A tandem oxidative dearomatization/intramolecular Diels-Alder reaction: a short and efficient entry into tricyclic system of maoecrystal V

Article abstract of DOI:10.1016/j.tetlet.2010.04.082

A short and efficient route to tricyclic ring system containing bridged bicyclo[2.2.2]octanone annulated with a lactone ring present in the maoecrystal is described. In-situ generation of spiroepoxycyclohexa-2,4-dienone and intramolecular cycloaddition are the key features of our approach.

Full text of DOI:10.1016/j.tetlet.2010.04.082

Tetrahedron Letters 51 (2010) 3337–3339
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A tandem oxidative dearomatization/intramolecular Diels–Alder reaction: a
short and efficient entry into tricyclic system of maoecrystal V
a
b
Vishwakarma Singh a, , Pravin Bhalerao , Shaikh M. Mobin
*
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
b National Centre for Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient route to tricyclic ring system containing bridged bicyclo[2.2.2]octanone annulated
with a lactone ring present in the maoecrystal is described. In-situ generation of spiroepoxycyclohexa-
2,4-dienone and intramolecular cycloaddition are the key features of our approach.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 April 2010
Revised 16 April 2010
Accepted 20 April 2010
Available online 24 April 2010
Keywords:
Spiroepoxycyclohexa-2,4-dienone
Diels–Alder reaction
Intramolecular cycloaddition
Tandem reaction
Oxidative dearomatization
Recently maoecrystal V (1) (Fig. 1), a diterpene, was isolated
from Chinese herb Isodon eriocalyx by Sun and co-workers.1 It
exhibits potent inhibitory activity against HeLa cells and thus ap-
pears to be a promising anticancer agent.1 Maoecrystal V possess
a highly complex and functionalized pentacyclic molecular archi-
tecture that contains a bridged bicyclo[2.2.2]octane framework
annulated with a lactone ring and a spirocyclic six-membered ring
along with a five-membered ring ether. The complex structure of 1
coupled with its biological potential has stimulated significant
interest in its synthesis.2 Though synthesis of maoecrystal V has
not been achieved yet, several research groups have reported
imaginative approaches towards its synthesis.2
In view of the contemporary interest in maoecrystal and our
continuing interest in the creation of molecular complexity from
aromatics,7 we considered developing a simple, efficient and ste-
reo-selective route to tricyclic compounds 2 (Fig. 1) containing a
bridged bicyclo[2.2.2]octanone ring annulated with a lactone ring
which comprises the structure of maoecrystal V. We wish to report
our exploratory results herein.
Rapid generation of molecular complexity from simple precur-
sors is one of the important features of synthesis design and devel-
opment of methodology.3 Tandem reactions and multicomponent
reactions are often employed to achieve these objectives.4 Recently,
the reactive species derived from arenols such as cyclohexa-2,4-die-
none ketals and congeners have proved to be an important tool and
provided an efficient method for the synthesis of a diverse array of
molecular structures and natural products.5–7 We have a long stand-
ing interest in the chemistry of 6,6-spiroepoxycyclohexa-2,4-die-
Figure 1. Structure of maoecrystal V (1) tricyclic compound 2 and the aromatic
precursor 3.
nones, especially in its inverse demand p4s 2s cycloaddition and
+ p
the chemistry of adducts in ground and excited states.7
* Corresponding author. Tel: +91 22 2576 7168; fax: + 91 22 2576 7152.
E-mail address: vks@chem.iitb.ac.in (V. Singh).
Figure 2. Cyclohexa-2,4-dienone 4 and spiroepoxycyclohexane-2,4-dienone 5.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.082

3338
V. Singh et al. / Tetrahedron Letters 51 (2010) 3337–3339
Conceptually, the tricyclic lactone of type 2 may be directly ob-
tained by intramolecular Diels–Alder reaction in the cyclohexa-
2,4-dienone of type 4 (Fig. 2). However, compound 4 is inaccessible
as it is a tautomer of the corresponding phenol.
Hence, we considered employing an equivalent of the dienone 4
especially the 6,6-spiroepoxycyclohexa-2,4-dienone 5. We contem-
plated that intramolecular endo-cycloaddition in embellished spi-
roepoxycyclohexa-2,4-dienone 5 would provide tricyclic keto-
epoxide 6 and that manipulation of the oxirane ring and reduction
of the double bond would lead to desired tricyclic lactone 2 (Scheme
1). The spiroepoxycyclohexa-2,4-dienone 5 was thought to be
generated by oxidative dearomatization of aromatic precursor 3.
There are several key features of our strategy. For example, all the
carbon atoms of the tricyclic intermediate 2 and the required func-
tional groups are derived from the aromatic precursor 3. Remark-
ably, the bridged bicyclic system annulated with the lactone ring
required in the intermediate 2 is present in latent form in the precur-
sor 3 and it is generated in a single stereo-selective step.
Scheme 2. Synthesis of aromatic precursor 3. Reagents and conditions: (i) p-TsOH,
dimethoxypropane, acetone, rt, 72.5%; (ii) OsO4, NMO, aq. acetone, 90%; (iii) NaIO4,
aq. MeCN, 0 °C, 2 h, 81%; (iv) NaBH4, aq. MeOH, 99%; (v) acrolyl chloride, CH2Cl2,
diisopropyl ethyl amine, DMAP, 95%; (vi) aq. HCl, THF, rt, 91.8%.
In order to realize the aforementioned objective, the o-hydroxy-
methyl phenol 3 was easily prepared from the readily available7c
compound 7 (Scheme 2). Thus, protection of 1,3-diol group as ace-
tonide followed by oxidative cleavage of the double bond and
reduction of the resulting aldehyde gave the compound 8 in excel-
lent yield. Acylation of 8 with acrolyl chloride followed by hydro-
lysis of the acetonide efficiently furnished the desired precursor 3.
Towards the oxidative dearomatization and intramolecular
cycloaddition, a solution of compound 3 in acetonitrile was oxi-
dized with aq. NaIO4 following a procedure developed earlier in
our laboratory.8 Chromatography of the product mixture furnished
the tricyclic keto-epoxide 6 as a consequence of intramolecular
cycloaddition along with the dimer 9, the latter arising as a result
of intermolecular cycloaddition between two moles of the cyclo-
hexa-2,4-dienone 5 (Scheme 3).
It appeared that intermolecular cycloaddition between two mo-
les of cyclohexa-2,4-dienone 5 is competing to a significant extent
under the aforementioned mild reaction conditions. Therefore, it
was thought that pyrolysis of 9 may also generate the species 5
which may undergo efficient intramolecular cycloaddition as a re-
sult of thermal activation. Indeed, heating the dimer 9 at 140 °C
gave the desired adduct 6 in high yield as a consequence of ret-
ro-Diels–Alder/Diels–Alder cascade (Scheme 3).9
Scheme 3. Synthesis of tricyclic keto-epoxide 6.
J2 = J3 = 4.5 Hz, 1H) for OCH2 protons of the lactone ring. In addi-
tion, signals were observed at d 3.06–2.90 (complex, m, 2H),
2.78–2.66 (m, 1H), 2.40–2.32 (merged m, 2H), 2.06–1.74 (complex
m, 1H). 13C NMR of adduct 6 also corroborated with its structure as
it exhibited characteristic signals at d 202.1, 172.2 and 137.4, 132.1
for the carbonyl carbons and olefinic carbons, respectively. Further
signals were observed at d 65.2, 57.1, 53.5, 51.0, 39.3, 37.8, 26.1
and 24.0 for other carbons. These spectral features suggested the
gross structure of adduct. However, in order to ascertain the
endo-stereochemistry and stereochemistry at the spiro-oxirane
centre, X-ray crystal structure was undertaken which confirmed
its structure (Fig. 3).
The structure of adduct 6 was deduced from the following spec-
tral characteristics and further confirmed through single crystal X-
ray analysis. Thus, the IR spectrum of 6 showed two absorption
bands at 1744 and 1733 cmÀ1 for the carbonyl groups. The 1H
NMR spectrum (300 MHz) displayed characteristic signals at d
6.65 (dd, J1 = 8.1 Hz, J2 = 6.9 Hz, 1H) and 5.84 (d, J = 8.1 Hz, 1H)
for olefinic protons. The difference in the chemical shift of the ole-
It may be worth noting the stereoselectivity during the afore-
mentioned cycloaddition as well as rapid generation of complex
and functionalized molecular structure from a simple aromatic
precursor. Further the presence of
a-keto-epoxide functionality
in the adduct
manipulation.
6 provided a unique opportunity for further
finic protons is a manifestation of homoconjugation of the C@C p-
bond with the carbonyl group in a bridged bicyclo[2.2.2]octane
framework. This clearly indicated that cycloaddition had occurred.
Similarly, the methylene group of spiro-oxirane ring appeared as
part of AB pattern at distinct chemical shifts d 3.20 (JAB = 6.2 Hz,
1H) and 2.92 (part of AB system partly merged with another m,
JAB = 6.2 Hz, 1H). Further signals were observed at d 4.47 (dd of part
of an AB system, JAB = 12.2 Hz, J2 = 6.1 Hz, J3 = 3 Hz, 1H), 4.30
(superimposed dd of part of an AB system, JAB = 12.2 Hz,
Scheme 1. Strategy for the synthesis of compound 2.
Figure 3. X-ray crystal structure of adduct 6.

V. Singh et al. / Tetrahedron Letters 51 (2010) 3337–3339
3339
Scheme 4. Synthesis of tricyclic intermediate 2.
4. (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, 2006; (b) Ugi, I. Pure Appl.
Chem. 2001, 73, 187.
Thus, the adduct 6 was treated with Zn in the presence of NH4Cl
in aq. MeOH at ambient temperature (ꢀ30 °C) which gave the b-
hydroxyketone 10 in excellent yield (93%) which upon Jones’
oxidation and decarboxylation furnished the keto-lactone 11
(Scheme 4). Catalytic hydrogenation of 11 readily gave the desired
compound 2 which represents the tricyclic core of maoecrystal V.
The structure of all the compounds was clearly revealed from their
spectral data.9
In summary, we have presented an efficient and stereo-selec-
tive route to tricyclic core structure of maoecrystal V from a simple
aromatic precursor. A tandem oxidative dearomatization of appro-
priately appended o-hydroxymethylphenol and intramolecular
5. (a) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856–866; (b) Magdziak, D.;
Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383–1429; (c) Quideau, S.;
Pouysegu, L.; Deffieux, D. Synlett 2008, 467–495; (d) Pouysegu, L.; Deffieux, D.;
Quideau, S. Tetrahedron 2010, 66, 2235–2261. and references therein.
6. (a) Berube, A.; Drutu, I.; Wood, J. L. Org. Lett. 2006, 8, 5421–5424; (b) Luo, S.-Y.;
Jang, Y.-I.; Liu, J.-Y.; Chu, C.-S.; Liao, C.-C.; Hung, S.-C. Angew. Chem., Int. Ed. 2008,
47, 8082–8085; (c) Mehta, G.; Maity, P. Tetrahedron Lett. 2008, 49, 318–322; (d)
Wenderaski, T. A.; Huang, S.; Pettus, T. R. R. J. Org. Chem. 2009, 74, 4104–4109;
(e) Mehta, G.; Sen, S. Tetrahedron Lett. 2010, 51, 503–507.
7. (a) Singh, V. Acc. Chem. Res. 1999, 32, 324–333; (b) Singh, V.; Praveena, G. D.;
Karki, K.; Mobin, S. M. J. Org. Chem. 2007, 72, 2058–2067; (c) Singh, V.; Sahu, P.
K.; Sahu, B. C.; Mobin, S. M. J. Org. Chem. 2009, 74, 6092–6104.
8. Singh, V.; Porinchu, M.; Vedantham, P.; Sahu, P. K. Org. Synth. 2005, 81, 171–177.
9. All the compounds were thoroughly characterized with the help of spectral data.
cycloaddition gave
a tricyclic adduct having bridged bicy-
Data for adduct 6: mp 139–140 °C. IR mmax (KBr): 1744, 1731 cmÀ1 1H NMR
.
clo[2.2.2]octanone framework annulated with the lactone ring.
Manipulation of the oxirane ring and the double bond furnished
the desired intermediate. The present methodology constitutes a
nice example of creation of molecular complexity from aromatics
which is an important aspect of synthesis design.3
(300 MHz, CDCl3): d 6.65 (dd, J1 = 8.1 Hz, J2 = 6.9 Hz, 1H) and 5. 84 (d, J = 8.1 Hz,
1H), 4.47 (dd of part of an AB system, JAB = 12.2 Hz, J2 = 6.1 Hz, J3 = 3 Hz, 1H),
4.30 (superimposed dd of part of an AB system, JAB = 12.2 Hz, J2 = J3 = 4.5 Hz, 1H),
3.20 (part of an AB system JAB = 6.2 Hz, 1H) and 2.92 (part of AB system partly
merged with another m, JAB = 6.2 Hz, 1H), 3.06–2.90 (complex, m, 2H), 2.78–2.66
(m, 1H), 2.40–2.32 (merged m, 2H), 2.06–1.74 (complex m, 1H). 13C NMR
(100 MHz, CDCl3):
d 202.1, 172.2 (CO groups) and 137.4, 132.1 (olefinic
carbons), 65.2, 57.1, 53.5, 51.0, 39.3, 37.8, 26.1, and 24.0 for other carbons.
HRMS (ESI) m/z: 221.0808 (M+H)+; C12H13O4 requires 221.0814.
Acknowledgement
Crystal data: C12H12O4, Mol. Wt. 220.22. Crystal size = 0.23 Â 0.18 Â 0.13 mm.
ꢀ
Space group: Triclinic P, Z = 2, a = 6.5009(5), b = 8.2023 (5), c = 9. 5100 (8) Å,
We are grateful to the Department of Science and Technology
(DST), New Delhi for continued financial support. One of us (P.B.)
is thankful to CSIR, New Delhi for a fellowship. We also thank
DST for the creation of a National Centre for Single Crystal X-ray
diffraction facility.
a
= 102. 097(6), b = 97.030(7),
volume = 490.33 (6) Å3, T = 150(2) K,
collected/unique 3382/1723, [R(int) = 0.0258], final
R1 = 0.0404, wR2 = 0.1144. indices all data = R1 = 0.0499, wR2 = 0.1183.
c
= 93.250 (6)°. Dc: 1.492 mg/m3, crystal
c
= 0.71073 Å F (000) = 232. Reflections
indices [I >2 (I)],
R
r
R
Crystallographic data has been deposited with Cambridge Crystallographic
data Centre, CCDC No. 771301. Copy of the data can be obtained, free of charge,
on application to CCDC. E-mail. Deposit@ccdc.cam.ac.uk.
Data for compound 11: mp 92–93 °C. IR mmax (KBr): 1731, 1715 cmÀ1 1H NMR
.
References and notes
(400 MHz, CDCl3): d 6.63 (dd, J1 = 8 Hz, J2 = 7 Hz, 1H), 5.73 (d, J = 7 Hz, 1H), 4.46–
4.40 (complex m, 1H), 4.28–4.20 (complex m, 1H), 3.14–3.08 (br m, 1H), 2.98 (t
of d, J1 = 15 Hz, J2 = 4.2 Hz, 1H), 2.30–2.22 (complex m, 1H), 2.20–2.16 (m, 2H),
2.06–1.88 (m, 3H). 13C NMR (100 MHz, CDCl3): d 207.9, 172.9, 140.0, 130.5, 65.5,
50.8, 38.8, 38.4, 31.7, 27.8, 26.3. HRMS (ESI) m/z: 193.0861 (M+H)+; C11H13O3
requires 193.0865.
1. Li, S.-H.; Wang, J.; Niu, X.-M.; Zhang, H.-J.; Sun, H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.;
Zhang, Q.-T. Org. Lett. 2004, 6, 4327–4330.
2. (a) Gong, J.; Lin, G.; Li, C.-H.; Yang, Z. Org. Lett. 2009, 11, 4770–4773; (b) Krawczuk,
P. J.; Schone, N.; Baran, P. S. Org. Lett. 2009, 11, 4774–4776; (c) Peng, F.; Yu, M.;
Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 6586–6587; (d) Nicolaou, K. C.; Dong,
L.; Deng, L.; Talbot, A. C.; Chen, D. Y.-K. Chem. Commun. 2010, 46, 70–72.
3. (a) Chanon, M.; Baron, R.; Baralotto, C.; Julliard, M.; Hendrickson, J. B. Synthesis
1998, 1559–15583; (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–
281; (c) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley and
Sons: New York, 1989.
Data for compound 2: mp 104–105 °C. IR mmax (KBr): 1742, 1723 cmÀ1 1H NMR
.
(400 MHz, CDCl3): d 4.40–4.29 (m, 1H), 4.15–4.00 (m, 1H), 2.85–2.80 (m, 1H),
2.74–2.70 (m, 1H), 2.50–2.20 (m, 4H), 2.00–1.60 (m, 5H), 1.45–1.30 (m, 1H). 13C
NMR (100 MHz, CDCl3): d 212.2, 173.7, 65.4, 44.3, 43.5, 38.4, 29.3, 27.2, 26.4,
25.94, 25.90. HRMS (ESI) m/z: 195.1022 (M+H)+; C11H15O3 requires 195.1021.