First total synthesis of paracaseolide A

Article abstract of DOI:10.1021/ol301481t

The first total synthesis of the paracaseolide A, a very unusual tetraquinane oxa-cage bislactone recently isolated from the mangrove Sonneratia paracaseolaris, has been achieved. The final step and culmination of the eight-step synthetic sequence is a [4 + 2] dimerization of a 4-hydroxybutenolide, generated by singlet oxygen-mediated oxidation of a furan precursor.

Full text of DOI:10.1021/ol301481t

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3565–3567
First Total Synthesis of Paracaseolide A
Dimitris Noutsias and Georgios Vassilikogiannakis*
Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Iraklion, Crete, Greece
vasil@chemistry.uoc.gr
Received May 30, 2012
ABSTRACT
The first total synthesis of the paracaseolide A, a very unusual tetraquinane oxa-cage bislactone recently isolated from the mangrove Sonneratia
paracaseolaris, has been achieved. The final step and culmination of the eight-step synthetic sequence is a [4 þ 2] dimerization of a
4-hydroxybutenolide, generated by singlet oxygen-mediated oxidation of a furan precursor.
An investigation into the stem bark of Chinese man-
grove plants, belonging to the genus Sonneratia, resulted
recently in the isolation by Guo and his co-workers1 of a
very unusual R-alkylbutenolide dimer which was named
paracaseolide A (1, Scheme 1). Structural elucidation
techniques revealed the presence of a rare tetraquinane
bislactone skeleton bearing two adjacent linear alkyl
chains on the convex face of its oxa-cage-like structure.
Natural product 1 showed significant inhibitory activity
against dual specificity phosphatase CDC25B, with an
IC50 value of 6.44 μM.1 CDC25B is a key enzyme required
for cellcycle progressionand has beenobserved in a variety
of cancers and is associated with tumor aggressiveness and
poor prognosis.2 Herein, we report the first total synthesis
of the highly complex molecular architecture that is para-
caseolide A.
“ideal synthesis”5 as possible. Our synthesis of paracaseolide
A was developed with these ideas in mind and with the goal
of rapidly increasing molecular complexity with minimal use
of concessionary steps.4b Even the use of the TBS-group is
nontraditional as it serves several constructive purposes
alongside its more conventional protecting role (vide infra).
The isolation team had proposed a very reasonable
biosynthetic path for the assembly of paracaseolide A with
a [4 þ 2] dimerization of the R-alkenyl-γ-hydroxybuteno-
lide 4 at its heart (Scheme 1). We would like to add to the
proposal that a concerted DielsꢀAlder6 cycloaddition of the
starting E,E-diene 4 would be expected to afford the C7 dias-
tereoisomer of the natural product, compound 2 (Scheme 1).
Although a stepwise DielsꢀAlder reaction cannot be ex-
cluded, we believe that a concerted DielsꢀAlder reaction
might be occurring followed by a fast epimerization of the
readily epimerizable C7-center of the initially formed diaster-
eoisomer 2, leading to the formation of the natural com-
pound 1 (Scheme 1). This type of epimerization should be
thermodynamically favored since it repositions the long linear
alkyl chain (appended at C7), from the concave to the convex
face of the cage-like structure. Following these considera-
tions, our synthetic design (Scheme 1) hinged upon the
use of this bioinspired [4 þ 2]-dimerization of R-alkenyl-
γ-hydroxybutenolide 4, and as such, it followed in the
The primary goal of our research is to develop methods
that provide more efficient and effective responses to
synthetic challenges, particularly in the context of tradi-
tional intransigent polyoxygenated target structures.3 Thus,
in any given piece of work, we are aiming to achieve as
many of the recently delineated4 and exacting criteria for
(1) Chen, X.-L.; Liu, H.-L.; Li, J.; Xin, G.-R.; Guo, Y.-W. Org. Lett.
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Vassilikogiannakis, G. Green Chem. 2012, 14, 601.
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T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657. (c) Newhouse, T.; Baran,
P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010.
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Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784.
(6) For a review of the use of the DielsꢀAlder reaction in synthesis,
see: (a)Nicolaou, K. C.;Snyder, S. A.;Montagnon, T.;Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668. For review and discussion of
biomimetic DielsꢀAlder strategies, see: (b) de la Torre, M. C.; Sierra, M. A.
Angew. Chem., Int. Ed. 2004, 43, 160. (c) Stocking, E. M.; Williams, R. M.
Angew. Chem., Int. Ed. 2003, 42, 3078. For a review of DielsꢀAlder-type
natural products, see: (d) Ichihara, A.; Oikawa, H. Curr. Org. Chem. 1998,
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r
10.1021/ol301481t
2012 American Chemical Society
Published on Web 06/26/2012

Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of the Dimerization Precursor R-Alkenyl-
γ-hydroxybutenolide 4
R-alkenyl-γ-hydroxybutenolide4could be accessed through
the singlet oxygen photooxygenation of an appropriately
substituted furan precursor.
footsteps of other successful and elegant syntheses
that have utilized DielsꢀAlder-dimerizations to access
complicated architectures.7 It was anticipated that the
With this in mind our investigation began with synthesis
of the requisite furan photooxygenation precursor 11
which was accomplished as shown in Scheme 2. Lithiumꢀ
halogen exchange of 1-iodotridecane (6) followed by addi-
tion to 3-furaldehyde resulted in the formation of furanol 7.
The resultant hydroxyl functionality then served another
useful purpose when it was utilized to effect a regioselective
silylation of the furan (at the 2-position as opposed to the
less hindered 5-position, 7 f 9). Specifically, 3-(R-trialky-
lsilyloxy)alkylfuran 8 underwent a [1,4] OfC silyl migra-
tion8 to furnish 2-trialkylsilyl-3-(R-hydroxy)alkylfuran 9
(Scheme 2). After acidic dehydration using p-TsOH, the
remaining unsubstituted ortho-position of the furan was
methylated using standard conditions to afford the
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Org. Lett., Vol. 14, No. 14, 2012

photooxygenation precursor furan 11. The presence of the
TBS group at the 2-position of the furan not only guaran-
teed the regioselective methylation of position 5 but also
directed the regioselectivity of the singlet oxygen (1O2)
oxidation9 such that it yielded exclusively the requisite
R-substituted γ-hydroxybutenolide 4. In contrast to this
clear and desired regioselective outcome, it is well-known
that γ-hydroxybutenolides prepared by photooxygenation
of 3-alkyl furans are mixtures of R- and β-alkyl γ-hydroxy-
butenolides,10aꢀc or solely the β-regioisomers when Hunig’ s
base is included.10cꢀj Thus, through a short and high
yielding synthetic sequence, R-alkenyl-γ-hydroxybuteno-
lide 4 was synthesized.
Scheme 3. Bioinspired [4 þ 2] Dimerization of 4-Hydroxybute-
nolide 4 to Paracaseolide A
With the monomer 4 in hand, the stage was now set to
explore the ambitious bioinspired [4 þ 2] dimerization/
ketalization/epimerization sequence to reach our target,
paracaseolide A. Unfortunately, heating of a toluene solu-
tion of 4 at 110 °C in a sealed tube for 12 h resulted in
formation of the R,γ-disubstituted butenolide 13 in 42%
isolated yield (Scheme 3). A mechanistic explanation for
the formation of compound 13 invokes an intramolecular
oxa-Michael type addition of the open keto-acid form 12
as shown in Scheme 3. In order to avoid this unwanted
reaction (4 f 13) and favor the desired bimolecular [4 þ 2]
dimerization, we opted to investigate increasing the con-
centration. To our satisfaction when the reaction was
performed neat in a sealed tube at 110 °C for 12 h,
formation of a 3:1 mixture of the natural product para-
caseolide A (1) vs the R,γ-disubstituted butenolide 13
was observed by 1H NMR analysis of the crude reaction
mixture. Chromatographic separation of the two pro-
ducts afforded the clean natural product 1 in 59%
isolated yield.
In summary, an extremely short (eight steps in total,
starting from commercially available compounds), fast
(executed easily in 4ꢀ5 days), and efficient protocol
(15% overall yield) has been developed for the first total
synthesis of paracaseolide A (1). The synthetic sequence
involves transformation of a simple and readily accessible
furan substrate into the desired 4-hydroxybutenolide
4 using a singlet oxygen-mediated oxidation.3,11 This
4-hydroxybutenolide is the precursor for the final bioin-
spired [4 þ 2]-dimerization/ketalization/epimerization
that gives rise to the natural product paracaseolide A. This
atom-12 and step-economic13 protocol, which utilizes en-
vironmentally benign oxygen from the air as the oxidant
and which uses a bioinspired [4 þ 2]-cycloaddition to
accomplish a rapid increase of molecular complexity in
one synthetic operation, represents an achievement that
takes us a step, albeit a small one, toward achieving the
prized goal of an ideal synthesis.4
€
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€
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Chem. Soc. 2002, 124, 13171. (f) Demeke, D.; Forsyth, C. J. Org. Lett.
2003, 5, 991. (g) Miyaoka, H.; Yamanishi, M.; Kajiwara, Y.; Yamada,
Y. J. Org. Chem. 2003, 68, 3476. (h) Cheung, A. K.; Murelli, R.; Snapper,
M. L. J. Org. Chem. 2004, 69, 5712. (i) Izzo, I.; Avallone, E.; Della
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Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Union’s Seventh Framework Pro-
gramme (FP7/2007-2013)/ERC Grant Agreement No.
277588. We also thank Prof. Robert Stockman and Mr.
George Procopiou (University of Nottingham) for their
help in taking HRMS.
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A.; De Roman, M.; Urones, J. G. J. Org. Chem. 2005, 70, 9480.
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M. T.; Wexler, S.; Burstain, I. G.; Denny, R.; Schenck, G. O.; Schulte-
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Biomol. Chem. 2011, 9, 2031. (g) Vassilikogiannakis, G.; Alexopoulou,
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Supporting Information Available. Experimental proce-
dures, full spectroscopic data, and copies of 1Hand13CNMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Trost, B. M. Science 1991, 254, 1471.
(13) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
The authors declare no competing financial interest.
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