Total synthesis of (+)-aureol

Article abstract of DOI:10.1021/ol301715u

A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimet

Full text of DOI:10.1021/ol301715u

ORGANIC
LETTERS
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Total Synthesis of (þ)-Aureol
Kevin K. W. Kuan, Henry P. Pepper, Witold M. Bloch, and Jonathan H. George*
School of Chemistry & Physics, University of Adelaide, North Terrace,
Adelaide SA 5005, Australia
jonathan.george@adelaide.edu.au
Received June 22, 2012
ABSTRACT
A total synthesis of the marine sponge meroterpenoid (þ)-aureol has been achieved in 12 steps (6% overall yield) from (þ)-sclareolide. Key steps
of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction.
Marine sponges are a rich source of biologically active
hydroquinone sesquiterpenes, such as (þ)-aureol (1)
(Figure 1). (þ)-Aureol was first isolated from the Carib-
bean marine sponge Smeonspongia aurea in 1980 by
Faulkner,1 and it was also subsequently isolated from the
Verongula gigantea marine sponge in 2000.2 The aureol
structure contains a compact tetracyclic ring system, with
four contiguous stereocenters and a cis-relationship be-
tween the two cyclohexane rings of the decalin fragment.
(þ)-Aureol shows selective cytotoxicity against human
tumor cells, including nonsmall cell lung cancer A549
and colon adenocarcinoma HT-29 cells.3 It has also been
shown to possess potent anti-influenza A virus activity.4
Semisynthetic derivatives of aureol have shown promising
activity against Hepa59t/VGH, KB and Hela tumor cell
lines.5 Since the isolation of (þ)-aureol, a number of structu-
rally related tetracyclic meroterpenoid natural products with
similar antiviral and antitumor activities have been discov-
ered, such as strongylin A (2)6 and stachyflin (3).7 Several
related natural products with a trans-decalin structure have
also been isolated, including cyclosmenospongine (4).8
(þ)-Aureol has previously been synthesized by Katoh
from a methyl analogue of the (ꢀ)-WielandꢀMischer
ketone,9 and (ꢀ)-aureol has recently been synthesized by
Marcos from ent-halimic acid as a chiral pool starting
material.10 (()-Stachyflin has been synthesized by the
Shionogi research group,11 and (þ)-stachyflin has recently
been synthesized by Katoh.12 An enantioselective ap-
proach to the tetracyclic core structure of the aureol family
has been reported by Cramer.13
(1) Djura, P.; Stierle, D. B.; Sullivan, B.; Faulkner, D. J.; Arnold, E.;
Clardy, J. J. Org. Chem. 1980, 45, 1435.
(2) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Magno, S.;
Pansini, M. J. Nat. Prod. 2000, 63, 263.
(3) Longley, R. E.; McConnell, O. J.; Essich, E.; Harmody, D. J. Nat.
Prod. 1993, 56, 915.
(4) Wright, A. E.; Cross, S. S.; Burres, N. S.; Koehn, F. PCT WO
9112250A1, August 22, 1991 (Harbor Branch Oceanographics Institution,
USA).
(5) Shen, Y; Liaw, C.; Ho, J.; Khalil, A. T.; Kuo, Y. Nat. Prod. Res.
2006, 20, 578.
(8) Utkina, N. K.; Denisenko, V. A.; Scholokova, O. V.; Virovaya,
M. V.; Prokof’eva, N. G. Tetrahedron Lett. 2003, 44, 101.
(9) (a) Sakurai, J.; Oguchi, T.; Watanabe, K.; Abe, H.; Kanno, S.;
Ishikawa, M.; Katoh, T. Chem.;Eur. J. 2008, 14, 829. (b) Nakatani, M.;
Nakamura, M.; Suzuki, A.; Fuchikama, T.; Inoue, M.; Katoh, T.
ARKIVOC 2003, 8, 45. (c) Suzuki, A.; Nakatani, M.; Nakamura, M.;
Kawaguchi, K.; Inoue, M.; Katoh, T. Synlett 2003, 329. (d) Nakamura,
M.; Suzuki, A.; Nakatani, M.; Fuchikami, T.; Inoue, M.; Katoh, T.
Tetrahedron Lett. 2002, 43, 6929.
(10) Marcos, I. S.; Conde, A.; Moro, R. F.; Basabe, P.; Diez, D.;
Urones, J. G. Tetrahedron 2010, 66, 8280.
(6) Wright, A. E.; Rueth, S. A.; Cross, S. S. J. Nat. Prod. 1991, 54,
1108.
(11) Taishi, T.; Takechi, S.; Mori, S. Tetrahedron Lett. 1998, 39, 4347.
(12) (a) Sakurai, J.; Kikuchi, T.; Takahasi, O.; Watanabe, K.; Katoh,
T. Eur. J. Org. Chem. 2011, 2948. (b) Watanabe, K.; Sakurai, J.; Abe, H.;
Katoh, T. Chem. Commun. 2010, 46, 4055.
(13) Ngoc, D. T.; Albicker, M.; Schneider, L.; Cramer, N. Org.
Biomol. Chem. 2010, 8, 1781.
(7) (a) Kamigauchi, T.; Fujiwara, T.; Tani, H.; Kawamura, Y.;
Horibe, I. PCT WO 9711947A1, April 3, 1997 (Shionogi & Co., Ltd.,
Japan). (b) Minagawa, K.; Kouzuki, S.; Yoshimoto, J.; Kawamura, Y.; Tani,
H.; Iwata, T.; Terui, Y.; Nakai, H.; Yagi, S.; Hattori, N.; Fujiwara, T.;
Kamigauchi, T. J. Antibiot. 2002, 55, 155. (c) Minagawa, K.; Kouzuki,
S.; Kamigauchi, T. J. Antibiot. 2002, 55, 165.
r
10.1021/ol301715u
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origin,14 we were interested in developing a concise synthe-
sis of (þ)-aureol (1). It was our intention to use the
proposed biosynthesis of 1 as a guideline for our retro-
synthetic analysis, as outlined in Scheme 2. We believed
that 1 could be generated from the hydroquinone 8 by a
biomimetic acid mediated cyclization, presumably involv-
ing the carbocation 7 as an intermediate. Compound 8
could be formed from addition of the aryllithium derived
from aryl bromide 10 to aldehyde 9 followed by deoxy-
genation and deprotection steps. Aldehyde 9 could conceiv-
ably be obtained from 11 by a one-carbon dehomologation
sequence. Acetate 11 could be derived from the tertiary
alcohol 12 via a biomimetic sequence of 1,2-hydride and
methyl shifts, and 12 could be formed by reduction and
monoprotection of the cheap, enantiopure terpenoid start-
ing material (þ)-sclareolide (13).15 Importantly, the late
stage introduction of the hydroquinone motif in this strategy
should allow easy access to related natural products and
synthetic derivatives for further biological evaluation.
Figure 1. Representative members of the aureol family of ses-
quiterpenoid natural products.
Scheme 2. Biosynthetically Inspired Retrosynthesis of (þ)-
Aureol
The biosynthesis of (þ)-aureol (1) presumably involves
stereoselective cyclization of polyene 5 (which could be
derived from the union of farnesyl pyrophosphate and
hydroquinone) to generate the tertiary carbocation 6
(Scheme 1). This carbocation could then undergo a se-
quence of stereospecific 1,2-hydride and methyl shifts to
give a second tertiary carbocation 7, which could be
attacked by the adjacent hydroquinone to give 1.
Scheme 1. Proposed Biosynthesis of (þ)-Aureol
We have previously observed a related sequence of
stereospecific 1,2-hydride and methyl shifts in the conver-
sion of 14 to 15 as part of a biomimetic study of simplified
labdane rearrangements (Scheme 3),16 so we anticipated
As part of our continuing interest in the synthesis of
biologically active meroterpenoids of marine sponge
(15) For a review of the use of (þ)-sclareolide in the synthesis of
terpenoid natural products, see: Frija, L. M. T.; Frade, R. F. M.;
Afonso, C. A. M. Chem. Rev. 2011, 111, 4418.
(16) George, J. H.; McArdle, M.; Baldwin, J. E.; Adlington, R. M.
Tetrahedron 2010, 66, 6321.
(14) (a) George, J. H.; Baldwin, J. E.; Adlington, R. M. Org. Lett.
2010, 12, 2394. (b) Pepper, H. P.; Kuan, K. K. W.; George, J. H. Org.
Lett. 2012, 14, 1524.
B
Org. Lett., Vol. XX, No. XX, XXXX

that the conversion of 12 to 11 would be possible by
treatment with a strong Lewis acid.
determined by single crystal X-ray crystallography of the
3,5-dinitrobenzoate derivative 17.17
Synthesis of the key aldehyde intermediate 9 from 16
required the excision of one carbon atom, accomplished
using a GriecoꢀSharpless elimination protocol18 followed
by oxidative cleavage of the resultant terminal alkene
(Scheme 5). Thus, treatment of alcohol 16 with o-
NO2C6H4SeCN and n-Bu3P gave 18 in 88% yield, which
underwent oxidative syn-elimination on exposure to H2O2
to give alkene 19 in 77% yield. Dihydroxylation of 19 with
OsO4/NMO then gave a diol as a mixture of diastereomers
that underwent oxidative cleavage with NaIO4 to give
aldehyde 9. Yields for these latter two steps were modest,
presumably due to the relatively hindered nature of the
terminal alkene of 19.
Scheme 3. Conversion of 14 to 15 via Stereospecific 1,2-Hydride
and Methyl Shifts
Our synthesis of (þ)-aureol (1) commenced with reduction
of (þ)-sclareolide 13 using LiAlH4 to give a diol, which was
selectively protected at the primary alcohol using Ac2O in
pyridine to give the acetate ester 12 in good yield (Scheme 4).
Scheme 5. Synthesis of Aldehyde 9 via a One-Carbon Deho-
mologation Pathway
Scheme 4. Synthesis of Alcohol 16 via Stereospecific 1,2-Hy-
dride and Methyl Shifts
Scheme 6. Alternative Synthesis of Alkene 19 via Elimination of
a Benzyl Ether
The dehydration of primary alcohol 16 to give terminal
alkene 19 could alternatively be achieved via a [2,3]-Wittig
type fragmentation of a benzyl ether (Scheme 6). In this
The first key step in the overall synthesis was the BF3-
mediated rearrangement of 12 to give 11, which occurred
via stereospecific 1,2-hydride and methyl shifts to generate
the desired product as a single stereoisomer in 70% yield.
Basic hydrolysis of acetate 11 then gave alcohol 16. The
relative stereochemistry of 16 at C-8 and C-9 was
(17) Crystallographic data for the structures of 17 (CCDC 881566)
and 22 (CCDC 895904) have been deposited with the Cambridge
Crystallographic Data Centre. Copies of these data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif.
(18) (a) Majectich, G.; Grieco, P. A.; Nishizawa, M. J. Org. Chem.
1977, 42, 2327. (b) Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975,
40, 947.
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yielding than the GriecoꢀSharpless protocol, the Komada
reaction is perhaps preferable on a larger scale as it avoids
the generation of stoichiometric selenium and phosphorus
waste products.
Scheme 7. Synthesis of (þ)-Aureol
Treatment of aryl bromide 1020 with t-BuLi formed an
aryllithium species that was added to aldehyde 9 to give
secondary alcohol 20 as a mixture of diastereomers
(Scheme 7). Deoxygenation of 20 under Birch reduction
conditions then gave 21 in 78% yield over the two steps.
Removal of the TBS protecting groups with TBAF then
gave hydroquinone 8, which was treated with BF3 Et2O at
3
ꢀ60 to ꢀ20 °C to give (þ)-aureol (1) in 66% yield for the
key cyclization step. This cyclization reaction has pre-
viously been reported by Marcos for the synthesis of (ꢀ)-
aureol.10 Spectroscopic data for synthetic (þ)-aureol (1)
were identical to those of the natural compound.1 Inter-
estingly, whenthe reactionmixturewas allowed towarmto
room temperature, we found the rearranged 7-membered
cyclic ether 22 was the major product. The structure of 22
(as proven by X-ray crystallography17) is similar to that of
the natural product dactyloquinone C21 and is presumably
formed from carbocation 7 via a 1,2-hydride shift.
In conclusion, we have completed an efficient synthesis
of (þ)-aureol (1) in 12 steps and 6% overall yield from (þ)-
sclareolide (10). Key steps of the synthesis include a
biomimetic sequence of 1,2-hydride and methyl shifts,
and a biomimetic cycloetherification reaction. The overall
strategy involves late stage addition of the aromatic ring
system, potentially allowing access to related natural
products, such as strongylin A and stachyflin, and syn-
thetic derivatives thereof for further analysis as antiviral
and antitumor agents.
Acknowledgment. We thank Mr. Philip Clements
(University of Adelaide) for assistance with NMR studies.
case, alcohol 16 was benzylated under standard conditions
to give the corresponding benzyl ether in 83% yield.
Treatment of this compound with 3 equiv of n-BuLi at
ꢀ78 °C according to the procedure of Kodama furnished
the terminal alkene 19 in 54% yield via sigmatropic
rearrangement of a benzylic anion.19 Although lower
Supporting Information Available. Synthetic procedures
and analytical data for compounds 1, 8, 9, 11, 12, and
16ꢀ22. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Mitome, H.; Nagasawa, T.; Miyaoka, H.; Yamada, Y.; van
Soest, R. W. M. Tetrahedron 2002, 58, 1693.
(19) Matsushita, M.; Nagaoka, Y.; Hioki, H.; Fukuyama, Y.;
Kodama, M. Chem. Lett. 1996, 25, 1039.
(20) Willis, J. P.; Gogins, K. A. Z.; Miller, L. L. J. Org. Chem. 1981,
46, 3215.
The authors declare no competing financial interest.
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