A new strategy for the synthesis of sphingosine analogues. Sphingofungin F

Full text of DOI:10.1021/ja981141s

6818
J. Am. Chem. Soc. 1998, 120, 6818-6819
Scheme 1. Retrosynthetic Analysis
A New Strategy for the Synthesis of Sphingosine
Analogues. Sphingofungin F
Barry M. Trost* and Chul Bom Lee
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed April 6, 1998
Sphingosines, compounds consisting of polar polyhydroxyl
amino head groups and long lipid chains, are membrane con-
stituents involved in a number of cellular events including protein
binding (GPI anchors) and transmembrane signaling.1 A related
series of compounds wherein the primary alcohol is oxidized to
a carboxylic acid such as sphingofungin B (1)2 or possesses a
concise synthesis of sphingofungin F in which all stereochemistry
emanates from a new asymmetric alkylation in which an asym-
metric palladium complex differentiates between enantiotopic
leaving groups of a gem-diacetate and enantiotopic faces of an
azlactone enolate.
Scheme 1 illustrates the retrosynthetic analysis whereby the
major disconnection splits the molecule into the lipid tail 5 and
the polar head 6, the latter being the challenging fragment. If
two of the hydroxyl groups derive from a distereoselective cis-
dihydroxylation, the serine analogue 7 becomes a precursor. The
stereochemistry of the C-3 hydroxyl group was inverted from the
natural product to address the known effects of such allylic
functionality on the diastereoselectivity of the osmium catalyzed
dihydroxylation.9 Such quaternary serine analogues 7 may derive
from our newly developed asymmetric alkylation of azlactones
with gem-diacetates, in this case requiring 8 and 9, respec-
tively.10,11
The gem-diacetate 9, derived from the corresponding known
aldehyde,12 is available in two steps from commercially available
cis-2-butene-1,4-diol, in quantitative yield by ferric chloride (0.1
mol%) catalyzed addition of acetic anhydride.11 The Pd catalyzed
alkylation must control both relative and absolute stereochemistry.
For example, by using triphenylphosphine as the ligand, the two
diastereomers 10 and 11 (as their racemates) are formed in a 1:1.6
ratio at room temperature. Thus, the chiral ligand must override
the intrinsic bias of the substrates to provide 7.
quaternary center such as sphingofungin F (2)3 were found to
inhibit the biosynthesis of sphingolipids due to their activity as
serinepalmitoyl transferase inhibitors.4 These compounds are also
strikingly similar to myriocin (3),5 a compound shown to be 10-
100 times more potent than cyclosporin A.6 Mycestericin D (4),
a deoxy analogue, and its dihydro and 3-epi isomer have also
been isolated.7 The biological importance of these compounds
stimulated a number of synthetic efforts largely making use of
the “chiral pool”.8 The difficulties of creating quaternary centers
asymmetrically in catalytic procedures and the noted biological
activity of these analogues led us to develop a general strategy
to this series. We now report the successful realization of a
(1) Reviews: (a) Hannun, Y. A. Sphingolipid-Mediated Signal Transduc-
tion; Chapman & Hall: New York, NY, 1997. (b) Merrill, A. H., Jr.; Sweeley,
C. C. In Biochemistry of Lipids, Lipoproteins and Membranes; Vance, D. E.,
Vance, J., Eds.; Elsevier Science B. V.: Amsterdam, 1996; pp 309-339. (c)
Hakomori, S. Sphingolipid Biochemistry. In Handbook of Lipid Research;
Kafner, J. N., Hakomori, S., Eds.; Plenum: New York, 1983; Vol. 3, p 1. (d)
Ariga, T.; Jarvis, W. D.; Yu, R. K. J. Lipid Res. 1998, 39, 1. (e) Igarashi, Y.
J. Biochem. 1997, 122, 1080. (f) Hannun, Y. A. Science 1996, 274, 1855. (g)
Shayman, J. A. J. Am. Soc. Nephrol. 1996, 7, 171. (h) Spiegel, S.; Milstein,
S. J. Membr. Biol. 1995, 146, 225. See, also: (i) Nugent, T. C.; Hudlicky, T.
J. Org. Chem. 1998, 63, 510 and references cited therein. (j) Kobayashi, S.;
Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998,
120, 908 and references cited therein.
Performing the alkylation of the sodium salt of the azlactone
8 (NaH, THF) and gem-diacetate 9 with the catalyst derived from
π-allylpalladium chloride dimer (0.5%) and ligand 1213 (1.5%)
(2) (a) VanMiddlesworth, F.; Giacobbe, R. A.; Lopez, M.; Garrity, G.;
Bland, J. A.; Bartizal, K.; Fromtling, R. A.; Polishook, J.; Zweerink, M.;
Edison, A. M.; Rozdilsky, W.; Wilson, K. E.; Monaghan, R. L. J. Antibiot.
1992, 45, 861. Structure elucidation: (b) VanMiddlesworth, F.; Dufresne, C.;
Wincott, F. E.; Mosley, R. T.; Wilson, K. E. Tetrahedron Lett. 1992, 33,
297.
(3) Horn, W. S.; Smith, T. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G.
L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thrornton, R. A.; Mandala,
S. M. J. Antibiot. 1992, 45, 1692.
(4) Zweerink, M. M.; Edison, A. M.; Well, G. B.; Pinto, W.; Lester, R. L.
J. Biol. Chem. 1992, 267, 25032.
(5) Myriocin (ISP-I, thermozymocidin) has been isolated from various
strains, see: (a) Kluepfel, D.; Bagli, J.; Chrest, A. K.; Sehgal, C. V. J. Antibiot.
1972, 25, 109. Bagli, J. F.; Kluepfel, D. J. Org. Chem. 1973, 38, 1253. (b)
Aragozzini, F.; Marachini, P. L.; Craveri, R. Tetrahedron 1972, 28, 5493. (c)
Sasek, V.; Sailer, M.; Vokoun, J.; Musilek, V. J. Basic Microbiol. 1989, 29,
383. (d) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama,
R.; Yoneta, M.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47, 208.
(6) (a) Reference 5d. (b) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita,
T.; Kawasaki, T. Biochem. Biophys. Res. Commun. 1995, 211, 396.
(7) Fujita, T.; Hamamichi, N.; Kiuch, M.; Matsuzaki, T.; Kitao, Y.; Inoue,
K.; Hirose, R.; Yoneta, M.; Sasaki, S.; Chiba, K.; Fujita, T.; Inoue, K.;
Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Yoneta, M.; Hoshino,
Y.; Okumoto, T. J. Antibiot. 1996, 49, 846. Sasaki, S.; Hashimito, R.; Yoneta,
M.; Sasaki, S.; Inoue, K.; Ikumoto, T.; Hirose, R.; Chiba, K.; Hoshino, Y.;
Okumoto, T.; Fujita, T. J. Antibiot. 1994, 47, 420.
(8) For total synthesis of myriocin, see: (a) Banfi, L.; Bretta, M. G.;
Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc., Chem. Commun. 1982,
488. Banfi, L.; Bretta, M. G.; Colombo, L.; Gennari, C.; Scolastico, C. J.
Chem. Soc., Perkin Trans. 1 1983, 1613. (b) Yoshikawa, M.; Yokokawa, Y.;
Okuno, Y.; Murakami, N. Chem. Pharm. Bull. 1994, 42, 994. Yoshikawa,
M.; Yokokawa, Y.; Okuno, Y.; Murakami, N. Tetrahedron 1995, 51, 6209.
(c) Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita,
T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097. (d) Hatakeyama, S.; Yoshida,
M.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto, T.; Yamada, H.; Nishizawa,
M. Tetrahedron Lett. 1997, 45, 7887. For formal synthesis of myriocin see:
(e) Rao, A. V. R.; Gurjar, M. K.; Devi, T. R.; Kumar, K. R. Tetrahedron
Lett. 1993, 34, 1653. (f) Deloisy, S.; Thang, T. T.; Olesker, A.; Lukas, G.
Tetrahedron Lett. 1994, 35, 4783. For total synthesis of sphingofungin B and
F, see: (g) Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto,
S. Synlett 1997, 301 and ref 1j. For total synthesis of sphingofungin D, see:
(h) Chida, N.; Ikemoto, H.; Noguchi, A.; Amano, S.; Ogawa, S. Nat. Prod.
Lett. 1995, 6, 295. For formal synthesis of sphingofungin D, see: (i) Mori,
K.; Otaka, K. Tetrahedron Lett. 1994, 35, 9207.
(9) (a) Cha, J. K.; Kim, N.-S. Chem. ReV. 1995, 95, 1761. (b) Cha, J. K.;
Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(10) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36, 2635.
(11) Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995, 117,
7247.
(12) Quimpere, M.; Ruest, L.; Deslongchamps, P. Synthesis 1992, 132.
(13) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
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S0002-7863(98)01141-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/25/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6819
Scheme 2. Asymmetric Synthesis of Polar Head Group from
14
by inversion with neighboring group participation by simple
activation of the hydroxyl group of 18b, which directly formed
oxazoline 19a. The aldehyde 20 underwent the iodomethylenation
with low valent chromium to generate the E-alkene 21 exclu-
sively.18
The final stage of the synthesis (eq 3) added all of the remaining
carbon atoms by Suzuki cross-coupling (5% (dppf)PdCl2, 5% Ph3-
As, Cs2CO3, DMF-THF-H2O, room temperature)19 with the
organoborane 22 formed in situ by hydroboration of the ethylene
ketal of alkene 5 (derived in 3 steps from commercially available
heptanoyl chloride)20 to give alkene 23 in 94% yield. Oxidative
at -5 °C in THF gave a 10.5:1 ratio of 10 and 11, isolated in
70% and 5% yields respectively. Both diastereomers have an ee
of 89% as determined by chiral HPLC. Methanolysis (1% CSA
or p-TsOH, CH3OH, room temperature) of 10 gave a quantitative
yield of the protected amino acid 13. Dihydroxylation of alkene
13 (eq 1, 2% OsO4, NMO)14 proceeded best in moist methylene
chloride to give a single product 14 in which the initial diol
spontaneously lactonized. In contrast to the excellent diastereo-
cleavage of the PMB group (CAN, CH3CN, H2O, room temper-
ature, 93% yield) effected simultaneous hydrolyses of the ketal
and the oxazoline to give keto alkene 24. Base hydrolysis (1 N
NaOH, reflux) and neutralization with Amberlite IRC-76 produced
sphingofungin F, mp 143-5 °C (lit. mp 142-4 °C), identical
spectroscopically to the natural product. Our [R]D of +0.99 (c
0.25, CH3OH) compared to the reported [R]D +0.8 (c 0.33, CH3-
OH) confirms the identity of the absolute configuration.
The efficiency of this synthesis is noted in that it requires only
15 linear steps from commerically available cis-2-butene-1,4-diol
and proceeds in 17% overall yield. All the stereochemistry
derives from that established in the asymmetric palladium
catalyzed alkylation. It is noteworthy that the route provides ready
access to a number of diastereomers. For example, the epimer
at C-3 would derive by taking 14 through the synthesis without
inversion. Access to 17 provides the epimers at C-4 and C-5.
Variation of the azlactone would also allow variation of the alkyl
substituent. Finally, the lipid tail can readily be varied in the
cross-coupling reaction. The success of the palladium-catalyzed
alkylation demonstrates a high level of catalyst control of
diastereoselectivity, further demonstrating the potential selectivity
that the complexes bearing these bidentate ligands like 12 may
exert beyond enantioselectivity.
selectivity in the dihydroxylation of 13 to give 14, inverting the
C-3 hydroxyl group first to form 15 and then performing the
dihydroxylation (eq 2) gave a 1:5 ratio of 16 and 17 in 95% yield.
Asymmetric dihydroxylation (AD-mix-R)15 was unable to over-
come this latter substrate controlled diastereoselectivity (1:2.3,
100% yield).
The relative stereochemistry of 17 was established by X-ray
crystallography and therefore allows the assignment of the minor
lactone as shown in 16. Correlation of 14 with 16 therefore
establishes the relative configuration of 14.16 The absolute
configuration for asymmetric alkylations of 9 was established by
the O-methyl mandelate method17 and, in this case, was ultimately
verified by correlation of our synthetic product to the natural
material.
Acknowledgment. We thank the National Institutes of Health, General
Medicinal Sciences Institute, and the National Science Foundation for
their generous support of our programs. Mass spectra were provided by
the Mass Spectrometry Facility, University of San Francisco, supported
by the NIH Division of Research Resources.
Supporting Information Available: Experimental procedures and
characterization data for 10, 11, 13-19, 21, 23, 24, and 2 (15 pages,
print/PDF). See any current masterhead page for ordering information
and Web access instructions.
Scheme 2 outlines the synthesis of the fully elaborated head
fragment. Setting the proper configuration at C-3 was achieved
JA981141S
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