An epoxide ring-opening approach for a short and stereoselective synthesis of icetexane diterpenoids

Article abstract of DOI:10.1016/j.tetlet.2009.11.108

A new approach for the synthesis of the core skeleton of icetexane diterpenoids is presented and deals with an epoxide ring-opening reaction by metallated aromatic compounds. Employing this strategy, a short synthesis of an icetexane analogue of brussonol was achieved in just four steps from 2-allyl-cyclohexanone.

Full text of DOI:10.1016/j.tetlet.2009.11.108

Tetrahedron Letters 51 (2010) 686–688
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An epoxide ring-opening approach for a short and stereoselective synthesis of
icetexane diterpenoids
*
Adriana Carita, Antonio C. B. Burtoloso
Instituto de Química de São Carlos, Universidade de São Paulo, CEP 13560-970 São Carlos, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for the synthesis of the core skeleton of icetexane diterpenoids is presented and deals
with an epoxide ring-opening reaction by metallated aromatic compounds. Employing this strategy, a
short synthesis of an icetexane analogue of brussonol was achieved in just four steps from 2-allyl-
cyclohexanone.
Received 3 November 2009
Revised 23 November 2009
Accepted 24 November 2009
Available online 29 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The icetexane diterpenoids encompass a variety of bioactive
and structurally interesting compounds.1 Possessing in its tricyclic
skeleton a cyclohexane ring, a central seven-membered ring, and
an aromatic ring (or a quinone), these compounds include diter-
penes such as brussonol 1, demethylsalvicanol 2, salviasperanol
3, isopisiferin 4, rosmaridiphenol 5, barbatusol 6, cyclocoulterone
7, and komaroviquinone 8, among others (Fig. 1).
different and vast biological activities. In fact, anti-Chagasic, anti-
cancer, antibacterial, antifungal, and anti-Leishmania activities
are some of the characteristics found in many of these diterpenes.1
Considering that, as well as the modest number of different short
approaches to prepare such a nice and vast class of compounds de-
scribed in the literature2, we decided to investigate the synthesis of
the core structure of these diterpenes. We envisioned accomplish-
ing this by employing an epoxide ring-opening reaction as a key
strategy3, followed by Friedel–Crafts or Friedel–Crafts-type cycli-
zation reactions (Scheme 1).
According to the diverse array of structures found in the icetex-
anes, it is expected that each subclass of these diterpenes possess
It is worth mentioning that intermediates like C were already
employed in the total synthesis of important icetexane diter-
penes2a,l, but are generally prepared by multi-step protocols and
in low overall yields starting from B. An epoxide strategy, however,
would reach the same intermediates in just two steps from a
substituted cyclohexanone and would bring all the correct stereo-
centers attached in the epoxide structure. Herein, we not only
HO
O
HO
O
HO
OH
OH
OH
OH
H
H
brussonol 1
demethylsalvicanol 2
salviasperanol 3
HO
OH
OH
O
H
MeO
OP
OMe
R
tricyclic core
of icetexane
diterpenoids
OMe
R'
H
H
M
OMe
R'
isopisiferin 4
rosmaridiphenol 5
H
O
B
MeO
OP
OMe
R
R
epoxide
opening
strategy
HO
O
O
O
O
OH
OMe
OMe
R
OH
+
O
O
O
R'
H
O
O
OH
A
H
H
H
H
O
cyclocoulterone 7
OH
OH
komaroviquinone 8
C
P = protecting group
M = Li, Mg or Cu
barbatusol 6
H
MeO
OMe
R
Figure 1. Some icetexane diterpenoids.
O
R'
H
H
* Corresponding author. Tel.: +55 16 3373 8641; fax: +55 16 3373 9952.
E-mail address: antonio@iqsc.usp.br (A.C.B. Burtoloso).
Scheme 1. Epoxide ring-opening approach for the icetexane synthesis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.108

A. Carita, A. C. B. Burtoloso / Tetrahedron Letters 51 (2010) 686–688
687
mercially available and easily prepared 2-allyl-cyclohexanone 104,
using a Corey–Chaykovsky epoxidation reaction5 (Scheme 2).
Treatment of 10 with trimethylsulfoxonium iodide and potassium
tert-butoxide, in DMSO, furnished cis epoxide 9 in 71%. Although
the cis stereochemistry outcome is the one expected according to
the literature for reactions with mono 2-substituted cyclohexa-
nones and trimethylsulfoxonium iodide6,7, we decided to prove it
by comparative analysis. Since epoxide 9 is unknown, it was con-
verted to its tertiary alcohol derivative, whose 1H and 13C NMR
data matched perfectly with the one of known alcohol 118 (Scheme
2).
O
S
I
O
OH
O
t-BuO-K+
O
H3CO OCH3
DMSO
5h
H
(+) 9
10 83%
71%
p-TsOH, 150 0
C
single isomer
epoxide stereochemistry proof
CH3MgBr or CH3Li
THF, -78 to 0 oC
OH
Me
O
H
O
LiAlH4, THF
r.t., 3h
After the synthesis of epoxide 9 and a great number of different
employed conditions (Table 1), we found that refluxing 9 and 12 in
tetrahydrofuran, in the presence of TMEDA for 1 h, was the best
protocol to prepare adduct 13.9 Interestingly, when the reaction
was carried out at room temperature, an inseparable mixture of
13 and a structurally similar side product was observed. This side
product was totally suppressed under heating conditions. In this
case, adduct 9 was isolated in 45–55% yield (Table 1, entry 11).
To show the applicability of the present strategy, we decided to
convert adduct 13 into aldehyde 15 in order to investigate cycliza-
tion approaches toward the icetexane core (Scheme 3). Recently
and during the investigation of our work, a total synthesis of brus-
sonol employing an interesting Marson-type Friedel–Crafts alkyl-
ation from a methoxy-ketal and BF3ÁEt2O was described in the
literature.2l Based on this work, we wondered if we could employ
10
H
11
9
known compound
Scheme 2. Synthesis and stereochemistry assign of epoxide 9.
present our results in this epoxide opening strategy, but also show
the applicability of this approach by preparing a brussonol ana-
logue in just four steps from commercially available 2-allyl-
cyclohexanone.4
We started our study by investigating the best reaction condi-
tions for the epoxide ring-opening reaction between racemic epox-
ide 9 and the lithium anion of 1,2-dimethoxybenzene. Epoxide 9
was readily prepared as a single isomer in just one step from com-
Table 1
Epoxide ring-opening study
MeO
OH
OMe
O
H
OMe
reaction
conditions
Li
OMe
+
13
H
12
9
Entry
Epoxide (equiv)
Lithium anion (equiv)
Reaction conditions
13 (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
1
1
1
1
1
2
2
2
2
2
2
1
2
2
3
2
THF, 25 °C, 8 h
THF, 25 °C, 8 h
Traces
ꢀ10%
THF, CuCN, 0–25 °C, 8 h
THF, TMEDA, CuCN, 0–25 °C, 8 h
THF, TMEDA, 25 °C, 8 h
THF, DMPU, 25 °C, 8 h
THF, TMEDA, 25 °C, 16 h
THF, TMEDA, 25 °C, 8 h
Et2O, TMEDA, 25 °C, 8 h
THF, TMEDA, BF3ÁEt2O, À78–0 °C, 4 h
THF, TMEDA, reflux, 1 h
THF, TMEDA, MgBr2, 0–25 °C, 8 h
Traces
Traces
20–30%
Traces
ꢀ35%
ꢀ20%
ꢀ25%
10
11
12
Traces
45–55%
Traces
OMe
Li
OMe
MeO
OTMS
MeO
OMe
OTMS
OMe
NMO, OsO4,
THF: H2O,
NaIO4
O
reflux, 60 min.
THF, TMEDA,
SnCl4 or
14
15
BF3.OEt2
H
quench with TMSCl
H
,
H
O
DCM
9
70%
56%
-78 oC to rt
MeO
OMe
MeO
MeO
OMe
OMe
Cl3Sn
MeO
O
OMe
O
H
O
O
X-
H
OSnCl3
(or OTMS)
H
O
H
H
H
+ TMSCl
SnCl4
(+) 16 90-95%
brussonol analogue
Scheme 3. Application of the epoxide ring-opening strategy. Synthesis of a brussonol analogue from epoxide 9.

688
A. Carita, A. C. B. Burtoloso / Tetrahedron Letters 51 (2010) 686–688
2. For recent synthesis of icetexane diterpenoids, see: (a) Sengupta, S.; Drew, M. G.
B.; Achari, B.; Mukhopadhyay, R.; Banerjee, A. K. J. Org. Chem. 2005, 70, 7694–
7700; (b) Padwa, A.; Boonsombat, J.; Rashatasakhon, P.; Willis, J. Org. Lett. 2005,
7, 3725–3727; (c) Simmons, E. M.; Sarpong, R. Org. Lett. 2006, 8, 2883–2886; (d)
Majetich, G.; Li, Y.; Zou, G. Heterocycles 2007, 73, 217–225; (e) Majetich, G.; Yu,
J.; Li, Y. Heterocycles 2007, 73, 227–235; (f) Srikrishna, A.; Beeraiah, B.
Tetrahedron: Asymmetry 2007, 18, 2587–2597; (g) Simmons, E. M.; Yen, J. R.;
Sarpong, R. Org. Lett. 2007, 9, 2705–2708; (h) Majetich, G.; Yu, J. Org. Lett. 2008,
10, 89–91; (i) Majetich, G.; Zou, G. Org. Lett. 2008, 10, 81–83; (j) Majetich, G.;
Zou, G.; Grove, J. Org. Lett. 2008, 10, 85–87; (k) Padwa, A.; Chughtai, M. J.;
Boonsombat, J.; Rashatasakhon, P. Tetrahedron 2008, 64, 4758; (l) Martinez-
Solorio, D.; Jennings, M. P. Org. Lett. 2009, 11, 189–192; (m) Majetich, G.; Grove,
J. L. Org. Lett. 2009, 11, 2904–2907.
the same Marson-type cyclization conditions directly on aldehyde
15 and achieve the synthesis of a brussonol analogue in a tandem
fashion. To verify that, TMS-protected aldehyde 15 was prepared in
two steps from epoxide 9, using our epoxide-opening approach,
and submitted to the presence of SnCl4 or BF3ÁEt2O. To our delight,
in the presence of these Lewis acids, TMS-protected aldehyde 15
was directly converted in 90–95% yield into brussonol analogue
16 in a possible series of cascade events: (i) removal of TMS; (ii)
cyclization to its ketal; (iii) formation of the oxonium ion; and
(iv) Marson-type Friedel–Crafts cyclization to 16 (Scheme 3).
As a conclusion, after a thorough investigation, the epoxide ring-
opening strategy (key step of the present strategy) was accom-
plished, furnishing 13 in 45–55% yields. With the present strategy,
cyclized product 16 was easily prepared in a short sequence of reac-
tions, employingtheconditions(Marson-typecyclization)described
by Solorio and Jennings. The use of other epoxides and metallated
aromatic rings, and the application of this epoxide ring-opening
strategy in the synthesis of other icetexane diterpenes are now being
investigated and will be reported in due course.
3. During the same time we were working on this project, a similar approach was
investigated with no success.2l
4. (a) Manning, P. T.; Misko, T. P. U. S. patent 2005025620, 2005.; (b) Howard, W.
L.; Lorette, N. B. Org. Synth. 1962, 42, 34–35.
5. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
6. Weijers, C. A. G. M.; Meeuwse, P.; Herpers, R. L. J. M.; Franssen, M. C. R.;
Sudhoelter, E. J. R. J. Org. Chem. 2005, 70, 6639–6646.
7. Caldwell, J. J.; Craig, D. Angew. Chem., Int. Ed. 2007, 46, 2631–2634.
8. Nishizawa, M.; Iwamoto, Y.; Takao, H.; Imagawa, H.; Sugihara, T. Org. Lett. 2000,
2, 1685–1687.
9. Experimental procedure for the synthesis of adduct 13: To a solution of 1,2-
dimethoxybenzene (1.1 mL, 9.0 mmol) in 30 mL of dry tetrahydrofuran (THF), at
0 °C, was added 6.7 mL (9.0 mmol) of a 1.35 M solution of BuLi in hexanes. After
stirring the solution for 2.5 h at room temperature, 1.4 mL (9.0 mmol) of
tetramethylethylenediamine (TMEDA) was added at once and the solution
heated to reflux. Next, 456.0 mg (3.0 mmol) of epoxide 9 in 3.0 mL of dry THF
was added and the solution stirred for 1 h under these conditions. The reaction
was then cooled to room temperature and 30 mL of saturated NH4Cl aqueous
solution was added to quench the reaction, followed by extraction with EtOAc
(3 Â 20 mL). Next, the organic phase was dried with Na2SO4, filtered, and
evaporated to furnish a crude yellow oil. Column chromatography purification
(1:4/EtOAc–hexanes) provided a mixture of tertiary alcohol 13 and remaining
1,2-dimethoxybenzene. Removal of 1,2-dimethoxybenzene (50 °C at 0.1 mmHg
or doing a second purification in 3:2/CH2Cl2–hexanes, furnished 478.0 mg (55%)
of pure alcohol 13. 1H NMR (200 MHz, CDCl3): d = 1.00–1.80 (3 m, 9H), 2.05 (m,
1H), 2.54 (d, J = 13.5 Hz, 1H), 2.60 (m, 1H), 2.91 (s, 1H, OH), 3.27 (d, J = 13.5 Hz,
1H), 3.84 (s, 3H), 3.86 (s, 3H), 4.90–5.20 (m, 2H), 5.70–6.00 (m, 1H), 6.65–7.05
(m, 3H); 13C NMR (50 MHz, CDCl3): d = 21.8, 25.3, 27.4, 34.1, 36.8, 41.6, 45.5,
55.7, 60.3, 73.5, 110.8, 115.4, 123.8, 124.4, 131.8, 138.7, 147.1, 152.7; IR (neat,
cmÀ1): 3494, 2930, 2854, 1637, 1583, 1477, 1269, 1083, 750, 609; MS-ESI: 313.4
(M+Na), 273.4, 231.4; MS-APCI: 273.1 (M+1ÀH2O), 231.1.
Acknowledgments
We thank FAPESP (Research Supporting Foundation of the State
of São Paulo) for financial support and CNPq for the fellowship to A.
Carita. We also thank Professor Daniel Cardoso and Professor Ro-
berto Berlinck (IQSC, USP) for the mass spectrometer analysis.
Supplementary data
Supplementary data (NMR (1H NMR and 13C NMR) and MS spectra
for compounds 9, 11, 13, 15 and 16) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.11.108.
References and notes
1. Simmons, E. M.; Sarpong, R. Nat. Prod. Rep. 2009, 26, 1195–1217.