Enantioselective total synthesis of (+)-jasplakinolide

Article abstract of DOI:10.1021/ol070855h

An enantioselective total synthesis of (+)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The β-amino acid uni

Full text of DOI:10.1021/ol070855h

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2425-2427
Enantioselective Total Synthesis of
)-Jasplakinolide
(+
Arun K. Ghosh* and Deuk Kyu Moon
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
akghosh@purdue.edu
Received April 12, 2007
ABSTRACT
An enantioselective total synthesis of (
syn-aldol, ortho-ester Claisen rearrangement followed by efficient conversion to a cyanide. The
diastereoselective manner utilizing nucleophilic addition to a chiral sulfinimine. Yamaguchi macrocyclization and removal of the protecting
group provided a convenient access to ( )-jasplakinolide.
+
)-jasplakinolide is described. The synthesis of the polyketide template utilized a diastereoselective
â
-amino acid unit was constructed in a highly
+
Jasplakinolide (1), a 19-membered cyclic depsipeptide,
initially was isolated from the marine sponge Jaspis splen-
dens in 1986.1 It was later found in other marine sponges,
including Auletta sp., H. minor, and Cymbastela sp.2 Jas-
plakinolide exhibited a number of very interesting biological
properties. It is active against 36 human solid tumor types
in cell culture assays.3 It has also exhibited other important
biological properties, including insecticidal, antifungal, and
antihelminthic activities.4 The mechanism of action is known
to involve stabilization of actin filaments by binding to
F-actin similar to phalloidin.5 Preclinical trials of jasplakino-
lide were carried out by the National Cancer Institute as an
anti-actin agent. However, the study was terminated as it
showed significant toxicity.6 Jasplakinolide is often used as
a molecular probe for actin polymerization studies. Its
biological properties and structural features attracted attention
for total synthesis7 and structural modification.8 We recently
reported an enantioselective total synthesis of (-)-doliculide,
(5) (a) Mayer, A. M. S. Pharmacology 1999, 41, 159. (b) Bubb, M. R.;
Spector, I.; Beyer, B. B.; Fosen, M. K. J. Biol. Chem. 2000, 275, 5163. (c)
Fabian, I.; Halperin, D.; Lefter, S.; Mittelman, L.; Altstock, R. T.; Seaon,
O.; Tsarfaty, I. Blood 1999, 93, 3994.
(6) Bubb, M. R.; Senderowicz, A. M. J.; Sausville, E. A.; Duncan, K.
L. K.; Korn, E. D. J. Biol. Chem. 1994, 269, 14869.
(7) (a) Grieco, P. A.; Hon, Y. S. J. Am. Chem. Soc. 1988, 110, 1630. (b)
Chu, K. S.; Negrete, G. R.; Konopelski, J. P. J. Org. Chem. 1991, 56, 5196.
(c) Imaeda, T.; Rao, A. V.; Gurjar, M. K.; Nallaganchu, B. R.; Bhandari,
A. Tetrahedron Lett. 1993, 34, 7085. (d) Hanada, Y.; Shioiri, T. Tetrahedron
Lett. 1994, 35, 591. (e) Hirai, Y.; Yokota, K.; Momose, T. Heterocycles
1994, 39, 603.
(8) (a) Marimganti, S.; Yasmeen, S.; Fischer, D.; Maier, M. E. Chem.s
Eur. J. 2005, 11, 6687. (b) Tabudravu, J. N.; Morris, L. A.; Milne, B. F.;
Jaspars, M. Org. Biomol. Chem. 2005, 5, 745.
(1) (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986,
27, 2797. (b) Zabriskie, T. M.; Klocke, J. A.; Ireland, C. M.; Marcus, A.
H.; Molinski, T. F.; Faulkner, D. J.; Xu, C.; Clardy, J. C. J. Am. Chem.
Soc. 1986, 108, 3123.
(2) Isolation: (a) Crews, P.; Farias, J. J.; Emrich, R.; Keifer, P. A. J.
Org. Chem. 1994, 59, 2932. (b) Talpir, R.; Benayahu, Y.; Kashman, Y.;
Pannell, L.; Schleyer, M. Tetrahedron Lett. 1994, 35, 4453. (c) Chevallier,
C.; Richardson, A. D.; Edler, M. C.; Hamel, E.; Harper, M. K.; Ireland, C.
M. Org. Lett. 2003, 5, 3737.
(3) Inman, W.; Crews, P. J. Am. Chem. Soc. 1989, 111, 2822.
(4) (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986,
27, 2797. (b) Braekman, J. C.; Daloze, D.; Moussiaux, B. J. Nat. Prod.
1987, 50, 994. (c) Takayuki, I.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1994, 35, 591.
10.1021/ol070855h CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/08/2007

another cyclic depsipeptide isolated from Dolabella auricu-
laria by Ishiwata and co-workers.9 Using synthetic doliculide,
we established that it too arrests cell growth at the G2/M
phase of the cell cycle by interfering with normal actin
assembly similar to jasplakinolide.10 Doliculide exhibited no
toxicity. Structural similarities of doliculide and jasplakino-
lide suggest that both compounds bind to the same site on
F-actin. To investigate structure-activity studies of jasplakino-
lide, we sought an efficient synthesis of jasplakinolide for
further structural modification. Herein we report an enantio-
selective total synthesis of (+)-jasplakinolide. The synthesis
features asymmetric synthesis of 8-hydroxynonenoic acid 3
and (R)-â-tyrosine unit 4.
Scheme 1. Synthesis of Carboxylic Acid 3
Our convergent approach to jasplakinolide synthesis is
shown in Figure 1. As shown, 1 is derived from hydroxyl
astereoselectively introduced the R-methyl carbonyl function-
ality through 1,4-chirality transfer.12 The Claisen rearrange-
ment presumably proceeded through a chair-like transition
state as shown in 7 that accounts for the observed diastereo-
selectivity as well as the E-olefin geometry in 8. Ethyl ester
8 was converted to cyanide 9 by reduction with LiBH4 and
EtOH13 followed by Mitsunobu reaction of the resulting alco-
hol using acetone cyanohydrin in the presence of diisopropyl
azodicarboxylate and triphenylphosphine.14 Nitrile 9 was
obtained in 62% yield in a two-step sequence. Reduction of
nitrile with Raney nickel in the presence of NaH2PO3, pyri-
dine, and aqueous acetic acid provided the corresponding
aldehyde.15 Reaction of aldehyde with methylmagnesium bro-
mide afforded diastereomeric alcohols 10 and 11 as a 1:1 mix-
ture in 73% yield in two steps. The alcohols were separated
by flash column chromatography over silica gel. Mitsunobu
inversion16 of (R)-alcohol 10 with Ph3P and p-NO2-benzoic
acid in the presence of diisopropyl azodicarboxylate followed
by ester hydrolysis of the resulting benzoate derivative with
potassium carbonate in ethanol furnished the desired (S)-
alcohol 11. Protection of alcohol 11 with TBSOTf, Et3N at
23 °C, and saponification with aqueous lithium hydroxide
furnished 8-hydroxynonenoic acid 3 in 93% yield.
Figure 1. Retrosynthetic analysis of (+)-jasplakinolide.
acid 2 by a macrocyclization reaction. Macrocyclic precursor
2 would be obtained by coupling of the polypropionic acid
segment 3 and tripeptide 4. The tripeptide fragment is
composed of amino acids, (R)-2-bromoabrine, (R)-â-tyrosine,
and (S)-alanine.
The synthesis of protected 8-hydroxynonenoic acid 3 is
shown in Scheme 1. Asymmetric aldol addition of the boron
enolate derived from oxazolidinone 5 with methacrolein gave
the aldol adduct 6 in 94% yield.11 Allylic alcohol 6 was sub-
jected to acid-catalyzed ortho ester Claisen rearrangement with
triethyl orthopropionate at 140 °C for 1 h to afford γ,δ-
unsaturatedester8in93%yieldasamixture(7:1by1HNMR)
of diastereomers. This Claisen rearrangement protocol di-
(12) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227.
(13) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro,
J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307.
(14) (a) Wilk, B. K. Synth. Commun. 1993, 23, 2481. (b) Aesa, M. C.;
Baan, G.; Noak, L.; Szantay, C. Synth. Commun. 1995, 25, 1545.
(15) (a) Compagnone, R. S.; Rapoport, H. J. Org. Chem. 1986, 51, 1713.
(b) Backeberg, O. G.; Staskun, B. J. J. Chem. Soc. 1962, 3961.
(16) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(b) Mitsunobu, O. Synthesis 1981, 1 and references cited therein.
(9) Ghosh, A. K.; Liu, C. Org. Lett. 2001, 3, 635.
(10) Bai, R.; Covell, D. G.; Liu, C.; Ghosh, A. K.; Hamel, E. J. Biol.
Chem. 2002, 277, 32165.
(11) (a) Gage, J. R.; Evans, D. A. Organic Syntheses; Wiley & Sons:
New York, 1993; Collect. Vol. 8, p 339. (b) Evans, D. A.; Fitch, D. M. J.
Org. Chem. 1997, 62, 454.
2426
Org. Lett., Vol. 9, No. 12, 2007

Diastereoselective synthesis of desired (R)-â-tyrosine
derivative was achieved using an asymmetric protocol
developed by Davis and co-workers,17 as shown in Scheme
2. Aldehyde 12 was readily prepared by protection of
Scheme 3. Synthesis of (+)-Jasplakinolide
Scheme 2. Synthesis of â-Amino Acid Units 14 and 4
4-hydroxybenzaldehyde with TIPSOTf and triethylamine in
CH2Cl2 at 0 °C for 3 h. Reaction of 12 with enantiopure
p-toluenesulfinamide in CH2Cl2 in the presence of Ti(OEt)4
at 40 °C afforded sulfinimine 13 in 87% yield. Reaction of
13 with enolate derived from methyl acetate in diethyl ether
at -78 °C afforded the corresponding addition product as a
single diastereomer (by 1H NMR). Treatment of this resulting
sulfinamide with trifluoroacetic acid in CH2Cl2 removed the
N-sulfinyl auxiliary and afforded (R)-â-tyrosine derivative
14 in 65% yield in two steps. Construction of the tripeptide
fragment 4 was then achieved by coupling reaction of known
dipeptide 157b with 14 in the presence of DCC in THF at 0
°C for 12 h. Removal of the BOC group by exposure to
trifluoroacetic acid in CH2Cl2 provided amino ester 4 in 81%
yield.
The final assembly of jasplakinolide fragments is il-
lustrated in Scheme 3. The coupling of the above amino ester
4 with 8-hydroxynonenoic acid 3 in the presence of DCC
and HOBT in THF at -20 to 0 °C for 24 h furnished
coupling product 16 in 80% yield. Saponification of 16 with
aqueous LiOH at 23 °C affected removal of the TIPS group
and afforded the corresponding phenolic acid. Treatment of
the resulting phenolic acid with TIPSOTf in the presence of
2,6-lutidine at 23 °C for 2 h followed by exposure of the
resulting TIPS derivative with aqueous potassium carbonate
afforded seco acid 2 in 77% yield in three steps. Acid 2 was
subjected to Yamaguchi macrolactonization protocol18 with
2,4,6-trichlorobenzoyl chloride in the presence of DMAP to
provide the corresponding macrolactone in 82% yield.
Removal of the TIPS group by treatment of the macrolactone
with TBAF in THF at 0 °C for 10 min furnished synthetic
(+)-jasplakinolide (1, [R]23 +67.7, c 0.2, CH2Cl2). The
D
spectral data (1H and 13C NMR) of synthetic (+)-jasplakino-
lide are identical with those reported for the natural (+)-
jasplakinolide.6
In summary, we have achieved an enantioselective syn-
thesis of (+)-jasplakinolide (1). The convergent synthesis
features diastereoselective syn-aldol, ortho-ester Claisen
rearrangement and asymmetric synthesis of the (R)-â-tyrosine
derivative. The synthesis will provide a convenient access
to a variety of jasplakinolide derivatives. Structural modifica-
tions of jasplakinolide are currently in progress.
Acknowledgment. Financial support of this work is
provided in part by the National Institutes of Health and
Purdue University. We also thank Dr. Dongwoo Shin for
preliminary experiments, and Mr. Kai Xi for helpful discus-
sion.
Supporting Information Available: Experimental pro-
cedures, spectral data for compounds 1-4, 6, 8-11, 13, 14,
and 16, and 1H NMR and 13C NMR spectra for compounds
1, 2, 4, 8-11, 13, 14, and 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1990, 55, 7.
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