Total synthesis of (±)-frondosin B

Article abstract of DOI:10.1021/ol701633z

An expeditious reaction sequence featuring a microwave-assisted tandem 5-exo cyclization-Claisen rearrangement process was used to assemble the A/B ring system of frondosin B. Completion of the target natural product was achieved in 38.2% yield over an ei

Full text of DOI:10.1021/ol701633z

ORGANIC
LETTERS
2007
Vol. 9, No. 19
3837-3840
Total Synthesis of (±)-Frondosin B
Xin Li and Timo V. Ovaska*
Department of Chemistry, Connecticut College, 270 Mohegan AVenue,
New London, Connecticut 06320
tVoVa@conncoll.edu
Received July 12, 2007
ABSTRACT
An expeditious reaction sequence featuring a microwave-assisted tandem 5-exo cyclization
−Claisen rearrangement process was used to
assemble the A/B ring system of frondosin B. Completion of the target natural product was achieved in 38.2% yield over an eight-step linear
sequence.
Five structurally related sesquiterpene hydroquinones, fron-
dosins A-E (Figure 1), were isolated in 1997 from the
Institute extracted frondosins A and D from another sponge,
Euryspongia sp.2 Interestingly, this organism apparently
manufactures the two frondosins as complementary enantio-
mers with opposite optical rotations compared to those
present in Dysidea frondosa.2
All members of the frondosin family have been found
to exhibit biological activity as antagonists of interleukin-8
(IL-8) and inhibitors of protein kinase C in the low
micromolar range.2 Interleukin-8 is a neutrophil-activating
peptide, which is produced by several cell types in response
to inflammatory stimuli,3 and it is now known to also play
an important role in tumor progression and metastasis in
several human cancers,4 including lung cancers.4b
Importantly, it was recently demonstrated that compounds
which inhibit the actions of IL-8 also inhibit HIV-1 replica-
tion.5 In fact, frondosins A and D have been found to exhibit
(2) Hallock, Y. F.; Cardellina, J. H., II; Boyd, M. R. Nat. Prod. Lett.
1998, 11, 153.
Figure 1. Frondosins A-E.
(3) (a) Seitz, M.; Dewald, B.; Gerber, N.; Baggiolini, M. J. Clin. InVest.
1991, 87, 463-469. (b) Miller, E. J.; Cohen, A. B.; Nagao, D.; Griffith, R.
J.; Maunder, R. J.; Martin, T. R.; Weiner-Kronish, J. P.; Sticherling, M.;
Christophers, E.; Matthay, M. A. Am. ReV. Respir. Dis. 1992, 146, 247.
(4) (a) Brat, D. J.; Bellail, A. C.; Van Meir, E. G. Neuro-oncol. 2005, 7,
122. (b) Zhu, Y. M.; Webster, S. J.; Flower, D.; Woll, P. J. Br. J. Cancer
2004, 91, 1970. (c) Yuan, A.; Chen, J. J.; Yao, P. L.; Yang, P. C. Front.
Biosci. 2005, 853.
Micronesian marine sponge Dysidea frondosa by Freyer et
al.1 Shortly thereafter, investigators at the National Cancer
(1) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz,
A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047.
(5) Lane, B. R.; Lore, K.; Bock, P. J.; Andersson, J.; Coffey, M. J.;
Strieter, R. M.; Markovitz, D. M. J. Virol. 2001, 75, 8195.
10.1021/ol701633z CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/22/2007

HIV-inhibitory activity in the National Cancer Institute’s
primary anti-HIV assay2 through an unknown mechanism.
Structurally, the frondosins feature a unique bicyclo[5.4.0]-
undecane sesquiterpene core which, with the exception of
frondosin A, is part of a fused tetracyclic framework.
Although the bicyclo[5.4.0]undecane (A-B ring system)
fragment is nearly identical in all members of this class, the
principal structural variation between them lies in the
constitution of the C-D ring fragment.
Scheme 1. Retrosynthetic Analysis for the Synthesis of
Frondosin B
The unique structural features of the frondosins coupled
with their therapeutic potential as novel anti-inflammatory,
anti-tumor, and anti-HIV agents have sparked considerable
interest in their total synthesis by several research groups.
As a result of these efforts, (()-frondosin C was recently
synthesized by Ovaska et al.,6 and total syntheses of
frondosin B have been reported by three groups: Danishefsky
and co-workers7 achieved the synthesis of the (+)-enantiomer
of frondosin B in 0.8% overall yield over 18 steps; Trauner’s
group prepared (-)-frondosin B in 7.3% overall yield over
a 20-step sequence;8 and Flynn et al.9 recently disclosed their
elegant synthesis of racemic frondosin B in 32% overall yield
over a six-step sequence.
In this communication, we wish to report a novel and
efficient total synthesis of (()-frondosin B. The sequence
compares favorably with existing strategies and highlights
the synthetic utility of a tandem 5-exo cyclization/Claisen
rearrangement process, first observed by Marvell et al.10
and developed further in our laboratory, as a convenient
general route to seven-membered ring-containing ring sys-
tems.6,11 This methodology involves a base-catalyzed in-
tramolecular oxyanionic cyclization of appropriately substi-
tuted 4-pentyn-1-ols, followed by in situ Claisen rearrange-
ment of the intermediate 2-alkylidenetetrahydrofurans. We
anticipated this methodology to be particularly well suited
for the construction of frondosin B, which incorporates a
seven-membered ring at the core of the tetracyclic ring
system.
could be achieved in potentially two additional steps from 4
through regioselective R-methylation and subsequent O-
demethylation of the para-dimethoxy-substituted aromatic
ring.
We have recently demonstrated that the bicyclo[5.4.0]-
undecane system 6 lacking the requisite gem-dimethyl moiety
on the A ring is readily prepared via the cyclization/Claisen
rearrangement strategy analogous to that shown in Scheme
1.14 However, considering that the more substituted R
position of the cycloheptenone ring is benzylic and presum-
ably more acidic, it was not obvious that this compound
could be regioselectively methylated at the less substituted
carbon. Pleasingly, it was found that on treatment with
LHMDS followed by the addition of MeI under kinetic
conditions, 6 was smoothly converted to 7 with complete
regio- and stereocontrol in excellent yield (Scheme 2). With
As shown retrosynthetically in Scheme 1, it was envisioned
that the key bicyclo[5.4.0]undecanyl system 4 could be
assembled in a single operation from alcohol 3, which, in
turn, would be available through a simple coupling reaction
involving vinyl iodide 212 and aldehyde 1, prepared in a
single step from the corresponding known alcohol.13 It was
expected that the synthesis of the benzofuran precursor 5
Scheme 2. Synthesis of a Bicyclic Ketone Model System
(6) Li, X.; Kyne, R. E.; Ovaska, T. V. Tetrahedron 2007, 63, 1899.
(7) Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am.
Chem. Soc. 2001, 123, 1878.
(8) (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569. (b) Hughes, C. C.; Trauner, D. Tetrahedron 2004, 60, 9675.
(9) Kerr, D. J.; Willis, A. C.; Flynn, B. L. Org. Lett. 2004, 6, 457.
(10) Marvell, E. N.; Titterington, D. Tetrahedron Lett. 1980, 2123.
(11) (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. (f) Martinez, I.; Alford, P.
E.; Ovaska, T. V. Org. Lett. 2005, 7, 1133. (g) Li, X.; Kyne, R. E.; Ovaska,
T. V. Org. Lett. 2006, 8, 5153.
this encouraging result, the applicability of this strategy to
the total synthesis of frondosin B could be explored.
The requisite alkynol precursor 3 for this sequence was
prepared in a straightforward manner in 93% yield from
1-iodo-6,6-dimethylcyclohex-1-ene12 and aldehyde 1 as
shown in Scheme 3. On exposure to catalytic MeLi and
microwave irradiation, 3 was readily converted to the
expected 6-7 bicyclic ring system 4 in 80% yield. Notably,
(12) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett.
1983, 24, 1605.
(13) Brimble, M. A.; Pavia, G. S.; Stevenson, R. J. Tetrahedron Lett.
2002, 43, 1735.
(14) Li, X.; Ovaska, T. V. J. Org. Chem. 2007, 72, 6624.
Org. Lett., Vol. 9, No. 19, 2007
3838

Scheme 3. Synthesis of Bicyclic Ketone 8
Scheme 4. Attempted Isomerization of 8 to 9
8 to isomerization stems, in part, from the sterically con-
gested environment near the double bond (Figure 2).
As an alternative strategy, it was envisaged that double
bond isomerization could also be achieved at the end of the
synthetic sequence following installation of the benzofuran
moiety. It was reasoned that, with the tetracyclic system in
place, the overall ring geometry would be considerably more
planar and, additionally, the formation of a more conjugated
system through a double bond shift should be energetically
favored.
the initially observed 3:1 diastereomer ratio could be
improved significantly (7:1) simply by exposing the mixture
to MeONa in refluxing methanol, allowing the preparation
of the desired isomer of 4 in 70% yield from 3.
As outlined in the retrosynthetic analysis (Scheme 1), it
was envisioned that formation of the key benzofuran system
could be achieved through a straightforward acid-catalyzed
intramolecular cyclization reaction involving one of the OH
groups of the benzene-1,4-diol moiety in 5 and the proximal
B ring carbonyl carbon.16 However, our initial efforts to
generate the requisite benzene-1,4-diol precursor 5 through
a simple deprotection reaction involving both methoxy
groups met with failure (Scheme 4). Consequently, the direct
deprotection strategy was abandoned in favor of a highly
efficient two-step sequence involving standard oxidative
demethylation of 8 with ceric ammonium nitrate17 and
reduction of the resulting para-quinone derivative 10 by
catalytic hydrogenation (Scheme 5). Upon exposure to BF3‚
Upon methylation under kinetic conditions using LHMDS
as the base, ketone 4 was converted to the bicyclic ketone 8
in a regiospecific manner as a single diastereomer in 92%
isolated yield. The relative stereochemistry of this key
intermediate was unequivocally established by single-crystal
X-ray analysis (Figure 2).15
Scheme 5. Completion of the Total Synthesis of Frondosin B
Figure 2. ORTEP drawing of compound 8 derived from a single-
crystal X-ray analysis (arbitrary numbering of atoms).
To install the necessary tetrasubstituted double bond at
the A/B ring junction, it was envisioned that the trisubstituted
double bond in 8 could be readily isomerized under a variety
of conditions to provide compound 9. However, all attempts
to achieve this transformation were unsuccessful, and in most
cases, the starting material was recovered unchanged (Scheme
4). It is reasonable to assume that the observed resistance of
Et2O at 0 °C, the hydroquinone intermediate 5 cyclized
readily to provide the complete frondosin B ring system 11
in 91% yield over three steps.
(15) The crystallographic data for compound 8 have been deposited with
the Cambridge Crystallographic Data Center (CCDC 656193).
(16) Kang, W.-B.; Sekiya, T.; Toru, T.; Ueno, Y. Bull. Chem. Soc. Jpn.
1989, 62, 3752.
Org. Lett., Vol. 9, No. 19, 2007
3839

The final double bond isomerization was achieved ac-
cording to the plan simply by treating 11 with catalytic TsOH
in refluxing benzene. In addition to the desired (()-frondosin
B, the product mixture consisted of a small quantity of
unidentified impurities; however, these were readily removed
from the desired product by standard column chromatogra-
family as well as other cycloheptanoid natural products are
currently ongoing in our laboratories.
Acknowledgment. This research was supported by grants
from the National Institutes of Health (NIGMS). T.V.O. also
gratefully acknowledges support from the Hans and Ella
McCollum-Vahlteich ’21 endowment. The authors wish to
thank Dr. Jon Bordner and Mr. Ivan Samardjiev of Pfizer,
Inc., for performing the single-crystal X-ray analysis of
compound 8.
1
phy. Comparison of the H and 13C NMR spectra of the
synthetic product with those of the naturally occurring
frondosin B1 unambiguously confirmed that the target
structure had indeed been synthesized.
In conclusion, the total synthesis of (()-frondosin B was
achieved in 38.2% overall yield over eight linear steps. The
key operation in the sequence is the efficient formation of
intermediate 8 bearing the 6-7 core of frondosin B. Studies
toward the total syntheses of other members of the frondosin
Supporting Information Available: Full experimental
details, characterization data, and copies of 1H and 13C NMR
spectra for all new compounds are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Tremblay, M. S.; Sames, D. Org. Lett. 2005, 7, 2417.
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