Use of allylic strain to enforce stereochemistry. Direct syntheses of 7,8-dihydroxycalamenene and mansonone C

Article abstract of DOI:10.1021/ol0621194

Direct syntheses of 7,8-dihydroxycalamenene and mansonone C were achieved. The cis-stereochemistry required for the synthesis of 7,8-dihydroxycalamenene was introduced by an intramolecular cyclization directed by allylic strain.

Full text of DOI:10.1021/ol0621194

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5315-5316
Use of Allylic Strain To Enforce
Stereochemistry. Direct Syntheses of
7,8-Dihydroxycalamenene and
Mansonone C
George A. Kraus* and Insik Jeon
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
gakraus@iastate.edu
Received August 28, 2006
ABSTRACT
Direct syntheses of 7,8-dihydroxycalamenene and mansonone C were achieved. The cis-stereochemistry required for the synthesis of 7,8-
dihydroxycalamenene was introduced by an intramolecular cyclization directed by allylic strain.
Allylic 1,3-strain has been used in acyclic systems to direct
the introduction of new stereogenic centers.1 Notable ex-
amples include the work of Kishi,2 Adam,3 and Giese.4 We
are not aware of any application of allylic strain to control
the relative stereochemistry in disubstituted tetralins. Tetralins
such as 1, 3, and 4 have attracted considerable synthetic
attention (Figure 1).5 7,8-Dihydroxycalamenene (1a) exhibits
extracted from the heartwood of Mansonia altissima,8 was
found to possess promising antifungal, larvicidal, and anti-
oxidant properties.9 Schmalz recorded a synthesis of 1a using
arenechromium complexes to introduce the relative stereo-
chemistry.10
Many synthetic approaches to these compounds begin with
natural products such as menthone wherein the relative
stereochemistry has already been established.11
Several researchers have noted that attempts to install
stereochemistry by epimerization or by cyclization onto the
aromatic ring have led to mixtures.12,13 We report herein that
a system such as 5, wherein allylic strain between G and
(5) Erogorgiaene (3): Rodriguez, A. D.; Ramirez, C. J. Nat. Prod. 2001,
64, 100. Elisapterosin B (4): Rodriguez, A. D.; Ramirez, C.; Rodriguez, I.
I.; Barnes, C. L. J. Org. Chem. 2000, 65, 1390.
(6) Wahyouno, S.; Hoffmann, J. J.; Bates, R. B.; McLaughlin, S. P.
Phytochemistry 1991, 30, 2175.
Figure 1. Tetralin-derived products and mansonone C.
(7) Mathela, D. K.; Mathela, C. S.; Dev, V. J. Indian Chem. Soc. 1984,
61, 792.
(8) Marini Betto`lo, G. B.; Casinovi, C. G.; Galeffi, C. Tetrahedron Lett.
1965, 4857.
(9) Tiew, P.; Ioset, J.-R.; Kokpol, U.; Chavasiri, W.; Hostettmann, K.
Phytother. Res. 2003, 17, 190.
useful anti-infective activity.6 Hydroxycalamenene (1b) was
isolated from Hypericum elodeoides.7 Mansonone C (2),
(10) Schmalz, H. G.; Hollander, J.; Arnold, M.; Duerner, G. Tetrahedron
Lett. 1993, 34, 6259.
(11) Serra, S.; Fuganti, C. Tetrahedron Lett. 2005, 46, 4769.
(12) Ramaiah, P.; Rao, A. S. Synth. Commun. 1989, 19, 931.
(13) Beckwith, P. L. M.; Ghisalberti, E. L.; Jefferies, P. R.; Raston, C.
L.; White, A. H. Aust. J. Chem. 1988, 41, 351.
(1) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841. Johnson, F. Chem.
ReV. 1968, 68, 375.
(2) Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 4343.
(3) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(4) Giese, B.; Bulliard, M.; Zeitz, H. G. Synlett 1991, 425.
10.1021/ol0621194 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/20/2006

the methyl group forces the methyl group to be axial as the
six-membered ring is being formed, affords exclusively the
cis-stereoisomer 7 (Scheme 1).
Scheme 3
Scheme 1
with the anion of 1,2-bis(methoxymethoxy)-3-methylbenzene
(Scheme 4). The resulting alkoxide was in situ acetylated
by the addition of acetic anhydride. The displacement of the
acetate to the corresponding methyl group was achieved
using Me3Al to afford 15. In order to enhance the stability
for the acid-mediated cyclization, MOM protecting groups
were converted to the more stable methyl ether 16. It was
then oxidized and acetylated by the same methods used to
generate 8. Cyclization of 17 using trifluoroacetic acid in
acetic acid at 70 °C for 12 h followed by deprotection by
the use of BBr3 generated 7,8-dihydroxycalamenene (1a) in
two steps (30% yield). Interestingly enough, mansonone C
(2) was also obtained from the same reaction in two steps
(46% yield). The direct synthesis of 7,8-dihydroxycala-
menene (1a) demonstrates the advantage of employing the
concept of allylic strain in organic synthesis.
In order to evaluate the directing effect, we first synthe-
sized allylic acetate 8 (Scheme 2). Allylic acetate 8 was
synthesized starting from 6-methyl-5-hepten-2-one and the
anion of 1,4-dimethoxybenzene. Dehydroxylation of the
resulting benzylic alcohol using Li/NH3 followed by allylic
oxidation by the method of Sharpless14 yielded an allylic
alcohol which, upon acetylation, afforded 8. Surprisingly,
cyclization of allylic acetate 8 using the conditions of Ma
and Zheng15 afforded tetralin 10 and naphthalene 11 in 51%
and 37% yields, respectively. Compound 9, the expected
product, was not isolated.
Scheme 4
Scheme 2
Acknowledgment. We thank the National Institutes of
Health (Grant No. P01 ES12020) and the Office of Dietary
Supplements for partial financial support through the Center
for Research on Botanical Dietary Supplements at Iowa State
University.
We believe that compounds 10 and 11 result from a novel
cation-mediated disproportionation reaction. Comparison of
the NMR spectrum of 10 with that of the literature
compound13 showed that the cis-stereoisomer was exclusively
formed.
In support of this allylic strain assisted stereoselective
cyclization, we have found that cyclization of allylic acetate
12, which does not contain the directing group G, affords
tetralin 13 as a 1.3:1 mixture of diastereomers (Scheme 3).
With the stereochemistry of 10 established, we began the
synthesis of 1a by the reaction of 5-methyl-4-hexen-1-al16
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0621194
(15) Ma, S.; Zhang, J. Tetrahedron 2003, 59, 6273.
(16) Kraus, G. A.; Kim, J. Org. Lett. 2004, 6, 3115.
(14) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526
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