Versatile synthetic method for sphingolipids and functionalized sphingosine derivatives via olefin cross metathesis

Article abstract of DOI:10.1021/ol062258l

A highly efficient and versatile method for the synthesis of various sphingolipids, such as sphingomyelin, ceramide, sphingosine, sphingosine 1-phosphate, and functionalized sphingosine derivatives, was established by two types of combinations of the olefin cross metathesis reaction. One reaction was between the same olefin part and appropriate amino alcohols, which were prepared starting from N-Boc-L-serine, and the other was between appropriate olefins and the same amino alcohol.

Full text of DOI:10.1021/ol062258l

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5569-5572
Versatile Synthetic Method for
Sphingolipids and Functionalized
Sphingosine Derivatives via Olefin
Cross Metathesis
Tetsuya Yamamoto, Hiroko Hasegawa, Toshikazu Hakogi, and
Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin UniVersity, 2-1 Gakuen, Sanda,
Hyogo 669-1337, Japan
katsumura@ksc.kwansei.ac.jp
Received September 12, 2006
ABSTRACT
A highly efficient and versatile method for the synthesis of various sphingolipids, such as sphingomyelin, ceramide, sphingosine, sphingosine
1-phosphate, and functionalized sphingosine derivatives, was established by two types of combinations of the olefin cross metathesis reaction.
One reaction was between the same olefin part and appropriate amino alcohols, which were prepared starting from N-Boc-
L-serine, and the
other was between appropriate olefins and the same amino alcohol.
Sphingolipids, such as sphingomyelin 1, ceramide 2, sphin-
gosine 3, and sphingosine 1-phosphate 4, are regarded as
lipid secondary messengers in mammalian cells and cell
membranes, as shown in Figure 1, and are now accepted to
play an important role in signal transduction and molecular
recognition processes in cell membranes.1 Meanwhile, sphin-
gomyelin 1 is known as a major component to form a raft
domain, which is proposed as a particular organism in a
mammalian cell membrane to efficiently transmit various
biological signals.2 Thus, a great deal of attention has been
devoted to studies of the biological processes regulated by
sphingolipids, and hence an efficient method for the synthesis
of these sphingolipids along with their various kinds of
analogues is strongly desired.
Figure 1. Metabolic pathway of sphingolipids.
10.1021/ol062258l CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/01/2006

In the course of our study on sphingolipid synthesis, we
previously reported the syntheses of not only various sphingo-
lipids, such as natural sphingomyelin, ceramide, sphingo-
sine, sphingosine 1-phosphate, and their short chain ana-
logues,3 but also fluorescence4 and photoaffinity labeled
sphingolipids.5 During synthetic studies of these sphingolipid
derivatives, including those possessing fluorescence and
photoaffinity groups in the backbone skeleton, a further
convenient and versatile method for providing them has been
strongly required. Then, we investigated the olefin cross
metathesis reaction6 between 1-pentadecene and disubstituted
olefines having amino alcohol functions, which were pre-
pared starting from our chiral oxazolidinone ester.7 At nearly
the same time, two groups independently reported the
synthesis of sphingosine 38 and ceramide 29 by utilizing an
olefin cross metathesis reaction. One used monosubstituted
olefin with chiral oxazoridinone alcohol prepared from
divinylcarbinol,8 and the other used monosubstituted olefin
with protected aminodiol prepared from D-tartrate.9 However,
the reported procedures including our results did not show
the essential versatility of this very attractive olefin cross
metathesis method. In this paper, we disclose highly efficient
and versatile syntheses of sphingomyelin 1, ceramide 2,
sphingosine 3, and sphingosine 1-phosphate 4 from common
olefin part A and appropriate amino alcohol part B by olefin
cross metathesis as a simple and practical procedure.
Furthermore, we disclose that the olefin cross metathesis
method is also effective for the preparation of fluorescence
and photoaffinity labeled sphingosine derivatives 28 and 29
(Figure 2).
Table 1. Preparation of Intermediate 8
a Isolated yields.
excellent yield in three steps without column chromatogra-
phy. Introduction of a vinyl group with the Grignard reagent
provided vinyl ketone 7 in 92% yield. Then, anti-selective
reduction of obtained R,â-unsaturated ketone 7 was inves-
tigated (Table 1). Although lithium aluminumhydride reduc-
tion gave the corresponding alcohol in 82% yield, stereo-
selectivety was 3:2 of anti- and syn-derivatives by 1H NMR
(entry 1). Treatment with L-Selectride and diisobutylalumi-
num 2,6-di-tert-butyl-4-methylphenoxide11 (entries 2 and 3)
gave unsatisfactory results. Diisobutylaluminum hydride
treatment gave product in 49% yield, whose stereoselectivity
was 14:1 (entry 4). Gratifyingly, when lithium tri-tert-
butoxyaluminohydride was employed in ethanol at -78 °C,3d,12
the desired anti-product 8 was obtained in 96% yield as a
sole stereoisomer. It is noteworthy that under the same
reaction conditions, the reduction of enone 9, obtained from
7 and 1-pentadecene 16 by olefin cross metathesis, unexpect-
edly afforded the corresponding saturated alcohol 10 with
anti-stereochemistry that resulted from 1,4-addition followed
Figure 2. Versatile synthetic method for sphingolipids and
derivatives.
(3) (a) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda,
K.; Katsumura, S. J. Org. Chem. 2002, 67, 4839. (b) Hakogi, T.; Taichi,
M.; Katsumura, S. Org. Lett. 2003, 5, 2801. (c) Hasegawa, H.; Yamamoto,
T.; Hatano, S.; Hakogi, T.; Katsumura, S. Chem. Lett. 2004. 33, 1592. (d)
Hakogi, T.; Fujii, S.; Morita, M.; Ikeda, K.; Katsumura, S. Bioorg. Med.
Chem. Lett. 2005, 15, 2141. (e) Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda,
K.; Katsumura, S. Tetrahedron Lett. 2006, 47 2627.
(4) Hakogi, T.; Shigenari, T.; Katsumura, S.; Sano, T.; Kohno, T.;
Igarashi, Y. Bioorg. Med. Chem. Lett. 2003, 13, 661.
(5) Shigenari, T.; Hakogi, T.; Katsumura, S. Chem. Lett. 2004, 33, 594.
(6) (a) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Germany,
2003. (b) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900 and references therein.
Substrate B for the olefin cross metathesis was synthesized
starting from L-serine 5 through intermediary alcohol 8, as
shown in Table 1. Thus, tert-butoxycarbonyl protection of
5, followed by the Weinreb amide formation,10 and the
protection of the primary hydroxyl group produced 6 in
(1) For recent reviews on signal transduction mediated by sphingolipids,
see: (a) Sphingolipid Metabolism and Signaling MinireView Series; Smith,
W. L., Merrill, A. H., Jr., Eds.; J. Biol. Chem. 2002, 277, 25841. (b)
Cremesti, A. E.; Goni, F. M.; Kolesnick, R. FEBS Lett. 2002, 531, 47 and
references therein.
(2) (a) Suzuki, A.; Igarashi, Y. Protein Nucleic Acid Enzyme 2002, 47,
315. (b) Simons, K.; Ikonen, E. Science 2000, 290, 1721. (c) Simons, K.;
Ikonen, K. Nature 1997, 387, 569 and references therein.
(7) Katsumura, S.; Kondo, A.; Han, Q. Chem. Lett. 1991, 1, 1245.
(8) Torssell. S.; Somfai, P. Org. Biomol. Chem. 2004, 2, 1643.
(9) Rai, A. N.; Basu, A. Org. Lett. 2004, 6, 2861.
(10) So, R. C.; Ndonye, R.; Izmirian, D. P.; Richardson, S. K.; Guerrera,
R. L.; Howell, A. R. J. Org. Chem. 2004, 69, 3233.
(11) (a) Murakami, M.; Iwama, S.; Fujii, S.; Ikeda, K.; Katsumura, S.
Bioorg. Med. Chem. Lett. 1997, 7, 1725. (b) Iguchi, S.; Nakai, H.; Hayashi,
M.; Yamamoto, H. J. Org. Chem. 1979, 44, 1363.
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by stereoselective reduction in 96% yield along with a small
amount of desired unsaturated alcohol 17.
Table 2. Olefin Cross Metathesis Reaction
Allyl alcohol 8, a synthetic precursor of sphingosine, was
transformed into amino alcohol segments 11-15 of sphin-
golipid synthesis by olefin cross metathesis protocol (segment
B) (Scheme 1). Thus, removing the protecting group at the
Scheme 1. Preparation of Substrates of Olefin Cross
Metathesis Reaction
primary hydroxyl group of 8 produced diol 11 in 97% yield,
which is also a synthetic precursor of sphingosine. Exchang-
ing the Boc group of 11 into an acyl group afforded 12 in
47% yield, a precursor of ceramide. Treatment of 11 with
trimethylphosphite and carbon tetrabromide3d,13 in pyridine
at -15 °C produced dimethylphosphate 13 in 77% yield, a
precursor of sphingosine 1-phosphate. Furthermore, reaction
of 11 with 2-bromoethyl dimethylphosphite3d produced the
corresponding allyl alcohol 14 in 64% yield, which was
transformed into 15 by acylation. Both 14 and 15 were
synthetic precursors of sphingomyelin. Thus, amino alcohol
derivatives 8 and 11-15 were easily prepared and used as
the substrates of the olefin cross metathesis reaction. Another
segment A, 1-pentadecene 16, was synthesized by the Swern
oxidation of commercially available 1-tetradecanol followed
by the Wittig olefination.
a Isolated yields. b A quantity of 0.01 equiv of Grubbs catalyst was used.
successfully obtained in 75% yield as a mixture of E:Z )
15:1. Diol 11 also produced desired coupling product 18 in
58% yield, which was easily transformed to sphingosine 3
by trifluoroacetic acid treatment in 79% yield (Scheme 2).
Scheme 2. Syntheses of Sphingolipids
With substrates 8 and 11-15 in hand, the cross metathesis
coupling reaction between substrate 8, 11-15, and olefin
16 was examined (Table 2). After detailed investigation, we
found the following suitable conditions. Thus, substrate 8
was stirred with 4 equiv of olefin 16 and 0.03 equiv of
Grubbs catalyst second generation in dichloromethane for 2
h at reflux. The reaction proceeded smoothly, and desired
coupling product 17 was obtained in 72% yield as sole (E)-
stereoisomer, and the homocoupling product of 8 was not
N-Acyl diol 12 directly afforded ceramide 2 in 56% yield
by the same coupling procedure. This is a simple and
practical synthesis of ceramide 2. Phosphate 13 also suc-
ceeded in coupling to produce 19, which was treated with
1
observed in its H NMR.14 When we used the catalyst at
0.01 equiv under the same reaction condition, desired 17 was
(12) Hofmann, R. V.; Maslouh, N. Lee, F.-C. J. Org. Chem. 2002, 67,
1045.
(13) (a) Szulc, Z. M.; Hannun, Y. A.; Bielawska, A. Tetrahedron Lett.
2000, 41, 7821. (b) Oza, V. B.; Corcoran, R. C. J. Org. Chem. 1995, 60,
3680.
(14) The olefin 16 that was recovered as a mixture with its dimer could
be used for the cross metathesis coupling reaction. The ratio of olefin 16 in
the mixture was determined by H NMR.
1
Org. Lett., Vol. 8, No. 24, 2006
5571

bromotrimethylsilane in acetonitrile to afford sphingosine
1-phosphate 4 in 57% yield. Furthermore, phosphates 14 and
15, which are amino alcohol segments for olefin cross
metathesis, expectedly afforded desired coupling products
20 and 21 in 70% and 55% yield, respectively. Treatment
of 21 with Me3N in MeOH produced sphingomyelin 1 in
70% yield. Thus, sphingomyerin 1, ceramide 2, sphingosine
3, and sphingosine 1-phospate 4 were simply and easily
synthesized from L-serine by the olefin cross metathesis
method.
Table 3. Olefin Cross Metathesis Reaction between 8 and
Some Olefin Parts A
The next attempts was a synthesis of the backbone skeleton
having various functional groups at the terminal. In this case,
compound 8 was fixed as amino alcohol part B, and
compounds 22-25 were used as olefin part A (Table 3).
Compound 22 was obtained from octanal by the Wittig
reaction, and fluorescence and photoaffinity labeled olefins
24 and 25 were prepared from commercially available
alcohol 23 by a previously reported procedure.4,5 Olefin cross
metathesis reactions between 8 and 22-25 were employed
under the same reaction conditions as 16 with 8 and 11-
15, respectively. The results are listed in Table 3. The
reaction of hydroxyl compound 23 and fluorescence labeled
compound 24 with amino alcohol 8 afforded coupling
products 27 and 28 in 76% and 57% yield, respectively. In
the case of photoaffinity labeled olefin 25, although this
olefin gradually decomposed at the reflux temperature of
CH2Cl2, the coupling reaction at room temperature produced
the desired product 29 in 58% yield along with decomposed
products. Thus, the olefin cross metathesis method is actually
effective and versatile for providing various kinds of sphin-
golipid derivatives.
a Isolated yields. b Reaction was proceeded under room temperature for
30 min.
steps. The olefin cross metathesis method was also effective
for providing functionalized sphingolipid derivatives.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
In conclusion, we synthesized various sphingolipids includ-
ing sphingomyelin 1, ceramide 2, sphingosine 3, and sphingo-
sine 1-phosphate 4 by utilization of the olefin cross metath-
esis reaction between 1-pentadecene 16 and amino alcohol
derivatives 8 and 11-15, which were derived starting from
L-serine through intermediate 8 by vinyl group introduction
followed by highly anti-stereoselective reduction as key
Supporting Information Available: General method and
1
optical rotation; H NMR, IR, and MS data; and spectra of
the corresponding compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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