5212
D. S. Reddy et al. / Tetrahedron Letters 46 (2005) 5211–5213
from readily available precursors 5 and 6 in just three
i. NaIO4, aq. THF
ii. Et3N, Et2O
COOMe
Me
COOMe
OH
steps. Key to the overall efficiency of this approach
was the use of a highly diasteroselective and regioselec-
tive Diels–Alder/aldol sequence. The synthesis confirms
the structural assignment of 1. The inherent flexibility
of this approach is that by changing the diene one can
synthesize other members of this group and related com-
pounds. The synthesis of other members and adaptation
to an asymmetric version will be the subject of future
work from our group.
HO
Me
CHO
(> 95% E)
COOMe
Ph3P
CHO
5
94%
OMe
OH
EtCOOH
or
O
Hg(OAc)2
(> 95% E)
~150 o
C
Acknowledgements
6
85-90%
We thank Dr. ReddyÕs Laboratories Ltd for financial
support and encouragement. Help from the analytical
department in recording spectral data is appreciated.
Scheme 2.
The synthesis commenced with the pivotal Diels–Alder
reaction between dienophile 5 and diene 6 using
MeAlCl2 in a toluene–dichloromethane mixture.5 To
our delight, we obtained the desired transformation to
furnish 76 in 62% isolated yield with excellent endo selec-
tivity and regioselectivity (dr > 9:1). The highly selective
intermolecular Diels–Alder reaction established the req-
uisite stereochemistry of the three contiguous stereo-
genic centers of this group of natural products. The
diastereo- and regioselectivity of the DA reaction is in
agreement with the literature precedence.7 The un-
wanted double bond was removed from 7 using AdamÕs
catalyst under hydrogen atmosphere to provide 86 in
quantitative yield, which on aldol condensation using
15% KOH in methanol furnished the target compound
1 in 78% isolated yield. It is also interesting to note that
we did not see any epimerization at the center bearing
the carboxylic ester group under basic conditions
(Scheme 3). The spectral data of 1 were compared with
those of the natural product1 and they were found to be
identical.8 It is also noteworthy to mention that we have
prepared the natural product noreremophilane 1 in good
quantity (ꢀ0.2 g) using this route, which can be used for
biological assays.
References and notes
1. Zhao, Y.; Jia, Z.; Peng, H. J. Nat. Prod. 1995, 58, 1358–
1364.
2. For the syntheses of eremophilanes/bakkanes and related
compounds: (a) Fischer, N. H.; Oliver, E. J.; Fischer, H. D.
In Progress in the Chemistry of Organic Natural Products;
Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer:
New York, 1979; Vol. 38, Chapter 2; (b) Silva, L. F., Jr.
Synthesis 2001, 671–689; (c) Brocksom, T. J.; Coelho, F.;
Depres, J.-P.; Greene, A. E.; Freire de Lima, M. E.;
Hamelin, O.; Hartmann, B.; Kanazawa, A. M.; Wang, Y. J.
Am. Chem. Soc. 2002, 124, 15313–15325; (d) Back, T. G.;
Nava-Salgado, V. O.; Payne, J. E. J. Org. Chem. 2001, 66,
4361–4368; (e) Srikrishna, A.; Nagaraju, S.; Venkateswarlu,
S.; Hiremath, U. S.; Reddy, T. J.; Venugopalan, P. J. Chem.
Soc., Perkin Trans. 1 1999, 2069–2076; (f) Srikrishna, A.;
Reddy, T. J. Arkivoc 2001, 9–19, Part (viii) and references
cited therein.
3. Reddy, D. S. Org. Lett. 2004, 6, 3345–3347.
4. Previously, compound 5 was prepared from dimethyl
fumarate using ozonolysis followed by Wittig olefination:
Fontana, A. J. Org. Chem. 2001, 66, 2506–2508.
5. For other related Diels–Alder reactions (a) Bonnesen, P. V.;
Puckett, C. L.; Honeychuck, R. V.; Hersh, W. H. J. Am.
Chem. Soc. 1989, 111, 6070–6081; (b) Hashimoto, Y.;
Nagashima, T.; Kobayashi, K.; Hasegawa, M.; Saigo, K.
Tetrahedron 1993, 49, 6349–6358; (c) Winkler, J. D.; Kim,
H. S.; Kim, S.; Penkett, C. S.; Bhattacharya, S. K.; Ando,
K.; Houk, K. N. J. Org. Chem. 1997, 62, 2957–2962; (d)
Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A.
J. Chem. Soc., Perkin Trans. 1 1998, 3471–3478; (e) Ge, M.;
Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927–1929; (f)
Reddy, D. S.; Kozmin, S. A. J. Org. Chem. 2004, 69, 4860–
4862; (g) Kraus, G. A.; Kim, J. J. Org. Lett. 2004, 6, 3115–
3117.
In conclusion, the first synthesis of racemic noreremo-
philane 1 was achieved in 48% overall yield starting
MeOOC
H
Me
PtO2, H2
MeAlCl2
O
5 + 6
EtOAc
100%
toluene:DCM
-78 oC to RT
62%
H
6. Spectral data of 7: IR (Neat): 1722 cmÀ1 1H NMR
;
O
7
(400 MHz, CDCl3): d 9.69 (s, 1H), 5.70 (m, 2H), 3.68 (s,
3H), 3.03 (m, 1H), 2.54–2.39 (m, 4H), 2.21 (m, 1H), 2.13 (s,
3H), 1.76 (m, 1H), 1.52 (m, 1H), 1.25 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 207.5, 204.9, 174.1, 126.9, 125.3, 51.4,
49.2, 44.9, 42.0, 40.9, 38.8, 29.6, 25.8, 15.6; MS (CI): 253
MeOOC
MeOOC
H
Me
Me
15% KOH
O
O
(M++1); 8: IR (Neat): 1720 cmÀ1 1H NMR (400 MHz,
;
MeOH
78%
CDCl3): d 9.67 (s, 1H), 3.65 (s, 3H), 2.98 (m, 1H), 2.47 (m,
1H), 2.39 (m, 1H), 2.13 (s, 3H), 1.85 (m, 1H), 1.79–1.61 (m,
6H), 1.53 (m, 1H), 1.33 (m, 1H), 1.23 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 207.9, 205.5, 174.2, 50.3, 42.2, 41.4,
40.6, 39.4, 29.5, 24.3, 21.8, 19.8, 17.0; MS (CI): 255 (M++1).
H
H
O
8
1
Scheme 3.