Asymmetric total synthesis of (+)-danicalipin A

Article abstract of DOI:10.1021/ol1029518

A convergent asymmetric total synthesis of (+)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by 1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.(Figure Presented)

Full text of DOI:10.1021/ol1029518

ORGANIC
LETTERS
2011
Vol. 13, No. 5
908–911
Asymmetric Total Synthesis of
(þ)-Danicalipin A
Takehiko Yoshimitsu,* Ryo Nakatani, Akihiro Kobayashi, and Tetsuaki Tanaka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, Japan
yoshimit@phs.osaka-u.ac.jp
Received December 6, 2010
ABSTRACT
A convergent asymmetric total synthesis of (þ)-danicalipin A is accomplished, in which two chlorinated fragments are stereoselectively joined by
1,3-dipolar coupling, leading to the confirmation of the absolute configuration of the natural product.
Certain types of algae produce unique molecules that are
necessary for survival in the natural environment. Poly-
chlorosulfolipids have been shown to exist in some algae
and feature heavily chlorinated linear hydrocarbon motifs
that are rarely seen in other natural products. The dawn of
polychlorosulfolipid research was first recorded in the
literature that described the discovery of unusual sulfoli-
pids from the freshwater alga Ochromonas danica in the late
1960s by the groups of Haines, Elovson, and Vagelos.1a-j
Shortly after that discovery, various chlorosulfolipids from
other species were identified by several research groups,
including those of Mercer and Davies.1k-n More recently,
Gerwick and co-workers discovered malhamensilipin A, a
biologically active chlorosulfolipid metabolite from the
cultured freshwater alga chrysophyte Poterioochromonas
malhamensis.2 However, details of the stereochemical struc-
tures of chlorosulfolipids had long been unclear until quite
recently due to the lack of means to elucidate their complex
stereochemistry, and this had led to the delay in under-
standing their properties at the molecular level.
In 2001, Fattorusso, Ciminiello, and co-workers es-
tablished the stereochemistry of a cytotoxic hexachlorosul-
folipid (Mytilipin A) isolated from Adriatic mussels3a by
conducting extensive NMR studies using Murata’s
(2) (a) Chen, J. L.; Proteau, P. J.; Roberts, M. A.; Gerwick, W. H.;
Slate, D. L.; Lee, R. H. J. Nat. Prod. 1994, 57, 524–527. (b) Gerwick,
W. H. Biochim. Biophys. Acta 1994, 1211, 243–255. (c) Gerwick, W. H.;
Roberts, M. A.; Proteau, P. J.; Chen, J. L. J. Appl. Phycol. 1994, 6, 143–
149. Recently, the revised structure of this natural compound was
reported:(d) Pereira, A. R.; Byrum, T.; Shibuya, G. M.; Vanderwal,
C. D.; Gerwick, W. H. J. Nat. Prod. 2010, 73, 279–283.
(3) (a) Ciminiello, P.; Fattorusso, E.; Forino, M.; Di Rosa, M.;
Ianaro, A.; Poletti, R. J. Org. Chem. 2001, 66, 578–582. The name
‘mytilipin’ was associated with the mussel from which it was extracted
(communicated with Prof. Fattorusso and Prof. Ciminiello).
(b) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, F.;
Magno, S.; Di Rosa, M.; Ianaro, A.; Poletti, R. J. Am. Chem. Soc.
2002, 124, 13114–13120. (c) Ciminiello, P.; Dell’Aversano, C.;
Fattorusso, E.; Forino, M.; Magno, S.; Di Meglio, P.; Ianaro, A.;
Poletti, R. Tetrahedron 2004, 60, 7093–7098. For reviews, see:
(d) Ciminiello, P.; Dell’Aversano, C.; Fattorusso, E.; Forino, M.;
Magno, S. Pure Appl. Chem. 2003, 75, 325–336. (e) Ciminiello, P.;
Fattorusso, E. Eur. J. Org. Chem. 2004, 2533–2551. (f) Chao, C.-H.;
Huang, H.-C.; Wang, G.-H.; Wen, Z.-H.; Wang, W.-H.; Chen, I.-M.;
Sheu, J.-H. Chem. Pharm. Bull. 2010, 58, 944–946.
(1) (a) Haines, T. H.; Pousada, M.; Stern, B.; Mayers, G. L. Biochem.
J. 1969, 113, 565–566. (b) Elovson, J.; Vagelos, P. R. Proc. Natl. Acad.
Sci. U.S.A. 1969, 62, 957–963. (c) Elovson, J.; Vagelos, P. R. Biochem-
istry 1970, 9, 3110–3126. (d) Mooney, C. L.; Mahoney, E. M.; Pousada,
M.; Haines, T. H. Biochemistry 1972, 11, 4839–4844. (e) Mooney, C. L.;
Haines, T. H. Biochemistry 1973, 12, 4469–4472. (f) Haines, T. H. In
Lipids and Biomembranes of Eukaryotic Microorganisms; Erwin, J. A.,
Ed.; Academic Press: New York, 1973; pp 197-232. (g) Haines, T. H.
Annu. Rev. Microbiol. 1973, 27, 403–412. (h) Elovson, J. Biochemistry
1974, 13, 3483–3487. (i) Elovson, J. Biochemistry 1974, 13, 2105–2109.
(j) Chen, L. L.; Pousada, M.; Haines, T. H. J. Biol. Chem. 1976, 251,
1835–1842. (k) Thomas, G.; Mercer, E. I. Phytochemistry 1974, 13, 797–
805. (l) Mercer, E. I.; Davies, C. L. Phytochemistry 1974, 13, 1607–1610.
(m) Mercer, E. I.; Davies, C. L. Phytochemistry 1975, 14, 1545–1548.
(n) Mercer, E. I.; Davies, C. L. Phytochemistry 1979, 18, 457–462.
r
10.1021/ol1029518
Published on Web 02/02/2011
2011 American Chemical Society

J-based configuration analysis (JBCA),4 which was later
utilized in the stereochemical assignment of undecachloro-
sulfolipid (Mytilipin B),3b a cytotoxin that is structurally far
more complex than hexachlorosulfolipid. Okino and co-
workers also applied the Murata method to the elucidation
of the stereochemistry of danicalipin A (1).5 Besides such
progress in structural analysis, the recent development of a
synthetic means to install chlorine functionalities has allowed
synthetic chemists to gain access to this class of natural
compounds.6 In this context, avid research aimed at the
establishment of stereoselective routes to chlorosulfolipids
has culminated in the total synthesis of (()-hexachlorosul-
folipid by Carreira and co-workers7 and in the syntheses of
(()-danicalipin A (1)8 and (þ)-malhamensilipin A by
Vanderwal’s group,9 all of which have revealed the unique
reactivity of the chlorinated molecular architecture toward
chemical reactions.
Scheme 1. Retrosynthesis of (þ)-Danicalipin A
Our group has also been engaged in the synthesis of
natural chlorosulfolipid toxins and has developed a
method for the asymmetric construction of chlorinated
hydrocarbon motifs relevant to the polychlorosulfo-
lipids.10 Application of the method has allowed us to ac-
complish the asymmetric total synthesis of (þ)-hexachlo-
rosulfolipid.11 As part of our continuing efforts to establish
a chlorosulfolipid library that would enable us to pursue
structure-activity relationship studies of this new class of
natural toxins, we have initiated a research program to devise
an enantioselective access to the algal toxin (þ)-danicalipin A
(1). In the present study, we disclose a convergent asymmetric
total synthesis of (þ)-danicalipin A (1), in which two chlori-
nated fragments are stereoselectively joined by a 1,3-dipolar
coupling reaction, establishing a successful route to the
polychlorinated molecular architecture.
(þ)-Danicalipin A (1), isolated from the cellular and
flagellar membranes of the freshwater alga Ochromonas
danica, contains six chlorine atoms in its linear hydro-
carbon motif bearing two sulfates. The chemical synthesis of
this molecule in the racemic form was recently accomplished
by Vanderwal and co-workers, which features the sequen-
tial use of stereoselective chlorination of an unsaturated
hydrocarbon motif.8 Okino’s group also succeeded in the
isolation of natural (þ)-danicalipin A (1) from the cultured
chrysophyte O. danica (IAM CS-2) and confirmed its
absolute stereochemistry and toxicological properties.5
Our convergent synthesis of danicalipin A is retro-
synthetically outlined in Scheme 1. In our approach, target
compound 1 was dissected into two parts, i.e., C12-C22
fragment 4 and C1-C11 fragment 5. C12-C22 unit 4 was
prepared in an enantiomerically pure form from a dichlor-
ide readily obtainable from a chiral epoxide. C1-C11
fragment 5, a 1,3-dipolar precursor, would be connected
to fragment 4, giving rise to the whole hydrocarbon motif
bearing oxygen functionalities suitable for the stereoselec-
tive installation of two more chlorine atoms at a later stage.
C12-C22 fragment 4 was synthesized from known
chiral epoxy alcohol 6 with 80% ee, which was prepared
by the asymmetric epoxidation of commercially available
cis-2-nonene-1-ol (Scheme 2).12 Epoxy alcohol 6 was in-
itially protected as pivalate 7 (95%), which, by dichlorina-
tion with the chlorophosphonium reagent generated in situ
from NCS and triphenylphosphine, furnished dichloride 8
in 86% yield. DIBAL reduction of resultant dichloride 8
allowed the removal of the ester group, providing alcohol 9
in 94% yield. This compound 9 was then oxidized with
Dess-Martin periodinane to furnish unstable aldehyde i,
which was immediately reacted with vinylmagnesium
bromide at -78 to 0 °C in Et2O to deliver alcohol 10
stereoselectively. The facial selectivity observed for the
(4) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana,
K. J. Org. Chem. 1999, 64, 866–876.
(5) Kawahara, T.; Kumaki, Y.; Kamada, T.; Ishii, T.; Okino, T.
J. Org. Chem. 2009, 74, 6016–6024.
(6) (a) Shibuya, G. M.; Kanady, J. S.; Vanderwal, C. D. J. Am. Chem.
Soc. 2008, 130, 12514–12518. (b) Kanady, J. S.; Nguyen, J. D.; Ziller, J. W.;
Vanderwal, C. D. J. Org. Chem. 2009, 74, 2175–2178. For a review, see:
Bedke, D. K.; Vanderwal, C. D. Nat. Prod. Rep. 2011, 28, 15–25.
(7) (a) Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature 2009, 457,
573–576. For the related study, see:(b) Nilewski, C.; Geisser, R. W.;
Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 15866–15876.
(8) (a) Bedke, D. K.; Shibuya, G, M.; Pereira, A. R.; Gerwick, W. H.;
Haines, T. H.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 7570–7572.
(b) While this manuscript was under review, asymmetric total synthesis of
(þ)-danicalipin A was reported;Umezawa, T.; Shibata, M.; Kaneko, K.;
Okino, T.; Matsuda, F. Org. Lett. 2011, ASAP (DOI: 10.1021/ol102882a).
(9) Bedke, D. K.; Shibuya, G, M.; Pereira, A. R.; Gerwick, W. H.;
Vanderwal, C. D. J. Am. Chem. Soc. 2010, 132, 2542–2543.
(10) (a) Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009,
74, 696–702. For the recent development of this method in catalysis, see:
(b) Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678–4681.
(11) Yoshimitsu, T.; Fukumoto, N.; Nakatani, R.; Kojima, N.;
Tanaka, T. J. Org. Chem. 2010, 75, 5425–5437.
1
vinylation (ds =1.7: 1 determined by H NMR analysis
of the crude mixture; for details, see Supporting Information)
can be rationalized by considering the Cornforth transition
(12) (a) Burke, C. P.; Shi, Y. Org. Lett. 2009, 11, 5150–5153.
€
(b) Kanerva, L. T.; Vanttinen, E. Tetrahedron: Asymmetry 1993, 4,
85–90. (c) Yu, L.; Wang, Z. J. Chem. Soc., Chem. Commun. 1993, 232–
234. The enantiomeric purity of this epoxide was determined by the
Mosher method. For details, see the Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
909

Scheme 2. Synthesis of C12-C22 Fragment 4
Scheme 4. Completion of Total Synthesis of (þ)-Danicalipin A
via 1,3-Dipolar Coupling between C1-C11 Fragment 5 and
C12-C22 Fragment 4
Scheme 3. Synthesis of C1-C11 Fragment 5
The preparation of C1-C11 fragment 5 was initiated by
the sequential chlorination of diene 11 (E/Z = 3:2), which
was prepared by the Wittig methoxy alkenylation of 10-
undecenal (Scheme 3). The chlorination of diene 11 with
NCS, followed by treatment of the resultant crude mixture
with TFA, gave an R-chloroaldehyde that, by enamine
formation with t-BuNH2 followed by further chlorination
with NCS in one pot, furnished R,R-dichloroimine 12.14
Hydrolysis of imine 12 with 3 N HCl, followed by reduction
of the resultant aldehyde (structure not shown) with NaBH4
in MeOH, afforded β,β-dichloroalcohol 13 in 63% overall
yield from diene 11. Then, the hydroxyl group of compound
13 was silylated with TBSOTf in the presence of 2,6-lutidine
to provide TBS ether 14 in 95% yield. Alcohol 15 was
prepared in 84% yield in two steps by cleaving the terminal
double bond of 14 by ozonolysis, followed by the reduction
of the resultant aldehyde with NaBH4. Iodination of the
hydroxyl group and subsequent substitution of the resultant
iodide with sodium nitrite in DMF furnished C1-C11
fragment 5 in 60% yield.15 With these two fragments 4 and
5, the intermolecular nitrile oxide 1,3-dipolar assembly was
examined (Scheme 4).
state model.13 Fortunately, numerous efforts at this stage to
increase the ee of enantiomerically enriched intermediate 10
eventually led to the discovery that an enzymatic separation
using Lipase PS IM Amano was best suited for obtaining the
optically pure material. Enantiomerically pure alcohol 10
was then transformed into C12-C22 fragment 4 (>99% ee)
by protecting the hydroxyl group as TBS ether.
(14) Vanderwal’sgroupreportedthedichlorinationofatert-butyl aldimine
ꢀ
derived from 11-bromoundecanal with NCS. See ref 8a; also, see: Verhe, R.;
De Kimpe, N.; De Buyck, L.; Schamp, N. Synthesis 1975, 455–456.
(15) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron:
Asymmetry 2000, 11, 3063–3068.
(13) For instances, see: (a) Cee, V. J.; Cramer, C. J.; Evans, D. A.
J. Am. Chem. Soc. 2006, 128, 2920–2930. (b) Kang, B.; Britton, R. Org.
Lett. 2007, 9, 5083–5086.
910
Org. Lett., Vol. 13, No. 5, 2011

After numerous attempts were made to optimize the
reaction conditions, we found that desired isoxazoline 3
could be successfully produced in a ratio of C13/C14
anti/syn = 7.3: 1 (determined by 1H NMR analysis) by
the slow and stepwise addition of phenyl isocyanate into
the mixture of compound 4 and nitro compound 5 in
heating toluene.16 The preferential formation of desired
C13/C14 anti-isoxazoline 3 can be rationalized by con-
sidering a stereoelectronically favored transition state
of substrate 4, as proposed by Houk and co-workers.17
The anti-stereochemistry of the C13/C14 positions of
isoxazoline 3 was confirmed by its derivatization into an
epoxide by the Payne-type rearrangement.18 Isoxazo-
line 3 was then reduced with molybdenum hexacarbonyl
in aqueous MeCN to afford an aldol (structure not
shown) in 81% yield.19,20 The anti-diol motif necessary for
the installation of chlorine atoms at the C11 and C13
positions was successfully furnished by the anti-selective
reduction of the aldol under Evans conditions to afford diol
2 (anti/syn = 6:1 by 1H NMR analysis).21,22 The next task
was to chlorinate both hydroxyl groups at C11 and C13
positions of compound 2. This transformation was carried
out using Ph3P/NCS to provide desired chlorinated motif 17
albeit in moderate yield (38%) along with some byproducts,
including an olefin.23 Then, removal of the two TBS groups
of compound 17 under acidic conditions (97%), followed by
the stereoisomeric members of danicalipin. We plan to utilize
synthetic danicalipin A in toxicological research to under-
stand how it exerts its toxicity. The next task will include the
preparation of the stereoisomers of (þ)-danicalipin A by
adopting the present route, which would enable us to pursue
structure-activity relationship studies that would provide
vital clues to understand the properties of chlorosulfolipids.
Studies along this line will be disclosed in due course.
Acknowledgment. We express our sincere appreciation to
Professor Toshikatsu Takanami and Ms. Tamami Koseki of
Meiji Pharmaceutical University (MPU) for conducting
mass spectroscopic analysis. This work was partialy sup-
ported by a Grant-in-Aid for Scientific Research on Innova-
tive Areas [No. 22136006] from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (T.Y.).
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H/13C NMR spectra
of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(22) The anti-stereochemistry of major diol 2 was unambiguously
established by NOE analysis of benzylidene acetal 19 derived from diol 2
(for details, see Supporting Information.). NOE analysis of acetal 19
revealed the proximity of the benzylic proton to the C11 and C14
protons, suggesting the anti-relationship between C11 and C13 config-
urations. Further 13C NMR analysis of corresponding acetonides 20 and
21 that were prepared from anti-diol 2 and its syn-isomer with 2,2-
dimethoxypropane in the presence of PPTS, respectively, allowed us to
confirm that the stereochemical assignments of both isomers perfectly
matched those predicted by Rychnovsky’s empirical rule. anti-Aceto-
nide 20 showed carbon resonances for the acetonide methyl groups in the
range 25.8-24.7 ppm, while syn-isomer 21 has methyl resonances at 29.9
and 19.7 ppm.(a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945–948. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetra-
hedron Lett. 1990, 31, 7099–7100.
sulfation of the resultant diol 18 with SO3 Py in DMF,24
3
smoothly delivered natural (þ)-sulfolipid 1 in 94% yield.
The identity of synthetic diol 18 and danicalipin A (1) was
unambiguously confirmed by comparison with re-
ported spectroscopic data; the 1H and 13C NMR data
of diol 18 and synthetic (þ)-danicalipin A (1) were in
good agreement with those reported by Okino’s group
and Vanderwal’s group.25
In conclusion, the asymmetric total synthesis of natural
(þ)-danicalipin A (1) was accomplished. Our synthesis
features 1,3-dipolar addition that unifies chlorinated frag-
ments 4 and 5 to effect the stereoselective construction of the
requisite molecular framework of (þ)-danicalipin A, leading
to the confirmation of the reported absolute configuration of
the natural product. The present route, simply by switching
the starting materials, would provide a flexible route to all of
(16) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339–
5342.
(17) Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J. Am. Chem.
Soc. 1986, 108, 2754–2755.
(18) For details, see Supporting Information.
(19) (a) Zhang, D.; Miller, M. J. J. Org. Chem. 1998, 63, 755–759.
(b) Zhang, D.; Suling, C.; Miller, M. J. J. Org. Chem. 1998, 63, 885–888.
(c) Zhang, D.; Ghosh, A.; Suling, C.; Miller, M. J. Tetrahedron Lett.
1996, 37, 3799–3802.
(20) (a) For pioneering studies on the use of isoxazolines as latent
aldol motifs, see: Curran, D. P. Adv. Cycloaddit. 1988, 1, 129. (b) Curran,
D. P. J. Am. Chem. Soc. 1982, 104, 4024–4026. (c) Torssell, K.; Zeuthen,
O. Acta Chem. Scand. Ser. B 1978, 32, 118. Excellent developments of
this concept in polyketide synthesis; for a recent instance, see:Lohse-
Fraefel, N.; Carreira, E. M. Chem.;Eur. J. 2009, 15, 12065–12081 and
references cited therein.
(23) The major byproduct was an olefin (40% yield) that possessed a
double bond at C12. A small amount of diastereomeric chloride,
tentatively assigned as an (11S,13S)-syn-isomer, was also produced
(5% yield), suggesting that anchimeric assistance of the neighboring
chlorine atom may take place. The details will be reported in due course.
(24) It has been reported that SO3 Py was not suitable for the
3
installation of the sulfate functionality to diol 18 due to the occurrence
of desulfation during workup and purification (ref 8a). We found that
direct filtration of the reaction mixture to ensure the removal of the
residual reagents prior to the chromatographic purification of the crude
residue was essential for the successful isolation of danicalipin A (for
details, see Supporting Information).
(25) Optical rotation of diol 18 [R]25 þ33.1 (c 0.71, MeOH); lit.5
D
[R]22 þ35.9 (c 0.005, MeOH). Optical rotation of synthetic (þ)-
D
(21) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
danicalipin A (1) [R]26 þ33.0 (c 0.40, MeOH); lit.5 [R]25 þ12.8
D
(c 0.2, MeOH); lit.8 [R]24DD þ38 (c 0.78, solvent not indicated).
Org. Lett., Vol. 13, No. 5, 2011
911