Syntheses of β- And γ-fluorophenyl cis- and trans-α-methylene-γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2014.07.106

Preparation of a series of cis-γ-fluorophenyl-β-phenyl-α-methylene-γ-butyrolactones is reported via 'allylboration' of fluorobenzaldehydes with (E)-methyl 3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)acrylate. The corresponding trans-γ-

Full text of DOI:10.1016/j.tetlet.2014.07.106

Tetrahedron Letters 55 (2014) 5722–5726
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses of b- and
c
-fluorophenyl cis- and trans-a-methylene-c-
butyrolactones
⇑
P. Veeraraghavan Ramachandran , Hari Narayanan G. Nair, Pravin Gagare
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Preparation of a series of cis-c-fluorophenyl-b-phenyl-a-methylene-c-butyrolactones is reported via
‘allylboration’ of fluorobenzaldehydes with (E)-methyl 3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxa-
Received 6 May 2014
Revised 23 July 2014
Accepted 25 July 2014
Available online 1 August 2014
borolan-2-yl)methyl)acrylate. The corresponding trans- -fluorophenyl lactones were prepared either
c
(i) via ‘allylboration’ using the (Z)-reagents or (ii) via an indium triflate-mediated isomerization of the
cis-products. The difficulty in isomerizing difluorinated cis-products confirms the probable intermediacy
of carbocations. Finally, the synthesis of cis-b-fluorophenyl-c-phenyl-a-methylene-c-butyrolactones was
achieved via an indium-catalyzed allylation–lactonization of aldehydes with (Z)-2-(bromomethyl)-3-
(fluorophenyl)acrylates.
Keywords:
Allylboration
Lactones
Fluorolactones
Indium triflate
Isomerization
Ó 2014 Elsevier Ltd. All rights reserved.
The transcription factor nuclear factor-kappa B (NF-jB) is
R3 R4
O
R1
R2
receiving enormous attention since it regulates genes that influ-
ence the inflammatory response, cell growth, survival, chemoresis-
tance, angiogenesis, invasion and metastasis.1 In light of its diverse
O
O
O
O
effects on multiple tumorigenic processes, NF-
target for inhibition in cancer cells. Naturally occurring com-
pounds, such as parthenolide (Fig. 1), a sesquiterpene -methy-
lene- -butyrolactone (AMGBL) isolated from the herb feverfew
have been shown to inhibit NF-
B.2 The AMGBL framework is pres-
jB is an attractive
Parthenolide
AMGBL
Figure 1. Bio-active AMGBLs.
a
c
j
O
110 o
24 h
C
O
O
p-TSA
ent in a large number of natural products and possesses a variety of
biological properties.3
rt, 8 h
O
R'
OMe
O
cat. In(OTf)3
rt, 6 h
O
O
+
We had recently reported organoborane-mediated methodolo-
gies to construct a variety of AMGBL in a stereospecific manner
(Scheme 1)4 providing a unique opportunity to study their activity
Ph
H
cat. Yb(OTf)3
rt, 36 h
B
Ph
R'
Ph
cis-AMGBL
R'
O
trans-AMGBL
against various diseases related to NF-
cers. These processes were exploited to tailor a series of
lene- -butyrolactones and conduct structure activity
j
B, including various can-
Scheme 1. Preparation of cis- and trans-AMGBL
a-methy-
c
a
relationship (SAR) on growth suppression of three human pancre-
atic cancer cell lines (Panc-1, MIA PaCa-2, and BxPc-3). This sys-
tematic study established a discernible relationship between the
substitution pattern of AMGBL and their anti-proliferative activity
AMGBLs using our aforementioned protocols for examining their
bio-activity. Also, we were interested in probing the effect of
fluorine atoms during the isomerization for the preparation of
trans-b,c-diaryl AMGBLs. The results are presented herein.
and revealed that b,c-diaryl-AMGBLs, particularly those with a
We began our synthesis with the preparation of (E)-methyl
3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-
acrylate (1) as reported by us earlier via the Baylis–Hillman
reaction or vinylalumination of benzaldehyde (Scheme 2).4a
‘Allylborations’ of o-, m-, and p-fluorobenzaldehydes (2a, 2b, and
2c, respectively) with 1 were carried out in refluxing toluene,
when the reaction was complete within 40 h. Lactonization to the
trans-relationship exhibited a higher potency than parthenolide.5
In view of the success of fluoroorganic molecules in medicinal
chemistry6 we were interested in the preparation of fluoroaryl
⇑
Corresponding author.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
http://dx.doi.org/10.1016/j.tetlet.2014.07.106
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

P. V. Ramachandran et al. / Tetrahedron Letters 55 (2014) 5722–5726
5723
O
corresponding AMGBL was carried out with the intermediate
cis-product by exchanging the solvent with dichloromethane,
followed by the addition of p-toluenesulfonic acid (p-TSA) and
warming to 40 °C. The lactonization was complete within 5 h
(TLC) and workup provided the fluorinated cis lactones 3a–c in
83–85% overall yields (Scheme 2) (Table 1).
The reaction was then extended to difluorobenzaldehydes.
Thus, 2,3- (2d), 2,4- (2e), 2,5- (2f), 2,6- (2g), 3,4- (2h), and 3,5-
(2i)—difluorobenzaldehydes were ‘allylborated’ with 1 and lacton-
ized in the presence of p-TSA. Upon workup as above, all of the
reactions, except the reaction of 2g provided the corresponding
CuCl, LiCl
KOAc, DMF
1. a) DIBALH/NMO
b) PhCHO
MeO
O
OAc O
Ph
OMe
O
Ph
OMe
B
2. AcCl, Pyridine
O
O
O
O
O
1
B
B
O
MeO
Ar
O
O
O
B
p-TSA
O
ArCHO
B
O
O
O
CO2Me
O
CH2Cl2
Toluene
reflux
Ar
Ph
40 oC, 5 h
Ar
3a-j, >99% cis
60-95% yield
Ph
Ph
cis-
c-difluorophenyl b-phenyl AMGBLs (3) in 76–87% yields
Scheme 2. Vinylalumination of benzaldehyde and formation of
phenyl cis-AMGBL.
c-fluorophenyl b-
(Table 1). 2,6-Difluorobenzaldehyde provided the lactone in only
Table 1
Preparation of cis-b-phenyl-
c
-fluorophenyl-
a
-methylene-
c
-lactones via ‘allylboration’a
Entry
Aldehyde
Structure
F
AMGBL
Structure
Yieldb
%
drc
2
3
cis
trans
O
CHO
F
O
1
2
2a
2b
3a
3b
85
84
>99
<1
Ph
O
F
CHO
O
>99
>99
>99
>99
<1
<1
<1
<1
F
Ph
O
CHO
O
O
F
F
3
4
5
2c
2d
2e
3c
3d
3e
83
82
85
Ph
O
F
F
F
CHO
F
F
Ph
O
F
CHO
O
O
F
Ph
F
F
CHO
F
O
6
2f
3f
87
>99
<1
Ph
O
F
F
F
F
CHO
O
F
7
8
2g
2h
3g
3h
60
95
>99
>99
<1
<1
F
Ph
O
F
F
CHO
O
F
F
Ph
O
F
CHO
O
O
F
9
2i
2j
3i
3j
76
90
>99
>99
<1
<1
F
Ph
O
F
F
F
CHO
10
F
Ph
F
F
F
a
b
c
Reactions were carried out in toluene at 110 °C for 40 h, followed by treatment with p-TSA in CH2Cl2 at rt for 5 h. See experimental in supplementary information.
Isolated yield after chromatography.
Determined by 1H NMR of the crude reaction mixture.

5724
P. V. Ramachandran et al. / Tetrahedron Letters 55 (2014) 5722–5726
O
60% yield. 2,3,5-Trifluorobenzaldehyde (2j) was also included in
the series and the corresponding cis-lactone 3j was obtained in
90% yield.
Having achieved the preparation of the cis-lactones, we
progressed toward the preparation of the trans-lactones. The prep-
O
O
1.
O
O
Ph
B
O
O
O
+
O
Ar
Toluene, reflux
2. TfOH (1 eq.)
Ph
Ar
Ar
Ph
aration of trans-b,c-disubstituted a-methylene-c-butyrolactones
2
3
5
3a, 5a
Ar = 2-F-Ph,
Ar = 3-F-Ph,
Ar = 4-F-Ph,
dr = 3 : 17
dr = 3 : 17
dr = 3 : 17
with the cis-product forming E-reagent 1 via isomerization of the
reaction intermediate with catalytic amounts of Lewis acids, such
as indium triflate has been described by us earlier.4b The reaction
is believed to proceed via a carbocation mechanism, supported
by the difficulty in isomerization of the intermediates derived from
the reaction of benzaldehydes substituted with electron-with-
drawing groups. In such cases, the isomerization was forced by
using a strong Bronsted acid, such as trifluoromethanesulfonic
acid.4c We were concerned about the isomerization of the interme-
diates derived from ring-fluorinated benzaldehydes since the
introduction of fluorine atoms on the aromatic ring could destabi-
lize the carbocation intermediate (Scheme 3).
3b 5b
,
3c 5c
,
Scheme 4. ‘Allylboration’–iosmerization–lactonization.
Table 2
Preparation of c-fluorophenyl b-phenyl trans-a-methylene-c-lactones via ‘allylbora-
tion’–isomerizationa
Entry
Aldehyde
AMGBL
Yieldb
%
drc
2
Structure
5
Structure
trans cis
F
O
CHO
Indeed, attempted isomerization of the intermediate formed
from the reaction of 1 and 2a using the typical 0.2 equiv of indium
triflate resulted in partial isomerization producing a 3:1 mixture of
the lactone favoring the cis-isomer. Increasing the amount of the
Lewis acid resulted in a low yield of the product lactone. Addition
of a molar equiv of trifluoromethanesulfonic acid to the reaction
mixture after the initial ‘allylboration’ (Scheme 4) resulted in the
formation of a 17:3 mixture of the isomeric lactones favoring the
trans-isomer. Fortunately, the diastereomers could be readily sep-
arated by silica gel column chromatography (Table 2). Similar
results were obtained with fluorobenzaldehydes 2b and 2c as well.
However, the isomerization became increasingly difficult with the
increase in the number of fluorine atoms on the aromatic ring. For
all of the difluorobenzaldehydes, only 30% of reaction intermedi-
ates were converted to the trans-isomer with 1 equiv of trifluoro-
methanesulfonic acid. Replacing toluene with more polar
solvents, such as DMF and DMSO did not alter the result
appreciably.
F
O
1
2
2a
5a
85
85
85
85
15
15
Ph
O
F
F
CHO
CHO
O
2b
2c
5b
5c
F
F
Ph
O
O
3
86
85
15
Ph
a
Reactions were carried out in toluene at 110 °C for 40 h, followed by treatment
with triflic acid in CH2Cl2 at rt for 3 h. See experimental in supplementary information.
b
Isolated yield after chromatography.
Determined by 1H NMR of the crude reaction mixture.
c
We then resorted to the direct synthesis of trans-c-fluorophenyl
O
O
O
COOEt
Ph
Ph
O
B
b-phenyl AMGBLs using the isomer of the reagent, (Z)-ethyl 3-phe-
nyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)acry-
late (4).4a The reagent 4 was prepared via the iodomethylboronate-
mediated homologation7 of the vinylaluminum reagent derived
from the corresponding propiolate (Scheme 5).8 Treatment of this
reagent with all of the mono-, di- and trifluorinated benzaldehydes
(2a–j), in the presence of indium triflate, provided trans-lactones
Ar
1. DIBALH/NMO
O
O
O
In(OTf)3, 10 h, rt
81-99%
I
O
O
2.
Ar
Ph
B
4
5a j
-
>99% trans
81-99% yield
Scheme 5. Synthesis of
c
-fluorophenyl, b-phenyl-trans-AMGBL.
O
B
In(OTf)3
CO2Me
O
B
O
O
In(OTf)3
O
O
Ph
O
F
O
O
F
+
O
O
Ph
B
CO2Me
OMe
F
O
In(OTf)3
Ph
Ph
F
F
F
O
O
O
B
O
Me
+
O
O
Me
O
Ph
O
O
B
O
Ph
(TfO)3In
Scheme 3. Proposed mechanism.

P. V. Ramachandran et al. / Tetrahedron Letters 55 (2014) 5722–5726
5725
Table 3
O
OH
O
O
O
DABCO
OMe
rt, 6 h
HBr in AcOH
rt, 1 h
Preparation
of
trans-b-phenyl-
c
-fluorophenyl-
a
-methylene-
c
-lactones
via
Ar
OMe
‘allylboration’a
Ar
OMe
Ar
H
Br
Entry
Aldehyde
Structure
F
AMGBL
Yieldb
%
drc
trans cis
2a: Ar = 2-F-Ph
7a-b, d, i, k
6a-b, d, i, k
2b
: Ar = 3-F-Ph
2
5
Structure
PhCHO
In
THF:H2O
rt, 3h
2d: Ar = 2,3-F2-Ph
2i: Ar = 3,5-F2-Ph
O
O
O
2k
: Ar = 4,CF3-Ph
Ph
Ar
OH
CHO
F
O
p-TSA
CH2Cl2, rt, 12 h
85-91%
O
1
2
2a
2b
5a
94
96
>99
>99
<1
<1
OMe
Ar
Ph
9a-b, d, i, k
Ph
O
8a-b, d, i, k
F
CHO
O
5b
5c
5d
5e
Scheme 6. Synthesis of b-fluorophenyl c-phenyl cis-AMGBL.
F
Ph
O
CHO
Table 4
O
O
Preparation of cis-b-fluorophenyl-
c
-phenyl-
a
-methylene-
AMGBL
Structure
c-lactones
F
F
3
4
5
2c
2d
2e
95
97
93
>99
>99
>99
<1
<1
<1
Entry
Aldehyde
Structure
F
Yielda
%
Ph
O
F
F
2
9
F
F
F
CHO
CHO
F
F
O
O
O
CHO
1
2
3
2a
9a
9b
9d
9i
89
91
90
89
O
O
O
Ph
O
Ph
Ph
Ph
F
CHO
F
F
O
O
2b
2d
F
Ph
F
F
F
F
F
F
CHO
CHO
CHO
F
O
6
2f
5f
98
>99
<1
Ph
O
F
F
F
O
O
F
F
4
5
2i
O
O
CHO
F
O
F
F
Ph
Ph
F
7
8
2g
2h
5g
5h
81
91
>99
>99
<1
<1
CHO
Ph
O
CF3
2k
9k
85
F3C
F
F
CHO
O
F
F
a
Isolated yield of pure cis-diastereomer after chromatography from 8.
Ph
O
Unfortunately, the synthesis of the latter AMGBLs demands the con-
struction of the corresponding fluorophenyl-substituted reagent 1
for each fluoro-analog. To expedite their synthesis, we explored a
simpler route. Among the various approaches for the synthesis of
AMGBL’s,3,9 a common approach is the allylation of aldehydes
using an in situ generated allylindium, followed by an acid cata-
lyzed lactonization.10 Accordingly, the allyl alcohol (6) from the
Baylis–Hillman reaction of each of the fluorophenyl aldehydes
and methyl acrylate was brominated using HBr in acetic acid to
form 7 in 89–98% yields. The indium-mediated Barbier-type
F
CHO
CHO
O
O
F
9
2i
2j
5i
5j
99
98
>99
>99
<1
<1
F
F
Ph
O
F
F
10
F
Ph
F
F
F
reaction of 7 with benzaldehyde provided the necessary cis-
a-
methylene- -hydroxyester 8 exclusively, which was lactonized in
85–91% yields in the presence of catalytic p-TSA (Scheme 6)
(Table 4). Thus, we could achieve the synthesis of the required
c
a
Reactions were carried out in toluene at rt for 10 h, followed by treatment with
In(OTf)3 in toluene at rt. See experimental in supplementary information.
b
Isolated yield after chromatography.
c
Determined by 1H NMR of the crude reaction mixture.
cis-b-fluorophenyl-
In conclusion, we have described the syntheses of a series of
fluoro-analogs of cis- and trans- -fluorophenyl b-phenyl -methy-
lene-
-butyrolactones.11 While the cis-isomers could be readily
c-phenyl AMGBLs.
c
a
(Scheme 5) in 91–98% yields within 10 h at room temperature (rt)
(Table 3). Again, 2,6-difluorobenzaldehyde provided the lactone in
a relatively lower (81%) yield (Table 3, entry 7).
It must be noted that the isomerization of the product from
reagent 1 occurs at 110 °C over 40 h, whereas no isomerization
was observed with reagent 4 at rt over 10 h.
c
synthesized with the E-reagent, the trans-isomers were synthe-
sized either with the Z-reagent or via isomerization. However,
the presence of fluorine atoms on the benzene ring destabilizes
the intermediate carbocations, resulting in only partial isomeriza-
tion. Finally, the synthesis of a series of cis-b-fluorophenyl-
c-
Having successfully synthesized both cis- and trans-
phenyl-b-phenyl AMGBLs, we decided to include b-fluorophenyl-
-phenyl AMGBLs also in the structure–activity relationship study.
c
-fluoro-
phenyl- -methylene- -butyrolactones was achieved via a Barbier
type reaction. Examination of the biological properties of these
novel fluorolactones is in progress.
a
c
c

5726
P. V. Ramachandran et al. / Tetrahedron Letters 55 (2014) 5722–5726
10. Kim, K. H.; Lee, H. S.; Kim, S. H.; Lee, K. Y.; Lee, J.-E.; Kim, J. N. Bull. Korean Chem.
Acknowledgments
Soc. 2009, 30, 1012–1020.
11. General procedure for the synthesis of cis-b-phenyl-c-(fluorophenyl)-a-methylene-
We thank the Herbert C. Brown Center for Borane Research for
financial assistance of this project.
c-butyrolactone (3). The fluorinated benzaldehyde (5 mmol) was added to a
solution of the substituted E-allylboronate 1 (1.81 g, 6 mmol), prepared as
described earlier,4c in toluene and refluxed at 110 °C for 40 h. Upon completion
of the reaction (TLC), the solvent was evaporated under vacuum and the crude
mass was dissolved in CH2Cl2. p-TSA (20%) was added and refluxed at 40 °C for
5 h followed by the addition of 30% aq H2O2 (2 mL), methanol (2 mL) and pH 7
buffer and stirred overnight. The crude product was extracted with Et2O and
the combined organic layer was dried over anhydrous Na2SO4, concentrated,
and purified by silica gel chromatography (hexanes/ethyl acetate :: 95:5).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
07.106.
General procedure for the synthesis of trans-b-phenyl-c-(fluorophenyl)-a-
methylene- -butyrolactone (5): The fluorinated benzaldehyde (5 mmol) was
c
added to a solution of the substituted Z-allylboronate, prepared as described
before4a (1.9 g, 6 mmol) in toluene, followed by indium triflate (0.67 g,
0.12 mmol) and stirred at rt for 10 h. Upon completion of the reaction (TLC),
the mixture was washed with water, extracted with Et2O, the combined
organics was dried over anhydrous Na2SO4, concentrated, and purified by flash
column chromatography (silica gel, hexanes/ethyl acetate: 95:5) to obtain the
product 5.
General procedure for the preparation of methyl 3-(fluorophenyl)-4-hydroxy-2-
methylene-4-phenylbutanoate (8). Benzaldehyde (3.0 mmol) was added to the
solution of (Z)-methyl 2-(bromomethyl)-3-(fluorophenyl)acrylate (7)10
(3 mmol) in THF (4.5 mL) and water (3 mL). In (3.6 mmol) was added to this
solution. The reaction mixture was stirred at rt for 3 h. Upon completion (TLC),
water (20 mL) was added to the reaction mixture and extracted using ethyl
acetate (3 Â 30 mL). The combined organic layer was washed with brine, dried
over anhyd Na2SO4, concentrated and purified by flash column chromatogra-
phy to obtain 8.
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c-phenyl-a-methy-
lene- -butyrolactone (9). p-Toluenesulfonic acid was (0.1 mmol) was added to a
c
solution of 8 and stirred the content at rt for 12 h. Upon completion (TLC),
water (10 mL) was added to the reaction mixture and extracted using
dichloromethane (2 Â 20 mL). The combined organics was washed with brine,
dried over anhydrous Na2SO4, concentrated and purified by flash column
chromatography to obtain 9.
8. Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy, M. V. R. J. Org. Chem.
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