 301.0838.
(±) 2-Ethyl-3-(hydroxy(phenyl)methyl)chroman-4-one (5-16). To a solution of 5-15 (5
mg, 0.02 mmol) in EtOAc (0.5 mL) was added 10% Pd/C (1.0 mg). The reaction solution
was purged with H2 then stirred under an atmosphere of H2 for 5 hours. The solution
was filtered over celite then concentrated. The product was isolated in quantitative yield
after purification by column chromatography with spectroscopic data that matched
previously reported data. The relative stereochemistry was assigned by analogy to a
literature compound.194 Rf = 0.22 (20% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ
7.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.52 (ddd, J = 8.4, 7.8, 1.5 Hz, 1H), 7.46 (d, J = 7.3 Hz,
2H), 7.41 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.03 (t, J = 7.8, 1H), 6.97 (d, J =
8.4 Hz, 1H), 5.00 (d, J = 9.1 Hz, 1H), 4.05 (ddd, J = 9.1, 5.0, 2.3 Hz, 1H), 2.73 (dd, J =
9.1, 2.3 Hz, 1H), 2.65 (s, 1H), 1.81 (m, 1H), 1.46 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 194.0, 159.1, 141.2, 136.8, 129.0, 128.6, 127.4, 127.0, 121.5,
159
120.3, 118.4, 79.9, 73.2, 58.1, 24.9, 10.0. HRMS (ESI) m/z: [M+Na]+ Calculated for
C18H18O3Na+ 305.1148; found 305.1161.
Preparation of Methylase Inhibitors
Figure 5-4. Preparation of 4-4
3-methylenepiperidin-2-one (4-4). Preparation of 4-4 was achieved from ethyl 2-
oxopiperidine-3-carboxylate using a known literature procedure.235 The obtained
spectroscopic data matched previously reported data.
3-(hydroxymethyl)benzaldehyde (4-6).236 Compound 4-6 was synthesized via a
known literature procedure from isophthalaldehyde. The spectroscopic data match
previously reported data.
3-formylbenzyl 4-methylbenzenesulfonate (4-7). To a solution of 4-6 (30 mg, 0.22
mmol) in CHCl3 (0.22 mL) at 0 °C was added distilled pyridine (36 µL, 0.44 mmol)
followed by p-toluenesulfonylchloride (63 mg, 0.33 mmol). The reaction was stirred for 2
hours then quenched with water and extracted with CH2Cl2. The organic layer was
washed with 1N HCl, followed by saturated aqueous NaHCO3. The organic layer was
160
then dried with MgSO4, filtered and concentrated. The product was purified by column
chromatography and obtained as a colorless oil (56% yield). Rf = 0.21 (30%
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H),
7.80 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H),
7.33 (d, J = 8.1 Hz, 2H), 5.12 (s, 2H), 2.44 (s, 3H).13C NMR (126 MHz, CDCl3) 191.5,
145.1, 136.6, 134.6, 134.1, 132.9, 130.2, 129.9, 129.4, 129.2, 127.9, 70.7, 21.6.; HRMS
(ESI) m/z: [M+Na]+ Calculated for C15H14O4SNa 313.0505; found 313.0510.
3-(cyclopropyl(hydroxy)methyl)benzyl 4-methylbenzenesulfonate (4-8). A freshly
prepared solution of cyclopropylmagnesium bromide in THF (0.7 M, 2.25 mL) was
added dropwise to a solution of 4-7 (188 mg, 0.65 mmol) in THF (3.2 mL) at -78 °C. The
reaction was allowed to stir for 10 minutes then quenched with saturated aqueous
NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered and concentrated. The product was purified by column chromatography
and obtained with sufficient purity for the following step (79% yield). Product is unstable
and will decompose overnight. Rf = 0.23 (30% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.36 – 7.27 (m, 3H), 7.26 (s,
1H), 7.17 (d, J = 7.7 Hz, 1H), 5.06 (s, 2H), 3.97 (d, J = 8.4 Hz, 1H), 2.44 (s, 3H), 1.85
(bs, 1H) 1.22 – 1.08 (m, 1H), 0.68 – 0.59 (m, 1H), 0.55 (m, 1H), 0.46 (m, 1H), 0.35
(m,1H). 13C NMR (126 MHz, CDCl3) δ 145.0, 144.6, 133.5, 133.4, 130.0, 128.8, 128.1,
127.8, 126.9, 126.3, 78.2, 72.1, 21.8, 19.4, 3.7, 3.1; HRMS (ESI) m/z: [M+Na]+
Calculated for C18H20O4SNa 355.0975; found 355.0989.
161
3-(cyclopropylmethyl)benzyl 4-methylbenzenesulfonate (4-9). Triethylsilane (1.8
mL, 11.6 mmol) was added to a solution of 4-8 (384 mg, 1.16 mmol) in CH2Cl2 (5.8 mL).
The reaction was cooled to 0 °C and trifluoroacetic acid (177 µL, 2.32 mmol) was added
dropwise. Stirring was continued for 2 hours then the reaction was quenched with
saturated aqueous NaHCO3. The organics were extracted with CH2Cl2, dried over
MgSO4, filtered and concentrated. The product was purified by column chromatography
and obtained as a colorless oil (64% yield). Rf = 0.47 (20% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.27 (m, 2H), 7.17
– 7.13 (m, 2H), 5.10 (s, 2H), 2.54 (d, J = 5.0 Hz, 2H), 2.48 (s, 3H), 1.09 – 0.89 (m, 1H),
0.56 (m, 2H), 0.22 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 144.9, 142.9, 133.6, 133.3,
130.0, 129.3, 128.8, 128.19, 126.3, 72.4, 40.3, 21.9, 11.9, 4.9; HRMS (ESI) m/z:
[M+Na]+ Calculated for C18H20O3SNa 339.1025; found 339.1014.
1-(3-(cyclopropylmethyl)benzyl)-3-methylenepiperidin-2-one (4-10). To a solution of
NaH (22 mg, 0.84 mmol) in THF (0.8 mL) at 0 °C was added a solution of 4-4 (97 mg,
0.84 mmol) in toluene (1.0 mL). After stirring for 1 hour, a solution of 4-9 (230 mg, 0.7
mmol) in THF (0.8 mL) was added. The reaction was allowed to warm to room
temperature overnight then concentrated. The product was purified by flash column
chromatography (65% yield). Rf = 0.18 (20% EtOAc/hexanes); 1H NMR (500 MHz,
162
CDCl3) δ 7.24 (t, 7.5 Hz, 1H), 7.17 (d, 7.5 Hz, 1H), 7.14 (s, 1H), 7.10 (d, 7.5 Hz, 1H)
6.28 (q, J = 1.7 Hz, 1H), 5.32 (q, J = 1.7 Hz, 1H), 4.66 (s, 2H), 3.30 (t, J = 5.9 Hz, 2H),
2.59 (m, 2H), 2.53 (d, J = 6.9 Hz, 2H), 1.84 (p, J = 5.9 Hz, 2H), 1.02 – 0.92 (m, 1H),
0.56 – 0.47 (m, 2H), 0.22 – 0.16 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.5, 142.7,
138.0, 137.2, 128.7, 128.3, 127.6, 125.8, 122.2, 50.9, 47.9, 40.4, 30.4, 23.4, 12.0, 4.8;
HRMS (ESI) m/z: [M+Na]+ Calculated for C17H21NONa 278.1515; found 278.1529.
5-(3-(cyclopropylmethyl)benzyl)-1-oxa-5-azaspiro[2.5]octan-4-one (4-11). To a
solution of 4-10 (200 mg, 0.78 mmol) in CH2Cl2 (4.0 mL) was added m-perchlorobenzoic
acid (270 mg, 1.56 mmol). The reaction was stirred for 24 h at room temperature then a
saturated solution of sodium bisulfate was added and the organics extracted. The
organic layer was then washed with saturated NaHCO3 twice, dried over MgSO4, filtered
and concentrated. The product was obtained in quantitative yield and used without
further purification.
3-((benzylamino)methyl)-1-(3-(cyclopropylmethyl)benzyl)-3-hydroxypiperidin-2-
one (4-14). A mixture of 4-11 (6.5 mg, 0.024 mmol) and benzyl amine (3 µL, 0.026
mmol) in MeOH (0.15 mL) was placed in a microwave vial. The reaction was
microwaved for 10 minutes at 300 W. The desired product was isolated after flash
163
column chromatography using a gradient of 70-100% EtOAc/hexanes (28% yield). Rf =
0.29 (6% MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.35 – 7.01 (m, 9H), 4.53 (s,
2H), 3.85 (ABq, J = 13.7 Hz, = 9.1 Hz, 2H), 3.27 – 3.12 (m, 2H), 2.95 (d, J = 11.9
Hz, 1H), 2.58 (d, J = 11.9 Hz, 1H), 2.51 (d, J = 7.0 Hz, 2H), 2.06 – 1.91 (m, 2H), 1.90 –
1.79 (m, 1H), 1.74 (m, 1H), 0.95 (m, 1H), 0.54 – 0.48 (m, 2H), 0.18 (m, 2H). HRMS
(ESI) m/z: [M+H]+ Calculated for C24H31N2O2 379.2380; found 379.2376.
Figure 5-5. Preparation of 4-13
(2-(benzyloxy)phenyl)methanamine (4-13). Compound 5-9 was synthesized from 2-
hydroxybenzonitrile 5-17 via known literature procedure with spectroscopic data
matching the previously reported data.237 Reduction using LAH following a similar
literature procedure193 yielded the desired product 4-13, which was used without further
purification.
3-(((2-(benzyloxy)benzyl)amino)methyl)-1-(3-(cyclopropylmethyl)benzyl)-3-
hydroxypiperidin-2-one (4-15). A mixture of 4-11 (38 mg, 0.14 mmol) and (2-
(benzyloxy)phenyl)methanamine (30 mg, 0.14 mmol) in MeOH (0.5 mL) was placed in a
microwave vial. The reaction was microwaved for 10 minutes at 300 W. The desired
product was isolated after flash column chromatography using a gradient of 70-100%
164
EtOAc/hexanes (53% yield). Rf = 0.26 (6% MeOH/CH2Cl2) 1H NMR (500 MHz, CDCl3) δ
7.44 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.24 – 7.18 (m,
2H), 7.16 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.96 – 6.89 (m, 2H),
5.10 (s, 2H), 4.53 (s, 2H), 3.91 (ABq, J = 14.1 Hz, = 30.4 Hz, 2H), 3.29 – 3.09 (m,
2H), 2.95 (d, J = 11.9 Hz, 1H), 2.59 (d, J = 11.9 Hz, 1H), 2.51 (d, J = 6.9 Hz, 2H), 1.95
(m, 2H), 1.83 (m, 1H), 1.75 (m, 1H), 0.95 (m, 1H), 0.50 (m, 2H), 0.18 (m, 2H). HRMS
(ESI) m/z: [M+H]+ Calculated for C31H36N2O3 485.2799; found 485.2806.
1-(3-(cyclopropylmethyl)benzyl)-3-hydroxy-3-(((2-
hydroxybenzyl)amino)methyl)piperidin-2-one (4-16). Compound 4-15 (12 mg, 0.02
mmol) was dissolved in EtOAc (0.4 mL) and 10% Pd/C (3.0 mg) was added. The
reaction was run under an atmosphere of H2 for 1.5 hours then filtered and
concentrated. The desired product was obtained (82% yield) after column
chromatography using a gradient of CH2Cl2, then CH2Cl2:Et3N (10:0.1), then
MeOH:CH2Cl2:Et3N (0.1:10:0.1). Rf = 0.26 (6% MeOH/CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.24 (t, J = 7.6 Hz, 1H), 7.20 – 7.13 (m, 2H), 7.08 (s, 1H), 7.03 (d, J = 7.6 Hz,
1H), 6.99 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 4.53
(ABq, J = 14.6 Hz, = 19.1 Hz, 2H), 4.17 (d, J = 13.7 Hz, 1H), 3.89 (d, J = 13.7 Hz,
1H), 3.21 (m, 2H), 2.87 (ABq, J = 12.0 Hz, = 34.4 Hz, 2H), 2.51 (d, J = 5.1 Hz, 2H),
2.24 – 2.10 (m, 1H), 1.94 – 1.82 (m, 2H), 1.81 – 1.67 (m, 1H), 0.93 (m, 1H), 0.53 – 0.46
165
(q, 4.7 Hz, 2H), 0.17 (q, J = 4.7 Hz, 2H). HRMS (ESI) m/z: [M+H]+ Calculated for
C24H31N2O3 395.2329; found 395.2326.
tert-butyl 5-methyl-1,3-dioxoisoindoline-2-carboxylate (4-20). A solution of 4-
methylphthalic anhydride (500 mg, 3.0 mmol) and urea (205 mg, 3.3 mmol) in xylenes
(2.5 mL) was heated at reflux for 16 hours. The reaction was cooled to room
temperature, filtered and washed with ethanol. To the crude 4-methylphthalimide (290
mg, 1.8 mmol) in CH3CN (6 mL) was added DMAP (3 mg, 0.027 mmol) and Boc2O (412
mg, 1.9 mmol). The reaction was allowed to stir at room temperature for 1.5 hours then
purified by flash column chromatography (82% yield). The product was obtained as a
white solid. Rf = 0.30 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J =
7.8 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 2.53 (s, 3H), 1.63 (s, 9H).13C NMR
(75 MHz, CDCl3) δ 164.2, 164.1, 146.8, 146.6, 135.8, 131.5, 128.6, 124.5, 124.1, 85.1,
27.9, 22.0.
tert-butyl 5-(bromomethyl)-1,3-dioxoisoindoline-2-carboxylate (4-21). A solution of
4-20 (410 mg, 1.6 mmol) and benzoyl peroxide (5.0 mg, 0.02 mmol) in CCl4 (2.0 mL)
was heated to reflux. N-bromosuccinimide (307 mg, 1.7 mmol) was then added and the
reaction was stirred for 5 hours, after which it was cooled to room temperature and
166
ether was added. The solids were filtered off and the product was obtained following
flash column chromatography as a white solid (47% yield). Rf =0.50 (30%
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H),
7.82 (d, J = 7.9 Hz, 1H), 4.57 (s, 2H), 1.63 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 163.6,
163.5, 146.6, 145.8, 135.8, 131.9, 130.9, 124.8, 124.7, 85.6, 31.1, 28.0. HRMS (ESI)
m/z: [M+Na]+ Calculated for C14H14BrNO4Na+ 361.9998; found 362.0012.
3-(benzylamino)propenamide (4-23). Benzyl amine (1.1 g, 10 mmol) and acrylamide
(711 mg, 10 mmol) were heated neat at reflux for 16 hours. The resulting oil was used
without further purification in the following step.
tert-butyl 5-(((3-amino-3-oxopropyl)(benzyl)amino)methyl)-1,3-dioxoisoindoline-2-
carboxylate. A solution of 3-(benzylamino)propanamide (75 mg, 0.4 mmol), 4-21 (143
mg, 0.4 mmol) and K2CO3 (115 mg, 0.8 mmol) in DMF (2 mL) was stirred at room
temperature for 3 hours. To the resulting mixture was added water and then extracted
with EtOAc. The organic layer was washed multiple times to remove excess DMF then
dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash
column chromatography (84% yield over two steps) with sufficient purity for the
167
following deprotection step. Rf = 0.37 (100% EtOAc); 1H NMR (500 MHz, CDCl3) δ
7.89 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.34 – 7.22 (m, 5H), 6.46
(s, 1H), 5.92 (s, 1H), 3.72 (s, 2H), 3.61 (s, 2H), 2.81 (t, J = 6.6 Hz, 2H), 2.43 (t, J = 6.6
Hz, 2H), 1.62 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 174.4, 164.3, 164.0, 148.1, 146.8,
137.9, 135.6, 131.6, 130.2, 129.0, 128.7, 127.7, 124.4, 124.4, 85.4, 58.6, 58.1, 50.1,
33.7, 28.0. HRMS (ESI) m/z: [M+H]+ Calculated for C24H28N3O5 438.2023; found
438.2018.
3-(benzyl((1,3-dioxoisoindolin-5-yl)methyl)amino)propenamide (4-18). Compound
4-24 (130 mg, 0.29 mmol) was dissolved in 4N HCl/dioxane (1.6 mL) and stirred for 3
hours at room temperature. The crude mixture was concentrated and washed with
CHCl3. To the resulting solid was added EtOAc and saturated aqueous NaHCO3 and
the organics were extracted. The desired product was obtained after flash column
chromatography (16% yield). Rf = 0.31 (100% EtOAc); 1H NMR (500 MHz, CDCl3) δ
9.27 (s, 1H), 7.82 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.28 (m,
5H), 6.65 (s, 1H), 6.22 (s, 1H), 3.71 (s, 2H), 3.65 (s, 2H), 2.83 (t, J = 6.3 Hz, 2H), 2.46
(t, J = 6.3 Hz, 2H). HRMS (ESI) m/z: [M+H]+ Calculated for C19H20N3O3 338.1499; found
338.1505.
168
3-((4-chlorobenzyl)amino)propenamide (4-28). A mixture of 4-chlorobenzylamine
(113 mg, 0.8 mmol) and acrylamide (57 mg, 0.8 mmol) were heated in EtOH (0.4 mL) at
reflux for 24 hours. The resulting crude mixture was used without further purification in
the following step.
tert-butyl 5-(((3-amino-3-oxopropyl)(4-chlorobenzyl)amino)methyl)-1,3-
dioxoisoindoline-2-carboxylate. A solution of 4-28 (140 mg, 0.7 mmol), 4-21 (239 mg,
0.7 mmol) and K2CO3 (195 mg, 1.4 mmol) in THF (3.5 mL) was stirred at room
temperature for 6 hours. To the resulting mixture was added water and then extracted
with EtOAc. The organic layer was washed with brine then dried over MgSO4, filtered
and concentrated. The crude mixture was purified by flash column chromatography
(23% yield over two steps) with sufficient purity for the following deprotection step. Rf =
0.41 (100% EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.88 (m, 2H), 7.74 (d, J = 7.7 Hz, 1H),
7.31 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 3.71 (s, 2H), 3.58 (s, 2H), 2.82 (t, J =
6.7 Hz, 2H), 2.43 (t, J = 6.7 Hz, 2H), 1.63 (s, 9H).
169
3-((4-chlorobenzyl)((1,3-dioxoisoindolin-5-yl)methyl)amino)propenamide (4-25).
Compound 4-29 (83 mg, 0.18 mmol) was dissolved in 4H HCl/dioxane (1.0 mL) and
stirred for 1 hour at room temperature. The crude mixture was concentrated and CH2Cl2
was added along with saturated aqueous NaHCO3. The organics were collected, dried
over MgSO4, filtered and concentrated. The desired product was obtained after flash
column chromatography (24% yield). 1H NMR (500 MHz, CDCl3) δ 8.74 (s, 1H), 7.81 (s,
1H), 7.78 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.26 (d,
J = 8.3 Hz, 2H), 6.31 (s, 1H), 5.96 (s, 1H), 3.69 (s, 2H), 3.60 (s, 2H), 2.81 (t, J = 6.6 Hz,
2H), 2.43 (t, J = 6.6 Hz, 2H); HRMS (ESI) m/z: [M+H]+ Calculated for C19H19N3O3Cl
372.1109; found 372.1104.
3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzaldehyde (4-32). To a flask containing
3-hydroxy-4-chlorobenzaldehyde (150 mg, 1.0 mmol) and imidazole (90 mg, 1.4 mmol)
in DMF (4.5 mL) was added TBSCl (171 mg, 1.2 mmol). The reaction was stirred for 2
hours at room temperature then water was added and the reaction extracted with
EtOAc. The organic layer was washed with 1N HCl, dried over MgSO4, filtered and
concentrated. The product was isolated by flash column chromatography as a brown-
170
orange oil (97% yield). Rf = 0.53 (10% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ
9.91 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.0, 1.8 Hz, 1H), 7.37 (d, J = 1.8 Hz,
1H), 1.05 (s, 9H), 0.27 (s, 6H).; 13C NMR (75 MHz, CDCl3) δ 190.9, 152.5, 136.1, 133.0,
131.1, 124.0, 119.9, 25.7, 18.4, -4.2.
3-((3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzyl)amino)propenamide (4-34). A
mixture of 4-32 (250 mg, 0.92 mmol), 3-aminopropanamide (81 mg, 0.92 mmol), MgSO4
(166 mg, 1.4 mmol) and Et3N (0.38 mL, 2.8 mmol) was added to a reaction flask. The
solids were then dissolved in CH2Cl2 (0.4 mL) and EtOH (0.4 mL) then stirred at room
temperature for 2 hours. The reaction mixture was filtered over cotton, concentrated and
redissolved in EtOH (0.6 mL). To the crude mixture, 10% Pd/C (1.7 mg) was added and
the reaction was placed under an atmosphere of H2. The reaction was stirred for 15
minutes then the mixture was filtered over celite and concentrated. The crude product
was used without further purification in the next step.
tert-butyl 5-(((3-amino-3-oxopropyl)(3-((tert-butyldimethylsilyl)oxy)-4-
chlorobenzyl)amino)methyl)-1,3-dioxoisoindoline-2-carboxylate (4-35). A mixture of
4-34 (94 mg, 0.27 mmol), 4-21 (93 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) in
171
THF (1.4 mL) was stirred at room temperature for 2 hours. The reaction was filtered and
the product was purified by flash column chromatography (48% yield over two steps).
1H NMR (500 MHz, CDCl3) δ 7.90 – 7.84 (m, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.28 (d, J =
8.7 Hz, 1H), 6.83 (m, 2H), 6.14 (s, 1H), 5.50 (s, 1H), 3.72 (s, 2H), 3.54 (s, 2H), 2.81 (t, J
= 6.6 Hz, 2H), 2.42 (t, J = 6.6 Hz, 2H), 1.63 (s, 9H), 1.03 (s, 9H), 0.22 (s, 6H).
3-((4-chloro-3-hydroxybenzyl)((1,3-dioxoisoindolin-5-
yl)methyl)amino)propenamide (4-30). A solution of 4-35 (20 mg, 0.03 mmol) in 4N
HCl/dioxane (0.3 mL) was stirred at room temperature for 1 hour. The mixture was then
concentrated and EtOAc was added. The reaction was neutralized with saturated
aqueous NaHCO3 and the organic layer was extracted. The organics were dried over
MgSO4, filtered and concentrated. The crude product was purified by prep TLC in 5%
MeOH/CHCl3 (run 2x, 23% yield).1H NMR (500 MHz, Methanol-d4) δ 7.83 (s, 1H), 7.77
(d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.80
(d, J = 8.1 Hz, 1H), 3.72 (s, 2H), 3.55 (s, 2H), 2.79 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 6.9
Hz, 2H). HRMS (ESI) m/z: [M+H]+ Calculated for C19H18ClN3O4H+ 388.1059; found
388.1067.
172
3-((3,5-bis((tert-butyldimethylsilyl)oxy)benzyl)amino)propenamide (4-40). A mixture
of 3,5-bis((tert-butyldimethylsilyl)oxy)benzaldehyde238 4-39 (100 mg, 0.27 mmol), 3-
aminopropanamide (24 mg, 0.27 mmol), MgSO4 (50 mg, 0.41 mmol) and Et3N (115 µL,
0.82 mmol) was added to a reaction flask. The solids were then dissolved in CH2Cl2 (0.3
mL) and EtOH (0.3 mL) then stirred at room temperature for 2 hours. The reaction
mixture was filtered over cotton, concentrated and redissolved in EtOH (2.7 mL). To the
crude mixture, 10% Pd/C (12 mg) was added and the reaction was placed under an
atmosphere of H2. The reaction was stirred for 30 minutes then the mixture was filtered
over celite and concentrated. The crude product was purified by column
chromatography using a 2-10% MeOH/CH2Cl2 gradient (70% yield).1H NMR (300 MHz,
Methanol-d4) δ 6.49 (d, J = 2.1 Hz, 2H), 6.24 (t, J = 2.1 Hz, 1H), 3.70 (s, 2H), 2.87 (t, J =
6.7 Hz, 2H), 2.45 (t, J = 6.7 Hz, 2H), 1.00 (s, 18H), 0.21 (s, 12H).
tert-butyl 5-(((3-amino-3-oxopropyl)(3,5-bis((tert-
butyldimethylsilyl)oxy)benzyl)amino)methyl)-1,3-dioxoisoindoline-2-carboxylate
(4-41). A mixture of 4-40 (73 mg, 0.17 mmol), 4-21 (57 mg, 0.17 mmol) and K2CO3 (46
173
mg, 0.33 mmol) in THF (0.85 mL) was stirred at room temperature for 16 hours. The
reaction was filtered and the product was obtained after column chromatography using
70% EtOAc/hexanes (52% yield). 1H NMR (300 MHz, CDCl3) δ 7.89 – 7.85 (m, 2H),
7.74 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 2.2 Hz, 21H), 6.26 (t, J = 2.2 Hz, 1H), 3.72 (s, 2H),
3.49 (s, 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.44 (t, J = 6.5 Hz, 2H), 1.63 (s, 9H), 0.97 (s, 18H),
0.18 (s, 12H).
3-((3,5-dihydroxybenzyl)((1,3-dioxoisoindolin-5-yl)methyl)amino)propenamide (4-
36). A solution of 4-41 (60 mg, 0.09 mmol) in 4N HCl/dioxane (0.5 mL) was stirred at
room temperature for 1.5 hours. The mixture was then concentrated and EtOAc was
added. The reaction was neutralized with saturated aqueous NaHCO3 and the organics
were extracted 4 times with EtOAc. The organics were dried over MgSO4, filtered and
concentrated. The crude product was recrystallized in MeOH (48% yield). Rf = 0.19
(10% MeOH/CH2Cl2); 1H NMR (300 MHz, Methanol-d4) δ 7.85 (s, 1H), 7.81 (d, J = 7.8
Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 2.2 Hz, 2H), 6.13 (t, J = 2.2 Hz, 1H), 3.71
(s, 2H), 3.49 (s, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H). HRMS (ESI) m/z:
[M+H]+ Calculated for C19H20N3O5 370.1397; found 379.1398.
174
(E)-3-(3,5-bis((tert-butyldimethylsilyl)oxy)phenyl)acrylonitrile (4-44). To a solution
of 3,5-bis((tert-butyldimethylsilyl)oxy)benzaldehyde 4-39 (1.0 g, 2.7 mmol) and diethyl
cyanomethylphosphonate 4-43 (0.53 mL, 3.3 mmol) in THF (9.0 mL) was added KOtBu
(370 mg, 3.3 mmol). The reaction was stirred for 1 hour at room temperature then
quenched with water. The mixture was then extracted with EtOAc, dried over MgSO4,
filtered and concentrated. The colorless oil product was obtained after flash column
chromatography (72% yield). Rf = 0.56 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.29 (d, J = 16.6 Hz, 1H), 6.56 (d, J = 2.1 Hz, 2H), 6.42 (t, J = 2.1 Hz, 1H),
5.81 (d, J = 16.6 Hz, 1H), 1.01 (s, 18H), 0.23 (s, 12H); 13C NMR (126 MHz, CDCl3) δ
157.1, 150.4, 135.2, 118.0, 114.9, 112.4, 96.6, 25.6, 18.2, -4.4.
3-(3,5-bis((tert-butyldimethylsilyl)oxy)phenyl)propanenitrile (4-45). 10% Pd/C (75
mg) was added to a solution of 4-44 (760 mg, 2.0 mmol) in EtOH (15.0 mL). The
reaction was stirred under an atmosphere of H2 for 24 hours then filtered. The crude
reaction mixture was subjected to flash column chromatography to afford the product as
a colorless oil (61% yield). Rf = 0.51 (10% EtOAc/hexanes); 1H NMR (500 MHz, CDCl3)
δ 6.34 (d, J = 2.0 Hz, 2H), 6.25 (t, J = 2.0 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.58 (t, J =
175
7.5 Hz, 2H), 0.99 (s, 18H), 0.21 (s, 12H); 13C NMR (126 MHz, CDCl3) δ 157.0, 140.2,
119.2, 113.5, 111.1, 31.7, 25.8, 19.4, 18.4, -4.2.
3-(3,5-bis((tert-butyldimethylsilyl)oxy)phenyl)propan-1-amine. To a solution of 4-45
(450 mg, 1.1 mmol) in Et2O (11.0 mL) was added lithium aluminum hydride (110 mg, 2.9
mmol). The reaction was allowed to stir for 16 hours then quenched using the Fieser
method. The mixture was dried over MgSO4 then filtered and concentrated. The crude
product was directly subjected to the following conditions without further purification.
3-((3-(3,5-bis((tert-butyldimethylsilyl)oxy)phenyl)propyl)amino)propenamide (4-
47). A mixture of 4-46 (330 mg, 0.8 mmol) and acrylamide (60 mg, 0.8 mmol) in EtOH
(50 μL) was stirred at 50 °C for 2 hours. After concentration, the crude mixture was used
in the next step without further purification.
176
tert-butyl 5-(((3-amino-3-oxopropyl)(3-(3,5-bis((tert-
butyldimethylsilyl)oxy)phenyl)propyl)amino)methyl)-1,3-dioxoisoindoline-2-
carboxylate (4-48). To a round bottom flask was added 4-47 (300 mg, 0.6 mmol), 4-21
(218 mg, 0.6 mmol) and K2CO3 (177 mg, 1.3 mmol). The solids were dissolved in DMF
(3.2 mL) and the reaction was stirred at room temperature for 1 hour then quenched
with water and extracted with EtOAc. The organic layer was washed with brine, dried
over MgSO4, filtered and concentrated. The product was obtained after flash column
chromatography as a colorless oil (65% over 3 steps). Rf = 0.51 (10% MeOH/CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 7.89 – 7.79 (m, 2H), 7.69 (d, J = 7.8, 1H), 6.63 (s, 1H),
6.23 (d, J = 2.2 Hz, 2H), 6.15 (t, J = 2.2 Hz, 1H), 5.54 (s, 1H), 3.71 (s, 2H), 2.76 (t, J =
6.5 Hz, 2H), 2.45 (m, 4H), 2.35 (t, J = 6.5 Hz, 2H), 1.77 (p, J = 7.2, 2H), 1.62 (s, 9H),
0.95 (s, 18H), 0.16 (s, 12H).
3-((3-(3,5-dihydroxyphenyl)propyl)((1,3-dioxoisoindolin-5-
yl)methyl)amino)propenamide (4-42). A solution of 4-48 (240 mg, 0.33 mmol) in 4N
177
HCl/dioxane (1.5 mL) was stirred at room temperature for 1.5 hours. The reaction was
then concentrated until a solid formed. To the solid was added EtOAc and saturated
aqueous NaHCO3 to neutralize the mixture. The mixture was stirred until all solids had
dissolved then extracted multiple times with EtOAc. The organic layer was dried over
MgSO4, filtered and concentrated. A column in 5-10% MeOH/CH2Cl2 provided the
product as a tan solid (74% yield). Rf = 0.19 (10% MeOH/CH2Cl2); 1H NMR (500 MHz,
acetone-d6) δ 7.85 (m, 2H), 7.75 (dd, J = 7.3 Hz, 1.3 Hz, 1H), 7.08 (s, 1H), 6.34 (s, 1H),
6.24 – 6.13 (m, 3H), 3.82 (s, 2H), 2.85 (t, J = 7.3 Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.46
(m, 4H), 1.86 – 1.73 (p, J = 7.3 Hz, 2H); 13C NMR (126 MHz, acetone-d6) δ 174.3,
169.2, 169.0, 158.9, 148.4, 145.1, 134.9, 133.8, 132.3, 123.5, 123.2, 107.3, 100.6, 58.4,
53.7, 50.7, 33.9, 33.8, 29.0; HRMS (ESI) calc’d for C21H24N3O5 [M+H]+ 398.1710, found
398.1708.
178
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BIOGRAPHICAL SKETCH
Lindsey is a native of Wilson, North Carolina. She has two siblings, a younger
and an older sister, Jamie and Barbara. Her parents are Patricia and James DeRatt Jr.
In 2008, she moved from Wilson to Wilmington, NC to pursue a degree at the University
of North Carolina at Wilmington. She began undergraduate research in Dr. Jeremy
Morgan’s lab working with graduate student Katie Scholl in 2011. Her research was
focused on a boron-tethered Diels-Alder reaction. In 2012, she graduated summa cum
laude with University honors from UNCW with a Bachelor of Science in chemistry with a
minor in mathematics. From there, she decided to head south to the University of
Florida, where she started her doctoral degree in the fall of 2012 under the guidance of
Dr. Aaron Aponick. In the Aponick group, she had numerous research focuses which
included a total synthesis, a methodology and the design of small molecules for cancer
therapy. She received her Ph.D. from the University of Florida in the summer of 2017.