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Syntheses of Functionalized Tropones and
Retinoic Acid Analogs
Bin Zhao
Department of Chemistry
McGill University
Montreal, Quebec, Canada
September 2010
A thesis submitted to McGill University in partial fulfillment of the
requirements for the degree of a Masters of Science
© Bin Zhao, 2010
2
Abstract
The synthesis of highly substituted tropones is a very difficult task due to the lack
of available synthetic methods. A one pot strategy for formation of cycloheptadiene
acetal using a conjugate addition followed by cross coupling and divinylcyclopropane
rearrangement was explored. Oxidation of the expected product under acidic condition
would in theory afford the desired tropones. Addition of vinyl cuprates to a
cyclopropenone acetal was successfully developed. Also, in a model system, the
subsequent Pd(PPh3)4 catalyzed cross-coupling reaction between a cyclopropyl cuprate
and a vinyl iodide was successful. However, in the desired system, cross- coupling
between vinylcyclopropyl cuprates and the substituted vinyl iodide necessary for
CP-225,917 synthesis could not be achieved.
In a second project, synthesis of hybrid molecules combining a functional unit of
retinoic acid analogs with a functional unit for histone deacetylase activity are
presented. Retinoic acid analogs were synthesized via condensation of tetrahydro-
tetramethylnaphthalene carboxylic acid with aromatic amines possessing Zn binding
functional groups. Additional hybrids were prepared by a metal catalyzed cross
coupling strategy. These hybrid molecules were assessed by collaborators and found
to be fully bifunctional molecules. One structure, a hydroxamic acid analog of known
retinoid TTNN, proved to be particularly effective against several retinoid resistant
cancer cell lines.
3
Résumé
La synthèse de tropones hautement substituées est une tâche particulièrement
difficile dû au manque de méthodes de synthèse appropriées. Nous avons exploré une
stratégie pour la formation d’un acétal cycloheptadiène en une étape, à partir d’une
addition conjuguée, suivie par un couplage croisé et d’un réarrangement de
cyclopropane divinylique. Une oxydation sous conditions acides du produit attendu
pourrait générer des tropones multisubstituées.
L’addition conjuguée de vinyl cuprate sur un acétal de cyclopropénone a été
développée avec succès. De plus, dans un système modèle et grâce à la catalyse par le
Pd(PPh3)4, le couplage croisé entre un cyclopropyl cuprate et un iodure de vinyle a été
réussi. Par contre, le couplage nécessaire pour la synthèse de la molécule CP-225,917,
soit une réaction entre des iodures de vinyle substitués et des vinylcyclopropyl
cuprates, n’a pu être réalisé.
Un second projet comportant la synthèse de molécules hybrides est présenté. Ces
hybrides combinent des groupements fonctionnels d’analogues connus de l’acide
rétinoïque avec des groupements fonctionnels possédant une activité sur les histones
déacétylases. Les analogues de l’acide rétinoïque ont été créés grâce à la condensation
d’acides carboxyliques tétrahydrotétraméthylnaphthalène avec des amines aromatiques
possédant des groupements fonctionnels capables de se lier au zinc. D’autres hybrides
ont été préparés via une stratégie de couplage croisé à l’aide de catalyseur métallique.
Ces hybrides furent testés par des collaborateurs et leur activité bifonctionnelle a été
prouvée.
Une molécule en particulier, un acide hydroxamique analogue du rétinoïde TTNN,
a démontré une efficacité notable contre plusieurs lignées cellulaires cancéreuses
résistantes aux rétinoïdes.
4
Acknowledgements
I would like to acknowledge my supervisor, Prof. James L. Gleason, for providing
me the opportunity to work on this challenging project, as well as his supervision on
my research project.
I would like to thank all the past and present members of the Gleason lab for their
kind of support, including Dr. David Soriano Del Amo, Dr. Marc Lamblin, Erica
Tiong, Rodrigo Mendoza Sanchez, Daniel Rivalti, Melanie Burger, Jean-François
Lacroix, Laurie Lim, Jeffrey St Denis, Joshua Chin and Shuo Xing. Thanks to Dr.
James Ashenhurst and Dr. Tim Cernak who mentored me in the early days of graduate
school. I deeply thank Christian Drouin and Jonathan Hudon for helpful suggestion
and discussion throughout my Master studies.
I would also like to thank Dr. Paul Xia and Dr. Frederick Morin for explaining the
operation of NMR instruments, to Dr. Nadim Saadeh and Dr.Alain LeSimple for
HRMS measurements. Much thanks to Professor Karine Auclair for the use of her
HPLC instrument and Kenward Vong for his assistance in the operation of the HPLC
instrument.
I am very grateful to my parents and my aunt, Yuehua Lu, for their unconditional
love and support. Finally, I want to record my thanks to my wife, Yu Ling Zhang,
whose moral and practical support encourage me to cope with all the pressure over the
past years.
5
Abbreviation
Ac Acetyl
SAHA Suberoylanilide hydroxamic acid
APL Acute Promyelocytic Leukemia
ATRA All-trans-retinoic acid
aq. Aqueous
Br. Broad
Bu Butyl
0C Degree Celsius
d Doublet
δ Chemical shift
DIPEA N,N-Diisopropylethylamine
DMAP 4-(Dimethylamino)pyridine
DMF N,N-Dimethylforamide
DMSO Dimethyl sulfoxide
DPPA Diphenylphosphoryl azide
Equiv Equivalent
Et Ethy
Et3N Triethylamine
EtOAc Ethyl acetate
FMO Frontier molecular orbital
FPP Farnesyl pyrophosphate
GAPs GTPase-activating- proteins
GEFs Guanine Nucleotide Exchange Factors
g Gram
HATs Histone acetyltransferases
6
HDACs Histone deacetylases
HDACis Histone deacetylases inhibitors
HMG-CoA Hydroxymethylglutaryl-coenzyme A
HOMO Highest occupied molecular orbital
HPLC High performance liquid chromatography
4-HPR (4-hydroxyphenyl) retinamide
Hr Hour
HRMS High resolution mass spectroscopy
Hz Hertz
IR Infrared
LBD Ligand binding domain
LUMO Lowest unoccupied molecular orbital
M Molar
m Multiplet
Me Methyl
MeOH Methanol
ACN Acetonitrile
mg milligram
Mg Magnesium
ml milliliter
mmol millimole
mol mole
MS Mass spectroscopy
NaB sodium butyrate
NMR Nuclear magnetic resonance
PH Hydrogen ion concentration
7
Ph Phenyl
ppm Part per million
Pr Propyl
RA Retinoic acid
RAR Retinoic acid receptor
Rf Retention factor
RN1 retinoyloxymethyl butyrate
r.t. Room temperature
SAR Structure-activity relationship
s Singlet
sat. Saturated
SQS Squalene synthase
t Triplet
TBS tert-Butyldimethylsilyl
TBSCI Tert-butyldimethylsilyl chloride
Tf Triflic
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
TSA Trichostatin A
TTNN 5',6',7',8'-Tetrahydro-5',5',8',8'-Tetramethyl(2,2'-binaphthalene)-6-carboxylic
acid
TMS Trimethylsilyl
VDR Vitamin D3 receptor
ZBG Zn binding group
8
Table of Contents
Abstract 2
Résumé 3
Acknowledgements 4
Abbreviations 5
Table of Contents 8
List of Figures 11
List of Schemes 12
Chapter One Synthesis of Functionalized Tropone 14
1. Introduction 14
1.1 CP-225,917 and CP-263,114 14
1.2. Tropone 18
1.3. [6+4] Cycloaddition 20
1.4. Approaches to substituted tropone 24
2. Approaches to desired tropone 27
2.1. Addition reaction in desired system using vinyl cuprate reagent 28
2.2. Cross coupling reaction 30
2.3. Addition reaction in desired system using vinylmagnesium
reagent or vinyllithium reagent
37
9
3. Conclusions 41
Chapter Two Synthesis of Retinoic Acid Analogs 42
1. Introduction 42
1.1 Retinoids 43
1.1.1 Biological roles 44
1.1.2 Mechanism of action 45
1.2. Histone deacetylases (HDACs) and histone deacetylases
inhibitors (HDACis)
47
1.2.1 HDACs 47
1.2.2. HDACis 48
1.3. Problems of retinoid treatment in cancer 49
1.4. Retinoid-HDACi hybrid drugs 49
1.5 Design of RAR agonist/HDACi hybrids 53
2. Synthesis of retinoic acid analogs (75-83) 56
2.1. Synthesis of compound 75 56
2.2. Synthesis of compound 76 59
2.3. Synthesis of compound 77 59
2.4. Synthesis of compound 78 62
2.5. Synthesis of compound 79 63
10
2.6. Synthesis of compound 80, 81 and 82 65
2.7. Synthesis of compound 83 68
3. Assay of biological activities 70
4. Conclusions 72
Chapter Three Experimental Section 73
References 107
11
List of Figures
Figure 1. Structure of CP-225,917 (1) and CP-263,114 (2)
Figure 2. Simplified depiction of cholesterol biosynthetic pathway3
Figure 3. Ras switch function in normal untransformed cells6
Figure 4.Structure of colchiicine, purpurogallin, eupenifeldin and hinokitiol
Figure 5. The coefficients of frontier orbital of tropone and cyclopetadiene
Figure 6. Frontier orbital and secondary interaction in [6+4] addition
Figure 7. The structure of all-trans retinoic acid 53
Figure 8. Mechanisms of transcriptional repression and activation by RAR–RXR
heterodimers 52
Figure 9. Chemical Structures of TSA, SAHA, NaB, RN1, TTNN and AM580
Figure 10. The structure of retinoic acid analogs (75-83)
12
List of Schemes
Scheme 1. Retrosynthetic analysis of CP-225,917 (1)
Scheme 2. Resonance between tropone and tropylium ion
Scheme 3. [6+4] cycloaddition of substituted tropone with substituted cyclopetadiene
Scheme 4. [6+4] cycloaddition in model system
Scheme 5. Two selected methods for tropone synthesis and its derivative20
Schem 6. Cycloaddition of acetylene with betaine
Scheme 7. Anicaux’s method to prepare 4-substituted tropone
Scheme 8. Attempt to prepare a highly substituted tropone 32
Scheme 9. Nakamura’s method to prepare cycloheptadienone ketal 41
Scheme 10. Plan for synthesis of desired tropone 6
Scheme 11. Synthesis of 37 and 52
Scheme 12. Addition reaction in desired system
Scheme 13. Synthesis of 44 and 58 and the cross coupling attempt
Scheme 14. Synthesis of vinyliodide 59
Scheme 15. Cross coupling reaction in model system
Scheme 16. Cross coupling reaction in the desired system
Scheme 17. Retrosynthesis of divinylcyclopropane acetal
Scheme 18. Several attempts toward synthesis of divinylcyclopropane acetal
Scheme 19. Plan for synthesis of divinylcyclopropane acetal using Grignard reagent
Scheme 20. Addition reaction in desired system using vinylmagnesium reagent
13
Scheme 21. Addition in desired system using vinyllithium reagent
Scheme 22. Synthesis of 87
Scheme 23. Synthesis of 88
Scheme 24. Synthesis of 75
Scheme 25. Synthesis of 76
Scheme 26. Condensation reaction of aromatic acid 87 and amine 96
Scheme 27. Protection of 96 with TBSCl
Scheme 28. Synthesis of 77 in route a and b
Scheme 29. Synthesis of 103
Scheme 30. Synthesis of 78
Scheme 31. Synthesis of 108
Scheme 32. Negishi cross-coupling reaction between 103 and 108 proves to be problematic
Scheme 33. Synthesis of 79
Scheme 34. Synthesis of 112
Scheme 35. Synthesis of 80
Scheme 36. Synthesis of 81
Scheme 37. Synthesis of 82
Scheme 38. Synthesis of 83
14
Chapter One
Synthesis of Functionalized Tropones
1. Introduction
1.1. CP-225,917 and CP-263,114
In 1997, CP-225,917 (1) and CP-263,114 (2) were discovered by researchers at
Pfizer1 where they were extracted from an unidentified fungus obtained from the twigs
of a juniper tree in Texas. Those molecules, also referred to as the phomoidrides, are
members of the nonadride class of polyketide natural products. After the discovery of
phomoidride A and B, their biological roles were investigated. It was found that they
have inhibitory activities against the mammalian enzymes squalene synthase (SQS)
and Ras farnesyl transferase.1,2
O
O
OH
O
O
HO2C CH3
O
CH3
O
OH
CP-225,917 (1)
O
O
O
O
O
HO2C CH3
OCH3
CP-263,114 (2)
O
14 17
9
14 17
9
(Phomoidride A) (Phomoidride B)
Figure 1. Structure of CP-225,917 (1) and CP-263,114 (2)
High cholesterol is one of the main risk factors for atherosclerotic vascular
diseases, which is the leading cause of death in North America. In cholesterol
15
biosynthesis, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase is the key
rate-limiting enzyme. Inhibition of this enzyme through the class of drugs known as
statins is one of the most popular means of lowering cholesterol levels in patients with
or at risk of cardiovascular diseases. However, relatively rare side effects with the use
of statins include an increase in liver enzymes and myopathy.3 Therefore, alternative
treatments are desired. Another downstream enzyme in the cholesterol biosynthesis
pathway is squalene synthase, which functions to regulate the first committed step of
hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic
pathway (Figure 2).3 Squalene synthase catalyzes the reaction of two molecules of
farnesyl pyrophosphate (FPP) to pre-squalene diphosphate, which is then converted to
squalene.4,5
Since squalene is a biochemical precursor to cholesterol, inhibiting
squalene synthase presents an attractive means of cholesterol reduction. Phomoidride
A and B inhibit squalene synthase from rat liver microsomes with IC50 values of 43
μM and 160 μM respectively.2
Ras proteins are critical to the control of normal and transformed cell growth,
which can be highlighted by the fact that they are commonly mutated in about 30% of
human cancers.6 Ras, located at the inner surface of the plasma membrane, is a GTP-
hydrolyzing protein that serves as a molecular switch. In normal untransformed cells,
upon receiving signals from membrane-bound receptors (PDGF, EGF, integrins), Ras
binds to GTP and becomes active by the help of Guanine Nucleotide Exchange Factors
(GEFs). Subsequent GTP hydrolysis to GDP is then induced by GTPase-activating-
16
proteins (GAPs), which returns Ras to its inactive form (Figure 3).6 In the case of
oncogenic mutations, GTP hydrolysis by Ras is prevented. It produces a constitutively
active protein, which stimulates uncontrolled cellular proliferation leading to tumor
formation.7 To perform its cellular function, Ras must be conjugated to lipid and
localized at the plasma membrane. This process is achieved by the help of farnesyl
transferase. Phomoidride A and B inhibit Ras farnesyl transferase with IC50 values of 6
μM and 20 μM respectively.1 Therefore, as inhibitors of farnesyl transferase, which
consequently prevents conditions for Ras activation, phomoidrides have been
considered as potential anti-cancer drugs.
HO2CSCoA
OHO
HMG-CoA
HMG-CoA
reductase
HO2COH
HO
Mevalonic acid
OPP
Farnesyl pyrophosphate
Squalene synthase
Squalene
HH
HOCholestrol
H
Figure 2. Simplified depiction of cholesterol biosynthetic pathway3
17
Ras-GTP Ras-GDP
GADs
GEFs(Active) (Inactive)
Figure 3. Ras switch function in normal untransformed cells6
The structures of CP-225,917 (1) and CP-263,114 (2) were characterized using a
variety of analytical data and extensive NMR analysis, and the absolute
stereochemistry was assigned in the course of a total synthesis by K.C. Nicolaou.8
Both molecules possesses highly oxygenated structural features, including a
bicyclo[4.3.1] ring system, a bridgehead olefin, a lactol or lactol acetal moiety, a
maleic anhydride moiety, a quaternary center at C14, and two olefinic side chains.
CP-225,917 (1) can be converted to CP-263,114 (2) when treated with an acid
(MsOH)9. Likewise for the reverse transformation, compound 2 can be converted to
compound 1 when treated with base (LiOH ).9 This suggests that synthesis of one of
these molecules can provide both compounds.
Owing to their interesting biological properties and more importantly their
structural complexity, the phomoidride molecules have been a target of considerable
synthetic interest. To date, four completed total synthesis have been reported along
with numerous studies directed toward the synthesis of the phomoidride core.10
18
O
O
HO2C
HO2CCH3
O
CH3
O
OH
O
O
O
O
X
O
O
O
X
+
O
O
OH
O
O
HO2C CH3
O
CH3
O
OH
CP-225,917 (1)
26
9
16
13
CH2OTBS
CH2OTBS
[6+4]
56
3
4
Scheme 1. Retrosynthetic analysis of CP-225,917 (1)
Our retrosynthetic analysis of CP-225,917 (1) is shown in Scheme 1.10c
The
synthesis hinges on a [6+4] cycloaddition of a tropone with a substituted
cyclopentadiene to forge the bicyclic core of the molecule. While simple model
tropones have been used in our synthetic studies to date, it is necessary to develop a
synthetic route to 3,4,6-trisubstituted tropone 6, the key building block required for the
projected final total synthesis of the natural product.
1.2. Tropone
Tropone 7, or 2,4,6-cycloheptatrien-l-one, consists of a seven membered ring with
three conjugated double bonds group and a ketone group. The molecule has been
19
known since 1951. Early theoretical research suggested that tropone might have
aromatic characteristics due to the formation of a tropylium ion 8 (Scheme 2).
However, subsequent experimental data suggests that tropone 7 is basically a
conjugated triene ketone with little or no aromatic delocalization.11
OO
7 8
Scheme 2. Resonance between tropone and tropylium ion
The tropone moiety is found in numerous natural products, many of which possess
interesting biological activity, including colchicines (antimitotic agent),12
purpurogallin (antioxidant agent),13,14
hinokitiol (antibacterial/antifungal agent)15
and
eupenifeldin (cytotoxic/antitumor agent)16
(Figure 4). These compounds have attracted
significant synthetic efforts and several completed total synthesis have been
achieved.17
Also, tropone and its derivatives are useful synthetic intermediates for the
introduction of a seven-membered ring into polycyclic molecules. In particularly,
tropone enters into a variety of cycloaddition reaction resulting in the formation of
[6+4], [2+4], [4+2], [3+6], [8+2], [8+3] adducts.
20
O
OMe
MeO
MeO NHAc
Colchicine
OOH
OH
Purpurogallin
O
O
HO
OH
OH
OHO
OOH
Eupenifeldin Hinokitiol
HO
MeO
HO
Figure 4. Structure of Colchiicine, Purpurogallin, Eupenifeldin and Hinokitiol
1.3 [6+4] cycloaddition
The most notable and best explored cycloaddition of tropone is the [6+4] reaction
with dienes. The frontier orbital coefficients of tropone and cyclopetadiene are shown
in Figure 5. From frontier molecular orbital (FMO) theory, it was suggested that C-2
and C-7 of tropone should be the preferential site for cycloaddition reactions.18
The
[6+4] cycloadduct results from the interaction of the tropone LUMO with the HOMO
of cyclopentadiene. The [4+2] cycloadducts may also be formed under conditions of
high temperature and long reaction times. The stereoselectivity of [6+4] addition
favors the exo-adduct 9 rather than endo-adduct 10. This can be explained by the
presence of destabilizing antibonding interactions in the endo transition state (Figure
6).
21
O O.653
-.187-.393
-.093
.326
.521
-.232
-.418
HOMO LUMO
HOMO LUMO
.32
.18
.29
.17
-.393
-.093
.326
-.521
.232
.418
.29
.17
.32
.18
Figure 5. The coefficients of frontier orbital of tropone and cyclopentadiene
O primary bondinginteraction
9Exo transition state
O
antibonding 10
Endo transition syate
O
O
Figure 6. Frontier orbital and secondary interaction in [6+4] addition
The regioselectivity of [6+4] cycloadditions between substituted tropones and
substituted diene can also be predicted by FMO theory.18
Garst has reported that
reaction of electron-poor tropones with electron-rich dienes was governed by primary
22
FMO interactions and provided “even” regioisomers which arises from maximum
overlap of the FMOs of the two addends.19
In this study, “even” regioselectivity is used
to refer to the amount of atoms between the functional groups along the shortest path.
In our preliminary studies, cycloaddition of 3-substituted tropone 11 with
2-triethylsilyloxycyclopentadiene 12 provided cycloadduct 13 in good yield.10c
Similarly, cycloadduct 15 was obtained when 4-substituted tropone 14 was used
(Scheme 3). As with the Garst studies, the [6+4] adduct was the “even” regioisomer in
all the above cases. When diester tropone 16 was used, a 1:1 mixture of regioisomers
was obtained due to the similar orbital coefficient magnitudes at C-2 and C-7 of
tropone. These examples were also the first Lewis acid catalyzed [6+4] cycloadditions
of a tropone with a diene. Based on model studies above, it was obvious that a
successful synthetic strategy towards CP molecule could not include the full maleic
anhydride unit in the tropone, as this would not afford good regioselectivity in the [6+4]
cycloaddition. We thus investigated a simple model where one of the carbonyls would
enter in reduced form. Cycloaddition of trisubstituted tropone 19 with cyclopentadiene
12 successfully afforded sole regioisomer 20 in 75% (Scheme 4).
Encouraged from these studies, we designed a [6+4] cycloaddition strategy which
would employ 3,4,6-trisubstituted tropone 6 with silyloxy diene 5 to provide tricyclic
structure 4, which might be a potential precursor to the bicyclo[4,3,1]decadienone core
of CP 225,917 (Scheme 1). Following formation of a quaternary center carboxylic acid
from C-6 and a maleic anhydride moiety from C-3 and C-4 would finish the
23
installation of left hand half of the CP molecule. Synthesis of highly functionalized
non-symmetrical tropone 6 was thus an important goal for our CP synthesis.
O
EtO2C
11
EtO2C
OOTES
12
ZnCl2, Et2O
13
O
O
EtO2C14
EtO2C
OOTES
12
ZnCl2, Et2O
O
15
O
EtO2C
EtO2C
16
EtO2C
EtO2C
O
OTES
12
ZnCl2, Et2O
O
17
EtO2C
O
18
O
EtO2C
1:1 mixture65% yield
Scheme 3. [6+4] cycloaddition of substituted tropone with substituted cyclopetadiene
24
O
EtO2C
Me
19
Me
EtO2C
O
Me
OTES
12
ZnCl2, Et2O
O
20
Me
Scheme 4. [6+4] cycloaddition in model system
1.4. Approaches to substituted tropones
A number of methods exist for the synthesis of tropone and its derivatives. Two
selected methods are shown in Scheme 5.20
In route A, tropone was prepared by
exhaustive bromination-debromination of cycloheptanone 21 followed by catalytic
reduction. 2-Phenyltropone has been obtained by an adaptation of this method. In route
B, cyclodehydration of compound 23 provides tropone 24. This has been widely used
in the synthesis of aromatic troponoids.
O O O
BrBr
Br21
22 7
Br2
AcOH H2/BaSO4(a)
PPAO
(b)
23 24
COOH
Scheme 5. Two selected methods for tropone synthesis and its derivative
Among the synthetic strategies towards substituted tropones, cycloaddition
25
reaction can be a very powerful method.21-27
For example, Roberts reported that the
cycloaddition of acetylene 25 with1-phenyl-3-hydroxypyridium 26 leads to
cycloadduct 27. Subsequent oxidation with MCPBA produces tropone 16 via
chelotropic loss of nitrosobenzene (Scheme 7).28
However, prior attempts to prepare
our desired tropones using a similar strategy were not very successful, as the
cycloaddition and subsequent oxidation suffered from low reproducibility.
MeO2C CO2Me
NOMeO2C
MeO2C
PhO
MeO2C
MeO2C25 27 16
MCPBA
N
OH
Ph
26
Cl
Schem 6. Cycloaddition of acetylene with betaine
Ring expansion of arenes is also a common route towards the preparation of the
cyclohetatriene system reported in various syntheses.29-33
Among them, Anicaux’s
method attracted our attention34
(scheme 7). It involves the ring expansion reaction of
anisole 28 with ethyl diazoacetate 29 using rhodium acetate as catalyst. The resulting
mixture of ring expanded products is separated and then isomerized via a thermal
1,5-hydrogen shift to produce cycloheptatriene 31. Oxidation of 31 with bromine
provided 4-substituted tropone 14 in good yield, which was used in our model [6+4]
cycloaddition reactions as described above. However, because the required ratio of
anisole to ethyl diazoacetae is a minimum of 20:1, it becomes impractical to prepare
26
desired tropone 6 on multigram scale by adaptation of Anicaux’s procedure.
OMe OMe
EtO2C
[1,5] shift
OMe O
2830 31 14
Rh2TFA4
N2CHCO2Et
29 Br2
EtO2C EtO2C
Scheme 7. Anicaux’s method to prepare 4-substituted tropone
A very recent method for the synthesis of a highly substituted tropone 32 was
investigated by Neenah Navasero within our lab.35
This method started from simple
and commercial materials to prepare linear diene 33, which was subjected to ring
closing metathesis reaction conditions to provide cycloheptene 34. Compound 34 was
oxidized with DMP resulting in cycloheptenone 35 with 48% yield. However,
attempted oxidation with IBX-MPO for form tropones was unsuccessful (Scheme 8).
34 35 32
DMP
IBX-MPO48%
OHOBn
OH
Grubbs 2
3334
BnO
OH
HO
OBnBnO
OH
HO
OBnBnO
OH
O
OBnBnO
O
O
OBnBnO
Scheme 8. Attempt to prepare a highly substituted tropone 32
27
2. Approach to desired tropone 6
As is shown in the examples above, the synthesis of complex tropones are not so
easy to achieve. Thus, my research involved developing an efficient method for the
synthesis of highly functionalized non-symmetrical tropone 6 based on precedent by
the work of Nakamura who reported that hexenyl cuprate 36 undergoes conjugate
addition across the double bond of cyclopropenone acetal 37 to provide cyclopropyl
cuprate 38. Subsequent cross coupling of 38 with hexenyl iodide 39 in the presence of
Pd(Ph3P)4 affords 4,5-dibutylcycloheptadienone acetal 41 in 67% yield via
[3,3]-sigmatropic rearrangement of the intermediate divinylcyclopropane acetal 40
(scheme 9).36
OO
Bu)2CuLi
OO
Bu
Cu
BuI
Pd(PPh3)4
OO
Bu Bu
OO
Bu Bu
36
3738
39
40 41
Scheme 9. Nakamura’s method to prepare cycloheptadienone ketal 41
Inspired by this work, we investigated the possible adaptation of this strategy for
the synthesis of highly functionalized tropones. In theory, formation of
cycloheptadiene acetal 46 (Scheme 10) might be achieved using a conjugate addition
28
of vinyl cuprate 42 to cyclopropenone acetal 37 followed by cross coupling with
triflate funanone 44 and subsequent divinylcyclopropane acetal rearrangement. The
product of this one-pot protocol might then be oxidized under acidic conditions to
afford the desired tropone 6.
TBSO )2CuLi
Pd(PPh3)4
OO
42
37
44
45
O
O
TBSO
O
O
OO
O
O
O
O
46
6
TfO
TBSO
TBSO
O O
OO
Cu
43
TBSO
O
Scheme 10. Plan for synthesis of desired tropone 6
2.1 Addition reaction in desired system using vinyl cuprate reagent
29
The synthesis of cyclopropenone acetal 37 began with commercially available
1,3-dichloroacetone 47. Protection with neopentyl glycol 49 in refluxing toluene and
catalytic p-toluenesulfonic acid with azeotropic removal of H2O afforded
2,2-bis-(chloromethyl)-5,5- dimethyl-1,3-dioxane 50 in 86% yield. Compound 50 was
then treated with sodium amide in liquid ammonia and quenched with ammonium
chloride to provide cyclopropenone acetal 37 in 40% yield37
(Scheme 11).
O
Cl Cl
+
OHOH
TsOH H2O
Toluene
86%
OO
1. NaNH2/Liq.NH3
2.NH4Cl
40%OO
47 50 3749
HI
TMSCl,H2O
NaI, CH3CN
rt., 1hr
TBSCl
imidazoleDMAP
CH2Cl2
48 51
63% over tow steps
ClCl
OHHO I
52
TBSO
Scheme 11. Synthesis of 37 and 52
Vinyl iodide 52 was prepared by Markovnikov addition of hydrogen iodide,
generated in situ from chlorotrimethylsilane/sodium iodide/water, to 3-butyn-1-ol 48 in
acetonitrile at room temperature to form 3-hydroxy-2-iodo-1-butene 51 without further
purified.38
Silylation of 51 with tert-butyldimethylsilyl chloride (TBSCl) in the
presence of catalytic DMAP produced silyl ether 52 in 63% yield over two steps
(Scheme 11).
30
52 53 42
OO
tBuLiEther
CuBr/DMSEther
Ether
OO
TBSOCu
43
NH4Cl
77%
OO
TBSO
56
TBSO I TBSO Li TBSO )2CuLi
37
Scheme 12. Addition reaction in desired system
With compounds 37 and 52 in hand, the cyclopropene addition reaction was
investigated. Vinyllithium 53 could be prepared by lithium-iodide exchange reaction
between 52 and 2.1 equiv of t-butyllithium in diethyl ether at -78 0C. Addition of
vinyllithium 53 to 0.5 equiv of CuBr/DMS generated Gilman type vinylcuprate 42,
which was treated with cyclopropenone acetal 37 to provide presumed vinyl
cyclopropyl cuprate 43. After workup with aqueous ammonium chloride,
vinylcyclopropane acetal 56 was obtained in 77% yield (Scheme 12).
2.2 Cross coupling reaction
With the confirmation that we could add vinyl cuprate to 37, we were in a position
to attempt cross coupling of the presumed intermediate cuprate 43 with vinyl triflate
31
44. The necessary coupling partner 44 was readily prepared in 53% yield by treatment
of tetronic acid 57 with triflic anhydride in methylene chloride.39
Unfortunately,
Pd(PPh3)4 catalyzed cross coupling between the presumed vinyl cyclopropyl cuprate
43, which was prepared as shown in Scheme 12, and triflate funanone 44 did not work
(Scheme 13). When bromo-funanone 58, which was prepared by bromination of
tetronic acid with oxalyl bromide/DMF40
, was used, cross coupling also failed
(Scheme 13).
OO
TBSOCu
43
Tf2O
DIPEA44 X=OTf 53%58 X=Br 69%
O
X
O
Pd(PPh3)4
OO
O
O
(a)
(b)
or (CoBr)2
DMF
42 + 3744 or 58
O O
HO
O O
X
TBSO
57
Scheme 13. Synthesis of 44 and 58 and the cross coupling attempt
As an alternative to 4-substituted funanones, we chose to investigate vinyl iodide
59 as reactant in the cross coupling. The synthesis of vinyl iodide 59 started by
diprotection of 1,4-butyndiol 60 with tert-butyl dimethylsilyl chloride (TBSCl) to give
the bis(silyl) ether 61 in 96% yield. Hydrostannation of the protected acetylene
derivative 61 in the presence of PdCl2(PPh3)2 catalyst provided the vinylstannane 62
with the (E) configuration in 79% yield. Subsequent iododestanylation was carried out
32
using iodine in ether at room temperature producing vinyl iodide 59 in 82% yield
(scheme 15).41
HO OH TBSO OTBS
OTBSTBSO
SnBu3
OTBSTBSO
I
TBSClImidazole
CH2Cl2
96%
Bu3SnH
PdCl2(PPh3)4
THF
79%
I2ether
60 61
6259
Scheme 14. Synthesis of vinyliodide 59
To test cross-coupling of vinyl iodide 59, we prepared a simple cyclopropyl
cuprate by addition of lithium dibutyl cuprate to cyclopropene 37. To our delight, the
Pd(PPh3)4 catalyzed cross coupling of intermediate cuprate 63 with vinyl iodide 59
afforded disubstituted-cyclopropane acetal 64 in 67% yield (Scheme 15).
Unfortunately, this cross coupling process did not extend to cuprate 43, derivated from
addition of vinyl cuprate 42 to 37 (Scheme 16). Several catalysts, such as
Pd2(dba)3/PPh3, Pd(OAc)2/PPh3, Pd(OAc)2/dppe and Pd(OAc)2/PBu3, were examined,
but none gave any desired product.
33
OOCuBr/DMSEther
Ether
OO
Bu Cu
63
OTBSTBSO
I
64
59
THF
67%
Pd(PPh3)4
Li )2CuLi37
OO
Bu
OTBS
OTBS
Scheme 15. Cross coupling reaction in model system
OO
TBSOCu
43
OO
TBSO
OTBS
OTBS
OTBSTBSOI
59
Pd(PPh3)4
THF
42 +37
Scheme 16. Cross coupling reaction in the desired system
Based on the above results, it appeared impossible to introduce the second vinyl
group at the 2-position of 1-substituted cyclopropane acetal molecule by cross
coupling of a vinylcyclopropyl cuprate 43 and vinyl iodide 59. Thus, three alternative
strategies for preparation of a functionallized divinylcyclopropane acetal were
34
considered. The first strategy involved conversion of vinyl cyclopropyl cuprate 43 to
66 followed by Pd-catalyzed cross coupling with an organometallic desired from vinyl
iodide 59 (Scheme 17a). The second strategy involved regioselective addition of 43 to
3-phenylselanylfuran- 2(5H)-one followed by selenoxide syn-elimination with NaIO4
in MeOH/H2O42
(Scheme 17b). The third strategy involved cis-conjugate addition to
methyl-2-butynoate 70 (Scheme 17c).
35
O O
OTBSO
O
OO
TBSO
OTBS
OTBS
OO
TBSOI
OTBS
OTBS
MOO
TBSOCu
(a)
OO
TBSO(b)O
O
OO
TBSO
O
OPhSe
OO
TBSOCu
O
PhSe
O
46 65
6643
46
45
6743 68
(c) 46
OO
TBSO
69
Me
OMe
O
MeO
O
Me
OO
TBSOCu
43
70
+
+
+
Scheme 17. Retrosynthesis of divinylcyclopropane acetal
36
The first step of each strategy was investigated but, as shown in scheme 18, each
was unsuccessful. In reaction a, treatment of intermediate cuprate 43 with iodine in
ether at room temperature afforded no iodinate products. In reaction b, regioselective
addition of intermediate cuprate 43 to 3-phenylselanylfuran- 2(5H)-one did not provide
the desired product 67. In reaction c, conjugate addition of intermediate cuprate 43 to
methyl-2- butynoate 70 also failed to produce expected product. Addition, no
identifiable product was isolated from above reaction a, b and c. We decided not to
make further attempt to investigate these reaction on our part.
OO
TBSOCu
43
(a)
I2,
ether OO
TBSOI
66
OO
TBSOCu
43
(b)
OPhSe
OOO
TBSO
O
OPhSe
67
OO
TBSOCu
43
(c)
MeO
O
Me70OO
TBSO
69
Me
OMe
O
68
Scheme 18. Several attempts toward synthesis of divinylcyclopropane acetal
37
2.3 Addition reaction in desired system using vinylmagnesium reagent or
vinyllithium reagent
It was obvious that a new efficient method was required for preparation of a
divinyl- cyclopropane acetal. A new plan, which was also inspired by Nakamura et.
al43
, involved a iron-catalyzed olefin carbometalation of a vinyl Grignard reagent with
37 which would yield a cyclopropyl grignard which might undergo addition to ketones.
Subsequent elimination of the tertiary alcohol would then produce a divinyl
cyclopropane for rearrangement(Scheme 19).
TBSO MgX
O O
FeCl3THF
-40 0C
O O
TBSOMgX
37
O O
TBSO
HO
OTBS
OTBS
O O
TBSO
HO
OTBS
OTBS
OTBS
O
TBSO71
Scheme 19. Plan for synthesis of divinylcyclopropane acetal using Grignard reagent
In order to test the feasibility of this new plan, we first undertook a study of
38
iron-catalyzed additions of vinyl Grignard to 37. We investigated three methods to
prepare the necessary vinyl magnesium reagent. These included the direct formation
using magnesium turnings, metal-halogen exchange with complex i-PrMgCl/LiCl44
and lithiation of vinyliodide 52 followed by transmetalation45
with freshly prepared
MgBr2. Subsequent addition of the vinylmagnesium reagent to cyclopropenone acetal
37 in presence of catalyst FeCl3 at -40 0C followed by workup with aqueous NH4Cl led
to vinylcyclopropane acetal 56 in 1%, 22% and 11% yield, respectively (Scheme 20).
39
TBSO I TBSO MgI52 72
MgTHF
O O
37 O O
TBSOMgI
O O
TBSO
NH4Cl
56 1% Yield
TBSO I TBSO MgCl
52 73
iPrMgCl/LiCl
THF
-40 0C O O
TBSOMgCl
O O
TBSO
NH4Cl
56
TBSO I TBSO MgI
52 74
tBuLi
ether
-70 0C
O O
O O
TBSOMgBr
O O
TBSO
56
22% Yield
TBSO Li53
MgBr2
ether
-70 0C
37
11% Yield
NH4Cl
a)
b)
O O
37
c)
Scheme 20. Addition reaction in desired system using vinylmagnesium reagent
40
We also attempted to use a vinyllithium reagent instead of the Grignard reagent.
Lithiation of vinyliodide 52 with t-BuLi led to the vinyllithium reagent 53. Addition of
53 to cyclopropenone acetal 37 in presence of catalyst FeCl3 at -700C followed by
workup with aqueous NH4Cl led to vinylcyclopropane acetal 56 in 6% yield. When the
catalyst Fe(acac)3 was used, the yield was 2% (Scheme 21). If no catalyst was used, no
addition was observed.
TBSO I52
tBuLi
ether
-70 0C
TBSO Li53
O O
FeCl3 or Fe(acac)3
THF,-70 0C
37
O O
TBSOLi
O O
TBSO
NH4Cl
56
2-6 % Yield
Scheme 21. Addition reaction in desired system using vinyllithium reagent
3. Conclusion
Attempts to prepare cycloheptadienes relevant to the synthesis of CP 225,917 have
been described. The synthetic route involved an addition reaction followed by cross
coupling and divinylcyclopropanone acetal rearrangement. Addition of vinyl cuprate
41
42 to cyclopropenone acetal 37 provided a simple vinyl cyclopropane in good yield.
When vinylmagnesium and vinyllithium reagents were used to replace vinyl cuprate
42, only low yield of addition products were obtained. In a model system, the
Pd(PPh3)4 catalyzed cross coupling reaction between butylcyclopropyl cuprate 63 and
vinyl iodide 59 produced disubstituted-cyclopropane acetal 64 in good yield. However,
in the desired system, the Pd(PPh3)4 catalyzed cross coupling reaction between 43 and
59 was unsuccessful.
42
Chapter Two
Synthesis of Retinoic Acid Analogs
1. Introduction
Cancer cells typically show altered cell morphology and physiology when
compared to normal cells as they display lower levels of differentiation and higher
levels of proliferation.46
Several forms of cancer, such as acute promyelocytic
leukemia, have been linked to decreased gene transcription,47
resulting in decreased
cell differentiation and uncontrolled growth.48
In the human acute leukemias,
chromosomal translocations in the genes encoding for transcription factors, including
T-cell acute lymphocytic leukemia 1 (TAL1), LIM domain only 2 (LMO2), acute
myeloid leukemia 1 (AML 1) and core-binding factor subunit beta (CBFβ), results in
altered regulatory activity thus interfering in the growth, differentiation and survival of
normal blood cell precursors.49,50
Abnormal activities of oncogenic and tumor
suppressive transcription factors have also been connected with solid tumor
pathogenesis.50
The relationship between growth, differentiation, neoplastic
transformation, and the expression of genes and tumor suppressor genes is complex.47
However, from recent knowledge of their underlying mechanisms, modulation of the
growth and differentiation of tumor cells is possible by various therapeutic strategies.
Differentiation therapy is an approach that can be described as a method to resume
normal growth patterns of cancerous cells. This is based on the concept that cancer
cells are arrested in an immature state that leads to the inability to control cell growth.
43
With the application of differentiation therapy, the process of maturation within these
cells is revived, leading to the halt of uncontrollable cell proliferation.46,47
Retinoids
induce regulatory functions in cell differentiation, proliferation, apoptosis and
morphogenesis in vertebrates, and have been known as popular
differentiation-inducing agents. 47
Retinoic acid is in clinical use for treatment of acute
promyelocytic leukemia (APL) and it and its analogs have been investigated for a
range of cancers.46
Histone deacetylase inhibitors (HDACis) are also considered as
differentiation-inducing agents because they are transcriptional modulators.47
1.1 Retinoids
Retinoids are a group of signaling molecules that function by interacting with
nuclear retinoid (RARα, RARβ and RARγ ) and rexinoid (RXRα, RXRβ and RXRγ )
receptors to regulate transcription.51
RARs are members of the superfamily of nuclear
homone receptors that work as RA inducible transcriptional activators. They function in
a heterodimeric form with retinoid-X-Receptors (RXRs) to upregulate transcription of
genes in the vicinity of retinoic acid response elements.50
Natural retinoids are normally obtained from dietary vitamin A, which is rich in
eggs, milk, butter and fish-liver oils and the provitamin beta-carotene of plants. All-trans
retinoic acid (ATRA) (figure 7 ) is the major signaling retinoid in the body, and mediates
its action through RAR–RXR heterodimers.52
44
OH
O
Figure 7. The structure of All-trans retinoic acid53
Natural retinoids, which are derived from the parent retinol, arise from four
isoprenoid units joined in a head-to-tail manner.54
They can be divided into three parts:
a trimethylated cyclohexene ring, a conjugated tetraene side chain, and a polar
functional head group (e.g. alcohol, aldehyde, acid).54
Due to the presence of the
conjugated system, retinoids are very easily oxidized and / or isomerized 54
. Thus
many synthetic retinoids have been developed.
1.1.1 Biological roles
Retinoids mediate many biological processes during embryonic development and
in adult life.52,53
They are essential for several biological processes, including growth
and development, reproduction, and cellular differentiation. Retinoids have these
biological processes in both normal and tumor cells, in vivo and in vitro. 53
Because of
their capability of controlling differentiation and apoptosis, they have pharmacological
potentials in the treatment and prevention of cancer.52
In fact, ATRA and some other
commercially available retinoids are generally applied in many cell differentiation
therapies.53
However, retinoids are toxic when taken in excess, irritating to the skin,
45
and are highly teratogenic.54
The biological roles of retinoids are achieved through their two groups of nuclear
receptor, RARs and RXRs, each of which has three isotypes α, β and γ. These
receptors possess different ligand specificity. 55
For example, ATRA can only bind and
trigger RAR receptors, whereas 9-cis RA can bind and activate both RARs and RXRs.
55 The class and isoform selectivity of retinoids is important in differentiation therapy.
Due to the ability of RXR to heterodimerize with a wide variety of nuclear receptors,
they have wide range of therapeutic uses, but also a corresponding concern for broad
toxicity. RAR agonists are thus expected to have more selective therapeutive activity
and the bulk of research has been in this area.
The degree of cell differentiation depends on the expression level of target genes
and the activity of target genes is determined, among many factors, by the
post-translational modification of the N-terminal tails of core histones by acetylation
and subsequent changes in chromatin structure.47
Upon binding to agonist or
antagonist, retinoid receptors act on the transcriptional complex by inducing chromatin
structural changes, resulting in activation or repression of target genes.
1.1.2 Mechanism of action
RARs and RXRs act mainly as RAR-RXR heterodimers.55
In the absence of RAR
ligands or in the presence of RAR antagonists, RAR-RXR heterodimers form
multi-protein complexes with nuclear receptor co-repressor (CoR), silencing mediator
46
for retinoid and thyroid receptors (SMRT) and histone deacetylases (HDACs), all of
which result in repression of gene transcription.52,55
In contrast, retinoid binding to the
heterodimers induces a conformational change in the ligand-binding domain (apo-LBD)
to generate the holo-LBD. This structural transition disrupts the intereaction with the
CoR and allows the recruitment of co-activators (CoAs) as well as RAR-RXR binding
to RARE’s (retinoic acid response elements). CoAs recruit (or pre-exist in a complex
with) histone acetyltransferases (HATs), which leads to the acetylation of histone
amino-terminal tails, resulting in chromatin decondensation. Then the basal
transcription machinery, containing thyroid-hormone-receptor-associated protein
(TRAP), vitamin D receptor-interacting protein (DRIP) or Srb and mediator
protein-containing complex (SMCC), is formed, initiating the target gene expression
(figure 8 ).52,55
47
Figure 8. Mechanisms of transcriptional repression and activation by RAR–RXR
heterodimers 52
1.2 Histone deacetylases (HDACs) and Histone deacetylases inhibitors (HDACis)
1.2.1 HDACs
As described above, HDACs are nuclear enzymes that play a critical role in
48
regulating gene expression. They catalyze the deacetylation of the N-acetyl lysine
residues of histones in chromatin thus affecting the accessibility of transcription
factors to DNA.56
The overall levels of acetylation are controlled by the balance
between the activities of histone acetyltransferases (HATs) and histone deacetylases
(HDACs).57
Imbalance of their activities has been implicated in cancer, and histone
deacetylase inhibitors (HDACis) display antiproliferation properties that have been
rendered them as potential clinical candidates.56
HDACs are separated into four main
classes based on their sequence homology and expression models. Class I and II and
IV HDACs are Zn-dependent deacetylases, whereas the Class III HDACs are
NAD-dependent deacetylases.57
1.2.2 HDACis
HDACis increase histone acetylation, which results in increased gene
expression.57-59
Overall, HDACis induce cellular arrest during the cell cycle, or induce
cells to undergo apoptosis or differentiation depending upon cell type.57
Because of
the diverse biological activities of HDACis, they have been used in the inhibition of
tumor growth. Numerous HDACis have been developed and are in various stages of
clinical development. HDACi structure generally consists of a zinc binding unit
attached via a linking chain to a “cap” group which binds at the HDAC surface. Many
zinc binding groups have been employed with the most common being hydroxamic
acid (e.g. SAHA, TSA, Figure 9) and carboxylic acids (e.g. valproic acid, butyric acid).
49
Notably, SAHA has been approved by FDA. In addition, HDACis can synergize with
other therapeutic approaches. They are able to increase the efficacy of other nuclear
receptor ligands, such as retinoids, in second cancer models.60,61
1.3 Problems of retinoid treatment in cancer
As described above, retinoids has been used in the treatment of several cancer,
including APL and neuroblastoma.62
However, a problem in this treatment is the rise of
retinoid resistance. In the treatment of epithelial tumors, retinoid therapy encounters
the loss of retinoid sensitivity associated with lack of RARβ2 expression due to
RARβ2 promotor hypermethylation and histone deacetylation.46,63
The resistance to
ATRA in APL has been overcome by co-treatment with the HDACi phenylbutyric
acid.64,65
In combination with retinoids, HDACi induce acetylation in RARβ2
hyper-methylated promoters leading to the re-expression of RARβ2, resulting in an
additive inhibitory effect on tumor cell growth in vitro and in vivo.66,62
Additive/synergistic growth inhibition of human prostate cancer cells has also been
reported from combination therapy.46
However, some similar patients did not respond
to this combination therapy.48
Improvement in the therapy is needed.
1.4 Retinoid-HDACi hybrid drugs
In drug discovery, the “one disease, one target” approach has dominated the
50
pharmaceutical industry.67
However, many diseases are still not well treated under this
paradigm. In order to enhance efficacy, polypharmacology, which develops drugs to
modulate multiple targets at the same time, is under consideration and development.67
The possible approaches include drug cocktails, muticomponent drugs and multiple
ligands.67
Firstly, the approach of drug cocktails can be defined by the concept of “2
tablets with 2 agents”, where different drugs for different targets are administered at
the same time. Secondly, the approach of muticomponent drugs follow a concept of “1
tablet with 2 agents”, where two or more agents are coformulated into a single tablet to
improve patient compliance.67
The combination therapies of retinoids and HDACis
that were described in the last section were administered as either drug cocktail or
muticomponent drugs. One disadvantage of having 2 drugs that rely heavily upon
each other for efficacy, which exists for both drug cocktail and multicomponent
strategies, is the unpredictable differences in the metabolism rates for each component
among patients.67
Finally, the last approach of multiple-ligand drugs follows a concept
of “1 tablet with 1 active agent that acts upon multiple biological targets”. The
difficulty of this method, however, is the design of the active agent such that it
possesses good affinity for multiple targets. This greatly increases the difficulty in the
design and optimization, but will eventually be advantageous in the later stages of the
drug discovery process due to the presence of only a single pharmacokinetic profile,
giving better drug delivery properties compared to two agents. In addition, a lower risk
of drug-drug interactions is also a benefit.67
51
In considering the disadvantages that retinoid/HDACi cocktail or multicomponent
drugs may possess, the aim of this project was to develop a hybrid drug which
combined an RAR agonist with an HDAC inhibitor. Hybrid molecules are defined as
chemical entities with different biological functions and dual activities, indicating that
a hybrid molecule often possesses two distinct pharmacophores.68
The synergistic
benefits between retinoids and HDACis have already been applied in drug discovery
research for cancer treatments. A novel prodrug of retinoic and butyric acids, RN1
(retinoyloxymethyl butyrate, Figure 9), was synthesized.48
First, in Acute
Promyelocytic Leukemia (APL) RA-sensitive NB4 cells, RN1 induced greater cell
differentiation than RA (retinoic acid) or NaB (sodium butyrate, Figure 9), and
inhibited cell growth to the same degree as RA or RA plus NaB. NaB alone had no
inhibition effect on cell growth.48
Secondly, in the RA-resistant APL NB4-MR4 cell
line, RN1 significantly inhibited cell growth while the treatment with RA or RA in
combination with NaB had no effect. RN1 partially induced differentiation and the
expression of RA target genes, and also caused apoptosis in RA-resistant R4 cells.48
Furthermore, RN1 arrested the growth and induced apoptosis in non-APL tumor cells.
In contrast, RN1 had no inhibition effect on growth in normal human peripheral blood
mononuclear cells.48
Through this research, RN1 may possess the potential to be used
in the treatment of tumors other than APL. Unfortunately, due to the instability of RN1,
its administration must quickly follow its synthesis. Also, the incorporated NaB moiety
in RN1 is one of the weakest HDACi known. Therefore, other HDACi’s, including the
52
FDA approved SAHA (Zolinza), could act as better candidates to combine with RA.
RN1 provided good underpinning for our development of a stable hybrid drug with the
hope of enhancing therapeutic efficacy in cancer treatment. There are several examples
of hybrid molecules. One example would be within our group where the design and the
synthesis of several hybrid drugs targeting nuclear receptors and HDAC have been
successfully. For instance, Triciferol, a hybrid molecule combining VDR (vitamin D3
receptor) agonist and HDAC inhibitory activities, was shown to be a more efficacious
antiproliferative and cytotoxic agent than natural vitamin D3 in four cancer cell models
in vitro.69
The experience on how to design hybrid molecules which combine activity
towards a nuclear receptor and HDAC, and the rational design principles should be
applicable to retinoic acid receptor agonist/HDACi hybrids. Notably, compared to
prodrugs such as RN1, hybrid molecules are expected to be more stable.
53
O
O
NH
OH
N
O O
Trichostain A(TSA)
HN
NH
OH
O
O
Suberoylanilide hydroxamic acid(SAHA)
O
O
RN1
ONa
O
Sodium butyrate(NaB)
OH
O
NH
O OH
O
TTNN AM580
Figure 9. Chemical Structures of TSA, SAHA, NaB, RN1, TTNN and AM580
1.5 Design of RAR agonist/HDACi hybrids70
In our group’s drug designs, 9 retinoid acid analogs (75-83) were planned, all
being hybrid molecules containing the core of retinoids merged with the Zn binding
functional group (figure 10). The design of these hybrids is based on structure-activity
relationship (SAR) and x-ray studies for ATRA/RAR and TSA/HDAC. The crystal
structures of ATRA and other agonist bound to RAR have revealed that there is a
large hydrophobic binding pocket consists mainly with hydrophobic residues (e.g. Phe,
Leu, Ile, Met) and a hydrophilic carboxylic acid binding region composed of 3 binding
54
residues (Ser129, Arg278, Lys236).71
The ligand binding interaction induces the
C-terminal H12 to seal its entry site. This can not only further stabilize the ligand, but
create a binding surface for transcriptional mediators. It also reveals that the -ionone
unit is closer to H11 and H12 leading to good van der waals interaction. Many
synthetic retinoids have been developed and most of them use a
1,1,4,4-tetramethyltetralin to replace the -ionone unit and tether this to a carboxylic
acid containing unit. Aromatic groups are used for the replacement of polyene chain in
the natural vitamin to mitigate its air-, light- and metabolic-instability. Therefore, the
acid region of ATRA was replaced by aromatic carboxylic acid in most cases.72
Addition, phenol-based retinoids have been reported (e.g. 4-HPR).72
The crystal
structure of TSA bound to archaebaterial HDAC1 homolog HDLP have revealed a
tube-like binding pocket possessing a zinc ion coordinated to residues of Asp168,
His170 and Asp 258 at the bottom of the tube.73
The hydroxamic acid forms a
bidentate chelate with the zinc ion. The diene chain is inserted into the narrow pocket,
making multiple contacts to the hydrophobic portion of the pocket. The dimethyl
-aniline group at the other end of TSA makes several hydrophobic contacts at the
surface groove at the outlet of the tube. The dienyl chain in TSA thus acts as linker,
tethering the zinc binding unit to a “cap” group which binds at the HDAC surface.74
Traditionally, long straight chains, either saturated or unsaturated, are mostly used as
linker. However, there are several recent examples of aromatic linkers. Besides the
hydroxamic acid are used commonly as zinc binding group (ZBG), other groups
55
including ortho-aminoanilides, thioglycolate amides, sulfonamides have been used.
Using simple rational design principles, it should be possible to design bifunctional
hybrid molecules that can act as both RAR agonists and HDACi's. First, we
incorporated the hydroxamic acid directly into the carboxylic acid site of known
retinoids (e.g. AM580, TTNN, figure 9) to add HDACi activity to these molecules. It
was expected that the hydroxamic acid would take part in hydrogen bonds, similar to
that of ATRA in LBD of RAR, while conveying the capacity to chelate the zinc ion in
the HDAC binding site. Based on this, hybide76, 78, 79 were designed. Secondly,
many retinoids utilize amides of p-aminobenzoic acid for the carboxylic acid region of
the molecule (e.g. AM580). Incorporation of second amino group in the aromatic ring
would transform this amide into an o-aminoanilides, a very common motif in HDACi's
which are entering clinical trials.74
Hybride 75 was designed based on this concept. In
addition, retinoids such as 4-HPR are known to have p-aminophenols and thus an
o-amino-p-phenoxyamide (e.g. 77) might also function as a retinoid/HDACi
bifunctional hybrid. Third, incorporation of the hydroxamic acid to known retinoid
backbones (e.g. 1,1,4,4-tetramethyltetralin) tethers with variable lengths to find a
best-fit with RAR carboxylic acid binding sites. With a modest tether length, these
structures are also expected to be excellent HDACi's, the 1,1,4,4-tetramethyltetralin
unit serving as the 'cap' group of the HDACi. Hybrid 80, 81, 82 were designed based
on this idea. Finally, another ZBG , thioglycolate amide, was used in hybid 83.
56
The goal of my research project was to synthesize the 9 retinoid acid analogs
described above, which would then be screened for biological activity by our
collaborators at the University of Montreal.
HN
O
NH
OH
O
NH
OH
O
NH
OH
O
NH
OH
O
OH
HN
O
SH
NH
NH2
O
NH
NH2
O
NH
O
7576
77 78
79 80
81 82
83
CO2HNHOH
O
OH
Figure 10. The structure of retinoic acid analogs (75-83)
2. Synthesis of retinoic acid analogs(75-83)
2.1 Synthesis of compound 75
57
The base of all our planned hybrids was a 1,1,4,4-tetramethyltetrahydro-
naphthalene which mirrors the ionone portion of retinoic acid. To prepare this unit,
2,5-dichloro-2,5-dimethylhexane 84 was prepared from the reaction of the
commercially available 2,5-dimethyl-2,5-hexanediol 85 with concentrated aqueous
HCl at room temperature. Friedel-Crafts alkylation of toluene with 84 in presence of
AlCl3 provided 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene 86 in 87% yield
over two steps. Oxidation of 86 by potassium permanganate gave 1,1,4,4,-
tetramethyl-6-carboxy-1,2,3,4-tetrahydronaphthalene 87 in 76% yield75
(Scheme 22).
OH
OH
Cl
ClMe
COOH
r.t
HCl
AlCl3
Toluene
KMnO4
Pyridine
8485 86
87
87% two steps
76%
Scheme 23. Synthesis of 87
To prepare our orthoamino anilides, methyl ester 88 was first prepared from
4-amino-3-nitrobenzoic 89 (Scheme 23). Aromatic acid 87 was activated with thionyl
chloride in CH2Cl2 to provide acid chloride 90, which was then directly coupled with
amine 88 to give nitro amide compound 91 in 52% yield over two steps.76
58
Hydrogenation of 91 under stand conditions (10% Pd-C and hydrazine hydrate in
EtOH) led to amine 92 in 81% yield, which was hydrolyzed to retinoic acid analog 75
in 73% yield (Scheme 24).
COOH
H2N
NO2
COOMe
H2N
NO2
MeOH, AcClreflux
96%
89 88
Scheme 23. Synthesis of 88
COOH
reflux
SO2Cl
CH2Cl2 Cl
O
NH
O OMe
O
NO2
COOMe
H2NNO2 88
DIPEADMAPovernight52% two steps
87 90
91
NH
O OMe
O
NH2
H2NNH2
HClPd/C
92 LiOH
THF/MeOH/H2O
73%
NH
O OH
O
NH2
75
81%
Scheme 24. Synthesis of 75
59
2.2. Synthesis of compound 76
To prepare our hybrid derived from AM 580, aromatic acid chloride 90 prepared above
was coupled with methyl para-amino benzoate 93 to provide amide 94 in 54% yield
over two steps. Hydroxyamination of ester 94 with 50% aqueous NH2OH in
THF/MeOH gave hydroxamic acid 76 in 51% yield77
(Scheme 25).
Cl
O
NH
O OMe
OCOOMe
H2N
DIPEADMAPovernight54% two steps90
94
90
NH
O NHOH
O
NH2OHTHF/MeOH
KOH
51%
76
Scheme 25. Synthesis of 76
2.3. Synthesis of compound 77
Condensation of acid chloride 90 and 4-amino-3-nitrophenol 96 provided ester 97
rather than the desired amide 95 as shown in scheme 26. We considered the possibility
that the ester 97 was kinetic product formed due to the increased acidity of the phenol
due to the o-nitro group. However, the ester 97 did not convert to 95 in refluxing
60
toluene over 24 hours. To attempt solve this problem, 96 was protected with TBSCl
provided compound 98 (Scheme 27).
Cl
O
NH
OOH
90
95
NO2
O
ONH2
NO2
OH
H2NNO2
96
DIPEA, DMAP
97
Scheme 26. Condensation reaction of aromatic acid 87 and amine 96
OH
H2N
NO2
OTBS
H2N
NO2
TBSClTHFimidazoleDMAP
93%
9698
Scheme 27. Protection of 96 with TBSCl
It was expected that condensation of 98 with acid chloride 90 would then furnish
the desired amide. However, to our surprise, diacylated compound 100 was obtained
exclusively in this coupling event, presumably via in situ TBS deprotection.
Hydrolysis of compound 100 eventually led to 95, which was followed by
hydrogenation in the presence of catalytic amounts of 10% Pd-C to provide
compound 77(Scheme 28, route a). Alternatively, compound 77 can be directly
obtained in 54% yield by condensation of 87 with 3,4-diaminophenol 10178
prepared
61
by hydrogenation of 4-amino-3-nitrophenol 96 (Scheme28, b and c). This useful
regioseletivity results from the presence of the hydroxyl group which serves to
increase electron density at the para-amino group.
Cl
O
NH
OOTBS
90
99
NO2
NH
OO
NO2
OTBS
H2NNO2
96
DIPEA, DMAP
100
a)
O
NaOH
H2O/MeOH/THF
NH
OOH
95
NO2
H2
Pd/CMeOH
NH
OOH
77
NH2
b)
Cl
O
90
OH
H2NNH2
101
HOBt, HBTUDMF54%
NH
OOH
77
NH2
OH
H2N
NO2
OH
H2N
NH2
H2
Pd/CMeOH
92%
96 101
c)
Scheme 29. Synthesis of 77 in route a and c
62
2.4. Synthesis of compound 78
To prepare the next series of hybrids, we required a bromotetrahydronaphthalene
which can be used for cross-coupling reactions. A double Friedel-Crafts alkylation of
bromobenzene 102 with 2,5- Dichloro- 2,5-dimethylhexane 84 produced
1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-bromo-naphthalene 103 in 96% yield.
(Scheme 29) 79
To prepare a hybrid of TTNN, a biaryl coupling was successfully
achieved using Negishi cross-coupling80
of the arylzinc reagent, prepared by treatment
of bromotetrahydronaphthalene 103 with nBuLi followed by metal exchange with
ZnCl2, and bromonaphthalene 104 in the presence of Ni(PPh3)4 catalyst to provide
biaryl 105 in 39% yield. Hydroxyamination of ester 105 by 50% aqueous NH2OH in
THF/MeOH afforded hydroxamic acid 78 in 47% yield (Scheme 30).
Cl
Cl
Br
102
AlCl3CH2CCl296%
Br
10384
Scheme 29. Synthesis of 103
63
Br
103
+
Br
OMe
O
104
nBuLi, THF,-750C;
ZnCl2, THF;
Ni(PPh3)4
39%
103
OMe
O
NH2
THF/MeOHKOH
47%
78
NHOH
O
Scheme 30. Synthesis of 78
2.5. Synthesis of compound 79
In order to prepare another biaryl, 3-(4’-bromophenyl)-(E)-propenoic acid
methylester 108 was prepared in 73% yield from a Wittig reaction between
4-bromobenzaldehyde 106 and Ylide 107 in water at 90 0C. (Scheme 31)
81 However,
Negishi cross-coupling between the arylzinc reagent, prepared by treatment of
bromotetrahydronaphthalene 103 with nBuLi followed by metal exchange with ZnCl2,
and 108 in the presence of Ni(PPh3)4 or Pd(PPh3)4 catalyst was unsuccessful (Scheme
32). Therefore, an alternative route was adopted for preparation of biaryl 109.
Bromotetrahydro- naphthalene 103 was treated with nBuLi, followed by addition of
triisopropylborate and then hydrolysis to arylboronic acid 110.82
Subsequent Suzuki
cross-coupling83
of arylboronic acid 110 with 108 in the presence of Pd(OAc)2/PPh3 as
64
catalyst afforded 109 in 42% yield. Hydroxyamination of ester 109 with 50% aqueous
NH2OH gave hydroxamic acid 79 in 61% yield (Scheme 33).
Br
H
O
+ Ph3POMe
OOMe
Br
OH2O
90 0C
73%
106 107 108
Scheme 31. Synthesis of 108
Br
103
1) nBuLi, THF, -75 0C
2) ZnCl2, THF
OMeBr
O3)
108
Ni(PPh3)4
or Pd(PPh3)4
OMe
O
109
Scheme 32. Negishi cross-coupling reaction between 103 and 108 proves to be
problematic
65
Br
103
OMe
O
109
nBuLi, THF;
B(iOPr)3B(OH)2
110
OMeBr
O
108
CsF, THF
Pd(OAc)2 +PPh3
42%
NHOH
O
79
NH2OH
THF/MeOHKOH
61%
Scheme 34. Synthesis of 79
2.6. Synthesis of compound 80, 81 and 82
We attempted to prepare a series of hybrids which lacked a second aromatic ring.
These molecules more closely resemble SAHA and other HDACis and we were
interested as to whether they would function as bifunctional hybrids. To prepare the
first of these, methyl 5-bromopentanoate 112 was obtained from 5-bromovaleric acid
111 in 90% yield. (Scheme 34) Alkylzinc reagent 113 was obtained by treatment of 112
with commercially available Zn powder (activated by the addition of
1,2-dibromoethane (5 mol%), TMSCl (1 mol%) and LiCl) in THF. Subsequent
coupling with aryl bromide 103 in the presence of Pd(PPh3)4 as catalyst provided ester
114 in a modest 15% yield. Hydroxyamination of ester 114 by 50% aqueous NH2OH
gave hydroxamic acid 80 in 45% yield (Scheme 35). 84
66
Br OH
O
Br OMe
OAcClMeOH
90%
111112
Scheme 34. Synthesis of 112
Br OMe
O
BrZn OMe
O
1mol% TMSCl
5mol% 1,2-dibromoethane
10mol% I2Zn,Li,THF, 50 0C
112113
Br
103
THF
Pd(PPh3)415% two steps
114
OMe
O
NHOH
ONH2OH
THF/MeOHKOH
45%
80
Scheme 35. Synthesis of 80
Synthesis of compound 81 was carried out in similar fashion. Ester 116 was
prepared from 6-bromohexanoic acid 115 in 89% yield. Alkylzinc reagent 117 was
obtained by treatment of 116 with commercially available Zn powder (activated by the
addition of 1,2-dibromoethane(5 mol%), TMSCl(1 mol%) and LiCl) in THF.
Subsequent coupling with aryl bromide 103 in the presence of Pd(PPh3)4 as catalyst
provided ester 119 in 7.9% yield. Hydroxyamination of ester 119 by 50% aqueous
67
NH2OH gave hydroxamic acid 81 in 52% yield (Scheme 36).84
1mol% TMSCl
5mol% 1,2-dibromoethane
10mol% I2Zn,Li,THF, 50 0C
Br
103
THF
Pd(PPh3)47.9% two steps
NH2OH
THF/MeOHKOH
HOBr
O
MeOBr
OAcClMeOH
89%115 116
MeOZnBr
O
117
118
OMe
O
81
NHOH
O
52%
Scheme 36. Synthesis of 81
Also, synthesis of compound 82 was carried out in similar fashion.
7-Bromoheptanol 119 was treated with DMSO/(COCl)2/Et3N in dichloromethane to
afford aldehyde 120 in 95% yield.85
Oxidation of aldehyde 120 to carboxylic acid 121
with NaClO2/NaH2PO4/H2O followed by treatment with acetyl chloride in methanol
provided ester 122 in 60% yield over two steps. Alkylzinc reagent 123 was obtained by
treatment of 122 with commercially available Zn powder (activated by the addition of
1,2-dibromoethane(5 mol%), TMSCl(1 mol%) and LiCl) in THF. Subsequent coupling
68
with aryl bromide 103 in the presence of Pd(PPh3)4 as catalyst provided ester 124 in
11% yield. Hydroxyamination of ester 124 by 50% aqueous NH2OH gave hydrxamic
acid 82 in 64% yield (Scheme 37).84
Br OH Br H
O
Oxalyl chloride
DMSO,Et3NCH2Cl2
95%119 120
Br OH
O
121
AcClMeOH
1mol% TMSCl
5mol% 1,2-dibromoethane
10mol% I2Zn,Li,THF, 50 0C
60% two steps
NaClO2
NaH2PO4
H2O
Br OMe
O
122
BrZn OMe
O
123
OMe
OBr
103
THF
Pd(PPh3)411% two steps
124
NHOH
O
82
NH2OH
THF/MeOHKOH
64%
Scheme 37. Synthesis of 82
2.7. Synthesis of compound 83
Finally, recent results from our lab indicate that thioglycolate amides are good
69
HDACis and we thus sought to introduce this zinc binding group in our retinoid
hybrids. Hydrolysis of ester 114 led to carboxylic acid 125, which could be subjected
to a Curtius rearrangement with DPPA(diphenylphosphoryl azide). The intermediate
isocyanate 126 was hydrolyzed with aqueous NaOH to afford amine 127 in 42% yield
over two steps. Coupling of protected thioglycolic acid 128 with amine 127 produced
the amide 129 in 99% yield. Deprotection of 129 led to the desired thiol 130 in 74%
yield (Scheme 38). 77
114
OMe
O
125
OH
ONaOH
THF/MeOHH2O
99%
DPPA
Et3toluene
126
N=C=ONaOHTHF
42% two steps
NH2
127
HOSAc
O
128
EDC HCl99%
HN
129
SAc
O
HN
SH
O
MeONaMeOH
74%83
Scheme 38. Synthesis of 83
3. Assay of biological activities70
70
The biological activities of hybrids (75, 76, 77 and 78) were determined through
assays performed by David Cotnoir-White (University of Montreal). All four hybrids
have strong RAR agonist activity while maintaining modest to strong HDACi activity.
Hybrid 76 had the highest overall potency while both hybrids 76 and 78 showed
anti-proliferative properties against several cell lines. Impressively, TTNN-based
hybrid 78 displayed highly promising anti-proliferative activity. The details are
described below.
1) Hybrid molecules showed similar apparent affinity for RARα as parental
compounds. A bioluminescence energy transfer (BRET) assay designed for co-activator
recruitment of RARα and characterized hybrids was employed, which monitors the
formation of the receptor-coactivator complex. Results show that all four hybrids were
as active as ATRA or 9-cis-RA at 1 µM. Notably, the RAR agonist activity of hybrid
78 was not interrupted by the incorporation of hydroxamic acids into retinoids.
2) Hybrids (76, 77, 78) were found to transcriptionally activate RA target genes to
varying degrees. The induction of several RAR target genes by these hybrids was
observed in RA responsive NB4 and MCF-7 cell lines as well as the retinoid resistant
MDA-MB-231 cell line. In NB4, hybrids 76, 77 strongly induced RARα, while hybrid
78 only had a very weak effect. However, C/EBP-epsilon was induced by all three
hybrids and this induction was significantly suppressed by the addition of an RAR
antagonist. On the other hand, hybrid 78 induced RAR in MCF-7 and MDA-MB-231
cells, but no induction was observed in the presence of ATRA or parent retinoid
71
TTNN.
3) HDACi activity was monitored by a fluorometric assay using an acetylated
lysine substrate which, upon treatment with purified HDACs followed by trypsin,
releases aminomethylcoumarin. Hybrids 76, 75, 77 and 78 had IC50's of 2.5 µM, 227
µM, 576 µM, and 5.0 µM respectively against HDAC3. HDAC6 activity of 78 was
assessed and found to have an IC50 of 148 nM. This range of potencies is similar to
those observed in related VDR agonist-HDACi hybrids (unpublished data). More
importantly, in breast cancer cell lines MCF7 and MDA-MB-231, prolonged treatment
with hybrid 78 caused p53 acetylation to levels similar to SAHA, an effect that is not
observed with its parental compound TTNN. This observation opens the door to
understanding a possible mechanism of action for the anti-proliferative property of
hybrid 78 in some breast cancer cell lines.
4) Tests were also performed to observe the effects of hybrids (76, 77, 78) on
proliferation, apoptosis and/or differentiation in leukemic and breast cancer cells. Cells
were treated with parental retinoids and the HDACi SAHA, alone and in combination,
as well as the hybrids at same concentrations. Cell growth was evaluated over a 3-7
day period using cell viability assays. Apoptosis was monitored by propidium iodide
staining and flow cytometry analysis. Hybrids 76 and 77 showed strong growth
inhibitory effects in RA-sensitive and RA-resistant acute myelogenous leukemia
(AML) cells, and they also induced granulocytic differentiation. These results are
consistent with the RARα BRET assay. Most importantly, hybrid 78, a RARβ/γ
72
selective retinoid TTNN hybrid, showed strong anti-proliferative activity in a
RA-resistant ALL cell line, REH, as evidenced by its potent induction of cell death. It
is also active in several breast cancer cell lines. Remarkably, Hybrid 78 had a strong
inhibition effect on the growth of MDA-MB-231 cells (a RA-resistant breast cancer
cell line), in which SAHA, a potent HDACi, only partially inhibited cell growth.
Furthermore, hybrid 78 exhibited only negligible effects on immortalized 184b5 cells,
indicating a potentially useful therapeutic window.
4. Conclusions
The synthesis of several retinoic acid analogs (75-83) has been described. Retinoic
acid analogs (75-77) were synthesized using condensation reaction sequence involving
tetrahydrotetramethylnaphthalene carboxylic acid and possible Zn binding functional
groups. Retinoic acid analogs (78-79) were prepared via Suzuki or Negishi
cross-coupling reaction between aromatic bromides and corresponding aromatic
boronic acid or zinc reagent. Retinoic acid analogs (80-82) were prepared by Pd(0)
catalyzed cross coupling reaction of aromatic bromide with non-activated alkyl halides.
Retinoic acid analogs (83) were synthesized using general method for formation of
amide bond. Alternative routes were required for preparation of compounds (80-82)
due to the low yield. From the biological assays completed to date, compound 78 has
enhanced anti-proliferative activity and potentially low toxicity which make it an
exciting lead as a novel anticancer drug.
73
Chapter Three
Experimental Section
General: All reactions were conducted in oven or flame-dried glassware under an
argon atmosphere with magnetic stirring unless noted otherwise. 1H and
13C spectra
were recorded on a 300MHz or 400MHz Varian Mercury, or 500MHz Varian Unity
spectrometer and chemical shift values are expressed in ppm (δ) relative to chloroform
(7.26 ppm, 77.0 ppm respectively). High-resolution mass spetra were obtained from
the Department of Chemistry or the Mass Spectrometry Unit at McGill University.
Infrared spectra were obtained using a Nicolet Avatar 360 FTIR spectrometer on
evaporated samples. Thin layer chromatography (TLC) was carried out on EMD glass
plates pre-coated with Silica gel 60 F-254. All plate were visualized by UV254 light
source or by staining with an aqueous solution of potassium permanganate. Flash
column chromatography was performed using Silica Gel F60 (Silicycle). Ether and
THF were distilled from sodium and benzophenone. Methylene chloride, toluene and
triethylamine were distilled from calcium hydride. Commercial reagents were used
without further purification unless otherwise noted.
74
Synthesis of 2,2-bis(chloromethyl)-5,5-dimethyl-1,3-dioxane (50):
O O
ClCl
A mixture of 1,3-neopentyl glycol (13.8 g, 0.132 mol, 1.1 equiv),
1,3-dichloroacetone (15.2 g, 0.12 mol, 1 equiv), p-toluenesulfonic acid (0.455 g, 2.4
mmol, 2 mol%) and toluene (10 mL) was heated to reflux for 19 hr in a
round-bottomed flask equipped with a Dean-Stark trap and a condenser. The reaction
was partitioned between hexane (50mL) and saturated sodium bicarbonate (20mL).
The organic phase was washed with brine and water, dried over MgSO4, filtered and
concentrated on a rotary evaporator. Purification by vacuum distillation (111-113 0C,
2.5 mmHg) afforded 2,2-bis(chloromethyl)- 5,5-dimethyl-1,3-dioxane(50)37
(22.0 g,
86%). Rf = 0.7 (40% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3 ) δ 3.76 (s, 4H),
3.54 (s, 4H), 0.97 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 97.4, 71.2, 42.1, 30.0, 22.6.
Synthesis of 6,6-dimethyl-4,8-dioxaspiro[2.5]oct-1-ene (37):
O O
A three-necked, round-bottomed flask was equipped with dry ice/acetone
condenser and placed in a dry ice/acetone bath. Gaseous ammonia was introduced to
the flask until 60mL of NH3 had been condensed and gentle stirring was started. The
NH3 inlet was replaced with a glass stopper the dry ice/acetone bath was replaced with
75
a -35 0C bath (dry ice/trichloroethylene). A crystal of hydrated ferric nitrate (0.045 g,
0.74 mmol, 0.25 mol%) was added. A small piece (about 1 mm) of sodium was added
to the resulting orange solution. The solution was stirred until the blue color
disappeared and pieces of sodium (3.2 g, 0.139 mol, 0.31 equiv) were added over 30
minutes. After 20 minutes, the cooling bath was replaced with a dry ice/acetone bath.
A solution of 2,2-bis(chloromethyl)- 5,5-dimethyl-1,3-dioxane (50) (9.545 g,
0.0448mol, 1 equiv) in dry ether (23 mL) was added dropwise to the slurry of sodium
amide in liquid ammonia over 1 hr. The cooling bath was removed, and the mixture
was stirred for 3 hr, then was cooled again with a dry ice/acetone bath. After 10 min,
solid ammonium chloride (9.59 g, 0.179 mol, 4 equiv) was added in several portions
over 30 min. The dry ice condenser removed and the ammonia was allowed to
evaporate. The cooling bath was replaced with a water bath (room temperature), and a
mixture of dry ether and dry pentane (40 mL) was added over 20 min with vigorous
stirring. After evaporation of most of the ammonia (2 hr), the solution was filtered by
suction through a pad of celite 521. The filter cake was washed with ether (3 X 10 mL).
The combined filtrate was washed with brine and water, dried over MgSO4, filtered
and concentrated on a rotary evaporator. Purification by vacuum distillation (60-61 0C,
6-8 mmHg) afforded 6,6-dimethyl-4,8-dioxaspiro[2.5]oct-1- ene (37) (2.46 g, 40%).37
Rf = 0.3 (10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 3.61 (s,
2H), 1.04 (s,6H); 13
C NMR (75 MHz, CDCl3) δ 125.7, 81.2, 76.7, 30.5, 22.4.
Synthesis of tert-butyl(3-iodobut-3-enyloxy)dimethylsilane (52):
76
TBSO I
To a slurry mixture of NaI (6.0 g, 40mmol, 1 equiv) in MeCN (30 mL) at room
temperature was added TMSCl (5.08 ml, 40 mmol, 1 equiv) followed by H2O (0.36 ml,
20 mmol, 0.5 equiv). After 10 min, a solution of 3-butyn-1-ol (48) (1.4 g, 20 mmol, 0.5
equiv) in MeCN (5.0mL) was added to the mixture and the resulting mixture was
allowed to react for 1 hr at room temperature. The reaction was quenched with water
(60 mL) and the mixture was extracted with ether (3x50 mL). Drying over MgSO4,
filtration and concentration on a rotary evaporator gave the crude iodo alcohol (3.82
g).
The crude iodo alcohol was dissolved in dichloromethane (100 mL) and cooled to
0 0C. To the stirred solution was added TBSCl (2.59 g, 21.2 mmol, 1.1 equiv),
imidazole (1.44 g, 21.2 mmol, 1.1 equiv), and DMAP (5 mg). The resulting mixture
was stirred at room temperature overnight. The reaction was quenched with water (60
mL) and the mixture was extracted with ether (3 X 50 mL). The combined extracts
were washed with brine and water, dried over MgSO4, filtered and concentrated on a
rotary evaporator. Purification by column chromatography using EtOAc/Hexane (1%)
as eluent afforded tert-butyl (3-iodobut-3-enyloxy)-dimethylsilane (52) (3.64g, 63%
over two steps). Rf = 0.4 (2% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3 ) δ 6.08 (s,
1H), 5.76 (s, 1H), 3.72 (d, J=6Hz, 2H), 2.59 (d, J=6Hz), 0.89 (s, 9H), 0.07 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 127.6, 107.8, 61.9, 48.6, 26.1, 18.5, -5.0.
77
Addition Reaction in desired system to prepare tert-butyl(3-(6,6-dimethyl-
4,8-dioxaspiro[2.5]octan-1-yl)but-3-enyloxy)dimethylsilane (56):
O O
TBSO
To a solution of vinyl iodide (52) (385.2 mg, 1.234 mmol, 1 equiv) in 12 mL of
ether at -78 0C was added dropwise a 2.25 M solution of t-BuLi in hexane (1.13 mL,
2.63 mmol, 2.05 equiv). After stirring at -78 0C for an addition 10 min, the cooling
bath was removed and the mixture was allowed to warm and was stirred at room
temperature for 1 hr. The mixture was recooled to -78 0C and added via a cannula to a
suspension of CuBr/DMS (126.8 mg, 0.617 mmol, 0.5 equiv) in ether (5 mL) at -78 0C.
After stirring at -78 0C for another 15 min, then the cooling bath was removed. The
mixture was stirred at room temperature for 15 min and recooled to-78 0C. A solution
of 6,6-dimethyl-4,8-dioxaspiro[2.5]oct-1- ene (37) (86.4 mg, 0.617 mmol, 0.5 equiv)
in ether (1.6 mL) was added. The reaction mixture was stirred at -780C for 15 min. The
cooling bath was removed and the reaction mixture was quenched with aqueous NH4Cl
(25 mL) and the mixture was extracted with ether (3 X 30 mL). The combined extracts
were washed with brine and water, dried over MgSO4, filtered and concentrated on a
rotary evaporator. Purification by column chromatography using EtOAc/Hexane (2%)
as eluent afforded compound 56 (155.4 mg, 77%). Rf = 0.3 (5% EtOAc/Hexane); 1H
NMR (400 MHz, CDCl3 ) δ 4.85 (s, 1H), 4.76 (s,1H), 3.83-3.72 (m, 2H), 3.57-3.40 (m,
78
4H), 2.39 (t, J=6.8Hz, 2H), 1.79-1.75 (m, 1H), 1.21-1.06 (m, 2H), 1.03 (s, 3H), 0.95 (s,
3H), 0.89 (s, 9H), 0.06 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 141.2, 111.1, 91.0, 76.5,
76.3, 62.7, 40.8, 30.8, 30.6, 26.1, 22.6, 22.5, 18.5, 17.7, -5.0.
Synthesis of 2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodec-6-yne (61):
TBSO OTBS
A solution of butyne-1,4-diol (2.55 g, 29.6 mmol, 1 equiv), imidazole (4.75 g,
69.75 mmol, 2.4 equiv), DMAP (355 mg, 2.96 mmol, 0.1 equiv) in CH2Cl2 (200 mL)
was stirred for 5 min. TBSCl (10.5 g. 69.75 mmol, 2.4 equiv) was added to the mixture
and stirred for 1.5hr at room temperature. The reaction was quenched with 10%
aqueous potassium carbonate (100 mL) and the mixture was extracted with ether (3 X
100 mL). The combined extracts were washed with brine and water, dried over MgSO4,
filtered and concentrated on a rotary evaporator. Purification by column
chromatography using EtOAc/Hexane (2%) as eluent afforded alkyne (61) (8.84 g,
96%).41
Rf = 0.4 (5% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3) δ 4.34 (s, 4H),
0.90 (s, 18H), 0.11 (s, 12H); 13
C NMR (75 MHz, CDCl3) δ 83.5, 52.0, 26.0, 18.5, -4.9.
Synthesis of (E)-2,2,3,3,10,10,11,11-octamethyl-6-(tributylstannyl)-4,9-dioxa-3,10-
disiladodec-6-ene (62):
OTBSTBSO
SnBu3
79
To a solution of alkyne (61) (1.93 g, 6.13 mmol, 1 equiv) in THF (15 mL)
containing PdCl2(PPh3)2 (86.1 mg, 0.123 mmol, 2 mol%), Bu3SnH (1.95 ml, 7.36
mmol, 1.2 equiv.) was added dropwise at room temperature. After 20 min, the THF
was evaporated in vacuo. The oily residue was purified by column chromatography
using EtOAc/Hexane (1%) as eluent afforded vinylstannane (62) (2.96 g, 79%).41
Rf =
0.4 (2% EtOAc/Hexane); 1
H NMR (400 MHz, CDCl3 ) δ 5.68-5.50 (m, 1H), 4.37-4.16
(m, 4H), 1.51-1.25 (m, 18), 0.92-0.85 (m, 27H), 0.07 (s, 6H), 0.06 (s, 6H); 13
C NMR
(75 MHz, CDCl3) δ 148.0, 137.3, 64.8, 61.1, 29.4, 27.6, 26.3, 26.1, 18.7, 18.5, 13.9,
10.4, -4.8, -5.1.
Synthesis of (E)-6-iodo-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodec-
6-ene (59):
OTBSTBSO
I
To a solution of vinylatannane (62) (2.95 g, 4.89 mmol, 1 equiv) in ether (23 mL),
a solution of iodine (1.24 g, 4.89 mmol, 1 equiv) in ether (16 mL) was added dropwisw
at room temperature. After 5.5 hr, the reaction mixture was evaporated in vacuo.
Purification by column chromatography using EtOAc/Hexane (2%) as eluent afforded
vinyliodide (59) (1.77 g, 82%).41
Rf= 0.4 (5% EtOAc/Hexane); 1H NMR (400 MHz,
CDCl3 ) δ 6.37 (s, 1H), 4.25 (s, 2H), 4.24 (s, 2H), 0.92 (s, 9H), 0.89 (s, 9H), 0.11 (s,
6H), 0.08 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 141.8, 103.9, 66.5, 61.6, 26.11, 26.0,
80
18.5, 18.5, -4.8, -5.0.
Cross coupling in model system to prepare (Z)-6-(2-butyl-6,6-dimethyl-4,8-
dioxaspiro[2.5]octan-1-yl)- 2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-
disiladodec-6-ene (64):
O O
Bu
OTBS
OTBS
To a suspension of CuBr/DMS (60.1 mg, 0.292 mmol, 1 equiv) in ether (1 mL), a
2.63 M solution of nBuLi (0.23 mL, 0.585 mmol, 2 equiv.) was added dropwise at -78
0C. After 15 min, the cooling bath was removed and stirred at r.t. for 10 min. Then the
reaction mixture was recooled to -78 0C. To this mixture, a solution of cyclopropenoen
acetal (37) (42.1 mg, 0.292 mmol, 1 equiv) in ether (0.3mL) was added at -78 0C. After
30 min, a solution of vinyliodide (59) (389 mg, 0.877 mmol, 3 equiv) and Pd(PPh3)4
(24 mg, 7 mol%) in THF (4 mL) was added at -780C. The cooling bath was removed
and let it warmed to r.t.. After this mixture was stirred for 7 hr, quenched with 33%
(NH4)2SO4 (7 mL) and the mixture was extracted with ether (3 X 10 mL). The
combined extracts were washed with water and brine, dried over MgSO4, filtered and
concentrated on a rotary evaporator. Purification by column chromatography using
Ether/Petroleum Ether (1%) as eluent afforded compound 64 (104 mg, 67%). Rf = 0.7
81
(5% Ether/Petroleum Ether); 1H NMR (400 MHz, CDCl3 ) δ 5.57 (t, J=6Hz, 1H),
4.27-4.05 (m, 4H), 3.55-3.44 (m, 4H), 1.79 (d, J=10.8Hz, 1H), 1.43-1.27 (m, 7H), 1.08
(s, 3H), 0.92-0.85 (m, 24H), 0.06 (s, 6H), 0.06 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ
133.9, 127.4, 76.2, 75.5, 31.8, 30.9, 30.5, 30.2, 28.9, 26.1, 22.8, 22.7, 22.3, 21.3, 18.5,
14.2, -4.8, -5.0, -5.1.
Synthesis of 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (86):
Me
2,5-Dimeththyl-2,5-hexanediol (1.02 g, 6.93 mmol, 1 equiv) was combined with
reagent grade concentrated HCl (16 mL, 180 mmol, 26 equiv) and stirred at r.t. for 3 hr.
The reaction was quenched with water (2 0mL) and the mixture was extracted with
CH2Cl2 (3 X 20 mL). The combined extracts were washed with water and brine, dried
over MgSO4, filtered. Concentration on a rotary evaporator afforded crude
2,5-dichlorol-2,5-hexanediol (84). To a solution of 2,5-dichlorol-2,5-hexanediol (1.28
g, 6.93 mmol, 1 equiv) in toluene (1.2 mL, 10.4 mmol, 1.5equiv) and CH2Cl2 (14 mL),
aluminum chloride (46.4 mg, 0.35 mmol, 5 mol%) was added at 5 0C. The mixture was
warmed to r.t. and stirred for 30 min. The reaction was quenched with water (10 mL)
and the mixture was extracted with hexane (3 X 10 mL). The combined extracts were
washed with water and brine, dried over MgSO4, filtered and concentrated on a rotary
82
evaporator. Purification by column chromatography using EtOAc/Hexane (1%) as
eluent afforded 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (86) (1.24 g, 87%
over two steps).75
Rf = 0.6 (2% EtOAc/Hexane); 1H NMR (300 MHz, CDCl3 ) δ 7.21
(d, J=7.6Hz, 1H), 7.12 (s, 1H), 6.96 (dd, J=8, 1.2Hz, 1H), 2.31 (s, 3H), 1.68 (s, 4H),
1.28 (s, 6H), 1.27 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 144.8, 142.0, 134.9,
127.2,126.7, 126.2, 35.4, 35.3, 34.3, 34.1, 32.1, 32.0.
Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
(87):
COOH
A round-bottomed flask equipped with a stirrer and reflux condenser was charged
with 1,1,4,4,6- pentamethyl-1,2,3,4-tetrahydronaphthalene (86) (1.24 g, 6.1 mmol, 1
equiv), sodium hydroxide (0.36 g, 9.16 mmol, 1.5 equiv), pyridine (4.2 mL) and water
(2.1 mL). The flask was heated in oil bath and maintained at 95 0C. Potassium
permanganate (2.41 g, 15.26 mmol, 2.5 equiv) was added in portions. The reaction
mixture was heated and stirred for addition 2 hr. Then ethanol (0.4 mL) was added.
After being cooled, the reaction mixture was suction filtered and the collected
manganese dioxide was washed with 2 N solution of NaOH (10 mL). The combined
filtrate was concentrated and acidified with 10% sulfuric acid. The flocculent
precipitate was collected by suction filtration, and redissolved in ether. Dried over
83
MgSO4 and filtered. Concentrated on a rotary evaporator afforded compound (87)
(1.07 g, 76%).75
1H NMR (200 MHz, CDCl3 ) δ 8.06 (d, J=1.8, 1H), 7.84 (dd, J=8.4,
1.8Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 1.70 (s, 4H), 1.31 (s, 6H), 1.30 (s, 6H); 13
C NMR
(75 MHz, CDCl3) δ 172.1, 151.6, 145.5, 129.1, 127.3, 127.1, 126.6, 35.0, 34.9, 34.6,
31.9, 31.8.
Synthesis of methyl 3-nitro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-
2-carboxamido)benzoate (91):
NH
O OMe
O
NO2
A mixture of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
(87) (39 mg, 0.168 mmol, 1 equiv), thionyl chloride (0.34 mL) and dichloromethane (1
mL) was heated at reflux for 4 hr. After removal of the solvent, a mixture of methyl
4-amino-3- nitrobenzoate (33 mg, 0.168 mmol, 1 equiv), dichloromethane (1 mL),
DIPEA (0.07 mL, 0.42 mmol, 2.5 equiv) and DMAP (2.1 mg, 0.017 mmol, 10 mol%)
was added to the residue and stirred overnight at r.t. The reaction was quenched with
water (5 mL) and the mixture was extracted with dichloromethane (3 X 5 mL). The
combined extracts were washed with water and brine, dried over MgSO4, filtered and
concentrated on a rotary evaporator. Purification by column chromatography using
EtOAc/Hexane (3%) as eluent afforded compound (91) (35.9mg, 52% over two
84
steps).76
Rf = 0.6 (20% EtOAc/Hexane); 1H NMR (300 MHz, CDCl3 ) δ 11.56 (s, 1H),
9.15 (d, J=8.7Hz, 1H), 8.96 (d, J=2.1Hz, 1H), 8.32 (dd, J=9, 2.1Hz, 1H), 7.97 (d,
J=2.1Hz, 1H), 7.72 (dd, J=8.4,2.1Hz, 1H), 7.47 (d, J=8.4Hz, 1H), 3.96 (s, 3H), 1.73 (s,
4H), 1.36 (s, 6H), 1.32 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 166.3, 164.9, 151.0,
146.3, 139.3, 136.9, 135.8, 131.0, 127.9, 127.7, 126.4, 124.9, 124.5, 121.7, 52.8, 35.01,
34.9, 34.7, 32.0, 31.8, 29.9.
Synthesis of methyl 3-amino-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene
-2-carboxamido)benzoate (92):
NH
O OMe
O
NH2
To a suspension of 10% Pd-C (23 mg), 5% HCl (0.02 mL) and methyl 3-nitro-4-
(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene- 2-carboxamido)benzoate (91)
(30.3 mg, 0.074 mmol, 1 equiv) in ethanol (0.14 mL), hydrazine hydrate (0.02 mL,
0.303 mmol, 4.1 equiv) was added, and the resulting mixture was stirred overnight at
r.t. Then the reaction mixture was diluted with ethanol (2 mL) and ethyl acetate (2 mL).
The Pd-C was removed by filtration through Celite 521. The filtrate was washed with
water and brine, dried over MgSO4, filtered and concentrated on a rotary evaporator.
Purification by column chromatography using EtOAc/Hexane (5%) as eluent afforded
compound (92) (22.8 mg, 81%). Rf = 0.2 (20%EtOAc/Hexane); 1H NMR (300 MHz,
85
CDCl3 ) δ 8.21 (s, 1H), 7.89 (d, J=2.1Hz, 1H) 7.59 (dd, J=8.4,2.1Hz, 1H) 7.49 (s, 3H),
7.37 (d, J=8.4Hz, 1H), 3.87 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6H), 1.29(s, 6H); 13
C NMR
(75 MHz, CDCl3) δ 167.0, 166.3, 149.9, 146.0, 139.5, 131.2, 130.1, 128.0, 127.3,
126.4, 124.2, 124.1, 121.7, 120.0, 52.3, 35.0, 34.9, 34.8, 34.7, 32.0, 31.9.
Synthesis of 3-amino-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-
2-carboxamido)benzoic acid (75):
NH
O OH
O
NH2
To a solution of methyl 3-amino-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-
naphthalene-2-carboxamido)benzoate (92) (57.9 mg, 0.152 mmol, 1 equiv) in
THF/H2O/MeOH (0.9 ml:0.3 ml:0.3 ml), a solution of 1N lithium hydroxide
monohydrate (0.31 ml, 0.304 mmol, 2 equiv) was added, and the resulting mixture was
stirred at r.t. for 12 hr. After most of the THF and MeOH was evaporated, the aqueous
phase was acidified with 1N HCl to PH 5.5 and extracted with ethyl acetate to afford
the compound (75) (40.7 mg, 73%).1H NMR (300 MHz, CDCl3 ) δ 8.44 (s, 1H), 7.91
(d, J=1.2Hz), 7.62 (d, J=8.4, 1H) 7.50-7.48 (m, 3H), 7.34 (d, J=8.1Hz, 1H), 1.68 (s,
4H), 1.28 (s, 6H), 1.27 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 171.4, 166.7, 149.9,
145.9, 139.3, 131.1, 130.7, 127.4, 127.2, 126.5, 124.4, 122.6, 120.6, 35.0, 34.9, 34.8,
86
34.6, 31.9, 31.9; HRMS (ESI): m/z calcd. for [( M+H)+]=367.2022, found=367.2019.
Synthesis of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-
carboxamido)benzoate (94):
NH
O OMe
O
A mixture of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid
(87) (72.3 mg, 0.311 mmol, 1 equi), thionyl chloride (0.63 mL) and dichloromethane
(2 mL) was heated at reflux for 4 hr. After removal of the solvent, a mixture of methyl
4-amino- benzoate (47 mg, 0.311 mmol, 1 equiv), dichloromethane (1.5 ml), DIPEA
(0.11mL, 0.622 mmol, 2 equiv) and DMAP (3.9 mg, 0.0311 mmol, 10 mol%) was
added to the residue and stirred overnight at r.t. The reaction was quenched with water
(5 mL) and the mixture was extracted with dichloromethane (3 X 5 mL). The
combined extracts were washed with water and brine, dried over MgSO4, filtered and
concentrated on a rotary evaporator. Purification by column chromatography using
EtOAc/Hexane (5%) as eluent afforded compound (94) (61.4 mg, 54% over two
steps).76
Rf = 0.4 (20% EtOAc/Hexane); 1H NMR (200 MHz, CDCl3 ) δ 8.45 (s, 1H),
7.98 (s, 1H), 7.94 (s, 1H), 7.85 (d, J=1.6Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.55 (dd,
J=8.4,1.6Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 3.85 (s, 3H), 1.65 (s, 4H), 1.24 (s, 12H); 13
C
NMR (75 MHz, CDCl3) δ 166.9, 166.7, 149.9, 146.0, 142.8, 131.8, 131.0, 127.2, 126.3,
87
125.6, 124.0, 119.5, 52.2, 35.1, 34.9, 34.8, 34.6, 31.9, 31.8.
Synthesis of N-(4-(hydroxycarbamoyl)phenyl)-5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalene-2-carboxamide (76):
NH
O NHOH
O
To a solution of compound (94) (15.2 mg, 0.0416 mmol, 1 equiv) in THF (1 mL)
and MeOH (1 mL) at 0 0C was added a 50% aqueous solution of NH2OH (2.5 mL,
41.6 mmol, 1000equiv.) followed by a 1M solution of KOH (0.3 mL, 0.29 mmol, 7
equiv.). The reaction mixture was stirred at r.t. for 27 hr. This mixture was acidified
with citric acid to PH 4 and extracted with ethyl acetate. The combined extracts were
washed with water and brine, dried over Na2SO4, filtered and concentrated on a rotary
evaporator. Purification by octadecyl-functionalized silica gel column chromatography
using MeOH/H2O (5% to 95%) as eluent afforded compound (76) (7.8 mg, 51%).77
1H
NMR (400 MHz, CD3OD ) δ 7.93 (s, 1H), 7.84-7.75 (m, 4H), 7.69 (d, J=6.8Hz, 1H),
7.46 (d, J=7.6Hz), 1.74 (s, 4H), 1.34 (s, 6H), 1.31 (s, 6H); 13
C NMR (75 MHz, CD3OD)
δ 168.0, 166.6, 149.4, 145.4, 142.2, 131.8, 130.3, 127.6, 127.6, 126.8, 126.2, 124.4,
120.3, 120.0, 34.9, 34.7, 34.3, 34.2, 30.9, 30.8; HRMS (ESI): m/z calcd. for
[( M+H)+]=367.2022, found=367.2015.
88
Synthesis of N-(2-amino-4-hydroxyphenyl)-5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalene-2-carboxamide (77):
NH
NH2
OOH
HBTU (109.6 mg, 0.289 mmol, 1.1 equiv) was added to a solution of 3,4-
diaminophenol (32.6 mg, 0.263 mmol, 1 equiv), compound (87) (61 mg, 0.263 mmol,
1 equiv), HOBt (177.4 mg, 1.313 mmol, 5 equiv) and DIPEA (0.14 mL, 0.789 mmol, 3
equiv) in DMF (2 mL) at r.t. The resulting mixture was maintained at r.t. and stirred
for 14 hr. Then the reaction mixture was diluted with ethyl acetate and poured into
water (5 mL). This mixture was extracted with ethyl acetate (3 X 5 mL). The
combined extracts were washed with water and brine, dried over MgSO4, filtered and
concentrated on a rotary evaporator. Purification by column chromatography using
EtOAc/Hexane (2% to 10%) as eluent afforded compound (77) (48 mg, 54%). Rf =
0.45 (70% EtOAc/Hexane); 1H NMR (400 MHz, CD3OD) δ 7.95 (d, J=2Hz, 1H), 7.69
(dd, J=8,2Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 6.95 (d, J=8Hz, 1H), 6.35 (d, J=2.4Hz, 1H),
6.22 (dd, J=8.4, 2.4Hz, 1H), 1.74 (s, 4H), 1.33 (s, 6H), 1.30 (s, 6H); 13
C NMR (75
MHz, CD3OD) δ 168.2, 156.9, 149.1, 145.2, 144.0, 131.4, 127.7, 126.7, 126.2, 124.5,
116.4, 105.7, 103.6, 34.9, 34.7, 34.3, 34.2, 30.9, 30.8; HRMS (ESI): m/z calcd. for
[( M+H)+]=339.2073, found=339.2090.
89
Synthesis of 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (103):
Br
To a solution of 2,5-dichlorol-2,5-hexanediol (84) (180.3 mg, 0.946 mmol, 1 equiv)
and bromobenzene (386.4 mg, 2.365 mmol, 2.5 equiv) in dichloromethane (1 mL),
aluminium trichloride (13 mg, 0.0946 mmol, 10 mol%) was added at r.t. The resulting
mixture was stirred overnight at r.t. The reaction was quenched with water (5 mL) and
the mixture was extracted with ethyl acetate (2 X 5 mL). The combined extracts were
washed with 5% aqueous solution of NaHCO3, water and brine, dried over MgSO4,
filtered and concentrated on a rotary evaporator. Purification by column
chromatography using hexane as eluent afforded compound (103) (242.7 mg, 96%). Rf
= 0.7 (Hexane); 1H NMR (500 MHz, CDCl3 ) δ 7.43 (d, J=2Hz, 1H), 7.25 (dd,
J=8.5,2Hz, 1H), 7.19 (d, J=8.5Hz, 1H), 1.69 (s, 4H), 1.29 (s, 6H), 1.27 (s, 6H); 13
C
NMR (125 MHz, CDCl3) δ 147.6, 144.1, 129.6, 128.9, 128.7, 119.66, 35.1, 35.0, 34.7,
34.3, 32.0, 31.8.
Synthesis of methyl 5',5',8',8'-tetramethyl-5',6',7',8'-tetrahydro-2,2'-binaphthyl-
6-carboxylate (105):
90
O
OMe
To a solution of aromatic bromide (103) (96.9 mg, 0.363mmol, 1 equiv) in THF (1
mL) at -78 0C, a 2.56 M solution of nBuLi (0.29 mL, 0.74 mmol, 2 equiv) was added.
After stirring at -78 0C for 1 hr, this solution of aryllithium reagent was added to a
mixture of ZnCl2 (99 mg, 0.73 mmol, 2 equiv) in THF (1 mL) which had been
precooled to -78 0C. After 1 hr at -78
0C and 1 hr at r.t., the resultant arylzinc mixture
was added to a solution of methyl 6-bromo-2-naphthoate (82 mg, 0.309 mmol, 0.85
equiv) and Ni(PPh3)4 (6.9 mg, 0.0073 mmol, 2 mol%) in THF (0.6 mL) which had
been precooled to 5 0C. The reaction mixture was allowed to warm to r.t. over 30 min
period and stirred for additional 30 min at r.t.. The reaction was quenched with ice (2 g)
and 10% aqueous HCl (2 mL) and the mixture was extracted with ether (2 X 5 mL).
The combined extracts were washed with sat. aqueous solution of NaHCO3, water and
brine, dried over MgSO4, filtered and concentrated on a rotary evaporator. Purification
by column chromatography using EtOAc/Hexane (10%) as eluent followed by
crystallization from ether at -20 0C afforded compound (104) (52.7 mg, 39%). Rf = 0.3
(20% EtOAc/Hexane); 1H NMR (300 MHz, CDCl3 ) δ 8.63 (s, 1H), 8.10 (d, J=1.8Hz,
1H), 8.07 (d, J=1.5Hz, 1H), 8.04 (s, 1H), 8.01 (d, J=8.7Hz, 1H), 7.94 (d, J=8.7Hz, 1H),
7.81 (dd, J=8.7,1.8Hz, 1H), 7.66 (d, J=2.1Hz, 1H), 7.50 (dd, J=8.1,1.8Hz, 1H), 7.45 (d,
J=8.4Hz, 1H), 1.75 (s, 4H), 1.39 (s, 6H), 1.35 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ
91
167.5, 145.7, 145.0, 141.5, 137.9, 136.0, 131.7, 131.0, 129.9, 128.5, 127.5, 127.3,
126.8, 125.9, 125.8, 125.4, 125.0, 52.5, 35.3, 35.2, 34.7, 34.4, 32.2, 32.1.
Synthesis of N-hydroxy-5',5',8',8'-tetramethyl-5',6',7',8'-tetrahydro-2,2'-
binaphthyl-6-carboxamide (78):
O
NH
OH
To a solution of compound (104) (9.2 mg, 0.0247 mmo, 1 equivl) in THF (1 mL)
and MeOH (1 mL) at 0 0C was added a 50% aqueous solution of NH2OH (1.6 ml, 24.7
mmol, 1000 equiv) followed by a 1 M solution of KOH (0.17 mL, 0.17 mmol, 7equiv).
The reaction mixture was stirred at r.t. for 50 hr. This mixture was acidified with citric
acid to PH 5 and extracted with ethyl acetate. The combined extracts were washed
with water and brine, dried over Na2SO4, filtered and concentrated on a rotary
evaporator. Purification by reverse phase HPLC using MeOH/H2O (5% to 95%) as
eluent afforded compound (78) (4.3 mg, 47%). 1H NMR (400 MHz, CD3OD ) δ 8.30 (s,
1H), 8.10 (s, 1H), 8.03-7.80 (m, 4H), 1.76 (s, 4H), 1.37 (s, 6H), 1.33 (s, 6H); 13
C NMR
(75 MHz, CD3OD) δ 168.2, 146.5, 145.7, 142.1, 138.8, 136.6, 133.0, 130.4, 129.7,
128.3, 127.5, 126.4, 125.9, 125.7, 124.9, 36.3, 36.1, 35.4, 35.1, 32.3, 32.2; HRMS
(ESI): m/z calcd. for [( M-H)+]=372.1964, found=372.1970.
92
Synthesis of (E)-methyl 3-(4-bromophenyl)acrylate (108):
Br
OMe
O
A mixture of 4-bromobenzaldehyde (185 mg, 1 mmol, 1 equiv) and
(methoxycarbonyl methylene)- triphenylphosphorane (502 mg, 1.5 mmol, 1.5 equiv) in
deionized water (5 mL) was stirred at 90 0C for 20 min. The reaction mixture was
cooled to r.t. and extracted with dichloromethane (2 X 5 mL). The combined extracts
were washed with water and brine, dried over MgSO4, filtered and concentrated on a
rotary evaporator. Purification by column chromatography using EtOAc/Hexane (2 %)
as eluent afforded compound (108) (176 mg, 73%). Rf = 0.6 (20% EtOAc/Hexane); 1H
NMR (300 MHz, CDCl3 ) δ 7.62 (d. J=15.9Hz, 1H), 7.51 (m, 2H), 7.38 (m, 2H), 6.42
(d, J=15.9Hz, 1H), 3.80 (s, 3H); 13
C NMR (75 MHz, CDCl3) δ 167.4, 143.7, 133.5,
132.3, 129.6, 124.8, 118.7, 52.0.
Synthesis of (E)-methyl 3-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)phenyl)acrylate (109):
OMe
O
To a solution of 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (103)
(461 mg, 1.725 mmol, 1 equiv) in THF (2.5 mL) at -780C, a 2.436 M solution of
93
nBuLi (1.14 mL, 2.76 mmol, 1.6 equiv) was added in one portion. After the mixture
was stirred at -78 0C for 40 min, (i-PrO)3B (1.2 mL, 5.175 mmol, 3 equiv) was added.
After the reaction mixture was stirred at -78 0C for 20 min, the cooling bath was
removed. This mixture was then stirred at r.t. overnight. The reaction was quenched
with 10% aqueous HCl (15 ml) and the mixture was extracted with EtOAc (2 X 100
mL). The combined extracts were washed with water and brine, dried over Na2SO4,
filtered. Concentration on a rotary evaporator afforded 5,5,8,8-
tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-ylboronic acid (110), which was used
directly for Suzuki coupling without further purified.
A mixture of (E)-methyl 3-(4-bromophenyl)acrylate (108) (125.5 mg, 0.521 mmol,
1 equiv), CsF (146 mg, 1.042 mmol, 2 equiv), Pd(OAc)2 (7 mg, 0.0312 mmol, 6 mol%)
and PPh3 (32.7 mg, 0.1247 mmol, 0.24 equiv) in THF (15 mL) was stirred at r.t. for 30
min. A solution of 5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid
(110) (241.7 mg, 1.042 mmol, 2 equiv) in THF (5 mL) was added to above mixture
and heated to reflux. After 22 hr, the reaction mixture was cooled to r.t. and diluted
with EtOAc. This mixture was washed with water and brine, dried over MgSO4,
filtered and concentrated on a rotary evaporator. Purification by column
chromatography using EtOAc/Hexane (2%) as eluent afforded compound (109) (76.2
mg, 42%). Rf = 0.5 (10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3 ) δ 7.74 (d,
16Hz, 1H), 7.62-7.54 (m, 5H), 7.41-7.38 (m, 2H), 6.49 (d, J=18Hz, 1H), 3.82 (s, 3H),
1.73 (s, 4H), 1.35 (s, 6H), 1.32 (s, 6H); 13
C NMR (75MHz, CDCl3) δ 167.8, 145.6,
94
145.0, 144.8, 143.7, 137.5, 133.1, 128.7, 127.6, 127.4, 125.4, 124.5, 117.5, 51.9, 35.3,
35.2, 34.6, 34.4, 32.1, 32.0.
Synthesis of (E)-N-hydroxy-3-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)phenyl)acrylamide (79):
NHOH
O
To a solution of compound (109) (20.5 mg, 0.059 mmol, 1 equiv) in THF (1.5 mL)
and MeOH (1.5 mL) at 0 0C was added a 50% aqueous solution of NH2OH (3.6ml, 59
mmol, 1000 equiv) followed by a 1 M solution of KOH (0.42 mL, 0.413 mmol,
7equiv). The reaction mixture was stirred at r.t. for 46 hr. This mixture was acidified
with 1 N citric acid to PH 5 and extracted with ethyl acetate. The combined extracts
were washed with water and brine, dried over Na2SO4, filtered and concentrated on a
rotary evaporator. Purification by reverse phase HPLC using MeOH/H2O (5% to 95%)
as eluent afforded compound (79) (12.5 mg, 61%). 1H NMR (300 MHz, CD3OD ) δ
7.62-7.39 (m, 8H), 6.49 (d, J=15.9Hz, 1H), 1.74 (s,4H), 1.34 (s, 6H), 1.30 (s, 6H); 13
C
NMR (75 MHz, CD3OD) δ 165.2, 145.2, 144.5, 143.0, 139.9, 137.4, 133.6, 128.1,
127.0, 127.0, 124.7, 124.0, 116.8, 35.1, 34.9, 34.1, 33.9, 31.1, 31.0; HRMS (ESI): m/z
calcd. for [( M-H)+]=348.1964, found=348.1960.
95
Synthesis of methyl 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-
pentanoate (114):
OMe
O
A Schlenk flask was charged with LiCl (53.2 mg, 1.254 mmol, 1 equiv) and dried
under vacuum at 160 0C for 30 min. Zinc powder (246 mg, 3.762 mmol, 3 equiv) was
added to the flask, and the mixture of LiCl and Zn was dried again under the same
conditions for additional 30 min. After the mixture was allowed to cool to r.t., THF
(1.25 mL) was added. The resulting suspension was treated with 1,2-dibromoethane
(0.00545 mL, 0.0627 mmol, 5 mol%) and heated with a heat gun until foaming. The
process was repeated twice. TMSCl (0.0016 mL, 0.0125 mmol, 1 mol%) was added
and the mixture was stirred for 20 min. To this mixture, a solution of I2 (32 mg, 0.1254
mmol, 10 mol%) in THF (0.3 mL) was added followed by a solution of methyl
5-bromoveratrole (244.6 mg, 1.254 mmol, 1 equiv) in THF (1.3 mL). This reaction
mixture was heated to 50 0C and stirred for 24 hr. The oil bath was removed and the
mixture was cooled down to r.t. To this alkylzinc bromide-lithium chloride complex, a
solution of aromatic bromide (103) (134 mg, 0.502 mmol, 0.4 equiv) and Pd(PPh3)4
(23.2 mg, 0.02 mmol, 4 mol%) in THF (1 mL) was added at r.t.. This mixture was
stirred at r.t. overnight. The reaction was quenched with sat. aqueous NH4Cl and the
96
mixture was extracted with EtOAc. The combined extracts were washed with water
and brine, dried over MgSO4, filtered and concentrated on a rotary evaporator.
Purification by column chromatography using EtOAc/Hexane (2%) as eluent afforded
compound (114) (22.7 mg, 15%).84
Rf = 0.4 (10% EtOAc/Hexane); 1H NMR (400
MHz, CDCl3 ) δ 7.21 (d, J=7.6Hz, 1H), 7.08 (s, 1H), 6.94 (d, J=7.6Hz, 1H), 3.66 (s,
3H), 2.57 (t, J=7.6Hz, 2H), 2.34 (t, J=7.6Hz, 2H), 1.69-1.63 (m, 8H), 1.27 (s, 6H), 1.26
(s, 6H); 13
C NMR (75 MHz, CDCl3) δ 174.4, 144.8, 142.4, 139.2, 126.6, 126.5, 125.8,
51.7, 35.5, 35.4, 35.3, 34.4, 34.2, 3.18, 3.16, 3.12, 3.13, 25.0.
Synthesis of N-hydroxy-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)pentanamide (80):
NHOH
O
To a solution of compound (114) (17.1 mg, 0.0565 mmol, 1 equiv) in THF (1 mL)
and MeOH (1 mL) at 0 0C was added a 50% aqueous solution of NH2OH (3.5 mL,
56.5 mmol, 1000 equiv) followed by a 1 M solution of KOH (0.4 mL, 0.4 mmol, 7
equiv). The reaction mixture was stirred at r.t. for 16 hr. This mixture was acidified
with 1N citric acid to PH 5 and extracted with ethyl acetate. The combined extracts
were washed with water and brine, dried over Na2SO4, filtered and concentrated on a
rotary evaporator. Purification by reverse phase HPLC using MeOH/H2O (5% to 95%)
97
as eluent afforded compound (80) (7.7 mg, 45%). 1H NMR (400 MHz, CD3OD ) δ
7.18 (d, J=8.4Hz, 1H), 7.08 (s, 1H), 6.90 (d, J=8.4Hz, 1H), 2.54 (t, J=6.8Hz, 2H), 2.10
(t, J=6.8Hz, 2H), 1.67-1.60 (m, 8H), 1.24 (s, 6H), 1.23 (s, 6H); 13
C NMR (125 MHz,
CD3OD) δ 171.5, 144.1, 141.7, 138.8, 126.0, 125.9, 125.3, 34.9, 34.9, 34.8, 33.6, 33.4,
32.2, 30.8, 30.7, 25.0; HRMS (ESI): m/z calcd. for [( M+H)+]=304.2271,
found=304.2267.
Synthesis of methyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)hexanoate (118):
OMe
O
A Schlenk flask was charged with LiCl (74 mg, 1.745 mmol, 1 equiv) and dried
under vacuum at 160 0C for 30 min. Zinc powder (345 mg, 5.24 mmol, 3 equiv) was
added to the flask, and the mixture of LiCl and Zn was dried again under the same
conditions for additional 30 min. After the mixture was allowed to cool to r.t., THF
(1.5 mL) was added. The resulting suspension was treated with 1,2-dibromoethane
(0.0076 mL, 0.0627 mmol, 5 mol%) and heated with a heat gun until foaming. The
process was repeated twice. TMSCl (0.0023 ml, 0.0125 mmol, 1 mol%) was added and
the mixture was stirred for 20 min. To this mixture, a solution of I2 (32 mg, 0.1254
mmol, 10 mol%) in THF (0.3 mL) was added followed by a solution of methyl
6-bromohexanoate (367.1 mg, 1.756 mmol, 1 equiv) in THF (1.5 mL). This reaction
98
mixture was heated to 50 0C and stirred for 26 hr. The oil bath was removed and the
mixture was cooled down to r.t. To this alkylzinc bromide-lithium chloride complex, a
solution of aromatic bromide (103) (187.7 mg, 0.7024 mmol, 0.4 equiv) and Pd(PPh3)4
(32.4mg, 0.028 mmol, 4 mol%) in THF (1 ml) was added at r.t.. This mixture was
stirred at r.t. overnight. The reaction was quenched by sat. aqueous NH4Cl and the
mixture was extracted with EtOAc. The combined extracts were washed with water
and brine, dried over MgSO4, filtered and concentrated on a rotary evaporator.
Purification by column chromatography using EtOAc/Hexane (2%) as eluent afforded
compound (118) (17.6 mg, 7.9%).84
Rf = 0.4 (10% EtOAc/Hexane); 1H NMR (300
MHz, CDCl3 ) δ 7.22 (d, J=8.1Hz, 1H), 7.10 (d, J=1.8Hz, 1H), 6.95 (dd, J=8.1,1.8Hz,
1H), 3.68 (s, 3H), 2.56 (t, J=7.8Hz, 2H), 2.33 (t, J=7.8, 2H), 1.71-1.58 (m, 8H),
1.44-1.36 (m, 2H), 1.28 (s, 6H), 1.28 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 174.5,
144.8, 142.3, 139.6, 126.5, 126.5, 125.8, 51.7, 35.7, 35.4, 35.3, 34.4, 34.3, 34.1, 32.1,
32.1, 31.3, 29.2, 25.1.
Synthesis of N-hydroxy-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)hexanamide (81):
NHOH
O
To a solution of compound (109) (11.7 mg, 0.037 mmol, 1 equiv) in THF (1 mL)
and MeOH (1 mL) at 0 0C was added a 50% aqueous solution of NH2OH (1.1 mL,
99
16.5 mmol, 500 equiv) followed by a 1 M solution of KOH (0.26 mL, 0.26 mmol, 7
equiv). The reaction mixture was stirred at r.t. for 16 hr. This mixture was acidified
with 1N citric acid to PH 5 and extracted with ethyl acetate. The combined extracts
were washed with water and brine, dried over Na2SO4, filtered and concentrated on a
rotary evaporator. Purification by reverse phase HPLC using MeOH/H2O (5% to 95%)
as eluent afforded compound (81) (6.1mg, 52%). 1H NMR (400 MHz, CD3OD ) δ
7.17 (d, J=8Hz, 1H), 7.07 (s, 1H), 6.89 (d, J=7.6Hz, 1H), 2.52 (t, J=6.8Hz, 2H), 2.07 (t,
J=6.4Hz, 2H), 1.66-1.57 (m, 8H), 1.36-1.32 (m, 2H), 1.24 (s, 6H), 1.23 (s, 6H); 13
C
NMR (75 MHz, CD3OD) δ 171.5, 144.1, 141.6, 139.1, 125.9, 125.8, 125.3, 35.0, 34.9,
34.9, 33.6, 33.4, 30.9, 30.9, 28.4, 25.2; HRMS (ESI): m/z calcd. for
[( M+H)+]=318.2428, found=318.2421.
Synthesis of 7-bromoheptanal (120):
Br H
O
To a solution of DMSO (0.31 mL, 4.357 mmol, 2.4 equiv) in dichloromethane (17
mL) at -78 0C, oxalyl chloride (0.19 mL, 2.18 mmol, 1.2 equiv) was added dropwise.
The mixture was stirred for 10 min and a solution of 7-bromoheptan-1-ol (354 mg,
1.815 mmol, 1 equiv) in dichloromethane (3.6 mL) was added. After stirring at -78 0C
for 15 min, Et3N (1.27 mL, 9.08 mmol, 5 equiv) was added. The resulting mixture was
stirred at -78 0C for 30 min and at r.t. for 2.5 hr. The reaction was quenched by sat.
100
aqueous NH4Cl and the mixture was extracted with ether. The combined extracts were
washed with water and brine, dried over MgSO4, filtered and concentrated on a rotary
evaporator. Purification by column chromatography using EtOAc/Hexane (2%) as
eluent afforded compound (120) (332.7 mg, 95%).85
Rf = 0.5 (20% EtOAc/Hexane);
1H NMR (400 MHz, CDCl3 ) δ 9.76 (t, 1.6Hz, 1H), 3.39 (t, J=7.8Hz, 2H), 2.44 (dt,
J=7.2Hz,1.6Hz, 2H), 1.88-1.81 (m, 2H), 1.67-1.60 (m, 2H), 1.49-1.32 (m, 4H); 13
C
NMR (75 MHz, CDCl3) δ 202.8, 43.9, 33.9, 32.7, 28.4, 28.1, 22.0.
Synthesis of methyl 7-bromoheptanoate (122):
Br OMe
O
To a solution of the 7-bromoheptanal (120) (439.6 mg, 2.28 mmol, 1 equiv) and
2-methyl-2-butene (10 mL) in tBuOH (40 mL), a solution of NaClO2 (617 mg, 6.83
mmol, 3 equiv) and NaH2PO4 (1.57 g, 11.39 mmol, 5 equiv) in H2O (40 mL) was
added at r.t.. This mixture was stirred at r.t. for 2 hr. The reaction was quenched with
H2O and the mixture was extracted with ether. The combined extracts were washed
with brine, dried over MgSO4, filtered. Concentration on a rotary evaporator afforded
crude 7-bromoheptanoic acid (121), which was directly used in the next reaction
without further purified.
Acetyl chloride (0.5 mL) was added to a solution of 7-bromoheptanoic acid (121)
prepared above in MeOH (7 mL) and this mixture was stirred at r.t. overnight.
101
Amberlite IRA-67 resin was added and the mixture was stirred for 15 min, filtered,
drived over MgSO4, filtered, concentrated on a rotary evaporator. Purification by
column chromatography using EtOAc/Hexane (2%) as eluent afforded compound (122)
(304mg, 60% over two steps). Rf = 0.3 (10% EtOAc/Hexane); 1H NMR (400 MHz,
CDCl3 ) δ 3.66 (s,3H), 3.40 (t, 6.6Hz, 2H), 2.31 (t, J=7.2Hz, 2H), 1.90-1.83 (m, 2H),
1.69-1.59 (m, 2H), 1.48-1.31 (m, 4H); 13
C NMR (75 MHz, CDCl3) δ 174.3, 51.7, 34.1,
34.0, 32.7, 28.4, 28.0, 24.9.
Synthesis of methyl 7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)heptanoate (124):
OMe
O
A Schlenk flask was charged with LiCl (46 mg, 1.09 mmol, 1 equiv) and dried
under vacuum at 160 0C for 30 min. Zinc powder (213 mg, 3.26 mmol, 3 equiv) was
added to the flask, and the mixture of LiCl and Zn was dried again under the same
conditions for additional 30 min. After the mixture was allowed to cool to r.t., THF
(1.5 mL) was added. The resulting suspension was treated with 1,2-dibromoethane
(0.0047 mL, 0.0542 mmol, 5 mol%) and heated with a heat gun until foaming. The
process was repeated twice. TMSCl (0.0014 mL, 0.0109 mmo, 1 mol%l) was added
and the mixture was stirred for 20 min. To this mixture, a solution of I2 (27.5 mg,
102
0.109 mmol, 10 mol%) in THF (0.3 mL) was added followed by a solution of methyl
6-bromohexanoate (241.9 mg, 1.09 mmol, 1 equiv) in THF (1 mL). This reaction
mixture was heated to 50 0C and stirred for 26 hr. The oil bath was removed and the
mixture was cooled down to r.t. To this alkylzinc bromide-lithium chloride complex, a
solution of aromatic bromide (103) (145 mg, 0.55 mmol, 0.5 equiv) and Pd(PPh3)4 (25
mg, 0.0217 mmol, 4 mol%) in THF (1 mL) was added at r.t.. This mixture was stirred
at r.t. overnight. The reaction was quenched with sat. aqueous NH4Cl and the mixture
was extracted with EtOAc. The combined extracts were washed with water and brine,
dried over MgSO4, filtered and concentrated on a rotary evaporator. Purification by
column chromatography using EtOAc/Hexane (2%) as eluent afforded compound (124)
(39.4mg, 11%).84
Rf = 0.4 (10% EtOAc/Hexane); 1H NMR (400 MHz, CDCl3 ) δ 7.21
(d, J=7.6Hz, 1H), 7.08 (d, 1.6Hz, 1H), 6.93 (dd, J=8,1.6Hz, 1H), 3.66 (s, 3H), 2.53 (t,
J=6Hz, 2H), 2.30, J=7.6Hz, 2H), 1.66-1.55 (m, 8H), 1.36-1.31 (m, 4H), 1.27 (s, 6H),
1.26 (s, 6H); 13
C NMR (125 MHz, CDCl3) δ 173.2, 143.5, 141.0, 138.5, 125.3, 125.27,
124.6, 50.4, 34.6, 34.2, 34.1, 33.1, 33.1, 32.9, 30.8, 30.2, 28.1, 28.0, 23.9.
Synthesis of N-hydroxy-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2-yl)heptanamide (82):
NHOH
O
103
To a solution of compound (124) (11.5 mg, 0.0354 mmol, 1 equiv) in THF (1 mL)
and MeOH (1 mL) at 0 0C was added a 50% aqueous solution of NH2OH (2.2 mL,
35.4 mmol, 1000 equiv) followed by a 1 M solution of KOH (0.25 mL, 0.25 mmol, 7
equiv). The reaction mixture was stirred at r.t. for 16 hr. This mixture was acidified
with 1N citric acid to PH 5 and extracted with ethyl acetate. The combined extracts
were washed with water and brine, dried over Na2SO4, filtered and concentrated on a
rotary evaporator. Purification by reverse phase HPLC using MeOH/H2O (5% to 95%)
as eluent afforded compound (82) (6.2 mg, 64%). 1H NMR (400 MHz, CD3OD ) δ
7.17 (t, J=8Hz, 1H), 7.07 (s, 1H), 6.89 (t, J=7.6Hz, 1H), 2.51 (t, J=7.2Hz, 2H), 2.06 (t,
J=7.6Hz, 2H), 1.66 (s, 4H), 1.58 (m, 4H), 1.38-1.36 (m, 4H), 1.24 (s, 6H), 1.23 (s, 6H);
13C NMR (125 MHz, CD3OD) δ 171.6, 144.1, 141.5, 139.2, 125.9, 125.8, 125.3, 35.1,
34.9, 34.9, 33.6, 33.4, 32.3, 31.2, 30.9, 28.6, 28.5, 25.3; HRMS (ESI): m/z calcd. for
[( M+H)+]=330.2433, found=330.2430.
Synthesis of 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pentanoic
acid (125):
OH
O
To a solution of methyl 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2–
104
yl )pentanoate (114) (118.4mg, 0.392 mmol, 1 equiv) in THF/H2O/MeOH (3 mL: 1
mL : 1 mL), a solution of 1N lithium hydroxide monohydrate (0.79 mL, 0.79 mmol, 2
equiv) was added, and the resulting mixture was stirred at r.t. for 20 hr. After most of
the THF and MeOH was evaporated, the aqueous phase was acidified with 1N solution
of HCl to PH 5.5 and extracted with ethyl acetate to afford the compound (125) (89.4
mg, 99%).1H NMR (300 MHz, CDCl3 ) δ 7.24 (d, J=8.1Hz, 1H), 7.13 (d, J=1.5Hz, 1H),
6.97 (dd, J=7.8,1.8Hz, 1H), 2.61 (t, J=6.9Hz, 2H), 2.42 (t, 7.2Hz, 2H), 1.71 (m, 8H),
1.31 (s, 6H), 1.30 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 180.4, 144.9, 142.4, 139.1,
126.6, 126.5, 125.9, 35.5, 35.4, 35.4, 34.4, 34.2, 34.1, 32.1, 32.1, 31.0, 24.7.
Synthesis of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)butan-
1-amine (127):
NH2
To a solution of carboxylic acid (125) (102 mg, 0.354 mmol, 1 equiv) in toluene
(2 mL) was added Et3N (0.0543 mL, 0.389 mmol, 1.1 equiv) followed by DPPA
(0.076 mL, 0.354 mmol, 1 equiv). The mixture was stirred at r.t. for 30 min, and then
heated to reflux overnight. After concentration on a rotary evaporator, the crude
isocyanate (126) was treated with 2 N solution of NaOH (2.7 mL) and THF (7 mL)
and stirred at r.t. for 30 min. The resulting solution was extracted with CH2Cl2 (2 X 30
mL). The combined extracts were washed with water and brine, dried over MgSO4,
105
filtered and concentrated on a rotary evaporator. Purification by column
chromatography using Et3N/MeOH/EtOAc (10:10:80) as eluent afforded compound
(127) (38.4 mg, 42%). Rf = 0.3 (Et3N/MeOH/EtOAc=10:10:80); 1H NMR (400 MHz,
CDCl3 ) δ 7.21 (d, J=8Hz, 1H), 7.10 (d, J=1.6, 1H), 6.95 (dd, J=8,1.6Hz, 1H), 2.75 (t,
J=6Hz, 2H), 2.58 (t, J=7.2Hz, 2H), 1.67-1.52 (m, 8H), 1.28 (s, 6H), 1.27 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 144.8, 142.3, 139.4, 126.6, 126.5, 125.8, 42.0, 35.7, 35.4,
35.3, 34.4, 34.1, 32.1, 32.1, 28.9.
Synthesis of S-2-oxo-2-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)butylamino)ethyl ethanethioate (129):
HN
SAc
O
To a solution of the amine (127) (16.7 mg, 0.0644 mmol, 1 equiv) and
2-(acetylthio)acetic acid (26 mg, 0.193 mmol, 3 equiv) in dichloromethane (1.5 mL) at
0 0C, EDC/HCl (37 mg, 0.0773 mmol, 3 equiv) was added. The reaction mixture was
stirred at r.t. overnight and diluted with dichloromethane (30 mL).This mixture was
washed with 0.5 N solution of HCl (2 X 15 mL), sat. NaHCO3 (2 X 15 mL) and brine,
dried with Na2SO4 and concentrated on a rotary evaporator. Purification by column
chromatography using EtOAc/Hexane (5%) as eluent afforded compound (129) (24
mg, 99%).77
Rf = 0.5 ( 40% EtOAc/Hexane); 1H NMR (300 MHz, CDCl3 ) δ 7.21 (d,
J=8.1Hz, 1H), 7.08 (d, J=1.8Hz), 6.93 (dd, J=8.1,1.8Hz, 1H), 6.18 (br. s, 1H), 3.56 (s,
106
2H), 3.25 (q, J=6.6Hz, 2H), 2.56 (t, J=7.8Hz, 1H), 2.39 (s, 3H), 1.67-1.52 (m, 8H),
1.27 (s, 6H), 1.26 (s, 6H); 13
C NMR (75 MHz, CDCl3) δ 196.2, 168.2, 144.9, 142.5,
139.1, 126.6, 126.5, 125.8, 39.9, 35.4, 35.4, 35.3, 34.4, 34.1, 33.3, 32.1, 32.1, 30.5,
29.3, 28.8.
Synthesis of 2-mercapto-N-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-
2- yl)butyl)acetamide (83):
HN
SH
O
A desoxygenated solution of MeONa (3.6 mg, 0.0655 mmol, 1 equiv) in MeOH
(1.5 mL) was added to S-2-oxo-2-(4-(5,5,8,8-tetramethyl-5,6,7,8-
tetrahydronaphthalen-2- yl)butylamino)ethyl ethanethioate (129) (24.6 mg, 0.0655
mmol, 1 equiv). The solution was stirred at r.t. for 4 hr. The reaction was quenched
with AcOH (2 mL) and concentrated on a rotary evaporator. The residue was diluted
with EtOAc (30 mL) and washed with water and brine, dried over Na2SO4, filtered and
concentrated on a rotary evaporator. Purification by column chromatography using
EtOAc/Hexane (5%) as eluent afforded compound (83) (16 mg, 74%).77
Rf = 0.4 (40%
EtOAc/Hexane); 1H NMR (400 MHz, CDCl3 ) δ 7.21 (d, J=7.6Hz, 1H), 7.08 (s, 1H),
6.94 (dd, J=8,2Hz, 1H), 6.68 (br. s, 1H), 3.31 (q, J=6.4, 2H), 3.23 (d, J=8.8Hz, 2H),
2.58 (t, J=7.2Hz, 2H), 1.83 (t, J=8.8Hz, 1H), 1.67-1.57 (m, 8H), 1.27 (s, 6H), 1.26 (s,
107
6H); 13
C NMR (75 MHz, CDCl3) δ 169.2, 144.9, 142.5, 139.1, 126.7, 126.5, 125.8,
40.0, 35.4, 35.4, 35.3, 34.4, 34.1, 32.1, 29.4, 28.8, 28.5; HRMS (ESI): m/z calcd. for
[( M-H)+]=332.2048, found=332.2048.
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