Total synthesis of (±)-scuteflorin A

Article abstract of DOI:10.3987/COM-10-12030

A highly efficient synthesis was developed for the first total synthesis of scuteflorin A. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12030

HETEROCYCLES, Vol. 81, No. 11, 2010
2593
HETEROCYCLES, Vol. 81, No. 11, 2010, pp. 2593 - 2598. © The Japan Institute of Heterocyclic Chemistry
Received, 29th July, 2010, Accepted, 31st August, 2010, Published online, 2nd September, 2010
DOI: 10.3987/COM-10-12030
TOTAL SYNTHESIS OF (±)-SCUTEFLORIN A
a
b
c
a
Fang Tan, Liu-Lan Shen, Young-Shin Kwak, * and Jin-Hyun Jeong *
a
Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee
University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea,
b
jeongjh@khu.ac.kr, School of Pharmaceutical Engineering, ShenYang
Pharmaceutical University, 103 WenHua Road, ShenHe District, ShenYang,
c
LiaoNing 110016, P. R. China, liulanx@gmail.com, and Bio Therapeutic
Research Institute, Korea Research Institute of Bioscience & Biotechnology
(KRIBB), 685-1 Yangcheong-ri, Ochang-eup, Cheongwon-gun, ChungBuk
3
63-883, Republic of Korea, yskwak@kribb.re.kr
Abstract – A highly efficient synthesis was developed for the first total synthesis
of scuteflorin A. © 2010 Elsevier Science. All rights reserved.
Scutellaria lateriflora L. (also called “American skullcap”) has long been used as an herbal medicine for
treating neurological disorders such as anxiety, nervous tension, and convulsions in North America and
1
Europe. The therapeutic benefit of S. lateriflora has been validated by demonstrating significant
2
,3
anxiolytic effects of its aqueous extracts in rodent models and in healthy human volunteers. In a recent
study to reveal the chemical constituents of S. lateriflora extract, two new coumarins, scuteflorin A
4
((+)-1) and B ((+)-2), have been isolated and the fully characterized structures are shown in Figure 1.
O
O
4
O
O
O
2
8
O
O
O
O
O
O
O
O
O
O
O
O
scuteflorin A (()-1)
scuteflorin B (()-2)
decursin (3)
Figure 1
5
Scuteflorin A ((+)-1) is a very close analog of decursin (3), differing from 3 only in C-4’s oxidation state,
and 3 therefore may be a precursor of (+)-1 via a biotransformation. Decursin (3) is a well-known

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HETEROCYCLES, Vol. 81, No. 11, 2010
5
cytotoxic PKC activator and was also isolated from S. lateriflora extract in the same study. To
unambiguously explain the mechanism of the in vivo pharmacology of 3, profiling the biological activity
and the toxicity of its potential metabolites is important, as in (+)-1. We thus sought to develop an
efficient synthesis of 1, and to assess its biological significance and its analogs to expedite the
structure–activity relationship (SAR) study of scuteflorin and decursin analogs and to determine their
therapeutic potential. We describe here the first total synthesis of (±)-scuteflorin A (1), with the aim of
developing efficient syntheses of its analogs for biological evaluation.
H
O
O
R
O
B
A
B
C
O
HO
OH
O
O
O
O
O
4
C-3 derivatives
7
Scheme 1. Retrosynthetic analysis of 1 from its C-3 derivatives
Our retrosynthetic analysis for 1 was developed with a view to designing a versatile synthetic route to 1
and its analogs, as depicted in Scheme 1. We envisioned that the advanced intermediate 7 should be a
strategically convenient dividing point for approaching 1 and its C-3 derivatives. In turn, 2,4-
dihydroxybenzaldehyde (4) would be a good motif for the B ring, potentially giving easy access to the
formation of the A and C rings.
4
CHO
a
b
c
7
4
O
OH
O
O
O
f
5
6
O
O
MeO OMe
HO
e
HO
d
1
O
O
O
O
O
8
9
Scheme 2. Reagents and conditions: (a) 2-methyl-3-butene-2-ol, HCO
Ph P=CHCO Et, Et NPh, reflux, 0.5 h, 82%; (c) ceric ammonium nitrate, Et
0 min, 72%; (d) PhI(OAc) , KOH, MeOH, rt, 20 h; (e) 3 M HCl, MeOH, rt, 30 min, 64% for two steps;
f) senecioyl chloride, pyridine, CH Cl , rt, 3 h, 96%.
2
H, reflux, 4h, 57%; (b)
3
2
2
2
O–AcOH–H O, water bath,
2
3
2
(
2
2
The synthesis of 1 is summarized in Scheme 2. In refluxing formic acid, 2,4-dihydroxybenzaldehyde (4)
underwent an electrophilic alkylation with 2-methyl-3-buten-2-ol, followed by spontaneous cyclic ether

HETEROCYCLES, Vol. 81, No. 11, 2010
2595
6
formation to afford 5 in a moderate 57% yield. Wittig olefination of 5 in refluxing diethylaniline was
7
accompanied by an intramolecular esterification to afford the unsaturated lactone 6 in 82% yield.
Oxidation of the methylene group (C-4) of 6 was achieved using ceric ammonium nitrate and provided
8
9
the desired subtarget 7 in 72% yield. C-3 hydroxylation of 6 by iodobenzene diacetate in MeOH was
accompanied by dimethylketal formation and produced 7. The crude 7 was then immediately treated with
3
M HCl and transformed to the desired ketone 9 in 64% yield for the two steps. Finally, O-acylation of 9
with senecioyl chloride in the presence of pyridine provided racemic (±)-scuteflorin A (1), in an excellent
yield. The spectral data of the synthetic racemic (±)-scuteflorin A (1) were identical to those reported for
4
(
+)-1 from a natural source.
In conclusion, we demonstrated the first total synthesis of racemic (±)-scuteflorin A (1) in a highly
efficient manner, attesting to the viability of our synthetic strategy for the future SAR study of scuteflorin
and decursin derivatives. Asymmetric synthesis of (+)-scuteflorin A ((+)-1) is currently under way. The
biological activity of scuteflorin and its derivatives is under investigation and will be reported in due
course.
GENERAL EXPERIMENTAL
Preparation of 5: 2-Methyl-3-butene-2-ol (0.70 mL, 6.7 mmol) was added to a solution of 4 (1.38 g, 10.0
mmol) in 10 mL of 95% HCO
room temperature. The reaction mixture was then poured into water (100 mL) with stirring and
neutralized with solid NaHCO to pH 7–8. The aqueous phase was extracted with EtOAc (3 × 50 mL).
The combined organic extracts were dried with anhydrous MgSO and the volatiles were removed in
vacuo. The crude product was purified by flash column chromatography using hexanes and EtOAc to
2
H and stirred. The mixture was heated at reflux for 4 h and then cooled to
3
4
–
1 1
afford 5 (0.76 g, 57%) as a white solid. Mp 97-98 °C. FT-IR (KBr): 1648 cm . H-NMR (CDCl
3
) δ ppm:
1
1
1
.36 (s, 6H), 1.83 (t, 2H, J = 6.6 Hz), 2.75 (t, 2H, J = 6.6 Hz), 6.32 (s, 1H), 7.21 (s, 1H), 9.66 (s, 1H),
1
3
1.06 (s, 1H). C-NMR (CDCl ) δ ppm: 21.45, 26.98, 26.98, 32.57, 76.27, 104.38, 113.78, 115.23,
3
+
35.30, 162.04, 162.14, 194.19. MS (ESI): C12
H
15
O
3
, 207.1 m/z, found 207.1 m/z (M+H) .
Preparation of 6: Carbethoxynethylenetriphenylphosphorane (1.15 g, 3.3 mmol) was added to a solution
of 5 (0.62 g, 3 mmol) in 12 mL of Et NPh and stirred. The stirred mixture was heated at reflux for 30 min.
The reaction mixture was then cooled and diluted with water, and extracted with EtOAc. The organic
extract was washed with 5% HCl, brine, dried with MgSO and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel to provide 6 (0.57 g, 82%) as a white solid. Mp
2
4
–
1 1
1
22-123 °C. FT-IR (KBr): 1724 cm . H-NMR (CDCl ) δ ppm: 1.57 (s, 6H), 1.85 (t, 1H), 2.82 (t, 1H),
3

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HETEROCYCLES, Vol. 81, No. 11, 2010
1
3
6
.19 (d, 1H, J = 9.5 Hz), 6.72 (s, 1H), 7.15 (s, 1H), 7.57 (d, 1H, J = 9.5 Hz). C-NMR (CDCl
3
) δ ppm:
2
1.91, 26.90, 26.90, 32.42, 75.78, 104.64, 112.20, 112.82, 118.41, 128.24, 143.36, 154.04, 157.76, 161.56.
+
+
HRMS (ESI): calcd for C H O , 231.1021 m/z (M+H) , found 231.1024 m/z (M+H) .
1
4
15
3
2
Preparation of 7: A solution of 6 (0.44 g, 1.8 mmol) in Et O (10 mL) was added to a well stirred solution
of acetic acid (10 mL) in water (10 mL). Ceric ammonium nitrate (1.97 g, 3.6 mmol) was added in small
portions to this stirred biphasic mixture. The reaction mixture was then heated in a water bath (20–30
min) with stirring. The reaction mixture was allowed to cool to room temperature and then diluted with
water. The precipitate was filtered and purified by flash column chromatography on silica gel using
–
1 1
hexane-EtOAc as the eluent to provide 7 (0.32 g, 72% yield). FT-IR (KBr): 1741, 1694 cm . H-NMR
CDCl ) δ ppm: 1.50 (s, 6H), 2.78 (s, 2H), 6.31 (d, 1H, J = 9.6 Hz), 6.84 (s, 1H), 7.67 (d, 1H, J = 9.6 Hz),
(
3
1
3
8
1
.03 (s, 1H). C-NMR (CDCl ), δ ppm: 26.72, 26.72, 48.65, 80.76, 105.61, 113.32, 114.04, 117.64,
3
+
13 4
27.37, 143.33, 159.27, 159.92, 162.39, 190.83. HRMS (ESI): calcd for C14H O , 245.0814 m/z (M+H) ,
+
found 245.0814 m/z (M+H) .
Preparation of 9: A solution of 7 (0.24 g; 1.0 mmol) in 10 mL of absolute MeOH was added to a stirred
solution of KOH (0.17 g, 3.0 mmol) in MeOH (5 mL) over a period of 5 min at 0 °C. The stirring was
continued and solid iodobenzene diacetate (0.39 g, 1.2 mmol) was added in three portions during 2 min
period. The resulting mixture was stirred for an additional hour at 0 °C and then overnight at room
temperature. Most of the MeOH was evaporated in vacuo and then water (20 mL) was added. After
saturating the mixture with K
2
CO
3
, it was extracted with EtOAc (3 × 20 mL). The combined EtOAc
and concentrated in vacuo. This crude product suggested
extracts were dried with anhydrous MgSO
4
–
1 1
dimethyl acetal, 8. FT-IR (KBr): 1737 cm . H-NMR (CDCl
3
), δ ppm: 1.41 (s, 3H), 1.53 (s, 3H), 3.25 (s,
3
1
1
H), 3.45 (s, 3H), 3.84 (s, 1H), 6.25 (d, 1H, J = 9.6 Hz), 6.79 (s, 1H), 7.65 (d, 1H, J = 9.6 Hz), 7.68 (s,
1
3
H). C-NMR (MeOH-d
4
), δ ppm: 26.26, 26.66, 49.02, 49.35, 71.42, 81.90, 97.44, 104.99, 113.22,
, 307.1182 m/z
13.44, 118.11, 131.10, 145.99, 156.75, 158.72, 163.16. HRMS (ESI): calcd for C16
19 6
H O
+
+
(
M+H) , found 307.1180 m/z (M+H) . The crude product was dissolved in 5 mL of 3 N HCl and stirred
for 30 min at room temperature. Water (20 mL) was added and the mixture was stirred for a further 10
min. The pH of the mixture was adjusted to basic with solid K CO and then the basic mixture was
2
3
extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were dried with MgSO and
4
concentrated in vacuo to give a solid crude product. The crude product was purified by silica gel column
chromatography using hexane and EtOAc to afford 9 (0.19 mg, 64%) as a white solid. Mp 144-145 °C.
-1 1
FT-IR (KBr): 1743, 1698 cm . H-NMR (CDCl ), δ ppm: 1.26 (s, 3H), 1.69 (s, 3H), 3.76 (s, 1H), 4.47 (s,
3
1
3
1
H), 6.34 (d, 1H, J = 9.6 Hz), 6.86 (s, 1H), 7.69 (d, 1H, J = 9.6 Hz), 8.00 (s, 1H). C-NMR (CDCl
3
), δ
ppm: 17.74, 26.70, 76.91, 84.78, 105.83, 113.69, 114.96, 116.15, 127.44, 143.05, 159.68, 159.70, 162.03,

HETEROCYCLES, Vol. 81, No. 11, 2010
2597
+
+
1
92.95. HRMS (ESI): calcd for C14
H
13
O
5
, 261.0763 m/z (M+H) , found 261.0763 m/z (M+H) .
Synthesis of 1: A solution of 9 (0.26 g, 1.0 mmol) and pyridine (0.08 mL, 1.0 mmol) in anhydrous
CH Cl (15 mL) was stirred in an ice bath. Senecioyl chloride (0.12 mL) was added slowly and the
2
2
reaction was stirred for 3 h. The reaction produced crystalline precipitates and was extracted with CH
2 2
Cl .
The CH Cl extract was washed with water and brine, and then dried with MgSO . The volatiles were
2
2
4
removed under reduced pressure and the crude product was purified by silica gel column chromatography
using hexane and EtOAc to afford 1 as a white solid (0.33 g, 96.5%). Mp 139-140 °C. FT-IR (KBr):
–
1
+
1
747, 1708 cm . HRMS (ESI): calcd for C H NaO , 365.1001 m/z (M+Na) , found 365.1004 m/z
19 18 6
+
1
(
M+Na) . H-NMR (MeOH-d
4
), δ ppm: 1.39 (s, 3H), 1.57 (s, 3H), 2.00 (d, 3H, J = 1.2 Hz), 2.22 (d, 3H, J
=
1.2 Hz), 5.73 (s, 1H), 5.86 (br, 1H), 6.35 (d,1H, J = 9.6 Hz), 6.93 (s, 1H), 7.95 (d, 1H, J = 9.6 Hz), 8.10
1
3
(
s, 1H). C-NMR (MeOH-d ), δ ppm: 18.70, 19.42, 25.09, 26.38, 75.90, 82.77, 105.20, 114.32, 114.33,
4
1
14.36, 117.46, 127.80, 143.92, 159.69, 160.18, 160.31, 161.58, 164.93, 187.71. Comparison with natural
4
-1.
+
product : FT-IR: 2924, 1732, 1623cm HRMS (ESI): m/z 365.1013 ((M+Na) , calcd for 365.1001).
1
4
H-NMR (MeOH-d ), δ ppm: 1.39 (s, 3H), 1.58 (s, 3H), 1.97 (d, 3H, J = 1.2 Hz), 2.20 (d, 3H, J = 1.1 Hz),
5
.71 (s, 1H), 5.85 (br, 1H), 6.36 (d,1H, J = 9.6 Hz), 6.90 (s, 1H), 8.04 (d, 1H, J = 9.6 Hz), 8.11 (s, 1H).
1
3
C-NMR (MeOH-d
4
), δ ppm: 20.1, 20.5, 26.2, 27.5, 76.5, 83.6, 106.0, 115.1, 115.5, 115.6, 118.2, 128.7,
1
44.5, 159.9, 160.5, 160.6, 162.2, 165.23, 187.8.
ACKNOWLEDGMENT
This work was supported by a Korea Research Foundation grant funded by the Korean government
(MOEHRD; KRF-2005-041-E00499).
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