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Syracuse University Syracuse University
SURFACE SURFACE
Dissertations - ALL SURFACE
August 2016
CONVENIENT ETHERIFICATION USING CONVENIENT ETHERIFICATION USING
TRICHLOROACETIMIDATES AND SYNTHESIS OF AMINOSTEROID TRICHLOROACETIMIDATES AND SYNTHESIS OF AMINOSTEROID
SHIP INHIBITORS SHIP INHIBITORS
Kyle Timothy Howard Syracuse University
Follow this and additional works at: https://surface.syr.edu/etd
Part of the Physical Sciences and Mathematics Commons
Recommended Citation Recommended Citation Howard, Kyle Timothy, "CONVENIENT ETHERIFICATION USING TRICHLOROACETIMIDATES AND SYNTHESIS OF AMINOSTEROID SHIP INHIBITORS" (2016). Dissertations - ALL. 658. https://surface.syr.edu/etd/658
This Dissertation is brought to you for free and open access by the SURFACE at SURFACE. It has been accepted for inclusion in Dissertations - ALL by an authorized administrator of SURFACE. For more information, please contact [email protected].
Abstract
Alcohols are a common form of functionality in organic chemistry, and are often present
in biologically active molecules. The protection of hydroxy groups is crucial in long multi-step
synthetic routes, as the unprotected alcohol is typically not compatible with many reagents.
Alcohols are often protected as corresponding benzyl ether, which can then be removed when
desired to reveal the alcohol functional group. Classic methodology for protection of alcohols as
benzyl ethers requires harsh conditions utilizing strong acids and bases, which functions well for
simple substrates. In more complex multifunctional molecules this can lead to degradation and
side products. Therefore, there is a need for the development of milder conditions for the
protection of alcohols.
Recently a number of reagents have been developed to form benzyl ethers under mild,
neutral conditions that and do not disturb the sensitive functionality in complex molecules.
Many of these reagents have been based on imidate-type systems. The most common imidate
system, the trichloroacetimidate, is often utilized for the installation of ethers under Lewis acid
catalyzed conditions. Given their ready availability, a reevaluation of the reactivity of alcohols
and trichloroacetimidates has been undertaken. In many cases, simply heating the imidate with
an alcohol in refluxing toluene without an exogenous acid or base is an effective method for the
formation of the desired ether. This operationally simple procedure is most effective for
trichloroacetimidates that are precursors to highly stabilized cations (i.e. the 4-methoxybenzyl
and diphenylmethyl group). The use of this new procedure with a number of acid and base
sensitive substrates, which are protected in excellent yield without disturbing the delicate
functionality present in these molecules, is presented.
Cancer is a group of disorders that are all defined by abnormal cell growth in an
organism. This is a very broad set of diseases that can affect multiple organs. While classic
cancer treatments have focused on killing all cells that divide quickly, more modern treatments
attempt to selectively stop cancer progression by influencing cell signaling pathways. There are
many studies about how cancer cells coopt cell signaling pathways and use these systems, which
control cell growth in normal cells, to facilitate their own uncontrolled progression. One of the
major cell signaling pathways implicated in tumor development is the PI3K pathway, which is
governed by the kinase PI3K and the phosphatases PTEN and SHIP.
SHIP1 is an SH2-containing inositol 5’-phosphatase found in blood cells that is
responsible for the hydrolysis of phosphatidylinositol-3,4,5-trisphosphate to
phosphatidylinositol-4,5-bisphosphate. This enzyme is part of a major cellular signaling
pathway (the PI3K pathway) that controls many important cellular events such as proliferation,
differentiation and adhesion. SHIP1 inhibition has been found to increase blood cell production
and slow the growth of blood cancer cells. Certain aminosteroids show selectivity as SHIP1
inhibitors and therefore may have therapeutic applications. In this study, syntheses of a number
of aminosteroid derivatives were performed and these compounds are evaluated for their
potential as SHIP1 inhibitors.
CONVENIENT ETHERIFICATION USING TRICHLOROACETIMIDATES AND
SYNTHESIS OF AMINOSTEROID SHIP INHIBITORS
By
Kyle T. Howard
Bachelor of Science in Chemistry, York College of Pennsylvania, York, PA, 2010
Master of Philosophy in Chemistry, Syracuse University, Syracuse, NY, 2012
DISSERTATION
Submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Chemistry
Syracuse University
August 2016
Copyright © Kyle Howard 2016
All Rights Reserved
v
ACKNOWLEDGEMENTS
Pursuing my graduate degree at Syracuse University has been a challenging experience full of
learning, growth, and self-discovery. I consider myself very fortunate to have had this
experience. Along this journey I have met many people whom made me a better person.
Graduate school would have been extremely difficult without new friends and the support of
loved ones at home. To all these people, I owe immense gratitude.
First and foremost, I would like to thank my research advisor, Dr. John Chisholm. You are
truly a remarkable mentor. I admire your knowledge, patience, and ability to perform the many
jobs of an advisor. I am extremely grateful to have the opportunity to study under your
leadership. I know I would not have been successful at Syracuse University had it not been for
your guidance.
My laboratory mentors and coworkers, Dr. Dennis Viernes and Christopher Russo. I
appreciate all the laboratory training and guidance you gave me. Thank you for welcoming me
into the group and tolerating my endless questions.
My research coworkers, Arijit Adhikari, Daniel Wallach, Jigisha Shah, Brian Duffy,
Nivedita Mahajani, Otto Dungan, Bhaskar Joshi, and Alexandre Dixon. Thank you for
sharing in all the laboratory shenanigans, frustrations, successes, and celebrations.
Group members past and present, Matthew Linaburg, Patrick Stege, Brittni Kellum, Wilfried
Banko, Allen Prusinowski, Katie Armstrong, Lea Radal, and Tamie Suzuki. It has been a
pleasure getting to know you all.
Our research collaborator from SUNY Upstate Medical University, Dr. William Kerr and his
students Robert Brooks, Saundra Fernandes, Sonia Iyer, and Neetu Srivastava. Thank you
for the opportunity for this collaborative research.
Syracuse University professors, Dr. Nancy Totah, Dr. Yan-Yeung Luk, Dr. Daniel Clark, Dr.
Michael Sponsler, Dr. Kevin Sweder, Dr. James Hougland, Dr. James Kallmerten, Dr.
Weiwei Zheng. Thank you for your instruction and support during my time at SU.
My professors at York College of Pennsylvania. Dr. Kathleen Halligan, you have continued to
inspire me and support my career in chemistry. Thank you for investing so much time in me and
encouraging me to pursue a higher education. Dr. Gregory Foy, Dr. William Steel, Dr. James
Foresman, Dr. Keith Peterman, Professor William Glenwright, Professor Barbara Mowery
and Professor Tina Tao Maynes. I had such an amazing experience studying chemistry at YCP
and I owe it all to the great faculty of the chemistry department.
The staff of the Department of Chemistry, Cathy Voorhees, Jodi Randall, Joyce Lagoe, Linda
DeMauro, Deb Maley, Nancy Virgil, Anne Dovciak, Steve Rich, Sally Prasch, Michael
vi
Brandt, Deborah Kerwood, April LePage, and ElizaBeth Molloy. I appreciate all the help
you have extended to me.
To my amazing friends. Lauren Kaminsky, we started this journey together the first day of
orientation at YCP all the way to becoming doctors of chemistry at SU. Thank you doesn’t come
close to displaying my appreciation for you being an awesome person, roommate, and friend.
Susan Flynn, I am so thankful for meeting you my first year of grad school. Your humor and
kindness kept me going in the most stressful and difficult situations. Rabeka Alam and Jen
Elward, WE UNCLE BOBBY’S KIDS! Thank you for all the inside jokes, fun adventures, and
yummy dinner parties! Valerie Simons and Kathryn Roberts, thank you for being fantastic
roommates and allowing me to de-stress after a long day in the lab. Amanda Goulden, Keri
Diller, Cody Messinger, Matthew Artz, and Ashley Melber, thank you for visiting me in
Syracuse and being a constant support system when I visit home. You have truly been there for
me through the good times and the bad times. Erica Paige Monnin, you are one of the most
significant people in my life. I am so thankful for our friendship and you always having my
back. I hope we have many more days of coffee drinking, Taco Bell eating, and loving
friendship. Nick Goffard, Michael Riley, Kathy Calella, Brian Hopkins, Christopher
Griffith, Amit Taneja, Joey Simon, Tiffany Brec, Nicole Brec, Kerry Foxx, Justin McVey,
Alejandro Amezcua, Christina Rodgers, and Aerik Radley, thank you for accepting my
queerness and teaching me to be comfortable in my own skin. I value everything I have learned
from you and all the memories you created with me.
Lastly I have to thank my mother, father, and sister, Cheryl, Timothy, and Katelyn Howard.
Thank you for supporting my decision to attend graduate school. You all have been so
influential in my life and I cannot thank you enough for the constant support. The unconditional
love you displayed for me is amazing. I appreciate everything you have done for me from the
warm care packages in the cold Syracuse winter to the family trips to Niagara Falls and Mexico!
The sacrifices that you made were remarkable and I would not be here without you.
vii
TABLE OF CONTENTS
Abstract i
Title Page iii
Acknowledgements v
Table of Contents vii
List of Figures ix
List of Tables xi
Abbreviations and Acronyms xii
Dedication xvi
Chapter 1 FORMATION OF ETHERS UNDER MILD CONDITIONS
Abstract 1
Introduction 1
Formation of Ethers with Trichloroacetimidates 2
Protecting groups 2
Carbohydrates 3
Trifluoroacetimidates 3
Etherification using Triazinylammonium salts 4
Phosphinimidate Reagents 5
Etherification with Pyridinium Salts 5
References 7
Chapter 2 FORMATION OF PMB AND DPM ETHERS WITH
TRICHLOROACETIMIDATES UNDER THERMAL CONDITIONS
Abstract 9
Carboxylic acid esterification 9
Alkylation of thiols with trichloroacetimidates 14
Etherification of alcohols using trichloroacetimidates 16
Future Work 33
Experimental Procedures 34
Appendix A. 1H and 13C NMR Spectra Supplement to Chapter 2 63
References 140
Chapter 3 SYNTHETIC STUDIES TOWARD SHIP1 INHIBITORS
Abstract 146
PI3K Signaling Pathway 146
SHIP 149
Different isoforms 149
Structure of enzyme 150
X-ray structure of SHIP2 150
Rationale for SHIP Antagonist or Agonist 151
Cancer 151
Bone Marrow Transplantation 152
Stem Cell Mobilization and Transplantation 152
Blood Cell Production 153
viii
Obesity 153
Structure Activity Relationship/Design of Inhibitors 154
Tailless Steroid Derivatives 157
Results and Discussion 158
Conclusions 166
Experimental Procedures 167
Appendix B. 1H and 13C NMR Spectra Supplement to Chapter 3 184
References 195
CURRICULUM VITAE 199
ix
LIST OF FIGURES
Figure 1.1 Acid catalyzed DPM etherification with trichloroacetimidate 1.1 3
Figure 1.2 Glycosidic bond formation with trichloroacetimidate 3
Figure 1.3 Alkylation with trifluoroacetimidate 4
Figure 1.4 Ether Formation with Triazinylammonium salts 5
Figure 1.5 Alkylation with Phosphinimidates 5
Figure 1.6 Etherification with Pyridinium Salts 6
Figure 2.1 Proposed Mechanisms of PMB esterification 11
Figure 2.2 Esterification with DPM Imidate 14
Figure 2.3 Sulfide formation with imidates 15
Figure 2.4 Mechanistic Possibilities for thioether formation 16
with trichloroacetimidates
Figure 2.5 Thiol reaction with chiral imidate 16
Figure 2.6 Synthesis of DPM Imidate 18
Figure 2.7 Intercepting the DPM cation 19
Figure 2.8 The Overman rearrangement 19
Figure 2.9 Chiral DPM ethers 23
Figure 2.10 Neat PMB Ether Reactions 25
Figure 2.11 Concentration Studies 26
Figure 2.12 PMB Etherification with Cinnamyl Alcohol 27
Figure 2.13 PMB Etherification with Cinnamyl Alcohol in α,α,α-Trifluorotoluene 28
Figure 2.14 Hydrogen bonding in diols 32
Figure 2.15 One Pot PMB Etherification 33
Figure 3.1 The PI3K Pathway 148
Figure 3.2 The PI3K Signaling Cascade 149
x
Figure 3.3 Crystal Structure of SHIP2 150
Figure 3.4 SHIP Inhibitors 154
Figure 3.5 Aminosteroid Analogues 155
Figure 3.6 Structure Activity Relationship of the Aminosteroid SHIP inhibitors 155
Figure 3.7 Proposed model of active site for SHIP1 156
Figure 3.8 SHIP Inhibition with Aminosteroids 157
Figure 3.9 SHIP1 Inhibitors and Potential Analogues 158
Figure 3.10 Clemmensen Reduction of Trans-Androsterone 158
Figure 3.11 Synthesis of K185 161
Figure 3.12 Synthesis of K118 162
Figure 3.13 Synthesis of Aminosteroid K179 163
Figure 3.14 Synthesis of Alkene 3.16 164
Figure 3.15 Synthesis of Potential SHIP Inhibitor 3.17 165
Figure 3.16 %SHIP Inhibition with Aminosteroids 166
xi
LIST OF TABLES
Table 2.1 Esterification with PMB Imidate 12
Table 2.2 Solvent Screen of Etherification with DPM Imidate 20
Table 2.3 Etherification with DPM Imidate 21
Table 2.4 PMB Ether Solvent Screen 25
Table 2.5 PMB Etherifications in α,α,α-Trifluorotoluene 29
Table 2.6 PMB Etherification of Diols 32
Table 3.1 Clemmensen Reduction of Trans-Androsterone 159
Table 3.2 Hydrazone Reduction Conditions 160
xii
ABBREVIATIONS AND ACRONYMS
[α] Specific rotation
3AC 3α–aminocholestane
Akt Protein kinase B
Akt1 Protein kinase B 1
Akt2 Protein kinase B 2
AIBN Azobisisobutyronitrile
AML Acute myelogenous leukemia
Anal. Combustion elemental analysis
anhyd Anhydrous
ATG Authophagy–related
BAECs Bovine aortic endothelial cells
bFGF Basic fibroblast growth factor
BHT Butylated hydroxytoluene
BM Bone marrow
BMMC Bone marrow mast cell
bs Broad singlet
Btk Bruton’s tyrosine kinase
calcd Calculated
CD Crohn’s Disease
CF Cystic fibrosis
CI Chemical ionization
CLogP Calculated partition coefficient
cod 1,5–Cyclooctadiene
compd Compound
concd Concentrated
COSMIC College of Science Major Instrumentation
CSA Camphorsulfonic acid
Cy Cyclohexyl
Chemical shift in part per million
DCB 1,4–Dichlorobenzene
DCE 1,2–Dichloroethane
DCM Dichloromethane
DBU 1,8–Diazabicyclo[5.4.0]undec–7–ene
DEPT Distortionless enhancement by polarization transfer
DIAD Diisopropyl azodicarboxylate
DIBAL Diisobutylaluminum hydride
DMAP 4–Dimethyl aminopyridine
dba Dibenzylideneacetone
DMF Dimethylformamide
DMP Dess–Martin periodinane
DMPU 1,3–dimethyl–3,4,5,6–tetrahydro–2(1H)–pyrimidinone
DMSO Dimethyl sulfoxide
DPM Diphenyl methyl
EGF Epidermal growth factor
xiii
EGFR Epidermal growth factor receptor
ERK Extracellular regulated kinase
ES Embryonic stem
ESI Electrospray ionization
FP Fluorescence polarization
FT Fourier transform
Gab Grb2–associated binding
Glut4 Glucose transporter type 4
Grp1 General receptor for phosphoinositides 1
GSK3β Glycogen synthase kinase 3
GTP Guanosine triphosphate
GvHD Graft vs. Host disease
H&E Hematoxylin and Eosin
HGF Hepatocyte growth factor
HIV Human immunodeficiency virus
HMBC Heteronuclear multiple bond correlation
HRMS High–resolution mass spectroscopy
HSC Hematopoietic stem cells
HTS High–throughput screening
HWE Horner–Wadsworth–Emmons
IBD Inflammatory bowel disease
IC50 Half maximal inhibitory concentration
I–1,3,4,5–P4 Inositol–1,3,4,5–tetrakisphosphate
IL–1β Interleukin–1β
IP Inositol phospholipid
IP4 Inositol–1,2,4,5–tetrakisphosphate
JNK c–Jun N–terminal kinases
KD Equilibrium dissociation constant
LAH Lithium aluminum hydride
LDA Lithium diisopropylamine
lit. Literature value
LN Lymph node
MAP Mitogen–activated protein
MAPK Mitogen–activated protein kinases
m–CPBA meta–Chloroperoxybenzoic acid
MEF Mouse embryonic fibroblasts
Mes 2,4,6–Trimethylphenyl (mesityl)
MDCK Madin–Darby canine kidney
MG+ Malachite Green
MIR Myeloid immunoregulatory
MM Multiple myeloma
MOM Methoxymethyl
Ms Methylsulfonyl (mesyl)
MS Molecular sieves
MySCs Myeloid suppressor cells
NCI National Cancer Institute
xiv
NHK Nozaki–Hiyama–Kishi
NK Natural killer
NMO N–Methylmorpholine N–oxide
NMR Nuclear Magnetic Resonance
NO Nitrite
NOESY Nuclear Overhauser effect spectroscopy
PCC Pyridinium chlorochromate
PDC Pyridinium dichlorochromane
PDK1 Phosphatidylinositide kinase 1
PH Pleckstrin homology
PI3K Phosphatidylinositol–3–kinase
PI–3,4–P2 Phosphatidylinositol–3,4–bisphosphate
PI–3,4,5–P3 Phosphatidylinositol–3,4,5–trisphosphate
PIPn Phospoinositides
Piv Pivalate
PKB Protein kinase B
PLC–γ Phospholipase C–γ
PMB para-methoxybenzyl
PMP para–Methoxyphenyl
PPTS Pyridinium para–toluenesulfonate
PTEN Phosphatase and tensin homolog
PTH Parathyroid hormone
p–TsCl para–Toluenesulfonyl chloride
Ras Receptor tyrosine kinases
RBC Red blood cell
rt Room temperature
SAR Structure–activity relationship
Shc Src homology 2–containing
SH2 Src homology 2 containing
SHIP Src homology 2 domain–containing inositol 5’–phosphatase
SHIP1 Src homology 2 domain–containing inositol 5’–phosphatase 1
SNPs Single–nucleotide polymorphisms
TBAF Tetrabutylammonium fluoride
TBS tert–Butyldimethylsilyl
TBDPS tert–Butyldiphenylsilyl
TEMPO 2,2,6,6–Tetramethylpiperidin–1–oxyl
TES Triethylsilyl
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
TFP Tri–2–furylphosphine
THP Tetrahydropyran–2–yl
TMEDA N,N,N,N–Tetramethylethylenediamine
TMS Tetramethylsilane
THF Tetrahydrofuran
TIPS Triisopropyl
TLC Thin layer chromatography
xv
TMS Tetramethylsilane
Tf Trifluoromethanesulfonyl (triflyl)
Ts para–Toluenesulfonyl (tosyl)
V–ATPases Vacuolar (H+)–ATPases
Yphos Tyrosine phosphorylated
xvi
DEDICATION
For my family, Dad, Mom, Katelyn,
Grandpa Ed, Grandma Doris, Grandpa Frank and Grandma Ida.
“True wealth is having a healthy mind, body, and spirit. True wealth is having the knowledge to
maneuver and navigate the mental obstacles that inhibit your ability to soar. Remember to love
yourself, because if you can’t love yourself, how in the hell are you gonna love somebody else?”
-RuPaul
1
Chapter 1: Formation of Ethers Under Mild Conditions
Abstract:
Alcohols are common in organic molecules, and are often present in biologically active
natural products. The protection of hydroxy groups is critical in long multi-step synthetic routes,
as the unprotected alcohol is typically not compatible with many reagents. Alcohols are often
protected as benzyl ethers or substituted benzyl ethers, which can then be removed under a
variety of conditions when desired. Classic protection methods for alcohols as benzyl ethers
requires harsh conditions utilizing strong acids and bases, which functions well for simple
substrates. In more complex polyfunctional molecules this can lead to degradation and side
products. Therefore, there is a need for the development of milder conditions for the protection
of alcohols. Recently a number of reagents have been developed to form benzyl ethers under
mild, neutral conditions that and do not disturb sensitive functionality. This chapter provides
details of many of these reagents and summarizes the conditions needed to install the ethers
utilizing these new methods.
Introduction:
Ethers are of great value in organic synthesis since they can act as protecting groups for
sensitive alcohols.1,2 Simple and mild conditions are often desired to protect and deprotect
alcohol substrates as to minimize degradation of a multistep synthesis. There are many known
procedures to make ethers with the Williamson ether synthesis being a popular method. Another
classical method for ether synthesis is the Koenigs-Knorr reaction for glycoside formation. Both
methods employ the use of basic alkali metal alkoxides with alkyl halides. Alternatively ethers
may be formed from alcohols under acidic conditions. These methods can be problematic in the
2
protection of alcohols in complex molecules. For example, carbohydrates can undergo base
catalyzed migration of esters and silyl ethers. Silyl ethers and acetal linkages could also be
disturbed by acid catalyzed cleavage. Metal catalysts have also been employed for the formation
of ethers, however, they are usually expensive.3,4 Therefore, development of milder conditions
for the protection of complex alcohols so that other sensitive functionality is not disturbed in
complex molecules is an ongoing area of research.
Recently several different reagents have been advanced for the protection of alcohols in
complex molecules without disturbing delicate functionality. One often cited method is to use
the trichloroacetimidate to form the ether in the presence of a Brønsted or Lewis acid. This
methodology is especially useful for the introduction of benzyl, allyl, and 4-methoxybenzyl
ethers.5,6,7 Other benzylic ethers have also been formed under these conditions. For example, the
formation of DPM ethers have been reported with the use of trichloroacetimidates and Lewis
acids (Figure 1.1).8,9 Diphenylmethyl trichloroacetimidate can be easily prepared with
diphenylmethanol and trichloroacetonitrile and is stable at room temperature over long periods of
time. The facile formation of DPM ethers with DPM imidate in the presence of TMSOTf
worked well on various primary and secondary alcohols. This methodology was showcased in
the creation of glycosidic bonds. Because the diphenylmethyl group on an -alcohol at the 2-O
position sterically hinders α bond formation, it facilitates stereoselective β-glucopyranoside
formation.
3
Figure 1.1: Acid catalyzed DPM etherification with trichloroacetimidate 1.1
Schmidt and Michel have demonstrated a use for trichloroacetimidates in glycosidic bond
formation.10 Facile conversion of the glucopyranose to the corresponding imidate is done with
base and trichloroacetonitrile or aryl-substituted ketenimines. Then the isolated imidate can be
used for an acid catalyzed reaction with another glucopyranose to form a glycosidic bond (Figure
1.2). This methodology avoids using heavy metal salts such silver salts which were previously
utilized for glycoside synthesis.
Figure 1.2: Glycosidic bond formation with trichloroacetimidate
Trifluoroacetimidates have also been utilized in the benzylation of alcohols.11,12 These
imidates can be prepared from a one pot reaction of benzyl alcohols via perfluoro nitriles from an
amide dehydration. Perfluoro nitriles can be difficult to use since they are extremely volatile and
toxic. In a related study, Pohl investigated a number of N-aryl trifluoroacetimidates for the
installation of benzyl and allyl protecting groups on carbohydrates (Figure 1.3). These
trifluoroacetimidates are prepared from N-aryl trifluoroacetimidoyl chlorides, benzyl or allyl
alcohol and base. Employing an electron withdrawing phenyl group on the nitrogen of the
4
imidate allows for a more stable imidate but still provides reactivity as a leaving group. The
perfluoroacetimidates are stable at room temperature for several days. These imidates have been
reported to alkylate alcohols in one hour at room temperature. However, the alkylation employs
the use of an acid catalyst such as TfOH or TMSOTf.
Figure 1.3: Alkylation with Trifluoroacetimidate
Kunishima also established a method for preparing benzyl ethers at room temperature
with triazinylammonium salts (Figure 1.4). 4-(4,6-Diphenoxy-1,3,5-triazin-2-yl)-4-
benzylmorpholinium trifluoromethanesulfonate (DPT-BM) is prepared from 4,6-diphenoxy-2-
trifluoromethanesulfonyloxy-1,3,5-triazine and 4-benzylmorpholine.13 This triazinylammonium
salt is a non-hygroscopic, stable solid and can be stored at cold temperatures for long periods of
time. This reagent was used to benzylate primary, secondary and tertiary alcohols in high yields.
This alkylation also performed well on acid and base sensitive substrates such as acetoxy, β-
hydroxyester, and silyl groups. The major caveat with this reaction is that it uses MgO as an acid
scavenger and dehydrating reagent, which introduces another variable into the reaction and could
lead to degradation of sensitive molecules. Kunishima has also reported alkylation of alcohols
with benzyl or p-methoxybenzyl groups using 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) and
2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM), respectively.14, 15 However, this
method also uses catalytic acid to make the corresponding ethers.
5
Figure 1.4: Ether Formation with Triazinylammonium salts:
Phosphinimidates have also been explored for their use in the alkylation of alcohols
(Figure 1.5) under mild conditions.16 These stable imidates are made from alkyl
diphenylphosphinites and methanesulfonyl azide. The ether formation worked well when a
strong electron withdrawing group was bonded to the nitrogen of the phosphinimidate. The
alkylation was also quite general, and performed well on primary, secondary and tertiary
alcohols as well as carbohydrates. One drawback to using phosphinimidates as alkylating agents
is that they need catalytic amount of TMSOTf for the transformations to occur.
Figure 1.5: Alkylation with Phosphinimidates
Dudley has reported the protection of alcohols as benzyl and p-methoxybenzyl groups
using 2-benzyloxy-1-methylpyridinium triflate (Bn-OPT) and 2-(4-methoxybenzyloxy)-4-
methylquinoline, respectively, in refluxing α,α,α-trifluorotoluene (Figure 1.6).17 Bn-OPT is a
6
novel benzylation reagent for alcohols, stable solid, and preactivated. It is prepared by treating
2-benzyloxypyridine with methyl triflate and can be made in situ in the presence of alcohol. The
benzylation works well with primary, secondary, and tertiary alcohols. This etherification also
worked with β-hydroxyesters and trimethylsilylethanol. However, reaction with cinnamyl
alcohol only provided trace amounts of product. Additionally in order to prepare this reagent,
the toxic and carcinogenic methyl triflate must be prepared and used. Alkylation with 2-(4-
methoxybenzyloxy)-4-methylquinoline also worked on primary, secondary, and tertiary alcohols.
This method created by Dudley use additives such as MgO which is a mild base and desiccant to
scavenge acid or water. Therefore, this etherification could prove difficult with base sensitive
functionality.
Figure 1.6: Etherification with Pyridinium Salts
While many reagents have been created to address the problem of protecting alcohols
under mild conditions in sensitive systems, work towards a general, inexpensive and nontoxic
solution which does not require a strong acid catalyst is still ongoing. In the next chapter we will
discuss investigations into utilizing trichloroacetimidates for these transformations without the
addition of an acid promoter, providing an alternative solution for the formation of some esters
and ethers under mild conditions.
7
References
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Wiley & Sons: Hoboken, NJ, 2006; pp 610–611.
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8
16. Aoki, H.; Mukaiyama, T. Chem. Lett. 2005, 34, 1016-1017.
17. (a) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett. 2005, 3142-3144; (b) Poon,
K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth. 2007, 84, 295-305; (c) Albiniak,
P. A.; Dudley, G. B. Synlett. 2010, 841-851; (d) Tummatorn, J.; Albiniak, P. A.;
Dudley, G. B. J. Org. Chem. 2007, 72, 8962-8964; (e) Wang, T.-W.; Intaranukulkit,
T.; Rosana, M. R.; Slegeris, R.; Simon, J.; Dudley, G. B. Org. Biomol. Chem. 2012,
10, 248-250. (f) Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436-1437. (g)
Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923-3927.
9
Chapter 2: Formation of Esters, Thioethers and Ethers with Trichloroacetimidate
Electrophiles under Catalyst-Free Conditions
Abstract:
Many reagents have been developed to form benzyl ethers and esters under mild, neutral
conditions that and do not disturb the sensitive functionality in complex molecules. Most of
these reagents are based on acetimidate-type systems, as the rearrangement of these systems to
the corresponding acetamide provides a secondary thermodynamic driving force for the ether
formation. Trichloroacetimidates are effective at alkylating carboxylic acids, thiols, and alcohols
under Lewis acid catalyzed conditions, but little attention has been given to their reactivity under
catalyst free conditions. Given their ready availability, a reevaluation of the reactivity of
alcohols and trichloroacetimidates has been undertaken. In many cases, simply heating the
trichloroacetimidate with an alcohol in refluxing toluene without an exogenous acid or base is an
effective method for the formation of the desired ether. This operationally simple procedure is
most effective for trichloroacetimidates that are precursors to highly stabilized cations (i.e. the 4-
methoxybenzyl and diphenylmethyl group). Esters, thioethers and ethers were formed without
the use of an acid or base catalyst. Thermal etherification was performed under neutral
conditions with both the DPM and PMB trichloroacetimidate. The use of this new procedure
with a number of acid and base sensitive substrates, which are protected in excellent yield
without disturbing the delicate functionality present in these molecules, is presented.
1. Catalyst-Free Protection of Esters with Trichloroacetimidates
Carboxylic acids are often protected as esters in multistep organic synthesis. Popular ester
protecting groups for carboxylic acids include the 4-methoxybenzyl (PMB) and diphenylmethyl
(DPM) esters.1,2 These protecting groups are often used due to their ease of removal via treatment
10
with acid or by hydrogenation (they may also be removed by saponification).1-7 Carboxylic acids
are typically protected with a PMB group through alkylation reactions with the corresponding
halide and a strong base. DPM esters can be installed with acid catalysis using diphenylmethanol
as the electrophile or by treating the carboxylic acid with diphenyldiazomethane.8,9,10 The problem
with most of these protecting group installations is that they do not tolerate complex substrates
with sensitive functionality or they incorporate environmentally hazardous reagents.9
Trichloroacetimidates have been used for ester formation through their reaction with carboxylic
acids in the presence of an acid catalyst.11 There have been scattered reports of ester formation
with trichloroacetimidates without the addition of a catalyst, however. For example, Hayashi and
co-workers have reported the formation of a PMB ester without a catalyst using 4-methoxybenzyl-
2,2,2-trichloroacetimidate directly.3,4 Two other examples of catalyst free esterification are also
present in the literature, with glycosyl imidates and 2-phenylisopropyl trichloroacetimidate
undergoing these reactions.12,13 In the examples where a catalyst is not needed for esterification,
the imidate may be protonated by the carboxylic acid and then ionize to form a carbocation, which
is then trapped by the carboxylate anion. All of these examples of ester formation with
trichloroacetimidates use imidates that are precursors to stable carbocations. Loss of the imidate
and formation of trichloroacetamide thermodynamically facilitates the alkylation reaction. Given
that little was known about the scope of these reactions, an investigation using PMB and DPM
trichloroacetimidates to form their respective esters of carboxylic acids without an acid catalyst
was initiated.
The formation of esters from trichloroacetimidates may occur by either an SN1 or an SN2
mechanism (Figure 2.1 shows the possible mechanisms for the reaction of a carboxylic acid with
PMB trichloroacetimidate 2.1). For SN1 addition, the carboxylic acid substrate promotes the
11
reaction by protonating the basic imidate nitrogen. After acetamide 2.3 is formed, the carboxylate
anion can add to the PMB cation. In SN2 addition, the carboxylic acid adds to the benzylic position
of the PMB imidate causing the acetamide anion to form. The acetamide anion then removes the
hydrogen from the protonated acid, forming the PMB ester. A concerted SN2 mechanism involving
a 6-membered transition state between the carboxylic acid and the PMB imidate is also a
possibility.
Figure 2.1: Proposed Mechanisms of PMB esterification
12
Ester formation without the presence of an acid catalyst using PMB imidate 2.1 was
initially explored. PMB imidate 2.1 is commercially available and may also be easily prepared
from PMB alcohol and trichloroacetonitrile using DBU or NaH as a catalyst.14 Several carboxylic
acids were successfully treated with PMB imidate 2.1 to form their corresponding esters without
an added acid catalyst (Table 2.1).15 This simple reaction is carried out at room temperature in
dichloromethane. Diverse substrates tolerated the esterification such as alkanes, alkenes, alkynes,
and electron rich and electron poor benzoic acids. Under these conditions, carboxylic acids are
selectively protected over other functional groups such as alcohols.
Table 2.1: Esterification with PMB Imidate
Entry Compound % Yield
1
43%
2
60%
3
54%
4
64%
13
5
50%
6
63%
7
80%
8
51%
9
27%
10
25%
Ester formation was successful for the compounds in Table 2.1, resulting in moderate to
high yields. Esterification of acetylsalicylic acid gave the highest yield of 80%. The isobutyl
ester in entry 1 provided a low yield most likely due to steric effects from the isobutyl group on
the acid. Entries 2 and 7 demonstrate that ortho substituents are tolerated on benzoic acid
derivatives for this methodology, so some tolerance of sterically demanding substrates was
demonstrated. No isomerization was observed for the alkene in entry 3. Entries 4, 5 and 6
provided moderate yields most likely due to sterics from the bulky R groups next to the
14
carboxylic acids. The highly strained cyclopropyl carboxylic acid provided the respective PMB
ester in 51 % yield (entry 8), but no opening of the cyclopropane was observed. Entries 9 and 10
again gave lower yields due to sterics of the corresponding carboxylic acids. This study provides
evidence that PMB esters can be formed under mild reaction conditions using the
trichloroacetimidate, and provides a mild method which may be useful for forming PMB esters
in complex multifunctional substrates.15 Sterically hindered carboxylic acids may provide lower
yields due to sterics, however.
Building on the success with PMB trichloroacetimidate, diphenyl methyl
trichloroacetimidate was evaluated as an esterification reagent under catalyst-free conditions
(Figure 2.2). Diphenylmethyl trichloroacetimidate was postulated to be an effective alkylating
agent because it can lead to a stabilized carbocation, facilitating the SN1 substitution pathway
with a carboxylic acid. Also, it is a easy to handle white solid that is stable in cold storage for
long periods of time and can be easily prepared from the inexpensive diphenylmethanol in high
yield.16 Ester formation was successful for both tert-butylacetic acid 2.15 and adamantane-1-
carboxylic acid 2.18 with DPM imidate 2.16 under neutral conditions. Esterification of tert-
butylacetic acid gave a high yield of 92% while adamantane-1-carboxylic acid was not as
reactive which is most likely because of sterics. This study provides evidence that DPM esters
such as 2.17 and 2.19 may also be formed under mild reaction conditions using the
trichloroacetimidates.17
15
Figure 2.2: Esterification with DPM Imidate
2. Thioethers
Building on the esterification work, the alkylation of thiols was then attempted under
catalyst-free conditions. Thiols are less acidic than alcohols, but more acidic than alcohols, so
their alkylation was explored next. Sulfides are commonly present in molecules used for
pharmaceuticals, enzyme cofactors, and pesticides.18,19,20 Sulfides are often synthesized from the
alkylation of thiols with alkyl halides or alcohols.21 However, these classic methods employ the
use of an acid or base catalyst, which may provide problems in complex molecules.22
Trichloroacetimidates were effective in the alkylation of thiols to form thioethers without
the addition of an acid, base or metal catalyst (Figure 2.3). This new method for sulfide
formation involves simply refluxing the thiol and imidate in THF. Both alkyl and aromatic thiols
can be used with this method. Also, a variety of trichloroacetimidates including alkyl, allylic,
propargylic and benzylic imidates performed well in the alkylation reaction.23
16
Figure 2.3: Sulfide formation with imidates
Figure 2.4 shows two mechanistic possibilities for this thiol alkylation. Depending on the
electrophile, this reaction can proceed through either a SN1 or SN2 pathway. The first step for
both mechanisms is the imidate gets protonated by the thiol, creating a thiolate anion. Should the
electrophile be suitable for SN2 conditions, the sulfur anion will attack with the R’ group from the
protonated imidate and the acetamide 2.3 is formed directly. A concerted SN2 process as shown
in Figure 2.1 may also be possible with a thiol. For the SN1 pathway, the protonated imidate
forms the acetamide and an R’ cation. Then the thiolate will then attack the R’ cation to give the
thioether.
17
Figure 2.4 Mechanistic possibilities for thioether formation with trichloroacetimidates
Thiol displacement of methyl trichloroacetimidate under these conditions to form a
methyl thioether supported the SN2 mechanism. Furthermore, thiol reaction with chiral imidate
supports an SN2 mechanism (Figure 2.5). The reaction proceeded with inversion forming sulfide
2.28, with none of the retention product being observed by 1H NMR (the retention product was
independently synthesized for comparison).
Figure 2.5: Thiol reaction with chiral imidate
3. Ethers
After formation of sulfides with trichloroacetimidates under catalyst free conditions,
attention was turned to the etherification of alcohols. Trichloroacetimidates have been routinely
used to protect alcohols as ethers at room temperature in the presence of a Brønsted or Lewis
acid catalyst.24-29 Schmidt and co-workers have employed diphenylmethyl trichloroacetimidate
2.16 to make diphenylmethyl (DPM) ethers with a catalytic amount of TMSOTf in excellent
18
yields.16 The use of an acid catalyst for this reaction limits the substrates which can participate
in the etherification. An example of a problematic acid sensitive substrate would be β-
trimethylsilylethanol, which has been reported to be subjected to a Peterson elimination under
acidic conditions with a trichloroacetimidate.30 Other reagents similar to trichloroacetimidates
have also been developed for the synthesis of benzyl and PMB ethers.31,32 Additionally,
trifluoroacetimidate and phosphinimidate type reagents have been introduced for etherification,
however these systems still require the use of an acid cataylst.33,34
Diphenylmethyl (DPM) ethers are frequently used as protecting groups for alcohols in
organic synthesis.35 They can easily be removed through hydrogenation or with acidic
conditions making the DPM group useful in complex molecules where more than one protecting
group is in place.36,24 DPM ethers have also proven beneficial for enantioselective reactions
since the steric bulk of the group can show increased selectivity in some substrates.37 The DPM
group is also commonly used in medicinal chemistry since the phenyl rings add large
hydrophobic groups which increase the lipophilicity of biologically active molecules.38
Trichloroacetimidates have been utilized in the Chisholm laboratory to explore ester and
sulfide formation.15,17,23 Given the high reactivity of the PMB and DPM trichloroacetimidates
with carboxylic acids and thiols, these substrates were chosen for initial exploration as
etherification reagents under catalyst-free conditions. PMB and DPM ethers are also commonly
used protecting groups, so these methods should have some utility in the synthetic organic
community. Studies with DPM imidate 2.16 have shown that the rearrangement of the imidate
to the corresponding acetamide occurs when the imidate is refluxed in toluene. This type of
rearrangement is similar to reports of benzylic imidates undergoing rearrangement through a
cationic pathway in the presence of a strong acid.39 We hypothesized that under thermal
19
conditions a similar process occurs and the DPM imidate ionizes to form a DPM cation and
trichloroacetamide anion. The cation could be intercepted by an external nucleophile such as an
alcohol. This hypothesis would allow for the formation of DPM ethers under thermal conditions
without the use of an acid or base additive. Conditions have now been developed for ether
formation under neutral conditions without a catalyst, which typically proceed in moderate to
high yields with DPM and PMB imidates.40
Diphenylmethyl (DPM) imidate was synthesized from benzophenone (Figure 2.6).
Reduction of benzophenone to diphenylmethanol is easily done with sodium borohydride in
methanol. The treatment of the diphenylmethanol with trichloroacetonitrile (TCAN) in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provided DPM imidate 2.16. Alfa-Aesar
quotes diphenylmethanol at $25.97/mol, TCAN at $36.94/mol and $38.06/mol, allowing for a
very cost effective synthesis of DPM imidate. The DPM imidate 2.16 showed stability for long
periods of time when stored cold in a refrigerator and is very easy to handle since its physical
form is a white powder.
Figure 2.6: Synthesis of DPM Imidate
Earlier studies with DPM imidate 2.16 demonstrated that the imidate would rearrange to
the corresponding trichloroacetamide when refluxed in toluene (Figure 2.7). Rearrangements of
allylic trichloroacetimidates are known and usually occur through a concerted [3,3]-sigmatropic
rearrangement (the Overman rearrangement, Figure 2.8).41 However, this rearrangement is less
favorable for the DPM imidate. Instead, the rearrangement is believed to occur through a
20
cationic pathway, where the imidate ionizes under thermal conditions due to the stability of the
diphenylmethyl cation. This allows cation 2.32 and trichloroacetamide anion 2.31 to form. The
trichloroacetamide anion is a weak base and poor nucleophile with a pKa of approximately 11.41
An added external nucleophile, such as an alcohol, may therefore intercept the cation 2.32 and
form the corresponding DPM ether.
Figure 2.7: Intercepting the DPM cation
Figure 2.8: The Overman rearrangement
Our thermal etherification studies began with an exploration of reaction conditions. A
solvent screen with 1-octadecanol 2.34 and DPM imidate 2.16 showed that performing the
reaction in toluene at reflux gave the best isolated yield of the corresponding DPM ether product
(Table 2.2, entry 1). Lower temperatures in toluene provided a lower yield of the desired ether
21
product (entry 2), which was attributed to a slower reaction. Nonpolar solvents appeared to be
superior for the etherification reaction, with acetonitrile and DMF providing the lowest yields
(entries 8 and 9 respectively).
Table 2.2: Solvent Screen of Etherification with DPM Imidate
Entry Solvent Temperature (oC) % Yield
1 Toluene 111 85
2 Toluene 50 24
3 Trifluorotoluene 102 62
4 1,2-Dichloroethane 83 66
5 Dichloromethane 40 18
6 Tetrahydrofuran 66 36
7 1,4-Dioxane 101 60
8 Acetonitrile 82 28
9 Dimethylformamide 110 33
This catalyst-free etherification was then evaluated with a variety of alcohols to
determine the scope of the reaction (Table 2.3). The reaction provided very high yields with
benzyl alcohols in entries 1, 2, 3, and 4. Entries 5, 6, 7, 8 show allylic alcohols and phenol
derivatives also participate in this reaction. Propargyl alcohol (entry 12) also proved to be an
excellent reactant in the transformation, providing a 97% yield of propargyl ether product. The
etherification of secondary and tertiary alcohols (entries 9, 10, 11) also proceeded in high yields.
This is notable, as many other catalyst-free etherification conditions do not provide high yields
with tertiary alcohols.30 Entries 13, 14, and 15 demonstrate that more complex alcohols can be
protected with this methodology. Acid and base sensitive alcohols may also be protected with
22
this procedure as shown in entries 16-18. The protection of 2-trimethylsilyl ethanol to form ether
2.53 is particularly notable, as this substrate decomposes under acidic and basic conditions,30 yet
is effectively protected under the new thermal conditions. Diols may also be mono protected
with this methodology (entries 21-24), although the yields are moderate. In the case of mono
protection only one equivalent of DPM imidate was used for the ether formation. Small amounts
of diprotected ether were observed for the symmetrical diols. Entries 23 and 24 gave low yields
because of the difficult separation of the mixture of mono protected alcohols. These reactions
demonstrate that DPM ethers can be formed with neutral conditions using trichloroacetimidates.
The ability to monoprotect alcohols preferentially may be explained by the greater acidity of the
diol when the two alcohols form an intramolecular hydrogen bond, this was further explored
with PMB trichloroacetimidate and is discussed later in this chapter.
Table 2.3: Etherification with DPM Imidate
Entry Alcohol % Yield
1
94%
2
71%
3
92%
4
88%
23
5
91%
6
61%
7
53%
8
88%
9
93 %
10
85%
11
92%
12
97%
13
80%
14
80%
15
96%
16
65%
17
73%
18
79%
24
19
90%
20
91%
21
68%
22
40%
23
38%
24
19%
No racemization was observed in the formation of chiral ethers 2.54 and 2.55 through
chiral HPLC analysis (Figure 2.8). Chiral and racemic serine protected ethers were prepared for
comparison on chiral HPLC. The chiral HPLC traces show that no racemization occurs under
the thermal etherification conditions. The same was observed for chiral ethyl lactate 2.54
(Figure 2.9).
25
Figure 2.9: Chiral DPM ethers
Since ether formation from alcohols performed well with DPM imidate, a study was
initiated with 4-methoxybenzyl (PMB) imidate. Both the PMB and DPM imidates have been
shown to react with carboxylic acids to form esters without the need for an acid catalyst, so the
PMB ether may also be reactive enough to form ethers under thermal conditions. PMB ethers are
more common protecting groups for alcohols and can be easily removed under mild oxidation
conditions.1,2 Since the PMB imidate is an oil, PMB protection under solvent free conditions
26
was initially explored (Figure 2.10). These neat reactions were performed with either 1-
octadecanol or cinnamyl alcohol and 3 equivalents of PMB imidate at 110 oC overnight. This
resulted in a good yield for 1-octadecanol, but only a 17% yield of the cinnamyl ether was
obtained under these conditions. The addition of 10 mol% trichloroacetamide was also explored
to see if the acetamide was catalyzing the reaction. The yield improved slightly for cinnamyl
alcohol with the addition of trichloroacetamide but had little effect in the case with 1-
octadecanol. As these conditions were not general and yields were moderate, a solvent screen
was performed for the PMB etherifications (Table 2.4).
Figure 2.10: Neat PMB Ether Reactions
27
Table 2.4: PMB Ether Solvent Screen
Entry Solvent Temperature (oC) % Yield
1 Toluene 111 70
2 Toluene 80 27
3 Toluene 50 23
4 Trifluorotoluene 102 73
5 1,2-Dichloroethane 83 74
6 Dichloromethane 40 17
7 Dichloromethane r.t. 4
8 Tetrahydrofuran 66 40
9 1,4-Dioxane 101 25
10 Acetonitrile 82 18
11 Dimethylformamide 110 11
*0.25 M concentration
The solvent screen showed dichloroethane at reflux giving the best yield of PMB ether
2.60. -Trifluorotoluene and toluene gave good yields when used at reflux. More polar
solvents did not give good yields, as the imidate decomposed rapidly under these conditions.
Less polar solvents at lower temperatures typically returned starting material, leading to the
conclusion that a temperature in excess of 80 °C was required for the etherification. Alcohol
protection with PMB imidate was therefore initially explored in DCE at reflux. However, PMB
protection with DCE gave low yields on most substrates. Toluene was then tested as the solvent
in hopes that heating the reaction to a higher temperature would improve reaction yields. Figure
2.11 shows PMB etherification of 1-octadecanol (2.34) at concentrations of 0.25 M, 0.5 M, and
1.0 M. Both reactions at concentrations of 0.5 M and 1.0 M gave high yields. PMB
etherifications were then performed in toluene at 1.0 M.
28
Figure 2.11: Concentration Studies
Cinnamyl alcohol is an interesting substrate because it is an allylic alcohol. Protection of
allylic alcohols have been previously reported in low yields with some PMB etherification
reagents,42 so they were chosen as a test of the methodology. Figure 2.12 shows a study of the
PMB etherification of cinnamyl alcohol under various conditions. The etherifications were
carried out at 1 M concentration and went for 24 hours unless otherwise noted. PMB protection
of cinnamyl alcohol in toluene only yielded 28% of the ether product. One possibility for the
low yield is that adventitious water was hydrolyzing the imidate, which led to the low yield.
Therefore, a series of drying reagents were tested in the PMB etherification. Molecular sieves,
barium oxide and magnesium oxide all led to decreased yield for the etherification.
Trichloroacetamide was also tested as a possible catalyst for the etherification but these
conditions gave comparable yield of PMB protected cinnamyl alcohol as observed with the neat
conditions.
29
Figure 2.12: PMB Etherification with Cinnamyl Alcohol
Since PMB protection of cinnamyl alcohol in toluene with various additives gave poor
results, a new solvent was tested. Toluene may be destroying the imidate through a Friedel-
Crafts process (although these products were never observed directly by 1H NMR), so a more
electron deficient solvent that was less likely to undergo Friedel-Crafts alkylation was utilized.
Therefore, α,α,α-trifluorotoluene was explored as the solvent (Figure 2.13). The etherification in
α,α,α-trifluorotoluene gave a 52% yield of the PMB protected cinnamyl alcohol. The
etherification was allowed to proceed for two days in hopes of a higher product yield but the
yield decreased to 32%. This may mean that shorter reaction times should be explored as a
means to increase the reaction yield, but first a number of other alcohol substrates were evaluated
at the 24 h time point (Table 2.5).
30
Figure 2.13: PMB Etherification with Cinnamyl Alcohol in α,α,α-Trifluorotoluene
Since α,α,α-trifluorotoluene provided the PMB protected cinnamyl alcohol in moderate
yield, α,α,α-trifluorotoluene was chosen as the solvent for substrate testing. The results of PMB
etherification in α,α,α-trifluorotoluene are shown in Table 2.5. Entries 1-4 demonstrate that the
methodology performs well with electron rich and electron poor benzyl alcohols. Propargyl
alcohol gave an 85% yield of its PMB ether; however, the tertiary propargyl alcohol yielded no
reaction product (entries 5-6). Other tertiary alcohols, like adamantyl alcohol, did provide some
product although the yields were more moderate than observed for the DPM imidate. Entry 8
demonstrates PMB etherification of an electron poor phenol works with a 76% yield. The
dihydrocholesterol derivative, a secondary alcohol, in entry 11 provided a 55% yield, which
again is lower than was observed for secondary alcohols in the case of the DPM imidate. Entries
9-10 and 12-16 are more complex examples that are acid and base sensitive. These examples
gave moderate to low yields demonstrating the PMB imidate is significantly less reactive than
the DPM imidate. Further studies on the reaction conditions or the use of a more reactive
imidate (like 2,4-dimethoxybenzyl or 2,6-dimethoxybenzyl) may be required to access a more
general system for the benzyl protection of alcohols.
31
Table 2.5: PMB Etherifications in α,α,α-Trifluorotoluene
Entry Product % Yield
1
81%
2
78%
3
85%
4
67%
5
85%
6
NR
7
40%
8
76%
9
33%
32
10
15%
11
55%
12 68%
13
58%
14
25%
15
61%
16
23%
PMB etherification was also performed on a number of diols (Table 2.6). The lower
reactivity of the PMB imidate may be beneficial in these cases, as higher selectivity may be
accessed for these systems. Entry 1 shows the mono PMB protected 1,4-butanediol in 59 %
yield. This yield is expected since in the presence of one equivalent of imidate a 2:1:1 mixture
of mono product: dialkylated product: starting material is predicted. Entry 2 is the dialkylated
product of 1,4-butanediol and was obtained in only a 41% yield. Primary alcohols can
selectively be protected in the presence of secondary and tertiary alcohols (entries 3, 4). Some
33
diols undergo monoprotection in much higher yields than could be anticipated a priori, for
example entries 5 and 6 were obtained in 80% and 79% yield respectively.
Table 2.6: PMB Etherification of Diols
Entry Product % Yield
1
59%a
2
41%b
3
34%a
4
68%a
5
80%a
6
79%a
7
36%a
a 1 eq. of PMB imidate was used.
b 3.3 eq. of PMB imidate were used.
The yield of the monoprotected product in these reactions is significantly higher than one
would predict based on statistical reactivity of the diols. The ability of these systems to form 5
34
and 6 membered hydrogen bonds (Figure 2.14) may explain this reactivity. One of the
hydrogens becomes more acidic when the diol is participating in this hydrogen bonding, leading
to the selective formation of the monoprotected ether. This intramolecular H-bonding is not
possible after monoprotection. The alkyne in entry 7 restricts that capability for hydrogen
bonding and therefore gave a lower yield of the monoprotected product (36%), further
supporting the role of hydrogen bonding in these systems.
Figure 2.14: Hydrogen bonding in diols
A one-pot PMB etherification from 4-methoxybenzyl alcohol was also attempted (Figure
2.15). In this procedure, the PMB imidate is generated in situ and not isolated. After the PMB
imidate is observed by TLC, 4-nitrobenzyl alcohol was added. This alcohol was chosen because
of its high reactivity in the PMB etherification. These experiments were performed in both
toluene and α,α,α-trifluorotoluene. The reaction in toluene only gave 15% yield of PMB
protected product while the reaction in α,α,α-trifluorotoluene gave 34% yield of product. These
poor yields may be due to the imidate forming in low yield in these solvents, as typically the
imidate formation is performed in diethyl ether.
35
Figure 2.15: One Pot PMB Etherification
Conclusions and Future Work
Thermal etherification was successful with both DPM and PMB imidate. Neutral,
thermal conditions do not require an acid or base catalyst for etherification. The DPM imidate
was found to be more reactive under these conditions, and therefore the method was more
general with regard to the alcohol substrates. This novel methodology allows for alcohol
protection on sensitive substrates. Chirality centers are also undisturbed when subjected to the
reaction conditions. Trichloroacetimidates were used to alkylate carboxylic acids and thiols as
well. Etherification using trichloroacetimidates under mild conditions will continue to be
explored. Further investigation using different substrates will be conducted. Etherification of
alcohols with other imidates will also be studied using similar, neutral conditions. Imidates with
more electron rich groups, such as 2,4- or 2,6-dimethoxybenzylimidate, will be tested to see if
reaction conditions and yields improve as compared to the 4-methoxybenzyl
trichloroacetimidate.
36
Experimental Procedures
General Information. All anhydrous reactions were run under a positive pressure of argon or
nitrogen. All syringes, needles, and reaction flasks required for anhydrous reactions were dried in
an oven and cooled under an N2 atmosphere or in a desiccator. DCM and THF were dried by
passage through an alumina column by the method of Grubbs.1 Triethylamine was distilled from
CaH2. All other reagents and solvents were purchased from commercial sources and used without
further purification.
Analysis and Purification. Analytical thin layer chromatography (TLC) was performed on
precoated glass backed plates (silica gel 60 F254; 0.25 mm thickness). The TLC plates were
visualized by UV illumination and by staining. Solvents for chromatography are listed as
volume:volume ratios. Flash column chromatography was carried out on silica gel (40-63 μm).
Melting points were recorded using an electrothermal melting point apparatus and are uncorrected.
Elemental analyses were performed on an elemental analyzer with a thermal conductivity detector
and 2 meter GC column maintained at 50 °C.
Identity. Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance spectra were
recorded at 300 or 400 MHz and 75 or 100 MHz respectively. The chemical shifts are given in
parts per million (ppm) on the delta (δ) scale. Coupling constants are reported in hertz (Hz). The
spectra were recorded in solutions of deuterated chloroform (CDCl3), with residual chloroform (
7.26 ppm for 1H NMR, δ 77.23 ppm for 13C NMR) or tetramethylsilane ( 0.00 for 1H NMR,
0.00 for 13C NMR) as the internal reference. Data are reported as follows: (s = singlet; d = doublet;
t = triplet; q = quartet; p = pentet; sep = septet; dd = doublet of doublets; dt = doublet of triplets;
td = triplet of doublets; tt = triplet of triplets; qd = quartet of doublets; ddd = doublet of doublet of
doublets; br s = broad singlet). Where applicable, the number of protons attached to the
37
corresponding carbon atom was determined by DEPT 135 NMR. Infrared (IR) spectra were
obtained as thin films on NaCl plates by dissolving the compound in CH2Cl2 followed by
evaporation or as KBr pellets.
4-methoxybenzyl 3,3-dimethylbutanoate 2.5
In a flame dried 50 mL round bottom flask, tert-butylacetic acid (400 mg, 3.44 mmol) was
dissolved in dry dichloromethane (14 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.934
g, 3.44 mmol) was added. The reaction was stirred at room temperature for 24 hours. The
reaction was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried
with sodium sulfate and concentrated. Purification was done with flash column chromatography
(10% ether/hexane) to give a clear oil (346 mg, 43%). TLC Rf = 0.58 (15% ethyl
acetate/hexanes); IR (neat) 2957, 2836, 1731, 1515 cm-1; 1H NMR (300 MHz, CDCl3): δ 7.30 (d,
J = 9.0 Hz, 2H), 6.89 (d, J = 8.6, 2H), 5.04 (s, 2H), 3.81 (s, 3H), 2.22 (s, 2H), 1.01 (s, 9H); 13C
NMR (75 MHz, CDCl3): δ 172.3, 159.7, 130.2, 128.5, 114.0, 65.8, 55.3, 48.1, 30.9, 29.8. Anal
calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.37; H, 8.37.
38
4-methoxybenzyl 2-methoxybenzoate 2.6
In a flame dried 50 mL round bottom flask, o-anisic acid (400 mg, 2.63 mmol) was dissolved in
dry dichloromethane (11 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.486 g, 5.26 mmol)
was added. The reaction was stirred at room temperature for 24 hours. The reaction was taken
up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried with sodium
sulfate and concentrated. Purification was done with flash column chromatography (10% ethyl
acetate/hexanes) to give a clear oil (433 mg, 60%). TLC Rf = 0.56 (25% ethyl acetate/hexanes);
IR (neat) 2956, 2837, 1724, 1514, 1245 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 9.8 Hz,
1H), 7.37-7.47 (m, 3H), 6.89-6.97 (m, 4H), 5.29 (s, 2H), 3.88 (s, 3H), 3.79 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.0, 159.6, 159.4, 133.6, 131.7, 130.0, 128.4, 120.1, 113.9, 112.1, 66.4,
56.0, 55.3.
(E)-4-methoxybenzyl but-2-enoate 2.7
Lit. Ref.: Matsuo, J.; Kozai, T.; Ishibashi, H. Org. Lett. 2006, 8 (26), pp 6095–6098.
In a flame dried 50 mL round bottom flask, crotonic acid (400 mg, 4.65 mmol) was dissolved in
dry dichloromethane (19 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.972 g, 6.98 mmol)
was added. The reaction was stirred at room temperature for 24 hours. The reaction was taken
up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried with sodium
sulfate and concentrated. Purification was done with flash column chromatography (10% ethyl
acetate/hexanes) to give a clear oil (515 mg, 54%). TLC Rf = 0.25 (15% ethyl acetate/hexanes);
39
IR (neat) 3001, 2955, 2837, 1716, 1613, 1515, 1249 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31
(d, J = 8.7 Hz, 2H), 6.93-7.06 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 5.87 (d, J = 15.0 Hz, 1H), 5.10
(s, 2H), 3.80 (s, 3H), 1.86 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 159.7,
145.0, 130.1, 128.4, 122.7, 114.0, 65.8, 55.3, 18.0.
4-methoxybenzyl-1-adamantanoate 2.8
Lit. Ref.: Rolfe, A.; Loh, J. K.; Maity, P. K.; Hanson, P. R. Org. Lett. 2011, 13, 4-7.
In a flame dried 50 mL round bottom flask, 1-adamantanecarboxylic acid (400 mg, 2.22 mmol)
was dissolved in dry dichloromethane (9 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate
(1.255 g, 4.44 mmol) was added. The reaction was stirred at room temperature for 24 hours.
The reaction was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times,
dried with sodium sulfate and concentrated. Purification was done with flash column
chromatography (10% ether/hexanes) to give a clear oil (426 mg, 64%). TLC Rf = 0.65 (25%
ethyl acetate/hexanes); IR (neat) 2999, 2906, 2851, 1724, 1514, 1229 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.03 (s, 2H), 3.81 (s, 3H), 1.71-2.00
(m, 15H); 13C NMR (75 MHz, CDCl3) δ 177.6, 159.5, 129.6, 128.8, 113.9, 65.7, 55.3, 40.8,
38.9, 36.6, 28.1.
40
(S)-4-methoxybenzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate 2.9
Lit. Ref.: Yamada, I.; Noyori, R. Organic Letters, 2000, 2, 3425 – 3427.
In a flame dried 10 mL round bottom flask, (S)-(-)-α-(trifluoromethyl)phenylactic acid (50 mg,
0.214 mmol) was dissolved in dry dichloromethane (1 mL). 4-methoxybenzyl 2,2,2-
trichloroacetimidate (12 mg, 0.428 mmol) was added. The reaction was stirred at room
temperature overnight. The reaction was taken up in ethyl acetate, washed with sat. aq. sodium
bicarbonate three times, dried with sodium sulfate and concentrated. Purification was done with
flash column chromatography (10% ether/hexanes) to give a clear oil (38 mg, 50%). TLC Rf =
0.36 (25% ethyl acetate/hexanes); IR (neat) 2954, 2841, 1747, 1516, 1248, 1174 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.26-7.46 (m, 6H), 6.88 (d, J = 8.7 Hz, 2H), 5.29 (q, J = 11.8 Hz, 2H), 3.81
(s, 3H), 3.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 160.0, 132.3, 130.5, 129.6, 128.4,
127.3, 126.8, 125.2, 121.4, 114.0, 67.9, 55.5, 55.3.
4-methoxybenzyl 2,2-diphenylacetate 2.10
In a flame dried 50 mL round bottom flask, diphenylacetic acid (400 mg, 1.88 mmol) was
dissolved in dry dichloromethane (8 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.062 g,
41
3.76 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction
was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried with
sodium sulfate and concentrated. Purification was done with flash column chromatography
(10% ethyl acetate/hexanes) to give an orange solid (394 mg, 63%). TLC Rf = 0.35 (25% ethyl
acetate/hexanes); IR (KBr) 3028, 2956, 2836, 1734, 1612, 1514, 1250, 1145 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.26-7.34 (m, 11H), 6.90 (d, J = 8.6 Hz, 2H), 5.17 (s, 2H), 5.09 (s, 1H), 3.84 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 172.5, 159.8, 138.8, 130.2, 128.8, 128.7, 127.9, 127.4,
114.0, 66.9, 57.2, 55.4.
4-methoxybenzyl 2-acetoxybenzoate 2.11
In a flame dried 50 mL round bottom flask, acetylsalicylic acid (400 mg, 2.22 mmol) was
dissolved in dry dichloromethane (9 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.255 g,
4.44 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction
was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried with
sodium sulfate and concentrated. Purification was done with flash column chromatography
(10% ethyl acetate/hexanes) to give a clear oil (534 mg, 80%). TLC Rf = 0.69 (25% ethyl
acetate/hexanes); IR (neat) 2957, 2837, 1769, 1720, 1610, 1515, 1248 1195 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.04 (d, J = 1.7 Hz, 1H), 7.54 (t, J = 9.0 Hz, 1H), 7.29-7.38 (m, 3H), 7.09 (d, J =
9.0 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.24 (s, 2H), 3.81 (s, 3H), 2.13 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 169.8, 164.6, 159.9, 150.7, 133.2, 132.1, 130.5, 127.7, 126.1, 123.9, 123.5,
114.3, 67.0, 55.4, 20.8. Anal calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.60; H, 5.17.
42
4-methoxybenzyl cyclopropanecarboxylate 2.12
In a flame dried 50 mL round bottom flask, cyclopropane carboxylic acid (400 mg, 4.65 mmol)
was dissolved in dry dichloromethane (19 mL). 4-methoxybenzyl 2,2,2-trichloroacetimidate
(1.600 g, 5.66 mmol) was added. The reaction was stirred at room temperature for 24 hours.
The reaction was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times,
dried with sodium sulfate and concentrated. Purification was done with flash column
chromatography (10% ethyl acetate/hexanes) to give a clear oil (493 mg, 51%). TLC Rf = 0.53
(25% ethyl acetate/hexanes); IR (neat) 3011, 2956, 2836, 1724, 1613, 1515, 1249, 1166 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.30 (d, J= 8.6 Hz, 2H), 6.88 (d, J= 8.7 Hz, 2H), 5.05 (s, 2H), 3.78 (s,
3H), 1.59-1.67 (m, 1H), 0.94-1.08 (m, 2H), 0.78-0.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
174.7, 159.6, 130.1, 128.3, 113.9, 66.1, 55.2, 13.0, 8.5.
4-methoxybenzyl 3-(2,4-dichlorobenzyloxy)thiophene-2-carboxylate 2.13
In a flame dried 50 mL round bottom flask, 3-(2,4-dichlorobenzyloxy)thiophene-2-carboxylic
acid (400 mg, 1.32 mmol) was dissolved in dry dichloromethane (3 mL). 4-methoxybenzyl
2,2,2-trichloroacetimidate (746 mg, 2.64 mmol) was dissolved in dry dichloromethane (3 mL)
and added to the round bottom flask. The reaction was stirred at room temperature for 24 hours.
43
The reaction was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times,
dried with sodium sulfate and concentrated. Purification was done with flash column
chromatography (10% ethyl acetate/hexanes) to give a white solid (153 mg, 27%). mp = ; TLC
Rf = 0.58 (25% ethyl acetate/hexanes); IR (neat) 2954, 1682, 1588, 1544, 1431, 1384, 1248 cm-1;
1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.34-7.43 (m, 3H), 7.15 (d, J = 6.0 Hz,
1H), 6.89-6.92 (m, 3H), 5.30 (s, 2H), 5.71 (s, 2H), 3.81 (s, 3H).
4-methoxybenzyl 2-(diphenylphosphino)benzoate 2.14
In a flame dried 50 mL round bottom flask, 2-(diphenylphosphino)benzoic acid (400 mg, 1.31
mmol) was dissolved in dry dichloromethane (2.5 mL). 4-methoxybenzyl 2,2,2-
trichloroacetimidate (746 mg, 2.64 mmol) was dissolved in dry dichloromethane (2.5 mL) and
added to the round bottom flask. The reaction was stirred at room temperature for 24 hours. The
reaction was taken up in ethyl acetate, washed with sat. aq. sodium bicarbonate three times, dried
with sodium sulfate and concentrated. Purification was done with flash column chromatography
(1:1 ethyl acetate/hexanes) to give a clear oil (139 mg, 25%). TLC Rf = 0.26 (60% ethyl
acetate/hexanes); IR (neat) 3056, 1727, 1612, 1514, 1248, 1118 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.86-7.90 (m, 1H), 7.39-7.68 (m, 13H), 7.07 (d, J = 14.2 Hz, 2H), 6.78 (d, J = 9.0, 2H),
4.90 (s, 2H), 3.78 (s, 3H).
44
O
OH
O CCl3
NH
DCM, 24 h92%
O
O
benzhydryl 3,3-dimethylbutanoate 2.17
In a flame dried 50 mL round bottom flask, tert-butylacetic acid (0.33 mL, 2.58 mmol) was
dissolved in dry dichloromethane (10 mL). Benzhydryl 2,2,2-trichloroacetimidate (1.101 g, 3.35
mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction was
concentrated. Purification was done with flash column chromatography (1% ethyl
acetate/hexanes) to give a clear oil (0.669 g, 92%). TLC Rf = 0.79 (10% ethyl acetate/hexanes);
1H NMR (300 MHz, CDCl3): δ 7.26-7.37 (m, 9H), 6.89 (s, 1H), 2.32 (s, 2H), 0.99 (s, 9H); 13C
NMR (75 MHz, CDCl3): δ 171.4, 140.6, 128.6, 127.9, 127.4, 76.7, 48.2, 31.1, 29.8. Anal. Calcd
for C19H22O2: C, 80.82; H, 7.85. Found: C, 81.11; H, 8.03.
benzhydryl-1-adamantanoate 2.19
In a flame dried 25 mL round bottom flask, adamantane-1-carboxylic acid (0.300 g, 1.66 mmol)
was dissolved in dry dichloromethane (7 mL). Benzhydryl 2,2,2-trichloroacetimidate (0.710 g,
2.16 mmol) was added. The reaction was stirred at room temperature for 24 hours. The reaction
was concentrated. Purification was done with flash column chromatography (1% ethyl
acetate/hexanes) to give an orange solid (0.177 g, 31%). TLC Rf = 0.64 (10% ethyl
acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.23-7.36 (m, 16H), 6.83 (s, 1H), 2.03 (bs, 4H),
45
1.96 (bs, 9H), 1.73 (bs, 9H); 13C NMR (75 MHz, CDCl3) δ 176.5, 142.4, 140.9, 128.6, 128.5,
127.9, 127.6, 127.4, 127.1, 80.1, 76.3, 40.9, 39.0, 36.7, 28.1. Anal. Calcd for C24H26O2: C,
83.20; H, 7.56. Found: C, 83.17; H, 7.85.
General Procedure for Forming Sulfides from Trichloroacetimidates:
The thiol was placed in a dry round bottom flask and dissolved in anhydrous THF (or toluene) to
a concentration of 0.2 M. The trichloroacetimidate (1.2 equiv) was then added and the reaction
was warmed to reflux. After 18 hours the reaction was cooled to room temperature and
concentrated under reduced pressure. The residue was then pre-adsorbed on silica gel and
purified by column chromatography. Alternatively, the residue can be dissolved in ethyl acetate,
washed with 2M aq. NaOH (3x), dried (Na2SO4) and concentrated (this workup removes the
trichloroacetamide byproduct). For some sulfides this workup provided analytically pure
material, in others the residue is purified by silica gel chromatography to provide the pure sulfide
product.
5-[(3-Methyl-2-butenyl)thio]-1-phenyl-1H-tetrazole 2.21.
Cream colored solid (0.250 g, 98%). mp =38.6-39.9°C; TLC Rf = 0.72 (30% ethyl acetate /70%
hexanes); IR (neat) 3062, 3015, 2981, 2928, 2895 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61-7.55
(m, 5H), 5.44-7.37 (m, 1H), 4.04 (d, J = 8.0 Hz, 2H), 1.73 (s, 6H) . Anal calcd for C12H14N4S: C,
58.51; H, 5.73, N, 22.74. Found: C, 58.29; H, 5.54; N, 22.39.
46
1-Phenyl-5-[[(2E)-3-phenyl-2-propen-1-yl]thio]-1H-tetrazole 2.22.
Lit. Ref.: Han, X.; Wu, J. Org. Lett. 2010, 12, 5780-5782.
Yellow oil (0.264 g, 95%). TLC Rf = 0.63 (30% ethyl acetate /70% hexanes); 1H NMR (400
MHz, CDCl3) δ 7.61-7.55 (m, 5H), 7.39- 7.27 (m, 5H), 6.72 (d, J = 15.6 Hz, 1H), 6.41-6.31 (m,
1H), 4.23 (d, J = 8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 153.9, 136.2, 135.4, 133.8, 130.3,
130.0, 128.8, 128.3, 126.7, 124.0, 122.6, 36.1.
5-(Isopropylthio)-1-phenyl-1H-tetrazole 2.23.
Lit. Ref.: Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505-11515.
Yellow oil (0.689 g, 38%). TLC Rf = 0.64 (35% DCM /65% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.58-7.52 (m, 5H), 3.42 (heptet, J = 6.5 Hz, 1H), 1.51 (d, J = 6.5 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 154.1, 133.7, 130.1, 129.7, 124.0, 39.8, 23.3.
General Procedure for the Formation of DPM Ethers from Alcohols under Thermal
Conditions:
The alcohol was placed in a 25 mL flame dried round bottom flask and dissolved in anhydrous
toluene to a concentration of 0.25 M. The trichloroacetimidate (1.2 equiv) was added and the
reaction warmed to reflux. After 18 hours, the reaction was cooled to room temperature and
concentrated under reduced pressure. The residue was pre-adsorbed on silica gel and purified by
silica gel column chromatography. The residue can be dissolved in ethyl acetate, washed with
2M aq. NaOH (3x), dried (Na2SO4) and concentrated (this workup removes the
trichloroacetamide byproduct).
47
Octadecyloxydiphenylmethane 2.35.
White solid (0.273 g, 85%). mp = 47-48 °C; TLC Rf = 0.80 (10% ethyl acetate/hexanes); IR (solid
film from CH2Cl2) 3027, 2923, 2852, 1493, 1453, 1097 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.21-
7.37 (m, 10H), 5.33 (s, 1H), 3.44 (t, J = 6.6 Hz, 2H), 1.60-1.67 (m, 2H), 1.26 (m, 30H), 0.88 (t, J
= 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 142.9, 128.5, 127.5, 127.2, 83.8, 69.4, 32.2, 30.1,
29.94, 29.91, 29.87, 29.85, 29.7, 29.6, 26.5, 22.9, 14.3 (several signals in the aliphatic region were
not resolved). Anal calcd for C31H48O: C, 85.26; H, 11.08. Found: C, 85.18; H, 11.13.
Benzyloxydiphenylmethane 2.36.
Lit. Ref.: Xu, Q.; Xie, H.; Chen, P.; Yu, L.; Chen, J.; Hu, X. Green Chem. 2015, 17, 2774-2779.
Clear oil (0.238 g, 94%). TLC Rf = 0.92 (25% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3)
δ 7.24-7.42 (m, 15H), 5.46 (s, 1H), 4.56 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 142.4, 138.6, 128.6,
128.6, 127.9, 127.72, 127.65, 127.3, 82.7, 70.7.
48
(4-Methoxybenzyloxy)diphenylmethane 2.37.
Lit. Ref.: Kalutharage, N.; Yi, C. S. Org. Lett. 2015, 17, 1778-1781.
Clear oil (0.314 g, 71%). TLC Rf = 0.50 (10% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3)
δ 7.24-7.41 (m, 12H), 6.91 (d, J = 8.7 Hz, 2H), 5.45 (s, 1H), 4.50 (s, 2H), 3.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.3, 142.4, 130.6, 129.5, 128.5, 127.6, 127.3, 113.9, 82.2, 70.3, 55.4.
(((4-Nitrobenzyl)oxy)methylene)dibenzene 2.39.
Off-white solid (0.460 g, 88%). mp = 62-64 °C (DCM); TLC Rf = 0.59 (40% DCM/60% hexanes);
IR (solid film from CH2Cl2) 3062, 3028, 2922, 2857, 1493, 1347, 1288 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.25-7.40 (m, 10H), 5.46 (s, 1H), 4.62
(s, 2H); 13C NMR (75 MHz, CDCl3) δ 147.4, 146.1, 141.6, 128.6, 127.8, 127.7, 127.0, 123.6, 83.5,
69.5. Anal calcd for C20H17NO3: C, 77.22; H, 5.37; N, 3.49. Found: C, 77.20; H, 5.31; N, 3.44.
Cinnamyloxydiphenylmethane 2.43.
Lit. Ref.: Zhang, W.; Haight, A. R.; Hsu, M. C. Tetrahedron Lett. 2002, 43, 6575-6578.
49
White solid (0.395 g, 88%). mp = 55-57 °C; TLC Rf = 0.58 (25% ethyl acetate/hexanes); 1H NMR
(300 MHz, CDCl3) δ 7.23-7.42 (m, 15H), 6.63 (d, J = 15.9 Hz, 1H), 6.32-6.41 (m, 1H), 5.51 (s,
1H), 4.20 (dd, J = 6.0, 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 142.3, 136.9, 132.3, 128.6,
128.5, 127.7, 127.5, 127.1, 126.6, 126.3, 82.8, 69.4.
Diphenyl(prop-2-ynyloxy)methane 2.47.
Lit. Ref.: Louvel, J.; Carvalho, J. F. S.; Yu, Z.; Soethoudt, M.; Lenselink, E. B.; Klaasse, E.;
Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2013, 56, 9427-9440.
Yellow oil (0.384 g, 97%). TLC Rf = 0.86 (10% ethyl acetate/hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.24-7.40 (m, 10H), 5.68 (s, 1H), 4.17 (d, J = 2.4 Hz, 2H), 2.46 (t, J = 2.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 141.3, 128.6, 127.9, 127.5, 81.8, 79.9, 74.8, 56.0.
((Cyclohexyloxy)methylene)dibenzene 2.44.
Lit. Ref.: Bhaskar, G.; Solomon, M.; Babu, G.; Muralidharan, D.; Perumal, P. T. Indian J.
Chem., Sect. B. 2010, 49B, 795-801.
Clear oil (0.494 g, 93%). TLC Rf = 0.68 (10% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3)
δ 7.24-7.40 (m, 10H), 5.58 (s, 1H), 3.35-3.44 (m, 1H), 1.93 (dd, J = 9.0, 6.0 Hz, 2H), 1.76-1.82
50
(m, 2H), 1.41-1.58 (m, 3H), 1.26 (q, J = 8.3 Hz, 3H); 13C NMR (75MHz, CDCl3) δ143.3, 128.4,
127.31, 127.26, 80.1, 75.1, 32.5, 26.0, 24.2.
((1-Phenylethoxy)methylene)dibenzene 2.38.
Lit. Ref.: Sciebura, J.; Gawronski, J. Tetrahedron: Asymmetry 2013, 24, 683-688.
Clear oil (0.434 g, 92%). TLC Rf = 0.85 (10% acetone/hexanes); 1H NMR (300 MHz, CDCl3) δ
7.20-7.41 (m, 15H), 5.31 (s, 1H), 4.51 (q, J = 6.6 Hz, 1H), 1.53 (d, J = 6.3 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 143.9, 143.0, 142.2, 128.7, 128.4, 128.3, 127.73, 127.70, 127.67, 127.3, 127.1,
126.7, 80.2, 75.1, 24.5.
((tert-Pentyloxy)methylene)dibenzene 2.45.
Lit. Ref.: Buckley, A.; Chapman, N. B.; Dack, M. R. J.; Shorter, J.; Wall, H. M. J. Chem. Soc., B
1968, 631-638.
Clear oil (0.489 g, 85%). TLC Rf = 0.92 (10% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3)
δ 7.41 (d, J = 6.9 Hz, 4H), 7.33 (t, J = 7.2 Hz, 4H), 7.20-7.26 (m, 2H), 5.60 (s, 1H), 1.62 (q, J =
7.5 Hz, 2H), 1.17 (s, 6H), 0.91 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6, 128.3,
127.0, 126.9, 76.9, 75.6, 34.8, 26.1, 8.9.
51
1-(Benzhydryloxy)adamantane 2.46.
Orange solid (0.383 g, 92%). mp = 64-66 °C; TLC Rf = 0.71 (10% ethyl acetate/hexanes); IR (solid
film from CH2Cl2) 3025, 2905, 2850, 1492, 1451, 1354, 1082 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.20-7.39 (m, 10H), 5.80 (s, 1H), 2.14 (s, 3H), 1.83 (bs, 6H), 1.62 (bs, 6H); 13C NMR (100 MHz,
CDCl3) δ 145.3, 128.2, 127.2, 126.9, 74.4, 73.8, 43.0, 36.6, 30.8. Anal calcd for C23H26O: C, 86.75;
H, 8.23. Found: C, 86.72; H, 8.18.
2-((Benzhydryloxy)methyl)-3-phenyloxirane 2.51.
Lit. Ref.: Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1997, 62, 4970-
4982.
Clear oil (0.255 g, 65%) TLC Rf = 0.50 (10% ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3)
δ 7.25-7.44 (m, 15H), 5.53 (s, 1H), 3.86 (dd, J = 11.5, 3.1 Hz, 1H), 3.80 (d, J = 2.0 Hz, 1H) 3.66
(dd, J = 5.3, 11.5 Hz, 1H), 3.29-3.32 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 141.99, 141.94,
137.1, 128.7, 128.6, 128.4, 127.8, 127.77, 127.5, 127.3, 127.2, 125.9, 84.1, 68.9, 61.4, 56.1.
52
(2-(Benzhydryloxy)ethyl)trimethylsilane 2.53.
Pale yellow oil (0.368 g, 79%). TLC Rf = 0.56 (15% DCM/5% triethylamine/ 80% hexanes); IR
(solid film from CH2Cl2) 3087, 3063, 3029, 2953, 2892, 1452, 1317, 1249 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.36 (dd, J = 6.3, 1.2 Hz, 4H), 7.30 (t, J = 6.6 Hz, 4H), 7.22-7.25 (m, 2H), 5.35 (s,
1H), 3.56 (t, J = 6.0 Hz, 2H), 1.03 (t, J = 6.0 Hz, 2H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 144.0, 129.6, 128.5, 128.2, 84.6, 67.6, 19.7, 0.0; Anal calcd for C18H24OSi: C, 76.00; H, 8.50;
Found: C, 75.77; H, 8.62.
2-(Benzhydryloxy)isoindoline-1,3-dione 2.49.
Lit. Ref.: Reddy, C. R.; Radhika, L.; Kumar, T. P.; Chandrasekhar, S. Eur. J. Org. Chem. 2011,
2011, 5967-5970.
Yellow solid (0.323 g, 80%). mp = 160-162 °C; TLC Rf = 0.29 (10% acetone/hexanes); 1H NMR
(300 MHz, CDCl3) δ 7.66-7.76 (m, 4H), 7.52-7.56 (m, 4H), 7.29-7.39 (m, 6H), 6.53 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 163.8, 137.9, 134.4, 128.9, 128.8, 128.5, 128.4, 123.4, 89.7.
53
(S)-Benzyl 3-(benzhydryloxy)-2-(((benzyloxy)carbonyl)amino)propanoate 2.55.
Clear oil (0.273 g, 91%). [α]𝐷21.6 -12.5 (c 1.26, CHCl3); TLC Rf = 0.18 (10% ethyl acetate/hexanes);
IR (solid film from CH2Cl2) 3434, 3341, 3062, 3030, 2949, 2876, 1722, 1498, 1339, 1197, 1067
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.07-7.30 (m, 20H), 5.63 (d, J = 12.0 Hz, 1H), 5.19 (s, 1H),
5.12 (d, J = 4.0 Hz, 2H), 5.04 (s, 2H), 4.49 (dt, J = 2.8 Hz, 1H), 3.84 (dd, J = 9.4, 2.8 Hz, 1H),
3.60 (dd, J = 9.4, 3.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ170.3, 156.1, 141.6, 141.4, 136.4,
135.4, 128.7, 128.65, 128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.0, 126.9, 84.2, 69.0, 67.4, 67.2,
54.8 . (note: two signals in the aromatic region were not resolved.) Anal calcd for C31H29NO5: C,
75.13; H, 5.90; N, 2.83. Found: C, 74.94; H, 5.97; N, 3.00. Chiral HPLC analysis: Chiralcel OD
(heptane/2-PrOH = 90/10, 1.0 mL/min, 254 nm, 25 °C): t(S enantiomer) = 16.7 min, t(R enantiomer) = 23.9
min.
Methyl 2,3,4-Tri-O-benzyl-6-O-diphenylmethyl-α-D-glucopyranoside 2.52.
Lit. Ref.: Ali, I. A. I.; El Ashry, E. S. H.; Schmidt, R. R. Eur. J. Org. Chem. 2003, 4121-4131.
Clear colored oil (0.750 g, 73%). TLC Rf = 0.43 (15% ethyl acetate/85% hexanes); 1H NMR (300
MHz, CDCl3) δ 7.55-7.18 (m, 25 H), 5.50 (s, 1H), 5.13 (d, J = 10.8 Hz, 1H), 4.98 (t, J = 11.1 Hz,
54
2H), 4.93 (d, J = 12.0 Hz, 1H), 4.82 (d, J = 11.7 Hz, 1H), 4.80 (d, J = 3.6 Hz, 1H), 4.68 (d, J =
11.1 Hz, 1H), 4.16 (t, J = 9.3 Hz, 1H), 3.89-3.99 (m, 1H), 3.77-3.84 (m, 3H), 3.72 (dd, J = 3.6,
9.6 Hz, 1H), 3.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 142.2, 142.1, 138.8, 138.3, 138.2, 128.5,
128.4, 128.36, 128.1, 127.9, 127.8, 127.7, 127.5, 127.4, 127.2, 126.9, 98.1, 84.1, 82.3, 80.1, 78.0,
75.9, 75.1, 73.4, 70.3, 67.9, 55.1.
(3S,5S,8R,9S,10S,13R,14S,17R)-3-(Benzhydryloxy)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene 2.48.
White solid (0.374 g, 87%). [α]𝐷21.6 +12.4 (c 1.04, CHCl3); mp = 127-129 °C; TLC Rf = 0.74 (10%
ethyl acetate/hexanes); IR (solid film from CH2Cl2) 3027, 2930, 2865, 1493, 1452, 1381, 1062 cm-
1; 1H NMR (300 MHz, CDCl3) δ 7.16-7.34 (m, 10H), 5.54 (s, 1H), 3.28-3.38 (m, 1H), 0.63-1.92
(m, 46H); 13C NMR (75 MHz, CDCl3) δ 143.3, 128.4, 127.4, 127.3, 80.3, 76.5, 56.7, 56.5, 54.6,
45.0, 42.8, 40.3, 39.7, 37.2, 36.4, 36.0, 35.95, 35.7, 35.3, 32.3, 29.1, 28.7, 28.5, 28.2, 24.4, 24.0,
23.0, 22.8, 21.4, 18.9, 12.5, 12.3. Anal calcd for C40H58O: C, 86.58; H, 10.54. Found: C, 86.59; H,
10.68.
55
Ethyl 3-(benzhydryloxy)-3-phenylpropanoate 2.50.
White solid (0.178 g, 96%). mp = 73-74 °C; TLC Rf = 0.53 (10% ethyl acetate/hexanes); IR (solid
film from CH2Cl2) 3061, 3028, 2980, 1736, 1493, 1453, 1268, 1172, 1052 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.19-7.40 (m, 15H), 5.24 (s, 1H), 4.81 (ddd, J = 1.3, 4.9, 9.0 Hz, 1H), 4.00-4.23
(m, 2H), 2.96 (ddd, J = 1.4, 9.0, 14.7 Hz, 1H), 2.65 (ddd, J = 1.2, 4.9, 14.7 Hz, 1H), 1.21 (td, J =
1.1, 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 142.8, 141.3, 140.7, 128.8, 128.6, 128.3,
128.2, 128.0, 127.9, 127.24, 127.16 126.7, 80.11, 75.7, 60.6, 44.0, 14.3. Anal calcd for C24H24O3:
C, 79.97; H, 6.71. Found: C, 79.96; H, 6.88.
(R)-Ethyl 2-(benzhydryloxy)propanoate 2.54.
Lit. Ref.: Steinbeck, M.; Frey, G. D.; Schoeller, W. W.; Herrmann, W. A. J. Organomet. Chem.
2011, 696, 3945-3954.
Clear oil (0.434 g, 90%). [α]𝐷21.6 -103.8 (c 1.04, DCM); TLC Rf = 0.57 (10% ethyl
acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.26-7.41 (m, 10H), 5.57 (s, 1H), 4.16-4.28 (m,
2H), 4.08 (q, J = 6.0 Hz, 1H), 1.49 (d, J = 9.0 Hz, 3H), 1.30 (t, J = 9.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 173.6, 142.1, 141.1, 128.7, 128.4, 128.0, 127.7, 127.6, 127.5, 82.8, 72.7, 61.0,
56
19.0, 14.4. Chiral HPLC analysis: Chiralcel OD (heptane/2-PrOH = 99/1, 1.0 mL/min, 254 nm, 25
°C): t(R enantiomer) = 5.3 min, t(S enantiomer) = 5.8 min.
((4-Methoxyphenoxy)methylene)dibenzene 2.40.
Lit. Ref.: Bordwell, F. G.; Harrelson, J. A., Jr. J. Org. Chem. 1989, 54, 4893-4898.
Orange solid (0.424 g, 91%). mp = 84-85 °C; TLC Rf = 0.42 (10% acetone/hexanes); 1H NMR
(300 MHz, CDCl3) δ 7.26-7.43 (m, 10H), 6.88 (d, J = 9.1 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 6.11
(s, 1H), 3.73 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 154.2, 152.4, 141.7, 128.7, 127.8, 127.1,
117.4, 114.7, 82.8, 55.7.
((4-Nitrophenoxy)methylene)dibenzene 2.41.
Lit. Ref.: Maslak, P.; Guthrie, R. D. J. Am. Chem. Soc. 1986, 108, 2628-2636.
Pale yellow colored solid (0.310 g, 61%). mp = 157-158 °C; TLC Rf = 0.36 (10% ethyl acetate/90%
hexanes); 1H NMR (300 MHz, CDCl3) δ 8.13 (d, J = 9.0 Hz, 2H), 7.28-7.42 (m, 10H), 7.02 (d, J
= 9.3 Hz, 2H), 6.31 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 162.9, 141.6, 139.8, 128.8, 128.3, 126.7,
125.8, 115.9, 82.5.
57
Methyl 3-(benzhydryloxy)thiophene-2-carboxylate 2.42.
White solid, (0.280 g, 53%). mp = 105-106 °C; TLC Rf = 0.3 (10% ethyl acetate/90% hexanes);
IR (solid film from CH2Cl2) 3061, 3028, 2948, 1711, 1538, 1228, 1062 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 7.6 Hz, 4H), 7.35 (t, J = 7.2 Hz, 4H), 7.25–7.28 (m, 3H), 6.74 (d, J = 5.6 Hz,
1H), 6.27 (s, 1H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4, 160.1, 141.2, 130.4, 128.9,
128.1, 126.7, 118.7, 111.6, 85.0, 51.8. Anal calcd for C19H16O3S: C, 70.35; H, 4.97; Found: C,
70.26; H, 5.02.
1-methoxy-4-((1-phenylethoxy)methyl)benzene 2.66
Lit. Ref.: Bartels, B.; Hunter, R. J. Org. Chem., 1993, 58, 6756–6765.
In a 10 mL flame dried round bottom flask, 1-phenylethanol (0.366 g, 3.0 mmol) was dissolved
in anhydrous trifluorotoluene (3 mL). PMB imidate (1.690g, 6.0 mmol) was added to the flask.
The reaction refluxed for 20 hours. The reaction was concentrated. Purification was done using
column chromatography (10% ethyl acetate/hexanes) followed by column chromatography (50%
CH2Cl2) to give product as a clear colorless oil (0.477 g, 67%).
TLC Rf = 0.52 (10% ethyl acetate/90% hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.20 (m,
6H), 6.85 (d, J = 8.7 Hz, 2H), 4.46 (q, J = 6.6 Hz, 1H), 4.23 (dd, J = 11.4, 46.8 Hz, 2H), 3.75 (s,
3H), 1.45 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 143.9, 130.8, 129.4, 128.6,
127.5, 126.4, 113.9, 77.0, 55.3, 24.3;
58
4-methoxybenzyl benzyl ether 2.63.
Lit. Ref.: Baltzly, R.; Buck, J. S. J. Am. Chem. Soc., 1943, 65, 1984–1992
81% yield, clear colored oil. TLC Rf = 0.54 (20% ethyl acetate/80% hexanes); 1H NMR (400
MHz, CDCl3) δ 7.34-7.23 (m, 7 H), 6.87 (d, J = 8.4 Hz, 2 H), 4.51 (s, 2 H), 4.48 (s, 2 H), 3.77 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ 159.1, 138.3, 130.3, 129.3, 128.3, 127.7, 127.5, 113.7,
71.6, 55.2.
bis(4-methoxybenzyl)ether 2.64.
Lit. Ref.: Felix, D., Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. HCA, 1969, 1030–1042.
78% yield, clear colored oil. TLC Rf = 0.50 (20% acetone/80% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.27 (d, J = 8.8 Hz, 4 H), 6.87 (d, J = 8.8 Hz, 4 H), 4.50 (s, 4 H), 3.78 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 159.1, 130.4, 129.3, 113.7, 71.4, 55.2.
1-methoxy-4-(4-nitro-benzyloxymethyl)-benzene 2.65.
85% yield, dark yellow colored oil. TLC Rf = 0.45 (10% acetone/90% hexanes); IR (neat) 3109,
3076, 3003, 2935, 2838, 1561, 1342, 1302, 1246; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2
Hz, 2 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 2 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 4.61 (s, 2
H), 4.55 (s, 2 H), 3.81 (s, 3 H); 13 C NMR (100 MHz, CDCl3) δ 159.5, 147.3, 146.1, 129.6,
59
129.5, 129.3, 127.8, 123.6, 114.4, 113.9, 72.5, 70.5, 55.3, 44.9; Anal. Calcd for C15H15NO4: C,
65.92; H, 5.53; N, 5.13. Found: C, 65.80, H, 5.41, N, 5.00.
N-(4-methoxybenzyloxy)phthalimide.
Lit. Ref.: Ramsay, S. L.; Freeman, C.; Grace, P. B.; Redmond, J. W.; MacLeod, J. K.
Carbohydrate Research. 333. 59-71.
58% yield, white colored solid. mp = 134.9-136.3°C (ethyl acetate); TLC Rf = 0.28, 0.57 (20%
ethyl acetate/80% hexanes); 1H NMR (300 MHz, CDCl3) δ 7.82-7.71 (m, 4 H) 7.45 (d, J = 8.4
Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 5.15 (s, 2 H), 3.80 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
163.5, 160.4, 134.3, 131.6, 128.8, 125.8, 123.4, 113.9, 79.4, 55.2.
(4-Methoxyphenyl)methyl propargyl ether 2.67.
Lit. Ref.: Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org. Chem., 1989, 54, 5854–5855
82% yield, Clear oil. TLC Rf = 0.41 (10% Ethyl acetate/90% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.32 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 1.8 Hz, 2 H), 4.57 (s, 2 H), 4.17 (d, J = 2.4 Hz, 2
H), 3.82 (s, 3 H), 4.55 (s, 2 H), 2.52 (d, J = 2.4 Hz, 1 H).
1-((4-methoxybenzyl)oxy)-2-nitrobenzene 2.70.
60
76% yield, yellow oil. TLC Rf = 0.30 (10% ethyl acetate/90% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.83 (dd, J = 1.6, 8.1 Hz, 1H), 7.49 (ddd, J = 1.7, 7.5, 8.4 Hz, 1H), 7.38 (d, J = 8.6 Hz,
2H), 7.14 (dd, J = 1.0, 8.5 Hz, 1H), 7.02 (td, J = 0.9, 7.6 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 5.16
(s, 2H), 3.81 (s, 3H).
(2-((4-methoxybenzyl)oxy)ethyl)trimethylsilane 2.74.
68% yield, red oil. TLC Rf = 0.76 (10% ethyl acetate/90% hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.1 Hz, 1H), 4.40 (s, 2H), 3.78 (s, 3H), 3.54 (td, J
= 0.9, 8.1 Hz, 2H), 0.97 (td, J = 0.9, 8.1 Hz, 2H), 0.00 (s, 9H).
(E)-1-((cinnamyloxy)methyl)-4-methoxybenzene 2.62.
Lit. Ref.: Charette, A. B. Synlett 2002, 176-178.
52% yield, yellow oil. TLC Rf = 0.70 (25% ethyl acetate/75% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 7.2 Hz, 2H), 7.34-7.30 (m, 4H), 7.25 (d, J = 6.3 Hz, 1H), 6.90 (d, J = 8.6
Hz, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.33 (dt, J = 6.0, 15.9 Hz, 1H), 4.52 (s, 2H), 4.18 (dd, J = 1.4,
6.0 Hz, 2H), 3.82 (s, 3H).
1-methoxy-4-((octadecyloxy)methyl)benzene 2.60.
Lit. Ref.: Kurosu, M. Synthesis 2009, 3633-3641.
61
96 % yield, white solid. mp = 45.6-46.5°C (dichloromethane). TLC Rf = 0.82 (10% ethyl
acetate/90% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.7
Hz, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 1.63-1.56 (m, 2H), 1.36-1.25 (m,
34H), 0.88 (t, J = 6.6 Hz, 3H).
ethyl 3-((4-methoxybenzyl)oxy)-3-phenylpropanoate 2.77.
61% yield, clear oil. TLC Rf = 0.47 (10% ethyl acetate/90% hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.39-7.29 (m, 5H), 7.19 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.83 (q, J = 5.1
Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.23 (d, J = 11.1 Hz, 1H), 4.17-4.06 (m, 2H), 3.80 (s, 3H),
2.85 (dd, J = 9.0, 15.0 Hz, 1H), 2.59 (dd, J = 4.8, 15.3 Hz, 1H), 1.20 (t, J = 7.2 Hz, 3H).
3-[(4-Methoxybenzyl)oxy]propan-1-ol 2.84.
Lit. Ref.: Adje, N.; Breuilles, P.; Uguen, D. Tetrahedron Lett. 1993, 34, 4631-4634.
79% yield, pale yellow oil. TLC Rf = 0.43 (50 % ethyl acetate/50 % hexanes ); 1H NMR (300
MHz, CDCl3) δ 7.28 (d, J = 8.7 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 4.48 (s, 2 H), 3.84 (s, 3 H),
3.80 (t, J =5.5 Hz, 2 H), 3.67 (t, J =5.8 Hz, 2 H), 2.17 (bs, 1 H), 1.88 (q, J =5.7 Hz, 2 H).
2-(4-Methoxybenzyloxy)ethanol 2.83.
62
Lit. Ref.: Kukase, K.; Tanaka, H.; Toriib, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389-392.
80% yield, yellow oil. TLC Rf = 0.32 (50 % ethyl acetate/50 % hexanes ); 1H NMR (300 MHz,
CDCl3) δ 7.30 (d, J = 7.8 Hz, 2 H), 6.92 (d, J = 11.6 Hz, 2 H), 4.53 (s, 2 H), 3.84 (s, 3 H), 3.78
(t, J =4.7 Hz, 2 H), 3.61 (t, J =4.8 Hz, 2 H), 1.85 (bs, 1 H).
4-[(4-Methoxyphenyl)methoxy]-2-butyn-1-ol 2.85.
Lit. Ref.: Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto, T.;
Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 38, 7887-7890.
36% yield, yellow oil. TLC Rf = 0.52 (50 % ethyl acetate/50 % hexanes ); 1H NMR (300 MHz,
CDCl3) δ 7.30 (d, J = 6.6 Hz, 2 H), 6.91 (d, J = 11.6 Hz, 2 H), 4.56 (s, 2 H), 4.36 (t, J =1.8 Hz, 2
H), 4.21 (t, J =2.1 Hz, 2 H), 3.84 (s, 3 H).
63
Appendix A. 1H AND 13C NMR SPECTRA SUPPLEMENT TO
CHAPTER 2
9 8 7 6 5 4 3 2 1 ppm
1.012
2.222
3.806
5.037
6.870
6.899
7.284
7.312
7.313
9.0
0
1.8
5
2.9
0
1.9
7
1.6
3
1.6
0
O
O
OMe
4-methoxybenzyl 3,3-dimethylbutanoate
64
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
29.768
30.934
48.079
55.333
65.772
114.001
128.455
130.234
159.668
172.326
4-methoxybenzyl 3,3-dimethylbutanoate
O
O
OMe
9 8 7 6 5 4 3 2 1 ppm
3.784
3.872
5.281
6.885
6.914
6.937
6.962
7.376
7.405
7.430
7.433
7.438
7.457
7.463
7.787
7.792
7.813
7.819
3.0
8
3.0
0
2.0
3
3.5
2
2.4
8
0.7
4
O
O
OMeOMe
4-methoxybenzyl 2-methoxybenzoate
65
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm55.323
56.012
66.395
112.096
113.966
114.332
120.097
120.150
128.423
130.046
131.756
133.648
159.371
159.607
166.040
O
O
OMeOMe
4-methoxybenzyl 2-methoxybenzoate
9 8 7 6 5 4 3 2 1 ppm
1.850
1.855
1.873
1.879
3.800
5.104
5.841
5.846
5.893
5.898
6.864
6.874
6.880
6.896
6.903
6.912
6.941
6.964
6.987
6.992
7.010
7.016
7.039
7.062
7.260
7.288
7.297
7.326
7.336
2.8
8
3.0
0
2.0
0
0.6
8
1.7
1
0.6
9
1.6
4
O
O
OMe
(E)-4-methoxybenzyl but-2-enoate
66
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
18.023
55.279
65.835
113.969
122.676
128.364
130.094
145.034
159.647
166.443
(E)-4-methoxybenzyl but-2-enoate
O
O
OMe
9 8 7 6 5 4 3 2 1 ppm
1.656
1.666
1.706
1.747
1.894
1.903
2.002
3.806
5.030
6.869
6.875
6.891
6.898
7.257
7.258
7.279
7.286
6.7
7
9.5
9
3.0
0
2.1
0
1.6
8
1.7
7
O
O
OMe
(3r,5r ,7r )-4-methoxybenzyl adamantane-1-carboxylate
67
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
28.049
36.593
38.903
40.806
55.310
65.656
113.939
128.778
129.593
159.490
177.587
O
O
OMe
(3r,5r ,7r )-4-methoxybenzyl adamantane-1-carboxylate
9 8 7 6 5 4 3 2 1 ppm
3.503
3.506
3.812
5.228
5.267
5.311
5.350
6.853
6.863
6.869
6.885
6.892
6.901
7.260
7.279
7.288
7.294
7.317
7.328
7.342
7.348
7.354
7.362
7.369
7.376
7.389
7.432
7.459
2.7
7
3.0
0
2.0
4
1.7
3
3.9
7
1.6
5
O
O
OMeMeO CF3
(S)-4-methoxybenzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
68
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
55.314
55.535
67.897
113.992
121.412
125.235
126.746
127.322
128.393
129.586
130.542
132.326
159.966
166.516
(S)-4-methoxybenzyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
O
O
OMeMeO CF3
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
3.836
5.093
5.167
6.881
6.904
6.910
7.260
7.282
7.288
7.301
7.308
7.316
7.333
7.344
3.0
0
0.8
5
2.0
3
1.7
6
10.2
9
O
O
OMe
4-methoxybenzyl 2,2-diphenylacetate
69
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
55.403
57.194
66.928
114.028
127.394
127.968
128.723
128.783
130.237
138.809
159.778
172.520
4-methoxybenzyl 2,2-diphenylacetate
O
O
OMe
10 9 8 7 6 5 4 3 2 1 0 ppm
2.124
3.815
5.241
6.880
6.897
6.905
6.927
6.934
7.067
7.070
7.094
7.097
7.252
7.261
7.269
7.272
7.294
7.297
7.319
7.323
7.346
7.368
7.375
7.517
7.522
7.542
7.547
7.568
7.574
8.033
8.039
8.059
8.065
2.7
6
3.0
0
1.9
6
1.7
6
0.7
4
2.6
6
0.8
2
0.7
2
O
O
OMe
O
O
4-methoxybenzyl 2-acetoxybenzoate
70
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
20.827
55.349
66.978
114.099
123.459
123.931
126.118
127.722
130.447
132.089
133.986
150.706
159.894
164.591
169.760
4-methoxybenzyl 2-acetoxybenzoate
O
O
OMe
O
O
9 8 7 6 5 4 3 2 1 ppm
0.829
0.842
0.846
0.856
0.868
0.985
0.997
1.006
1.012
1.021
1.037
1.586
1.601
1.613
1.616
1.628
1.639
1.644
1.655
1.670
3.780
5.051
6.869
6.898
7.281
7.310
1.9
6
1.8
6
0.7
4
3.0
0
2.0
0
1.7
4
1.7
0
O
O
OMe
4-methoxybenzyl cyclopropanecarboxylate
71
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
8.499
12.960
55.211
66.085
113.930
128.296
130.053
159.628
174.744
4-methoxybenzyl cyclopropanecarboxylate
O
O
OMe
9 8 7 6 5 4 3 2 1 ppm
3.828
5.220
5.263
6.849
6.868
6.878
6.885
6.900
6.907
7.134
7.141
7.162
7.169
7.260
7.354
7.372
7.379
7.382
7.411
7.429
7.520
7.548
3.0
0
3.6
5
2.5
7
0.6
9
0.4
0
2.0
2
0.6
4
0.6
6
4-methoxybenzyl 3-((2,4-dichlorobenzyl)oxy)thiophene-2-carboxylate
O
OOMe
S
OCl
Cl
72
9 8 7 6 5 4 3 2 1 ppm
3.783
4.904
6.758
6.787
7.056
7.085
7.392
7.397
7.402
7.415
7.420
7.425
7.430
7.441
7.450
7.466
7.473
7.478
7.489
7.494
7.499
7.505
7.514
7.519
7.528
7.536
7.543
7.554
7.562
7.578
7.584
7.601
3.0
0
2.1
4
1.8
6
1.8
5
13.4
0
0.9
0
O
O
P
MeO
4-methoxybenzyl 2-(diphenylphosphino)benzoate
73
9 8 7 6 5 4 3 2 1 ppm
1.685
1.695
1.728
1.776
1.954
1.964
2.035
6.834
7.249
7.252
7.256
7.260
7.268
7.277
7.283
7.296
7.300
7.305
7.309
7.312
7.330
7.337
7.344
7.355
7.359
0.4
9
7.1
0
7.0
0
3.1
5
0.8
1
10.0
0
(3r ,5r ,7r )-benzhydryl adamantane-1-carboxylate
O
O
2.19
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm
28.089
36.645
38.933
40.988
76.337
127.050
127.858
128.607
140.841
176.526
O
O
2.19
(3r ,5r ,7r )-benzhydryl adamantane-1-carboxylate
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
ODPM16 8
91
ODPM16 8
92
ODPM11
93
ODPM11
94
ODPM
MeO12
95
ODPM
MeO12
96
ODPM
O2N13
97
ODPM
O2N13
98
ODPM
14
99
ODPM
14
100
ODPM
15
101
ODPM
15
102
ODPM
16
103
ODPM
16
104
ODPM
17
105
ODPM
17
106
ODPM
18
107
ODPM
18
108
ODPM
19
109
ODPM
19
110
DPMO
O
20
111
DPMO
O
20
112
DPMOSiMe321
113
DPMOSiMe321
114
N
O
O
DPMO
22
115
N
O
O
DPMO
22
116
117
118
O OMe
OBnBnO
BnO
DPMO
24
119
O OMe
OBnBnO
BnO
DPMO
24
120
DPMOH
HH
H
H
25
121
DPMOH
HH
H
H
25
122
OEt
DPMO O
26
123
OEt
DPMO O
26
124
OEt
O
DPMO 27
125
OEt
O
DPMO 27
126
NOBn
O
Cbz
H
DPMO28
127
NOBn
O
Cbz
H
DPMO28
128
DPMO OMe29
129
DPMO OMe29
130
DPMO NO230
131
DPMO NO230
132
SMeO2C
DPMO
31
133
SMeO2C
DPMO
31
134
ODPM
32
135
ODPM
32
136
10% 2-Propanol/Hexane
Chiracel OD
NOBn
O
DPMO
Cbz
H
(±)-23
137
10% 2-Propanol/Hexane
Chiracel OD
NOBn
O
DPMO
Cbz
H
(-)-23
138
1% 2-Propanol/Hexane
Chiracel OD
OEt
O
DPMO (±)-27
139
1% 2-Propanol/Hexane
Chiracel OD
OEt
O
DPMO (-)-27
140
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146
Chapter 3: Modulation of SHIP for Therapeutic Purposes
Abstract:
The SH2-containing inositol 5’-phosphatase-1 (SHIP1) is an enzyme found in blood cells
that is responsible for the hydrolysis of phosphatidylinositol-3,4,5-trisphosphate to
phosphatidylinositol-4,5-bisphosphate. This enzyme is part of a major cell signaling pathway
(the PI3K pathway) that affects many important cellular functions such as proliferation,
differentiation and adhesion. SHIP1 inhibition has been found to increase blood cell production
and slow the growth of blood cancer cells, and therefore SHIP1 inhibition with small molecules
is being explored. High throughput screening small molecule libraries identified several SHIP1
inhibitors including 3α-aminocholestane (3AC). 3AC and certain other aminosteroids show
selectivity as SHIP1 inhibitors and therefore may have therapeutic applications. Further
synthetic studies have been undertaken to determine which portions of the aminosteroid SHIP1
inhibitor are important for biological activity. In addition, modifications to the molecule which
improve solubility and potency have also been pursued in order to facilitate the evaluation of
these inhibitors in other biological settings. In this chapter the syntheses of a number of
aminosteroid derivatives and the evaluation of these compounds for their potential as SHIP1
inhibitors is described.
PI3K Signaling Pathway
When eukaryotic cells shuttle information about changes in the extracellular environment
to the nucleus the signals must cross the cell membrane. Enzymes on the interior of the cell
membrane are integral to this process, as they initiate signaling cascades inside the cell that
involves a complex system made up of both enzymes and second messengers such as
147
phosphatidylinositols. Phosphatidylinositols play a prominent role in cell signaling. These lipids
are intercalated on the interior of the cell membrane and are used to assist in the transduction of
signals across the plasma membrane from the external environment to the nucleus.
Phosphatidylinositol signaling has a major influence in cell division and survival.1,2 This
signaling also plays a role in cell differentiation and adhesion.1,2
One of the best known phosphatidylinositol signaling pathways is mediated by
phosphatidylinositol-3-kinase, PI3K. PI3K is responsible for phosphorylating
phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2, to form phosphatidylinositol-3,4,5-
trisphosphate, PI(3,4,5)P3 (Figure 3.1). When activated, PI3K can rapidly synthesize PI(3,4,5)P3,
which then activates a number of protein kinases resulting in an accelerating signal cascade
through the cytoplasm to the nucleus. Aberrant activation of PI3K is known to lead to cancer.3,4
The phosphatase and tensin homolog protein, PTEN, also regulates this pathway. The PTEN
protein exerts its influence on the pathway by acting as a 3' inositol phosphatase, reversing the
PI3K reaction by hydrolyzing PI(3,4,5)P3 back to PI(4,5)P2. This function of PTEN is crucial, as
PTEN knockout mice quickly develop terminal cancer.5,6 Other inositol phosphatases hydrolyze
PI(3,4,5)P3 to PI(3,4)P2, a second, but distinct inositol bisphosphate. In blood cells (and other
cells related to the hematopoietic system), SH2-containing inositol 5’-phosphatase or SHIP1, is
the inositol phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2.2,7 Unlike PTEN, SHIP1
knockout mice are viable and do not develop terminal cancer, although their immune system is
modified.8,9
148
Figure 3.1: The PI3K Pathway
Many other signaling enzymes are involved in the transmission of the PI3K signal in
order for it to reach the nucleus and exert its effects on cellular metabolism (Figure 3.2). After
PI(3,4,5)P3 is formed from PI3K, it binds with the protein kinase PDK1. PDK1 then
phosphorylates a second protein kinase AKT, which is activated and begins to phosphorylate a
number of other protein kinases.10 Both PI(3,4,5)P3 and PI(3,4)P2 are required in the signaling
pathway in order to fully activate AKT.11,12 Once activated, AKT controls the activation and
inhibition of different functions relating to cellular survival and proliferation. One kinase that
AKT activates is mTOR, which controls regulatory cell growth pathways. Inhibition at the start
of the PI3K signaling pathway would cut off the branching of signals and may restore normal
control of cell growth.
149
Figure 3.2: The PI3K Signaling Cascade13
SHIP
SHIP plays a significant role in regulation of the PI3K signaling pathway. By
hydrolyzing PI(3,4,5)P3 to PI(3,4)P2, SHIP modulates the intensity of the signal and influences
immune response and cellular division.14,15,16 There are three major paralogs of the SHIP
enzyme: SHIP1, SHIP2, and sSHIP. The expression of SHIP1 occurs primarily in blood and
bone marrow cells. SHIP2 is expressed in a wide variety of cells throughout the rest of the body.
The sSHIP enzyme is only expressed in stem cells. A genetic study of SHIP1 determined that
the enzyme plays a role in blood cell biology and immunology.14,15,16 Most importantly for this
study, it was found that SHIP1 inhibition induces apoptosis in blood cancer cells.9 This
implicates the development of SHIP1 inhibitors as a possible treatment for hematopoietic
neoplasms.
RTK
PPP
P
PTEN
PI3K
p85
P P
PSHIP P P INPP4 P
AktP
PPDK1/mTORC2
NF-kB BAD FKHR mTORGSK3b
P P P PP
GlucoseMetabolism
CellGrowth
Cell Survival
BtkPLCg
ARFGAPs
ARFGEFs
RhoGEFs
Inflammation AutophagyCell
Migration
PI(4,5)P2 PI(3,4,5)P3 PI(3,4)P2PI(3)P
TAPP Irgm1
Autophagy
150
Attempts at crystallizing the whole SHIP enzyme have not been successful. Potter and
coworkers were able to obtain a crystal structure of a portion of the SHIP2 enzyme containing
the active site (Figure 3.3).17 The crystal structure was obtained when a biphenyl 2,3’,4,5’,6-
pentakisphosphate (BiPh(2,3’,4,5’,6)P5) synthetic ligand was bound to the catalytic site of the
SHIP2 protein. The biphenyl phosphate ligand bonds to the polar residues in the SHIP2 active
site through hydrogen bond interactions in the binding pocket. The 5' phosphate of
BiPh(2,3',4,5',6)P5 mimics the 5'-phosphatase of PI(3,4,5)P3. This phosphate shows hydrogen
bonds to Arg682, Tyr661 and Arg611. The hydrogen-bonding network forces the phosphate into
a conformation where hydrolysis is facilitated. Molecular modeling studies have implicated that
a loop of the enzyme (the PI4M loop) near the active site folds over the (BiPh(2,3’,4,5’,6)P5)
ligand and encloses it after it binds to SHIP2. Analysis of SHIP2 binding to the small molecule
is an excellent starting point for the development of small molecule inhibitors.
Figure 3.3: Crystal Structure of SHIP2
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Rationale for SHIP Antagonist or Agonist
Control of PI(3,4,5)P3 production plays a critical role in signal transduction in the PI3K
pathway. A possible way to govern PIP3 production is manipulation of the phosphatase enzyme
SHIP. Inhibition of the SHIP enzyme would stop PI(3,4,5)P3 from hydrolyzing to PI(3,4)P2
while upregulating SHIP would convert all PI(3,4,5)P3 to PI(3,4)P2. As both PI(3,4,5)P3 and
PI(3,4)P2 are required for full activation of AKT, both inhibition and upregulation of SHIP may
significantly affect the PI3K signaling pathway and could lead to blood cancer cell apoptosis
depending on the molecular pathology of the neoplasm. There are many possible uses for SHIP
inhibitors including cancer, bone marrow transplantation, stem cell mobilization and
transplantation, blood cell production, and obesity.
Cancer
The PI3K-AKT-mTOR pathway is intimately involved in cell survival and therefore has
become a focus for cancer treatment.18,19,20 SHIP1, SHIP2 and PTEN are the enzymes
predominantly responsible for controlling the AKT-mTOR signaling, which influences the
survival of cancer cells and tumors. Since SHIP1 is primarily expressed in hematopoietic cells,
SHIP1 inhibition may be used for therapeutic treatment regarding human blood cell cancers such
as leukemia and multiple myeloma.8
Modulation of the other paralogs of SHIP may also be a useful strategy in the treatment
of other types of cancer. SHIP2 overexpression has been implicated in the development of breast
cancer, for example.7 SHIP2 causes an increase in EGF-induced signaling for various breast
cancers which is atypical. High levels of EGF-induced signaling can lead to an increase of
cellular proliferation for the cancer cells.21 Various breast cancer cells lines overexpress SHIP2
such as MDA-MB-231, SKBR-3, MDA-468, MDA-436, MCF-7 and ZR-75. SHIP2 inhibition
152
for the MDA-MB-231 breast cancer cell line showed a dramatic decrease in cell proliferation
demonstrating SHIP2’s potential for therapeutic cancer treatment of breast cancer.
Bone Marrow Transplantation
Small molecule SHIP1 inhibitors could also be effective at minimizing complications for
bone marrow transplant recipients and the management of myelodysplastic syndromes.22,23
SHIP1 inhibitors show potential for therapeutic possibilities in treating Graft vs Host disease
(GvHD) caused by bone marrow transplants.24 Bone marrow transplants play a considerable role
in organ transplants, as well as treatment of cancer and genetic disorders.23 However, these
transplants are risky due to the occurrence of GvHD which can cause rejection of the transplant
and ultimately death. Experiments have shown that transplants of mismatched bone marrow
grafts are well tolerated in SHIP1 knockout mice, as these mice possess a modified immune
system which tolerates the grafts. These mice do well with bone marrow transplants because
they do not develop GvHD due to an increased expression of human T regulatory cell numbers.
Even multiple kinds of mismatched bone marrow grafts are successful in SHIP1 knockout
mice.25 SHIP1 inhibitors therefore have therapeutic potential in the area of organ transplants and
engraftments.
Stem Cell Mobilization and Transplantation
The proliferation of hematopoietic STEM cells (HSCs) is increased in SHIP1 knockout
mice.26 Significantly more HSCs are found in the plasma of SHIP1 knockout mice instead of
typically being found in the bone marrow.8 This suggests the use of a SHIP1 inhibitor could be
used to mobilize STEM cells from the bone marrow to the bloodstream. Once in the
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bloodstream, the HSCs are much easier to harvest so they can then be used in HSC
transplantation.
Blood Cell Production
SHIP1 inhibitors may be effective as a means to boost or protect blood cell production in
cancer patients, helping prevent disease or infection as a result of neutropenia.22,23,26 SHIP1
inhibition in the PI3K signaling pathway leads to an increase of PI(3,4,5)P3 which causes an
increase in cell division specific to blood cells. A small molecule SHIP1 inhibitor could be taken
orally and used in cancer treatment where chemotherapy and radiation kill healthy hematopoietic
cells. Typically protein based growth factors are now used for this purpose, but because of their
peptidic nature these drugs must be given intravenously. In vivo studies with mice indicated an
increase of blood cell production after the mice were administered a SHIP1 inhibitor.8 These in
vivo mice studies demonstrate the therapeutic potential of SHIP1 inhibitors for blood cell
production after chemotherapy or radiation poisoning.27,28
Obesity
SHIP1 inhibition may be used to treat inflammatory pathways that can lead to obesity.
By inhibiting SHIP1, expression of immunoregulatory cells is increased and can promote a lean-
body state. Studies using mice that were fed a high fat diet showed a loss of body weight and fat
content when treated with a SHIP1 inhibitor. Use of a SHIP1 inhibitor in adult aged mice
diminished inflammation in the visceral adipose tissue (VAT) which can cause obesity. These
mice lost body fat and also gained lean muscle mass, despite being on a high calorie diet. Thus
the use of a SHIP1 inhibitor could be a successful treatment for diet-associated obesity.29
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Structure Activity Relationships
High throughput screening with small molecule libraries discovered four types of SHIP
inhibitors8, 35 have been discovered and they fall into the categories of aminosteroids (3.4),
quinoline aminoalcohols (3.5), tryptamines (3.6) and thiophenes (3.7). An example of each can
be seen in Figure 3.4. The aminosteroid 3AC (3.4) demonstrated selectivity for SHIP1 over
other inositol phosphatases unlike 3.5 and 3.6, which are unselective SHIP1/SHIP2 inhibitors,
and thiophenes (like 3.7) which are selective small molecule SHIP2 inhibitors. The parent
compound, 3AC (3.4), was unfortunately found to have very poor water solubility.
Figure 3.4: SHIP Inhibitors
To address the poor water solubility, a number of analogs were synthesized.30
Androsterone derivative 3.9, (Figure 3.5), is more soluble in water and has a higher potency as a
SHIP1 inhibitor. Compound 3.9 is not a selective SHIP1 inhibitor, however, as it shows equal
inhibition of SHIP1 and SHIP2. Acylation or alkylation of the amine significantly reduced
inhibitory activity. Moreover, the inclusion of polar functional groups on the D ring was shown
to decrease activity vs. SHIP1, like in the case of compound 3.13.
155
Figure 3.5: Aminosteroid Analogues
From these structure activity studies, a general impression of the binding pocket for the
aminosteroids can be proposed. This model indicates that polar functionality is tolerated on the
A ring while only hydrophobic groups are allowed on ring D (Figure 3.6).8
Figure 3.6: Structure Activity Relationship of the Aminosteroid SHIP inhibitors
The known crystal structure of SHIP2 led to our own molecular modeling of the SHIP1
active site.17 Using the SHIP2 x-ray structure as a guide, a model of the SHIP1 active site was
constructed in silico. Figure 3.7 shows this proposed model of the active site of SHIP1 and a
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model with aminosteroid 3AC docked in the active site. The model for SHIP1 is based on the
crystal structure of the SHIP2 active site, but many of the residues near the active site have been
changed as they are different than those found in SHIP2. The largest changes are seen in the
PI4M loop region (Figure 3.7). In the model of 3.4 binding to SHIP1, the C17 sidechain on the D
ring of the aminosteroid is in the PI4M loop region. In the crystal structure for SHIP2 there is a
threonine in the PI4M loop region, however, in SHIP1 there is a more lipophilic tyrosine. This
difference in amino acids may explain the selectivity of the inhibition for SHIP1 when we have a
sidechain at C17.
Figure 3.7: Proposed model of active site for SHIP1
Figure 3.8 shows the % inhibition of aminosteroid inhibitors 3.4 (3AC), 3.9 (K185), and
3.14 (K118) in the malachite green assay for phosphatase activity. 3AC showed selective
inhibition for SHIP1, where as K185 and K118 showed inhibition for both SHIP1 and SHIP2.
157
Figure 3.8: SHIP Inhibition with Aminosteroids
Since androsterone derivative 3.9 (K185) showed improved solubility and an increased
activity as a SHIP1 inhibitor from 3.4 (3AC), aminosteroids without or with a smaller carbon
chain on the D ring were synthesized (Figure 3.9). Based on the molecular modeling studies, it
was thought that an aminosteroid with a smaller carbon chain on the D ring would maintain
selectivity for SHIP1 while maintaining the improved water solubility. The aminosteroid 3.9
was not only synthesized on large scale but the β form of the aminosteroid (K118) was
synthesized as well. In addition, two aminosteroid derivatives with alkenes on the D ring of the
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
3AC K185 K118
% In
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158
steroid were synthesized. Finally, an aminosteroid with a methyl group on the D ring was
prepared.
Figure 3.9: SHIP1 Inhibitors and Potential Analogues
Androsterone derivatives
For the synthesis of analogue 3.9, a supply of steroid 3.19 was needed as the starting
material. Reduction of androsterone 3.18 through a Yamamura-Clemmensen reduction was
explored for this purpose as an alternative to the Wolff-Kishner (Figure 3.10), which was
providing irreproducible yields.31
Figure 3.10: Clemmensen Reduction of Trans-Androsterone
The Clemmensen reduction was thought to be a more attractive methodology because the
reaction is faster and proceeds at a lower temperature than the Wolff-Kishner reduction.31 The
reaction was optimized by varying the amounts of zinc metal and TMSCl used, as well as the
reaction time and concentration. Eventually an 85% yield of the desired product was obtained.
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However, when the reaction scale was increased to two grams, only 56% yield was obtained
(Table 3.1). Also, 1H NMR spectra showed an unidentified minor impurity in the product that
could not be removed. This impurity did not appear in the product when a Wolff-Kishner
reduction was used.
Table 3.1: Clemmensen Reduction of Trans-Androsterone
Entry mmol
Zn/TMSCl
Equivalents
Zn/ TMSCl
Concentration
(M) Time
Percent
yield
1 20/20 100/100 0.01 1 hour 81
2 20/20 100/100 0.01 24 hours 49
3 5/5 25/25 0.01 1 hour 60
4 20/20 100/100 0.04 1 hour 78
5 2/2 10/10 0.1 1 hour 52
6 4/4 20/20 0.1 1 hour 42
7 4/4 20/20 0.04 1 hour 54
8 8/8 40/40 0.04 1 hour 76
9 20/5 100/25 0.04 5 hours 85
10 20/5 100/25 0.04 1 hour 80
11 723/181 100/25 0.04 1 hour 56a
a 2 gram scale (7.23 mmol)
To circumvent the Clemmensen and Wolff-Kishner reactions, hydrazone 3.20 was
prepared (Table 3.2).32 This hydrazone may then be reduced with a number of reducing agents.
Though the proposed synthetic route will introduce more steps to the original synthesis,
producing steroid 3.19 under mild conditions in high yield on large scale was key to our efforts.
Ketone 3.18 was converted to the hydrazone 3.20 by refluxing with hydrazine in ethanol. Crude
hydrazone 3.20 was then exposed to different reduction conditions (Table 3.2), including
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exposure to either potassium tert-butoxide or potassium bis(trimethylsilyl) amide. The reaction
was also performed at room temperature in DMSO or refluxed in toluene. However, none of the
reaction conditions gave a high yield of the product.
Table 3.2: Reduction of Hydrazone 3.20
Entry Base Solvent Temperature Time % Yield
1 KOC(CH3)3 Toluene 110oC 5 hours --
2 KOC(CH3)3 DMSO rt 16 hours --
3 KOC(CH3)3 DMSO rt 8 hours 9 %
4 KOC(CH3)3 DMSO rt 24 hours --
5 KHMDS DMSO rt 22 hours 6%
6 KOC(CH3)3 Toluene 110oC 24 hours 2%
Because of the low yield observed in the preparation of 3.19 through hydrazone removal
of 3.20, the Wolff-Kishner reaction was re-explored. A modified Wolff-Kishner reaction was
employed for the ketone reduction of the androsterone where diethylene glycol was used to
conduct the reaction in a much higher temperature.33 In addition, a brine solution was used in the
workup and methyl tert-butyl ether was used in the extraction in place of HCl and DCM, which
facilitated the isolation of the reaction product.33 The extraction with brine and MTBE was very
clean and contained no precipitates. When DCM and HCl were employed the extraction was
messy and contained insoluble salts making the extraction difficult. The cleaner extraction
conditions with MTBE and brine allowed for a higher yield of product. These conditions
allowed for the large scale reduction of ketone 3.18 with a 69% yield. Later it was found that
water generated by the formation of the hydrazide was lowering the boiling point of the reaction
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mixture in the Wolff-Kishner reaction, which was the cause for the more moderate yields on
large scale. Simply distilling off approximately half the diethylene glycol removed the water and
led to consistently high yields of the desired product.
A large scale synthesis of aminosteroid 3.9 (K185) was needed by our collaborators for
biological testing. Using the modified Wolff-Kishner conditions, androsterone was reduced to
alcohol 3.19. A Mitsunobu reaction was performed on alcohol 3.19 to convert it to phthalimide
3.21. Phthalimide was used for the installation of the nitrogen because of its easy reduction to an
amine. The phthalimide group was then removed with hydrazine to give amine 3.22. HCl (g)
was used to form the aminosteroid salt 3.9 (Figure 3.11).
Figure 3.11: Synthesis of Aminosteroid K185
The aminosteroid K118 (3.14) was synthesized on large scale, as this molecule also
shows significant activity as a SHIP inhibitor and good water solubility properties. Alcohol 3.19
was subjected to a Mitsunobu reaction with iodomethane to provide iodide 3.23. Iodide 3.23 was
displaced with sodium azide to give β azide 3.24. Initially, a lithium aluminum hydride
reduction was used to reduce the azide 3.24 to amine 3.25. However, the aluminum salt
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impurities from the hydride reduction proved difficult to remove. Instead, Staudinger conditions
were used to reduce azide 3.24 to amine 3.25. Amine salt 3.14 was then formed utilizing the
reaction of hydrogen chloride (HCl) gas with amine 3.25 (Figure 3.12).
Figure 3.12: Synthesis of Aminosteroid K118
For the synthesis of aminosteroid K179 (3.15), trans-androsterone was used as the
starting material. The ketone on the D ring first needed to be converted to an internal alkene. In
order to accomplish this transformation, a Shapiro reaction was investigated. Androsterone 3.18
was initially converted to tosylhydrazone 3.26.34 A Shapiro reaction using methyl lithium was
used to transform the tosylhydrazone to alkene 3.27.34 Mitsunobu reaction with DPPA was then
used to introduce the azide in steroid 3.28. Azide 3.28 was reduced to amine 3.29 using lithium
aluminum hydride, and aminosteroid salt 3.15 (K179) was formed using a solution of HCl in
ether and amine 3.29 (Figure 3.13).
163
Figure 3.13: Synthesis of Aminosteroid K179
In addition, the synthesis of aminosteroid 3.16 was performed in a similar manner to the
synthesis of alkene 3.15. A Wittig reaction was performed on trans-androsterone 3.18 which
allowed for the installation of external alkene on the D ring of the steroid. Initially, sodium
hydride was used for the Wittig reaction but no product was observed, perhaps because the
sodium hydride had degraded over time. The use of n-butyl lithium instead of sodium hydride
gave a product yield of 79% for this Wittig reaction. The alcohol 3.30 was then converted to
phthalimide 3.31 through a Mitsunobu reaction. Aminosteroid salt 3.16 was made from alkene
3.32 using HCl in methanol/ethyl acetate (which was conveniently formed by the addition of
acetyl chloride to methanol, followed by the addition of ethyl acetate) to provide the amine salt.
164
Figure 3.14: Synthesis of Alkene 3.16
The synthesis of amine hydrochloride salt 3.17 was then attempted starting with the
reduction of alkene 3.30. The reduction of the alkene on the D ring of 3.30 was performed using
a palladium catalyzed hydrogenation. This reaction allowed for the installation of a methyl
group on the D ring of the steroid nucleus. The stereochemistry of the methyl group is assumed
to be controlled by the nearby axial methyl group, which precludes axial attack and leads
selectively to the product shown. The alcohol 3.33 was then subjected to a Mitsunobu reaction to
provide phthalimide 3.34. Removal of the phthalimide group with hydrazine then gave amine
3.35. Aminosteroid salt 3.17 was formed utilizing HCl (g) and amine 3.35 (Figure 3.15).
165
Figure 3.15: Synthesis of Potential SHIP Inhibitor 3.17
After the proposed SHIP inhibitors were synthesized, they were tested for inhibition of
both SHIP1 and SHIP2 utilizing the malachite green assay.8 The results are shown in Figure
3.16. K185 (3.9) and K118 (3.14) were also included for comparison since they show inhibition
of SHIP1 and SHIP2. However, K185 demonstrated higher toxicity in mice studies than K118.
An exploration of β-isomers may lead to a less toxic SHIP inhibitor. K179 (3.15) was active for
inhibition of both SHIP1 and SHIP2. The biological activity of aminosteroids 3.16 and 3.17 is
still being explored. These studies demonstrate that a longer alkyl C-17 chain on the D ring of
the steroid maybe necessary for selective SHIP1 inhibition. Additionally a C16-C17 alkene is
tolerated in the binding pocket, opening the way for the preparation of other analogs with
substitution at C17 and unsaturation at C16-C17.
166
Figure 3.16: % SHIP Inhibition of Aminosteroids with K179
Conclusions
A number of aminosteroid derivatives were synthesized and tested for their ability to
inhibit SHIP. Removal of the C-17 carbon chain on the D-ring of the steroid was explored. The
steroids 3.9 (K185), 3.14 (K118), and 3.15 (K179) showed high potency but lost selectivity for
SHIP1 inhibition. Molecular modeling predicted a need for a long carbon chain at C-17 for
selective binding to SHIP1 over SHIP2. Aminosteroids with alkenes on the C-17 carbon were
synthesized and showed activity as SHIP inhibitors. Installing alkenes allows for
functionalization of the D ring of the steroid, with the goal being installation of the shortest
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
3AC K185 K118 K179
% In
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SHIP1 SHIP2
167
carbon chain that maintains SHIP1 selectivity but also provides a compound with good water
solubility so it may be used in animal studies. Further studies of the aminosteroid with smaller
carbon chains on the D-ring are now being conducted. These aminosteroids show activity for the
treatment of blood cancer cells and may have uses in the treatment of obesity.
Experimental Procedures
General Information. All anhydrous reactions were run under a positive pressure of argon or
nitrogen. All syringes, needles, and reaction flasks required for anhydrous reactions were dried in
an oven and cooled under an N2 atmosphere or in a desiccator. DCM and THF were dried by
passage through an alumina column. Triethylamine was distilled from CaH2. All other reagents
and solvents were purchased from commercial sources and used without further purification.
Analysis and Purification. Analytical thin layer chromatography (TLC) was performed on
precoated glass backed plates (silica gel 60 F254; 0.25 mm thickness). The TLC plates were
visualized by UV illumination and by staining. Solvents for chromatography are listed as
volume:volume ratios. Flash column chromatography was carried out on silica gel (40-63 μm).
Melting points were recorded using an electrothermal melting point apparatus and are uncorrected.
Elemental analyses were performed on an elemental analyzer with a thermal conductivity detector
and 2 meter GC column maintained at 50 °C.
Identity. Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance spectra were
recorded at 300 or 400 MHz and 75 or 100 MHz respectively. The chemical shifts are given in
parts per million (ppm) on the delta (δ) scale. Coupling constants are reported in hertz (Hz). The
spectra were recorded in solutions of deuterated chloroform (CDCl3), with residual chloroform (
7.26 ppm for 1H NMR, δ 77.23 ppm for 13C NMR) or tetramethylsilane ( 0.00 for 1H NMR,
0.00 for 13C NMR) as the internal reference. Data are reported as follows: (s = singlet; d = doublet;
168
t = triplet; q = quartet; p = pentet; sep = septet; dd = doublet of doublets; dt = doublet of triplets;
td = triplet of doublets; tt = triplet of triplets; qd = quartet of doublets; ddd = doublet of doublet of
doublets; br s = broad singlet). Where applicable, the number of protons attached to the
corresponding carbon atom was determined by DEPT 135 NMR. Infrared (IR) spectra were
obtained as thin films on NaCl plates by dissolving the compound in CH2Cl2 followed by
evaporation or as KBr pellets.
5–Androstan–3–ol (3.19)
Lit. Ref.: Norden, S.; Bender, M.; Rullkötter, J.; Christoffers, J. Eur. J. Org. Chem. 2011. 4543–
4550.
In a flame–dried flask, potassium hydroxide (4.764 g, 84.9 mmol) was dissolved in diethylene
glycol (41 mL) by heating. The solution was cooled to rt before adding trans–androsterone (6 g,
20.7 mmol) and hydrazine hydrate (3 mL, 62.1 mmol). The solution was heated to reflux. After 24
h, the solution was cooled to rt and the reaction mixture was quenched by adding brine (600 mL).
The mixture was extracted with MTBE (3 x 200 mL). The organic layers were collected, combined,
dried over magnesium sulfate, filtered, and concd under reduced pressure. Purification was done
with column chromatography (20% ethyl acetate/hexanes) to give 3.19 as a white solid (3.946 g,
69%). 3.19. mp = 149.3–150.7 oC (DCM) (Lit: 151–152 oC); TLC Rf = 0.33 (ethyl acetate:hexane,
1:4); IR (KBr) 3350, 2930, 2845, 1447, 1377, 1133 cm–1; 1H NMR (300 MHz, CDCl3) 3.58
(hept, J = 4.9 Hz, 1H), 1.76–1.82 (m, 1H), 1.70–1.75 (m, 2H), 1.65–1.69 (m, 2H), 1.61–1.63 (m,
169
1H), 1.57–1.60 (m, 1H), 1.52–1.57 (m, 2H), 1.47–1.50 (m, 1H), 1.40–1.45 (m, 1H), 1.33–1.39 (m,
1H), 1.29–1.30 (m, 1H), 1.22–1.28 (m, 4H), 1.04–1.17 (m, 4H), 0.9–1.02 (m, 1H), 0.85–0.93 (m,
2H), 0.80 (s, 3H), 0.68 (s, 3H) 0.60–0.65 (m, 1H); 13C NMR (75 MHz, CDCl3) 71.6, 54.8, 54.7,
45.1, 41.0, 40.6, 39.1, 38.4, 37.3, 36.1, 35.8, 32.7, 31.7, 29.0, 25.7, 21.5, 20.7, 17.7, 12.6.
3–Phthalimido–5–androstane (3.21)
In a 100 mL round bottom flask, 5–androstan–3–ol 3.19 (1.0 g, 3.62 mmol) was dissolved in
dry THF (36 mL). Triphenylphosphine (1.138 g, 4.34 mmol) was added into the solution
followed by diisopropyl azodicarboxylate (DIAD) (0.86 mL, 4.34 mmol). The resulting yellow
solution was stirred continuously at rt for 10 min before adding phthalimide (639 mg, 4.34
mmol). The solution was stirred continuously at rt. After 24 h, the reaction mixture was concd
and the residue was purified with column chromatography (hexanes) to give 3.21 as a white solid
(0.927 g, 63%). 3.21. TLC Rf = 0.39 (10% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ
7.78-7.83 (m, 2H), 7.67-7.74 (m, 2H), 4.49-4.51 (m, 1H), 0.81-2.12 (m, 33H), 0.73 (s, 3H).
3–amino–5–androstane (3.22)
170
Lit. Ref.: Cowell, D. B.; Davis, A. K.; Mathieson, D. W.; Nicklin, P. D. J. Chem. Soc., Perkin
Trans. 1. 1974, 1505-1513.
In a 250 mL round bottom flask 3–Phthalimido–5–androstane 3.21 (1.413 g, 3.48 mmol) was
suspended in 70 ml MeOH. Hydrazine (13 mL, 271 mmol) was added and the reaction refluxed
for one hour. The solvent was evaporated and the residue was dissolved in DCM (20 mL). The
solution was extracted with NaOH (20 mL, 1M) 5 times. The organic layers were collected,
combined, dried with sodium sulfate, filtered and concentrated. Purification was done with
column chromatography (90:9:1 DCM:MeOH:NH4OH) to give 3.22 as a clear oil (724 mg,
75%). 3.22. IR (KBr) 2926, 2855, 1472, 1378, 1124, 753 cm–1; 1H NMR (300 MHz, CDCl3)
3.18 (bs, 1H), 1.71–1.73 (m, 2H), 1.65–1.69 (m, 3H), 1.61–1.63 (m, 1H), 1.59–1.60 (m, 1H),
1.55–1.57 (m, 2H), 1.50–1.53 (m, 1H), 1.40–1.45 (m, 3H), 1.30–1.32 (m, 1H), 1.23–1.29 (m,
3H), 1.18–1.21 (m, 3H), 1.14–1.18 (m, 2H), 1.07–1.10 (m, 2H), 0.89–1.99 (m, 2H), 0.78 (s, 3H),
0.69 (s, 3H).
3–Amino–5–androstane hydrochloride (3.9)
The –amine 3.22 (1.135 g, 4.12 mmol) was dissolved in diethyl ether (5 mL). Hydrogen chloride
(g), resulting from sulfuric acid being added to sodium chloride, was bubbled into the diethyl ether
which resulted in precipitate formation. The suspension was filtered. The precipitate was collected
and dried under vacuum to afford amine salt 3.9 (1.139 g, 89%) as a white solid. 3.9. mp = 252.2
oC (diethyl ether) (dec.); IR (KBr) 3320, 2945, 1619, 1495, 1443, 1379 cm–1; 1H NMR (300 MHz,
171
CDCl3) 8.45 (bs, 3H), 3.60 (bs, 1H), 1.84 (bs, 2H), 1.62–1.69 (m, 8H), 1.51–1.58 (m, 4H), 1.37–
1.44 (m, 1H), 1.23–1.29 (m, 2H), 1.09–1.20 (m, 4H), 0.92–1.07 (m, 3H), 0.79 (s, 3H), 0.69 (s,
3H); ); 13C NMR (75 MHz, CD3OD) 54.2, 53.3, 48.0, 41.0, 40.6, 38.9, 38.8, 36.3, 36.0, 32.3,
31.6, 28.6, 25.6, 25.0, 20.9, 20.7, 17.8, 11.6. Anal calcd for C19H34ClN: C, 73.16; H, 10.99; N,
4.49. Found: C, 73.56; H, 11.19; N, 4.50.
(3R,5S,8S,9S,10S,13S,14S)–3–iodo–10,13–dimethylhexadecahydro–1H–
cyclopenta[a]phenanthrene (3.23)
In a flame dried round bottom flask, –alcohol 3.19 (1.00 g, 3.62 mmol) and triphenylphosphine
(1.138 g, 4.34 mmol) were dissolved in dry benzene (20 mL). A solution of DIAD (0.86 mL, 4.34
mmol) in dry benzene (8 mL) was added dropwise over several minutes followed by a solution of
iodomethane (0.27 mL, 4.34 mmol) in dry benzene (8 mL). The resulting milky yellow solution
was stirred continuously at rt. After approximately 24 h, the reaction mixture was concd and the
residue was purified through flash column chromatography eluting with hexane which afforded
3.23 (1.194 g, 85%) as a white solid. 3.23. 1H NMR (300 MHz, CDCl3) 4.94 (quint, J = 2.6 Hz,
1H), 1.91 (pt, J = 15.4, 3.3 Hz, 1H), 1.70–1.76 (m, 1H), 1.66–1.69 (m, 2H), 1.59–1.64 (m, 3H),
1.56–1.58 (m, 1H), 1.52–1.54 (m, 1H), 1.49 (t, J = 3.3 Hz, 1H), 1.45 (t, J = 2.2 Hz, 1H), 1.39–1.43
(m, 1H), 1.30–1.36 (m, 1H), 1.28 (d, J = 4.0 Hz, 1H), 1.22–1.26 (m, 2H), 1.18–1.21 (m, 1H), 1.13–
1.17 (m, 2H), 1.07–1.11 (m, 1H), 0.97–1.04 (m, 1H), 0.89–0.95 (m, 1H), 0.83–0.87 (m, 1H), 0.79
(s, 3H), 0.69 (s, 3H).
172
(3S,5S,8S,9S,10S,13S,14S)–3–azido–10,13–dimethylhexadecahydro–1H–
cyclopenta[a]phenanthrene (3.24)
In a flame dried–round bottom flask, iodide 3.23 (1.483 g, 3.84 mmol) and sodium azide (2.496 g,
38.4 mmol) were suspended in dry DMF (20 mL). The suspension was heated to 80 oC. After 5
hours, the solution was cooled at rt before quenching the reaction by adding water (200 mL). The
quenched reaction mixture was extracted with diethyl ether (3 x 200 mL). The organic layers were
collected, combined, dried over magnesium sulfate, filtered, and concd under reduced pressure.
Purification using flash column chromatography with hexane was done to afford azide 3.24 (0.859
g, 74%) as white solid. 3.24. TLC Rf = 0.38 (hexanes); 1H NMR (300 MHz, CDCl3) 3.25 (dt, J
= 12.9, 4.5 Hz, 1H), 1.78–1.86 (m, 1H), 1.72–1.76 (m, 1H), 1.64–1.71 (m, 2H), 1.58–1.63 (m, 2H),
1.52–1.57 (m, 2H), 1.48–1.51 (m, 1H), 1.44–1.47 (m, 1H), 1.40–1.43 (m, 1H), 1.33–1.39 (m, 1H),
1.20–1.31 (m, 4H), 1.02–1.19 (m, 4H), 0.83– 0.99 (m, 3H), 0.80 (s, 3H), 0.68 (s, 3H), 0.61–0.70
(m, 1H).
3β–Amino–5–androstane (3.25)
173
Lit. Ref.: Cowell, D. B.; Davis, A. K.; Mathieson, D. W.; Nicklin, P. D. J. Chem. Soc., Perkin
Trans. 1. 1974, 1505-1513.
In a flame dried flask, azide 3.24 (1.694 g, 5.62 mmol) and triphenylphosphine (2.938 g, 11.2
mmol) was dissolved in dry THF (26 mL). The solution was stirred continuously at rt. After
approximately 2 hours, water (7 mL) was added and the solution was heated to reflux overnight.
The solution was cooled at rt. The organic layer was collected, dried over sodium sulfate, and
concd under reduced pressure. Purification was done with column chromatography (90:9:1 DCM:
MeOH: NH4OH) to give 3.25 as a clear oil (1.456 g, 94%). 3.25. 1H NMR (300 MHz, CDCl3)
2.59-2.74 (m, 1H), 1.99 (bs, 2H), 0.61-1.73 (m, 35H).
3β–Amino–5–androstane hydrochloride (3.14)
Lit. Ref.: Cowell, D. B.; Davis, A. K.; Mathieson, D. W.; Nicklin, P. D. J. Chem. Soc., Perkin
Trans. 1. 1974, 1505-1513.
The β–amine 3.25 (1.456 g, 5.29 mmol) was dissolved in diethyl ether (10 mL). Hydrogen chloride
(g), resulting from sulfuric acid being added to sodium chloride, was bubbled into the diethyl ether
solution which resulted in precipitate formation. The suspension was filtered. The precipitate was
collected and dried under vacuum to afford amine salt 3.14 (1.589 g, 96%) as a white solid. 3.14.
mp = 276.2 oC (diethyl ether) (dec.); IR (KBr) 3449, 2928, 2361, 1984, 1451, 1377 cm–1; 1H NMR
(300 MHz, CDCl3) 8.29 (bs, 3H), 3.13 (bs, 1H), 1.99 (app d, 1H), 1.55–1.580 (m, 10H), 1.38–
1.48 (m, 2H), 1.23–1.35 (m, 4H), 1.06–1.19 (m, 4H), 0.89– 1.02 (m, 3H), 0.84 (s, 3H), 0.68 (s,
3H); 13C NMR (75 MHz, CDCl3) 54.7, 54.5, 51.5, 45.3, 41.0, 40.6, 39.0, 36.9, 35.9, 35.7, 33.3,
174
32.4, 28.5, 27.1, 25.7, 21.3, 20.7, 17.8, 12.5. Anal calcd for C19H34ClN: C, 73.16; H, 10.99; N,
4.49. Found: C, 72.96; H, 10.80; N, 4.31.
(3S,5S,8S,9S,10S,13S,14S)-10,13-Dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-
3-ol (3.19).
Lit. Ref.: Xu, S.; Toyama, T.; Nakamura, J.; Arimoto, H. Tetrahedron Letters. 2010, 51, 4534-
4537.
In a round bottom flask, trans-androsterone (58 mg, 0.20 mmol) was dissolved in 3:1
methanol/dichloromethane (5 mL) and cooled to 0oC. Zinc (1.308 g, 20 mmol) was added to the
solution followed by chlorotrimethylsilane (0.635 mL, 5 mmol) dropwise at 0oC. The reaction
was stirred for 1 hour. Solid sodium bicarbonate (2.016 g, 24 mmol) was added to quench the
reaction. The mixture was filtered and the filtrate was concentrated. The residue was diluted
with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic
layer was dried using sodium sulfate, filtered and concentrated. Purification was done with flash
column chromatography (25% ethyl acetate/hexanes) to give solid 3.19 (44 mg, 80%). 3.19. mp
= 149-150oC (CDCl3); TLC Rf = 0.33 (25% ethyl acetate/hexanes); IR (neat) 3349, 2930, 2844
cm-1; 1H NMR (300 MHz, CDCl3) δ 3.59 (m, 1H), 0.59-1.82 (m, 34H).
175
N'-((3S,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-tetradecahydro-2H-
cyclopenta[a]phenanthren-17(14H)-ylidene)-4-methylbenzenesulfonohydrazide
Lit. Ref.: Anderson, A.; Boyd, A.C.; Clark, J.K.; Fielding, L.; Gemmell, D.K.; Hamilton, N.M;
Maidment, M.S.; May, V.; McGuire, R.; McPhail, P.; Sansbury, F.H.; Sundaram, H.; Taylor, R.
J. Med. Chem. 2000, 43, 4118-4125.
In a 50 mL round bottom flask, trans-androsterone (2.00 g, 6.89 mmol), p-toluene sulfonyl
hydrazide (1.42 g, 7.62 mmol), and p-toluene sulfonic acid monohydrate (20 mg, 0.1 mmol)
were dissolved in ethanol (10 mL). The reaction refluxed overnight. The next day additional p-
toluene sulfonyl hydrazide (700 mg) and p-toluene sulfonic acid monohydrate (20 mg) were
added. The reaction refluxed for another 5 hours. The solvent was evaporated under reduced
pressure. Purification was done with flash column chromatography (1:1 ethyl acetate/hexanes)
to give KTH-1-123 as white solid (4.006 g, 63%). mp = 161-186oC (1:1 ethyl acetate/hexanes);
TLC Rf = 0.08 (25% ethyl acetate/hexanes); IR (neat) 3400, 3200, 2926, 1597, 1333, 1165 cm-1;
1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 3.50-3.58 (m,
1H), 2.42 (s, 3H), 0.77-2.22 (m, 28H).
176
(3S,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-ol (3.27)
Lit. Ref.: Anderson, A.; Boyd, A.C.; Clark, J.K.; Fielding, L.; Gemmell, D.K.; Hamilton, N.M;
Maidment, M.S.; May, V.; McGuire, R.; McPhail, P.; Sansbury, F.H.; Sundaram, H.; Taylor, R.
J. Med. Chem. 2000, 43, 4118-4125.
In a flame dried 50 mL round bottom flask, 3.26 was dissolved in dry THF (11 mL) and cooled
to 0oC. Methyl lithium (3 M in diethoxymethane, 2.4 mL, 7.19 mmol) was added dropwise over
5 minutes. A precipitate formed and redissolved as methyl lithium addition continued. The red
solution was stirred at room temperature for 24 hours. Methyl lithium (3 M in diethoxymethane,
1.2 mL, 3.6 mmol) was added to the flask and the reaction stirred for 6 hours. The reaction was
quenched with slow addition of water, then diethyl ether was added. The mixture was acidified
with 2 M hydrochloric acid. The organic layer was separated, washed with water twice then
brine once, dried with sodium sulfate and concentrated. Purification was done using column
chromatography (15% ethyl acetate/hexanes) to give 3.27 as a white solid (248 mg, 41%). 3.27.
mp = 114-118oC (15% ethyl acetate/hexanes); TLC Rf = 0.40 (25% ethyl acetate/hexanes); IR
(neat) 3246, 3044, 2934, 2846, 1449, 1042 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.83 (d, J = 9.3
Hz, 1H), 5.66-5.70 (m, 1H), 3.53-3.64 (m, 1H), 0.75-2.13 (m, 28H).
(3R,5S,8R,9S,10S,13R,14S)-3-azido-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-
tetradecahydro-1H-cyclopenta[a]phenanthrene (3.28)
177
Lit. Ref.: Amiranashvili, L. Sh.; Sladkov, V. I.; Levina, I. I.; Men'shova, N. I.; Suvorov, N.
N. Journal of Organic Chemistry USSR. 1990, 26, # 9.1 p. 1629-1632.
In a 50 mL round bottom flask, alcohol 3.27 (0.24 g, 0.875 mmol) was dissolved in dry THF (9
mL). Triphenylphosphine (0.23 g, 0.875 mmol) was added into the solution followed by
diisopropryl azodicarboxylate (DIAD) (0.17 mL, 0.875 mmol). The resulting yellow solution
was stirred continuously at rt for 10 min before adding diphenylphosphoryl azide (0.23 mL, 1.05
mmol). The solution was stirred continuously at rt. After 24 h, the reaction mixture was concd
and the residue was purified with column chromatography to give 3.28 as a white solid (0.193 g,
74%).%). 3.28. TLC Rf = 0.33 (Hexanes); 1H NMR (300 MHz, CDCl3) δ 5.81-5.83 (m, 1H),
5.69-5.70 (m, 1H), 3.87-3.89 (m, 1H), 0.75- 1.89 (m, 28H).
(3R,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-amine (3.29)
In a flame dried round bottom flask, LAH (0.085 g, 2.13 mmol, 95%) was suspended in dry THF
(2.5 mL). The suspension was cooled at 0 oC using ice/water cold bath before adding the solution
of –azide 3.28 (0.193 g, 0.645 mmol) in dry THF (2.5 mL). The solution was warmed to rt and
then refluxed for 5 hours. The reaction was then cooled to rt before diluting the solution with
THF (5 mL). The diluted reaction mixture was cooled at 0 oC and quenched using a Fieser
method.5 The reaction mixture was stirred continuously until it turned into a milky white
suspension. The suspension was then filtered through celite and washed with THF. The filtrate
was dried over sodium sulfate and concd under reduced pressure. Purification was done with
column chromatography (90:9:1 DCM: MeOH: NH4OH) to afford –amine 3.29 (0.113 g, 64%).
178
3.29. TLC Rf = 0.23 (90:9:1 DCM: MeOH: NH4OH); 1H NMR (300 MHz, CDCl3) δ 5.79-5.82
(m, 1H), 5.67-5.68 (m, 1H), 3.16 (s, 1H), 0.73-1.87 (m, 28H).
(3R,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-amine hydrochloride (3.15)
The –amine 3.29 (0.100 g, 0.366 mmol) was dissolved in diethyl ether (5 mL). A solution of
hydrogen chloride in diethyl ether (0.37 mL, 2 M) was added dropwise which resulted in
precipitate formation. The suspension was filtered and the precipitate was collected, washed with
diethyl ether, and dried under vacuum to afford amine salt 3.15 (0.106 g, 94%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 7.98 (bs, 3H), 5.84 (bs, 1H), 5.68 (bs, 1H), 3.34 (bs, 1H), 0.72-
2.03 (m, 34H). Anal calcd for C19H32ClN: C, 73.63; H, 10.41; N, 4.52. Found: C, 73.31; H, 10.15;
N, 4.73.
(3S,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylene-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-ol (3.30)
Lit. Ref.: Norden, S.; Bender, M.; Rullkötter, J.; Christoffers, J. Eur. J. Org. Chem. 2011. 4543–
4550.
179
[Ph3PMe]Br (6.144 g, 17.2 mmol) was suspended in dry THF (24 mL). The suspension was
cooled to 0oC and n-butyl lithium was added slowly (6.88 mL, 17.2 mmol, 2.5 M in hexanes). A
solution of 3.18 (1.0 g, 3.44 mmol) in dry THF (33 mL) was added dropwise, and the resulting
mixture was stirred at reflux for 20 hours. After cooling to room temperature, some water was
added dropwise, and then the mixture was diluted with water (200 mL) and diethyl ether (200
mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2 X 150
mL). The combined organic layers were dried MgSO4, filtered, and concentrated. Purification
was done with column chromatography (1:1 Et2O: hexanes) to yield 3.30 (0.782 g, 79 as a white
solid. 3.30. TLC Rf = 0.57 (2:1 Et2O:hexanes); 1H NMR (300 MHz, CDCl3) δ 4.61 (s, 1H), 4.59
(s, 1H), 3.49-3.67 (m, 1H), 2.50-2.63 (m, 1H), 2.12-2.31 (m, 1H), 0.65-1.82 (m, 30H).
2-((3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylene-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-yl)isoindoline-1,3-dione (3.31)
In a 100 mL round bottom flask, 5–androstan–3–ol 3.30 (0.782 g, 2.71 mmol) was dissolved
in dry THF (27 mL). Triphenylphosphine (0.852 g, 3.25 mmol) was added into the solution
followed by diisopropryl azodicarboxylate (DIAD) (0.64 mL, 3.25 mmol). The resulting yellow
solution was stirred continuously at rt for 10 min before adding phthalimide (478 mg, 3.25
mmol). The solution was stirred continuously at rt. After 24 h, the reaction mixture was concd
and the residue was purified with column chromatography (5% ethyl acetate/hexanes) to give
3.31 as a white solid (0.639 g, 56%). 3.31. TLC Rf = 0.53 (10% ethyl acetate/hexanes); 1H NMR
180
(300 MHz, CDCl3) δ 7.79-7.82 (m, 2H), 7.68-7.71 (m, 2H), 4.62 (s, 1H), 4.61 (s, 1H), 4.49-4.51
(m, 1H), 2.40-2.59 (m, 1H), 0.78-2.31 (m, 32H).
(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylene-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-amine (3.32)
In a 250 mL round bottom flask, steroid 3.31 (0.639 g, 1.53 mmol) was suspended in 77 ml
MeOH. Hydrazine (5.8 mL, 119 mmol) was added and the reaction refluxed for one hour. The
solvent was evaporated and the residue was dissolved in DCM (150 mL). The mixture was
extracted with a NaOH solution (150 mL, 1M) 5 times. The organic layers were collected,
combined, dried with sodium sulfate, filtered and concentrated. Purification was done with
column chromatography (90:9:1 DCM:MeOH:NH4OH) to give 3.32 as a clear oil (384 mg,
87%). 3.32. TLC Rf = 0.09 (90:9:1 DCM:MeOH:NH4OH); 1H NMR (300 MHz, CDCl3) δ 4.61
(s, 1H), 4.59 (s, 1H), 3.22 (bs, 1H), 2.41-2.71 (m, 3H), 2.20-2.26 (m, 1H), 0.73-1.80 (m, 34H).
(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylene-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-amine hydrochloride (3.16)
In a flame dried 50 mL round bottom flask, MeOH (0.11 mL, 2.61 mmol) was suspended in
ethyl acetate (5 mL) and cooled to 0oC. Acetyl chloride (0.19 mL, 2.61 mmol) was added slowly
181
and the reaction stirred for 10 minutes. Amine 3.32 was dissolved in a small amount of ethyl
acetate and added to the flask. A white solution formed. The mixture stirred for 30 minutes. The
product was filtered and dried under vacuum to give 3.16 as a white solid (0.067 g, 40%). 3.16
1H NMR (300 MHz, CD3OD) δ 4.59 (s, 1H), 4.57 (s, 1H), 3.49 (bs, 1H), 2.42-2.59 (m, 1H),
2.10-2.29 (m, 1H), 0.73-2.01 (m, 52H). Anal calcd for C20H34ClN: C, 74.16; H, 10.58; N, 4.32.
Found: C, 74.17; H, 10.47; N, 4.42.
(3S,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethyl-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-ol (3.33)
Lit. Ref.: Norden, S.; Bender, M.; Rullkötter, J.; Christoffers, J. Eur. J. Org. Chem. 2011. 4543–
4550.
In a flame dried 100 mL round bottom flask, steroid 3.30 (0.69 g, 2.4 mmol) was dissolved in
isopropanol (24 mL). Palladium on carbon was added to the flask (0.077g, 0.72 mmol) and the
mixture was put under vacuum. Hydrogen gas was added after the vacuum was removed and the
mixture stirred at 65oC for 17 hours. The mixture was filtered through silica (ether) and
concentrated to give 3.33 as a white solid (0.629 g, 90%). 3.33. TLC Rf = 0.53 (25% ethyl
acetate/hexanes) 1H NMR (300 MHz, CDCl3) δ 3.53-3.62 (m, 1H), 0.72-1.89 (m, 37H), 0.52 (s,
3H).
182
2-((3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethyl-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-yl)isoindoline-1,3-dione (3.34)
In a flame dried 100 mL round bottom flask, alcohol 3.33 (0.629 g, 2.17 mmol) was dissolved in
dry THF (22 mL). Triphenylphosphine (0.682 g, 2.6 mmol) was added into the solution followed
by diisopropryl azodicarboxylate (DIAD) (0.52 mL, 2.6 mmol). The resulting yellow solution
was stirred continuously at rt for 10 min before adding phthalimide (0.383 g, 2.6 mmol). The
solution was stirred continuously at rt. After 24 h, the reaction mixture was concd and the residue
was purified with column chromatography (hexanes) to give 3.34 as a white solid (0.445 g,
49%). 3.34 1H NMR (300 MHz, CDCl3) δ 7.79-7.82 (m, 2H), 7.68-7.70 (m, 2H), 4.47-4.52 (m,
1H), 0.73-2.1 (m, 36H), 0.54 (s, 3H).
(3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethyl-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-amine (3.35)
In a 50 mL round bottom flask, steroid 3.34 (0.445 g, 1.06 mmol) was suspended in 11 ml
MeOH. Hydrazine (4 mL, 82.7 mmol) was added and the reaction refluxed for one hour. The
solvent was evaporated and the residue was dissolved in DCM (20 mL). The mixture was
extracted with a NaOH solution (20 mL, 1M) 5 times. The organic layers were collected,
183
combined, dried with sodium sulfate, filtered and concentrated. Purification was done with
column chromatography (90:9:1 DCM:MeOH:NH4OH) to give 3.35 as a clear oil (215 mg,
70%). 3.35 1H NMR (300 MHz, CDCl3) δ 3.18 (bs, 1H), 0.71-1.75 (m, 38H), 0.53 (s, 3H).
(3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethyl-hexadecahydro-1H-
cyclopenta[a]phenanthren-3-amine hydrochloride (3.17)
Amine 3.35 (0.215 g, 0.743 mmol) was dissolved in diethyl ether (10 mL). Hydrogen chloride
(g), resulting from sulfuric acid being added to calcium chloride, was bubbled into the diethyl
ether solution which resulted in precipitate formation. The suspension was filtered. The
precipitate was collected and dried under vacuum to afford amine salt 3.17 (0.184 g, 76%) as a
white solid. 3.17 1H NMR (300 MHz, CDCl3) δ 8.45 (bs, 3H), 3.60 (bs, 1H) 0.73-1.82 (m, 35H),
0.53 (s, 3H). Anal calcd for C20H36ClN: C, 73.69; H, 11.13; N, 4.30. Found: C, 73.73; H, 10.81;
N, 4.26.
184
Appendix B. 1H AND 13C NMR SPECTRA SUPPLEMENT TO
CHAPTER 3
9 8 7 6 5 4 3 2 1 ppm
0.685
0.805
0.806
0.890
0.931
1.085
1.099
1.107
1.110
1.114
1.129
1.135
1.143
1.171
1.221
1.225
1.234
1.239
1.249
1.261
1.265
1.269
1.272
1.292
1.302
1.306
1.343
1.376
1.402
1.409
1.421
1.449
1.459
1.528
1.536
1.547
1.558
1.561
1.569
1.577
1.591
1.596
1.602
1.618
1.627
1.663
1.668
1.682
1.694
1.707
1.718
1.727
1.738
3.587
43.0
4
1.0
0
H
H
H H
HO
3.19
(3S,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol
185
9 8 7 6 5 4 3 2 1 ppm
0.698
0.851
0.882
0.898
0.922
0.937
0.952
0.961
0.977
1.105
1.111
1.124
1.142
1.155
1.167
1.220
1.227
1.236
1.262
1.275
1.292
1.334
1.376
1.402
1.556
1.567
1.582
1.595
1.600
1.608
1.616
1.625
1.643
1.652
1.665
1.671
1.677
1.683
1.698
1.709
1.716
1.729
1.834
1.858
1.867
4.501
7.678
7.688
7.696
7.697
7.706
7.795
7.804
7.813
7.823
3.0
0
28.7
1
0.8
6
1.7
8
1.5
4
NH
H H
H
O
O 3.21
2-((3R,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)isoindoline-1,3-dione
186
9 8 7 6 5 4 3 2 1 ppm
1.180
1.190
1.200
1.212
1.225
1.252
1.261
1.298
1.362
1.388
1.395
1.434
1.442
1.475
1.493
1.502
1.514
1.546
1.556
1.587
1.608
1.615
1.639
1.655
1.667
1.695
1.705
1.715
2.401
3.212
40.0
5
2.4
4
1.0
0
H
H
H H
H2N 3.22
(3R,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H -cyclopenta[a]phenanthren-3-amine
9 8 7 6 5 4 3 2 1 ppm
0.991
1.015
1.027
1.070
1.094
1.129
1.158
1.195
1.228
1.283
1.368
1.391
1.433
1.548
1.578
1.603
1.618
1.628
1.652
1.691
1.831
3.607
8.446
32.9
0
1.0
0
2.3
8
H
H
H H
H3NCl 3.9
(3R,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-aminium chloride
187
9 8 7 6 5 4 3 2 1 ppm
0.691
0.799
0.860
0.914
0.950
0.991
1.088
1.132
1.142
1.150
1.155
1.164
1.169
1.181
1.191
1.200
1.227
1.241
1.253
1.263
1.281
1.294
1.318
1.413
1.420
1.432
1.443
1.452
1.460
1.482
1.494
1.505
1.529
1.539
1.549
1.569
1.574
1.579
1.583
1.596
1.605
1.612
1.622
1.631
1.636
1.642
1.669
1.674
1.681
1.686
1.698
1.709
1.724
1.737
4.949
37.5
4
0.8
1
1.0
0
H
H H
H
I3.23
(3R,5S,8S,9S,10S,13S,14S)-3-iodo-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene
9 8 7 6 5 4 3 2 1 ppm
0.686
0.805
0.899
0.934
0.990
1.089
1.104
1.109
1.113
1.131
1.142
1.148
1.155
1.173
1.236
1.249
1.262
1.275
1.281
1.286
1.297
1.303
1.315
1.338
1.378
1.407
1.419
1.448
1.453
1.489
1.495
1.507
1.532
1.540
1.545
1.548
1.553
1.564
1.574
1.595
1.601
1.606
1.620
1.631
1.675
1.688
1.698
1.717
1.729
1.738
1.750
1.794
1.800
3.258
46.2
0
1.0
0
H
H H
H
N3 3.24
(3S,5S,8S,9S,10S,13S,14S)-3-azido-10,13-dimethylhexadecahydro-1H -cyclopenta[a]phenanthrene
188
9 8 7 6 5 4 3 2 1 ppm
0.657
0.662
0.683
0.785
0.873
0.890
0.909
0.914
0.930
0.973
1.084
1.097
1.105
1.127
1.132
1.162
1.169
1.202
1.207
1.214
1.222
1.237
1.253
1.266
1.276
1.294
1.307
1.400
1.407
1.419
1.431
1.439
1.446
1.496
1.505
1.556
1.564
1.567
1.589
1.595
1.600
1.617
1.625
1.647
1.657
1.666
1.679
1.687
1.700
1.711
1.716
1.720
1.729
1.988
4.0
3
3.0
0
23.7
4
2.2
4
0.8
8
H
H
H H
H2N 3.25
(3S,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-amine
9 8 7 6 5 4 3 2 1 ppm
1.144
1.170
1.185
1.200
1.208
1.231
1.260
1.271
1.298
1.342
1.380
1.405
1.446
1.478
1.506
1.525
1.545
1.572
1.587
1.603
1.626
1.656
1.672
1.681
1.723
1.758
1.793
1.806
1.976
2.021
3.126
8.304
4.8
4
31.5
0
1.0
5
1.0
0
2.5
7
H
H
H H
H3NCl 3.14
(3S,5S,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-aminium chloride
189
9 8 7 6 5 4 3 2 1 ppm
0.768
0.806
0.919
0.961
0.975
1.005
1.020
1.062
1.082
1.184
1.196
1.234
1.258
1.282
1.298
1.310
1.324
1.340
1.355
1.367
1.383
1.415
1.426
1.465
1.580
1.662
1.675
1.688
1.701
1.716
1.731
1.761
1.786
1.806
1.828
1.886
1.927
2.009
2.045
2.069
2.189
2.216
2.423
2.454
3.579
4.108
4.132
7.260
7.276
7.303
7.786
7.806
7.812
7.833
0.9
6
3.0
0
26.4
0
1.0
2
3.5
2
0.8
3
0.3
1
0.6
6
1.7
0
0.3
2
1.9
1
HO
H
H
H H
NNHTos
3.26
N'-((3S,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyldodecahydro-1H-cyclopenta[a]phenanthren-17(2H,10H,14H)-ylidene)-4-methylbenzenesulfonohydrazide
9 8 7 6 5 4 3 2 1 ppm
0.726
0.746
0.760
0.837
0.969
0.981
1.013
1.234
1.248
1.263
1.275
1.296
1.305
1.311
1.323
1.335
1.343
1.353
1.373
1.385
1.387
1.411
1.418
1.424
1.468
1.511
1.525
1.535
1.543
1.551
1.559
1.566
1.574
1.583
1.591
1.597
1.658
1.669
1.678
1.690
1.703
1.712
1.730
1.740
1.881
1.886
1.889
3.588
5.684
5.689
5.694
5.699
5.815
5.820
5.823
42.5
9
1.2
2
1.0
0
1.0
0
HO
H
H
H H
3.27
(3S,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol
190
9 8 7 6 5 4 3 2 1 0 ppm
0.825
0.843
0.859
1.061
1.190
1.201
1.212
1.235
1.254
1.268
1.284
1.300
1.324
1.337
1.350
1.359
1.379
1.388
1.402
1.422
1.430
1.439
1.453
1.466
1.477
1.488
1.498
1.510
1.520
1.529
1.549
1.561
1.566
1.584
1.669
1.681
1.695
1.706
1.716
1.726
1.735
1.743
1.880
1.885
1.887
3.874
3.884
3.892
5.691
5.696
5.701
5.818
5.821
5.826
5.829
3.0
0
23.2
2
0.9
9
0.9
2
0.8
3
0.7
1
0.7
0
H
H H
H
N3
3.28
(3R,5S,8R,9S,10S,13R,14S)-3-azido-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene
9 8 7 6 5 4 3 2 1 ppm
0.683
0.747
0.779
0.813
1.055
1.192
1.200
1.214
1.224
1.243
1.256
1.267
1.279
1.296
1.317
1.334
1.349
1.409
1.418
1.429
1.461
1.468
1.476
1.492
1.499
1.506
1.526
1.553
1.565
1.578
1.590
1.602
1.679
1.692
1.704
1.709
1.721
1.729
1.742
1.833
1.841
1.866
1.878
1.884
1.891
1.916
1.921
1.929
3.213
5.689
5.694
5.699
5.820
5.825
47.1
9
1.3
8
1.0
1
1.0
0
H2NH
H H
H
3.29
(3R,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-3-amine
191
10 9 8 7 6 5 4 3 2 1 0 ppm
1.144
1.187
1.233
1.269
1.314
1.339
1.374
1.389
1.412
1.460
1.471
1.542
1.565
1.611
1.652
1.756
1.817
1.845
1.897
2.012
2.019
2.033
2.041
2.060
2.071
2.082
2.091
3.605
5.639
5.644
5.658
5.663
5.784
5.789
5.803
5.808
8.432
29.2
1
0.7
9
1.0
0
0.7
5
0.7
5
2.7
0
H3NH
H H
H
Cl
3.15
(3R,5S,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-aminium chloride
9 8 7 6 5 4 3 2 1 ppm
0.768
0.825
0.944
0.959
0.979
0.987
1.001
1.017
1.037
1.147
1.176
1.188
1.218
1.233
1.255
1.259
1.269
1.275
1.289
1.310
1.341
1.351
1.361
1.377
1.391
1.416
1.429
1.519
1.544
1.552
1.561
1.570
1.577
1.587
1.598
1.611
1.632
1.644
1.669
1.696
1.708
1.718
1.738
1.750
1.764
1.778
1.788
1.807
1.818
1.827
3.592
4.605
4.613
4.620
33.6
7
0.9
6
0.8
8
0.8
2
2.0
0
HOH
H H
H
3.30
(3S,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-ol
192
9 8 7 6 5 4 3 2 1 ppm
0.778
0.867
0.891
0.950
0.975
0.988
1.019
1.026
1.170
1.199
1.211
1.240
1.250
1.280
1.289
1.321
1.333
1.361
1.380
1.394
1.419
1.573
1.592
1.605
1.619
1.642
1.657
1.673
1.684
1.710
1.722
1.735
1.783
1.794
1.822
1.834
1.861
1.870
1.910
2.035
2.242
4.491
4.501
4.509
4.611
4.619
7.676
7.687
7.695
7.705
7.792
7.802
7.810
7.821
32.0
2
0.9
1
0.9
3
2.0
0
1.8
1
1.5
6
NH
H H
H
O
O3.31
2-((3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)isoindoline-1,3-dione
10 9 8 7 6 5 4 3 2 1 0 ppm
0.514
0.731
0.753
0.771
0.784
0.806
0.815
0.946
0.966
0.985
1.002
1.008
1.023
1.044
1.139
1.167
1.182
1.194
1.208
1.216
1.239
1.252
1.266
1.294
1.308
1.331
1.345
1.367
1.380
1.406
1.419
1.450
1.482
1.501
1.556
1.592
1.602
1.615
1.634
1.649
1.658
1.667
1.679
1.690
1.721
1.732
1.749
1.761
1.789
1.800
2.231
2.445
4.593
4.601
4.606
33.8
7
1.0
2
3.0
7
0.9
1
2.0
0
H2NH
H H
H
3.32
(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-amine
193
9 8 7 6 5 4 3 2 1 ppm
0.556
0.732
0.774
0.808
0.831
0.851
0.866
0.877
0.999
1.014
1.020
1.035
1.183
1.196
1.214
1.226
1.238
1.248
1.257
1.267
1.277
1.289
1.301
1.311
1.317
1.325
1.331
1.346
1.374
1.392
1.403
1.410
1.445
1.455
1.536
1.587
1.592
1.621
1.632
1.652
1.664
1.674
1.686
1.702
1.714
1.747
1.759
1.783
1.794
1.804
3.489
4.578
4.585
4.592
52.0
9
1.0
3
0.6
5
1.5
2
2.0
0
0.3
4
H3NH
H H
H
Cl 3.16
(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-aminium chloride
10 9 8 7 6 5 4 3 2 1 0 ppm
0.530
0.722
0.792
0.806
0.813
0.829
0.904
0.916
0.920
0.929
0.945
0.956
0.968
0.979
1.054
1.071
1.093
1.109
1.118
1.132
1.148
1.157
1.185
1.194
1.199
1.208
1.227
1.232
1.238
1.251
1.262
1.269
1.283
1.293
1.304
1.324
1.345
1.375
1.500
1.519
1.537
1.544
1.554
1.568
1.632
1.644
1.655
1.673
1.686
1.697
1.709
1.740
1.752
1.775
3.589
3.0
0
36.9
2
0.2
1
0.8
6
HOH
H H
H
3.33
(3S,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-3-ol
194
10 9 8 7 6 5 4 3 2 1 0 ppm
0.541
0.733
0.809
0.831
0.855
0.910
0.934
0.943
0.970
0.982
1.002
1.102
1.125
1.154
1.185
1.195
1.219
1.232
1.250
1.263
1.293
1.306
1.330
1.346
1.355
1.378
1.420
1.441
1.554
1.570
1.582
1.596
1.601
1.609
1.621
1.630
1.639
1.650
1.663
1.672
1.679
1.702
1.715
1.822
1.861
1.870
7.677
7.687
7.694
7.696
7.705
7.793
7.803
7.811
7.822
3.2
0
35.6
1
1.0
0
1.9
7
1.6
8
NH
H H
H
O
O3.34
2-((3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)isoindoline-1,3-dione
9 8 7 6 5 4 3 2 1 ppm
0.524
0.717
0.766
0.781
0.790
0.802
0.825
0.913
0.926
0.953
0.965
0.988
1.123
1.150
1.159
1.172
1.182
1.192
1.203
1.218
1.234
1.247
1.291
1.327
1.344
1.376
1.399
1.411
1.419
1.430
1.437
1.445
1.452
1.466
1.481
1.489
1.516
1.525
1.539
1.547
1.560
1.569
1.582
1.594
1.599
1.604
1.627
1.639
1.651
1.669
1.681
1.692
1.734
1.748
3.3
4
37.7
0
1.0
0
H2NH
H H
H
3.35
(3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-amine
195
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9 8 7 6 5 4 3 2 1 ppm
1.009
1.021
1.074
1.089
1.116
1.147
1.184
1.208
1.231
1.290
1.313
1.344
1.365
1.509
1.560
1.576
1.627
1.646
1.724
1.736
1.753
1.765
1.809
1.822
3.598
8.447
3.0
0
34.8
3
0.0
3
0.9
7
2.6
4
H3NH
H H
H
Cl
3.17
(3R,5S,8S,9S,10S,13R,14S,17S)-10,13,17-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-aminium chloride
196
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16. Desponts, C.; Hazen, A. L.; Paraiso, K. H. T.; Kerr, W. G. Blood. 2006, 107, 4338-4345.
17. Mills, S. J., C. Persson, G. Cozier, M. P. Thomas, L. Tresaugues, C. Erneux, A. M. Riley,
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2008, 29, 25–34.
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23. Ghansah, T.; Paraiso, K. H. T.; Highfill, S.; Desponts, C.; May, S.; McIntosh, J. K.;
Wang, J.-W.; Ninos, J.; Brayer, J.; Cheng, F.; Sotomayor, E.; Kerr, W. G. J. Immunol.
2004, 173, 7324-7330.
24. Wang, J.–W.; Howson, J. M.; Ghansah, T.; Desponts, C.; Ninos, J. M.; May, S. L.;
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25. Wahle, J. A.; Paraiso, K. H. T.; Costello, A. L.; Goll, E. L.; Sentman, C. L.; Kerr, W. G.
J. Immunol. 2006, 176, 7165–7169.
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29. Srivastava, N.; Iyer, S.; Sudan, R.; Youngs, C.; Engelman, R. W.; Howard, K. T.; Russo,
C. M.; Chisholm, J. D.; Kerr, W. G. JCI Insight, Accepted.
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Kyle Timothy Howard
Department of Chemistry [email protected] 1-014 Center for Science and Technology 717-318-8885 Syracuse, NY 13244-4100
Education
Ph.D. Chemistry, Advisor: Prof. John D. Chisholm, Syracuse University. Anticipated August 2016.
M.Phil. Chemistry, Advisor: Prof John D. Chisholm, Syracuse University. May 2012.
B.S. Chemistry (major) and Mathematics (minor), York College of Pennsylvania. May 2010.
Honors
William D. Johnson Award for Outstanding Graduate Teaching (2015)
Publications
1. Howard, K. T.; Duffy, B. C.; Linaburg, M. R.; Chisholm, J. D. “Formation of DPM ethers using O-diphenylmethyl trichloroacetimidate under thermal conditions.” Org. Biomol. Chem., 2016, 14, 1623-1628. DOI: 10.1039/C5OB02455B.
2. Howard, K. T.; Chisholm, J. D. “Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis.” Org. Prep. Proced. Int., 2016, 48:1, 1-36. DOI: 10.1080/00304948.2016.1127096. [Invited Review, Peer Reviewed]
3. Srivastava, N.; Iyer, S.; Sudan, R.; Youngs, C.; Engelman, R. W.; Howard, K. T.; Russo, C. M.; Chisholm, J. D.; Kerr, W. G. “SHIPi promotes an immunoregulatory milieu in adipose tissue to reverse age- and diet- associated obesity and metabolic syndrome.” JCI Insight, Accepted.
4. Fernandes, S.; Brooks, R.; Park, M-Y.; Srivastava, N.; Russo, C.M.; Howard, K.T.; Chisholm, J.D.; Kerr W.G. “SHIP Inhibition Enhances Murine Autologous and Allogeneic Hematolymphoid Cell Transplantation.” EBioMedicine, 2015, 2, 205-213. DOI:10.1016/j.ebiom.2015.02.004
5. Duffy, B.C.; Howard, K. T.; Chisholm, J. D. “Alkylation of Thiols using Trichloroacetimidates under Neutral Conditions.” Tetrahedron Lett. 2015, 56, 3301-3305. DOI:10.1016/j.tetlet.2014.12.042
6. Shah, J.P.; Russo, C.M.; Howard, K. T.; Chisholm, J. D. “Spontaneous Formation of PMB Esters Using 4-Methoxybenzyl-2,2,2-trichloroacetimidate.” Tetrahedron Lett. 2014, 55,1740-1742. DOI:10.1016/j.tetlet.2014.01.097
7. Adhikari, A.A.; Shah, J.P.; Howard, K. T.; Russo, C. M.; Wallach, D. R.; Linaburg, M. R.; Chisholm, J. D. “Convenient Formation of DPM Esters Using
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Diphenylmethyl Trichloroacetimidate.” Synlett. 2014, 283-287. DOI: 10.1055/s-0033-1340293
8. Howard, K. T.; Duffy, B. C.; Mahajani, N.; Russo, C. M.; Wallach, D. R.; Wu, Y.; Chisholm, J. D. “Formation of PMB Ethers Under Thermal Conditions with 4-Methoxybenzyl-2,2,2-trichloroacetimidate.” In preparation.
Presentations
1. Howard, K. T.; Chisholm, J. D. “Convenient formation of PMB and DPM ethers with trichloroacetimidates under thermal conditions.” Presented at the 248th American Chemical Society National Meeting & Exposition, San Francisco, CA, August 10-14, 2014, ORGN-983. Poster presentation.
2. Howard, K. T.; Chisholm, J. D. “Convenient Formation of PMB and DPM Ethers with Trichloroacetimidates under Thermal Conditions.” Presented at the 31st Annual Graduate Student Symposium at the University at Buffalo, Buffalo, NY, May 19-21, 2014. Abstract P19. Poster presentation.
3. Howard, K. T.; Viernes, D. R.; Kerr, W. G.; Chisholm, J. D. Synthetic Studies on SHIP1 Inhibitors. Presented at the 38th Northeast Regional Meeting of the American Chemical Society, Rochester, NY, Sept. 30-Oct. 3, 2012, NERM-28. Poster presentation.
4. Howard, K. T.; Kaminsky, L.; Beck, J. J.; Halligan, K. M. Synthesis of a tricyclic natural product as a means to combat the navel orangeworm. Presented at the 239th American Chemical Society National Meeting & Exposition, San Francisco, CA, March 21-25, 2010, CHED-1142. Poster presentation.
Research Experience
Research Areas: Organic synthesis and medicinal chemistry, synthesis and structure activity relationship studies of SHIP inhibitors, formation of PMB and DPM ethers using trichloroacetimidates using thermal conditions. Lab Techniques: Characterization of novel organic compounds utilizing Nuclear Magnetic Resonance (NMR) Spectroscopy (1H, 13C), Infrared (IR) Spectroscopy, High Resolution Mass Spectroscopy (HRMS), Polarimetry, combustion analysis, Liquid Chromatography–Mass Spectrometry (LC–MS) and high pressure liquid chromatography, thin layer chromatography. Undergraduate Mentoring: Syracuse University undergraduate students and summer Research Experience for Undergraduates (REU) participants.
Teaching Experience
Graduate Teaching Assistant for Organic Chemistry I & II Recitations • Guest lectured for Organic Chemistry lecture when Professor was unavailable.
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• Designed worksheets, practice exams, and their corresponding answer keys for students. • Facilitated discussion relevant to organic chemistry topics discussed in the lecture. • Assisted in proctoring and grading exams. • Held weekly office hours for students to provide extra help.
Graduate Teaching Assistant for Organic Chemistry I & II Laboratory
• Conducts lectures relevant to the experiments to be performed. • Develop students’ knowledge in chemistry including laboratory techniques essential in handling glassware, reagents, and equipment.
References
1. Professor John D. Chisholm, Department of Chemistry, Syracuse University.
E-mail: [email protected]; Phone: (315) 443–6894.
2. Professor James Kallmerten, Department of Chemistry, Syracuse University.
E-mail: [email protected]; (315) 443-2854.
3. Professor Kathleen Halligan, Department of Chemistry, York College of
Pennsylvania. E-mail: [email protected]; (717) 815-6872.