Semisynthesis and pharmacological activities of Tetrac analogs: Angiogenesis modulators

Article abstract of DOI:10.1016/j.bmcl.2009.04.094

Novel Tetrac analogs were synthesized and then tested. Anti-angiogenesis efficacy was carried out using the Chick Chorioallantoic Membrane (CAM) model and the mouse matrigel model for angiogenesis. Pharmacological activities showed Tetrac can accommodate numerous modifications and maintain anti-angiogenesis activity.

Full text of DOI:10.1016/j.bmcl.2009.04.094

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3259–3263
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Semisynthesis and pharmacological activities of Tetrac analogs:
Angiogenesis modulators
Alexandre Bridoux a, Huadong Cui a, Evgeny Dyskin a, Murat Yalcin a,b, Shaker A. Mousa a,
*
a The Pharmaceutical Research Institute (PRI), Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
b Uludag University, Veterinary Medicine Faculty, Department of Physiology, Bursa, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel Tetrac analogs were synthesized and then tested. Anti-angiogenesis efficacy was carried out using
the Chick Chorioallantoic Membrane (CAM) model and the mouse matrigel model for angiogenesis. Phar-
macological activities showed Tetrac can accommodate numerous modifications and maintain anti-angi-
ogenesis activity.
Received 11 March 2009
Revised 17 April 2009
Accepted 21 April 2009
Available online 24 April 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Tetrac
Esterification
Silylation
HPLC
Angiogenesis
Nanopharmaceutical technology
Angiogenesis is a vascular event, which partly induces the
growth of new blood vessels into tumors by cell adhesion to the
ECM (Extra Cellular Matrix) and allows for tumor progression. To
improve treatment for brain cancer better, an orally active com-
pound with optimal therapeutic index which would inhibit patho-
logical angiogenesis with minimal impact on physiological
processes is critically needed. The thyroid hormone antagonists
(Tetrac and Triac) were found to perturb the angiogenesis process
stimulated by VEGF (Vascular Endothelial Growth Factor) or FGF
(Fibroblast Growth Factor) without influencing the preexisting
blood vessels.1 The site of action of the compounds was then found
bond and substituted by four iodide atoms. A MM2 energy minimi-
zation revealed the most stable conformation was obtained when
the two aromatic rings were in perpendicular planes and the io-
dides to be space filling and predominant in size (Fig. 1). This lipo-
philic core together with the hydrophilic head may confer to Tetrac
an ease to the passive diffusion across the lipid membrane of cells
by which the compound was observed to reach nuclear receptors.4
During the course of the planed semisynthesis of Tetrac nanoparti-
cles, which would allow keeping the neovascular activity without
interfering with the vascular events, a suitable protecting group
at the phenylacetic acid end of Tetrac was required as a first step
in the synthesis of the nanoparticle precursors. The molecule was
thus modulated in new more lipophilic ester analogs. Since the
association to the nano scale sized particles was conceived to occur
at the phenol’s OH, it was alkylated after the formation of the car-
to be at or near the integrin a
Vb3’s binding pocket.2,3 As in the case
of the achiral Tetrac 1, the only possible structural isomer (Cs) is a
low molecular weight compound with a core constituted by a phe-
nol linked to a phenylacetic acid function (pKa = 4.3) by an ether
Abbreviations: ECM, extra cellular matrix; VEGF, vascular endothelial growth
factor; FGF, fibroblast growth factor; TEA, triethylamine; DCM, dichloromethane;
TiPSCl, triisopropylsilyl chloride; Cs2CO3, cesium carbonate; MeOH, methanol; HPLC,
high pressure liquid chromatography; EtOH, ethanol; ddH2O, double distilled water;
Tetrac-OTiPS, triisopropylsilyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophe-
nyl)acetate; EBH, epibromohydrin; DEBHT, oxiran-2-ylmethyl-2-(4-(3,5-diiodo-4-
(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetate; EBH-Tetrac-OTiPS, triis-
opropylsilyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)-
acetate; SM, starting material.
Figure 1. Structure and 3D representation (MM2 energy minimization, cambridge
Soft Chem 3D Ultra program) of Tetrac 1.
* Corresponding author. Tel.: +1 518 694 7397; fax: +1 518 694 7567.
E-mail address: Shaker.Mousa@acphs.edu (S.A. Mousa).
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.04.094

3260
A. Bridoux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3259–3263
Table 1
Table 2
Structure of Tetrac analogs 2–9
Comparison between the reactivities of acetic acid and Tetrac
Reagents
Acetates
Tetrac esters
I
MeI
10, bp = 57 °Ca
11, bp = 77 °Ca
12, bp = 98 °Ca
ꢀ
O
R'O
I
EtI
ꢀ
R
tBuI
ꢀ
I
b
CBzCl
ꢀ
ꢀ
TMSCl
TiPSCl
TiPSN3
4-CF3Ph-(EtO)3Si
13, bp = 121 °Ca
ꢀ
14, bp = 153 °Ca
5, mp = 146 °C
ꢀ
ꢀ
O
ꢀ
ꢀ
a
Values were compared to those reported in the MERCK Index IXth edition.
ꢀ = no product was formed.
I
b
2-9
The first Tetrac analogs (Table 1) were prepared following liter-
Compounds
R
R0
H
ature methods. The methyl ester, analog 2, was prepared following
a described method7,8 in 61% yield. Analogs 3 and 4 were new
products of the same reaction and were prepared following an-
other described method for the synthesis of tert-butyl esters.9
Unexpectedly, the main product of the reaction was 4 (30%
yield).10 Compound 5 was new and synthesized by de-protonation
of Tetrac with TEA or Cs2CO3 in anhydride DCM and then by addi-
tion of TiPSCl.11
2
OMe
3
OtBu
H
4
H
N
N
5
6
OTiPS
H
Plus, as shown on Table 2, Tetrac was found to hardly react with
most of the esterifying halogenated agents used to probe the for-
mation of other esters.
O
O
O
O
O
This interesting feature was thought to be due to the deactivat-
ing effect of the 4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophe-
nyl. This was proven hereafter as the reactivity of acetic acid in
comparison to Tetrac was studied. All the compounds were sub-
mitted to a general method12 which consisted in adding a series
of several carbon based and silicon based protecting groups to
the starting material activated by Cs2CO3 towards the formation
of the esters (5, 10–14) (Fig. 2, Table 2). In the course of this study,
the formation of 2 was observed in high yield (90%) when Tetrac
was reacted with benzyl chloroformate in MeOH and at room tem-
perature. Analog 6 was then obtained by refluxing epibromohydrin
with 4 in anhydride dioxane (Table 1). Then numerous attempts to
condensate epibromohydrin with compound 5 were accomplished
by varying the concentration of the epoxide containing alkylating
agent (i.e., 1.0 equiv, 10.0 equiv, 100.0 equiv) and led to use the
HPLC technique to study the course of the reaction.
O
O
O
7
8
9
OTiPS
O
O
H
bon and silicon based esters (Table 1). The compounds were then
tested for their inhibition of angiogenesis; perhaps the epoxide,
when linked at the phenol’s OH, could interact with Serine or Tyro-
sine which were reported at or near the binding site of the integrin
receptor by Xiong et al.5,6
While optimizing the reaction conditions of the condensation of
(Tetrac-OTiPS (triisopropylsilyl-2-(4-(4-hydroxy-3,5-diiodo-
phenoxy)-3,5-diiodophenyl)acetate)) with epibromohydrin (EBH
(epibromohydrin)), 8 (DEBHT (oxiran-2-ylmethyl-2-(4-(3,5-diio-
5
Figure 2. Structures of 10–14.

A. Bridoux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3259–3263
3261
do-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetate))
was found to be the major side product. During the first attempt,
compound 8 was formed equivalently as 7 (EBH-Tetrac-OTiPS
(triisopropylsilyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phen-
oxy)-3,5-diiodophenyl)acetate)). In order to minimize the forma-
tion of 8, five experiments were subsequently completed and
were monitored by HPLC (Fig. 2). At first, several reaction condi-
tions were used to minimize the formation of 8 by temperature/
time control. The starting material was completely transformed
at 30 min and no evolution in the 7/8 ratio was detected over
90 min (Fig. 3A). The second experiment analyzed the effect of
using an excess of the base (Fig. 3B). Larger amount was found
to have minor effect on the course of the reaction as the 7/8 ratio
was just slightly higher at 30 min. In the third experiment, the
reaction kinetic was monitored at 5-min intervals from 0 to
30 min (Fig. 3C). The starting material was nearly consumed at
20 min and the 7/8 ratio decreased from 0.94 to 0.29 from 5 to
30 min. Interestingly, when using 1.0 equiv of TEA, no de-protec-
tion of 5 was detected over a period of 30 min (Fig. 3D) as only
one additional peak corresponding to the retention time of 7
was detected on the chromatogram by lowering the heating tem-
perature to 55 °C using 1.0 equiv of base and a large excess of epi-
bromohydrin at a reaction time of 150 min. Also, the reaction was
found to be neater in those conditions at a reaction time of 30 min
than longer. Thereafter, the reaction was performed on a larger
scale (300 mg) with 1.0 equiv of base and monitored over a
150 min period (Fig. 3E).
From 30 min to 150 min or longer, the 7/8 ratio stayed the same
(i.e., 0.73) together with the yield of transformation of the starting
material which was quantified to 47%. Using the optimized condi-
tions, the two steps synthesis developed to obtain compounds 5
and 7 were then condensed via a one pot semi-synthetic process
to obtain 7 in an overall 40% yield.13 Product 9 was then easily
re-crystallized in EtOH.
Figure 3. HPLC chromatograms showing the optimization steps for the synthesis of 7.

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A. Bridoux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3259–3263
Table 3
To investigate the structure–activity relationships, each com-
Anti-angiogenesis efficacy of Tetrac analogs in the CAM model
pound was tested for its ability to block angiogenesis in com-
parison to Tetrac. Inhibition of angiogenesis was measured by
the chicken embryo ChorioAllantoic Membrane (CAM) model14
(Fig. 4), a widely used in vivo study, which exposed the live
chicken embryo membrane to various stimulating and inhibi-
tory compounds and by the matrigel assay15 which exposed test
angiogenesis-inducing and inhibitory compounds to cold liquid
matrigel, a mix of several proteins which, after subcutaneous
injection, solidified and permitted the formation of new blood
vessels. FGF and Tetrac were used as controls in both assays
(Tables 3 and 4).
Compounds were considered to be strong inhibitors if they
achieved more than 50% inhibition as compared to the control. In
the CAM experiments, a majority of Tetrac analog compounds
showed a strong inhibitory effect on new blood vessel formation
within the range from 75% to 97% (Table 3), comparable to 85%
of Tetrac. In parallel, synthesized analogs 3, 4, 5, 6, 7, 8 and 9 were
tested for their ability to inhibit hemoglobin formation from matri-
Treatment
PBS
Mean branch pointsa
73
130 11
Mean % inhibition
6
—
—
FGF(1.25
l
g/ml)
FGF + Tetrac
FGF + 3
FGF + 4
FGF + 5
FGF + 6
FGF + 7
FGF + 8
FGF + 9
81
79
121
87 11
105
75 11
112 10
94 10
8
7
4
85 14c
88 13c
15
8
75 19c
44 13b
96 21c
31 18
62 18b
7
a
Data representing mean SEM, n = 8.
p <0.05.
p <0.001.
b
c
Table 4
Anti-angiogenesis efficacy of Tetrac analogs in the mouse-matrigel model
Hemoglobin (mg/
ml) SEMa
Mean inhibition of angiogenesis (%)b
gel. Tetrac (10 lg) significantly inhibited FGF induced angiogenesis
(90% inhibition). Tetrac analog compounds also blocked the FGF in-
duced angiogenesis in a comparable fashion to Tetrac (Table 4).
Inhibition with compounds 3, 4, 5, 6, 7, 8 and 9 was observed to
be strong. Any modulations on either or both sides of Tetrac did
not affect greatly the antagonist effect of the parent compound.
Though the inhibition of angiogenesis in the CAM assay by com-
pounds 4, 6 and 8 (Table 3) were not as strong as compounds 3,
5, 7 and 9, their activities were better in the matrigel assay.
As the highly stable tertbutyl-Tetrac ester 3, which can only be
deprotected in acidic conditions and the analog 7 which was pro-
tected at both ends showed the same activity at inhibiting FGF-in-
duced angiogenesis, the phenol and carboxylic acid were proven
here not to be mandatory for the activity of the molecule. Those re-
sults tend, in fact, to support the hypothesis of a specific binding
site on the integrin designed to interact with the tetraiodophen-
oxyphenol core of the thyroid hormones.
Control
0.3 0.1
2.4 0.4
—
—
FGF 100 ng
FGF + Tetrac 0.5 0.1c
90 13
95 14
104 12
104 14
80 16
100
100 14
100 12
FGF + 3
FGF + 4
FGF + 5
FGF + 6
FGF + 7
FGF + 8
FGF + 9
0.4 0.1c
0.2 0.1c
0.2 0.1c
0.7 0.1c
0.3 0.1c
0.3 0.1c
0.3 0.1c
9
a
Hemoglobin data represent mean SEM, n = 7–14.
Tetrac and analogs were tested at 10 lg/plug.
p <0.001.
b
c
In summary, the chemical reactivity of Tetrac was probed by
esterification and phenol alkylation reactions. An HPLC assisted
study allowed to optimize a convenient synthesis pathway to
the formation of the nanoparticle. The biological activities
showed any modulations did not suppress Tetrac’s potency at
inhibiting angiogenesis stimulated by FGF. The potent precursor
7
was considered for the conjugation to PLGA based
nanoparticles.
Control (PBS)
b-FGF
b-FGF + Tetrac
b- FGF + 3
b-FGF + 5
b-FGF + 7
Figure 4. Representative illustrations of the anti-angiogenesis effects of Tetrac and Tetrac analogs 3, 5 and 7.

A. Bridoux et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3259–3263
3263
13. Triisopropylsilyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-
diiodophenyl)acetate (7).
Acknowledgments
In anhydrous conditions, Tetrac (3.0 g, 4.0 mmol, 1.0 equiv) was suspended in
Thanks to Azopharma’s contribution in regards to the synthesis
and analytical characterization of the EBH-Tetrac-OTiPS compound,
the Rensselaer Polytechnic Institute (NMR analyses), to the Univer-
sity at Albany Proteomics Facility, the Center for Functional Genom-
ics for the MS analysis, to Dr. Huazhong HE, PRI for reviewing this
article and to Dr. Jay Jayaraman, PRI for his help and constant
support. We appreciate the partial funding of this work by the Char-
itable Leadership Foundation and the Medical Technology Acceler-
ation Program and the Pharmaceutical Research Institute.
anhydrous THF. TEA (559
stirring at room temperature for 5 min, TiPSCl (858
was added drop by drop. After stirring for 20 min, TEA (559
l
L, 4.0 mmol, 1.0 equiv) was then added. After
L, 4.0 mmol, 1.0 equiv)
L, 4.0 mmol,
l
l
1.0 equiv) was added and then epibromohydrin (3.3 mL, 40.0 mmol,
10.0 equiv) was added and the reaction medium was stirred at reflux (55 °C)
and monitored by TLC. After 12 h, the reaction medium was cooled, filtered and
the organic phase was evaporated. The crude product was then separated by
column chromatography (DCM/cyclohexane 90:10) to give triisopropylsilyl-2-
(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetate
(1.5 g, 1.6 mmol) as a solid.
Yield: 40%; white powder; recrystallization solvent: EtOAc; TLC: 0.24 (DCM);
mp = 120 °C; IR (
m
cmꢁ1): 1711 (CO); UV–vis (DMSO): kmax nm = 256; HPLC
(l
Bondapak C18): rt = 10.6 min (CH3CN/H2O 90:10); 1H NMR (DMSO-d6) d
(ppm): 7.80 (s, 2H, ArH), 7.16 (s, 2H, ArH), 4.10–4.15 (dd, J = 4.0 Hz, 1H, CH),
3.99–4.06 (dd, J = 5.5 Hz, 1H, CH), 3.61 (s, 2H, CH2), 2.92–2.93 (t, J = 4.0 Hz, 1H,
CH), 2.78–2.79 (dd, J1 = 4.0 Hz, J2 = 10.0 Hz, 1H, CH), 1.28–1.33 (m, 3H, 3 CH),
Supplementary data
1.05 (s, 18H,
6
CH3); MS (ESI+) m/z: 804.3 [(MꢁC9H21Si+H)+, 87], 826.9
Supplementary data for publication contain informations on the
protocols and the analytical characterizations of all molecules. Plus
were included the protocols for the angiogenesis assays, the NMR
spectra of compound 2, 7 and a 2D NMR analysis on the connectiv-
ity of compound 9. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.bmcl.2009.04.094.
[(MꢁC9H21Si+Na)+, 100]; MS (APCI+) m/z: 961.8 [(M+H)+, 20]; Anal. Calcd for
C26H32I4O5Si: C, 32.52; H, 3.36. Found: C, 32.70; H, 3.13.
14. Chick ChorioAllantoic Membrane model. Ten-day-old fertilized chicken eggs
were incubated at 37 °C with 55% relative humidity. In the dark with the help
of candling lamp and using a hypodermic needle a small hole was punctured in
the shell covering the air sac. A second hole was punctured on the wider side of
the egg above an avascular area of the embryonic membrane. An artificial air
sac was created below the second hole by applying gentle vacuum to the first
hole using a small rubber squeeze bulb. The vacuum caused the separation of
ChorioAllantoic Membrane (CAM) from the shell. An approximately 1.0 cm2
window was cut in the shell over the dropped CAM with the use of a mini drill.
The underlying CAM was accessed through this small window. Filter disks
References and notes
1. Mousa, S. A.; Bergh, J. J.; Dier, E.; Rebbaa, A.; O’Connor, L. J.; Yalcin, M.; Aljada,
A.; Dyskin, E.; Davis, F. B.; Lin, H. Y.; Davis, P. J. Angiogenesis 2008, 11, 183.
2. Cody, V.; Davis, P. J.; Davis, F. B. Steroids 2007, 72, 165.
3. Bergh, J. J.; Lin, H. Y.; Lansing, L.; Mohamed, S. N.; Davis, F. B.; Mousa, S.; Davis,
P. J. Endocrinolgy 2005, 146, 2864.
were punched using
a small puncher from filter paper #1 (Whatman
International, United Kingdom). Filter disks were soaked in 3 mg/mL
cortisone acetate solution (95% ethanol and water) and air-dried under
sterile condition. For inducing angiogenesis, sterile filter disks were saturated
with FGF (1 lg/mL) and control disks were saturated with PBS without calcium
4. Hill, S. R., Jr.; Barker, S. B.; McNeil, J. H.; Tingley, J. O.; Hibbett, L. L. J. Clin. Invest.
1960, 39, 523.
and magnesium.
Using sterile forceps one filter/CAM was placed from the window. The window
5. Xiong, J.-P.; Stehle, T.; Diefenbach, B.; Zhang, R.; Dunker, R.; Scott, D. L.;
Joachimiak, A.; Goodman, S. L.; Arnaout, M. A. Science 2001, 294, 339.
6. Xiong, J.-P.; Stehle, T.; Zhang, R.; Joachimiak, A.; Frech, M.; Goodman, S. L.;
Arnaout, M. A. Science 2002, 296, 151.
was sealed with Highland brand transparent tape. After 1 h, 10
lL of inhibitor
(1 M) was added on the FGF-stimulated CAMs topically. Control filter disks
l
received PBS without calcium and magnesium. After 48 h, CAM tissue directly
beneath filter disk was harvested and placed in a 35-mm Petri dish. Ten eggs/
treatments were used.
7. Wilkinson, J. H. Biochem. J. 1956, 63, 601.
8. Wilkinson, J. H. Int. Patent WO/805761, 1958.
9. Neises, B.; Steglich, W. Org. Synth. 1990, 7, 93.
10. Obtained after activation of Tetrac with dicyclohexylcarbodiimide (DCC) in
presence of 4-dimethylaminopyridine (DMAP).
11. Synthesis of triisopropylsilyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)
acetate (5): In anhydrous conditions, Tetrac (2.1 g, 2.9 mmol, 1.0 equiv) was
15. Mouse matrigel model of angiogenesis. Normal male mice (C57BL/6NCr) 6–
8 weeks of age and weighing ꢂ20 g were purchased from Taconic farm.
Animals were housed 4 per cage, in controlled conditions of temperature (20–
24 °C); humidity (60–70%) and 12 h light/dark cycle provided with food and
water ad libitum. Experimental protocol was approved by VA IACUC. Mice
were allowed to acclimate for 5 days prior to the start of treatments. Matrigel
(BD Bioscience, San Jose CA) was thawed overnight at 4 °C and placed on ice.
Aliquots of matrigel were placed into cold polypropylene tubes to prevent the
matrigel from solidifying and the angiogenesis promoter added to matrigel
with or without antagonist. Matrigel was subcutaneously injected as triple
suspended in THF. TEA (402
l
L, 2.9 mmol, 1.0 equiv) was added. After stirring
L, 2.9 mmol, 1.0 equiv) was added
at room temperature for 5 min, TiPSCl (618
l
drop by drop. After stirring for 20 min, the solvent was evaporated and the
crude product was precipitated with diethylether, filtrated and then
recrystallized to give triisopropylsilyl-2-(4-(4-hydroxy-3,5-diiodophenoxy)-
3,5-diiodophenyl)acetate (2.1 g, 2.3 mmol) as a powder.
injection per animal at 100 lL/animal. At day 14 post plug implant all animals
were killed in CO2 chamber and matrigel plugs were collected. Plug
hemoglobin content was analyzed from three implants/mice (n = 6 per
group) to measure angiogenesis.
Yield: 80%; white powder; recrystallization solvent: EtOH; TLC: 0.77 (DCM);
mp = 146 °C; IR (
m
cmꢁ1): 1701 (CO); UV–vis (DMSO): kmax nm = 228; HPLC
(l
Bondapak C18): rt = 1.5 min (CH3CN/buffer pH 4.0 70:30); 1H NMR (DMSO-d6)
Hemoglobin determination of angiogenesis in Matrigel plugs. The Matrigel plugs
dissected from the mice were carefully stripped of any remaining peritoneum.
The plugs were placed into 0.5 mL tube of ddH2O and homogenized for 5–
10 min. The samples were spun at 4000 rpm on a centrifuge for 10 min and the
supernatants collected for hemoglobin measurement. Fifty microliters of
supernatant were mixed with 50 mL Drabkin’s reagent and allowed to sit at
room temperature for 15–30 min, and then 100 mL of this mixture was placed
in a 96-well plate. Absorbance was read with a Microplate Manager ELISA
reader at 540 nm. Hemoglobin (Hb) concentration was determined by
comparison with a standard curve in mg/mL. Hemoglobin concentration is a
reflection of the number of blood vessels in the plugs.
d (ppm): 7.81 (s, 2H, ArH), 7.11 (s, 2H, ArH), 5.56 (br, 1H, OH), 3.61 (s, 2H, CH2),
1.27–1.33(m,3H,3CH),1.05–1.17(m,18H,6CH3);MS(ESI-)m/z:903.3[(MꢁH)ꢁ,
100]; Anal. Calcd for C23H28I4O4Si: C, 30.55; H, 3.12. Found: C, 30.47; H, 2.83.
12. Synthesis of triisopropylsilylacetate (14): In anhydrous conditions, acetic acid
(0.5 mL, 8.7 mmol, 1.0 equiv) was suspended in anhydrous DCM. Cs2CO3
(2.84 g, 8.7 mmol, 1.0 equiv) was then added. After stirring at room
temperature for 5 min, TiPSCl (1.86 mL, 8.7 mmol, 1.0 equiv) was added drop
by drop. The product was filtered and then concentrated.
Yield:99%;clearoil;TLC:0.77(DCM);bp = 153 °C;IR(
(CDCl3) d (ppm): 2.07 (s, 3H, CH3), 1.32 (m, 3H, 3 CH), 1.08–1.10 (m, 18H, 6 CH3).
m
cmꢁ1):1723(CO);1HNMR