Diastereoselective Total Synthesis of (±)-Toxicodenane A

Article abstract of DOI:10.1002/ejoc.201701219

The first total synthesis of tricyclic sesquiterpene (±)-toxicodenane A has been accomplished. This synthetic work was completed in 12 steps from dimedone through diastereoselective reductive desymmetrization of 2,2-disubstituted 5,5-dimethylcyclohexane-1

Full text of DOI:10.1002/ejoc.201701219

A Journal of
Accepted Article
Title: Diastereoselective Total Synthesis of (±)-Toxicodenane A
Authors: Toyoharu Kobayashi, Kotono Yamanoue, Hideki Abe, and
Hisanaka Ito
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701219
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701219
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10.1002/ejoc.201701219
European Journal of Organic Chemistry
FULL PAPER
Diastereoselective Total Synthesis of (±)-Toxicodenane A
Toyoharu Kobayashi,[a] Kotono Yamanoue,[a] Hideki Abe,[a] and Hisanaka Ito*[a]
Dedication ((optional))
Abstract: The first total synthesis of tricyclic sesquiterpene (±)-
O
HO
toxicodenane A has been accomplished. This synthetic work was
completed in 12 steps from dimedone utilizing diastereoselective
H
H
H
O
O
reductive
desymmetrization
of
2,2-disubstituted
5,5-
HO
dimethylcyclohexane-1,3-dione, stereocontrolled allylation, ring-
closing metathesis of diene compound yielding bicyclic compounds
having a 7-membered ring, and construction of the oxygen-bridged
moiety via neighboring group assisted ring-opening reaction of
epoxide as key steps.
HO
HO
toxicodenane A (1)
toxicodenane B (2)
toxicodenane C (3)
O
O
HO
toxicodenane E (5)
HO
Introduction
toxicodenane D (4)
In 2013, Cheng and co-workers reported the isolation of a
novel sesquiterpenoid, toxicodenane A (1), from the dried resin
of Toxicodendron vernicifluum, which is a traditional Chinese
medicine used for the treatment of gastritis, stomach cancer,
Figure 1. Structure of toxicodenane A and related compounds.
and atherosclerosis.1 The structure of 1,
a
tricyclic
Results and Discussion
sesquiterpenoid, was established through analysis of 2D NMR
spectra including COSY, HMBC, and ROESY experiments and
X-ray crystallographic diffraction as depicted in Figure 1.
The synthetic strategy for toxicodenane A (1) is outlined in
Figure 2. The target molecule 1 could be synthesized by
construction of the exo-methylene moiety from compound 6. The
oxygen-bridged compound 6 would be derived from compound 7
via epoxidation followed by ether cyclization. Bicyclic compound
7 would be constructed by RCM of compound 8, which was
derived from ketone 9 via stereocontrolled allylation. Ketone 9
could be synthesized by the diastereoselective reductive
desymmetrization of diketone 10, which was prepared from
commercially available dimedone (11).
Toxicodenane
A
(1)
possesses
a
unique
12-
oxatricyclo[7,2,1,01,6]dodecane skeleton and bears four
stereocenters including an all-carbon quaternary center. Related
cyclic sesquiterpenoids toxicodenanes B (2) and C (3), which
exhibit anti-diabetic nephropathy activity, were isolated along
with toxicodenane A. In addition, toxicodenanes D (4) and E (5)
were isolated from the same plant by the Cheng group in 2015.2
Although these toxicodenanes have unique structures and
biological activities, no total synthesis or synthetic studies have
been reported to date. The structural features of 1 attracted our
interest, and a synthetic study of toxicodenane A (1) was
initiated. Herein, we describe the first total synthesis of
toxicodenane A (1) in 12 steps utilizing the diastereoselective
OH
OH
O
O
reductive
desymmetrization
of
2,2-disubstituted
5,5-
dimethylcyclohexane-1,3-dione, stereocontrolled allylation, ring-
closing metathesis (RCM), and construction of the oxygen-
bridged moiety via neighboring group assisted ring-opening
reaction of epoxide as key steps.
HO
HO
toxicodenane A (1)
HO
7
6
stereocontrolled
allylation
O
OH
RCM
HO
HO
9
8
[a]
Dr. T. Kobayashi, K. Yamanoue, Dr. H. Abe, Prof. H. Ito
School of Life Sciences,
diastereoselective
reductive desymmetrization
O
O
Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: itohisa@toyaku.ac.jp
O
O
dimedone (11)
10
Supporting information for this article is given via a link at the end of
the document.
Figure 2. Synthetic strategy toward toxicodenane A.
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10.1002/ejoc.201701219
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Our synthetic study started by preparing diketone 10 from
dimedone (11) as shown in Scheme 1. Mono-methylation to the
activated methylene moiety of dimedone (11) using a modified
procedure reported by Franckevicius3 gave compound 12 in
83% yield. Although the direct introduction of the butenyl group
to compound 12 was attempted under several conditions, the
desired diketone 10 was obtained in low yield. Therefore,
diketone 10 was synthesized via a two-step operation. The
Michael addition of compound 12 with acrolein afforded known
aldehyde 134 in 86% yield, then a treatment of the resulting
aldehyde 13 with Tebbe reagent5 gave diketone 10 in 98% yield.
yield by reduction with L-Selectride, which is a bulky reductive
reagent, in THF at –78 °C (entry 4).
To invert the diastereoselectivity of the reductive
desymmetrization of diketone 10, the reduction of the enolate
form of 10 was attempted according to the modified procedure
reported by Simpkins6e (Scheme 2). Fortunately, treatment of 10
with LHMDS in THF at –78 °C for 1 h followed by the slow
addition of DIBALH at the same temperature provided the
desired keto alcohol 9 in 70% yield with 5:1 diastereoselectivity.
The stereoselectivity of the reductive desymmetrization via
enolate formation of diketone 10 was assumed to be due to the
preferentially approach of the hydride to the ketone of enolate A
from the side opposite the butenyl group.
O
O
O
MeI
H
, t-BuOK
1,4-dioxane,
t-BuOH
2.9 M NaOH aq.
100 oC, 16 h
83%
H–
O
rt, 22 h
86%
O
LHMDS, THF
O
dimedone (11)
12
–78 oC, 1 h
OLi
10
then
DIBALH
–78 oC, 15 h
O
O
HO
H–
O
Tebbe reagent
A
9
O
70%, 9:14 = 5:1
THF
0 oC, 1.5 h
98%
O
H
O
Scheme 2. The diastereoselective reductive desymmetrization of diketone 10
via enolate formation.
13
10
Scheme 1. Synthesis of diketone 10.
Treatment of 9 with allyl Grignard reagent in Et2O at –78 °C
gave compound 8 in 87% yield with 4:1 diastereoslectivity as
separable mixture using silica-gel column chromatography
(Scheme 3). To improve the stereoselectivity of the allylation,
the solvent, temperature, allylic metal reagents and protecting
group for the secondary alcohol were investigated. As a result,
we found out that the treatment of pivaloyl protected compound
15, which was prepared from 9 using pivaloyl chloride, with
Grignard reagent in Et2O at –78 °C afforded the allylated
compound 16 in 91% yield as the sole product.
Next, the diastereoselective reductive desymmetrization of
diketone 10 was attempted. Some examples of the
diastereoselective
reductive
desymmetrization
of
2,2-
6
disubstituted cyclohexane-1,3-dione have been reported, but
examples for 2,2-disubstituted 5,5-dimethylcyclohexane-1,3-
dione are very limited in the literature.7 Therefore, we
investigated the reaction conditions for this reductive
desymmetrization of diketone 10 (Table 1). First, treatment of
diketone 10 with NaBH4 in MeOH at –78 °C provided the keto
alcohols 9 and 14 in 77% yield in a ratio of 2:3 as inseparable
mixture by silica-gel column chromatography (entry 1). When
using THF as solvent, the keto alcohols 9 and 14 were obtained
in 61% yield in a 1:1 ratio (entry 2). The treatment with DIBALH
in CH2Cl2 at –78 °C provided the mixture of keto alcohols 9 and
14 along with the diol in a ratio of 2:2:5 (entry 3). The undesired
diastereomer 14 was obtained preferentially (1:3 ratio) in 58 %
OH
O
MgBr
Et2O
HO
HO
–78 oC, 4 h
87%, dr = 4:1
9
8
PivCl, DIPEA, DMAP
Table 1. Diastereoselective reductive desymmetrization of diketone 10.
CH2Cl2
reflux, 24 h
97%
O
O
conditions
10
+
OH
O
MgBr
Et2O
HO
HO
9
14
–78 oC, 3 h
91%, dr > 95:5
PivO
PivO
resulta
15
16
entry
conditions
NaBH4, MeOH, –78 o
C
77% (9:14 = 2:3)
61% (9:14 = 1:1)
– (9:14:diol = 2:2:5)
1
2
3
Scheme 3. Stereocontrolled allylation of ketones 9 and 15.
NaBH4, THF, 0 o
C
DIBALH, CH2Cl2, –78 o
C
With the successful stereocontrolled synthesis of compounds
8 and 16, we turned our attention to the construction of the
oxygen-bridged moiety. The RCM8 of diene compounds 8 and
16 using Grubbs second-generation reagent afforded the
bicyclic compounds 7 and 17 both in 96% yields. The treatment
L-Selectride, THF, –78 o
C
4
58% (9:14 = 1:3)
a The ratio of compound was determined by 1H NMR.
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10.1002/ejoc.201701219
European Journal of Organic Chemistry
FULL PAPER
attacks to C2a to afford compound 22, as described in the
possible mechanism in Figure 3.
of the bicyclic compounds 7 and 17 with m-CPBA in CH2Cl2 at
0 °C gave the corresponding epoxides 18 and 19 in 99% and
92% yields, respectively, as
a
sole products. The
stereochemistry of compound 19 was confirmed using X-ray
crystallographic analysis.9
OH
H
OH
O
O
2a
H+
OH
OH
Grubbs 2nd
m-CPBA
CH2Cl2
O
O
toluene
rt, 6 h
O
O
0 oC, 7 h
19
RO
RO
96% for 7
99%, dr >95:5 for 18
92%, dr >95:5 for 19
7 : R = H
8 : R = H
OH
OH
2a
96% for 17
17 : R = Piv
16 : R = Piv
O
OH
OH
O
O
O
O
O
22
ORTEP drawing of 19
RO
A
18 : R = H
19 : R = Piv
Figure 3. Possible mechanism for ether cyclization involving acid-mediated
epoxide ring-opening.
Scheme 4. Synthesis of epoxides 18 and 19.
Next, exo-methylene construction was achieved from
compound 22 via a two-step operation. Thus, the oxidation of
compound 22 with PCC gave the corresponding ketone 23 in
92% yield, followed by olefination of the ketone 23 using Tebbe
reagent to provide compound 24 in 81% yield. Finally, the
reduction of the pivaloyl group of 24 using DIBALH afforded the
target molecule 1 in 85% yield. Both the 1H and 13C NMR
spectra of synthetic 1 were identical with those of natural
toxicodenane A (1).1
To construct the oxygen-bridged moiety, the epoxides 18 and
19 were treated under acidic conditions. Unfortunately,
treatment of epoxide 18 with p-toluenesulfonic acid in THF at
room temperature provided the 3:1 mixture of undesired
compounds 20 and 21, which were bridged from the secondary
alcohol to the epoxide moiety, in 86% yield. On the other hand,
treatment of epoxide 19, which has a pivaloyl group, with p-
toluenesulfonic acid in THF under reflux afforded the desired
oxygen-brideged compound 22 in 76% yield.10
OH
O
Tebbe reagent
PCC
OH
OH
OH
O
OH
O
O
O
O
CH2Cl2
rt, 8 h
92%
THF
0 oC, 2 h
81%
TsOH
OH
PivO
THF
rt, 2 h
PivO
+
22
23
HO
86%
20
18
21
20:21 = 3:1
OH
OH
O
TsOH
THF
DIBALH
O
O
O
CH2Cl2
–78 oC, 2 h
85%
reflux, 6 h
76%
PivO
PivO
HO
toxicodenane A (1)
PivO
19
22
24
Scheme 5. Construction of oxygen-bridged moiety.
Scheme 6. Total synthesis of toxicodenane A (1).
In the ether cyclization involving acid-mediated epoxide ring-
opening, because of the epoxide and tertiary alcohol of
compound 19 are present on the same side of the molecule, the
backside attack of tertiary alcohol to epoxide is impossible. So,
we considered that the pivaloyl group is participated for this
reaction. Thus, the carbonyl group of pivaloyl ester attacks to
epoxide at C2a to form intermediate A, then tertiary alcohol
Conclusions
In conclusion, we have achieved the first total synthesis of
tricyclic sesquiterpene toxicodenane A (1) in 12 steps from
dimedone (11). The synthetic method involved the following
features: a) diastereoselective reductive desymmetrization of
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10.1002/ejoc.201701219
European Journal of Organic Chemistry
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compound 10; b) stereocontrolled allylation of the pivaloyl
protected compound 15; c) ring-closing metathesis of diene
compounds yielding bicyclic compounds having a 7-membered
ring; d) construction of the oxygen-bridged moiety via
neighboring group assisted ring-opening reaction of epoxide 19.
It is noteworthy that the pivaloyl group plays important role more
than protecting group: improving the diastereoselectivity of the
allylation and occurring the epoxide ring-opening reaction. This
synthetic strategy will be applicable to the synthesis of
toxicodenane A (1) in optically active form, which is now in
progress in our laboratory.
vacuo. The resulting residue was purified by column chromatography
(hexane-AcOEt, 6:1) to afford 10 (52 mg, 98%) as yellow oil: IR (neat,
cm–1) 2961, 1726, 1691, 1460, 1371, 1069; 1H NMR (400 MHz, CDCl3)
δ 5.73 (tdd, J = 16.4, 10.0, 5.9 Hz, 1H), 5.03-4.95 (m, 2H), 2.71 (d, J =
14.1 Hz, 2H), 2.48 (d, J =14.2 Hz, 2H), 1.94-1.88 (m, 2H), 1.84-1.79 (m,
2H), 1.24 (s, 3H), 1.08 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 209.9 (2C), 137.3, 115.5, 64.6, 51.4 (2C), 36.8, 30.7, 29.4, 28.7, 27.8,
18.2; HRESI calcd for C13H20O2Na [M+Na]+ 231.1361, found 231.1367.
(2S*,3S*)-2-(But-3-en-1-yl)-3-hydroxy-2,5,5-trimethylcyclohexan-1-
one
(9)
and
(2S*,3R*)-2-(but-3-en-1-yl)-3-hydroxy-2,5,5-
trimethylcyclohexan-1-one (14). To a stirred solution of 10 (50 mg, 0.24
mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in
THF, 0.29 mL, 0.29 mmol) at –78 °C under Ar, and the mixture was
stirred for 30 min at room temperature. Then to this solution was added
diisobutylaluminium hydride (1.0 M in THF, 0.79 mL, 0.79 mmol) at –
78 °C, and the mixture was stirred for 15 h at same temperature. The
reaction was quenched by adding with 1 M HCl aqueous solution, and
extracted with AcOEt. The combined organic layers were washed with
brine and dried over MgSO4. After the solvent was removed in vacuo, the
resulting residue was purified by column chromatography (hexane-AcOEt,
5:1) to give 9 and 14 (35 mg, 70%, 5:1 mixture) as a white solid: Data for
9 (white solid): mp = 84-85 °C; IR (KBr disk, cm–1); 3433, 2955, 1684,
1043, 1006; 1H NMR (400 MHz, CDCl3) δ 5.82-5.73 (m, 1H), 5.03-5.02
(m, 1H), 4.97-4.93 (m, 1H), 3.73 (dd, J = 11.7, 4.8 Hz, 1H), 2.41 (d, J =
13.3 Hz, 1H), 2.02 (dd, J = 13.7, 2.7 Hz, 1H), 2.02-1.95 (m, 1H), 1.90 (t, J
= 13.3 Hz, 1H), 1.83-1.58 (m, 4H), 1.15 (s, 3H), 1.09 (s, 3H), 0.88 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 213.2, 138.2, 114.8, 75.1, 54.1, 50.9, 42.6,
32.03, 31.98, 30.5, 27.8, 26.6, 18.1; HRESI calcd for C13H23O2 [M+H]+
211.1698, found 211.1693.
Experimental Section
All reactions involving air- and moisture-sensitive reagents were carried
out using standard syringe-septum cap techniques. Unless otherwise
noted, all solvents and reagents were obtained from commercial
suppliers and used without further purification. Routine monitoring of
reactions were carried out Merck silica gel 60 F254 TLC plates. Column
chromatography was performed on Kanto Chemical Silica Gel 60N
(spherical, neutral 60–230 µm) with the solvents indicated. Melting points
were taken on a Yanako MP-S3 micro melting point apparatus and are
uncorrected. 1H and 13C NMR spectra were measured with a Jeol ECZ-
400s (400 MHz) or a Burker AV-600 (600 MHz) spectrometer. Chemical
shifts were expressed in ppm using CHCl3 (7.26 ppm for 1H NMR, 77.0
ppm for 13C NMR) in CDCl3 as an internal standard. Infrared spectral
measurements were carried out with a JASCO FT/IR-4700 and only
noteworthy absorptions were listed. HRMS spectra measured on a
Micromass LCT spectrometer.
Data for 14 (colorless oil): IR (neat, cm–1) 3442, 2955, 1697, 1464, 1029,
1000; 1H NMR (400 MHz, CDCl3) δ 5.84 (tdd, J = 16.9, 10.0, 6.4 Hz, 1H),
5.07-5.01 (m, 1H), 4.97-4.93 (m, 1H), 3.99 (t, J = 7.8 Hz, 1H), 2.41 (d, J =
14.2 Hz, 1H), 2.09-2.03 (m, 3H), 1.82-1.75 (m, 3H), 1.63-1.55 (m, 2H),
1.11 (s, 3H), 1.07 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
213.7, 139.1, 114.5, 71.0, 53.4, 50.8, 42.8, 33.7, 32.1, 31.7, 28.7, 27.4,
18.1; HRESI calcd for C13H23ONa2 [M+Na]+ 233.1517, found 233.1510.
2,5,5-Trimethylcyclohexane-1,3-dione (12). To a stirred solution of
dimedone (11) (4.0 g, 28.5 mmol) in 2.9 M NaOH aqueous solution (10
mL) was added methyl iodide (8.1 g, 3.55 mL, 57.1 mmol) at 0 °C, and
the mixture was stirred for 16 h at 100 °C. The reaction mixture was
cooled to 0 °C, filtered under vacuo. The resulting solid was dissolved in
AcOEt and purified by column chromatography (hexane-AcOEt, 1:2) to
afford 12 (3.6 g, 83%) as a white solid: The spectral data of 12 was
identified with those of the previous report.3
(1S*,2S*,3S*)-1-Allyl-2-(but-3-en-1-yl)-2,5,5-trimethylcyclohexane-1,3-
diol (8). To a stirred solution of 9 (66 mg, 0.31 mmol) in Et2O (3 mL) was
added allylmagnesium bromide (1.0 M in Et2O, 0.75 mL, 0.75 mmol) at –
78 °C under Ar. After the reaction mixture was stirred for 4 h at same
temperature, the reaction was quenched by adding with NH4Cl aqueous
solution. The mixture was extracted with AcOEt and organic layers were
combined, washed with brine and dried over MgSO4. After the solvent
was removed in vacuo, the resulting residue was purified by column
chromatography (hexane-AcOEt, 5:1) to afford 8 (55 mg, 70%) as
colorless oil and C1- epimer (13 mg, 17%) as colorless oil.
3-(1,4,4-Trimethyl-2,6-dioxocyclohexyl)propanal (13). To
a stirred
solution of 12 (1.0 g, 6.54 mmol) in 1,4-dioxane (3.3 mL) and t-BuOH (6.5
mL) was added t-BuOK (9.2 mg, 0.082 mmol) in t-BuOH (0.3 mL) and
acrolein (458 mg, 8.17 mmol) in 1,4-dioxane (3.3 mL) at room
temperature. After the mixture was stirred for 22 h at same temperature,
the reaction was quenched by adding with acetic acid, and the mixture
was concentrated in vacuo. The resulting residue was extracted with
AcOEt. The combined organic layers were washed with 0.1 M NaOH
aqueous solution and brine, dried over MgSO4, and concentrated in
vacuo. The resulting residue was purified by column chromatography
(hexane-AcOEt, 4:1) to afforded 13 (1.18 g, 86%) as yellow oil: IR (neat,
cm–1); 2955, 1723, 1692, 1458, 1373, 1327, 1192, 1074; 1H NMR (400
MHz, CDCl3) δ 9.70 (s, 1H), 2.60 (s, 4H), 2.38 (t, J = 8.2 Hz, 2H), 2.06 (t,
J = 8.2 Hz, 2H), 1.28 (s, 3H), 0.98 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
209.7 (2C), 200.8, 63.4, 51.1 (2C), 39.1, 30.7, 28.7, 28.2, 27.1, 21.0;
HRESI calcd for C12H18O3Na [M+Na]+ 233.1154, found 233.1159.
Data for 8: IR (neat, cm–1); 3456, 2950, 2927, 1638, 1364, 994; 1H NMR
(400 MHz, CDCl3) δ 5.92-5.75 (m, 2H), 5.22-5.19 (m, 1H), 5.14-5.10 (m,
1H), 5.03-4.98 (m, 1H), 4.93-4.91 (m, 1H), 4.08 (dd, J = 10.0, 6.4 Hz, 1H),
2.36-2.03 (m, 4H), 1.67 (td, J = 14.2, 5.5 Hz), 1.53-1.45 (m, 2H), 1.32-
1.17 (m, 3H), 1.09 (s, 6H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 140.0, 133.9, 120.0, 113.9, 77.7, 72.4, 44.5, 44.4, 42.8, 42.2, 34.2, 31.0,
30.3, 29.8, 29.0, 15.4; HRESI calcd for C16H28O2Na [M+Na]+ 275.1987,
found 275.1979.
Data for C1-epimer: IR (neat, cm–1); 3398, 2950, 1638, 1595, 1246, 994;
1H NMR (400 MHz, CDCl3) δ 5.96-5.80 (m, 2H), 5.23-5.20 (m, 1H), 5.17-
5.10 (m, 1H), 5.05-5.00 (m, 1H), 4.94-4.92 (m, 1H), 4.21 (dd, J = 11.9,
4.6 Hz), 2.52-2.42 (m, 1H), 2.37 (dd, J = 16.9, 7.8 Hz, 1H), 2.30-1.99 (m,
3H), 1.73-1.40 (m, 5H), 1.29-1.18 (m, 2H), 1.11 (s, 3H), 0.91 (s, 3H), 0.82
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.6, 134.0, 120.1, 113.7, 78.5,
70.2, 46.3, 45.8, 43.8, 42.1, 34.4, 34.3, 31.0, 30.6, 28.7, 15.0; HRESI
calcd for C16H28O2Na [M+Na]+ 275.1987, found 275.1980.
2-(But-3-en-1-yl)-2,5,5-trimethylcyclohexane-1,3-dione (10). To
a
stirred solution of 13 (53 mg, 0.25 mmol) in THF (5 mL) was added
Tebbe reagent (0.5 M in toluene, 0.5 mL, 0.25 mmol) at 0 °C under Ar.
After the reaction mixture was stirred for 2 h at same temperature, the
reaction was quenched by adding with 30% NaOH aqueous solution. The
mixture was filtered under vacuo and the filtrate was concentrated in
(2S*,3S*)-2-(But-3-en-1-yl)-2,5,5-trimethyl-3-oxocyclohexyl pivalate
(15). To a stirred solution of 9 (42 mg, 0.20 mmol) in CH2Cl2 (4 mL) was
added N,N-diisopropylethylamine (77 mg, 0.10 mL, 0.59 mmol), N,N-
dimethyl-4-aminopyridine (12 mg, 0.10 mmol) and pivaloyl chloride (36
mg, 0.04 mL, 0.30 mmol) at 0 °C under Ar. After the reaction mixture was
refluxed for 24 h, to this mixture was added the N,N-
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10.1002/ejoc.201701219
European Journal of Organic Chemistry
FULL PAPER
1294,1184, 1169; 1H NMR (400 MHz, CDCl3) δ 5.90-5.83 (m, 1H), 5.58-
5.52 (m, 1H), 5.26 (dd, J = 10.5, 6.0 Hz, 1H), 2.74 (d, J = 14.6 Hz, 1H),
2.29-2.22 (m, 1H), 2.04-1.95 (m, 2H), 1.85-1.80 (m, 1H), 1.70-1.44 (m,
5H), 1.21 (s, 3H), 1.19 (s, 9H), 1.11 (s, 3H), 0.93 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 177.9, 133.7, 127.1, 76.5, 75.3, 45.1, 44.7, 40.7, 39.0,
38.6, 34.2, 31.2, 29.3, 27.4, 27.2 (3C), 22.4, 16.8; HRESI calcd for
C19H32O3Na [M+Na]+ 331.2249, found 331.2248.
diisopropylethylamine (77 mg, 0.10 mL, 0.59 mmol), N,N-dimethyl-4-
aminopyridine (12 mg, 0.10 mmol) and pivaloyl chloride (36 mg, 0.04 mL,
0.30 mmol), and the mixture was refluxed for 12 h. To this mixture was
added N,N-diisopropylethylamine (231 mg, 0.30 mL, 1.77 mmol), N,N-
dimethyl-4-aminopyridine (36 mg, 0.30 mmol) and pivaloyl chloride (108
mg, 0.12 mL, 0.90 mmol), and the mixture was refluxed for 3 h. The
reaction was quenched by adding with saturated NH4Cl aqueous solution,
and extracted with AcOEt. The combined organic layers were washed
with brine and dried over MgSO4. After the solvent was removed in vacuo,
the resulting residue was purified by column chromatography (hexane-
AcOEt, 20:1) to give 15 (56 mg, 97%) as a white solid: mp = 70-71 °C; IR
(KBr disk, cm–1); 2964, 1730, 1699, 1465, 1366, 1282, 1158; 1H NMR
(400 MHz, CDCl3) δ 5.82-5.73 (m, 1H), 5.03-4.99 (m, 1H), 4.98-4.95 (m,
1H), 4.88 (dd, J = 10.6, 5.5 Hz, 1H), 2.38 (d, J = 13.7 Hz, 1H), 2.12 (dd, J
= 13.7, 1H), 2.01-1.76 (m, 4H), 1.71-1.60 (m, 2H), 1.21 (s, 9H), 1.073 (s,
3H), 1.067 (s, 3H), 0.93 (s, 3H): 13C NMR (100 MHz, CDCl3) δ 211.7,
177.5, 138.0, 114.9, 76.1, 52.5, 51.1, 39.0, 38.9, 32.4, 31.64, 31.59, 27.8,
27.1 (3C), 26.8, 18.4; HRESI calcd for C18H31O3 [M+H]+ 295.2273, found
295.2266.
(1aS*, 2aR*, 6S*, 6aS*, 8aR*)-4,4,6a-Trimethyldecahydro-2aH-
benzo[4,5]cyclohepta[1,2-b]oxirene-2a,6-diol (18). To
a
stirred
solution of 7 (10 mg, 0.04 mmol) in CH2Cl2 (1 mL) was added 3-
chloroperbenzoic acid (12 mg, 0.0 mmol) at 0 °C under Ar. After the
reaction mixture was stirred for 7 h at same temperature, the reaction
was quenched by adding with saturated NaHCO3 aqueous solution. The
mixture was extracted with AcOEt and organic layers were combined,
washed with brine and dried over MgSO4. After the solvent was removed
in vacuo, the resulting residue was purified by column chromatography
(hexane-AcOEt, 3:1) to afford 18 (10 mg, 99%) as colorless oil: IR (neat,
cm–1); 3456, 2943, 1725, 1472, 1363, 1016, 993; 1H NMR (400 MHz,
CDCl3) δ 4.04 (dd, J = 11.5, 5.1 Hz, 1H), 3.07 (td, J = 7.3, 4.5 Hz, 1H),
2.85 (td, J = 6.8, 4.5 Hz, 1H), 2.18-2.11 (m, 1H), 1.95 (d, J = 3.6 Hz, 2H),
1.81 (d, J = 14.6 Hz, 1H), 1.58-1.50 (m, 3H), 1.49-1.32 (m, 3H), 1.17 (s,
3H), 1.07 (s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 77.7, 72.3,
55.0, 51.0, 45.5, 45.1, 42.4, 41.2, 34.6, 31.2, 29.0, 23.9, 23.8, 17.1;
HRESI calcd for C14H24O3Na [M+Na]+ 263.1623, found 263.1623.
(1S*,2S*,3S*)-3-Allyl-2-(but-3-en-1-yl)-3-hydroxy-2,5,5-
trimethylcyclohexyl pivalate (16). To a stirred solution of 15 (10.5 mg,
0.036 mmol) in Et2O (1 mL) was added allylmagnesium bromide (1.0 M in
Et2O, 0.09 mL, 0.09 mmol) at –78 °C under Ar. After the reaction mixture
was stirred for 3 h at same temperature, the reaction was quenched by
adding with NH4Cl aqueous solution. The mixture was extracted with
AcOEt and organic layers were combined, washed with brine and dried
over MgSO4. After the solvent was removed in vacuo, the resulting
residue was purified by column chromatography (hexane-AcOEt, 20:1) to
afford 16 (11 mg, 91%) as a white solid: mp = 67-68 °C; IR (KBr disk,
cm–1) 3446, 2926, 1704, 1641, 1479, 1363, 1289, 1171; 1H NMR (400
MHz, CDCl3) δ 5.92-5.75 (m, 2H), 5.28 (dd, J = 11.4, 4.6 Hz, 1H), 5.20
(dd, J = 10.1, 2.3 Hz, 1H), 5.14-5.09 (m, 1H), 5.04-4.99 (m, 1H), 4.95-
4.93 (m, 1H), 2.32-2.18 (m, 2H), 2.15-2.05 (m, 1H), 1.70 (td, J = 13.7, 5.0
Hz, 1H), 1.55-1.43 (m, 4H), 1.37-1.24 (m, 2H), 1.19 (s, 9H), 1.15 (s, 3H),
0.98 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.0, 139.8,
133.8, 120.0, 114.1, 77.2, 75.1, 44.5, 44.0, 41.7, 39.3, 38.9, 33.7, 31.7,
31.3, 30.9, 30.0, 27.2 (3C), 15.4; HRESI calcd for C21H36O3Na [M+Na]+
359.2562, found 359.2564.
(1aS*, 2aR*, 6S*, 6aS*, 8aR*)-2a-Hydroxy-4,4,6a-trimethyldecahydro-
2H-benzo[4,5]cyclopeta[1,2-b]oxiren-6-yl pivalate (19). To a stirred
solution of 17 (114 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added 3-
chloroperbenzoic acid (96 mg, 0.56 mmol) at 0 °C under Ar. After the
reaction mixture was stirred for 7 h at same temperature, the reaction
was quenched by adding with saturated NaHCO3 aqueous solution. The
mixture was extracted with AcOEt and organic layers were combined,
washed with brine and dried over MgSO4. After the solvent was removed
in vacuo, the resulting residue was purified by column chromatography
(hexane-AcOEt, 3:1) to afford 19 (111 mg, 92%) as a white solid: mp =
202-203 °C; IR (KBr disk, cm–1
) 3505, 2934, 1707, 1480, 1462,
1294,1185; 1H NMR (400 MHz, CDCl3) δ 5.23 (t, 1H, J = 8.3 Hz), 3.09 (td,
1H, J = 6.9, 4.6 Hz), 2.86 (td, 1H, J = 7.3, 4.5 Hz), 2.22-2.11 (m, 1H),
2.02-1.90 (m, 2H), 1.83 (d, 1H, J = 14.2 Hz), 1.76-1.70 (m, 1H), 1.62-1.52
(m, 4H), 1.40-1.36 (m, 1H), 1.23 (s, 3H), 1.19 (s, 9H), 0.98 (s, 3H), 0.97
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.8, 77.5, 75.0, 54.9, 50.9, 45.1,
44.9, 41.0, 39.0, 38.6, 34.5, 31.3, 28.7, 27.2 (3C), 25.4, 24.0, 16.8;
HRESI calcd for C19H32O4Na [M+Na]+ 347.2198, found 347.2200.
(1S*,4aS*,9aS*)-3,3,9a-Trimethyl-1,2,3,4,5,8,9,9a-octahydro-4aH-
benzo[7]annulene-1,4a-diol (7). To a stirred solution of 8 (76 mg, 0.30
mmol) in toluene (15 ml) was added Grubbs catalyst second generation
(2.6 mg, 3.0 mmol) at room temperature under Ar. After the reaction
mixture was stirred for 6 h at room temperature, the mixture was
concentrated in vacuo to give the crude products, which were purified by
column chromatography on silica gel (hexane/AcOEt, 5:1) to give 7 (65
mg, 96%) as a white solid: mp = 139-140 °C; IR (KBr disk, cm–1) 3418,
2943, 1434, 1342, 1188, 1080, 1036; 1H NMR (600 MHz, CDCl3) δ 5.87-
5.82 (m, 1H), 5.55-5.51 (m, 1H), 4.06 (dd, J = 12.1, 4.6 Hz, 1H), 2.74 (d,
J = 14.8 Hz, 1H), 2.22 (t, J = 14.7 Hz, 1H), 2.03-1.97 (m, 1H), 1.94 (d, J =
14.7 Hz, 1H), 1.78 (dd, J = 13.2, 9.0 Hz, 1H), 1.56-1.43 (m, 4H), 1.20 (s,
3H), 1.14 (s, 3H), 1.04 (d, J = 15.1 Hz, 1H), 0.92 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 133.7, 127.0, 76.8, 72.6, 45.6, 44.7, 42.5, 40.9, 34.4, 31.1,
29.5, 25.7, 22.3, 17.0; HRESI calcd for C14H24O2Na [M+Na]+ 247.1674,
found 247.1683.
(1S*, 4aR*, 6R*, 7R*, 9aS*)-3,3,9a-Trimethyldecahydro-1H-1,6-
epoxybenzo[7]annulene-4a,7-diol (20) and (1S*, 4aR*, 6S*, 7S*,
9aS*)-3,3,9a-trimethyldecahydro-1H-1,7-epoxybenzo[7]annulene-
4a,6-diol (21). To a stirred solution of 18 (31 mg, 0.13 mmol) in THF (3
mL) was added p-toluenesulfonic acid (12 mg, 0.06 mmol) at room
temperature under Ar. After the reaction mixture was stirred for 2 h at
same temperature, the reaction was extracted with Et2O and organic
layers were combined, washed with brine and dried over MgSO4. After
the solvent was removed in vacuo, the resulting residue was purified by
column chromatography (hexane-AcOEt, 1:2) to afford 20 and 21 (27 mg,
86%, 3:1 mixture) as colorless oil. Data for 20: IR (neat, cm–1); 3389,
2945, 1469, 1362, 1094, 1033; 1H NMR (400 MHz, CDCl3) δ 3.99-3.96
(m, 1H), 3.90 (ddd, J = 8.7, 5.5, 2.7 Hz, 1H), 3.83 (t, J = 2.7 Hz, 1H), 2.48
(dd, J = 15.1, 8.7 Hz, 1H), 2.14-2.10 (m, 1H), 2.06-1.92 (m, 2H), 1.74-
1.65 (m, 2H), 1.55-1.51 (m, 3H), 1.42 (ddd, J = 14.6, 11.9, 5.0 Hz, 1H),
1.27 (s, 3H), 0.97 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
81.7, 74.9, 74.2, 71.2, 52.1, 40.8, 40.2, 36.0, 35.9, 34.3, 31.8, 30.6, 29.3,
22.8; HRESI calcd for C14H24O3Na [M+Na]+ 263.1623, found 263.1614.
Data for 21: IR (neat, cm–1); 3389, 2930, 2862, 1466, 1086, 1048; 1H
(1S*,
4aS*,
9aS*)-4a-Hydroxy-3,3,9a-trimethyl-2,3,4,4a,5,8,9,9a-
stirred
octahadro-1H-benzo[7]annulene-1-yl pivalate (17). To
a
solution of 16 (10 mg, 0.03 mmol) in toluene (1.5 ml) was added Grubbs
catalyst second generation (0.3 mg, 0.3 mmol) at room temperature
under Ar. After the reaction mixture was stirred for
6 h at room
temperature, the mixture was concentrated in vacuo to give the crude
products, which were purified by column chromatography on silica gel
(hexane/AcOEt, 10:1) to give 17 (9.2 mg, 96%) as a white solid: mp =
143-144 °C; IR (KBr disk, cm–1) 3506, 2925, 1707, 1478, 1396, 1364,
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10.1002/ejoc.201701219
European Journal of Organic Chemistry
FULL PAPER
NMR (400 MHz, CDCl3) δ 4.29 (ddd, J = 10.0, 6.8, 3.2 Hz, 1H), 3.85-3.82
(m, 2H), 2.17 (dd, J = 14.2, 7.3 Hz, 1H), 2.06-1.90 (m, 3H), 1.83-1.65 (m,
3H), 1.59-1.52 (m, 2H), 1.25-1.19 (m, 1H), 1.23 (s, 3H), 0.97 (s, 3H), 0.87
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 77.8, 74.7, 73.3, 69.5, 51.3, 46.9,
39.1, 38.1, 37.0, 31.8, 30.6, 25.9, 23.7, 18.9; HRESI calcd for
C14H24O3Na [M+Na]+ 263.1623, found 263.1616.
Toxicodenane A (1). To a stirred solution of 24 (8.2 mg, 0.03 mmol) in
CH2Cl2 (1 mL) was added diisobutylaluminium hydride (1.0 M in hexane,
0.03 mL, 0.03 mmol) at –78 °C under Ar. After the mixture was stirred for
30 min at –78 °C, the reaction was quenched by adding with 1 M HCl
aqueous solution and stirred for 2 h at room temperature. The mixture
was extracted with AcOEt and organic layers were combined, washed
with brine and dried over MgSO4. After the solvent was removed in vacuo,
the resulted residue was dissolved in THF and 1 M HCl aqueous solution
was added at 0 °C. After the mixture was stirred for 2 h at room
temperature, saturated NaHCO3 aqueous solution was added, and
extracted with AcOEt. The combined organic layers were washed with
brine and dried over MgSO4. After the solvent was removed in vacuo, the
resulting residue was purified by column chromatography (hexane-AcOEt,
15:1) to afforded 1 (6.0 mg, 85%) as a white solid: mp = 151-153 °C; IR
(KBr disk, cm–1) 3410 (br), 2955, 2921, 2856, 1668, 1463, 1377, 1173,
1133, 1050, 1034, 1008, 764; 1H NMR (400 MHz, CDCl3) δ 4.84 (br s,
1H), 4.79 (br s, 1H), 4.48 (br s, 1H), 3.67 (dd, J = 3.6, 2.3 Hz, 1H), 3.62
(d, J = 16.9 Hz, 1H), 2.30 (dt, J = 16.5, 2.7 Hz, 1H), 2.20-2.08 (m, 2H),
1.89-1.84 (m, 2H), 1.45 (dt, J = 15.1, 2.3 Hz, 1H), 1.41-1.37 (m, 1H), 1.30
(d, J = 13.3 Hz, 1H), 1.16 (s, 3H), 1.08 (s, 3H), 1.02 (d, J = 8.7 Hz, 1H),
0.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.2, 101.3, 83.4, 79.1, 77.2,
45.4, 43.2, 41.2, 40.1, 35.2, 31.7, 29.9, 28.9, 26.0, 21.1; HRESI calcd for
C15H25O2 [M+H]+ 237.1855, found 237.1854.
(1S*, 4aR*, 6S*, 7R*, 9aS*)-6-Hydroxy-3,3,9a-trimethyldecahydro-4a,
7-epoxybenzo[7]annulen-1-yl pivalate (22). To a stirred solution of
epoxyde 19 (14.2 mg, 0.04 mmol) in THF (2 mL) was added p-
toluenesulfonic acid (4.2 mg, 0.02 mmol) at room temperature under Ar.
After the mixture was refluxed for 6 h, the reaction was quenched by
adding with saturated NaHCO3 aqueous solution. The mixture was
extracted with AcOEt and organic layers were combined, washed with
brine and dried over MgSO4. After the solvent was removed in vacuo, the
resulted residue was purified by column chromatography (hexane-AcOEt,
3:1) to afford 22 (9.9 mg, 76%) as a colorless oil: IR (neat, cm–1) 3424,
2951, 1726, 1477, 1396, 1365, 1283, 1144, 1025; 1H NMR (400 MHz,
CDCl3) δ 4.79 (dd, J = 4.1, 2.3 Hz, 1H), 4.21 (m, 1H), 4.07 (m, 1H), 3.27
(dd, J = 14.2, 7.4 Hz, 1H), 2.03-1.94 (m, 2H), 1.86-1.78 (m, 2H), 1.59-
1.53 (m, 2H), 1.47-1.36 (m, 2H), 1.24 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H),
1.06-1.03 (m, 1H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.6,
84.2, 82.9, 77.4, 76.5, 60.3, 47.1, 45.4, 39.3, 37.8, 34.7, 31.4, 29.3, 27.2
(3C), 26.1, 24.3, 20.1; HRESI calcd for C19H32O4Na [M+Na]+ 347.2198,
found 347.2198.
(1S*,4aR*,7R*,9aS*)-3,3,9a-trimethyl-6-oxodecahydro-4a,7-
Supporting Information
epoxybenzo[7]annulen-1-yl pivalate (23). To
a stirred solution of
1
(see footnote on the first page of this article): H-NMR and 13C-
alcohol 22 (48 mg, 0.15 mmol) in CH2Cl2 (3.7 mL) was added pyridinium
chlorochromate (48 mg, 0.22 mmol) at room temperature under Ar. After
the mixture was stirred for 8 h at room temperature, the mixture was
filtered under vacuo and the filtrate was concentrated in vacuo. The
resulting residue was purified by column chromatography (hexane-AcOEt,
15:1) to afford corresponding ketone (44 mg, 92%) as a white solid. mp =
72-73 °C; IR (KBr disk, cm–1) 2954, 1760, 1725, 1458, 1279, 1137, 1048;
1H NMR (400 MHz, CDCl3) δ 4.86 (dd, J = 4.1, 2.2 Hz, 1H), 4.03 (d, J =
4.1 Hz, 1H), 3.27 (d, J = 18.3 Hz, 1H), 2.36 (d, J = 17.8 Hz, 1H), 2.12 (tt,
J = 13.7, 5.5 Hz, 1H), 1.98 (d, J = 13.7 Hz, 1H), 1.90 (dd, J = 16.0, 4.1 Hz,
1H), 1.73 (td, J = 13.7, 5.5 Hz, 1H), 1.62-1.56 (m, 1H), 1.53-1.46 (m, 2H),
1.27 (s, 3H), 1.22 (s, 9H), 1.07 (s, 3H), 1.01 (s, 3H), 0.88 (t, J = 6.9 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 217.3, 177.6, 82.2, 78.2, 77.1, 48.8,
45.7, 39.3, 38.9, 37.9, 34.7, 31.4, 29.6, 27.3 (3C), 26.2, 23.6, 20.5;
HRESI calcd for C19H30O4Na [M+Na]+ 345.2042, found 345.2041.
NMR spectra of all compounds are provided in the supporting
information.
Acknowledgements
This work was supported financially by the Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
Keywords: sesquiterpenoid • toxicodenane• diastereoselective
synthesis • reductive desymmetrization • ether cyclization
Pivaloyl protected toxicodenane A (24). To a stirred solution of ketone
23 (7.3 mg, 0.02 mmol) in THF (0.5 mL) was added Tebbe reagent (0.5
M in toluene, 0.025 mmol, 0.05 mL) at 0 °C under Ar. After the reaction
mixture was stirred for 2 h at same temperature, the reaction was
quenched by adding with 30% NaOH aqueous solution. The mixture was
filtered under vacuo and the filtrate was extracted with AcOEt. The
combined organic layers were washed with brine and dried over MgSO4.
After the solvent was removed in vacuo, the resulting residue was
purified by column chromatography (hexane-AcOEt, 50:1) to give 23 (5.2
mg, 81%) as a white solid. mp = 59-60 °C; IR (KBr disk, cm–1) 2953,
2868, 1726, 1476, 1395, 1366, 1282, 1138, 1016; 1H NMR (400 MHz,
CDCl3) δ 4.86 (br s, 1H), 4.83 (dd, J = 4.2, 1.9 Hz, 1H), 4.80 (br s, 1H),
4.49 (br s, 1H), 3.47 (d, J = 15.1 Hz, 1H), 2.35 (dt, J = 16.5, 2.7 Hz, 1H),
2.12 (tdd, J = 12.8, 5.0, 3.2 Hz, 1H), 1.92-1.77 (m, 3H), 1.45 (dt, J = 15.6,
1.8 Hz, 1H), 1.40-1.31 (m, 2H), 1.24 (s, 9H), 1.18 (s, 3H), 1.08 (s, 3H),
1.02 (dd, J = 13.3, 5.0 Hz, 1H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 177.7, 152.7, 101.4, 83.0, 79.1, 77.5, 45.1, 43.0, 39.8, 38.9, 38.1, 34.9,
31.4, 29.5, 28.8, 27.3 (3C), 25.8, 21.1; HRESI calcd for C20H32O3Na
[M+Na]+ 343.2249, found 343.2247.
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European Journal of Organic Chemistry
FULL PAPER
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European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Total Synthesis
Toyoharu Kobayashi, Kotono
Yamanoue, Hideki Abe, Hisanaka Ito*
i) diastereoselective
reductive
desymmetrization
OH
O
i) ring-closing metathesis
O
ii) ether cyclization involving
ii) stereocontrolled
epoxide ring-oprning
Page No. – Page No.
HO
toxicodenane A
allykation
O
PivO
Diastereoselective Total Synthesis of
The first total synthesis of toxicodenane A has been accomplished in 12 steps
utilizing diastereoselective reductive desymmetrization, stereocontrolled allylation,
ring-closing metathesis, and construction of the oxygen-bridged moiety via
neighboring group assisted ring-opening reaction of epoxide as key steps.
(±)-Toxicodenane A
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