Concise asymmetric synthesis of (+)-conocarpan and obtusafuran

Article abstract of DOI:10.1055/s-0032-1317704

The asymmetric synthesis of three natural products: (+)-conocarpan, both (+)- and (-)- obtusafuran is disclosed. The highlights of the synthesis are the enantioselective hydrogenation of prochiral ketones via dynamic kinetic resolution to afford chiral alcohols. Intramolecular ring closure via either Sr reaction or metal-catalyzed C-O bond formation led to the construction of the trans-dihydrobenzofuran core. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317704

LETTER
▌189
lCettoerncise Asymmetric Synthesis of (+)-Conocarpan and Obtusafuran
Synthesis of (+)-Conocarpan and Obtusafuran
Cheng-yi Chen,* Mark Weisel
Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Fax +1(732)5945170; E-mail: Cheng_chen@merck.com
Received: 27.08.2012; Accepted after revision: 07.11.2012
to construct a cis-2-aryl-2,3-dihydrobenzofuran ring sys-
tem as a key step with decent enantioselectivity (84% ee).
The intermediate was further elaborated to afford the (–)-
epi-conocarpan (2) which was converted to (+)-conocar-
Abstract: The asymmetric synthesis of three natural products: (+)-
conocarpan, both (+)- and (–)- obtusafuran is disclosed. The high-
lights of the synthesis are the enantioselective hydrogenation of pro-
chiral ketones via dynamic kinetic resolution to afford chiral
alcohols. Intramolecular ring closure via either SNAr reaction or pan (1) upon treatment with base. Given the biological im-
metal-catalyzed C–O bond formation led to the construction of the
trans-dihydrobenzofuran core.
portance and structural uniqueness of these natural
products, we herein wish to report a concise and efficient
Key words: (+)-conocarpan, (+)- and (–)-obtusafuran, dynamic
kinetic resolution, SNAr reaction, metal-catalyzed C–O bond forma-
tion, trans-dihydrobenzofuran, 8,5′-neolignans, 8-aryl-2,3-dihydro-
benzofuran
asymmetric synthesis of both (+)-conocarpan (1) and (+)-
obtusafuran (3).
Me
Me
OH
O
8,5′-Neolignans containing an 8-aryl-2,3-dihydrobenzo-
furan skeleton are the most abundant natural products
found in several families of plants (Figure 1).1 These di-
hydrobenzofuran neolignans displayed a wide array of bi-
ological activities including cytotoxic, antiviral, and
antifungal peroperties.1 (+)-Conocarpan (1), for example,
was first isolated from the wood of Conocarpus erectus2
by Hayashi and Thomson in 1975 and exhibits a diverse
array of biological activities, including insecticidal, anti-
fungal, anti-inflammatory, and antitrypanosomal proper-
ties.3 Another structurally similar neolignan, (+)-
obtusafuran (3), isolated from Dalbergia obtusa,4 also ex-
hibits an array of interesting biological activities ranging
from anticarcenogenic to insect antifeedant.5 These mole-
cules vary in substitution but all share a trans-dihydroben-
zofuran heterocycle as a key structural element. The
diverse biological activities coupled with unique structur-
al features make this class of compounds an attractive
synthetic target. Consequently, a few stereocontrolled
syntheses of 2-aryl-2,3-dihydrobenzofuran derivatives
have been reported.6 Asymmetric syntheses, however, are
less common as only three asymmetric routes have been
described for (+)-conocarpan (1).7 Recently, Clive and
Stoffman correctly established the absolute configuration
of (+)-conocarpan (1) as 2S,3S through their asymmetric
synthesis of the enantiomer, (–)-(2R,3R)-conocarpan. Im-
portantly, this synthetic work led to the correction of the
absolute configuration of a number of other 8,5′-neolig-
nan natural products. Hashimoto et al. reported another
asymmetric synthesis of (+)-conocarpan (1) which was
generated from its epimer (–)-epi-conocarpan (2).8 This
catalytic asymmetric synthesis relied on an enantio- and
diastereoselective intramolecular C–H insertion reaction
(+)-conocarpan (1)
Me
Me
OH
O
(–)-epi-conocarpan (2)
Me
HO
O
MeO
(+)-obtusafuran (3)
HO
OMe
OH
HO
O
MeO
lawsonicin (4)
Figure 1 Selected examples of 8,5′-neolignans
We wish to devise a common strategy for the efficient
construction of the trans-configured dihydrobenzofuran
core in an enantioselective manner such that it can be ap-
plied to the synthesis of (+)-conocarpan (1), (+)-obtusafu-
ran (3), and their structural analogues. As shown in
Scheme 1, we envisioned that the trans-dihydrobenzofu-
ran core 5 could be prepared via an intramolecular C–O
bond formation from the corresponding ortho-halo carbi-
nol 6 either via a metal-catalyzed intramolecular C–O
bond formation (X = Br) or a simple SNAr reaction (X =
F). The two stereocenters in carbinol 6 could in turn be es-
tablished from the enantioselective reduction of ketone
via hydrogenation under dynamic kinetic resolution
(DKR)9 conditions. We have previously applied the con-
cept of using dynamic kinetic resolution to the efficient
synthesis of a potent CB-1 inverse agonist, taranabant,
where an acyclic ketone bearing an α-substituent group
was reduced in an enantioselective manner using
RuCl2[(R)-xylbinap][(R)-diapen] catalyst in the presence
SYNLETT 2013, 24, 0189–0192
Advanced online publication: 21.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317704; Art ID: ST-2012-R0717-L
© Georg Thieme Verlag Stuttgart · New York

190
C.-y. Chen, M. Weisel
LETTER
of KOt-Bu.10 A similar reaction was previously reported asymmetric hydrogenation was initially carried out in iso-
by us as a useful methodology for the establishment of propanol at 3.1 bar of hydrogen employing 1 mol% of
two consecutive chiral carbinol centers from prochiral ke- RuCl2[(S)-dm-segphos][(S)-diapen]13 as the chiral cata-
tones.11 The application of reactions based on dynamic ki- lyst and KOt-Bu as a base to facilitate epimerization of the
netic resolution to the synthesis of natural products, α-carbon center. The reaction, however, afforded a 1:1
however, has not been widely described.12 Herein, we mixture of two diastereomers (98.4% ee assayed for the
wish to demonstrate that this powerful synthetic method desired diastereoisomer 13). Apparently, the catalyst was
could be applied in the synthesis of two chosen targets, so effective for the asymmetric hydrogenation such that at
(+)-conocarpan and (+)-obtusafuran. Moreover, it is our high catalyst loading (1 mol%) no dynamic kinetic resolu-
hope that the methodology we developed for the synthesis tion was occurring. Lowering the catalyst to 0.1 mol% re-
of these two natural products can be readily extended to stored the dynamic kinetic resolution, giving the desired
the other 8,5′-neolignans with similar structural motifs.
diastereomer carbinol 13 in a nearly perfect selectivity
(99.1% ee, >50:1 dr) and excellent yield (95%). The intra-
molecular ring closure of 13 to form the trans-dihydro-
benzofuran ring via a SNAr reaction using KOt-Bu as base
in dioxane also went smoothly to afford trans-dihydro-
benzofuran 14 quantitatively. The propenyl moiety was
next installed in the 5-position of the phenyl ring using a
Suzuki coupling protocol to afford conocarpan methyl
ether 15 in 81% yield. Demethylation of the racemic
methyl ether to carocarpan was reported to proceed in
92% yield using excess Ph2PLi.14 We, however, were un-
able to achieve this efficiency as the protocol afforded
(+)-conocarpan (1) in only 35% yield. Attempts to facili-
tate demethylation of 15 using BBr3 completely decom-
posed the substrate. An alternative aiming for higher
efficiency was thus devised to carry out demethylation
and subsequent Suzuki coupling. We found that demeth-
ylation of methyl ether 14 using BBr3 in dichloromethane
afforded bromophenol 16 in 82% yield. Finally, the Suzu-
ki coupling reaction of bromophenol 16 with (E)-propenyl
boronic acid led to the natural product, (+)-conocarpan (1)
in 84% yield. The synthetic (+)-conocarpan (1) matches
with all reported characterization data of the isolated nat-
ural product.8
intramolecular
C–O bond
formation
Me
Me
Ar
Ar
R
R
OH
O
X
6
5
asymmetric
hydrogenation
2,3-dihydrobenzofuran
DKR
Me
methylation
arylation
Ar
OH
R
R
O
O
X
X
8
7
Scheme 1 Synthetic strategy for trans-dihydrobenzofuran cores
We chose (+)-conocarpan as our first synthetic target to
validate our strategy and planned to install the propenyl
group at a later stage of the synthesis via Suzuki coupling
with an aryl bromide species. The synthesis for (+)-cono-
carpan (1) began with a commercially available starting
material, 2′-fluoro-5′-bromophenyl acetic acid (9, Scheme
2). The acid was converted into acid chloride 10 followed
by Friedel–Crafts reaction with a slight excess of anisole
to afford ketone 11 in 92% yield over two steps. Methyl-
ation of ketone 11 using methyl iodide in the presence of
sodium hydride gave prochiral ketone 12 in 89% yield af-
ter crystallization.
Having successfully synthesized (+)-conocarpan (1), we
decided to extend the strategy of combining asymmetric
hydrogenation via DKR and intramolecular C–O bond
formation for the effective construction of trans-config-
ured dihydrobenzofurans to the enantioselective total syn-
thesis of another 8,5′-neolignan, (+)-obtusafuran (3). To
the best of our knowledge, no asymmetric synthesis of this
natural product has been reported. As shown in Scheme 4,
the prochiral ketone 20 was prepared in a straightforward
manner. Hence, 2-bromo-4-methoxy-5-hydroxylphenyl
acetic acid15 was converted to the corresponding Weinreb
amide 18 with sequential Weinreb amide formation and
protection of the hydroxyl group using tris(isopropyl)silyl
chloride (TIPSCl). The Weinreb amide was converted
into the ketone in a one-pot procedure via methylation and
phenylation to afford ketone 20 in 85% overall yield.
Br
Br
a
CO2H
COCl
F
F
9
10
92% over 2 steps
b
OMe
c
OMe
Me
Br
Br
89%
O
O
F
F
12
11
As shown in Scheme 5, asymmetric hydrogenation of ke-
tone 20 under identical conditions for 12 but using
RuCl2[(S)-dm-segphos][(S)-diapen] as catalyst afforded
the desired stereoisomer (21, 99.6% ee) exclusively in
92% yield. CuI-catalyzed intramolecular C–O bond for-
mation to construct the dihydrobenzofuran ring employ-
ing 8-hydroxyquinoline as ligand in the presence of
Scheme 2 Preparation of ketone 12. Reagents and conditions: a) cat.
DMF, (COCl)2 (1.2 equiv), CH2Cl2; b) anisole (2 equiv), AlCl3 (1.5
equiv), –5 °C to 23 °C; c) 65% NaH (1.3 equiv), MeI (1.2 equiv),
DMF.
As shown in Scheme 3, ketone 12 was next subjected to
asymmetric hydrogenation under DKR conditions. The
Synlett 2013, 24, 189–192
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (+)-Conocarpan and Obtusafuran
191
OMe
Me
OMe
Me
F
a
Br
Br
95%
OH
F
13, 99.1% ee
O
12
b
100%
Me
Me
Me
Me
Br
c
OMe
OMe
81%
O
O
15
14
d, ref. x
e
35%
82%
Me
Me
Br
c
OH
OH
84%
O
O
1
16
O
OMe
OMe
Ar2
P
H2
N
Cl
Ru
Cl
O
O
Ar =
Me
P
N
Ar2
H2
Me
O
RuCl2[(S)-dm-segphos][(S)-diapen]
Scheme 3 Asymmetric synthesis of (+)-conocarpan (1). Reagents and conditions: a) RuCl2[(S)-dm-segphos][(S)-diapen] (0.15 mol%), KOt-Bu
(20 mol%), H2 (100 psi), 2-PrOH (5 mL/g substrate); b) KOt-Bu (2 equiv), dioxane, 100 °C; c) PdCl2(dppf) (5 mol%), (E)-propenyl boronic
acid (2.0 equiv), toluene–K2CO3 (aq), 80 °C; d) excess Ph2PLi, THF; e) BBr3 (2 equiv), CH2Cl2, –20 °C to 23 °C.
OMe
Me
Me
HO
CO2H
HO
N
TIPSO
MeO
TIPSO
MeO
a
a
Me
MeO
Br
O
O
OH
92%
MeO
Br
Br
Br
17
18
20
21, 99.6% ee
93%
b
b
Me
Me
c
HO
TIPSO
MeO
OMe
N
Me
94%
TIPSO
MeO
TIPSO
O
O
Me
MeO
c, d
3
22
O
O
Br
MeO
Br
20
19
Scheme 5 Synthesis of (+)-obtusafuran (3). Reagents and conditions:
a) RuCl2[(S)-dm-segphos][(S)-diapen] (0.15 mol%), KOt-Bu (20
mol%), H2 (6.9 bar), 2-PrOH (5 mL/g substrate); b) CuI (5 mol%), 8-
hydroxyquinoline (10 mol%), Cs2CO3, toluene, 110 °C; c) n-Bu4NF
(1.5 equiv), THF.
Scheme 4 Preparation of ketone 20. Reagents and conditions: a) Me-
ONHMe, EDC, pyridine, MeCN; b) TIPSCl, imidazole, MeCN; c) Li-
HMDS, MeI; d) PhMgCl.
Cs2CO3 afforded trans-dihydrobenzofuran 22 in 93%
yield. TBAF-mediated desilylation of the TIPS ether 22 at
ambient temperature proceeded smoothly to afford (+)-
obtusafuran (3, 99.1% ee, 94% yield). The chemistry was
repeated using the S-catalyst unequivocally to deliver the
other enantiomer, (–)-obtusafuran (3, >99% ee).
synthesis of two natural products: (+)-conocarpan (1),
(+)- and (–)-obtusafuran (3). The efficiency of the two key
transformations in the syntheses is remarkable and we en-
vision that it could be readily applied to the synthesis of
other 8,5′-neolignans bearing trans-dihydrobenzofuran
cores.
In conclusion, we have demonstrated that the combination
of asymmetric hydrogenation via dynamic kinetic resolu-
tion (DKR) and intramolecular C–O bond formation
serves as an effective protocol for the construction of
trans-dihydrobenzofuran and ultimately leads to the total
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 189–192

192
C.-y. Chen, M. Weisel
LETTER
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The reaction mixture was cooled to ambient temperature and
the aqueous layer was removed. The organic layer was dried
over MgSO4, concentrated and the residue was subjected to
biotage separation to afford (+)-conocarpan (0.482 g, 1.809
mmol, 92% yield) as a white solid: mp 136–138 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.41 (d, J = 6.8 Hz, 3 H), 1.89
(d, J = 1.6, 6.7 Hz, 3 H), 3.42 (m, 1 H), 5.0 (br s, 1 H), 5.10
(d, J = 8.6 Hz, 1 H), 6.10 (dq, J = 6.7, 15.5 Hz, 1 H), 6.40
(dd, J = 1.6, 15.5 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.83 (m,
2 H), 7.16 (m, 2 H), 7.31 (m, 2 H). 13C NMR (125 MHz,
CDCl3) δ = 17.8, 18.4, 45.2, 92.6, 109.3, 115.5, 120.7,
123.0, 126.3, 127.9, 130.8, 131.3, 132.4, 132.9, 155.7,
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(16) Procedure for the preparation of (+)-obtusafuran:
Obtusafuran OTIP ether (22, 0.40 g, 0.969 mmol) and
tetrabutylammonium fluoride trihydrate (0.459 g, 1.454
mmol) in THF (4.00 ml) were stirred at ambient temperature
for 12 h to complete the desilylation reaction. Methyl tert-
butylether (5 mL) was added. The organic layer was washed
with water (2 × 5 mL), dried (Na2SO4) and concentrated in
vacuum to an oil. The oil was chromatographed over silica
gel, eluted with methyl tert-butylether–hexanes (1:3), to
afford (+)-obtusafuran (0.234 g, 0.931 mmol, 94% yield) as
a solid. mp 111–113 °C. [α]D25 +50 (c 0.33, MeOH) [lit. 4
[α]D25+47 (c 0.86, MeOH). 1H NMR (500 MHz, CDCl3)
δ = 1.41 (d, J = 6.7 Hz, 3 H), 3.40 (m, 1 H), 3.90 (s, 3 H),
5.14 (d, J = 8.5 Hz, 1 H), 5.29 (s, 1 H), 6.54 (s, 1 H), 6.76 (s,
1 H), 7.40 (m, 5 H). 13C NMR (125 MHz, CDCl3) δ = 18.5,
45.7, 56.3, 92.8, 94.2, 109.5, 122.9, 126.0, 128.2, 128.6,
140.0, 141.0, 146.3, 152.4. The enantiopurity of (+)-
conocarpan was determined to be 99.1% using Chiralcel OZ
column (250 × 4.6 mm), gradient method: 4% MeOH/25
mM IBA/CO2 for 4 min, then ramp at 6%/min to 40%
MeOH, hold 5 min, 15 min runtime, 200 bar, 35 °C, 3
mL/min, 215 nm, retention time: 9.56 min.
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74, 4418. (b) Procedure for the preparation of (+)-
conocarpan from bromophenol 16: To bromophenol 16
(0.60 g, 1.966 mmol) in toluene (7.20 mL) was added
potassium carbonate (0.815 g, 5.90 mmol), water (3.00 mL),
trans-1-propen-1-ylboronic acid (0.338 g, 3.93 mmol) and
[1,1′-bis(diphenylphospino)ferrocene]dichloropalladium(II)
(0.072 g, 0.098 mmol). The mixture was degassed via
nitrogen/vacuum followed by heating to 95 °C and kept at
Synlett 2013, 24, 189–192
© Georg Thieme Verlag Stuttgart · New York