Total synthesis of cytotoxic anhydrophytosphingosine pachastrissamine (Jaspine B)

Article abstract of DOI:10.1021/ol0473290

(Chemical Equation Presented) Starting from L-serine, a stereoselective synthesis of pachastrissamine, a structurally novel anhydrosphingosine derivative, is reported in this Letter.

Full text of DOI:10.1021/ol0473290

ORGANIC
LETTERS
2005
Vol. 7, No. 5
875-876
Total Synthesis of Cytotoxic
Anhydrophytosphingosine
Pachastrissamine (Jaspine B)
Pushpal Bhaket, Kay Morris, Christina S. Stauffer, and Apurba Datta*
Department of Medicinal Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
adutta@ku.edu
Received December 27, 2004
ABSTRACT
Starting from
Letter.
L-serine, a stereoselective synthesis of pachastrissamine, a structurally novel anhydrosphingosine derivative, is reported in this
Pachastrissamine (1, Figure 1), a naturally occurring novel
anhydrosphingosine derivative, has been isolated recently
from the Okinawan marine sponge Pachastrissa sp.1 Shortly
thereafter, another research group reported the isolation of
the same natural product from a different marine sponge,
Jaspis sp., and named it as jaspine B.2 The all-syn tri-
substituted tetrahydrofuran structural framework and the
(2S,3S,4S) absolute configuration of pachastrissamine (and
jaspine B) was assigned on the basis of high-resolution
NMR, mass spectral analysis, and chemical derivatization
studies. Pachastrissamine represents the first example of an
anhydrosphingosine structural feature in a natural product.
In anticancer assays, this novel sphingosine derivative
exhibited submicromolar cytotoxic activity against several
human cancer cell lines.1,2 The impressive biological activity,
novel structural features, and the lack of any total synthesis/
structure-activity relationship (SAR) studies on pachastris-
samine encouraged us to undertake a stereoselective total
synthesis of this interesting natural product. Accordingly,
starting from the natural amino acid L-serine and following
the strategy as shown below (Figure 1), we report herein a
total synthesis of pachastrissamine.
Figure 1. Pachastrissamine and retrosynthetic analysis.
tories,3 represents the key chiral template for our desired
synthesis. We envisioned that deprotection of the N,O-
acetonide linkage of 3 and subsequent Michael addition of
the resulting primary hydroxy group into the â-carbon of
the butenolide will result in the bicyclic lactone 2 as shown
(Figure 1). Stereselective formation of the cis-fused bicyclic
system 2 is predicted as a result of the highly unfavorable
ring strain associated with the alternative trans-ring junction
between the two five-membered rings. Standard functional
group transformations involving the right-hand side lactone
moiety is expected to complete the synthesis of the desired
Enantiopure aminobutenolide 3, easily obtainable from
L-serine by a recently developed method from our labora-
(1) Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.; Gravalos,
D. G.; Higa, T. J. Nat. Prod. 2002, 65, 1505-1506.
(2) Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetrahedron Lett.
2003, 44, 225-228.
(3) Bhaket, P.; Stauffer, C. S.; Datta, A. J. Org. Chem. 2004, 69, 8594-
8601.
10.1021/ol0473290 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/27/2005

all-syn tetrahydrofuran natural product 1. Details of the
studies thus undertaken are described below.
Starting from L-serine and following a recently developed
protocol,3 the chiral lactone 3 (Scheme 1) was prepared in
In conclusion, utilizing a chiral pool strategy involving
serine, the stereoselective total synthesis of a structurally
unique bioactive anhydrosphingosine natural product has
been achieved. A key step in the synthesis involves the facile
formation of the bicyclic lactone 2 via an intramolecular
conjugate addition process. Interestingly, the tetrahydrofu-
rofuranone structural core as present in 2 is found in several
natural products such as goniofufurones,4 lactonamycin,5
delesserine,6 dilaspirolactone,7 etc. Consequently, develop-
ment of methods for the efficient construction of similar
structural frameworks and their further application is an
active area of research.8 Additionally, as demonstrated in
the present research, the bicyclic lactone core of 2 can be
utilized as a versatile synthon toward accessing variously
substituted chiral tetrahydrofurans, a frequently encountered
heterocyclic core of considerable biological importance.9 It
is expected that, besides achieving an efficient total synthesis
of pachastrissamine, possible application of the strategy and
the approach described in the present study will also be of
potential use toward rapid synthesis of functionalized tet-
rahydrofurans of contemporary interest.10
Scheme 1
Acknowledgment. K.M. thanks the Madison and Lila
Self Foundation for a summer (undergraduate) research fel-
lowship. Financial support from the Herman Frasch Founda-
tion (American Chemical Society) is also gratefully acknowl-
edged.
Supporting Information Available: Full experimental
procedures, characterization data of all new products, and
copies of NMR (1H and 13C) spectra of compounds 2, 4, 5,
6, and 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
42% overall yield. Attempted hydrolysis of the N,O-acetonide
linkage of 3, followed by treatment of the crude product with
aqueous bicarbonate, directly afforded the bicyclic lactone
2 as the only product. The assigned stereochemistry and the
all-syn relationship between the three contiguous asymmetric
centers as present in 2 were confirmed on the basis of NOE
studies.
OL0473290
(4) Fang, X. P.; Anderson, J. E.; Chang, C. J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655-1661.
(5) Matsumoto, N.; Tsuchida, T.; Nakamura, H.; Sawa, R.; Takahashi,
Y.; Naganawa, H.; Iinuma, H.; Sawa, T.; Takeuchi, T.; Shiro, M. J. Antibiot.
1999, 52, 276-280.
As per our expectations, the favorable energetics involved
in the cis-fused [5,5] bicyclic ring forming reaction during
the above intramolecular Michael addition contributed to the
exclusive formation of product 2. Toward introduction of
the required tetradecyl side chain, the carbonyl group of the
lactone 2 was partially reduced to afford the lactol derivative
4. Standard Wittig olefination of the lactol with a C-12 alkyl
donor resulted in the incorporation of an inseparable mixture
of E- and Z-isomers of the corresponding C-14 olefinic side
chain. Interestingly, the C3-secondary oxyanion, generated
during the opening of the lactol, underwent spontaneous
intramolecular addition to the favorably disposed C4-NCbz-
carbonyl group, resulting in the concomitant formation of
the cyclic carbamate-protected tetrahydrofuran derivative 5.
Hydrogenation of the side chain double bond uneventfully
afforded the desired saturated derivative 6 in high yield.
Finally, alkaline hydrolysis of the cyclic carbamate culmi-
nated in an efficient synthesis of pachastrissamine (1). The
spectral and analytical data of 1 were in good conformity
with the reported values,2 thereby confirming its structural
and stereochemical integrity.
(6) Yvin, J. C.; Chevolot-Magueur, A. M.; Chevolot, L.; Lallemand, J.
Y.; Potier, P.; Guilhem, J. J. Am. Chem. Soc. 1982, 104, 4497-4498.
(7) Iwagawa, T.; Hase, T. Phytochemistry 1984, 23, 2299-2301.
(8) For representative examples, see: (a) Popsavin, V.; Grabez, S.;
Popsavin, M.; Krstic, I.; Kojic, V.; Bogdanovic, G.; Divjakovic, V.
Tetrahedron Lett. 2004, 45, 9409-9413. (b) Yang, G.; Hennig, L.;
Findeisen, M.; Oehme, R.; Giesa, S.; Welzel, P. HelV. Chim. Acta 2004,
87, 1794-1806. (c) Paddon-Jones, G. C.; Moore, C. J.; Brecknell, D. J.;
Koenig, W. A.; Kitching, W. Tetrahedron Lett. 1997, 38, 3479-3482. (d)
Kang, S. H.; Ryu, D. H. Tetrahedron Lett. 1997, 38, 607-610. (e) Lundt,
I.; Frank, H. Tetrahedron 1994, 50, 13285-13298. (f) Gracza, T.; Jager,
V. Synthesis 1994, 1359-1368. (g) Gracza, T.; Hasenohrl, T.; Stahl, U.;
Jager, V. Synthesis 1991, 1108-1118. (h) Vekemans, J. A. J. M.; Dapperens,
C. W. M.; Claessen, R.; Koten, A. M. J.; Godefroi, E. F.; Chittenden, G. J.
F. J. Org. Chem. 1990, 55, 5336-5344. (i) Gurjar, M. K.; Patil, V. J.;
Pawar, S. M. Carbohydrate Res. 1987, 165, 313-317.
(9) For recent reviews, see; (a) Elliott, M. C. J. Chem. Soc., Perkin Trans.
1 2002, 2301-2323. (b) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat.
Prod. 1999, 62, 504-540. (c) Norcross, R. D.; Paterson, I. Chem. ReV.
1995, 95, 2041-2114. (d) Harmange, J. C.; Figadere, B. Tetrahedron:
Asymmetry 1993, 4, 1711-1754. (e) Polyether Antiobiotics: Naturally
Occurring Acid Ionophores; Westley, J. W., Ed.; Marcel Dekker: New
York, 1982.
(10) After the submission of our manuscript, a total synthesis of
pachastrissamine was reported: Sudhakar, N.; Kumar, A. R.; Prabhakar,
A.; Jagadeesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325-327.
876
Org. Lett., Vol. 7, No. 5, 2005