Synthesis of fluorinated analogues of the immunosuppressive drug FTY720

Article abstract of DOI:10.1016/j.tet.2011.02.028

Four fluorinated derivatives of the immunosuppressive drug FTY720 were synthesized by a convergent strategy, using the Sonogashira coupling as the key reaction to assemble the two major fragments.

Full text of DOI:10.1016/j.tet.2011.02.028

Tetrahedron 67 (2011) 2542e2547
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Tetrahedron
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Synthesis of fluorinated analogues of the immunosuppressive drug FTY720
*
Rebecca Y.Y. Ko, John C.K. Chu, Pauline Chiu
Department of Chemistry and the Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong,
Pokfulam Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Four fluorinated derivatives of the immunosuppressive drug FTY720 were synthesized by a convergent
strategy, using the Sonogashira coupling as the key reaction to assemble the two major fragments.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 30 December 2010
Received in revised form 8 February 2011
Accepted 11 February 2011
Available online 17 February 2011
Keywords:
Immunosuppressive agent
FTY720
Fluorinated drugs
Sonogashira coupling
1. Introduction
including changes in lipophilicity, pKa, and the most stable con-
formations, leading to enhanced binding affinities at recognition
Myriocin (1) is an immunosuppressive natural product that has
been isolated from three different fungal sources, Myriococcum
albomyces, Mycelia sterilia and Isaria sinclairii (Fig. 1).1 Based on
structure activity relationship studies, FTY720 (2) was designed
and synthesized in 1995 as a simplified analogue of 1, and was
found to have higher potency in vitro and in vivo and with less side
effects compared with the parent compound (Fig. 1).2 FTY720 has
recently been approved by the FDA as the first oral and first-line
drug for the treatment of relapsing-remitting multiple sclerosis
(MS), an autoimmune disorder.3 Its biological activity has been
attributed to mimicking the MS-relevant metabolite, sphingosine
(3) (Fig. 1).4 Furthermore, 2 has been shown to induce apoptosis
across a panel of human cancer cell lines.5 In particular, studies at
our institution have demonstrated its promising therapeutic po-
tential in the treatment of liver6 and prostate cancers.7
sites, entry into alternative metabolic pathways or an increased
stability and bioavailability in organisms.11 Fluorination resulting in
the improvement of the pharmacological profile made way for
development of new drugs, such as the antibacterial flurithromycin
(7a), developed base on its parent erythromycin (7b); the anti-
hyperlipidemic ezetimib (8a) from its parent SCH 48461 (8b); and
anticancer valrubicine (9a) based on doxorubicin (9b), all of which
are currently on the market (Fig. 2).9,12 The fluorinated derivatives
showed an enhanced metabolic stability, bioavailability and/or re-
duced toxicity compared to their predecessors.
The occurrence of fluorine in pharmaceuticals by design has
become increasingly prevalent over the last twenty years. It has
been estimated that approximately 20% of pharmaceutical com-
pounds currently in use are fluorinated.8 Examples of fluorinated
drugs include the anticancer 5-fluorouracil (4), the antidepressant
fluoxetine (5) and the antiviral efavirenz (6) (Fig. 2).9,10 The ratio-
nale for this design strategy is that at a minimal cost in steric de-
mands, the replacement of hydrogen with electronegative fluorine
can introduce different physicochemical properties to the molecule,
Fig. 1. Myriocin (1), FTY720 (2), and sphingosine (3).
Due to the therapeutic potential of FTY720, many studies have
been carried out to explore the synthesis and bioactivities of its
analogues.2,13,14 In light of the biological significance of 2 and the
potential to improve the pharmacological profile of drugs using
* Corresponding author. Tel.: þ852 2859 8949; fax: þ852 2857 1586; e-mail
address: pchiu@hku.hk (P. Chiu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.028

R.Y.Y. Ko et al. / Tetrahedron 67 (2011) 2542e2547
2543
We have also considered that the aryl ring or the benzylic po-
sitions of 2 might be susceptible to oxidation by liver enzymes and
thus resulting in an attenuated metabolic stability. Fluorine was
introduced in 10aed to block these potentially metabolically labile
sites to undermine the putative oxidative processes.15 None of the
analogues 10aed are known in the literature (Fig. 3).
2.2. Retrosynthetic analysis
To maximize the efficiency of the synthesis, we sought to de-
velop a convergent and unified strategy towards all four of the
fluorinated analogues 10 (Scheme 1). We envisioned that all of
them could be obtained from a Sonogashira coupling reaction be-
tween a common intermediate alkyne 13 bearing the highly polar
terminus, and the corresponding fluorinated aryl iodides 12. The
desired analogues 10 could be obtained from 11 by an exhaustive
reduction which could in one step yield not only the ethylene linker
from the alkyne, but also a deprotection of the diol if it were pro-
tected as a benzylidene derivative. The common intermediate 13
could be accessed readily from commercially available tris
(hydroxymethyl)aminomethane 14.
Scheme 1. Retrosynthetic analysis.
Fig. 2. Examples of fluorinated drugs.
Coincidentally, about the time we had began our work on the
design and synthesis of analogues 10aed, Kim et al. published
a similar Sonogashira coupling strategy for the synthesis of the
parent compound FTY720.16 Other approaches to FTY720 and its
analogues have also been reported.2,13,14
fluorination as a strategy in medicinal chemistry, we initiated an
effort directed at the design and synthesis of some fluorinated
FTY720 analogues.
2. Results and discussion
2.3. Synthesis of 12d
2.1. Design of fluorinated analogues of FTY720
All of the aryl iodides 12 required for the synthesis of 10aed
were commercially available except for 12d, which was a novel
compound and had to be prepared (Scheme 2). A Grignard addition
by n-pentylmagnesium bromide to 4-iodobenzaldehyde 15, fol-
lowed by a Swern oxidation, afforded ketone 17. It was converted to
dithiane 18 in high yield. Fluorine was introduced by a desulfurative
fluorination of 18 using HF in the presence of NOBF4.17
The design and rapid synthesis of novel fluorinated analogues of
FTY720 was contingent on the availability of fluorinated aromatic
bromides or iodides. Most commercially available fluorinated aro-
matics were in the form of aryl fluorides or trifluoromethylarenes.
Access to other fluorinated analogues would require additional
synthetic efforts. With these considerations in mind, analogues
10aec were designed based on the commercial availability of the
corresponding fluorinated aromatic iodides (Fig. 3).
Scheme 2. Synthesis of aryl iodide 12d.
Fig. 3. Novel fluorinated analogues of FTY720 10aed.

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R.Y.Y. Ko et al. / Tetrahedron 67 (2011) 2542e2547
2.4. Synthesis of 10aed
4.2. Synthesis of aryl iodide 12d
The synthesis of alkyne 13a commenced with tris(hydroxyl-
methyl)aminomethane (Scheme 3). Protection of the amine with
Boc2O and the diol with benzaldehyde dimethyl acetal yielded al-
cohol 20, which was subject to a Swern oxidation to give aldehyde
21. Nucleophilic attack by deprotonated CH2Cl2 to give alcohol 22
and subsequent activation with mesyl chloride provide the requi-
site leaving groups in 23. Elimination was effected with MeLi to
provide alkyne 13a.18
4.2.1. Synthesis of 16. To a cooled (ꢀ78 ꢁC) and stirred solution of 15
(2.01 g, 8.65 mmol) in THF (80 mL) was added n-pentylmagnesium
bromide in THF (30 mL, 13.0 mmol). The reaction was stirred at
ꢀ78 ꢁC for 1.5 h. It was then poured into saturated NH4Cl and the
organic layer was separated. The aqueous layer was extracted with
EtOAc (3ꢂ100 mL) and the combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The residue was purified by flash chromatography
Scheme 3. Synthesis of fluorinated analogues 10aed.
We then executed the key Sonogashira coupling reactions. As
shown in Scheme 3, alkyne 13a was successfully coupled with all
aryl iodides 12aed in moderate yields to give disubstituted alkynes
11aed. Treatment of 11aed with hydrogen and palladium on car-
bon resulted in the concomitant reduction of the alkyne and
hydrogenolysis to deprotect the diol to yield 24aed. Finally,
deprotection of the Boc group afforded FTY720 analogues 10aed as
hydrochloric acid salts in quantitative yields.
(8% EtOAc in hexane) to afford 16 (1.58 g, 60% yield) as a colourless
oil. Rf (10% EtOAc in hexane) 0.36; 1H NMR (300 MHz, CDCl3)
7.67
d
(d, J¼8.4 Hz, 2H), 7.09 (d, J¼8.4 Hz, 2H), 4.65e4.59 (m,1H),1.82e1.64
(m, 3H), 1.43e1.28 (m, 6H), 0.87 (t, J¼4.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3)
d 144.6, 137.5, 128.0, 92.8, 74.1, 39.1, 31.7, 25.4, 22.6, 14.1; IR
(CH2Cl2): 3683, 2837, 2801, 2740, 1705, 1655, 1583, 1568, 1481, 1372,
1205, 1170, 1054; LRMS (EI): m/z 304 (10), 233 (100); HRMS (EI): m/z
calcd for C12H17OI 304.0321, found: 304.0324.
4.2.2. Synthesis of 17. To a round bottom flask containing (COCl)2
(0.53 mL, 6.07 mmol) in anhydrous CH2Cl2 (60 mL) at ꢀ78 ꢁC was
added DMSO (0.86 mL, 12.1 mmol) dropwise. After stirring for
15 min at ꢀ78 ꢁC, 16 (923.2 mg, 3.04 mmol) in CH2Cl2 (5 mL) was
added via cannula. At this temperature, the mixture was stirred for
1 h, followed by the addition of Et3N (3.4 mL, 24.3 mmol). The
mixture was stirred for 30 min at ꢀ78 ꢁC, then the cooling bath was
removed and the reaction was allowed to warm to room temper-
ature. Water was added and the aqueous layer was extracted with
CH2Cl2 (3ꢂ60 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concentrated in
vacuo to give 17 (859.3 mg, 97% yield) as a colourless oil. Rf (10%
3. Conclusion
We have successfully employed a convergent and unified
strategy to synthesize four fluorinated analogues of FTY720. The
common intermediate 13a was synthesized in six steps, which was
then parlayed into the four analogues 10aed in three additional
steps. We believe this approach can be readily extended to access
other analogues of FTY720 with aromatic ring variations and will
thus be useful in further studies on structure-activity relationships
of FTY720 analogues. The biological studies of these analogues will
be reported due course.
EtOAc in hexane) 0.79; 1H NMR (500 MHz, CDCl3)
d
7.82 (dd, J¼6.7,
4. Experimental
1.9 Hz, 2H), 7.67 (dd, J¼6.7, 1.8 Hz, 2H), 2.91 (t, J¼7.5 Hz, 2H),
1.75e1.69 (m, 2H), 1.37e1.34 (m, 4H), 0.91 (t, J¼2.7 Hz, 3H); 13C
4.1. General experimental
NMR (125 MHz, CDCl3) d 199.9, 137.9, 136.3, 129.5, 100.8, 38.5, 31.5,
24.0, 22.5, 14.0; IR (CH2Cl2):3689, 2963, 2929, 2855, 1685, 1582,
1393, 1006; LRMS (EI): m/z 302 (4), 259 (3), 231 (96), 203 (20);
HRMS (EI): m/z calcd for C12H15OI 302.0153, found: 302.0161. The
1H NMR spectroscopic data corresponded to those of 17 in
literature.19
All reactions were performed in oven-dried flasks under an inert
atmosphere of argon. Solvents were dried over calcium hydride
prior to use. Flash column chromatography was performed with E.
Merck silica gel 60 (230e400 mesh ASTM). TLC was performed
with E. Merck 0.2 mm pre-coated silica gel plates (Kieselgel 60
F254þ). 1H and 13C NMR spectra were recorded on Bruker DPX 300,
400 Fourier Transform spectrometers. IR spectroscopy was per-
formed with a Bio-Rad Fourier Transform 165 Spectrophotometer.
Mass spectra were recorded on a Finnigan MAT 95 Mass Spec-
trometer or API QSTAR PULSAR iLC/MS/TOF System.
4.2.3. Synthesis of 18. To a cooled (0 ꢁC) stirred solution of 17
(850 mg, 2.81 mmol) in anhydrous CH2Cl2 (25 mL) was added
dithioethane (5.9 mL, 7.03 mmol). BF3$Et2O (1.86 mL, 7.03 mmol)
was then added at 0 ꢁC and the reaction mixture was stirred at

R.Y.Y. Ko et al. / Tetrahedron 67 (2011) 2542e2547
2545
room temperature for 2 h. The reaction mixture was diluted with
hexane (20 mL) and washed with saturated NaHCO3 (20 mL) and
15% NaOH (20 mL), respectively. The organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The residue was purified by chromatography (5% EtOAc in
hexane) to afford 18 (1.01 g, 95% yield) as a pale yellow oil. Rf (pure
7.51e7.48 (m, 2H), 7.41e7.39 (m, 3H), 5.69 (br s,1H), 5.50 (s,1H), 4.28
(d, J¼11.3 Hz, 2H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 198.4,
155.8,137.1,129.4,128.4,125.9,101.7, 81.3, 69.6, 60.5, 28.3; IR (CHCl3):
3432, 2877, 1728, 1705, 1490, 1370, 1161; LRMS (EI): m/z 278
([MꢀCHO]þ,10), 221 (7),163 (5); HRMS (EI): m/z calcd for C15H20NO4
[MþꢀCHO]: 278.1392, found: 278.1392. The 1H NMR spectroscopic
data corresponded to those of 21 in literature.21
hexane) 0.53; 1H NMR (300 MHz, CDCl3)
d
7.61 (d, J¼8.3 Hz, 2H),
7.44 (d, J¼8.3 Hz, 2H), 3.42e3.31 (m, 2H), 3.24e3.14 (m, 2H),
2.32e2.27 (m, 2H), 1.23e1.20 (m, 6H), 0.82 (t, J¼6.7 Hz, 3H); 13C
4.3.3. Synthesis of 13a. To CH2Cl2 (6 mL, 93.3 mmol) was added
pre-cooled lithium diisopropylamide (160 mL, 0.22 M) in THF
dropwise at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for 15 min
and 21 (3.59 g, 11.7 mmol) in anhydrous THF (35 mL) was added via
cannula. The mixture was stirred at ꢀ78 ꢁC for 1.5 h and then
quenched with H2O (150 mL). The reaction mixture was stirred at
room temperature and saturated NH4Cl was added. The mixture
was extracted with EtOAc (3ꢂ200 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4 and
concentrated in vacuo. The residue was then diluted with anhy-
drous CH2Cl2 (85 mL). To this solution were added, Et3N (2.5 mL,
17.5 mmol) and MsCl (1.35 mL, 17.5 mmol) at 0 ꢁC. The reaction
mixture was stirred at room temperature for 18 h and then
quenched with H2O (100 mL) and extracted with CH2Cl2
(3ꢂ100 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4 and concentrated in vacuo. The resi-
due was then diluted with anhydrous THF (120 mL) and cooled to
ꢀ60 ꢁC. MeLi (40 mL, 1.6 M) was added dropwise. The reaction was
stirred at 0 ꢁC for 2 h and then quenched with H2O (100 mL) and
saturated NH4Cl. The mixture was extracted with EtOAc
(3ꢂ120 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography using 20% EtOAc
in hexane to afford 13a (2.30 g, 65% yield) as a white solid. Rf (10%
NMR (75 MHz, CDCl3)
d 145.4, 137.0, 129.4, 92.5, 73.9, 45.6, 39.2,
31.8, 27.6, 22.4, 14.0; IR (CH2Cl2): 3683, 2960, 2932, 2848, 1482,
1387, 1004; LRMS (EI): m/z 378 (2), 307 (100), 247 (8), 203 (2);
HRMS (EI): m/z calcd for C14H19IS2 377.9958, found: 377.9961.
4.2.4. Synthesis of 12d. To a plastic bottle containing NOBF4
(782 mg, 6.68 mmol), HF (3 mL) in anhydrous CH2Cl2 (15 mL) was
added via cannula at 0 ꢁC. Dithiane 18 (1.26 g, 3.34 mmol) in an-
hydrous CH2Cl2 (6 mL) was then added dropwise via cannula. The
reaction mixture was stirred at 0 ꢁC for 5 min and then warmed to
room temperature and stirred for another 10 min. The reaction
mixture was then poured into petroleum ether (80 mL) and
extracted with petroleum and CH2Cl2 (1:1, 3ꢂ50 mL). The organic
layer was then filtered through silica gel and concentrated in vacuo.
The residue was purified by chromatography (3% EtOAc in hexane)
to afford 12d (649.6 mg, 60% yield) as a pale yellow oil. Rf (10%
EtOAc in hexane) 0.72; 1H NMR (400 MHz, CDCl3)
d 7.76 (d,
J¼8.2 Hz, 2H), 7.20 (d, J¼8.3 Hz, 2H), 2.14e2.02 (m, 2H), 1.56e1.38
(m, 2H), 1.37e1.25 (m, 4H), 0.88 (t, J¼6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 137.6, 126.9, 126.9, 126.8, 95.8, 39.2, 38.9, 38.7,
31.4, 22.4, 22.2, 22.1, 22.1, 13.9; IR (CH2Cl2): 3684, 2958, 2937, 2845,
1433, 1392, 1387, 1007.
4.3. Synthesis of alkyne 13a
EtOAc in hexane) 0.34; 1H NMR (400 MHz, CDCl3)
d 7.50e7.46 (m,
2H), 7.21e7.37 (m, 3H), 5.51 (s, 1H), 5.25 (br s, 1H), 4.45 (d,
4.3.1. Synthesis of 20. To
a
stirred solution of 1920 (7.21 g,
J¼11.6 Hz, 2H), 3.99 (d, J¼10.4 Hz, 2H), 2.48 (s, 1H), 1.48 (s, 9H); 13C
32.6 mmol) and camphorsulfonic acid (757 mg, 3.26 mmol) in DMF
(40 mL) was added benzaldehyde dimethyl acetal (7.4 mL,
48.9 mmol). The mixture was stirred at room temperature over-
night and quenched with excess Et3N. The mixture was stirred for
20 min and poured into H2O, and extracted with EtOAc (3ꢂ150 mL).
The combined organic layers were washed with H2O, brine and
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography using 20% EtOAc
in hexane to afford 20 (6.53 g, 65% yield) as a white solid. Rf (20%
NMR (75 MHz, CDCl3) d 154.4, 137.2, 129.3, 128.4, 126.0, 101.9, 80.4,
79.4, 74.0, 73.0, 47.2, 28.4; IR (CHCl3): 3448, 3320, 2909, 2849, 1719,
1490, 1160, 1080; LRMS (EI): m/z 230 ([MꢀC4H9]þ, 6), 217 (3), 199
(3), 185(6), 172 (2); HRMS (EI): m/z calcd for C13H12 NO3
[MþꢀOC4H9]: 230.0817, found: 230.0817.
4.4. Synthesis of fluorinated analogues FTY720 10aed
4.4.1. Synthesis of 10a.
4.4.1.1. Synthesis of 11a. To a solution of compound 13a (125 mg,
0.412 mmol), and Et3N (1 mL) in DMF (4 mL), 1-iodo-3,5-bis(tri-
EtOAc in hexane) 0.48; 1H NMR (300 MHz, CDCl3)
d
7.53e7.50 (m,
2H), 7.44e7.35 (m, 3H), 5.63 (br s, 1H), 5.44 (s, 1H), 4.69 (br s, 1H),
4.21 (d, J¼11.7 Hz, 2H), 3.82 (d, J¼11.7 Hz, 2H), 3.70 (d, J¼6.6 Hz,
fluoromethyl)benzene (146 mL, 0.824 mmol), CuI (15.7 mg,
2H), 1.47 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
156.5, 137.5, 129.0,
0.082 mmol) and Pd(PPh3)4 (47.7 mg, 0.041 mmol) were added. The
reaction mixture was stirred at room temperature overnight and
filtered through a SiO2 pad. The residue was washed with 50% EtOAc/
hexane (4ꢂ15 mL) and concentrated in vacuo. The residue was pu-
rified by flash chromatography using 10% EtOAc in hexane to afford
11a (138 mg, 65% yield) as white solid. Rf (20% EtOAc in hexane) 0.71;
128.2, 125.9, 101.7, 80.4, 71.4, 64.4, 53.4, 28.2; IR (CHCl3): 3534,
3423, 2983, 2874, 1741, 1508, 1443, 1375, 1162, 1047; LRMS (EI): m/z
252 (6), 236 (5), 204 (35), 173 (15); HRMS (EI): m/z calcd for C12H14
N O5 (MþꢀC4H9) 252.0872, found: 252.0872. The 1H NMR spec-
troscopic data corresponded to those of 20 in literature.21
1H NMR (300 MHz, CDCl3)
d 7.89 (s, 2H), 7.82 (s, 1H), 7.54e7.51 (m,
4.3.2. Synthesis of 21. To a solution of oxalyl chloride (2.85 mL,
32.4 mmol) in CH2Cl2 (140 mL) at ꢀ78 ꢁC was added DMSO (4.6 mL,
64.9 mmol). The mixture was stirred for 15 min. Alcohol 20 (5.03 g,
16.3 mmol) in CH2Cl2 (15 mL) was added at ꢀ78 ꢁC. The mixture was
stirred for 30 min Et3N (18 mL, 130 mmol) was added at ꢀ78 ꢁC. The
resulting mixture was stirred for 30 min at ꢀ78 ꢁC. The reaction was
quenched with H2O (200 mL) and extracted with CH2Cl2
(3ꢂ150 mL). The combined organic layers were washed with brine
and dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash chromatography using 20% EtOAc
in hexane to afford 10 (4.01 g, 80% yield) as a white solid. Rf (10%
2H), 7.45e7.40 (m, 2H), 5.57 (s, 1H), 5.39 (br s, 1H), 4.55 (d, J¼11.3 Hz,
2H), 4.11 (d, J¼11.5 Hz, 2H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
154.3, 137.1, 131.9, 129.4, 128.4, 128.4, 126.0, 124.6, 122.1, 102.0, 88.3,
82.9, 80.5, 72.8, 47.9, 28.4; IR (CH2Cl2): 3702, 3669, 3602, 3426, 2983,
2923, 2869, 1720, 1606, 1491, 1457, 1385, 1372, 1181, 1142; LRMS (EI):
m/z 496 ([MþꢀF], 2), 459 (3), 430 (2), 399 (1); HRMS (EI): m/z calcd
for C25H23NO4F5 [MþꢀF]: 496.1544, found: 496.1547.
4.4.1.2. Synthesis of 24a. To
a solution of compound 11a
(100 mg, 0.194 mmol) in EtOAc (2 mL), Pd/C (30 mg, 0.0194 mmol)
was added and the reaction mixture was stirred at room temper-
ature overnight under a H2 atmosphere. The mixture was then
EtOAc in hexane) 0.43; 1H NMR (300 MHz, CDCl3)
d 9.59 (s, 1H),

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R.Y.Y. Ko et al. / Tetrahedron 67 (2011) 2542e2547
filtered using a Celite pad and washed with EtOAc (5ꢂ10 mL). The
combined organic layers were concentrated in vacuo. The residue
was purified by flash chromatography using 10% EtOAc in hexane to
afford 24a (71.1 mg, 85% yield) as a white solid. Rf (20% EtOAc in
a white solid. 1H NMR (500 MHz, CD3OD)
7.44 (d, J¼8.0 Hz, 2H), 3.70 (s, 4H), 2.78e2.75 (m, 2H), 1.99e1.96 (m,
2H); 13C NMR (125 MHz, CD3OD)
147.3, 130.2, 129.9, 127.0, 126.6,
124.9, 62.6, 62.2, 34.4, 30.1; IR (CHCl3): 3688, 3588, 3340, 2896,1606,
1509, 1457, 1408; LRMS (FAB): m/z 264 [MþꢀCl]; HRMS (FAB): m/z
calcd for C12H16NO2F3 [MþꢀCl]: 264.1217, found: 264.1211.
d
7.58 (d, J¼8.1 Hz, 2H),
d
hexane) 0.07; 1H NMR (300 MHz, CDCl3)
d 7.71 (s, 1H), 7.64 (s, 2H),
5.14 (br s, 1H), 3.86 (d, J¼11.3 Hz, 2H), 3.67 (d, J¼11.3 Hz, 2H),
2.79e2.75 (m, 2H), 2.63 (br s, 2H), 1.97e1.93 (m, 2H), 1.46 (s, 9H);
13C NMR (75 MHz, CDCl3)
d
156.3, 132.2, 131.9, 131.6, 131.4, 128.6,
4.4.3. Synthesis of 10c. 4.4.3.1. Synthesis of 11c. To a solution of
compound 13a (125 mg, 0.412 mmol), Et3N (1 mL) in DMF (4 mL),
pentafluoroiodobenzene (110 mL, 0.824 mmol), CuI (15.7 mg,
124.5, 122.3, 120.2, 80.5, 66.3, 59.1, 34.4, 29.6, 28.3; IR (CH2Cl2):
2683, 2426, 2976, 2942, 2861, 1714, 1616, 1519, 1500, 1465, 1381,
1175, 1136; LRMS (FAB): m/z 400 ([MþꢀCH2OH], 8), 345 (2), 300
(100), 227 (16); HRMS (EI): m/z calcd for C17H20NO3F6
[MþꢀCH2OH]: 400.1352, found: 400.1347.
0.066 mmol) and Pd(PPh3)4 (48 mg, 0.041 mmol) were added. The
reaction mixture was stirred at room temperature overnight and
filtered through a SiO2 pad. The residue was washed with 50%
EtOAc/hexane (4ꢂ15 mL) and concentrated in vacuo. The residue
was purified by flash chromatography using 10% EtOAc in hexane to
afford 11c (97.3 mg, 50% yield) as a white solid. Rf (10% EtOAc in
4.4.1.3. Synthesis of 10a. To a solution of compound 24a (20 mg,
0.0464 mmol) in dioxane (five drops), 6 M HCl (five drops) was
added and the mixture was stirred at room temperature overnight.
The mixture was dried by azeotropic evaporation with benzene and
pumped to dryness. Compound 10a (17 mg, quantitative) was
hexane) 0.46; 1H NMR (400 MHz, CDCl3)
d 7.52e7.49 (m, 2H),
7.43e7.38 (m, 3H), 5.57 (s, 1H), 5.57 (br s, 1H), 4.54 (d, J¼11.5 Hz,
2H), 4.10 (d, J¼11.6 Hz, 2H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3)
obtained as a white solid. 1H NMR (500 MHz, MeOD)
d
7.88 (s, 2H),
7.82 (s, 1H), 4.89 (s, 1H), 3.70 (s, 4H), 2.88e2.84 (m, 2H), 2.04e1.97
(m,2H); 13C NMR (125 MHz, MeOD)
146.0, 133.2,130.2,126.1,121.3,
d 154.2, 137.1, 129.5, 128.5, 126.1, 102.1, 77.3, 72.7, 48.2, 29.8, 28.9; IR
(CH2Cl2): 2429, 2982, 2936, 2872, 1723, 1456, 1393, 1369, 1170,
1083; LRMS (EI): m/z 413 ([MþꢀC4H8], 2), 277 (100), 259 (21), 233
(96); HRMS (EI): m/z calcd for C19H12NO4F5 [MþꢀC4H8]: 413.0694,
found: 413.0686.
d
62.6, 62.4, 34.3, 30.9; IR (CH2Cl2): 3166, 1738, 1603, 1376, 1271,
1048; LRMS (FAB): m/z 332; HRMS (FAB): m/z calcd for C13H16NO2F6
[MþꢀCl]: 332.1085, found: 332.1085.
4.4.3.2. Synthesis of 24c. To a solution of compound 11c (80 mg,
0.169 mmol) in EtOAc (2 mL), Pd/C (26 mg, 0.0169 mmol) was
added and the reaction mixture was stirred at room temperature
overnight under a H2 atmosphere. The mixture was then filtered
using a Celite pad and washed with EtOAc (5ꢂ10 mL). The com-
bined organic layers were concentrated in vacuo. The residue was
purified by flash chromatography using 10% EtOAc in hexane to
afford 24c (54 mg, 83% yield) as a white solid. Rf (20% EtOAc in
4.4.2. Synthesis of 10b.
4.4.2.1. Synthesis of 11b. To a solution of compound 130 (100 mg,
0.329 mmol) in Et3N (1 mL) and DMF (4 mL), iodobenzotrifluoride
(97 mL, 0.659 mmol), CuI (12.6 mg, 0.066 mmol) and Pd(PPh3)4
(38 mg, 0.033 mmol) were added. The reaction mixture was stirred
at room temperature overnight and filtered through a SiO2 pad. The
residue was washed with 50% EtOAc/hexane (4ꢂ15 mL) and con-
centrated in vacuo. The residue was purified by flash chromatog-
raphy using 10% EtOAc in hexane to afford 11b (95.4 mg, 65% yield)
as a white solid. Rf (10% EtOAc in hexane) 0.72; 1H NMR (400 MHz,
hexane) 0.14; 1H NMR (300 MHz, CDCl3)
J¼11.4 Hz, 2H), 3.66 (d, J¼11.3 Hz, 2H), 2.73 (t, J¼8.5 Hz, 2H),
1.89e1.83 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3)
156.2,
d 5.07 (br s, 1H), 3.88 (d,
d
CDCl3)
s, 1H), 4.53 (d, J¼11.3 Hz, 2H), 4.08 (d, J¼11.5 Hz, 2H), 1.59 (s, 9H);
13C NMR (75 MHz, CDCl3)
154.4, 137.2, 132.2, 129.4, 128.4, 126.1,
125.2, 102.0, 87.2, 84.4, 80.4, 73.0, 47.9, 28.4; IR (CHCl3): 3738, 2983,
2877, 1718, 1492, 1324, 1170, 1128, 1064; LRMS (EI): m/z 391
([MꢀC4H9]þ, 4), 361 (5); HRMS (EI): m/z calcd for C20H16 NF3O4
[MþꢀC4H9]: 391.1030, found: 391.1031.
d
7.58e7.49 (m, 6H), 7.44e7.38 (m, 3H), 5.56 (s, 1H), 5.33 (br
136.6, 80.4, 66.5, 59.0, 32.4, 31.6, 28.3; IR (CH2Cl2): 3154, 1738, 1453,
1386, 1171, 1058; LRMS (EI): m/z 354 ([MþꢀCH2OH], 8), 297 (34),
266 (23); HRMS (EI): m/z calcd for C15H17NO3F5 [eCH2OH]
354.1054, found: 354.1058.
d
4.4.3.3. Synthesis of 10c. To a solution of compound 24c (30 mg,
0.0778 mmol) in dioxane (six drops), 6 M HCl (six drops) was added
and the mixture was stirred at room temperature overnight. The
mixture was dried by azeotropic evaporation with benzene and
pumped to dryness. Compound 10c (25 mg, quantitative) was
4.4.2.2. Synthesis of 24b. To
a solution of compound 11b
(95.4 mg, 0.214 mmol) in EtOAc (2.5 mL), Pd/C (33 mg, 0.0214 mmol)
was added and the reaction mixture was stirred at room tempera-
ture overnight under a H2 atmosphere. The mixture was then filtered
using a Celite pad and washed with EtOAc (5ꢂ10 mL). The combined
organic layers were concentrated in vacuo. The residue was purified
by flash chromatography using 10% EtOAc in hexane to afford 24b
(68 mg, 88% yield) as a white solid. Rf (20% EtOAc in hexane) 0.29; 1H
obtained as a white solid. 1H NMR (500 MHz, MeOD)
d
3.70 (s, 4H),
2.80e2.76 (m, 2H), 2.01e1.95 (m, 2H); 13C NMR (125 MHz, MeOD)
136.9, 62.6, 62.4, 34.3, 30.1; IR (CH2Cl2): 3164, 2693, 2296, 1590,
d
1408; LRMS (FAB): m/z 286; HRMS (FAB): m/z calcd for C11H13NO2F5
[MþꢀCl]: 286.0860, found: 286.0866.
NMR (300 MHz, CDCl3)
d
7.53 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼7.1 Hz, 2H),
4.4.4. Synthesis of 10d. 4.4.4.1. Synthesis of 11d. To a solution of
compound 13a (68.3 mg, 0.225 mmol), Et3N (0.5 mL) in DMF
(2 mL),12d (182 mg, 0.563 mmol), CuI (8.6 mg, 0.045 mmol) and Pd
(PPh3)4 (26 mg, 0.023 mmol) were added. The reaction mixture was
stirred at room temperature overnight and filtered through a SiO2
pad. The residue was washed with 50% EtOAc/hexane (4ꢂ15 mL)
and concentrated in vacuo. The residue was purified by flash
chromatography using 10% EtOAc in hexane to afford 11d (63.3 mg,
57% yield) as a white solid. Rf (10% EtOAc in hexane) 0.49; 1H NMR
5.05 (br s, 1H), 3.88 (dd, J¼5.8, 11.4 Hz, 2H), 3.66 (dd, J¼6.1, 11.4 Hz,
2H), 3.28 (br s, 2H), 2.71e2.66 (m, 2H), 1.94e1.88 (m, 2H), 1.45 (s,
9H); 13C NMR (75 MHz, CDCl3)
d 156.4, 146.0, 128.7, 128.6, 128.3,
125.4, 80.3, 66.3, 59.2, 34.6, 29.6, 28.4; IR (CH2Cl2): 3615, 3421, 2977,
2929, 1684, 1624, 1503, 1449, 1368, 1322, 1260, 1160, 1119, 1059;
LRMS (EI): m/z 332 ([MꢀC2H6]þ, 18), 276 (35), 258 (14); HRMS (EI):
m/z calcd for C16H21NO3F3 [MþꢀC2H6]: 332.1479, found: 332.1474.
4.4.2.3. Synthesis of 10b. To a solution of compound 24b (30 mg,
0.0829 mmol) in dioxane (six drops), 6 M HCl (six drops) was added.
The mixture was stirred at room temperature overnight. The mix-
ture was dried byazeotropic evaporationwith benzene and pumped
to dryness. Compound 10b (25 mg, quantitative) was obtained as
(400 MHz, CDCl3)
d
7.52e7.48 (m, 4H), 7.40 (d, J¼7.0 Hz, 5H), 5.55 (s,
1H), 5.32 (br s, 1H), 4.52 (d, J¼11.3 Hz, 2H), 4.07 (d, J¼11.2 Hz, 2H),
2.14e2.02 (m, 2H), 1.49 (s, 9H), 1.39e1.36 (m, 2H), 1.29e1.27 (m,
4H), 0.86 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 154.3, 137.3,
131.9,129.4,128.4,126.0,125.0,125.0,124.9,123.6,122.9,101.9, 85.8,

R.Y.Y. Ko et al. / Tetrahedron 67 (2011) 2542e2547
2547
4. (a) Chiba, K. Pharmacol. Ther. 2005, 108, 308e319; (b) Baumruker, T.; Billich, A.;
Brinkmann, V. Expert Opin. Invest. Drugs 2007, 16, 283e289; (c) Brinkmann, V.
Br. J. Pharmacol. 2009, 158, 1173e1182.
84.9, 80.3, 73.1, 47.9, 39.2, 38.9, 38.7, 31.4, 28.4, 22.4, 22.2, 22.1, 22.1,
13.9; IR (CH2Cl2): 3683, 3428, 2960, 2934, 2868, 1715, 1673, 1618,
1501, 1456, 1393, 1368, 1328, 1168, 1136, 1078; LRMS (EI): m/z 442
(1), 413 (2), 308 (20), 289(30), 263 (56); HRMS (EI): m/z calcd for
C25H27NF2O4 442.1805, found: 442.1808.
5. (a) Hung, J.-H.; Lu, Y.-S.; Wang, Y.-C.; Ma, Y.-H.; Wang, D.-S.; Kulp, S. K.; Mu-
thusamy, N.; Byrd, J. C.; Cheng, A.-L.; Chen, C.-S. Cancer Res. 2008, 68,
1204e1212; (b) Van Meeteren, L. A.; Brinkmann, V.; Saulnier-Blache, J. S.;
Lynch, K. R.; Moolenaar, W. H. Cancer Lett. 2008, 266, 203e208; (c) Shen, Y.; Cai,
M.; Xia, W.; Liu, J.; Zhang, Q.; Xie, H.; Wang, C.; Wang, X.; Zheng, S. Cancer Lett.
2007, 254, 288e297; (d) Azuma, H.; Takahara, S.; Ichimaru, N.; Wang, J. D.; Itoh,
Y.; Otsuki, Y.; Morimoto, J.; Fukui, R.; Hoshiga, M.; Ishihara, T.; Nonomura, N.;
Suzuki, S.; Okuyama, A.; Katsuoka, Y. Cancer Res. 2002, 62, 1410e1419; (e)
Haruhito, A.; Shiro, T.; Shigeo, H.; Satoru, M.; Yoshinori, O.; Yoji, K. J. Urol. 2003,
169, 2372e2377; (f) Ubai, T.; Azuma, H.; Kotake, Y.; Inamoto, T.; Takahara, K.;
Ito, Y.; Kiyama, S.; Sakamoto, T.; Horie, S.; Muto, S.; Takahara, S.; Otsuki, Y.;
Katsuoka, Y. Anticancer Res. 2007, 27, 75e88.
6. (a) Lee, T. K.; Man, K.; Ho, J. W.; Wang, X. H.; Poon, R. T. P.; Xu, Y.; Ng, K. T.; Chu,
A. C.; Sun, C. K.; Ng, I. O.; Sun, H. C.; Tang, Z. Y.; Xu, R.; Fan, S. T. Clin. Cancer Res.
2005, 11, 8458e8466; (b) Ho, J. W. Y.; Man, K.; Sun, C. K.; Lee, T. K.; Poon, R. T. P.;
Fan, S. T. Mol. Cancer Ther. 2005, 4, 1430e1438; (c) Lee, T. K.; Man, K.; Ho, J. W.;
Sun, C. K.; Ng, K. T.; Wang, X. H.; Wong, Y. C.; Ng, I. O.; Xu, R.; Fan, S. T. Carci-
nogenesis 2004, 25, 2397e2405; (d) Lee, T. K.; Man, K.; Ho, J. W.; Wang, X. H.;
Poon, R. T.; Sun, C. K.; Ng, K. T.; Ng, I. O.; Xu, R.; Fan, S. T. Carcinogenesis 2005, 26,
681e687.
4.4.4.2. Synthesis of 24d. To a solution of compound 11d (50 mg,
0.101 mmol) in EtOAc (1.5 mL), Pd/C (16 mg, 0.0101 mmol) was
added and the reaction mixture was stirred at room temperature
overnight under a H2 atmosphere. The mixture was then filtered
using a Celite pad and washed with EtOAc (5ꢂ10 mL). The combined
organic layers were concentrated in vacuo. The residue was purified
by flash chromatography using 10% EtOAc in hexane to afford 24d
(34 mg, 80% yield) as a white solid. Rf (20% EtOAc in hexane) 0.27; 1H
NMR (300 MHz, CDCl3)
d
7.37 (d, J¼8.2 Hz, 2H), 7.22 (d, J¼8.1 Hz,
2H), 5.07 (br s, 1H), 3.87 (dd, J¼11.4, 5.9 Hz, 2H), 3.64 (dd, J¼11.4,
6.4 Hz, 2H), 3.48 (br s, 2H), 3.67e2.61 (m, 2H), 2.16e2.00 (m, 2H),
1.92e1.87 (m, 2H), 1.45 (s, 9H), 1.43e1.37 (m, 4H), 0.86 (t, J¼6.8 Hz,
7. (a) Zhou, C.; Ling, M.-T.; Lee, TK.-W.; Man, K.; Wang, X.; Wong, Y.-C. Cancer Lett.
2006, 233, 36e47; (b) Chua, C.-W.; Chiu, Y.-T.; Yuen, H.-F.; Chan, K.-W.; Man, K.;
Wang, X.; Ling, M.-T.; Wong, Y.-C. Clin. Cancer Res. 2009, 15, 4322e4335;
(c) Chua, C.-W.; Lee, DT.-W.; Ling, M.-T.; Zhou, C.; Man, K.; Ho, J.; Chan, F. L.;
Wang, X.; Wong, Y.-C. Int. J. Cancer 2005, 117, 1039e1048.
3H); 13C NMR (75 MHz, CDCl3)
d 156.4, 143.3, 135.4, 128.3, 125.3,
125.2, 125.1, 123.2, 80.3, 66.5, 59.3, 39.4, 39.1, 38.7, 34.9; IR (CH2Cl2):
3697, 3602, 3421, 2964, 2929, 2855, 1696, 1507, 1167; LRMS (EI): m/z
384 (8), 328 (10), 310 (12), 267 (12), 211 (21); HRMS (EI): m/z calcd
for C21H32O3NF2 384.4887, found: 384.4883.
ꢀ
ꢀ
ꢀ
8. Begue, J. P.; Bonnet-Delpon, D. Chimie Bioorganique et Medicinale du Fluor; EDP
Science/CNRS: Paris, 2005.
9. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320e330.
4.4.4.3. Synthesis of 10d. To a solution of compound 24d
(34 mg, 0.0819 mmol) in dioxane (six drops), 6 M HCl (six drops)
was added and the mixture was stirred at room temperature
overnight. The mixture was dried by azeotropic evaporation with
benzene and pumped to dryness. Compound 10d (29 mg, quanti-
tative) was obtained as a white solid. 1H NMR (300 MHz, CDCl3)
10. (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303e319; (b) Kirk, K. L. J.
Fluorine Chem. 2006, 127, 1013e1029.
€
€
11. (a) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-
€
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637e643; (b) Muller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881e1886; (c) Kirk, K. L. Curr. Top. Med. Chem.
2006, 6, 1447e1456.
ꢀ
ꢀ
12. Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992e1012.
13. (a) Durand, P.; Peralba, P.; Sierra, F.; Renaut, P. Synthesis 2000, 505e506;
(b) Kiuchi, M.; Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.;
Mishina, T.; Arita, M.; Nakao, N.; Ohtsuki, M.; Hoshino, Y.; Teshima, K.; Chiba,
K.; Sasaki, S.; Fujita, T. J. Med. Chem. 2000, 43, 2946e2961; (c) Kalita, B.; Barua,
N. C.; Bezbarua, M.; Bez, G. Synlett 2001, 1411e1414; (d) Seidel, G.; Laurich, D.;
d
7.64 (d, J¼8.0 Hz, 2H), 7.55 (d, J¼8.1 Hz, 2H), 3.93 (s, 4H),
2.97e2.93 (m, 2H), 2.37e2.33 (m, 2H), 2.22e2.18 (m, 2H), 1.60e1.52
(m, 6H), 1.10 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 142.9,
128.1, 125.0, 108.6, 61.1, 60.7, 38.5, 33.1, 31.1, 28.5, 22.1, 12.8; IR
(CH2Cl2): 3239, 3047, 2872, 2761, 1682, 1611, 1522, 1168,1057; LRMS
(FAB): m/z 316 [MþꢀHCl]; HRMS (FAB): m/z calcd for C17H28NO2F2
316.2084, found: 316.2088.
€
Furstner, A. J. Org. Chem. 2004, 69, 3950e3952; (e) Balasubramaniam, S.; An-
namalai, S.; Aidhen, I. S. Synlett 2007, 2841e2846.
14. (a) Kiuchi, M.; Adachi, K.; Kohara, T.; Teshima, K.; Masubuchi, Y.; Mishina, T.;
Fujita, T. Bioorg. Med. Chem. Lett. 1998, 8, 101e106; (b) Hinterding, K.; Albert, R.;
Cottens, S. Tetrahedron Lett. 2002, 43, 8095e8097; (c) Hinterding, K.; Cottens,
S.; Albert, R.; Zecri, F.; Buehlmayer, P.; Spanka, C.; Brinkmann, V.; Nussbaumer,
P.; Ettmayer, P.; Hoegenauer, K.; Gray, N.; Pan, S. Synthesis 2003, 1667e1670; (d)
Hale, J. J.; Yan, L.; Neway, W. E.; Hajdu, R.; Bergstrom, J. D.; Milligan, J. A.; Shei,
G.-J.; Chrebet, G. L.; Thornton, R. A.; Card, D.; Rosenbach, M.; Hughrosen;
Mandala, S. Bioorg. Med. Chem. 2004, 12, 4803e4807; (e) Kiuchi, M.; Adachi, K.;
Tomatsu, A.; Chino, M.; Takeda, S.; Tanaka, Y.; Maeda, Y.; Sato, N.; Mitsutomi,
N.; Sugahara, K.; Chiba, K. Bioorg. Med. Chem. 2005, 13, 425e432; (f) Clemens, J.
J.; Davis, M. D.; Lynch, K. R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2005, 15,
3568e3572; (g) Foss, F. W., Jr.; Clemens, J. J.; Davis, M. D.; Snyder, A. H.; Zigler,
M. A.; Lynch, K. R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2005, 15,
4470e4474; (h) Sun, C.; Bittman, R. J. Org. Chem. 2006, 71, 2200e2202; (i)
Nakamura, T.; Tsuji, T.; Iio, Y.; Miyazaki, S.; Takemoto, T.; Nishi, T. Tetrahedron:
Asymmetry 2006, 17, 2781e2792; (j) Li, Z.; Bittman, R. J. Org. Chem. 2007, 72,
8376e8382; (k) Nakayama, S.; Uto, Y.; Tanimoto, K.; Okuno, Y.; Sasaki, Y.; Na-
gasawa, H.; Nakata, E.; Arai, K.; Momose, K.; Fujita, T.; Hashimoto, T.; Okamoto,
Y.; Asakawa, Y.; Goto, S.; Hori, H. Bioorg. Med. Chem. 2008, 16, 7705e7714; (l)
Jiang, X.; Gong, B.; Prasad, K.; Repic, O. Org. Process Res. Dev. 2008, 12,
1164e1169; (m) Evindar, G.; Bernier, S. G.; Kavarana, M. J.; Doyle, E.; Lorusso, J.;
Kelley, M. S.; Halley, K.; Hutchings, A.; Wright, A. D.; Saha, A. K.; Hannig, G.;
Morgan, B. A.; Westlin, W. F. Bioorg. Med. Chem. Lett. 2009, 19, 369e372; (n)
Camp, S. M.; Bittman, R.; Chiang, E. T.; Moreno-Vinasco, L.; Mirzapoiazova, T.;
Sammani, S.; Lu, X.; Sun, C.; Harbeck, M.; Roe, M.; Natarajan, V.; Garcia, J. G. N.;
Dudek, S. M. J. Pharmacol. Exp. Ther. 2009, 331, 54e64.
Acknowledgements
The work described in this paper was supported by the Strategic
Research Themes Cancer (2005e2006) and Drugs (2008e2011) of
the University of Hong Kong. We thank Prof. Irene O.L. Ng for
helpful discussions.
Supplementary data
The 1H and 13C NMR spectra of 10a,b,d, 11aed, 12d, 13a, 16, 18
and 24aed are available. Supplementary data associated with this
article can be found in the online version at doi:10.1016/
j.tet.2011.02.028. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
15. For examples of the use of fluorination to increase the metabolic stabilities of
pharmaceutical agents, see Ref. 12.
16. Kim, S.; Lee, H.; Lee, M.; Lee, T. Synthesis 2006, 753e755.
17. York, C.; Surya Prakash, G. K.; Olah, G. A. Tetrahedron 1996, 52, 9e14.
18. Lane, J. W.; Halcomb, R. L. Tetrahedron 2001, 57, 6531e6538.
19. Yoshino, N.; Hamano, K.; Omiya, Y.; Kondo, Y.; Ito, A.; Abe, M. Langmuir 1995, 11,
1. (a) Kluepfel, D.; Bagli, J.; Baker, H.; Charest, M. P.; Kudelski, A. J. Antibiot. 1972,
25, 109e115; (b) Aragozzini, F.; Manachini, P. L.; Craveri, R.; Rindone, B.; Sco-
lastico, C. Tetrahedron 1972, 28, 5493e5498; (c) Fujita, T.; Inoue, K.; Yamamoto,
S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J.
Antibiot. 1994, 47, 208e215.
2. Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.;
Fujita, T. Bioorg. Med. Chem. Lett. 1995, 5, 853e856.
3. Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.;
Aradhye, S.; Burtin, P. Nat. Rev. Drug Discovery 2010, 9, 883e897.
466e469.
20. Segura, M.; Sansone, F.; Casnati, A.; Ungaro, R. Synthesis 2001, 2105e2112.
21. Schmidt, U.; Riedl, B. Synthesis 1993, 815e818.