First asymmetric total synthesis of (+)-curcutetraol

Article abstract of DOI:10.1016/j.tetlet.2008.02.094

The first asymmetric total synthesis of (+)-curcutetraol, a marine phenolic bisabolane-type sesquiterpene, was achieved in eight steps in ca. 50% overall yield. The chiral tertiary benzylic alcohol moiety in the o-position of a phenol was constructed in high optical yield (99% ee) by an asymmetric synthesis using a chiral aminal, (2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane.

Full text of DOI:10.1016/j.tetlet.2008.02.094

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2552–2554
First asymmetric total synthesis of (+)-curcutetraol
Chenxia Zhang, Suguru Ito, Naoya Hosoda, Masatoshi Asami *
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
Tokiwadai 79-5, Hodogaya-ku, Yokohama 240-8501, Japan
Received 21 January 2008; revised 14 February 2008; accepted 18 February 2008
Available online 21 February 2008
Abstract
The first asymmetric total synthesis of (+)-curcutetraol, a marine phenolic bisabolane-type sesquiterpene, was achieved in eight steps
in ca. 50% overall yield. The chiral tertiary benzylic alcohol moiety in the o-position of a phenol was constructed in high optical yield
(99% ee) by an asymmetric synthesis using a chiral aminal, (2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Curcutetraol; Sesquiterpene; Asymmetric total synthesis; Tertiary benzylic alcohol
Many phenolic sesquiterpenoids of the bisabolane
family have been isolated from both terrestrial and marine
organisms.1 In spite of their rather simple structures, they
often display characteristic biological activities.1,2
tertiary benzylic alcohol moiety in the o-position of a
phenol isolated from the marine environment. Although
Lindel and co-workers have reported a total synthesis of
racemic curcutetraol at the same time in seven steps in a
low overall yield, there is no report on the asymmetric syn-
thesis of (+)-1 to the best of our knowledge. Herein, we
report the first asymmetric total synthesis of (+)-1, apply-
ing an asymmetric synthesis of an a-hydroxy aldehyde
(+)-Curcutetraol (1), isolated from the bacterium CNH-
741 and the fungus CNC-979 by Lindel and co-workers in
2005, is a phenolic bisabolane-type sesquiterpene with a
tertiary benzylic alcohol moiety as a single stereogenic cen-
ter (Fig. 1).3 The structure of (+)-1 was determined on the
basis of an extensive NMR spectroscopic analysis, and its
absolute configuration was proposed to be S by the com-
parison of its experimental CD spectrum with the calcu-
lated one. To date, it is the most polar member of the
phenolic bisabolane sesquiterpenoids with its four hydroxy
groups and it is the first bisabolane sesquiterpenoid with a
using
a chiral aminal, (2R,5S)-2-methoxycarbonyl-3-
phenyl-1,3-diazabicyclo[3.3.0]octane (2).4
Our synthetic plan for the synthesis of (+)-1 is shown in
Scheme 1. We envisaged that (R)-a-hydroxy aldehyde 4
could be converted to the target compound (+)-1 via epox-
ide 3. (R)-Configuration of 4 should be constructed by the
stereoselective reaction of an acetyl aminal, (2R,5S)-2-
acetyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane (6), and aryl
Grignard reagent 5 based on the stereochemical course of
the reaction.4
HO
OH
OH
The synthetic route of (+)-curcutetraol (1) is summa-
rized in Scheme 2. Acetyl aminal 6 was obtained in 88%
yield by the reaction of methoxycarbonyl aminal 2 and
MeMgBr in the presence of MgCl2 after examinations of
the reaction conditions in detail (THF, ꢀ78 °C, 15 min).4
Considering the lability of tertiary benzylic alcohol moi-
ety at o-position of phenol under acidic conditions,5 silyl
ethers (triethylsilyl (TES), t-butyldimethylsilyl (TBDMS),
HO
(+)-curcutetraol (1)
Fig. 1. Structure of (+)-curcutetraol (1).
*
Corresponding author. Tel./fax: +81 45 339 3968.
E-mail address: m-asami@ynu.ac.jp (M. Asami).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.094

C. Zhang et al. / Tetrahedron Letters 49 (2008) 2552–2554
2553
RO
yield. The enantiomeric excess of 8 was 99% by chiral
HPLC analysis (Daicel Chiralcel OD-H (25 cm ꢂ 0.46 cm
i.d.); 254 nm UV detector; eluent, hexane/i-PrOH = 97/3;
flow rate, 0.5 mL/min; tR, 29.8 min, tS, 35.9 min)).7
OR
O
(+)-1
+
BrMg
RO
3
Then, monotosylation of diol 8 (TsCl, pyridine, rt, 4.5 h)
and treatment of the monotosylate with NaH (THF, 0 °C,
overnight) afforded almost pure epoxide 3, which was used
in the next step without purification. Epoxide 3 was treated
with 3-methyl-3-triethylsiloxybutylmagnesium bromide
(9)8 in the presence of CuI (THF, ꢀ10 °C, 1 h) to afford
a mixture of bis-SEM ether 10 and mono-SEM ether 11,
which was separated by column chromatography (Silica
RO
OH
CHO
RO
MgBr
RO
RO
4
5
+
N
N
N
N
O
O
Ph
Ph
H
H
21
gel 60 N, spherical, neutral, 63–210 lm) to give 10 (½aꢁD
OMe
Me
20
2
6
+6.1 (c 1.0, CHCl3)) and 11 (½aꢁD +3.55 (c 1.0, CHCl3))
in 52% and 47% yield from 8, respectively. Removal of
the SEM group and TES group of each 10 and 11 with
an excess amount of tetrabutylammonium fluoride (TBAF)
Scheme 1. Retrosynthetic analysis of (+)-curcutetraol (1).
or triisopropylsilyl (TIPS) ether) or trimethylsilylethoxy-
methyl (SEM) ether, which could be easily cleaved under
mild conditions by fluoride ion, were chosen as protective
groups of the hydroxy groups of Grignard reagent 5.
Among those protected 2-bromo-5-hydroxymethylphenol,6
the corresponding Grignard reagent was successfully pre-
pared only from bis-SEM ether by using activated magne-
sium turnings in the presence of 1,2-dibromoethane. (ꢀ)-2-
Hydroxy-2-[2-(2-trimethylsilylethoxymethoxy)-4-(2-trimeth-
˚
(MS 4 A, THF, reflux, 4–5 h) gave (+)-1 in 80% and 87%
˚
yield, respectively. Addition of 4 A molecular sieves
(crushed, activated) was effective to reduce the formation
of the corresponding ethoxymethyl ether.9 The spectro-
scopic data (1H and 13C NMR, IR) of synthetic (+)-1 were
in good accordance with those reported for the natural
product,3 although the specific rotation of the synthetic
23
(+)-1 (½aꢁD +5.9 (c 0.74, MeOH)) was slightly larger than
20
that of natural (+)-1 (½aꢁD +5.24 (c 0.74, MeOH)).10
29
ylsilylethoxymethoxymethyl)phenyl]propanal (4a) (½aꢁD
In conclusion, the first asymmetric total synthesis of (+)-
curcutetraol (1) was accomplished in eight steps with ca.
50% overall yield. The chiral tertiary benzylic alcohol moi-
ety in the o-position of a phenol was constructed in high
optical yield (99% ee) by an asymmetric synthesis of a-
hydroxy aldehyde 4a, having a chiral quaternary center,
starting from easily available chiral methoxycarbonyl
aminal 2. Although the absolute configurations of 4a and
(+)-1 have not been determined directly, it is reasonable
to assume that the absolute configuration of (+)-1 is S by
ꢀ61.8 (c 1.0, CHCl3)), a key intermediate for a synthesis
of (+)-1, was obtained in 82% yield by the reaction of
acetyl aminal 6 and Grignard reagent 5a (THF, ꢀ78 °C,
1 h) followed by the hydrolysis of the resulting hydroxy
aminal 7 under mild acidic conditions (2% aq HCl, Et2O,
0 °C, overnight). Reduction of 4a with sodium borohydride
(EtOH, rt, 30 min) gave (ꢀ)-2-[2-(2-trimethylsilylethoxy-
methoxy)-4-(2-trimethylsilylethoxymethoxymethyl)phenyl]-
25
propane-1,2-diol (8) (½aꢁD ꢀ3.1 (c 1.0, CHCl3)) in 83%
MgBr
OSEM
Ph
N
H
CHO
Me
CH2OH
HO Me
N
OSEM
HO
d
c
a
N
N
OSEM
OSEM
5a
N
N
HO
Me
O
O
Ph
Ph
OSEM
b
H
H
OMe
Me
OSEM
OSEM
4a
2
6
8
99% ee
OSEM
[α]2D5−3.1 (c 1.0, CHCl3)
[α]2D9−61.8 (c 1.0, CHCl3)
7
OTES
BrMg
SEMO
RO
HO
OH
OTES
h
OH
OH
e, f
9
O
g
SEMO
SEMO
HO
10 (R = SEM) [α]D21+6.1 (c 1.0, CHCl3)
3
(+)-curcutetraol (1)
[α]2D3+5.9 (c 0.74, MeOH)
+
11 (R = H)
[α]2D0+3.55 (c 1.0, CHCl3)
Scheme 2. Reagents and conditions: (a) MgCl2, THF, reflux, 1 h, then MeMgBr, THF, ꢀ78 °C, 88%; (b) 5a, THF, ꢀ78 °C, 1 h; (c) 2% aq HCl, Et2O, 0 °C,
ovn, 82% (from 6); (d) NaBH4, EtOH, rt, 30 min, 83%; (e) TsCl, pyridine, rt, 4.5 h; (f) NaH, THF, 0 °C, ovn; (g) 9, CuI, THF, ꢀ10 °C, 1 h, 99% (from 8;
˚
10, 52% and 11, 47%); (h) TBAF, MS 4 A, THF, reflux, 4–5 h, 80% from 10 and 87% from 11.

2554
C. Zhang et al. / Tetrahedron Letters 49 (2008) 2552–2554
analogy to results reported previously.4 The synthetic route
developed here can be applied to the synthesis of the ana-
logs and other related natural products. Further synthetic
studies are now in progress.
3. Mulhaupt, T.; Kaspar, H.; Otto, S.; Reichert, M.; Bringmann, G.;
¨
Lindel, T. Eur. J. Org. Chem. 2005, 334–341.
4. Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett. 1979, 705–708.
5. Miyazaki, H.; Honda, K.; Asami, M.; Inoue, S. J. Org. Chem. 1999,
64, 9507–9511.
6. (a) Buehler, C. A.; Harris, J. O.; Shacklett, C.; Block, B. P. J. Am.
Chem. Soc. 1946, 68, 574–577; (b) Canceill, J.; Collet, A. New J.
Chem. 1986, 10, 17–23.
Acknowledgment
7. When aryl lithium reagent 5b, prepared from bis-SEM ether of 2-
bromo-5-hydroxymethylphenol and butyllithium, was used in place of
We are grateful to Mr. Shinji Ishihara (Intrumental
Analysis Center of Yokohama National University) for
his technical assistance in the elemental analyses.
22
Grignard reagent 5a, 4a (½aꢁD ꢀ49.2 (c 1.0, CHCl3)) was obtained in
74% yield with 82% ee.
8. (a) Taber, D. F.; Joerger, J.-M. J. Org. Chem. 2007, 72, 3454–3457;
(b) Fall, Y.; Vitale, C.; Mourino, A. Tetrahedron Lett. 2000, 41, 7337–
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References and notes
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10. Selected data: (ꢀ)-2-Hydroxy-2-[2-(2-trimethylsilylethoxymethoxy)-4-
(2-trimethylsilylethoxymethoxymethyl)phenyl]propanal (4a): Color-
29
less oil; ½aꢁD ꢀ61.8 (c 1.0, CHCl3); IR (neat): mmax 3450, 2952, 2896,
1739 cmꢀ1 1H NMR (270 MHz, CDCl3): d (ppm) 9.76 (s, 1H), 7.47
;
(d, J = 7.9 Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 7.03 (dd, J = 7.9,
1.6 Hz, 1H), 5.25 (d, J = 6.9 Hz, 1H), 5.23 (d, J = 6.9 Hz, 1H), 4.74 (s,
2H), 4.57 (s, 2H), 4.06 (s, 1H), 3.63–3.74 (m, 4H), 1.65 (s, 3H), 0.91–
0.98 (m, 4H), 0.01 (s, 9H), ꢀ0.01 (s, 9H); 13C NMR (67.8 MHz,
CDCl3): d (ppm) 200.7, 154.1, 140.2, 128.5, 127.2, 121.1, 113.4, 94.2,
92.8, 78.0, 68.7, 66.8, 65.3, 21.7, 18.2, 18.0, ꢀ1.31, ꢀ1.36. Anal. Calcd
for C22H40O6Si2: C, 57.85; H, 8.83. Found: C, 57.99; H, 9.09.
(ꢀ)-2-[2-(2-Trimethylsilylethoxymethoxy)-4-(2-trimethylsilylethoxy-
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25
methoxymethyl)phenyl]propane-1,2-diol (8): Colorless oil; ½aꢁD ꢀ3.1
(c 1.0, CHCl3); IR (neat): mmax 3435, 2952, 2896, 1615, 1577,
; d (ppm) 7.42 (d,
1249 cmꢀ1 1H NMR (270 MHz, CDCl3):
J = 7.9 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.01 (dd, J = 7.9, 1.5 Hz,
1H), 5.32 (d, J = 6.9 Hz, 1H), 5.30 (d, J = 6.9 Hz, 1H), 4.75 (s, 2H),
4.56 (s, 2H), 3.97 (dd, J = 10.9, 5.3 Hz, 1H), 3.96 (s, 1H), 3.73–3.79
(m, 2H), 3.63–3.70 (m, 3H), 2.03 (dd, J = 6.9, 5.3 Hz, 1H), 1.56 (s,
3H), 0.93–1.00 (m, 4H), 0.02 (s, 9H), 0.00 (s, 9H); 13C NMR
(67.8 MHz, CDCl3): d (ppm) 154.4, 138.7, 131.6, 127.4, 121.0, 113.7,
94.1, 92.7, 75.1, 69.1, 68.8, 66.8, 65.2, 24.3, 18.1, 18.0, ꢀ1.31, ꢀ1.36.
Anal. Calcd for C22H42O6Si2: C, 57.60; H, 9.23. Found: C, 57.24; H,
9.27.
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23
(+)-Curcutetraol (1): Brownish oil; ½aꢁD +5.9 (c 0.74, MeOH); IR
(neat): mmax 3337, 2971, 1625, 1577, 1513, 1376, 1297, 1266, 1167,
; d (ppm) 7.10 (d,
1021 cmꢀ1 1H NMR (270 MHz, CD3OD):
J = 7.7 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 6.75 (br s, 1H), 4.50
(s, 2H), 1.70–1.98 (m, 2H), 1.57 (s, 3H), 1.20–1.48 (m, 4H), 1.10 (s,
3H), 1.09 (s, 3H); 13C NMR (67.8 MHz, CD3OD):
d (ppm)
156.7, 142.6, 131.1, 127.4, 118.6, 116.0, 77.9, 71.4, 64.8, 45.1, 44.4,
29.1, 20.1.