First approach to the frondosin C ring system via a tandem cyclization/Claisen rearrangement sequence

Article abstract of DOI:10.1021/ol050144o

(Chemical Equation Presented) A one-pot tandem 5-exo cyclization/Claisen rearrangement strategy is utilized as the key step in the straightforward construction of the tetracyclic ring system of frondosin C. This reaction is done under microwave irradiatio

Full text of DOI:10.1021/ol050144o

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1133-1135
First Approach to the Frondosin C Ring
System via a Tandem Cyclization/
Claisen Rearrangement Sequence
Isamir Mart´ınez, Philip E. Alford, and Timo V. Ovaska*
Department of Chemistry, Connecticut College, 270 Mohegan AVenue,
New London, Connecticut 06320
tVoVa@conncoll.edu
Received January 21, 2005
ABSTRACT
A one-pot tandem 5-exo cyclization/Claisen rearrangement strategy is utilized as the key step in the straightforward construction of the
tetracyclic ring system of frondosin C. This reaction is done under microwave irradiation in the presence of catalytic MeLi.
Five novel sesquiterpene hydroquinone derivatives, fron-
dosins A-E (Figure 1), were recently isolated from the
as novel antiinflammatory agents. Additionally, some mem-
bers of the frondosin family were found to exhibit anti-HIV
activity.2
The total synthesis of frondosin B was first achieved by
Danishefsky et al.3 in 2000 and, more recently, by the
Trauner4 and Flynn5 groups. The other members of the
frondosin family, however, have not yet been synthesized.
Herein, we describe the first approach to the frondosin C
ring system. This approach is based on our recent investiga-
tions involving a base-catalyzed tandem cyclization/Claisen
rearrangement as a route to cycloheptane-containing poly-
cyclic ring structures.6 The reaction sequence involves an
initial 5-exo dig cyclization of an appropriately substituted
(1) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz,
A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047.
(2) Hallock, Y. F.; Cardellina, J. H.; Boyd, M. R. Nat. Prod. Lett. 1998,
11, 153.
(3) (a) Danishefsky, S. J.; Inoue, M.; Frontier, A. J. Angew. Chem., Int.
Ed. 2000, 39, 761. (b) Inoue, M.; Carson, M. W.; Frontier, A. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 1878.
Figure 1. Structures of frondosins A-E.
(4) (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569. (b) Hughes, C. C.; Trauner, D. Tetrahedron 2004, 60, 9675.
(5) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004, 6, 457.
(6) (a) Ovaska, T. V.; Roark, J. L.; Shoemaker, C. M. Tetrahedron Lett.
1998, 39, 5705. (b) Ovaska, T. V.; Roses, J. B. Org. Lett. 2000, 2, 2361.
(c) Ovaska, T. V.; Reisman, S. E.; Flynn, M. A. Org. Lett. 2001, 3, 115.
(d) Ovaska, T. V.; Ravi Kumar, J. S.; Hulford, C. A.; O’Sullivan, M. F.;
Reisman, S. E. Tetrahedron Lett. 2002, 43, 1939. (e) McIntosh, C. E.;
Martinez, I.; Ovaska, T. V. Synlett 2004, 2579.
Micronesian marine sponge Dysidea frondosa.1 These com-
pounds were found to be antagonists of interleukin-8 (IL-
8), a neutrophil-activating peptide, which is produced by
various cell types in response to inflammation.1 Thus, IL-8
antagonists such as the frondosins hold therapeutic potential
10.1021/ol050144o CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/15/2005

4-alkyn-1-ol system followed by in situ Claisen rearrange-
ment of the intermediate 2-alkylidene tetrahydrofuran deriva-
tive (Scheme 1).7
Scheme 3
Scheme 1. Tandem Cyclization/Claisen Rearrangement as a
Route to Cycloheptane-Containing Polycyclic Ring Structures
It was envisioned that the tetracyclic frondosin C carbon
skeleton 5 might be constructed through a Claisen rearrange-
ment involving intermediate 4, which, in turn, would be
accessible via a base-catalyzed cyclization of acetylenic
alcohol 3 (Scheme 2). Formation of the requisite tertiary
alcohol would be effected by coupling the 6-alkoxy-2-
propargylindanone 1 with the vinylcerium derivative 2.
At this point, the stage was set for the key 5-exo
cyclization/Claisen rearrangement sequence, which proceeded
smoothly in the presence of catalytic MeLi (∼10 mol %) in
phenetole following 30 min of heating in a microwave oven
(Scheme 4). The tetracyclic ketone products 8a and 8b were
produced in 70 and 79% yields, respectively, after purifica-
tion by column chromatography.
Scheme 2. Retrosynthetic Analysis for the Construction of an
Advanced Intermediate in the Synthesis of Frondosin C
Scheme 4
To test the proposed strategy, two model systems were
prepared as shown in Scheme 3. Thus, commercially
available indanone and 6-methoxyindanone were converted
to the corresponding TMS silyl enol ethers and alkylated
with propargyl bromide under mild conditions in the presence
of cesium fluoride.8 The balance of the product mixture in
each case consisted of dialkylated material (typically 20-
30%) and hydrolyzed starting material. The latter undoubt-
edly resulted from premature quenching of the intermediate
enolate anion under the reaction conditions employed.9
Reaction of ketones 6a and 6b with 1-cyclohexenylcerium
dichloride, generated in situ from the corresponding vinyl-
lithium species, produced the acetylenic alcohols 7a and 7b
in 80 and 82% yields, respectively.
Installation of the requisite gem-dimethyl moiety on the
A ring of the frondosin C core required a slight modification
of the sequence depicted in Scheme 3 and involved the use
of 1-iodo-2,2-dimethylcyclohexene rather than 1-iodocyclo-
hexene10 as the starting material (Scheme 5). The synthesis
of this material was achieved in a few steps starting with
commercially available 3-methylcyclohexen-2-one as shown
in Scheme 5.
With vinyl iodide 9 in hand, preparation of the requisite
acetylenic alcohol 10 was achieved in a straightforward
(10) Barton, D. H. R.; Bashiardes, G.; Fourrey, J. L. Tetrahedron 1988,
44, 147.
(11) Minimum energy conformation shown was calculated using
MacroModel v. 8.5 with the MM3* forcefield and a GB/SA chloroform
solvent model.12 Structures were generated by a 5000 step low-mode
conformational search.13,14
(12) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am.
Chem. Soc. 1990, 112, 6127.
(7) For an early report of this sequence, see: Marvell, E. N.; Titterington,
D. Tetrahedron Lett. 1980, 2123.
(8) For a general procedure, see: Kita, Y.; Segawa, J.; Haruta, J.; Yasuda,
H.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1 1982, 1099.
(9) Conditions for the alkylation step have not been optimized. A more
direct alkylation using LDA for the initial R-deptotonation resulted in the
formation of even greater amounts of dialkylated products.
(13) Keseru, G. M.; Kolossvary, I. J. Am. Chem. Soc. 2001, 123, 12708.
(14) Keseru, G. M.; Kolossvary, I. J. Comput. Chem. 2001, 22, 21.
1134
Org. Lett., Vol. 7, No. 6, 2005

ring stereochemistry was secured by a series of one-
dimensional NOESY experiments (Figure 2).
Scheme 5
fashion and in high yield following metalation of 9 and
reaction of the resulting organocerium species 2 with ketone
6b (Scheme 6). Upon 30 min of microwave irradiation in
the presence of catalytic MeLi, 10 was smoothly converted
to the desired tetracyclic frondosin C analogue 11 in 82%
isolated yield.
Figure 2. Diagnostic nuclear Overhauser enhancements in 11.11
In conclusion, we have demonstrated that construction of
the tetracyclic frondosin C framework may be achieved in a
straightforward manner using a tandem 5-exo cyclization/
Claisen rearrangement strategy as the key ring-forming
operation in the overall sequence. Further studies employing
this methodology for the total synthesis of frondosin C as
well as other members of the frondosin family are currently
in progress in our laboratory. Results from these investiga-
tions will be communicated in due course.
Scheme 6
Acknowledgment. This research was supported by grants
from the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, the National
Institutes of Health (NIGMS), and the Camille and Henry
Dreyfus Foundation (Scholar-Fellow Program). T.V.O also
gratefully acknowledges support from the Hans and Ella
McCollum-Vahlteich ‘21 endowment.
Supporting Information Available: Full experimental
details and spectroscopic data on all previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The molecular structure of 11 was confirmed by a
combination of standard two-dimensional NMR techniques
(gradient COSY, gradient HSQC, gradient HMBC), and the
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