Enantioselective syntheses of (+)-decursinol and (+)-trans-decursidinol

Article abstract of DOI:10.1016/S0040-4039(01)01652-5

Selective and practical asymmetric syntheses of (+)-decursinol (1) and (+)-trans-decursidinol (2) have been achieved using naturally occurring umbelliferone, demethylsuberosin, and xanthyletin as the synthetic intermediates. The absolute stereochemistry was established in the late stage of synthesis by employing Jacobsen's enantioselective epoxidation conditions.

Full text of DOI:10.1016/S0040-4039(01)01652-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7641–7643
Enantioselective syntheses of (+)-decursinol and
(+)-trans-decursidinol
Sanghee Kim,a,* Hyojin Ko,a Soonjoo Son,a Kye Jung Shinb,* and Dong Jin Kimb
aNatural Products Research Institute, Seoul National University, 28 Yungun, Jongro, Seoul 110-460, South Korea
bKorea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea
Received 13 July 2001; accepted 31 August 2001
Abstract—Selective and practical asymmetric syntheses of (+)-decursinol (1) and (+)-trans-decursidinol (2) have been achieved
using naturally occurring umbelliferone, demethylsuberosin, and xanthyletin as the synthetic intermediates. The absolute
stereochemistry was established in the late stage of synthesis by employing Jacobsen’s enantioselective epoxidation conditions.
© 2001 Elsevier Science Ltd. All rights reserved.
(+)-Decursinol (1), (+)-trans-decursidinol (2) and their
ester derivatives 3–5 (Fig. 1) constitute a class of linear
dihydropyranocoumarin natural products.1 In particu-
lar, (+)-decursinol (1) and its ester derivatives, such as
decursin (3) and decursinol angelate (4), have received
considerable attention because of their diverse range of
interesting biological properties including protein
kinase related cytotoxicity,2,3 anti-helicobacter pylori
activity,4 and strong analgesic activity.5 The racemic
syntheses of 1 and 3 were reported by Steck in 1971.6
He constructed the C ring of decursinol by treatment of
the ortho-prenylated phenols with mCPBA under acidic
conditions. Recently, the asymmetric synthesis of (+)-
decursinol (1) and its related natural products were
independently achieved by the Shibasaki group7 and the
Han group,8 who used asymmetric enone epoxidation
and Jacobsen’s chromene epoxidation, respectively. The
racemic synthesis of 2 has been non-selectively achieved
from xanthyletin by peracetic acid treatment,9 but the
selective asymmetric synthesis of (+)-trans-decursidinol
(2) has not been reported yet.
In order to investigate the biochemical and pharmaceu-
tical effects of (+)-decursinol (1), (+)-trans-decursidinol
(2) and related derivatives, especially for pain relief
applications, we needed to synthesize these dihydro-
pyranocoumarins in large quantities. Here, we report
an efficient asymmetric synthetic route to (+)-decursinol
(1) and (+)-trans-decursidinol (2). In our synthesis, the
chirality was introduced in the late stage of synthesis,
and several naturally occurring coumarins were
employed as intermediates for our presumed
biomimetic synthetic approach.
OR
RO
RO
O
O
O
O
O
O
1 (+)-decursinol
R = H
2 (+)-trans-decursidinol
R = H
O
O
(+)-decursin
3
R =
(-)-decursindin
R =
5
O
4 (+)-decursinol angelate
In our retrosynthetic analysis, as summarized in
Scheme 1, we envisioned that the desired (+)-decursinol
(1) and (+)-trans-decursidinol (2) could be synthesized
from the common chiral intermediate 6 by chemo- and
regioselective epoxide ring opening reactions. The req-
uisite epoxide 6 could be obtained from naturally
occurring xanthyletin (7)1 by employing Jacobsen’s
enantioselective epoxidation conditions.10,11 Further
analysis indicated demethylsuberosin (8)1 should be an
ideal synthetic precursor for 7.
R =
Figure 1. Structures of (+)-decursinol (1), (+)-trans-decur-
sidinol (2) and their ester derivatives 3–5.
Keywords: decursinol; decursidinol; Jacobsen’s epoxidation;
biomimetic synthesis.
* Corresponding authors. Fax: 82-2-762-8322; e-mail: pennkim@
snu.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01652-5

7642
S. Kim et al. / Tetrahedron Letters 42 (2001) 7641–7643
O
, 2
O
O
O
O
O
O
HO
demethylsuberosin
8
O
O
xanthyletin
6
7
Scheme 1. Retrosynthetic analysis of 1 and 2.
The synthesis began from commercially available
umbelliferone (9), which was transformed into the
desired demethylsuberosin (8) in five steps according to
the previously established procedure of Harwood and
co-workers12 (Scheme 2). It was felt that these transfor-
mations offer the advantage of being able to selectively
generate the desired linear coumarin 8 on a multigram
scale without undertaking column chromatographic
purifications. Demethylsuberosin (8) was oxidized with
DDQ in refluxing benzene to give xanthyletin (7) in
60% yield.6 Unfortunately, in larger scale reactions (>5
g), the oxidation of 8 with DDQ yielded a significant
amount of chromane 10 (20–30%) along with chromene
7 (40–50%). Therefore, we have developed an alternate
route to obtain 7. Our synthetic sequence involves a
formic acid-catalyzed conversion of 8 to chromane 10
(98%), which was then oxidized with NBS/AIBN in
refluxing CCl4 to yield chromene 7 in 70% yield.
of trans-diol 2 and cis-diol 11 that were inseparable.
However, exposure of 6 to Ti(O-iPr)4 and H2O in THF
provided the desired (+)-trans-decursidinol (2) as the
only identifiable product in 93% yield.16 The improve-
ment of stereoselectivity in opening the epoxide 6 could
be understood by considering that the coordination of
the epoxy-pyran with the metal center occurred in a
bidentate manner, similar to that of Sharpless’s selec-
tive epoxy alcohol openings.17
Attempted hydrogenolysis of the epoxide 6 with Pd/C
for the transformation to (+)-decursinol (1) was non-
selective providing a mixture of product 1 and over-
reduced compound. However, reaction with Lindlar
catalyst under a hydrogen atmosphere cleanly reduced
epoxide 6 providing (+)-decursinol (1) in 95% yield. The
chemo- and regioselective reduction of epoxide 6 was
also achieved by using NaBH3CN and BF3·Et2O in
THF in 92% yield.18
With multigram quantities of xanthyletin (7) in hand,
we next investigated the regioselective asymmetric epoxi-
dation of 7. Treatment of 7 with a basic NaOCl solu-
tion in the presence of Jacobsen’s (S,S)-(+)-salen–
Mn(III) catalyst (1.9 mol%) provided the desired
epoxide 6 with very high enantioselectivity (97% ee)
in 78% yield.11,13,14 It was found that recrystallization
of the obtained 97% ee epoxide 6 from hexane:ethyl
acetate improved the enantiomeric purity to >99% ee.
In conclusion, the selective and practical asymmetric
syntheses of the linear dihydropyranocoumarin natural
products (+)-decursinol (1) and (+)-trans-decursidinol
(2) have been achieved using naturally occurring umbel-
liferone, demethylsuberosin, and xanthyletin as the syn-
thetic intermediates. The absolute stereochemistry was
introduced by employing Jacobsen’s enantioselective
epoxidation conditions. The method presented here
should allow access to the entire family of linear di-
hydropyranocoumarins including decursin and decur-
sidin from our key intermediate epoxide 6.
Treatment of epoxide 6 with HClO4 or HClO4/NaClO4
in aqueous THF15 gave the diol (90%) as a 5:1 mixture
g
a-e
ref 12
O
O
O
HO
O
O
HO
O
O
9 umbelliferone
8
10
f
h
O
HO
k or l
i
O
O
O
O
O
O
O
O
O
7
6
(+)-decursinol
1
j
OH
OH
O
HO
HO
O
O
O
O
O
(+)-trans-decursidinol
(-)-cis-decursidinol
11
2
Scheme 2. Reagents and conditions: (a) BnBr, K2CO3, acetone, reflux, 5 h, 99%; (b) NaOMe, MeOH, reflux, 6 h, 90%; (c) prenyl
bromide, K2CO3, acetone, reflux, 5 h, 90%; (d) PhNEt2, reflux, 16 h, 80%; (e) BCl3, CH2Cl2, 0°C, 2 h, 85%; (f) DDQ, benzene,
reflux, 3 h, 60%; (g) formic acid, reflux, 1 h, 98%; (h) NBS, AIBN, CCl4, reflux, 8 h, 70%; (i) Jacobsen’s (S,S)-(+)-salen–Mn(III)
cat., Clorox®, Na2HPO4, NaOH, CH2Cl2, 0°C, 6 h, 78%; (j) Ti(O-iPr)4, H2O, THF, rt, 4 h, 93%; (k) Lindlar cat., H2, EtOAc, rt,
2 days, 90%; (l) NaBH3CN, BF3·Et2O, THF, rt, 0.5 h, 92%.

S. Kim et al. / Tetrahedron Letters 42 (2001) 7641–7643
7643
Acknowledgements
This work was supported by Scigenic Co., Ltd.
References
1.08 g (78%) of the desired chiral epoxide 6 as a white
solid. H NMR (300 MHz, CDCl3): l 1.31 (3H, s), 1.61
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6.27 (1H, d, J=9.5 Hz), 6.77 (1H, s), 7.46 (1H, s), 7.63
(1H, d, J=9.5 Hz); [h]2D4=−274.7 (c 0.7, CHCl3).
1
14. The absolute configuration of epoxide 6 was re-confirmed
by transformation to the authentic natural compounds
(+)-1 and (+)-2. The enantiomeric excess of 6 was deter-
mined by chiral stationary phase HPLC analysis (CHI-
RALPAK AD-H, hexane/2-propanol (4:1, v/v), flow rate:
1.0 ml/min, retention time: 11.91 min (R,R)-isomer and
25.88 min (S,S)-isomer, detected at 254 nm).
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mg, 1.392 mmol) in dry THF (10 ml) was added Ti(O-
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of 7 was as follows. 14.3 ml of commercial household
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1
(93%) of 2 as a white solid. H NMR (300 MHz, CDCl3):
l 1.18 (3H, s), 1.46 (3H, s), 3.61 (1H, d, J=9.0 Hz), 3.64
(1H, brs, OH), 4.56 (1H, d, J=9.0 Hz), 6.04 (1H, d,
J=9.6 Hz), 6.54 (1H, s), 7.45 (1H, d, J=9.6 Hz), 7.49
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hexane/2-propanol (4:1, v/v), flow rate: 1.0 ml/min, reten-
tion time: 8.32 min (S)-isomer and 9.92 min (R)-isomer,
1
detected at 254 nm). H NMR (300 MHz, CDCl3): l 1.30
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(1H, dd, J=5.7, 16.8 Hz), 3.80 (2H, t, J=5.7 Hz), 6.16
(1H, d, J=9.6 Hz), 6.72 (1H, s), 7.11 (1H, s), 7.51 (1H, d,
J=9.6 Hz); [h]2D4=+10.5 (c 1.0, CHCl3).