Formal synthesis of (-)-oleocanthal by means of a SmI2-promoted intramolecular coupling of bromoalkyne with α,β-unsaturated ester

Article abstract of DOI:10.1016/j.tetlet.2012.04.085

A novel approach to the synthesis of (-)-oleocanthal starting from d-ribose, in which a SmI₂-promoted intramolecular coupling of bromoalkyne with α,β-unsaturated ester is a key step, has been developed.

Full text of DOI:10.1016/j.tetlet.2012.04.085

Tetrahedron Letters 53 (2012) 3342–3345
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Formal synthesis of (ꢀ)-oleocanthal by means of a SmI -promoted
2
intramolecular coupling of bromoalkyne with a,b-unsaturated ester
⇑
Kazunori Takahashi, Hiroshi Morita, Toshio Honda
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of (ꢀ)-oleocanthal starting from
2
D-ribose, in which a SmI -promoted
,b-unsaturated ester is a key step, has been developed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 3 March 2012
Revised 14 April 2012
Accepted 18 April 2012
Available online 25 April 2012
intramolecular coupling of bromoalkyne with
a
Keywords:
Oleocanthal
Samarium diiodide
Bromoalkyne–alkene coupling
Formal synthesis
Extra virgin olive oil
(
ꢀ)-Oleocanthal 1, isolated from extra virgin olive oil, is a
CHO
1
naturally occurring minor phenolic secoiridoid. Olive oil has being
consumed for many centuries in Mediterranean countries, and it is
known to reduce the risk of cardiovascular system diseases due to
both its high content of monounsaturated fatty acids and its high
content of anti-oxidative substances (Fig. 1).
CHO
O
O
OH
(
ꢀ)-Oleocanthal 1 shows both a potent NSAID (non-steroidal
Figure 1. Structure of (ꢀ)-oleocanthal.
anti-inflammatory drug) activity by inhibiting COX-1 and COX-2,
similar to ibuprofen, and an anti-oxidant activity. It has also been
2
reported that 1 prevents tau fibrillization of Ab amyloid to provide
novel therapies for neurodegenerative tauopathies such as
Alzheimer’s disease. Therefore, oleocanthal and its derivatives
Br
Br
SmI , HFIP
3
2
X
X
are expected to be important leads and scaffolds for the discovery
and development of drugs to treat inflammatory osteoarthritis and
Alzheimer’s disease. Oleocanthal 1 has received much attention
due to its attractive biological activities and also its unique struc-
tural features, and several synthetic methods have been developed
THF-HMPA
CO2R2
CO R2
R1
R1
2
X = CH2, O, NTs, R , R2 = alkyl
1
Scheme 1. SmI
2
-promoted intramolecular coupling reaction.
4
to date.
Recently, we have established a samarium diiodide-promoted
intramolecular coupling reaction of bromoalkynes with a,b-unsat-
urated esters that provides functionalized five-membered carbocy-
above methodology, and we decided to prepare Smith’s intermedi-
ate (ꢀ)-2 for synthesis of the target compound, because a coupling
product having a functionalized cyclopentane ring system with an
exo-bromomethylene unit seemed to be a structural feature closely
cles and heterocycles with high diastereoselectivities in excellent
5
yields (Scheme 1).
In our continuing work on the synthesis of biologically active
natural products by means of samarium diiodide, we were
interested in the synthesis of oleocanthal 1 by application of the
4a,b
related to Smith’s intermediate (ꢀ)-2.
We first attempted the synthesis of (+)-oleocanthal ent-1, an
antipodal form of the natural product, to investigate whether the
desired coupling could proceed smoothly or not, because we
thought that a precursor for the key coupling reaction could easily
⇑
Corresponding author. Tel./fax: +81 3 5498 5791.
E-mail address: honda@hoshi.ac.jp (T. Honda).
be prepared from a readily available chiral source, 2-deoxy-D-ribose.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.085

K. Takahashi et al. / Tetrahedron Letters 53 (2012) 3342–3345
3343
SmI -promoted
2
O
O
Negishi
O
cyclization
O
O
O
coupling
(
+)-Oleocanthal
ent-1
CO Me
CO Me
CO Me
2
2
Br
2
Br
(
+)-2
(+)-3
(+)-4
OR
OH
RO
HO
HO
CHO
O
OH
5
2-deoxy-D-ribose
Scheme 2. Retrosynthetic route to (+)-oleocanthal ent-1.
Our basic strategy for the synthesis of (+)-oleocanthal ent-1 is out-
lined in Scheme 2. The exo-ethylidene unit existing in Smith’s inter-
mediate will be derived from the corresponding exo-bromoalkene
O
O
CH PPh Br
3
3
O
O
n-BuLi, THF
IBX
(
+)-3 by palladium-catalyzed chemical modification with methyl-
6
CHO
zinc chloride. The functionalized cyclopentane derivative with a
bromoalkene unit will also be constructed by a samarium diio-
dide-promoted intramolecular coupling reaction of bromoalkynes
0 °C, 59%
OH
11
CH CN
3
reflux
12
O
O
P(OMe)2
(
+)-4 with
a
,b-unsaturated esters, obtained from 2-deoxy-
D
-ribose.
O
1. OsO4, NMO
PhB(OH) , CH Cl , rt
Thus, 2-deoxy-D-ribose was converted into acetonide 6, which
N2
O
2
2
2
(
+)-10
on treatment with Wittig reagent 7 furnished exclusively the
E-ester 8 in 74% yield. Swern oxidation of the hydroxy group of 8
afforded the known aldehyde 9.7 The product was then reacted
K2CO3, MeOH, 0 °C
2. NaIO -SiO
4 2
Ph PCHCO Me (7)
6 steps
3
2
total yields 7%
rt, 12% (4 steps)
with the Ohira–Bestmann reagent6 in the presence of K
13
2 3
CO to
afford alkyne derivative (+)-10 in trace, presumably due to its
instability under basic conditions (Scheme 3).
Scheme 4. Alternative synthesis of (+)-10.
Although this approach is still being explored, an alternative
route to (+)-1 in which introduction of the alkynl group is con-
ducted prior to construction of the
a
,b-unsaturated ester group,
Alkyne 10 was brominated with NBS and AgNO
3
in acetone to
was developed (Scheme 4). Wittig reaction of acetonide 6 with
give bromoalkyne 4, which on treatment with samarium diiodide
in THF-HMPA in the presence of hexafluoroisopropanol (HFIP) at
ꢀ10 °C for 1 h afforded the desired cyclopentane derivative 3 as a
mixture of diastereoisomers in 70% yield (Scheme 5).
Since the key intramolecular coupling of (+)-4 took place
successfully under the reaction conditions mentioned above, we
decided to start the synthesis of (ꢀ)-oleocanthal 1 along this strat-
egy. The novel synthetic route for 1 is illustrated in Scheme 6.
8
unstable ylide in THF provided the alkene 11 in 59% yield. The al-
9
kene 11 was oxidized with o-iodoxybenzoic acid (IBX) to the cor-
responding aldehyde 12, which was then treated with Ohira–
Bestmann reagent to afford alkyne derivative 13.
4
The resulting alkyne 13 was treated with OsO in the presence
of phenylboronic acid,10 followed by NaIO
on silica gel
11a
in the
4
presence of stable ylide 7,1 to afford an eneyne intermediate
1b
(
1
(
+)-10 in 12% over four steps. Attempted transformation of alcohol
1 into the eneyne derivative (+)-10 gave unsatisfactory results
six steps, total yield of 7%), prompting us to find another route.
D-Ribose was converted into acetonide 14 in 78% yield according
to the known procedure. Construction of the a,b-unsaturated es-
ter was accomplished by successive treatments of 14 with (i) IBX
and (ii) Wittig reaction of the resulting aldehyde, to give an unsatu-
rated ester derivative 15 in 89% yield over two steps. The ester 15
1
2
Although alkyne 10 was obtained only in a small amount, a key
coupling was attempted as follows.
OH
O
O
O
O
Ph3PCHCO2Me (7) O
benzoic acid
HO
DMP, PPTS
acetone
OH
O
OH THF, rt, 74%
OH
0
°C, 72%
2
-Deoxy-D-ribose
CO2Me
6
8
O
O
P(OMe)2
O
O
CHO
9
(
COCl) , DMSO
2
O
4 steps
total yields 3%
O
NEt , CH Cl
N2
3
2
2
-
20 to 0 °C, 71%
K2CO3, MeOH
°C to rt, 7%
0
CO Me
CO Me
2
2
(+)-10
Scheme 3. Preparation of alkyne derivative (+)-10.

3
344
K. Takahashi et al. / Tetrahedron Letters 53 (2012) 3342–3345
NBS
6
a
O
O
O
O
AgNO
CO Me SmI2, HMPA
5
3
2
acetone
HFIP, THF
(
+)-10
CO Me
2
3
a
rt, 74%
-10 °C, 70%
Br
Br
(+)-4
(+)-3
(5S:5R = 19:81)
Scheme 5. Attempted coupling reaction of (+)-10.
DMP, acetone
MeO C
HClO
then
4
HO
2
HO
IBX, CH
OMe
reflux
CN
O
3
O
Mg
O
OMe
OH
MeOH
MeOH
7
8%
-20 °C
89%
O
O
then
Ph PCHCO Me (
O
O
HO
OH
7)
3
2
0
°C to rt, 89%
D-ribose
1
4
15
O
O
P(OMe)2
O
N2
O
CO Me
CO Me
2
2
O
O
+
CHO
K CO , 0 °C
HO
CO
2
Me
2
3
1
6
(-)-10 (21%)
17 (17%)
Scheme 6. Preparation of alkyne derivative (ꢀ)-10.
1
3a
was treated with Mg powder in MeOH at ꢀ20 °C
to give a b,
SmI
2
-unsaturated ester 16, reported by Gallos,13b in 89% yield. Treat-
NBS
HMPA
HFIP
THF
c
AgNO
O
O
O
O
3
CO Me
2
ment of 16 with Ohira–Bestmann reagent resulted in simultaneous
formation of an alkyne group and double bond isomerization, pro-
viding the desired alkyne intermediate (ꢀ)-10 in 21% yield. Again,
the low yield in the formation of 10 might be due to its instability
under basic conditions, since the elimination product 17 was
obtained as the major side-product in 17% yield together with a
number of structurally unidentified decomposed products.
acetone
(-)-10
CO Me
2
rt
-10 °C
72%
Br
(-)-4
Br
9
4%
(
-)-3 (5S:5R = 81:19)
MeZnCl
O
ref. 4a,b
Pd(OAc) , PPh
2
3
O
CO Me
(-)-oleocanthal
Bromination of the resulting alkyne (ꢀ)-10 with NBS and AgNO
3
2
14
toluene, 120 °C
1%
in acetone afforded bromoalkyne (ꢀ)-4 in 94% yield. Treatment
of bromoalkyne (ꢀ)-4 with samarium diiodide in THF-HMPA in
the presence of HFIP at ꢀ10 °C for 1 h provided vinyl bromide
5
(
-)-2
1
5
(
ꢀ)-3 with an (E)-configuration, in a ratio of trans:cis = 81:19,
Scheme 7. Formal synthesis of (ꢀ)-oleocanthal 1.
in 72% yield. The stereochemistry of the product was unambigu-
ously determined on the basis of 2D NMR spectroscopy and NOE.
The stereoselectivity exhibited in the formation of trans-3 as the
major product can be rationalized by assuming that this cyclization
would proceed via the more sterically and energetically favorable
mediate (ꢀ)-2 in 51% yield (Scheme 7). The observed low yield
probably arose from a decomposition of the acetonide group at
relatively high temperature employed for this conversion.
1
D
8
(A) rather than (B) as depicted in Figure 2.
The specific optical rotation of the bicyclo derivative (ꢀ)-2 {½ ꢁ
a
1
8
D
Finally, palladium-catalyzed coupling reaction of vinyl bromide
ꢀ)-3 with methylzinc chloride in toluene gave the known inter-
ꢀ123.8 (c 0.45, CHCl
3
)} was identical to that reported ½
aꢁ
ꢀ128.4
4
a,b
(
3
(c 0.75, CHCl )] in the literature.
CO Me
H
H
2
Sm
Br
O
O
O
O
O
Br
Br
CO Me
2
H
OMe
O
O
(A)
trans-3
H
O
H
O
CO Me
2
Br
O
H
O
Sm
(
-)-4
O
Br
OMe
B)
cis-3
(
Figure 2. Plausible mechanism for the coupling of (ꢀ)-4.

K. Takahashi et al. / Tetrahedron Letters 53 (2012) 3342–3345
3345
Thus, a formal synthesis of (ꢀ)-oleocanthal 1 was achieved at
this stage; however, some improvement is required to optimize
the reaction sequences.
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(
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ꢀ)-oleocanthal 1 by employing a SmI
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2
2
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This research was supported financially in part by a Grant for
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Ministry of Education, Culture, Sports, Science and Technology of
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2
.
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1
8
14. Selected data for compound (ꢀ)-4: ½
a
ꢁ
ꢀ 49.7 (c 0.83, CHCl
3
); IR (neat) 2989,
D
ꢀ
1 1
1725, 1222 cm
; H NMR (400 MHz, CDCl ) d: 6.96 (1H, dt, J = 15.7, 7.1 Hz),
3
3
.
.
5.97 (1H, dt, J = 15.7, 1.5 Hz), 4.80 (1H, d, J = 5.5 Hz), 4.19 (1H, dt, J = 7.1,
5.5 Hz), 3.74 (3H, s), 2.73–2.56 (2H, m), 1.53 (3H, s), 1.35 (3H, s); 13C NMR
3
(100 MHz, CDCl ) d 166.3, 143.7, 123.4, 110.1, 76.1, 75.8, 69.5, 51.3, 48.2, 33.8,
27.5, 25.1; HRMS (CI) m/z 303 (M+H) Calcd for C12H O Br 303.0231. Found
16 4
4
(a) Smith, A. B., III; Han, Q.; Breslin, P. A. S.; Beauchamp, G. K. Org. Lett. 2005, 7,
303.0242.
1
9
5
075–5078; (b) Smith, A. B., III; Sperry, J. B.; Han, Q. J. Org. Chem. 2007, 72,
15. Selected data for compound (ꢀ)-3: ½
aꢁ
D
ꢀ138.9 (c 0.59, CHCl
3
); IR (neat) 2987,
ꢀ
1
1
6
891–6900; Racemic synthesis of oleocanthal: (c) English, B. J.; Williams, R. M.
1738, 1218 cm
;
H NMR (400 MHz, CDCl ) d: 6.35 (1H, dd, J = 2.3, 1.8 Hz),
3
Tetrahedron Lett. 2009, 50, 2713–2715; Synthetic studies of (±)-oleocanthal: (d)
Kueh, J. T. B.; O’Connor, P. D.; Hügel, H.; Brimble, M. A. ARKIVOC 2009, Vii, 58–
4.91 (1H, dd, J = 5.3, 1.8 Hz), 4.68 (1H, ddd, J = 5.3, 5.3, 2.0 Hz), 3.68 (3H, s),
3.34–3.32 (1H, m), 2.87 (1H, dd, J = 16.6, 4.0 Hz), 2.62 (1H, dd, J = 16.6, 8.5 Hz),
2.29 (1H, ddd, J = 9.0, 4.6, 2.0 Hz), 1.86 (1H, ddd, J = 14.6, 6.8, 5.5 Hz), 1.43 (3H,
7
1.
Takahashi, K.; Honda, T. Org. Lett. 2010, 12, 3026–3029. For recent reviews of
SmI -promoted reaction, see: (a) Soderquist, J. A. Aldrichimica Acta 1991, 24,
5–23; (b) Molander, G. A. Chem. Rev. 1992, 92, 29–68; (c) Molander, G. A. Org.
s), 1.33 (3H, s); 13C NMR (100 MHz, CDCl
) d 172.2, 149.8, 111.7, 105.1, 82.7,
80.2, 51.5, 38.3, 36.7, 34.8, 27.6, 25.8; HRMS (CI) m/z 291 (M+H-CH ) Calcd for
5
.
3
2
3
81
1
11 14 4
C H O Br 291.0055. Found 291.0025.