Concise synthesis of rodgersinol and determination of the C-10 absolute configuration

Article abstract of DOI:10.1021/jo061980u

Rodgersinol was synthesized via seven linear steps in 31% overall yield, and the absolute configuration of the C-10 stereogenic center was elucidated. The key feature of the synthesis involves the efficient Cu(II)-mediated coupling of two aromatic moietie

Full text of DOI:10.1021/jo061980u

Concise Synthesis of Rodgersinol and
Determination of the C-10 Absolute
Configuration
Seung-Yong Seo,† Jong-Wha Jung,† Jae-Kyung Jung,‡
Nam-Jung Kim,† Young-Won Chin,† Jinwoong Kim,†
and Young-Ger Suh*,†
College of Pharmacy, Seoul National UniVersity, Seoul 151-742,
Korea, and College of Pharmacy, Chungbuk National
UniVersity, Cheongju 361-763, Korea
FIGURE 1. Structures of rodgersinol and the anti-inflammatory
2-arylpropanoic acids.
ygsuh@snu.ac.kr
or biotransformational prodrug, while the (S)-2-arylpropanoic
acid2 moiety is well recognized in an important class of
nonsteroidal anti-inflammatory agents, such as ibuprofen and
naproxen.3
ReceiVed September 26, 2006
The exciting biological activity of rodgersinol, possessing the
unique 2-arylpropanol, combined with an effort to elucidate the
absolute configuration of the C-10 stereogenic center, led us to
undertake the total synthesis of rodgersinol. We herein report
the concise and versatile synthesis of both enantiomers of
rodgersinol (1).
In consideration of concise and convergent synthesis of 1,
we sought an efficient synthetic procedure for the common
intermediate 2, which could be readily transformed into both
enantiomers of 1 by the regio- and stereoselective methyl
additions to 2, followed by direct (E)-propenyl installation at
C-1 by Suzuki cross-coupling4 (Scheme 1). The chiral epoxide
of 2 would be efficiently prepared by sequential asymmetric
dihydroxylation5 of the diaryl ether 3 and epoxidation of the
resulting diol. With seeking efficient construction6 of the key
diaryl ether intermediate 3, we were intrigued by the pioneering
report by Evans7on Cu-mediated coupling. Thus, we considered
the coupling of the properly functionalized phenol 4 and the
boronic acid 5.
Rodgersinol was synthesized via seven linear steps in 31%
overall yield, and the absolute configuration of the C-10
stereogenic center was elucidated. The key feature of the
synthesis involves the efficient Cu(II)-mediated coupling of
two aromatic moieties for the diaryl ether intermediate and
the enantioselective construction of the hydroxypropyl sub-
stituent by a regio- and stereoselective methyl addition to
the chiral aryloxiranes in an inversion manner.
Our approach commenced with the preparation of the chiral
epoxide 2, as shown in Scheme 2. The reaction of 4-iodo-2-
vinylphenol 48 and boronic acid 5, in the presence of Cu(OAc)2
and Et3N, produced the coupling product 3 in 67% yield (91%
based on the recovered 4). The incomplete conversion was likely
Recently, rodgersinol (1) was isolated from the aerial parts
of Rodgersia podophylla, from which rhizomes have tradition-
ally been used for the treatment of enteritis and bacillary
dysentery as well as for pain relief. In particular, this novel
component exhibited significant inhibitory effects on both iNOS
and COX-2 expression in LPS-activated macrophages (IC50
values of 2 and 3 µM, respectively).1 The structural determi-
nation of 1, by an extensive spectroscopic analysis,1 revealed a
C-4 (refer to the numbering system of rodgersinol) diaryl ether
skeleton containing a p-hydroquinone, appended with a propenyl
group (C-1) and a hydroxylpropanyl group (C-3), as shown in
Figure 1. However, the absolute configuration of the C-10
stereogenic center remained undetermined. Interestingly, rodg-
ersinol, as a potential antiinflammatory agent, possesses a
2-arylpropanol moiety, which is rarely observed in natural
antiinflammatory products. It is usually found in an intermediate
(2) For a review on the synthesis of 2-arylpropanoic acid, see: Sonawane,
H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G. Tetrahedron: Asymmetry
1992, 3, 163-192.
(3) For selected reports, see: (a) Hayball, P. J. Drugs 1996, 52, 47-58.
(b) Landoni, M. F.; Soraci, A. Curr. Drug. Metab. 2001, 2, 37-51.
(4) For reviews on the Suzuki cross-coupling reaction, see: (a) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147-168.
(5) For reviews on asymmetric dihydroxylation, see: (a) Zaitsev, A. B.;
Adolfsson, H. Synthesis 2006, 11, 1725-1756. (b) Kolb, H. C.; VanNieu-
wenhze, M. S.; Sharpless, K. B. Chem. ReV. 1996, 94, 2483-2547. In this
case, neither the asymmetric epoxidation nor the asymmetric hydroboration
was sufficient for application to the stereoselective synthesis of 2-arylpro-
panol from the diaryl ether 3.
(6) For recent reviews on diaryl ether formation, see: (a) Sawyer, J. S.
Tetrahedron 2000, 56, 5045-5065. (b) Theil, F. Angew. Chem., Int. Ed.
1999, 38, 2345-2347. (c) Lindley, J. Tetrahedron 1984, 40, 1433.
(7) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937-2940. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933-2936.
* To whom correspondence should be addressed. Tel: 82-2-880-7875. Fax:
82-2-880-0649.
† Seoul National University.
‡ Chungbuk National University.
(1) Chin, Y.-W.; Park, E. Y.; Seo, S.-Y.; Yoon, K.-D.; Ahn, M.-J.; Suh,
Y.-G.; Kim, S. G.; Kim, J. Bioorg. Med. Chem. Lett. 2006, 16, 4600-
4602.
(8) The compound 4 was synthesized from the commercially available
4-iodosalicylaldehyde using Wittig olefination.
10.1021/jo061980u CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/14/2006
666
J. Org. Chem. 2007, 72, 666-668

SCHEME 1. Retrosynthetic Analysis of Rodgersinol (1)
epoxide 2 afforded the (R)-2-arylpropanol 8 as the major
product, with retention fashion in 75% yield and 89% ee,11,13b
along with a small amount of regioisomer (15%). The total
synthesis of (S)-rodgersinol (1) was completed by the Suzuki
reaction4,14 of 7 with (E)-propenylboronic acid and concurrent
TBS-deprotection in the presence of Pd(PPh3)4 and CsF.
Initially, the coupling product turned out to possess a mixture
of E/Z olefins in a 6.5:1 ratio, on the basis of spectral analysis.
However, the olefin isomerization catalyzed by (CH3CN)2PdCl2
provided the desired (S)-1 with only (E)-geometry.15 The (R)-1
was also synthesized from the aryl iodide 8, by analogy to
(S)-1.
1
The spectroscopic properties (IR, H and 13C NMR, MS) of
the synthetic rodgersinol were compatible with those of the
natural 1. The absolute configuration of the C-10 stereogenic
center of the natural 1 was determined as (S) by comparison16
SCHEME 2. Synthesis of the Chiral Epoxide 2
of the optical rotations [synthetic (S)-1, [R]20 -12.7 (c 0.17,
D
MeOH); natural 1, [R]20 -14.6 (c 0.04, MeOH)1] and their
D
retention times on chiral HPLC.
In conclusion, the first concise synthesis of (S)-(-)-rodgersi-
nol has been achieved via efficient diaryl ether formation,
together with the stereoselective methyl group addition to the
chiral aryloxirane, for elaboration of the 2-arylpropanol moiety.
The absolute configuration of the C-10 stereogenic center was
also determined through the present synthesis. Studies on the
biological properties of the (R)-antipode 1, as well as structural
analogues of (S)-rodgersinol based on the current synthetic route,
are progressing well.
due to the steric factor of the o-vinyl substituent.9 Sharpless
asymmetric dihydroxylation of 3 using AD-mix-â5,10 afforded
the diol 6 in 93% enantiomeric excess (ee).11 Selective tosylation
of the primary alcohol of 6 using dibutyltin oxide12 followed
by KO-t-Bu treatment of the resulting tosylate led to the
exclusive formation of the desired epoxide 2 in 80% overall
yield.
Having established a reliable route to the requisite chiral
epoxide 2, we focused on securing both enantiomers 7 and 8
via regio- and stereoselective epoxide opening by a methyl
addition. Pleasingly, we found that two different nonracemic
adducts, consisting of the 2-arylpropanol skeleton, could be
prepared by employing two types of protocols for the stereo-
selective methyl introduction13 at C-10 (Scheme 3). Upon methyl
cuprate treatment of (R)-epoxide 2, (S)-2-arylpropanol 7 was
produced in an inversion fashion in 70% yield and 91% ee.11,13a
On the other hand, methyl aluminum treatment of the same (R)-
Experimental Section
tert-Butyl(4-(4-iodo-2-vinylphenoxy)phenoxy)dimethylsilane
(3). To a solution of 4-iodo-2-vinylphenol 4 (0.98 g, 4.0 mmol),
boronic acid 5 (3.0 g, 12.0 mmol), and copper acetate (0.73 g, 4.0
mmol) in the presence of 4A molecular sieves in CH2Cl2 (20 mL)
was added triethylamine (2.8 mL, 20.0 mmol). The reaction mixture
was vigorously stirred for 24 h at ambient temperature and filtered
through a pad of Celite. The filtrate was concentrated in vacuo,
and the residue was purified via flash column chromatography on
silica gel (EtOAc/hexanes ) 1:100) to afford 1.2 g (67%) of 3 as
a colorless oil and 0.26 g of the starting phenol 4 (EtOAc/hexanes
1
) 1:5): FT-IR (thin film, neat) νmax 2929, 1501, 1229 cm-1; H
NMR (CDCl3, 300 MHz) δ 7.83 (d, 1H, J ) 2.2 Hz), 7.42 (dd,
1H, J ) 8.6, 2.2 Hz), 6.93 (dd, 1H, J ) 17.6, 11.2 Hz), 6.84-
6.75 (m, 4H), 6.51 (d, 1H, J ) 8.6 Hz), 5.76 (dd, 1H, J ) 17.6,
1.1 Hz), 5.30 (dd, 1H, J ) 11.1, 1.1 Hz), 0.96 (s, 9H), 0.18 (s,
6H); 13C NMR (CDCl3, 100 MHz) δ 155.0, 151.8, 150.6, 137.4,
135.3, 131.1, 129.9, 129.4, 121.0, 120.1, 119.9, 116.3, 86.1, 25.7,
18.2, -4.4; LR-MS (FAB) m/z 452 (M+); HR-MS (FAB) calcd
for C20H25IO2Si (M+) 452.0669, found 452.0667.
(9) The coupling reaction of an electron-poor phenol with an aldehyde
or ketone group instead of an alkyl group, such as 5-bromo-2-hydroxy-
benzaldehyde or 1-(5-bromo-2-hydroxyphenyl)ethanone, failed to provide
the desired product.
(10) Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785-3786.
(11) The enatiomeric excess (ee) was determined by chiral HPLC. For
details, see the Supporting Information.
(12) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450.
(13) (a) Botuha, C. B.; Haddad, M.; Larcheveque, M. Tetrahedron:
Asymmetry 1998, 9, 1929-1931. (b) The retention of the stereochemistry
is explained by an intramolecular methyl migration via aluminum-complexed
phenyloxirane through an intermediary carbenium ion while the inversion
can be understood by the BF3-promoted intermolecular backside attack of
the methyl nucleophile. Fukumasa, M.; Furuhashi, K.; Umezawa, J.;
Takahashi, O.; Hirai, T. Tetrahedron Lett. 1991, 32, 1059-1062. For reports
on related conditions, see: (c) Carde, L.; Davies, H.; Geller, T. P.; Roberts,
S. M. Tetrahedron Lett. 1999, 40, 5421-5424. (d) Takano, S.; Yanase,
M.; Sugihara, T.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1988,
1538-1540 and references therein.
(S)-2-(2-(4-(tert-Butyldimethylsilyloxy)phenoxy)-5-iodophenyl-
)propan-1-ol (7). To a solution of copper cyanide (114 mg, 1.25
mmol) in THF (1 mL) was added methyllithium (780 µL of 1.60
M solution in THF, 1.25 mmol) at -40 °C. The reaction mixture
was stirred for 30 min, and BF3‚OEt2 (157 µL, 1.25 mmol) and a
solution of the epoxide 2 (90 mg, 0.25 mmol) was added dropwise
at -80 °C. The reaction mixture was stirred for 2 h, quenched with
saturated aqueous NH4Cl and NH4OH, and then diluted with Et2O.
The organic phase was washed with water and brine, dried over
(14) For a report on related conditions, see: Miyata, O.; Takeda, N.;
Naito, T. Org. Lett. 2004, 6, 1761-1763. and references therein.
(15) Yu, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627-
4629.
(16) Optical rotation of the synthetic (R)-1: [R]20 +12.3 (c 0.05,
D
MeOH).
J. Org. Chem, Vol. 72, No. 2, 2007 667

SCHEME 3. Completion of Total Synthesis of Rodgersinol (1)
MgSO4, and concentrated in vacuo. Purification of the residue via
flash column chromatography on silica gel (EtOAc/hexanes ) 1:2)
afforded 65 mg (70%) of the 2-arylpropanol 7 as a colorless oil:
Purification of the residue via flash column chromatography on
silica gel (EtOAc/hexanes ) 1:2) afforded 44 mg (90%) of (E)-
isomer of (S)-rodgersinol 1 as a colorless oil: [R]20D -12.7 (c 0.17,
MeOH) (lit.1 natural 1 [R]20D -14.6 (c 0.04, MeOH)); FT-IR (thin
[R]20 -10.5 (c 1.7, CH3OH); FT-IR (thin film, neat) νmax 2927,
D
1501, 1228 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.55 (d, 1H, J )
2.2 Hz), 7.42 (dd, 1H, J ) 2.2, 8.6 Hz), 6.82-6.71 (m, 4H), 6.52
(d, 1H, J ) 8.6 Hz), 3.79-3.67 (m, 2H), 3.43 (m, 1H), 1.27 (d,
3H, J ) 6.9 Hz), 0.96 (s, 9H), 0.18 (s, 6H); 13C NMR (CDCl3, 75
MHz) δ 156.0, 151.8, 150.6, 136.8, 136.4, 121.0, 119.8, 86.3, 67.4,
35.5, 25.7, 18.2, 16.7, -4.5; LR-MS (EI) m/z 484 (M+); HR-MS
(EI) calcd for C21H29IO3Si (M+) 484.0931, found 484.0929.
(S)-Rodgersinol (1). To a refluxing solution of the 2-arylpro-
panol 7 (60 mg, 0.12 mmol), trans-propenylboronic acid (32 mg,
0.37 mmol), and cesium fluoride (73 mg, 0.50 mmol) in dioxane
(1 mL) was added Pd(PPh3)4 (15 mg, 0.01 mmol). The reaction
mixture was stirred for 3 h, cooled to ambient temperature, and
concentrated in vacuo. Purification of the residue via flash column
chromatography on silica gel (EtOAc/hexanes ) 1:2) afforded an
E/Z mixture (6.5:1) of rodgersinol 1.
1
film, neat) νmax 2924, 1505, 1214 cm-1; H NMR (CDCl3, 300
MHz) δ 7.22 (m, 1H), 7.12 (dd, 1H, J ) 2.2, 8.4 Hz), 6.89-6.69
(m, 5H), 6.37 (m, 1H), 6.18 (m, 1H), 4.88 (m, 1H), 3.82-3.69 (m,
2H), 3.45 (m, 1H), 1.86 (dd, 3H, J ) 1.5, 6.4 Hz), 1.28 (d, 3H, J
) 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 154.6, 151.4, 151.0,
133.9, 133.3, 130.3, 125.4, 124.9, 119.9, 119.7, 118.4, 116.3, 67.8,
35.6, 18.4, 16.8; LR-MS (EI) m/z 284 (M+); HR-MS (EI) calcd
for C18H20O3 (M+) 284.1412, found 284.1409.
Acknowledgment. This work was supported by the Center
for Bioactive Molecular Hybrids, Yonsei University.
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
To a solution of above rodgersinol 1 in CH2Cl2 (1 mL) was added
bis(acetonitrile)dichloride palladium(II) (3 mg, 0.01 mmol). The
reaction mixture was stirred for 12 h and concentrated in vacuo.
JO061980U
668 J. Org. Chem., Vol. 72, No. 2, 2007