Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2010 Addition / C-C Bond Cleavage Reactions of Vinylogous Acyl Triflates and Their Application to Natural Product Synthesis David Mack Jones Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected]
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Florida State University Libraries
Electronic Theses, Treatises and Dissertations The Graduate School
2010
Addition / C-C Bond Cleavage Reactionsof Vinylogous Acyl Triflates and TheirApplication to Natural Product SynthesisDavid Mack Jones
Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected]
The members of the committee approve the dissertation of David M. Jones
defended on December 3, 2009.
__________________________________ Gregory B. Dudley Professor Directing Dissertation
__________________________________ Kenneth Taylor University Representative
__________________________________ Jack Saltiel Committee Member
__________________________________
D. Tyler McQuade Committee Member
__________________________________
Kenneth Goldsby Committee Member
Approved: _____________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Graduate School has verified and approved the above-named committee
members.
iii
This manuscript is dedicated to my Mother and Father, without whom I would have been lost. Their constant and unwavering support has made all that I am,
and all that I will be, possible.
iv
ACKNOWLEDGEMENTS This body of work has been made possible not only through my hard work, but through the personal and academic support of many people. I would like acknowledge Professor Gregory Dudley. He was charged with the difficult task of not only providing challenging problems for me, his student, to explore, but also he had to provide an environment in which I could hone my own set of tools for future scientific endeavors. As a naïve 1st year graduate student I joined his research group and his constant guidance set me on the right path. As the years progressed he no longer provided answers, but only answered my questions with yet more questions. I remember being completely frustrated at the time with this tact. However now, in the waning moments of my graduate studies, I understand the role that a research advisor must play in the development of a Ph.D. student. I owe much to Dr. Dudley and I am very appreciative of his ability to change me from that naïve graduate student into the independent scientist that I have become today. I would also like to thank the members of the Dudley research group: Dr. Tim Briggs, who introduced me to lab techniques, and guided my early research; Dr. Shin Kamijo, who made my work possible through his early efforts; Dr. Doug Engel, who entered the lab at the same time as I and provided constant competition; Sami Tlais and Jingyue Yang, who often provided company late into the night in the lab; Marilda Lisboa, who provided several intermediates in my palmerolide research; and the rest of the members, past and present. I would like to acknowledge my family for providing constant support, financial and otherwise. Mom and Dad, you have truly been the foundation of my life. Although many times in grad school, you could not offer any advice to help me with my problems, you always made sure that I knew you would do anything in your power to help me. Amy, Laura, Ken, and your families, you have provided support to me in ways that you cannot even understand. I am thankful for your understanding of my inability to attend family gatherings, niece and nephew birthday parties, and other important milestones. Bamp, June, Grammy, and everyone else in the family, thank you. I would like to thank Kerri, a very big part of my life throughout graduate school; you have helped me through many difficult times. I would like to thank the Pritchard family for being like a second family to me. Thanks to Doug, Kerry, Phil, Chris, Antonio, Matt, Mike, Scott and all the other great friends in my life. I wish I had more space to mention all of those people that deserve recognition for supporting me in the generation of this manuscript, please forgive me for any omissions. Lastly, I would like to thank all of those who helped me edit this manuscript, without whom, this document would not have been possible: Kerry Gilmore, Sami Tlais, Marilda Lisboa, and Professor Dudley.
v
TABLE OF CONTENTS List of Tables .................................................................................. ….. vi List of Figures ................................................................................. ….. vii List of Abbreviations ....................................................................... ….. xii Abstract .................................................................................... ….. xviii
1. INTRODUCTION: C-C BOND CLEAVAGE AND FRAGMENTATION REACTIONS IN ORGANIC SYNTHESIS........ 1
2. SYNTHESIS OF (Z)-6-HENEICOSEN-11-ONE: THE SEX PHEROMONE OF THE DOUGLAS-FIR TUSSOCK MOTH ..... ….. 13
The Doulas-Fir Tussock Moth ........................................... ….. 13 Synthesis of (Z)-6-Heneicosen-11-one ............................. ….. 16 Experimental ..................................................................... ….. 21
3. A FRAGMENTATION / BENZANNULATION STRATEGY TO
PROVIDE ACCESS TO BENZO-FUSED INDANES ................. 37 Introduction ....................................................................... ….. 37 The Alcyopterosins ........................................................... ….. 37 Retrosynthetic Analysis of Alcyopterosin A ....................... ….. 53 Exploring Gold and Copper Catalyzed Benzannulations .. .. 59 Experimental ..................................................................... ….. 70
4. SYNTHESIS OF THE EASTERN HEMISPHERE (C1-C15)
OF PALMEROLIDE A ............................................................... ….. 115 Introduction ....................................................................... ….. 115 The Melanoma Problem .................................................... ….. 116 Palmerolide A ................................................................... ….. 121 Synthesis of the Eastern Hemisphere of Palmerolide A ... ….. 138 Experimental ..................................................................... ….. 145
5. RE-EXPLORING THE CLAISEN-TYPE CONDENSATIONS OF VINYLOGOUS ACYL TRIFLATES ...................................... ….. 170
New Insights into the Mechanism ..................................... ….. 170 Synthesis of -Ketophosphonates .................................... ….. 177 Experimental ..................................................................... ….. 184 REFERENCES .............................................................................. ….. 202 BIOGRAPHICAL SKETCH ............................................................. ….. 222
vi
LIST OF TABLES
Table 1: Scope of Original Fragmentation Reaction with Respect to Nucleophiles ............................................................................... 11 Table 2: Grignard Triggered Fragmentation of 2 ....................................... 20 Table 3: DNA Binding Assay Performed by Iglesias et al. ......................... 51 Table 4: Average Values (MG-MID) for In Vitro Antitumor Activity on the NCI 60-Cell Line Panel ................................................................ 52
Table 5: Preliminary Screening of Benzannulation Reactions of Substrates 84a-f.......................................................................... 65 Table 6: Selected Data from Nicolaou’s SAR Study (GI50 Values in M) .. 133 Table 7: Claisen-Type Condensation of Vinylogous Acyl Triflate 2 ........... 141 Table 8: Comparison of the Acidities of Several Acetophenone Phosphonate and Phosphine Oxide Derivatives in DMSO .......... 174 Table 9: Reactions of Vinylogous Acyl Triflates with 1.1 Equivalents of Dimethyl lithiomethylphosphonate (152b) ................................... 180 Table 10: Fragmentation of VAT 2 Using 1.1 Equivalents of Various Phosphonate Derived Nucleophiles .......................................... 182
vii
LIST OF FIGURES
Figure 1: Representative examples of the (1) Diels-Alder, (2) Michael Addition, (3) Evans Aldol, (4) and Sonogashira Cross Coupling Reactions in Synthesis ............................................................... 2 Figure 2: Examples of Tandem Bond Forming / Bond Breaking Strategies in Organic Synthesis .................................................................. 3 Figure 3: Examples of Transition Metal Catalyzed C-C Bond Cleavage Reactions in Synthesis ............................................................... 4
Figure 4: Possible Mechanistic Pathways of Grob Fragmentations .......... 6 Figure 5: General Representation of the Wharton Fragmentation ............ 6
Figure 6: Wood and Njardarson’s Wharton fragmentation approach to CP-263,114 ................................................................................ 7
Figure 7: Base Promoted Eschenmoser-Tanabe Fragmentation Process. ..................................................................................... 8
Figure 8: Mander’s Reduction-Epoxidation-Oxidation Solution for the Eschenmoser-Tanabe Fragmentation in the Synthesis of GB 13 ......................................................................................... 9
Figure 9: Comparison of the Eschenmoser-Tanabe Fragmentation and Enone Formation from Vinylogous Acid Esters .......................... 9
Figure 10: Mechanistic Hypothesis for the Fragmentation of Vinylogous Acyl Triflates .......................................................... 12
Figure 11: (a)64 A Male Specimen of the Douglas-Fir Tussock Moth; (b)64 Distribution of Host Type Where Douglas-Fir Tussock Moth Has Been Found; (c) the DFTM Sex Pheromone..................... 13
Figure 12: Smith’s Synthesis of the Sex Pheromone of the Douglas-Fir Tussock Moth ........................................................................... 17
Figure 13: Fetizon and Lazare’s Synthesis of Z6 ...................................... 17
Figure 14: Kocienski and Cernigliaro’s Synthesis of Moth Pheromone Z6 18
viii
Figure 15: Synthesis of (Z)-6-Heneicosen-11-one Using an ABC Strategy 21 Figure 16: Illudalane Skeleton and Alcyopterosin A .................................. 38
Figure 17: Proposed Biosynthetic Pathway to the Illudalanes. ................. 38 Figure 18: (eq. 1) Proposed Decomposition of Stearodelicone (21) Upon Absorption on Silica Gel, and (eq. 2) the Observed Reactions of Ptaquiloside (23) in the Presence of Acid and/or Base ........ 40 Figure 19: Representative Sample of Illudalane Structures Isolated from A. paessleri and A. grandis ...................................................... 41 Figure 20: Possible Traditional Reppe Reaction Involving Three Different Unsymmetrical Acetylenes ....................................................... 42 Figure 21: Typical Solutions for Chemo- and Regioselective Cyclotrimerization of Alkynes ................................................... 43 Figure 22: Representative Examples of Sato’s One-Pot Metalative Reppe Reactions ...................................................................... 44 Figure 23: Sato’s Synthesis of Alcyopterosin A ........................................ 44 Figure 24: Key Steps in the Syntheses of Alcyopterosin E (28) (eq. 1) and Alcyopterosin I (30) by Witulski and Snyder (eq. 2).. ......... 46 Figure 25: Synthesis of Iglesias’ Key Intermediate ................................... 47 Figure 26: Synthesis of Unnatural Alcyopterosin Analogs Performed by Iglesias et al ............................................................................. 48 Figure 27: Completion of Iglesias’ Synthesis of Alcyopterosin A. ............. 49 Figure 28: Compounds Known to Intercalate DNA. .................................. 50 Figure 29: Retrosynthetic Analysis of Alcyopterosin A Using a Fragmentation / Benzannulation Approach .............................. 54 Figure 30: AuCl3- and Cu(OTf)2-Catalyzed [4+2] Benzannulation Reactions Described by Asao and Yamamoto. ........................ 55 Figure 31: Proposed Mechanism of the [4+2] Cycloaddition Reactions of 56 and 57 Catalyzed by AuCl3 and Cu(OTf)2 / CF2HCO2H… 56
ix
Figure 32: Intramolecular Lewis Acid-Catalyzed [4+2] Benzannulation Reactions Studied by Asao and Yamamoto ............................. 57 Figure 33: Yamamoto’s Key Benzannulation in the Synthesis of (+)- Rubiginone B2 and (+)-Ochromycinone .................................... 57 Figure 34: Contrast Between Known Benzannulations and Desired Benzannulation ........................................................................ 58 Figure 35: Comparison of Known Benzannulations and Those of a New Methodology............................................................................. 60 Figure 36: Originally Considered Reactions to Access Fragmentation Pre-nucleophile 77 ................................................................... 61 Figure 37: Proposed Route to Benzannulation Substrates 84. ................. 62 Figure 38: Synthesis and Fragmentation Reaction of Aryltriazene 80. ..... 62 Figure 39: Synthesis of Benzannulation Substrates 84a-e. ...................... 63 Figure 40: Synthesis of Benzannulation Substrate 84f. ............................ 64 Figure 41: Direct Comparison of the Benzannulation Reactions of 84c and 84f ..................................................................................... 66 Figure 42: Alternative Synthesis of Benzannulation Substrate 89 ............ 67 Figure 43: Benzannulation Reactions of Compound 89 ............................ 68 Figure 44: Proposed Route to Vinyl Nucleophile 54 Using Negishi’s Z-Selective Bromoboration ....................................................... 69 Figure 45: Several Chemotherapeutic Agents Used in the Treatment of Melanoma ................................................................................ 120 Figure 46: The Report Issued to Baker from the National Cancer Institute’s 60-Cell Line Panel Toxicity Assay for Palmerolide A181 ....................................................................... 123 Figure 47: Palmerolide A and Other Members of the Palmerolide Natural Products with Major Distinctions Highlighted in Red Ovals ................................................................................ 124 Figure 48: Palmerolide A and Strategic Disconnections. .......................... 125
x
Figure 49: De Brabander’s Synthesis of the C16-C24 Fragment of . Palmerolide A ........................................................................... 126 Figure 50: De Brabander’s Synthesis of the C9-C15 Fragment of Palmerolide A ........................................................................... 126 Figure 51: De Brabander’s Synthesis of the C1-C8 Fragment of Palmerolide A ........................................................................... 127 Figure 52: Completion of De Brabander’s Synthesis of 109, a Diastereomer of Palmerolide A ................................................ 128 Figure 53: Synthesis of Nicolaou’s C16-C23 (112) and C8-C15 (116) Fragments ................................................................................ 129 Figure 54: Nicolaou’s Synthesis of C1-C8 Fragment of Palmerolide A ..... 130 Figure 55: Nicolaou’s End-Game Strategy for the Synthesis of 109 ......... 131 Figure 56: Key Analogs of Palmerolide A Developed by the Nicolaou Lab ........................................................................................... 132 Figure 57: Key Reactions in Maier’s Formal Synthesis of Palmerolide A .. 135 Figure 58: Hall’s Asymmetric Crotylboration en Route to Palmerolide A’s C16-C24 Fragment .................................................................. 136 Figure 59: Hall’s Unique Approach to Install the C7, C10, and C11 Stereocenters ........................................................................... 137 Figure 60: Brief Overview of the Addition / Bond Cleavage Reactions of Vinylogous Acyl Triflates .......................................................... 139 Figure 61: Synthesis and Nucleophile-Triggered Decompositions of DHP Triflates .................................................................................... 140 Figure 62: Retrosynthetic Analysis of Palmerolide A Using a Fragmentation Approach .......................................................... 140 Figure 63: Synthesis of the C1-C8 Olefination Reagent for the Synthesis of Palmerolide A ....................................................................... 142 Figure 64: Synthesis of Aldehyde 150, the C9-C15 Fragment of Palmerolide A ........................................................................... 143 Figure 65: Possible Michael Reaction of 155 ............................................ 144
xi
Figure 66: Completion of the Eastern Hemisphere (C1-C15) Fragment Synthesis ................................................................................. 144 Figure 67: Mechanism of the Classical Claisen Condensation of Ethyl Acetate ..................................................................................... 170 Figure 68: Proposed Mechanism for the Reaction Between 2 and 152a .. 171 Figure 69: Reported Claisen-Type Condensation Reactions of VAT 2 ..... 172 Figure 70: Observations Made During the Synthesis of the C1-C15 Fragment of Palmerolide A (Chapter 4) ................................... 173 Figure 71: Proposed Fragmentation Reaction Pathway Between 2 and 166 .................................................................................... 175 Figure 72: Proposed Mechanism of the Reaction Between VAT 2 and 152 ........................................................................................... 176 Figure 73: Common Methods for the Preparation of Phosphonates ......... 178 Figure 74: Synthesis of 180, an Analog of Phosphonate 178 ................... 181
xii
LIST OF ABBREVIATIONS
ABC addition / C-C bond cleavage Ac acetyl app apparent (spectral) Aq aqueous Ar aryl, argon BAIB bis(acetoxy)iodobenzene (phenyliodonium diacetate) BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl Bn benzyl BOLD bleomycin, vincristine, lomustine, and dacarbazine Bt. Bacillus thuringiensis n-Bu normal butyl t-Bu tertiary butyl c centi oC degrees Celsius ca. circa (approximately) Calcd calculated (in mass spectrometry) CBS Corey-Bakshi-Shibata reagent CD circular dichroism cf. confer (compare) CI chemical ionization (in mass spectrometry) CNS central nervous system
xiii
cod 1,5-cyclooctadiene CSA camphor-10-sulfonic acid d doublet (spectral) heat, double bond location chemical shift, in parts per million relative to tetramethylsilane dba dibenzylideneacetone DBU 1,8-diazabicylco[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess DEAD diethyl azodicarboxylate DHP 5,6-dihydro-2-pyrone DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMAP N,N-4-dimethylaminopyridine DMP Dess-Martin periodinane DMSO dimethylsulfoxide DNA deoxyribonucleic acid dr diastereomeric ratio DTFM Douglas-fir tussock moth DTIC dacarbazine E- entgegen or opposite (alkene geometry)
xiv
EDC-Cl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ee enantiomeric excess e.g. exempli gratia (for example) eq equation EI electron ionization (in mass spectrometry) EPA United States Environmental Protection Agency equiv equivalent(s) ESI electrospray ionization (in mass spectrometry) Et ethyl et al. et alii (and the others) EWG electron withdrawing group FAB fast-atom bombardment (in mass spectrometry) FT-IR Fourier-transformed infrared g gram(s) gem- geminal GI50 half maximal growth inhibitory concentration h hour(s) ha hectares Hex hexanes HIV human immuno-deficiency virus HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry HWE Horner-Wadsworth-Emmons
xv
Hz hertz IC50 half maximal inhibitory concentration i.e. id est (that is) Ipc isopinocamphenyl IR infrared J coupling constant reported in hertz (in NMR spectroscopy) wavelength L liter(s) LC50 median lethal dose LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide micro m multiplet (spectral), meter(s), milli m- meta- M moles per liter, mega mCPBA m-chloroperbenzoic acid Me methyl MG-MID meangraph midpoint min minute(s) MOM methoxymethyl mp melting point Ms methanesulfonyl n nano
xvi
NCI United States National Cancer Institute NMR nuclear magnetic resonance Nuc nucleophile OPP pyrophosphate p- para- PCC pyridinium chlorochromate Ph phenyl Pin pinacolato PMB p-methoxybenzyl ppm parts per million ppt precipitate PPTS pyridinium p-toluenesulfonate i-Pr isopropyl q quartet (spectral) RCM ring-closing metathesis ref reference retro retrograde r.t. room temperature s singlet (spectral) SAR structure-activity relationship SN2 substitution nucleophilic bimolecular t triplet (spectral) TBAF tetrabutylammonium fluoride
xvii
TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy free radical TES triethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TGI total growth inhibitory concentration THF tetrahydrofuran TIPS triisopropylsilyl TMS trimethylsilyl TMZ temozolomide Tol tolyl Ts p-toluenesulfonyl UV ultraviolet VAT vinylogous acyl triflate V-ATPases vacuolar adenosine triphosphatases wt. weight Z- zasammen or together (alkene geometry)
xviii
ABSTRACT
This dissertation describes the synthetic utility of tandem addition / C-C bond
cleavage reactions of vinylogous acyl triflates. The first chapter provides background
into carbon-carbon bond breaking reactions that have been applied in organic synthesis
and the preliminary data that allowed for the original work presented here. Chapter 2
explains the significance as well as the prior syntheses of a commercially important
moth pheromone, (Z)-6-heneicosen-11-one. The second chapter culminates in the
synthesis of the sex attractant through a fragmentation reaction made possible by the
direct extension of the initial nucleophile-triggered fragmentation studies to include the
use of Grignard reagents. Chapter 3 describes the application of the fragmentation
method, coupled to a benzannulation reaction, to afford penta- and hexasubstituted
indanes. This two step sequence provides the basis for future work directed toward the
synthesis of alcyopterosin A, a known cytotoxic agent with possible biological
applications.
The current difficulties pertaining to the treatment of melanoma are discussed in
Chapter 4. Recently, an exciting natural product that provides promising activity against
this horrible cancer was discovered. Palmerolide A has the ability to kill melanoma cells
selectively at low concentrations. The fragmentation method developed in these
laboratories provides entry into a key fragment. The Claisen-type condensation reaction
of vinylogous acyl triflates was expanded to the synthesis of a novel -ketophosphine
oxide olefinating reagent, which allowed for the rapid synthesis of the eastern
hemisphere (C1-C15) of this exciting natural product. Optimization of the Claisen-type
condensation reaction to provide the -ketophosphine oxide reagent, led to the optimal
reduction of the number of equivalents of the nucleophile. Intrigued by this, these
reactions were explored in more detail. The results of this investigation are described in
Chapter 5. The reduction in the number of equivalents of nucleophile, a key feature in
these reactions, may be attributed to the ability of the phosphorus atom to form of an
oxaphosphetane-like intermediate. As a result, new, potentially useful, -
ketophosphonates were synthesized.
1
CHAPTER 1
INTRODUCTION: C-C BOND CLEAVAGE AND FRAGMENTATION REACTIONS IN ORGANIC SYNTHESIS
Synthetic organic chemistry has largely focused on the use of carbon-carbon
bond forming reactions to assemble complex molecules. The means to install such
bonds is of the utmost importance. There is a constant struggle to provide new carbon-
carbon bond forming reactions that are tolerant to a diverse number of functional
groups, as well as reactions that are both regio- and stereoselective. Discoveries of
such reactions constantly expand the frontiers of organic chemistry. Tolerant and
selective C-C bond forming reactions, such as the Diels-Alder,1-4 Michael addition,5-8
Evans aldol,9 and Sonogashira10-12 reactions were at the forefront of chemistry at the
time of their discovery. These reactions have since been applied in the synthesis of
numerous complex molecules (Figure 1). If not for the innovation of such reactions, the
synthesis of many natural products would have proven to be a much more daunting
challenge; they have changed the way chemists have approached natural product
synthesis and have allowed the development of synthetic strategies which would have
otherwise been impossible.
The need to build up complexity quickly in synthesis requires bond forming
reactions. Not surprisingly, C-C bond breaking reactions receive far less attention.
However, these reactions often provide access to compounds that can be difficult to
prepare through other methods. Some of the most useful C-C bond breaking reactions
applied in organic synthesis are simply the reverse processes of C-C bond forming
events similar to those mentioned above (the aldol,13,14 Diels-Alder,15,16 and Michael
reactions,17,18 among others).
2
N
OO
MeO OMeO
O
(2.5 equiv)
r.t., 45 min97%
N
OO
MeO OMe
O
OH
H
Diels-Alder Reaction From Boger's Synthesis of Rubrolone Aglycon19
(1)
Tandem Michael-Addition Reactions From Ihara's Synthesis of ( )-Longiborneol20±
CO2Me
O LiHMDS(2 equiv)
THF
-78 oC, 1h,
then
0 oC, 3h
94%
CO2Me
O O
CO2Me
(2)
NO
O
Ph Me
O
1. Bu2BOTf, Et3N,
-5 oC, DCM; then add
O
H
12
2. MeOH, 30% H2O263%, 2 steps
NO
O
Ph Me
O OH
12
(3)
Sonogashira Reaction in Paterson's Synthesis of Callipeltoside aglycon22
(4)
O
O
OTBS
Me
MeO
I
O
Me Cl
HMe
MeOH +
O
O
OTBS
Me
MeO O
Me
Me
MeOH
Cl
1. Pd(Ph3P)2Cl2, CuI, HN(i-Pr)2, EtOAc
2. TBAF, THF3. PPTS, CH3CN, H2O 54% over 3 steps
Callipeltoside aglycon
3
Figure 1: Representative examples of the (1) Diels-Alder, (2) Michael Addition, (3)
Evans Aldol, and (4) Sonogashira Cross Coupling Reactions in Synthesis.
Often, reverse reactions are used in tandem with their forward counterparts to
access complex molecules. Figure 2 provides some representative examples that
3
demonstrate the utility of retrograde reactions in organic synthesis. Jacobi and co-
workers have utilized a Diels-Alder / retrograde Diels-Alder sequence to access (±)-
Petasalbine (scheme 1).23 Jacobi took advantage of the reactivity of oxazoles as diene
partners; after the cycloaddition reaction with a tethered alkyne, the heterocyclic
intermediate underwent a retro-Diels-Alder to afford the required furan moiety. In 2005,
Iwabuchi and co-workers synthesized cannabinoid receptor agonist (-)-CP55,940 using
a modified-proline catalyzed aldol reaction to achieve stereocontrol, followed by a retro-
aldol to generate the chiral cyclohexane carboskeleton (scheme 2).24
MeMe
H
OH
Me
N
O N
O
Me
MeOHH
-HCN
O
MeMe OHMe
H
Jacobi's Key Diels-Alder/Retro-Diels-Alder Reaction in the Synthesis of ( )-Petasalbine±
(1)
Diels-Alder
Retro-Diels-Alder
Iwabuchi's Aldol/Retro-Aldol Strategy in the Synthesis of (-)-CP55,940
O
CHO
NH
TBDPSO
CO2H
MeCN, rt., 68%(>99% de, 94% ee)
N
PO
OO
H O H
O OH
( )-Petasalbine±
O OMOM
cat. TsOHethylene glycol
xylene,reflux
O O
OO
OMe OMe
n-C6H13
n-C6H13
OH
n-C6H13
HO
OH
(-)-CP55,940
(2)
84%
68%2 steps
88%
49%3 steps
Figure 2: Examples of Tandem Bond Forming / Bond Breaking Strategies in Organic Synthesis.
4
Reactions such as the Cope rearrangement,25,26 as well as oxidative cleavages
of olefins27 and diols,28 represent some traditional C-C bond cleavage reactions.
Several new C-C bond breaking reactions have been made available through the
advance of transition metal chemistry. Although transition metal-catalyzed C-C bond
cleavage chemistry has made some headway in synthetic chemistry, many of these
reactions are heavily dependent on the presence of either highly strained bonds (e.g.
cyclopropane or cyclobutane moieties) or functional groups located about the reaction
site capable of coordinating to the metal center (Figure 3, scheme 1).29-33 The evolution
of metathesis catalysts has allowed for the development of ring opening metathesis
reactions, yet another defining example of C-C bond cleavage reactions in synthetic
chemistry (Figure 3, scheme 2).34-36
RR' O
OH
[Rh(OH)(COD)]2
(R)-BINAPToluene
up to 92% and 95% ee
R
O ORh
R'
O
R
R'
Rh
-carbon elimination
O
1,4-Rh shift
Rh
O
R
R'
O
"H+"
O
R
R'
O
Murakami's Asymmetric Rhodium Catalyzed Synthesis of 3,4-Dihydrocoumarins Through Cleavage of a
Cyclobutyl Intermediate37
(1)
Tandem Ring opening/Ring Closing Metathesis Strategy in Phillips' Synthesis of ( )-trans-Kumausyne38
(2)O
O Ru
PPh3
PPh3
PhClCl
CH2Cl2, H2C=CH2, r.t.83% O
O
±
H
H
O
BrHH
AcO
( )-trans-Kumausyne±
Figure 3: Examples of Transition Metal Catalyzed C-C Bond Cleavage Reactions in Synthesis.
5
Throughout the 1950’s and 60’s, Grob and co-workers carried out investigations
into heterolytic bond cleavage reactions of molecules consisting of various combinations
of carbons and heteroatoms.39-43 These reactions produce three distinct fragments /
products, and are thus referred to as Grob fragmentations. The three ―products‖
generated from the fragmentation are all included in the starting molecule with the
general formula a—b—c—d—X (Figure 4). ―X‖ is referred to as the nucleofuge; leaving
with the electron pair with which it was originally attached to the starting molecule, thus
it becomes more negative. Prior to fragmentation, the nucleofugal fragment can be
neutral (e.g. halide, sulfonate, or carboxylate) or charged (diazonium, oxonium,
ammonium or sulfonium). The electrofuge, a—b, loses a bonding pair of electrons and
becomes more positive. The electrofugal fragment is typically a carbonyl containing
compound; however, carbon dioxide, olefins, dinitrogen, immonium-, carbonium-, and
acylium ions have been generated as electrofuges. The central portion of the starting
material, c—d, becomes the unsaturated fragment. The most commonly encountered
unsaturated fragments are olefins, acetylenes, nitriles and imines.
The most probable mechanistic pathway (Figure 4) of the Grob fragmentation is
substrate dependent. Both steric and electronic properties of the substrate influence the
nature by which the fragmentation takes place. Very narrow stereochemical
requirements must be met in order to achieve proper orbital overlap for the one-step
synchronous (concerted) mechanism to proceed. The transition state of the concerted
process involves all five atoms, and thus, this mechanism is invoked usually in Grob
fragmentations of conformationally rigid molecules. If necessary orbital overlap is
insufficient or absent, the concerted process is not possible; in this case, a two-step
process (usually cationic) must take place if the fragmentation is to occur. A two-step
fragmentation pathway typically provides the possibility for side reactions (e.g.
elimination), making fragmentations that proceed through stepwise mechanisms less
useful.
6
ab
cd
X
a b c d XElectrofugal
fragmentUnsaturated
fragmentNucleofugal
fragment
(A) One-step synchronous:
(B) Two-step cationic:
ab
cd
XX-
ab
cd a b
+ +
c d+
Electrofuge Nucleofuge
(C) Two-step anionic:
ab
cd
XX- a b c d +c
dX
Figure 4: Possible Mechanistic Pathways of Grob Fragmentations.
P. S. Wharton pioneered the base-induced heterolytic fragmentation reaction of
bicyclic-1,3-diol monosulfonate esters, now referred to as a Wharton fragmentation
(Figure 5).44-47 Although the Wharton fragmentation falls into the category of a Grob
fragmentation, it is a more specific term referring to the synthesis of alkenes from 1,3-
diols. The most common substrates for the Wharton fragmentation are bicyclic-1,3-
hydroxy monotosylates or monomesylates generated from unsymmetrical 1,3-diols.
n
OH
OSO2R
n
base
O
Figure 5: General Representation of the Wharton Fragmentation.
The Wharton fragmentation is often employed for the synthesis of medium sized
rings which are difficult to prepare. The rate of fragmentation depends both on the ring
7
strain of the bicycle and the concentration of the base. Typically strong, non-
nucleophilic, bases (t-BuOK, NaH, dimsylsodium, etc.) are best for promoting the
fragmentation. Alkenes from the Wharton fragmentation are generated
stereospecifically from the bicyclic precursor. Wood and Njardarson successfully
applied the Wharton fragmentation in their approach to the bicyclic core of CP-263,114
(Figure 6).48 The synthetic strategy outlined by Wood highlights the utility of the Wharton
fragmentation, as the originally envisioned oxy-Cope rearrangement failed.
AcO
OH
MsCl, pyrDMAP
AcO
OMs
K2CO3, MeOH
Me Mer.t.
95%2 steps
AcO
Me
Figure 6: Wood and Njardarson’s Wharton fragmentation approach to CP-263,114.
During the time Grob was describing the fragmentation reactions that now bear
his name, Eschenmoser49,50 and Tanabe51,52 were independently exploring the ring
opening reaction of ,-epoxyhydrazones. The Eschenmoser-Tanabe fragmentation
process (Figure 7) is classified as a 7-centered Grob-type fragmentation process,
yielding an electrofugal fragment (ketone) tethered to the unsaturated fragment (alkyne)
and two nucleofugal fragments (N2 and typically an arylsulfinate).
8
O
O
R
R'
TsNHNH2
-H2O
N
O
R
R'
N
H
TsBase
N
O
R
R'
NTs
N
R
R'
NTs
O
O
R'
R
+N NTs +
Nucleofugal fragments
Unsaturated fragment
Nucleofugalfragment
Figure 7: Base Promoted Eschenmoser-Tanabe Fragmentation Process.
The substrates of the Eschenmoser-Tanabe fragmentation are typically prepared
in a multistep sequence from ,-unsaturated ketones; first through the epoxidation of a
cyclic enone, followed by a condensation reaction with tosyl hydrazide. The
fragmentation is induced by treatment with acid or base in a protic medium induces
fragmentation. Although the multistep sequence from cyclic enone to tethered keto-
alkyne has found some application as a synthetic strategy through the years,53-
58,79,80,86,114,117 it remains largely pedagogical. The substrates required for the
Eschenmoser-Tanabe process, epoxy hydrazones, can be difficult to prepare, as
illustrated by Mander’s synthesis of the Galbulimima alkaloid GB 13.55 Direct
epoxidation of the enone of the pentacyclic late-stage intermediate was unsuccessful. In
an effort to obtain the necessary epoxy hydrazone, a reduction-epoxidation-oxidation
sequence was performed (Figure 8). The possible difficulty in the synthesis of epoxy
hydrazones and the protic medium (commonly ethanol or acetic acid) present potential
drawbacks to the method.
9
H
H
H
OMOM
H
O
MOMO
1. LiAlH4, THF2. mCPBA, DCM
3. DMP, NaHCO3;
4. p-NO2ArSO2NHNH2,pyridine, EtOH, THF
59% 4 steps
O
H
H
H
OMOM
H
MOMO
Figure 8: Mander’s Reduction-Epoxidation-Oxidation Solution for the Eschenmoser-
Tanabe Fragmentation in the Synthesis of GB 13.
Prior to the description of the Eschenmoser-Tanabe fragmentation process,
Woods and Tucker described the reaction of vinylogous acid esters with
phenylmagnesium bromide, providing cyclic enones.59 This method has been utilized in
cyclic enones that are difficult to prepare using other methods.60 There is a marked
similarity between the presumed intermediates of the Eschenmoser-Tanabe
fragmentation and the synthesis of enones from vinylogous acid esters (Figure 9).
Although there is a parallel between the intermediates A and B, they diverge in the
manner by which they decompose.
NNHTs
OR'
R
R' OH
NNTs
R
A
- N2
- TsH
R'
O R
The Eschenmoser-Tanabe Fragmentation
Enone Formation from Vinlogous Acid Esters
OR2
R1
R3 OM
OR2
R1
B
- R2OH
R3O
R3 M H3O+R1
O
Figure 9: Comparison of the Eschenmoser-Tanabe Fragmentation and Enone Formation from Vinylogous Acid Esters.
10
In 2005, our lab sought to introduce an intermediate similar to B which would
allow for a fragmentation similar to the Eschenmoser-Tanabe fragmentation under mild
conditions in an aprotic solvent. Such a reaction would have important mechanistic
implications and would provide a new tool in the synthesis of complex molecules. A
crossover in the mechanistic pathway was envisioned to occur if the nucleofugacity of
the –OR2 group in intermediate B were increased.
Kamijo and Dudley carried out a preliminary investigation into a tandem
carbanion addition / C-C bond cleavage reaction that provided tethered alkynyl ketones
that are similar, yet regioisomeric, to those obtained by the Eschenmoser-Tanabe
fragmentation.61 A change in the –OR2 group from alkoxy (enone formation, Figure 9)
to trifluoromethanesulfonyloxy allowed for the desired crossover mechanism to take
place both in an aprotic medium and under mild conditions (displayed in Table 1).
Kamijo and Dudley found that the synthesis of vinylogous acyl triflates (2) was
general and high yielding. Symmetric diketones such as 1 were converted into
vinylogous acyl triflates (VATs), similar to 2, in nearly quantitative yields using a
modified procedure.62 The fragmentation reaction was optimized for the addition of
phenylmagnesium bromide, and ethereal solvents were found to provide the most
suitable environment for the fragmentation. Table 1 summarizes the original scope of
the fragmentation reaction with respect to nucleophiles explored by Kamijo and Dudley.
Nucleophiles with electron donating groups had significant effect and accelerated the C-
C bond cleavage process (entries 1—4 vs. entries 5—6), suggesting a transition state
with significant carbonyl character. Aryl organolithium reagents were also found to
trigger fragmentation more readily, presumably due to an increase in ionic character of
the alkoxide intermediate (entries 7—9).
11
Table 1: Scope of Original Fragmentation Reaction with Respect to Nucleophiles.61,a
Me
O
O 1.2 equiv Tf2O2.0 equiv pyridine
CH2Cl2, 95-100%
O
OTf
Me
1 2
R1 M
THF
R1
O Me
3
entry R1__M conditions 3 yield (%)b
1 Ph—MgBr 0 oC to r.t. 3a 80c
2 p-MeO—C6H4—MgBr 0 oC to r.t. 3b 86
3 m-MeO—C6H4—MgBr 0 oC to r.t. 3c 57
4 o-MeO—C6H4—MgBr 0 oC to r.t. 3d 34
5 p-Cl—C6H4—MgBr 0 — 60 oC 3e 61
6 2-thienyl—MgBr 0 — 60 oC 3f 63
7 Ph—Li -78 oC to r.t. 3a 93c
8 m-MeO—C6H4—Li -78 oC to r.t. 3g 78
9 o-MeO—C6H4—Li -78 oC to r.t. 3h 57
10 Me—Li -78 oC to r.t. 3i 65 a
Typical procedure: enol triflate 2 (0.55 mmol) in 2 mL cold THF was treated with R1—M (0.50 mmol). All
reactions complete within 90 min. b Isolated yield.
c Average of two runs.
The mechanistic hypothesis (Figure 10) that guided Kamijo and Dudley’s original
studies has many interesting qualities as well as some guiding assumptions: (1)
nucleophilic addition is fast and proceeds in a 1,2- fashion; (2) decomposition of
intermediate C is the rate limiting step; (3) lithium triflate is extruded from C as a
dissociated ion pair that subsequently recombines;63 (4) an increase in the ionic
character of C promotes fragmentation; and (5) the stability of the resulting alkynyl
ketone and the dissociated ion pair are reflected in the transition-state (concerted);
however a two-step mechanism cannot be ruled out.
12
O
Me
OTf
R1 Li
THF
R1 OMe
OTf
Li THFn
C2
O
R1
Me
3fast
- LiOTf
slow
Figure 10: Mechanistic Hypothesis for the Fragmentation of Vinylogous Acyl Triflates.61
The fragmentation was found to be general with respect to the VAT, affording
alkynyl ketones of varying tether lengths and substitution patterns. Having established a
nucleophile-triggered fragmentation pathway of vinylogous acyl triflates under mild
reaction conditions, the Dudley lab directed further efforts towards expanding the scope
of the fragmentation reaction. This dissertation is focused on the development of this
method as well as its uses as a strategy for obtaining complex intermediates capable for
application in the synthesis of natural products. Since the discovery of this new reaction,
we have demonstrated the value of vinylogous acyl triflates as useful tools in complex
molecule synthesis.
13
CHAPTER 2
SYNTHESIS OF (Z)-6-HENEICOSEN-11-ONE: THE SEX PHEROMONE OF THE DOUGLAS-FIR TUSSOCK MOTH
The Douglas-Fir Tussock Moth
The Douglas-fir tussock moth (DFTM), Orgyia pseudotsugata seen in Figure 11a,
is a major contributor to the defoliation of fir trees in the Pacific Northwest (Figure 11b).
The populations of the DFTM typically remain stable; however they can explode,
leading to significant defoliation.64 For instance, in 1974 a DFTM outbreak gave rise to
the defoliation of 279,000 hectares (ha) of forest. The Environmental Protection Agency
(EPA) allowed the use of DDT, an otherwise banned substance, on 161,000 ha of forest
in order to contain the outbreak.65 The discovery of the sex pheromone (Figure 11c) of
the DFTM in 1975,66 (Z)-6-Heneicosen-11-one (Z6) has played an integral role in the
defense against such outbreaks.
Figure 11: (a)64 A Male Specimen of the Douglas-Fir Tussock Moth; (b) 64 Distribution of
Host Type Where Douglas-Fir Tussock Moth Has Been Found; (c) The DFTM sex pheromone.
O
8
Z6
(a) (b)
(c)
14
Outbreaks in the population of the DFTM are typically short in duration, one to
two years. The defoliation caused by outbreaks of the DFTM may result in complete
tree death or in the top-kill of trees, which retards vegetation growth and may induce
susceptibility of the tree to other pests. The defoliation of forestland caused by the
DFTM also increases the risk and severity of forest fires. The preferred food source for
the DFTM varies regionally, however the Douglas-fir is the dominant food source in
most areas where they are found.67 The caterpillar larvae of the DFTM are the source of
the defoliation. They are incapable of flight and are limited to the environment of the
host tree. Newly hatched larvae feed on the current year’s foliage, as the larvae
continue to grow, their demand for food increases and both new and old vegetation is
consumed.68
After consuming copious amounts of vegetation, the larvae build their cocoon
and pupation begins. Female moths emerge from their cocoon approximately 2 weeks
later and mate soon after. Being unable to fly, the female moth is limited to the use of
chemical communication in the form of pheromones to attract sexual partners. During
the daylight hours of the male flight season, usually in the months from July to
November, the females release their sex pheromone to signal potential mates. The
females lay their eggs soon after mating and subsequently die.69
There are many natural controls by which the population of the DFTM is
regulated. Eggs are preyed upon by small birds and parasitized by small wasp species.
After hatching, the caterpillars are eaten by various predators such as birds, spiders and
other insects. Carcelia yalensis, a parasitic fly species, is one of the primary foes of the
DFTM larvae, laying eggs inside of the caterpillar, which then hatch and eat the
caterpillar from within.70 When moth densities approach outbreak levels, there is a
nuclear polyhedrosis virus that frequently infects many colonies of the moth. Once
infected, a moth’s internal organs liquefy. The virus is spread throughout the colony
when a diseased body ruptures and is spread on the surface of the vegetation, and is
later ingested by other members of the species. Routinely, the virus is fatal and
commonly spreads rampantly throughout the colony, thus resulting in outbreak
suppression.71
15
When the natural means by which the DFTM populations are regulated become
insufficient, outbreaks, and subsequent tree damage, may result. A well integrated
management program must be maintained in order to handle population outbreaks and
minimize destructive defoliation. The early detection of increasing populations is the
foundation of any management program. Because the DFTM population produces only
one generation per year, it is possible for outbreaks to be detected one to two years
prior to any significant defoliation. Early detection of population outbreaks is made
possible, primarily, through the annual monitoring of male populations. The males can
be lured into traps baited with the sex attractant (Z6, Figure 11c) of their female
counterparts, allowing for sampling to be performed.72
When an outbreak is perceived to be eminent, measures to suppress moth
populations are determined through careful analysis of the potential threat to the forest.
Most recently, biological insecticides have emerged as the preferred method for
suppressing populations of the DFTM. Biological insecticides are regarded as
environmentally benign, making them preferred over persistent chemical based
alternatives. The two most common biological agents used to collapse populations of
the DFTM are: Bacillus thuringiensis (Bt), marketed under several trade names (e.g.
ThuricideTM from Bonide Products, Inc.), as well as the aforementioned tussock moth
nucleopolyhedrosis virus (TM-Biocontrol-1, produced by the U.S. Forestry Service).73
These agents are very successful in decreasing the population of feeding larvae,
however they are only used once outbreak population levels have been reached. As a
result, significant defoliation remains possible.
Pheromones have been used as species selective management agents.74 The
sex pheromone of the DFTM offers a potentially new means of controlling moth
populations at pre-outbreak levels through mating disruption.73,75,76 By spraying
synthetic Z6, impregnated in controlled-release capsules, male moths become confused
and unable to chemo-locate their female mating partners. By disrupting the mating
habits of the DFTM, reductions in the number of caterpillars in the following year are
likely. In 2005, the EPA has registered the use of Hercon® laminated plastic bio-flake
formulation of Z6 for the control of tussock moths and other lepidopteran insects.77
16
Continued research will assist in providing the necessary data and determine the
efficacy of Z6 as a mating disruption agent suitable for wide spread use.
Synthesis of (Z)-6-Heneiosen-11-one
Since its isolation and characterization by Smith, Daterman, and Davies in
1975,66 (Z)-6-heneicosen-11-one has arguably been the most important factor in the
fight against severe defoliation by the DFTM. The use of Z6 in baited traps, allowing for
population analysis and outbreak detection, and its potential for mating disruption lends
credence to its commercial importance. There have been considerable efforts directed
towards the synthesis of the DTFM sex pheromone.78-92 Most synthetic approaches to
Z6 rely on one of two strategies: (1) elaboration of the moth pheromone through a
series of steps that piece together the carbon back bone originating with the C11
carbonyl / protected-carbonyl through carbon-carbon bond forming reactions like the
SN2 reaction, or (2) beginning with a cyclic starting material and performing a ring-
opening event to install the necessary carbons.
The first synthesis78 of the sex attractant of the DFTM (Figure 12) exemplifies the
first synthetic strategy. Smith and co-workers began their synthesis with the protection
of aldehyde 4 as a dithiane. The dithiane (5) was then deprotonated with n-butyllithium,
and the resulting anion was alkylated with 1-chloro-5-decyne. Subsequent deprotection
and reduction of the ketone afforded alcohol 6. A syn-hydrogenation and oxidation
provided Z6 in 44% over 6 steps.
17
HS SH
BF3 OEt2
98%
4 5
1. n-BuLi;
Cl
2. CuO, CuClAcetone/H2O
3. LiAlH58% over 3 steps
O
8
Z6
O
8 H 8 H
SSOH
8
1. H2, P-2 NiEthylene Diamine
2. CrO3, pyridine
77% 2 steps
6
Figure 12: Smith’s Synthesis of the Sex Pheromone of the Douglas-Fir Tussock Moth.
Fetizon and Lazare’s synthesis of the DFTM sex pheromone (Figure 13),81 in
some ways, represents a hybrid of the strategies highlighted above. Their synthesis
began with 2-hydroxytetrahydropyran (7). Although 7 is a cyclic starting material,
hydroxy-aldehyde 8 is present in an equilibrium amount. Fetizon and Lazare took
advantage of this equilibrium and olefinated the aldehyde using Wittig reagent 9 to
install the Z-olefin of 10. Oxidation of alcohol 10, addition of n-decylmagnesium
bromide, and oxidation of the resulting alcohol provided Z6 in short order (four steps)
from a simple starting material in 51%.
O
H
OH
O
OH
Ph3P
7 8
9OH 1. CrO3, pyridine
2. n-C10H21MgBr
3. CrO3, pyridine85% 3 steps
O
8
Z6
10
60%
Figure 13: Fetizon and Lazare’s Synthesis of Z6.
In 1976, Kocienski and Cernigliaro published the synthesis of (Z)-6-heneicosen-
11-one (Figure 14);79 their synthesis exemplified the second strategy towards Z6, the
18
utilization of a ring-opening reaction. The ring opening reaction that Kocienski and
Cernigliaro envisioned as providing efficient access to the moth pheromone was the
Eschenmoser-Tanabe fragmentation49-52 (discussed in Chapter 1). Beginning with
vinylogous acid ester 11, they performed the enone synthesis first described by Woods
and Tucker.59 With all the necessary carbons installed, epoxidation of enone 12,
followed by condensation with p-tosylhydrazide in an acetic acid / methylene chloride
reaction medium provided tethered alkynyl-ketone 14. The alkyne was then
hydrogenated using palladium on barium sulfate in methanol and pyridine. Z6 was
synthesized in 4 steps from vinylogous acid ester 11 in 61% yield. Interestingly, there
have been 2 other syntheses that have also applied an Eschenmoser-Tanabe
fragmentation reaction similar to Kocienski and Cernigliaro to synthesize Z6.80,86
OMe 1. n-C10H21MgBr,Et2O;
H3O+
93%
O
O6
H2O2, NaOH,MeOH
O
6
O
O
8
O
8
Z6
11 12 13
14
p-TsNHNH2
AcOH/CH2Cl2
95%
71%
H2, Pd/BaSO4
MeOH/Pyridine97%
Figure 14: Kocienski and Cernigliaro’s Synthesis of Moth Pheromone Z6.
Having disclosed a preliminary study into the carbanion-triggered addition / C-C
bond cleavage (ABC) fragmentation methodology (Chapter 1),61 our lab envisioned the
synthesis of the sex pheromone of the Douglas-fir tussock moth to highlight our new
method.93 The impetus for this endeavor was derived from the fact that alkyl Grignard
nucleophiles were beyond the scope of our original report. Alkyl Grignards are often
more accessible and, in many cases, more reasonably priced than the corresponding
organolithiums; for instance: n-decylmagnesium chloride, needed for the synthesis of
Z6, is commercially available, n-decyllithium is not; ethylmagnesium chloride is far
19
cheaper than ethyllithium ($36.40 / 100 mL of 2.0 M in Et2O vs. $77.80 / 100mL of 0.5 M
in 9:1 benzene / cyclohexane, respectively).94 We therefore set out to optimize the
reaction between VAT 2 and Grignard nucleophiles (Table 2).
Aryl Grignard reagents (e.g., entry 1) were found to trigger fragmentation under
our original conditions;61 however, alkyl Grignards were not competent partners (entry
2). A quick screening of the reaction medium (entries 2-4) revealed that toluene was the
preferred solvent in our addition / fragmentation method using alkyl Grignards. The
reaction of 2 in toluene with an ethereal solution of n-butylmagnesium chloride afforded
the desired alkynyl ketone 3j (entry 4). Benzylmagnesium bromide provided 3k in 73%
IR (neat) 3020, 1715, 1465, 1420, 1380 cm-1; HRMS (CI) Calcd for C21H39O ([M+H]+)
309.3157. Found 309.3185.
25
1H NMR and 13C NMR spectra:
O
Bu
Me
3j
26
O
Bu
Me
3j
27
O Me
Ph
3l
28
O Me
Ph
3l
29
O
C10H21
Me
3m
30
O
C10H21
Me
3m
31
O
OTf
15
32
O
OTf
15
33
O
C10H21
C5H11
16
34
O
C10H21
C5H11
16
35
C10H21
O
C5H21Z6
36
C10H21
O
C5H21Z6
37
CHAPTER 3
A FRAGMENTATION / BENZANNULATION STRATEGY TO PROVIDE ACCESS TO BENZO-FUSED INDANES
Introduction
This chapter provides a detailed study into gold and copper catalyzed
benzannulation reactions of o-alkynyl aryl ketones bearing tethered acetylenes. The
primary motivation for the aforementioned study is derived from a desire to apply the
fragmentation reactions developed in the Dudley laboratory to an efficient synthesis of
the alcyopterosins, a rare subclass of natural products. However, before tackling the
synthesis of the alcyopterosins, a new methodology was required.
A detailed background of the alcyopterosins, including previous synthetic
strategies and biological importance, will provide the necessary context for the
development of a new convergent synthetic strategy towards these natural products.
Furthermore, a critical evaluation of benzannulation reactions similar to those
envisioned necessary in our focused retrosynthesis will set the stage for the original
work presented here.
The goal of this work is to determine the optimal conditions governing
intramolecular benzannulation reactions, while at the same time providing a method to
prepare benzo-fused indanes. Our research has been designed to bridge the gap that
exists between known benzannulation reactions and those which are required for our
proposed synthesis. The results of this study will play a vital role in future synthesis of
these natural products, new analogs, and other substituted indanes.
The Alcyopterosins
The illudalane sesquiterpenes,97 which include the alcyopterosins, represent a
class of rarely encountered natural products. These secondary metabolites consist of
38
bicyclo[4.3.0]nonane carboskeleton as seen in Figure 16. In most cases the 6-
membered ring is aromatic.
Cl
Alcyopterosin AIlludalane Skeleton
Figure 16: Illudalane Skeleton and Alcyopterosin A.
The biosynthesis of the illudalanes (Figure 17) originates from farnesyl
pyrophosphate (17) via a humulene intermediate 18.98 The humulene intermediate is
theorized to undergo cyclization to provide a protoilludane 19; a subsequent
rearrangement could give rise to an illudane (20). From illudane intermediate 20, a bond
cleavage reaction and aromatization would afford a molecule with the illudalane
carboskeleton.
O P
O
O
O P
O
O
O
OPP17
18
H
19 20
aromatization
Aromatic IlludalaneSkeleton
bond cleavageand
Protoilludane Illudane
Figure 17: Proposed Biosynthetic Pathway to the Illudalanes.
The chemistry of protoilludanes and illudanes has been studied by several
researchers.99-105 Some members of these natural products have been found to be
unstable under acidic or basic conditions, leading to the formation of aromatic illudalane
39
sesquiterpenes. Sterner and co-workers reported that the protoilludane stearodelicone
(21) decomposes to illudalane 22 upon absorption onto silica gel (Figure 18, equation
1). The decomposition is presumably due to traces of acid in the silica gel resulting in
the protonation of the enone, cleavage of the cyclobutyl moiety, and aromatization of
the cyclohexyldienone.100
The degradation of ptaquiloside 23 (Figure 18, equation 2), the major illudane
toxin isolated from the bracken fern, was examined by Saito and co-workers.101 The
glycosidic bond of ptaquiloside is easily cleaved in the presence of acid or base. Upon
cleavage of the glycosidic bond, the resulting alcohol is eliminated to produce bracken
dienone (24). If acid is present the tertiary alcohol of 24 ionizes and the cyclopropyl ring
undergoes heterolytic cleavage, resulting in the aromatization of the cyclohexadienyl
moiety; the cation is thus trapped by water to produce 25. The fact that ptaquiloside and
stearodelicone decompose to form illudalane-type products seems to support the
likelihood of their biosynthesis from the protoilludanes and illudanes.
40
O
OR
R = stearoyl
21
silicagel
O
OR
O
OR
H
OH2
(1)
O
O
HOH
OHO
OH
OH
OH
22
H+/H2O
D-glucoseO
HO
D-glucose
-OH/H2O
(pH 8-11)
OOH23
24
25
(2)
H+/H2O
Figure 18: (eq. 1) Proposed Decomposition of Stearodelicone (21) Upon Absorption on Silica Gel, and (eq. 2) the Observed Reactions of Ptaquiloside (23) in the
Presence of Acid and/or Base.
The illudalanes are typically isolated from both fungi of the Basidomycotina
subdivision105 and ferns of the Pteridaceae family.107 As rare as the illudalanes isolated
from terrestrial sources are, the alcyopterosins are even more rare. This subclass of
natural products represents the first illudalanes isolated from marine sources. The
alcyopterosins were first isolated from a deep water soft coral species, Alcyonium
paessleri, in sub-Antarctic waters by Palmero and co-workers in 2000.108 In 2009,
Gavagnin and co-workers isolated several new members of the alcyopterosins from a
different soft coral species, Alcyonium grandis.109
The alcyopterosins (Figure 19) have an aromatized six-membered ring, and
almost all members have either a chlorine atom or a nitrate ester present on the
ethylene side chain. Prior to the discovery of the alcyopterosins, there had never been a
41
natural nitrate ester secondary metabolite isolated from a marine source, despite the
fact that nitrates are common solutes in seawater.108 Sulfates and phosphates, which
are other common marine nutrients, are frequently observed in natural products isolated
from marine organisms. The fact that the alcyopterosins have been isolated as nitrate
esters makes them even more remarkable.
Cl O2NO
O2NO
O2NO
OH
O
O2NO
O
O
Cl
HO
OH O2NO
HOOH
Cl
Cl
O
O
O
AcO
AcO
O
25 26 28
HO
O
29
27
30
OH
Figure 19: Representative Sample of Illudalane Structures Isolated from A. paessleri and A. grandis.
Several members of the illudalane sesquiterpenes possess some interesting
biological activities; antimicrobial,99,110 cytotoxic,103,111 and antispasmodic activities112
being among them. Extracts containing members of the alcyopterosins have also been
found to possess feeding-deterrent activity against a generalist Antarctic sea-star
predator (Odontaster validus), implicating their chemical evolution as a defensive
mechanism (further discussed in Chapter 4).109 Alcyopterosins A (25), C (26), and H
(27), are cytotoxic towards the HT-29 (human colon carcinoma) cell line at 10 g/mL in
42
a preliminary in vitro test; and alcyopterosin E (28) has mild cytotoxicity (IC50 = 13.5 M)
towards the Hep-2 (human larynx carcinoma) cell line.108 In addition, several synthetic
analogs of the alcyopterosins show interesting DNA-binding properties (vide infra).113
The fact that the alcyopterosins are rarely observed as secondary metabolites,
their unusual structure, and their potential biological applications, provides motivation to
select them as synthetic targets. Since the initial report of their isolation and structural
elucidation,108 there have been several synthetic efforts directed towards members of
this sub-class of the illudalane sesquiterpenoids and several analogs.113-117
Most synthetic approaches to the alcyopterosin natural products include a
convergent transition metal promoted cycloaddition reaction.114-117 Unsymmetrical
polysubstituted aromatic rings are often difficult to prepare via sequential electrophilic
aromatic substitution reactions. Such reactions often result in regioisomeric products
that have to be separated. Therefore, several convergent aromatic annulations methods
have been developed to solve this challenging problem. The next section will address
the cyclotrimerization of alkynes and other aromatic annulation methods for assembly of
the core arenes of the illudalane sesquiterpenes.
The cyclotrimerization of acetylenes was first developed by Reppe in 1948.118
This method would be of particular value if selectivity could be obtained when
performed on substituted acetylenes; for instance, when this method is applied for the
synthesis of substituted aromatic compounds from three unsymmetrical acetylenes, 38
homo- and cross-coupled products are possible (Figure 20).
U
V X
W Y
Z
+ +
V
U
V
U
V
U
V
U
V
Z
Y
U
X
X
W W
X
W
Y
Z Z
Y
Z
Y
W
V
U
X
W
X X
W W
Y
Z
X
V
U
W
X
V
U
Plus 31 Other Isomers!
Metal
Catalyst
Figure 20: Traditional Reppe Reaction Involving Three Different Unsymmetrical Acetylenes.
43
Most of the recent solutions to the aforementioned issues associated with the
cyclotrimerization of acetylenes rely on a limited number of strategies (Figure 21): (a)
homo-coupling of acetylenes;119-125 (b) cross-coupling involving at least one symmetrical
acetylene;126-129 or (c) cross-coupling of tethered alkynes.130-135
X
YMetal Catalyst
X
Y
X
Y
X
Y
(a)
(b)
Y
X
X
Y
Z
Y
X
X
X
X
X
Y
Z
X
X
XMetal Catalyst
n
Y
Z
W
X
(c)
W
Y
Z
X
n
Figure 21: Typical Solutions for Chemo- and Regioselective Cyclotrimerization of Alkynes.
In 2001, Fumie Sato published a preliminary investigation into a metalative
Reppe reaction that allowed the use of three different unsymmetrical alkynes, one of
which being ethynyl-p-tolylsulfone, to provide a functionalized metalated arene as a
single isomer (Figure 22, equation 1).136 In the following year, Sato and co-workers
expanded their metalative Reppe process to the synthesis of arenes metalated at the
benzylic position. This extension was made possible by the replacement of the
ethynylsulfone with propargyl bromide (Figure 22, equation 2).114 In either case, the
metalated species could be trapped with a variety of electrophiles (e.g., H+, D+, I2),
leading to the synthesis of some potentially valuable compounds.
44
+
CO2t-Bu
C6H13 C6H13
Ti(O-i-Pr)4 /
2 i-PrMgClTi(O-i-Pr)2
CO2Bu-t
C6H13
H
C6H13 SO2Tol
-50 oC -50 oC to r.t.
CO2Bu-t
TiX3
C6H13
C6H13
(1)
+
CO2t-Bu
SiMe3
C6H13
Ti(O-i-Pr)4 /
2 i-PrMgClTi(O-i-Pr)2
SiMe3
C6H13
H
t-BuO2C CH2Br
-50 oC -50 oC to r.t.
MeSi3
C6H13
t-BuO2C
TiX3
(2)
X = (O-i-Pr)2Br
X = (O-i-Pr)2(O2STol)
Figure 22: Representative Examples of Sato’s One-Pot Metalative Reppe Reactions.
The metalative Reppe reaction developed by Sato was also demonstrated to
transform tethered alkynes, along with an external acetylene, to provide access to
bicyclic arenes. The Sato laboratory utilized its new method to accomplish the first
synthesis of alcyopterosin A (25) (Figure 23). The synthesis began with the reaction
between acetylenic ester 31 and tethered diyne 32, to provide the substituted indane 33
in 73% yield after hydrolysis. Diyne 32 was synthesized in 6 steps from isophorone,
featuring an Eschenmoser-Tanabe fragmentation (discussed in Chapter 1). The ethyl
ester of 33 was manipulated through a reduction, oxidation, and olefination sequence to
provide the ethylene side chain of 34. The olefin was then subjected to hydroboration-
oxidation, followed by conversion of the resulting alcohol to a chloride using standard
reaction conditions. The reaction sequence provided alcyopterosin A in 6 steps and
26% yield from diyne 32.
45
CO2Et
Me
+
Br
O
1. H2O2, NaOH
2. TsNHNH2, AcOH
O
4-steps
Isophorone
Ti(O-i-Pr)4 /i-PrMgCl;
then H+
73%
CO2Et
1. LiAlH4, 91%
2. PCC, 96%3. Ph3P=CH2, 86%
1. BH3 THF;H2O2, NaOH, 67% Cl
2. SOCl2, Pyridine
70%25
31 32 33
34
Figure 23: Sato’s Synthesis of Alcyopterosin A.
Since Sato’s synthesis of alcyopterosin A, two other members of this subclass of
natural products, alcyopterosins E and I (28 and 30, respectively) were synthesized
using a transition metal-catalyzed [2+2+2] cycloaddition strategy.115,117 Witulski and co-
workers completed the synthesis of alcyopterosin E115 (28) and confirmed the absolute
configuration originally assigned by Palmero et al.108 From tethered triyne 35, they
installed the tricyclic core (36) of alcyopterosin E in one synthetic operation using
Wilkinson’s rhodium(I) catalyst (Figure 24, equation 1). Much like Sato’s synthesis,
Witulski’s synthesis relied on the Eschenmoser-Tanabe fragmentation of isophorone to
provide access to the gem-dimethyl moiety.
Snyder and Jones provided the first synthesis of alcyopterosin I (30) in 2009 to
highlighting their newly discovered intramolecular rhodium-catalyzed [2+2+2]
cycloaddition reactions of diynes and enones.117 Cyclization precursor 37 was prepared
through a sequential double bromide displacement of 1,4-dibromo-2-butyne, first with
the enolate of ethyl isobutyrate, then with 3-pentynol. Conversion of the ethyl ester to
the terminal enone of 37 was carried out through common organic transformations. The
46
cycloaddition reaction was carried out using Wilkinson’s catalyst, and a DDQ work-up
produced the tricyclic core of alcyopterosin I in 71% yield (Figure 24, equation 2).
H
O
H3C
O
Isophorone
10 mol % RhCl(PPh3)3,
H
OTs
O
H
OTs O
CH2Cl2, 40 oC
72%
(1)
(2)
O
EtO
Ethyl Isobutyrate
O1. RhCl(PPh3)3,
PhCl, mW, 150 oC
2. DDQ, r.t.71% 2 steps
O
O
O
35 36
37 38
Figure 24: Key Steps in the Syntheses of Alcyopterosin E (28) (eq. 1), and Alcyopterosin I (30) by Witulski and Snyder (eq. 2).
In contrast to the more academically attractive methods used to prepare the
members of the alcyopterosins described above, Iglesias and co-workers presented a
more conventional approach to alcyopterosin A and several unnatural analogs.113 In the
course of Iglesias’ synthetic pathway, several compounds possessing the illudalane
skeleton were obtained, allowing for structure-activity relationship (SAR) studies to be
conducted. The Iglesias synthesis began with the construction of key intermediate 40
(Figure 25). Friedel-Crafts acylation of 4-bromo-m-xylene (38)—itself prepared through
a bromination of m-xylene and purification—provided -chloroketone 39. Intermediate
indanone 40 was obtained upon a subsequent acid promoted Nazarov reaction.
47
Br Br
O
Br
O
38
Cl
39 40
O
Cl Cl
AlCl3, CS299%
conc. H2SO4
67%
Figure 25: Synthesis of Iglesias’ Key Intermediate.
Iglesias and co-workers employed intermediate 40 to synthesize a variety of
analogs of the alcyopterosins (Figure 26). A reduction of the benzylic ketone of 40
provided bromoindane 41; another Friedel-Crafts acylation installed the necessary
carbons for the ethylene side chain of the illudalane skeleton. With the -chloroketone
42 in hand, the synthesis of various side chain functionalities (compounds 43-47) was
made possible through the use of several reduction methods. Compounds 45, 46, and
47 demonstrate an interesting divergence in reactivity; the reaction of -chloroketone 42
with excess sodium borohydride in refluxing ethanol provided three different analogs
simply by increasing the reaction time. Compound 47, most similar to alcyopterosin A,
was treated with lithium aluminum hydride to afford compound 48.
48
40
NaCNBH3, ZnI2, DCE
78%
Br Br
O
ClCl
OCl
AlCl3, CS279%
41 42
"conditions"
Br
R
Conditions:
(a) NaCNBH3, ZnI2, DCE, reflux (b) CuCl, NaBH4, EtOH, reflux (c) NaBH4, EtOH reflux, 15 min (d) NaBH4, EtOH, reflux, 4 h (e) NaBH4, EtOH, reflux, 16 h
43: R = CH2Cl2I 28%
44: R = 24%
45: R = 43%
46: R = 42%
47: R = CH2CH2OH 41%
O
CCH3
CHCH2Cl
OH
HC CH2
O
47LiAlH4
67%
HO
48
Figure 26: Synthesis of Unnatural Alcyopterosin Analogs Performed by Iglesias et al.
Having synthesized several analogs lacking the gem-dimethyl substituents on the
indane skeleton, Iglesias and co-workers turned their attention to the synthesis of
alcyopterosin A (Figure 27). Double methylation of intermediate 40, followed by
reduction of the ketone, generated compound 49. Friedel-Crafts acylation using
chloroacetyl chloride and subsequent reduction provided analog 50. Alcyopterosin A
(25) was obtained through the reduction of the arylbromide (providing 51) and
conversion of the side-chain alcohol to the necessary chloride.
49
40
Br
1. MeI, NaH,Toluene, 66%
2. NaCNBH3,ZnI2, DCE
88%
Cl
OCl
1. AlCl3, CS2
Br
HO
O
Br
49 50
69%
LiAlH4HO
, 79%
2. NaBH4, EtOH, reflux, 16 h
42%
SOCl2, pyridine
51
Cl
25
78%
Figure 27: Completion of Iglesias’ Synthesis of Alcyopterosin A.
The Iglesias laboratory, with numerous alcyopterosin analogs in hand, turned
their attention to performing DNA binding experiments. The ability of the alcyopterosin
analogs to bind to DNA was evaluated by measuring their hypochromic (decreased
absorbance at 260 nm) and bathochromic (red-shift) effects on the UV absorbance
spectrum of DNA.137 They validated their experiment through comparison of their test
assays and known intercalating agents (m-AMSA, mitoxantrone, and bis-benzamide;
Figure 28).
50
OH
OH
O
O
HN
HN
HN
OH
NH
OH
Mitoxantrone
N
HN
MeOHN
SO2Me
m-AMSA
N
N
NH
NNH
N
OH
H Cl3
bis-benzamide, Hoechst No. 33258
Figure 28: Compounds Known to Intercalate DNA.
The degree of interaction was expressed as a ratio between the final absorbance
area after stirring the compound for 24 h with DNA (a24) and the initial absorbance area
at max (a0). Values of 1 or higher indicate lack of affinity and values of 0 indicate
complete binding. The results of the DNA binding affinity assay demonstrate that
alcyopterosin A and various alcyopterosin analogs are potent DNA ligands (Table 3).
The gem-dimethyl substitution modifies, only slightly, the DNA binding affinity of the
compounds tested (47 vs. 50, and 48 vs. 51); whereas the ethylene side chain was of
the utmost importance for DNA ligation (compounds 41 and 49 had very poor affinity for
DNA). Perhaps most interesting was the fact that the presence of the bromine increased
the degree of binding of the analogs containing the hydroxy-functionalized ethylene side
chain (compounds 47, 48, 50, and 51).
51
Table 3: DNA Binding Assay Performed By Iglesias et al.113
Compound a24/a0 Compound a24/a0
41 0.90 49 0.87
42 0.12 50 0.40
43 0.16 51 0.71
44 0.26 25 0.38
45 0.69 Mxa 0.00
46 0.47 m-Ab 0.54
47 0.59 B-bc 0.57
48 0.89
a mitoxantrone; b m-AMSA; c bis-benzamide.
Br
OCl
42
Cl
25
HO
Br
HO
Br
47 50
A preliminary test was then carried out by The National Cancer Institute (NCI).
Compounds 44, 47, and 50 were evaluated in a three cell-line one dose pre-screen to
determine if they possess any ability to inhibit the growth of tumor cells in vitro. The cell
lines were MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS). Compounds found to
reduce the growth of any of the three cell lines to 32% or less, when compared to
untreated cells, were considered a positive in vitro lead. Compound 44 was found not to
inhibit growth to any significant extent. Compound 50 was found to produce a 0%
relative growth rate on all three cell lines, and compound 47 had the same effect on two
of the cell lines (breast and lung).
Analogs 47 and 50, having passed the first criterion for activity, were then
subjected to further testing against a 60-cell line panel at varying concentrations (10-4 to
52
10-8 M). The cell lines consisted of subpanels representing melanoma, leukemia, and
cancers of the breast, prostate, lung, colon, ovary, kidney, and brain. Dose-dependent
responses were found for three different activity parameters: the molar concentration
required to cause 50% growth inhibition (GI50), the concentration required to completely
inhibit growth (TGI), and the concentration that leads to 50% cell death (LC50). The
meangraph midpoints (MG-MID) correspond to the average sensitivity exhibited by the
entire panel of cell lines to a specific compound. The comparison of the MG-MID and
the activity against specific cell lines is often used to determine a compound’s selective
activity.
Compounds 47 and 50 demonstrated promising activities in the in vitro antitumor
screening (Table 4). The concentrations that promoted cytostatic (MG-MID GI50) and
cytotoxic (MG-MID LC50) effects for compounds 47 and 50 were found to have a marked
difference (ca. 5-fold). The ability to selectively control cancer cell growth or induce cell
death is an interesting trait observed for these natural product analogs.
Table 4: Average values (MG-MID) for in vitro antitumor activity on the NCI 60-Cell Line
Panel
Compound MG-MIDa
Log10GI50b (GI50) Log10TGIc (TGI) Log10LC50
d (LC50)
47 -4.77 (17 M) -4.40 (40 M) -4.12 (76 M)
50 -4.71 (19 M) -4.41 (39 M) -4.14 (72 M) a MG-MID = meangraph midpoint, average across all cell lines tested.
b GI50 = concentration required to
inhibit cell growth by 50%. c TGI = concentration required to completely inhibit cell growth.
d LC50 =
concentration required to kill 50% of tumor cells.
HO
Br
HO
Br
47 50
53
Nearly all members of the 60-cell line panel were found to be responsive to compound
50, whereas compound 47 was found to be more selective towards leukemia and
cancers of lung, colon, and breast (GI50 < 15 M). The antitumor activity of compounds
47 and 50 observed by Iglesias support the findings that the gem-dimethyl substituents
have little effect on DNA binding affinity as discussed above. The lack of the gem-
dimethyl, on the contrary, produced an increase in the selectivity of compound 47’s
ability to inhibit tumor growth.
The studies performed by Iglesias and co-workers identified some new
interesting anticancer leads as well as a straightforward approach to the alcyopterosins.
Their research, and the studies conducted by the other researchers referenced above,
have provided insight into the synthesis of compounds from this interesting subclass of
natural products. As part of our lab’s research goals, ―to devise, develop, and apply new
ideas in organic chemistry to the efficient synthesis of interesting molecules,‖138 we
identified the alcyopterosin natural products as potential targets that could benefit from
our fragmentation methodology. The remainder of this chapter will demonstrate the
synthetic approach we devised to access these natural products and to provide the
foundation for future synthetic efforts.
Retrosynthetic Analysis of Alcyopterosin A
In an effort to apply the carbanion-triggered fragmentation reaction of vinylogous
acyl triflates (VATs) (discussed in the previous chapters) to the synthesis of additional
natural products, we identified the alcyopterosins, specifically, alcyopterosin A, as
potential targets. Our retrosynthetic analysis (Figure 29) began with bicyclic arene 52,
which we envisioned gaining access to via an unprecedented benzannulation reaction
of acyclic enediyne intermediate 53. Based on our previous work, we believed that a
reaction between the metalated vinyl pre-nucleophile 54 and VAT 55 (derived from
dimedone) would provide our key acyclic intermediate (53).
54
Cl
Alcyopterosin A
functional group
manipulation
Z
Z = COR, H
52
benzannulation
R
O
fragmentationX
R
+
OTf
O
53(25)
54 55
Figure 29: Retrosynthetic Analysis to Alcyopterosin A Using a Fragmentation /
Benzannulation Approach.
Our strategy to synthesize alcyopterosin A hinges upon two key synthetic
transformations: (a) the fragmentation of vinylogous acyl triflate 55, and (b) the
benzannulation of enediyne 53. The basis of the desired benzannulation reaction stems
from the work of Yoshinori Yamamoto, Naoki Asao, and other members of the
Yamamoto laboratory.139-142 The fragmentation reactions of vinylogous acyl triflates has
been addressed in previous chapters. The following section will provide the relevant
background of the Yamamoto / Asao methodology for benzannulation and significant
questions that must first be addressed in order for the successful implementation of our
strategy.
In 2002, Yamamoto and co-workers published a preliminary communication
regarding a regioselective AuCl3-catalyzed formal [4+2] cycloaddition reaction between
o-alkynylbenzaldehydes (56) and alkynes (57) to produce naphthyl ketones (58 and 59)
(Figure 30, equation 1).139 A more thorough full paper ensued the following year.140 The
detailed study chronicled this benzannulation and also provided insight into a similar
[4+2] benzannulation of o-alkynylbenzaldehydes (or enals) (60) and alkynes (57) using
a copper catalyst. The copper catalyst system, in contrast to gold, produced
debenzoylated arenes (61 and 62) (Figure 30, equation 2). Naphthalenes were
55
generated in most cases, but a few examples of simple benzene derivatives, derived
from enals (as would be required for the synthesis of the alcyopterosins), were included.
Similar benzannulation reactions have also been explored through the use of
electrophilic iodine sources as stoichiometric reagents, however they fall outside the
scope of this discussion.143,144
H
O
R1
+
R3
R2
3 mol % AuCl3
DCE, 80 oCR2
R3
O R1
+ R3
R2
O R1
H
O
Ph
+
R3
R2
5 mol % Cu(OTf)2
1 equiv CF2HCO2H
DCE, 80 to 100 oC
R2
R3
+ R3
R2
H H
58
R2 = EDG
major
59
R2 = EWG
major
56 57
61
R2 = EDG
major
62
R2 = EWG
major
60 57
(1)
(2)
Figure 30: AuCl3- and Cu(OTf)2-Catalyzed [4+2] Benzannulation Reactions Described By Asao and Yamamoto.
The proposed mechanisms of these benzannulation reactions are presented in
Figure 31. Upon treatment with the Lewis acid, the soft -system of the alkyne 56
undergoes coordination to the Lewis acid (MLn: AuCl3 or Cu(OTf)2), enhancing the
electrophilicity of the alkyne. Subsequent nucleophilic 6-endo-dig cyclization of the
carbonyl oxygen onto the electron-deficient alkyne (as seen in 65) would form ate-
complex 66. The [4+2] cycloaddition of 66 with alkyne 57 would form intermediate 68 via
67. In the case of AuCl3-catalysis, subsequent bond rearrangement (as shown in 69)
would afford ketones 58 and 59 and regenerate the AuCl3. However, in the case of the
Cu(OTf)2 / CF2HCO2H system, protonolysis of the copper-carbon bond of 68, followed
by the attack of the conjugate base on the oxocarbenium ion, would produce
56
intermediate 70. A retro-Diels-Alder reaction would then release a mixed anhydride and
lead to the formation of products 61 and 62.
O
H
R1
O
H
R1LnM
O
H
MLn
MLn
RYRX
O
MLn
RX
RY
OR1
LnM
RX
RY
OR1
LnM
RX
RY
O R1
RY
RX
H
O
H
R1 A
A = CF2HCO2H
RX
RY
RX
RY
H
R1
O
A
_56
65
R1
6667
68
57
69
70
58, 59
61, 62
Figure 31: Proposed Mechanism of [4+2] Cycloaddition Reactions of 56 and 57 Catalyzed by AuCl3 and Cu(OTf)2 / CF2HCO2H.
Having successfully carried out intermolecular [4+2] benzannulation reactions,
Yamamoto and co-workers turned their attention towards the synthesis of polycyclic
naphthalene derivatives through the use of tethered alkyne dienophiles.142 The ―top-
down approach‖ (Figure 32, equation 1), in which the tethered alkyne is linked through
the carbonyl group, was found to convert compound 71 into naphthyl ketone 72 in high
yields. Interestingly, the reaction was found to occur even in the absence of a Lewis
acid at high temperatures, albeit in low yield (34% at 80 oC for 10 days). A related ―top-
down‖ benzannulation (without the prepositioned benzene ring) is envisioned for our
synthesis of alcyopterosin A. These examples, although limited, are therefore highly
57
relevant to our studies. The ―bottom-up approach‖ (Figure 32, equation 2), in which the
tethered alkyne is linked through the aryl-alkyne group (73), provided corresponding
polycyclic ketone 74 in yields ranging from 66 to 91%.
O R
Ph
n
n = 3 and 4R = Ph, Bu, H, TMS
O R
n-3 "Top-Down"40 to 92%
71 72
R
O
H
3O
R
R = Ph, p-Tolyl, p-CF3C6H4, n-Bu, H, TIPS, (CH2)2OTIPS, I
"Bottom-Up"66 to 91%
(2)
(1)AuX3
AuX3
73 74
Figure 32: Intramolecular Lewis Acid-Catalyzed [4+2] Benzannulation Reactions
Studied by Asao and Yamamoto.
Yamamoto and co-workers applied the ―bottom-up‖ approach to the synthesis of (+)-
ochromycinone and (+)-rubiginone B2 (Figure 33), demonstrating the power of these
reactions in synthesis.145
CHO
OMe
OMeOMe
cat. AuX3
O
OMe
MeO
OMe
O
OR
O
O
R = OMe: (+)-rubiginone B2
R = OH: (+)-ochromycinone
Figure 33: Yamamoto’s Key Benzannulation in the Synthesis of (+)-Rubiginone B2 and (+)-Ochromycinone.
58
In their studies, Asao and Yamamoto provided few examples of intermolecular
benzannulation reactions between alkynyl-enal substrates and alkynes (i.e. lacking the
prepositioned benzene backbone).139-142 Of these reactions, only the Cu(OTf)2 /
CF2HCO2H catalytic system were reported (Figure 34). Moreover, there were no reports
of the intramolecular benzannulation reaction taking place when Cu(OTf)2 was used as
the Lewis acid. The lack of such results prompts the questions: (1) Is AuCl3 capable of
effectively inducing the benzannulation of dialkynyl-enones similar to 53, and (2) is the
Cu(OTf)2 / CF2HCO2H a competent catalyst system in inducing the intramolecular
benzannulation reaction?
R1
R2
O
H
R3
R5
R6
Cu / H+ R1
R2
R5
R6
Few Examples(Only Intermolecular)
O
R
Ph
Au
R
PhO
Few Examples(Only Benzo-Fused,
Only Phenyl Ketones)
Yamamotoand Asao
O
R
?
Z
Z = COR, H52
Needed for Synthesis ofAlcyopterosin A
53
Figure 34: Contrast Between Known Benzannulations and Desired Benzannulation.
Using our fragmentation chemistry in conjunction with a new focused
methodology, we could make considerable contributions to the Lewis acid-catalyzed
intramolecular benzannulation reaction. We envisioned the ―top-down‖ approach, as
outlined by Yamamoto and co-workers, as being well suited for the synthesis of
59
alcyopterosin A. Ultimately we would require entry into an indane system, as opposed to
the benzo-fused indanes, potentially available via the Yamamoto / Asao methodology.
The following section describes this new methodology, highlighting the use of
fragmentation reactions to provide the needed monocyclic benzannulation precursors.
Exploring Gold and Copper Catalyzed Benzannulations
Prior to launching into the synthesis of alcyopterosin A, we sought to explore the
―top-down‖ intramolecular benzannulation in more detail. The substrates included in the
previous study by Asao and Yamamoto only varied the substituent at the terminus of the
tethered alkyne.142 An investigation into the effect of the substituents on the alkyne to
which the Lewis acid coordinates is envisioned to provide valuable knowledge of the
electronic requirements for benzannulation and catalyst selection, which may prove
useful in the synthesis of alcyopterosin A (Figure 35). We chose to perform our study on
benzo-fused systems for two reasons: (a) they would be most similar to those studied
by Yamamoto and Asao, and (b) the substrates would be easier to prepare due to their
inability to isomerize (e.g. E-, Z-isomerization). We believed that through the use of our
fragmentation methodology we could provide access to the benzo fused substrates in
short order.
60
O
R
Ph
R
O Ph
AuX3Asao and Yamamoto
J. Org. Chem. 2005, 70, 3682-3685.
O
Me
R
Me
O R
R = Ph, Bu, H, TMS
AuCl3 or Cu(OTf)2
R = p-MeOPh, Ph, t-Bu, n-Bu, TMS, p-CF3Ph
Required for newfocused methodology
Figure 35: Comparison of Known benzannulations and Those of a New Methodology.
This investigation would provide new knowledge into the steric and electronic
requirements of the intramolecular gold and copper catalyzed benzannulation reactions,
and allow access to new substituted benzo-fused indanes (polysubstituted
naphthalenes). The results would thereby further the current understanding of these
reactions as well as establish the ground work for future applications to alcyopterosin
synthesis.
We began our study by preparing the necessary substrates for the new
benzannulation study. Initially we considered two different starting materials for the
generation of o-alkynyl-haloarenes (77), which would serve as pre-nucleophiles for our
fragmentation reaction: (a) 1,2-dibromobenzene (75); and (b) 2-bromoiodobenzene (76)
(Figure 36). Upon further analysis, we identified some potential drawbacks in our initial
strategy. Attempting a Sonogashira reaction between 75 and 1-hexyne using standard
reaction conditions, we obtained an inseparable mixture of compounds 77 and 78 (ca.
35% yield, 1:1); similar results are not an uncommon occurance.146 Performing the
Sonogashira reaction on dihaloarene 76 would provide a selective reaction because of
61
the increased reactivity of the iodide, however the cost of 76 makes it less attractive for
use in a model study.
Br
Br
H R
Sonogashiracoupling
R
Br
R
R
possible side product78
Br
I
H R
Sonogashiracoupling
R
Br
75
76
77
(a)
(b)
Figure 36: Originally Considered Reactions to Access Fragmentation Pre-nucleophile 77.
In an effort to circumvent the problems associated with the strategy outlined
above, we identified 2-iodoaniline (79) as a potential alternative to the synthesis of
benzannulation test substrates. The advantages to the use of 79 as a starting material
would be three-fold: (a) 79 is intermediately priced (25 g/ $99.00) compared to 75 (25 g/
$74.10) and 76 (25 g/ $121.50);94 (b) the synthesis of iodotriazene 80147 would allow for
a directed metalation reaction of an aryl iodide, rather than an aryl bromide (cf. 77), to
provide nucleophile 81; and (c) triazene 82 could be converted into iodide 83 for the
selective synthesis of benzannulation substrates 84 through a Sonogashira reaction
(Figure 37). In effect, triazene 82 serves as a masked iodide that is also capable of
directing metalation chemistry.
Because of the fact that aryl iodides are more reactive than aryl bromides in both
Sonogashira reactions and halogen-metal exchange reactions, coupled to the fact that
our proposed halogen-metal exchange is envisioned to proceed through a directed
metalation, we believed this strategy would provide a general and efficient approach to
the synthesis of compounds similar to 84.
62
I
NH2
HCl, NaNO2;
then R2NH
I
N
NN
R
R
R LiLi
N3R2directed
metalation
+
OTf
O
O
N3R2
fragmentation "Conditions"O
ISonogashira
coupling
RH
R
O
79 80 81
82 83 84
2
Figure 37: Proposed Route to Benzannulation Substrates 84.
Our strategy proved very effective towards the synthesis of our model
benzannulation substrates. Conversion of 79 to diethyl iodotriazene 80147 was carried
out using standard conditions; first conversion of the arylamine to the diazonium salt,
and then an in situ trapping of the diazonium with diethylamine. Halogen-metal
exchange and subsequent fragmentation of vinylogous acyl triflate 2 provided triazene
82 in 82% over 2 steps (Figure 38).
I
NH2
HCl, NaNO2;
then Et2NH
97%
I
N
NN
Et
Et79 80
n-BuLi, Et2O
-78 oC;
then 2,
-78 oC to r.t.
85%
O
N3Et2
82
Figure 38: Synthesis and Fragmentation Reaction of Aryltriazene 80.
Aryltriazenes, similar to 80 and 82, are bench stable and chromatographable;
they have been used extensively in the synthesis of a large variety of phenylacetylene-
based systems.148 Typically these aryltriazenes are converted to the corresponding
iodoarene in high yields by heating in iodomethane at temperatures in excess of 100
63
oC.149 In the case of electron deficient aryltriazenes, decomposition of the triazene in
iodomethane requires higher temperatures. The toxicity of iodomethane and the high
temperatures and pressures required for the decomposition of aryltriazenes to
iodoarenes prompted us to search out other methods for this transformation. We found
reports in the literature that electron-deficient aryltriazenes undergo decomposition to
afford iodoarenes in high yields upon treatment with sodium iodide and sulfonic acid
cation exchange resins (H+ form) in dry acetonitrile at 75 oC; methanesulfonic acid and
trifluoroacetic acid also provided the product in acceptable yields.150
Armed with this knowledge, we completed the synthesis of our model
benzannulation substrates (Figure 39). Using slightly modified conditions, camphor-10-
sulfonic acid (CSA) in place of the sulfonic acid exchange resin, aryltriazene 82 was
converted to an aryl iodide 83. Sonogashira coupling reactions between various
terminal acetylenes and aryl iodide 83 provided benzannulation precursors 84a-e.
82
10 equiv CSA2 equiv NaI,
CH3CN, 75 oC
(ca. 75%) I
O
83
5 mol % PdCl2(PPh3)2,
10 mol % CuI, Et3N, 50 oC
H R
O
R
84a: R = Ph84b: R = n-Bu84c: R = t-Bu84d: R = p-MeO-C6H484e: R = TMS
68%85%52%60%80%
Figure 39: Synthesis of Benzannulation Substrates 84a-e.
The coupling reaction between 83 and an electron-deficient acetylene (R = p-
CF3-C6H4) did not proceed to any significant extent. In an effort to synthesize a
substrate with an acetylene having an electronic deficiency, the trimethylsilyl (TMS)
substituent of 84e was cleaved using a methanolic solution of potassium carbonate
affording 85; a Sonogashira reaction was performed between 85 and 4-
iodobenzotrifluoride to provide 84f in 85% yield (Figure 40).
64
O
TMS
K2CO3, MeOH
r.t., 92%O
H8584e
5 mol % PdCl2(PPh3)2,
10 mol % CuI, Et3N, 50 oC
CF3
I85%
O
84f CF3
Figure 40: Synthesis of Benzannulation Substrate 84f.
With a series of benzannulation substrates in hand similar to those prepared by
Yamamoto, ranging from electron-rich (R = p-MeO-C6H4, 84d) to electron-poor (R = p-
CF3-C6H4, 84f), we began to examine the benzannulation reaction using the AuCl3 and
Cu(OTf)2 / CF2HCO2H catalyst systems. The electron-neutral substrate included in our
study (R = Ph, 84a) most resembles those examined by Yamamoto and Asao.142
However, only the gold catalyzed reaction was reported from their related studies.
Table 5 summarizes the results obtained in the preliminary screening of
benzannulation reactions. Substrates 84a (as suggested by the results of Yamamoto
and Asao) and 84b provided promising reactivity when AuCl3-catalysis was employed.
However, they provided a mixture of the decarbonylated / reduced product 87 and
ketone products (86a and 86b, respectively) in the presence of the Cu(OTf)2 /
CF2HCO2H catalyst system (entries 1 and 2). Entries 4 and 5 demonstrate that the
electronically rich alkynes (84d) and silylacetylenes (84e) are not competent
benzannulation substrates in the presence of either catalytic system. Most interesting to
our future synthetic efforts was the divergence in reactivity between substrates 84c and
84f; both substrates provided ketone products 86c and 86f in the presence of AuCl3, but
when the Cu(OTf)2 / CF2HCO2H catalyst system was applied, the t-butylacetylene
containing substrate (84c) provided reduced product 87 as the sole product and the
electronically deficient acetylenic substrate (84f) provided only the ketone product (86f)
(entries 3 and 6, respectively). Thus, employing the Cu(OTf)2 / CF2HCO2H catalyst
system, one can switch between the two reaction pathways by changing the acetylene
substituent from t-butyl to p-CF3-C6H4. Likewise, in 84c (R = t-Bu) one can select
65
between the two products by simply changing the catalyst system from AuCl3 to
Cu(OTf)2 / CF2HCO2H.
Table 5: Preliminary Screening of Benzannulation Reactions of Substrates 84a-f.a
O
R
Catalyst
DCE, 80 oC
1 to 1.5 hO R
+
H
84 86 87
Entry R Substrate AuCl3 Catalystb Cu(OTf)2 / CF2HCO2H
Systemc
86 Yield, %b 86 Yield, %d 87 Yield, %d
1 Ph 84a 86a 75 86a 65 87 23
2 n-Bu 84b 86c 70 86c 10 87 71
3 t-Bu 84c 86c 50 86c 0 87 71
4 p-MeO-C6H4 84d 86d 0e 86d 0e 87 0e
5 Me3Si 84e 86e 0e 86e 0e 87 0e
6 p-CF3-C6H4 84f 86f 76 86f 80 87 0 a
Reactions performed on 10 mg scale for screening purposes. b 5 mol % AuCl3.
c 5 mol % Cu(OTf)2, 1.0
equiv. CF2HCO2H. dIsolated yields.
e No reaction was detected by TLC after 15 h, substrates were
recovered.
After performing our preliminary study into the ―top-down‖ benzannulation
reaction of Yamamoto on our series of test substrates, we chose to carry out the
benzannulation of substrates 84c and 84f on a larger scale under the copper(II)
catalysis conditions to confirm our preliminary results and provide more accurate yields.
Indeed our results were confirmed: compound 84c provided the reduced product (87) in
88% yield (Figure 41, equation 1); whereas compound 84f lead to naphthyl ketone 86f
in 89% yield (Figure 41, equation 2).
66
O
84c
5 mol % Cu(OTf)2,1.0 equiv. CF2HCO2H
DCE, 80 oC
88% H
87
O
84f
5 mol % Cu(OTf)2,1.0 equiv. CF2HCO2H
DCE, 80 oC
89%
CF3
O
CF3
(1)
(2)
86f
Figure 41: Direct Comparison of the Benzannulation Reactions of 84c and 84f.
In an effort to demonstrate the ability of vinylogous acyl triflate 55 to undergo the
desired fragmentation chemistry, as well as the ability of a substrate containing the
gem-dimethyl on the alkyne tether to participate in the benzannulation reaction, we set
out to synthesize a benzo-fused compound similar to 53 in our retrosynthetic analysis of
alcyopterosin A (Figure 29). Due to the fact that vinylogous acyl triflate 55 was
considered precious material,i we modified our synthetic approach (Figure 42). We
began with a Sonogashira reaction between 3,3-dimethylbutyne and 2-iodo-aryltriazene
80, which provided an inseparable mixture of the desired compound 88 and
unidentifiable byproducts. Conversion of the resulting o-alkynyl-aryltriazene into the
corresponding iodoarene 88 was performed using our previously described conditions
(see page 63). This reaction also provided an inseparable mixture that contained our
desired product as the major component by 1H NMR. Performing halogen metal-
exchange on the mixture containing iodoarene 88, followed by treatment with 1.0
equivalent of vinylogous acyl triflate 55 provided the desired product (89) in 61% yield
(90% based on recovered triflate).
i Synthesized in 2 steps: (1) methylation of dimedone;
151 and (2) subsequent triflation using standard
conditions from Kamijo and Dudley’s initial report.61
67
N3Et2
It-BuH
1. PdCl2(PPh3)2,
CuI, Et3N, 50 oC
2. CSA, NaI, CH3CN
(ca. 82% over 2 steps)
In-BuLi, Et2O, -78 oC;
then
OTf
O
5580 88
61% (>90% brsm)
O
89
Figure 42: Alternative Synthesis of Benzannulation Substrate 89.
Compound 89 underwent the desired intramolecular [4+2] benzannulation
reaction under either the gold or copper catalytic systems in 83 and 75%, respectively
(Figure 43). Much like our previous experiments, in the presence of the Cu(OTf)2 /
CF2HCO2H catalyst system compound 89 underwent benzannulation and
decarbonylation to provide the substituted naphthalene derivative 90 (equation 1). The
reaction of compound 89 in the presence of AuCl3 led to the formation of the naphthyl
ketone product (91) (equation 2). Interestingly, the 1H NMR spectrum of ketone 91
suggests it exists as a racemic mixture of atropisomers.ii The gem-dimethyl groups are
diastereotopic; each methyl group of the carbon bearing the gem-dimethyl can be
distinguished and one of the adjacent methylene units of the partially saturated ring
appears as an AB quartet (see page 113). We believe that the divergence in reactivity
of compound 89 upon treatment with either the gold or copper catalyzed benzannulation
conditions will prove useful, if it is observed when performed on acyclic intermediate 53,
as in the synthesis of alcyopterosin A.
ii However a slow rotation about the arene-ketone bond on the NMR time scale cannot be ruled out.
68
O
89
5 mol % Cu(OTf)2,1.0 equiv. CF2HCO2H
DCE, 80 oC
83% H
90
O
89
5 mol % AuCl3,
DCE, 80 oC
75%
91
O
+
O
(1)
(2)
Figure 43: Benzannulation Reactions of Compound 89.
The newfound knowledge in the gold and copper benzannulation chemistry
enables a new strategy for the synthesis of benzo-fused indanes. These benzannulation
reactions contribute to the observations made by Yamamoto and Asao. In addition, the
ability to obtain either the ketone or decarbonylated benzannulated products selectively,
either through choice of catalyst or by altering the substrate, was previously unreported.
This provides synthetic versatility in the synthesis of substituted indanes. For the Dudley
lab, it is this flexibility that may be the key toward the future synthesis of alcyopterosin
A. Our approach to benzo-fused indanes has incorporated the use of aryltriazenes for
the synthesis of useful intermediates and the fragmentation of vinylogous acyl triflates.
We have demonstrated the ability of vinylogous acyl triflates 2 and 55 to undergo
fragmentation reactions to provide synthetically useful compounds.
In regards to the synthesis of alcyopterosin A, a recently published study has
provided the necessary method for the synthesis of vinyl nucleophile 54. Negishi and
co-workers published the synthesis of various (Z)-2-alkynyl-vinyl iodides in a highly
stereoselective fashion (≥98% Z) (Figure 44).152 Bromoboration of propyne and trapping
69
of the resulting vinyldibromoborane with pinacol diminishes the stereoisomerization of
92 to provide cyclic boronate 93. Compound 93 is stable to air for several days at room
temperature without any change in the NMR spectrum. Negishi coupling of vinyl
bromide 93 and the appropriate terminal acetylene, followed by subsequent exchange
of the boronate for an iodide should provide access to 54 in high yield and selectivity.
Me
H 1.1 equiv BBr3,CH2Cl2
-78 oC to r.t., 2hMe
BBr2H
Br
1.2 equiv pinacol
-78 oC to r.t., 1h
Me Br
H BO
O
(85%, > 98% Z)
NegishiCoupling
H t-Bu Me
H BO
O2 equiv I2,
3 equiv NaOH
THF-H2O, r.t. Me
IH
54
92 93
Figure 44: Proposed Route to Vinyl Nucleophile 54 Using Negishi’s Z-Selective
Bromoboration.
The detailed benzannulation studies presented above provide a firm foundation
for future synthetic efforts. We have confirmed the ability of the Cu(OTf)2 / CF2HCO2H
catalyst system to promote intramolecular benzannulation reaction. When coupled with
the chemistry developed by Negishi, the results of this study pave the way for a
convergent approach to access the alcyopterosins and various analogs thereof. The
application of the fragmentation / benzannulation strategy to the synthesis of
alcyopterosin A and analogs thereof is currently underway in the Dudley laboratory.
70
Experimental
General Information:
1H NMR and 13C NMR spectra were recorded on a Varian 300 (300 MHz), Bruker 400
(400 MHz), or Bruker 600 (600 MHz) spectrometer, using CDCl3 as the deuterated
solvent. The chemical shifts () are reported in parts per million (ppm) relative to the
residual chloroform peak (7.26 ppm for 1H NMR and 77.00 for 13C NMR). Coupling
constants (J) are reported in Hertz (Hz). IR spectra were recorded on a Perkin-Elmer
FT-IR spectrometer with diamond ATR accessory as thin film. Mass Spectra were
recorded on a JEOL JMS600H spectrometer. Yields refer to isolated material judged to
be > 95% pure by 1H NMR spectroscopy following silica gel chromatography, F-254
(230-499 mesh particle size). All chemicals were used as received unless otherwise
noted. Acetonitrile (CH3CN) was distilled from calcium hydride (CaH2) and stored over
molecular sieves. Diethyl ether (Et2O) was dried through a solvent purification system
packed with alumina and molecular sieves under an Ar atmosphere. 1,2-Dichloroethane
(DCE) was used as received with no further purification. Triethylamine and diethylamine
were distilled from CaH2 and stored over KOH pellets. The n-butyllithium (n-BuLi)
solutions were titrated with a known amount of menthol, using 1,10-phenanthroline as
an indicator, in a solution of ether. All reactions were carried out under an inert argon
atmosphere unless otherwise stated.
Synthesis of 3-trifluoromethanesulfonyloxy-2,5,5-trimethyl-2-cyclohexenone (55):
Dimedone was methylated using iodomethane in a 5M aqueous KOH solution by
analogy to a published procedure, see reference 150; the resulting 2,5,5-trimethyl-1,3-
cyclohexanedione was converted to the corresponding triflate using triflic anhydride and
pyridine by analogy to our published procedure, see reference 61. Clear oil; 1H NMR
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BIOGRAPHICAL SKETCH
Birth Place
Melrose, Massachusetts
February 3rd, 1981
Educational Background
Florida State University, Tallahassee, FL
August 2004 to December 2009 Ph.D. in Organic Chemistry (anticipated completion in December 2009) Research Advisor: Professor Gregory B. Dudley
Barry University, Miami Shores, FL
August 1999 to December 2003 B.S. degree in Chemistry, B.S. degree in Biology – cum laude Research Advisor: Professor Paul I. Higgs
The Canterbury School, Ft. Myers, FL
August 1995 to June 1999
Future Position
University of Pennsylvania, Philadelphia, PA
Beginning January 2010 Postdoctoral Research Associate Under the supervision of Professor Amos B. Smith, III
Awards and Honors
Gamma Sigma Epsilon, National Chemistry Honors Society (2002). Polymer Chemist Societies Award for Outstanding Performance in Organic
Chemistry (2002). Outstanding Graduating Senior for Performance in Physical Sciences,
Mathematics, and Computer Sciences, School of Arts and Sciences, Barry University (2003.
Golden Key, Graduate Student Honor Society (2007-2009).
223
Publications
(2) Jones, D. M.; Dudley, G. B. Synthesis of the C1-C15 region of palmerolide A using a refined Claisen-type addition / bond cleavage methodology. Synlett, in press.
(1) Jones, D. M; Kamijo, S.; Dudley, G. B. Grignard triggered fragmentation of vinylogous acyl triflates: synthesis of (Z)-6-heneicosen-11-one, the Douglas-fir tussock moth. Synlett 2006, 936-938.
Presentations
(2) ―Organic Synthesis and Methodology: Towards the Illudalane Sesquiterpenoids.‖ Jones, D. M.; Dudley, G. B. Presented at the Florida Annual Meeting and Exposition (FAME), Orlando, FL, Summer 2007.
(1) ―Grignard triggered fragmentation of vinylogous acyl triflates: synthesis of (Z)-6-
heneicosen-11-one, the Douglas-fir tussock moth.‖ Jones, D. M.; Kamijo, S.; Dudley, G. B. Presented at the 231st ACS Annual Meeting, Atlanta, GA, March 28th, 2006.
Posters
(2) ―An Addition / Fragmentation Approach to Palmerolide A.‖ Jones, D. M.; Jeong-Im, J.; Dudley, G. B. Presented at the Gordon Research Conference on Natural Products, Tilton, NH, July 26th-31st, 2009.
(1) ―Progress Towards Palmerolide A.‖ Jeong, J.; Jones, D. M.; Dudley, G. B. Presented at
The 236th ACS National Meeting, Philadelphia, PA, August 17th-21st, 2008.