Asymmetric Total Synthesis of Bacillariolide III, a Marine Oxylipin

Article abstract of DOI:10.1021/ol0363366

(Matrix presented) The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis (RCM).

Full text of DOI:10.1021/ol0363366

ORGANIC
LETTERS
2004
Vol. 6, No. 3
429-432
Asymmetric Total Synthesis of
Bacillariolide III, a Marine Oxylipin
Seung-Yong Seo,† Jae-Kyung Jung,‡ Seung-Mann Paek,† Yong-Sil Lee,†
,†,§
Seok-Ho Kim,† Kwang-Ok Lee,† and Young-Ger Suh*
College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea, Center for
BioactiVe Molecular Hybrids, Yonsei UniVersity, Seoul 120-749, Korea, and
College of Pharmacy, Chungbuk National UniVersity, Cheongju 361-763, Korea
ygsuh@snu.ac.kr
Received December 1, 2003
ABSTRACT
The asymmetric total synthesis of bacillariolide III has been achieved via 15 linear steps in 14.6% overall yield. The key feature of this synthetic
route involves the highly stereoselective construction of the vinyl-substituted bicyclic lactone by an intramolecular Pd(0)-catalyzed allylic
alkylation and its facile conversion to the hydroxy bicyclic lactone skeleton of bacillariolide III, induced by stereoselective vinylcerium addition
to the aldehyde. In addition, the (Z)-pentenoic acid was efficiently introduced by the internal hydroxy group tethered ring-closing metathesis
(RCM).
Bacillariolides I and II, which are new carbocyclic oxylipins,1
were isolated from the marine diatom Pseudonitzschia
multiseries, a causative organism of amnesic shellfish
poisoning, by Shimizu and Wang.2 The detailed structure
and absolute configurations of bacillariolide I, possessing
significant inhibitory activity against phospholipase A2
(PLA2), have been established based on extensive spectro-
scopic analyses in conjunction with the X-ray crystal-
lographic analysis of the (-)-camphanic acid derivative. On
the other hand, bacillariolide III, which was isolated from
the culture medium of the same marine diatom, was proposed
to be an extracellular metabolite derived from bacillariolide
Although the biological function of this extracellular
I by oxidative cleavage of the polyene side chain, especially
metabolite is still under investigation, the novel structural
at C-12 and C-13.3
features of bacillariolide III (1), involving the highly func-
tionalized cyclopentanol framework with four contiguous
stereocenters and the potential biological activity derived
† College of Pharmacy, Seoul National University.
§ Center for Bioactive Hybrids.
‡ Chungbuk National University.
(1) (a) Shimizu, Y. Chem. ReV. 1993, 93, 1685. (b) Gerwick, W. H.
Chem. ReV. 1993, 93, 1807. (c) Shimizu, Y. Annu. ReV. Microbiol. 1996,
50, 431.
(2) (a) Wang, R.; Shimizu, Y. J. Chem. Soc., Chem. Commun. 1990,
413. (b) Wang, R.; Shimizu, Y.; Steiner, J. R.; Clardy, J. J. Chem. Soc.,
Chem. Commun. 1993, 379.
from its structural resemblance to the well-known biologi-
cally important prostaglandins and jasmonates,4 led us to
undertake the total synthesis of bacillariolide III. We herein
report the asymmetric total synthesis of bacillariolide III,
which previously was reported only by Yamada and co-
workers.5
(3) Zheng, N.; Shimizu, Y. Chem. Commun. 1997, 399.
10.1021/ol0363366 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004

Our retrosynthetic analysis for bacillariolide III (1) is
illustrated in Scheme 1. In contemplating the synthesis of
Our synthesis commenced with the preparation of the
requisite allylic carbonate 5 for the key Pd(0)-catalyzed
cyclization, as shown in Scheme 2. Thus, the R,â-unsaturated
Scheme 1. Retrosynthesis of Bacillariolide III
Scheme 2
bacillariolide III, it was envisioned that the (Z)-pentenoic
acid side chain could be installed by the C5 hydroxy group
tethered ring-closing metathesis (RCM)6 from 3 and the
subsequent hydrolysis of the nine-membered lactone 2. The
crucial C7 stereochemistry of the hydroxy bicyclic lactone
3 would be established with stereoselective addition of a
vinyl organometallic reagent to the aldehyde, prepared by
oxidative cleavage of the vinyl substituent of the bicyclic
lactone 4. The initial vinyl addition product was expected
to spontaneously isomerize to the hydroxy bicyclic lactone
3. On the basis of the stereoselective Pd(0)-catalyzed
cyclization of allylic carbonate recently developed in our
laboratory,7 the requisite bicyclic lactone 4, corresponding
to the hydroxy-cyclopentane skeleton of the bacillariolide
series, would be efficiently prepared from the allylic carbon-
ate 5. The cyclization precursor 5 can be conveniently
derived from the known (R)-(-)-R-hydroxy-γ-butyrolactone.
This transformation involves a two-carbon homologation and
the introduction of benzenesulfonyl acetate, followed by
δ-lactone formation.
ester 7 was prepared from the known TBS-protected (R)-
(-)-R-hydroxy-γ-butyrolactone 68 in 85% yield by a con-
venient one-pot procedure, involving a DIBAL reduction
followed by a Horner-Wadsworth-Emmons reaction.9
Tosylation of the primary alcohol 7 and then DIBAL
reduction of the ester furnished the allylic alcohol 8 in 95%
overall yield. THP protection of the allylic alcohol 8 and
subsequent alkylation of the tosylate with benzenesulfonyl
acetate 10 provided the alkylation product 9. Concurrent
removal of both the TBS and THP protecting groups with
CSA and lactonization of the resulting hydroxy ester in the
presence of DBU afforded the δ-valerolactone, which was
subjected to ethoxycarbonylation to provide the allylic
carbonate 5.
With the requisite cyclization precursor 5 in hand, we
carried out a survey of diastereoselective Pd(0)-catalyzed
cyclizations under a variety of reaction conditions, including
different ligands and solvents as summarized in Table 1.
Initial treatment of 5 with 10 mol % of Pd(dppe)2 in THF
afforded the cyclization product as a mixture of 4 and 4′ in
78% yield, with a disappointingly low stereoselectivity (entry
1). Fortunately, the poor diastereoselectivity was solved by
the use of Pd(PPh3)4. The cyclization of 5 in the presence of
5 mol % of Pd(PPh3)4 in CH2Cl2 (entry 4) resulted in the
exclusive formation of the desired isomer 4, along with a
trace amount of the minor isomer 4′ (30:1), in 88% yield.
Interestingly, the cyclization in the presence of Pd(dba)2
(entry 7) showed the opposite diastereoselectivity, although
(4) For recent reviews related to prostaglandins and jasmonates, see: (a)
Straus, D. S.; Glass, C. K. Med. Res. ReV. 2001, 21, 185. (b) Prostaglandins,
Leukotrienes and Other Eicosanoids. From Biogenesis to Clinical Applica-
tions; Marks, F., Furstenberger, G., Eds.; Wiley-VCH: Weinheim, Germany,
1999. (c) Collins, P. W.; Djuric, S. W. Chem. ReV. 1993, 93, 1533. (d)
Cheong, J.-J.; Choi, Y. D. Trends Genet. 2003, 19, 409. (e) Liechti, R.;
Farmer, E. E. Science 2002, 296, 1649 and references therein.
(5) (a) Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron Lett. 1998,
39, 621. (b) Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron 2000, 56,
8083.
(6) For recent reviews concerning RCM reactions, see: (a) Grubbs, R.
H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schuster,
M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Armstrong,
S. K. J. Chem. Soc., Perkin Trans. 1 1997, 371. (d) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413. (e) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3013.
(7) (a) Suh, Y.-G.; Jung, J.-K.; Kim, S.-A.; Shin, D.-Y.; Min, K.-H.
Tetrahedron Lett. 1997, 38, 3911. (b) Suh, Y.-G.; Jung, J.-K.; Suh, B.-C.;
Lee, Y.-C.; Kim, S.-A. Tetrahedron Lett. 1998, 39, 5377. (c) Suh, Y.-G.;
Seo, S.-Y.; Jung, J.-K.; Park, O.-H.; Jeon, R.-O. Tetrahedron Lett. 2001,
42, 1691. (d) Suh, Y.-G.; Jung, J.-K.; Seo, S.-Y.; Min, K.-H.; Shin, D.-Y.;
Lee Y.-S.; Kim, S.-H.; Park, H.-J. J. Org. Chem. 2002, 67, 4127.
(8) (a) Shiuey, S. J.; Partridge, J. J.; Uskokovic, M. R. J. Org. Chem.
1988, 53, 1040. (b) Mulzer, J.; Mantoulidis, A.; Ohler, E. J. Org. Chem.
2000, 65, 7456.
(9) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27,
1257.
430
Org. Lett., Vol. 6, No. 3, 2004

Table 1. Pd(0)-Catalyzed Cyclization of Allylic Carbonate 5a
Scheme 3
entry
catalyst
solvent
yield (%)b
ratioc (4:4′)
1
2
3
4
5
6
7
8
Pd(dppe)2
Pd(dppe)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
THF
DMSO
THF
CH2Cl2
DMSO
CH3CN
DMSO
THF
78
33
65
88
57
59
27
d
2:1
1:1
5:1
30:1
10:1
1.1:1
1:2.4
Pd(dba)2
a Reactions were conducted with 10 mol % of Pd catalyst at 80 °C for
2 h except for the reaction of entry 4 performed with 5 mol % of Pd catalyst
under reflux for 1 h. b Isolated yields. c Determined by 300-MHz 1H NMR
spectra of the crude diastereomeric mixtures. d Not determined.
the yield was quite low. Notably, our methodology provides
the bicyclic lactone 4 as an excellent equivalent of the
thermodynamically less favorable cis-2,3-disubstituted-cy-
clopentanol system, which is not easily accessible by the
conventional cyclization methods.10
Having successfully addressed the synthesis of the bicyclic
lactone 4, we turned our attention to the facile transformation
of 4 into the bicyclic lactone 3, as well as to the stereose-
lective introduction of the C7 vinyl substituent, which is
essential for the projected RCM (Scheme 3). We initially
attempted to add the vinyl group to the aldehyde 11
possessing the benzenesulfonyl group. Thus, ozonolysis (O3,
CH2Cl2, then Me2S) of the cyclization adduct 4 and the
immediate subjection of the unstable aldehyde 11 to the
vinylation conditions (CH2CHMgBr, THF, -78 °C) gave the
transposed lactone 12 as a single diastereomer in low yield
(∼25%). This low yield seems to be due to the inherent
lability of the strained â-alkoxyaldehyde, which induces the
formation of the elimination and/or epimerization product.
Furthermore, the structural assignment of 12 by extensive
NOE studies revealed that the C7 stereochemistry is opposite
to the desired one. Other methods for stereoselective viny-
lation were also investigated, with little success.11 In light
of the fact that the cerium reagents react with the readily
enolizable carbonyl group,12 we considered the use of an
organocerium reagent for the pivotal vinylation of the
desulfonylated aldehyde. Thus, desulfonylation (6% Na-
Hg, B(OH)3, MeOH) of 4 without ring opening of the
bicyclic lactone7d and then direct vinylcerium addition to the
crude aldehyde 14, which was prepared by ozonolysis of
13, afforded the desired bicyclic intermediate 3 (65%) along
with a small amount of the undesired isomer (10%). The
stereoselectivity of vinylcerium addition to the aldehyde is
not readily explainable. However, this selectivity is likely
due to the preferred anti relationship of the polar groups, as
shown in conformation B, which minimizes the electronic
repulsion.13 The structure of 3, as well as the stereochem-
istries of its stereogenic centers, was confirmed by an
intensive analysis of the spectral data, including NOE studies.
To complete the synthesis of bacillariolide III, the C-5
hydroxy group of the vinylated bicyclic lactone 3 was
acylated with pentenoyl chloride to give the ester 15 as an
internal hydroxy group tethered RCM precursor.14 To our
delight, the ring-closing metathesis of diene 15 with the
second-generation Grubbs’ catalyst 16 proceeded smoothly,
to give the nine-membered lactone 2 with the desired (Z)-
geometry of the pentenoic side chain.15 It is noteworthy that
the ring-closing metathesis of the diene 15 under highly
diluted conditions (0.2 mM) was completed in 10 min, and
afforded the nine-membered lactone 2 along with little
dimerization product.
(10) (a) Trost, B. M.; Lee, P. H. J. Am. Chem. Soc. 1991, 113, 5076. (b)
Reference 6a and references therein.
(11) All attempts for the direct installation of the (Z)-pentenoic acid side
chain, however, were unsatisfactory.
Finally, hydrolysis of the nine-membered lactone 2,
followed by trifluoroacetic acid treatment, provided bacil-
(12) For reviews concerning organocerium compounds, see: (a) Liu, H.-
J.; Shia, K. S.; Shang, X.; Zhu, B.-Y. Tetrahedron 1999, 55, 3803. (b)
Takeda, N.; Imamoto, T. Org. Synth. 1999, 76, 228. (c) Imamoto, T.
Lanthanides in Organic Synthesis; Academic Press: London, UK, 1994; p
80. (d) Molander, G. A. Chem. ReV. 1992, 92, 29. (e) Imamoto, T. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 1, p 231.
(13) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1986,
27, 4011 and references therein.
(14) For recent examples of tethered ring-closing metathesis, see: (a)
Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am.
Chem. Soc. 2003, 125, 14702. (b) Van de Weghe, P.; Aoun, D.; Boiteau,
J.-G.; Eustache, J. Org. Lett. 2002, 4, 4105 and references therein.
Org. Lett., Vol. 6, No. 3, 2004
431

lariolide III (1) in 71% yield. The synthetic bacillariolide
III was identical with the natural product in all aspects,
including optical rotation.3,5b
In summary, we have achieved the asymmetric total
synthesis of bacillariolide III in 15 linear steps, with a 14.6%
overall yield. The key feature of this synthetic route involves
(1) the highly stereoselective construction of the cis-2,3-
disubstituted hydroxy-cyclopentane intermediate 4 via
Pd(0)-catalyzed allylic cyclization, (2) the stereoselective
vinylcerium addition, which induces its facile transformation
into the bicyclic lactone skeleton of bacillariolide III, and
(3) the efficient introduction of the (Z)-pentenoic acid side
chain by RCM. Our synthetic procedure is quite versatile
and expected to be widely utilized for the synthesis of
oxylipins and their structural analogues.
Acknowledgment. We thank Prof. H. Miyaoka, Tokyo
University of Pharmacy and Life Science, for kindly provid-
ing spectral data for bacillariolide III. This research was
supported by Grant 01-PJ2-PG6-01NA01-0002 (the Korea
Health 21 R&D project) from the Ministry of Health &
Welfare.
(15) For an example of the nine-membered lactone formation using RCM,
see: (a) Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka,
T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653. For selected examples of
the synthesis of nine-membered carbo- and heterocycles, see: (b) Crimmins,
M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548. (c) Delgado, M.; Martin,
J. D. Tetrahedron Lett. 1997, 38, 6299. (d) Bond, S.; Perlmutter, P.
Tetrahedron 2002, 58, 1779. (e) Bamford, S. J.; Goubitz, K.; van Lingen,
H. L.; Luker, T.; Schenk, H.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1
2000, 345. (f) Harris, P. W. R.; Brimble, M. A.; Gluckman, P. D. Org.
Lett. 2003, 5, 1847. (g) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org.
Lett. 2003, 5, 89.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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