Efficient synthesis of D-erythro-sphingosine and D-erythro-azidosphingosine from D-ribo-phytosphingosine via a cyclic sulfate intermediate

Article abstract of DOI:10.1021/jo0614543

The synthesis of naturally occurring D-erythro-sphingosine and synthetically useful D-erythro-2-azidosphingosine from commercially available D-ribo-phytosphingosine is described. An important feature of this synthesis is the selective transformation of the 3,4-vicinal diol of phytosphingosine into the characteristic E-allylic alcohol of sphingosine via a cyclic sulfate intermediate.

Full text of DOI:10.1021/jo0614543

Efficient Synthesis of D-erythro-Sphingosine and
D-erythro-Azidosphingosine from
D-ribo-Phytosphingosine via a Cyclic Sulfate
Intermediate
Sanghee Kim,*,†,‡ Sukjin Lee,† Taeho Lee,†,‡
Hyojin Ko,‡ and Deukjoon Kim†
College of Pharmacy, Seoul National UniVersity, San 56-1,
Shilim, Kwanak, Seoul 151-742, Korea, and Natural Products
Research Institute, College of Pharmacy, Seoul National
UniVersity, 28 Yungun, Jongro, Seoul 110-460, Korea
FIGURE 1. Chemical structures of compounds 1-3.
backbone of sphingolipids. Sphingoid bases are long-chain
aliphatic compounds typically possessing a 2-amino-1,3-diol
functionality. The most common naturally occurring sphingoid
bases of animal and plant tissues are D-erythro-sphingosine (1,
Figure 1) and D-ribo-phytosphingosine (2), respectively.4 They
are currently commercially available. While D-ribo-phytos-
phingosine is readily obtainable on an industrial scale from a
yeast fermentation process,5 D-erythro-sphingosine is available
only by chemical synthesis or laborious animal tissue extraction.
To meet the growing demand for D-erythro-sphingosine, a
number of synthetic methodologies have been reported.3,6 Many
syntheses start from various chiral pools such as carbohydrates
and amino acids, whereas other syntheses have employed
asymmetric induction such as Sharpless asymmetric epoxidation
and asymmetric aldol to install the absolute stereochemistry of
sphingosine. In addition, van Boom and co-workers recently
reported the efficient preparation of sphingosine 1 from another
sphingoid base, phytosphingosine 2, by employing the regiospe-
cific reduction of a Z-enol triflate intermediate7 or the TMSI/
DBN promoted selective eliminative epoxide opening of oxirane
intermediate8 as key steps. Their syntheses have several
advantages over other syntheses in that minimal protecting group
manipulations and purification steps are required, thereby
allowing the multigram synthesis of 1. However, their first
approach, via a Z-enol triflate intermediate, is hampered by the
use of rather expensive reagents and low-temperature manipula-
tion. Their second approach, via an oxirane intermediate, suffers
from an unwanted ditosylate as a side product.
pennkim@snu.ac.kr
ReceiVed July 13, 2006
The synthesis of naturally occurring D-erythro-sphingosine
and synthetically useful D-erythro-2-azidosphingosine from
commercially available D-ribo-phytosphingosine is described.
An important feature of this synthesis is the selective
transformation of the 3,4-vicinal diol of phytosphingosine
into the characteristic E-allylic alcohol of sphingosine via a
cyclic sulfate intermediate.
Sphingolipids are important structural and functional com-
ponents of the plasma membranes of essentially all eukaryotic
cells. They play critical roles in many physiological processes
including cell recognition, adhesion, and signaling.1 Over the
past decade, significant strides have been made in the elucidation
of biological function of sphingolipids. One of the remarkable
findings is the identification of sphingolipid metabolites as
second messengers, which provides the basis for the emerging
concept of sphingolipid metabolites as therapeutics with clinical
potential.2
While the interest in investigating the biological functions
of sphingolipids grew, efforts for the effective preparation of
natural and nonnatural sphingolipids have generated much
attention.3 One of the keys to their successful preparation is
the acquirement of appropriate sphingoid bases, the principal
Herein, we wish to report a new concise and efficient
synthetic route to sphingosine 1 and synthetically useful
(3) For recent reviews, see: (a) Liao, J.; Tao, J.; Lin, G.; Liu, D.
Tetrahedron 2005, 61, 4715-4733. (b) Curfman, C.; Liotta, D. Methods
Enzymol. 1999, 311, 391-440. (c) Koskinen, P. M.; Koskinen, A. M. P.
Synthesis 1998, 1075-1091.
(4) (a) Howell, A. R.; Ndakala, A. J. Curr. Org. Chem. 2002, 6, 365-
391. (b) Muralidhar, P.; Radhika, P.; Krishna, N.; Rao, D. V.; Rao, Ch. B.
Nat. Prod. Sci. 2003, 9, 117-142.
(5) Bae, J.-H.; Sohn, J.-H.; Park, C.-S.; Rhee, J.-S.; Choi, E.-S. Appl.
EnViron. Microbiol. 2003, 69, 812-819.
(6) Selected publications for recent syntheses of D-erythro-sphingosine
with citations, see: (a) Disadee, W.; Ishikawa, T. J. Org. Chem. 2005, 70,
9399-9406. (b) Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D. D. Org.
Lett. 2005, 7, 5805-5807. (c) Lu, X.; Bittman, R. Tetrahedron Lett. 2005,
46, 1873-1875. (d) Torssell, S.; Somfai, P. Org. Biomol. Chem. 2004, 2,
1643-1646. (e) Olofsson, B.; Somfai, P. J. Org. Chem. 2003, 68, 2514-
2517. (f) Raghaven, S.; Rajender, A. J. Org. Chem. 2003, 68, 7094-7097.
(g) Rai, A. N.; Basu, A. Org. Lett. 2004, 6, 2861-2863. (h) Merino, P.;
Kimenez, P.; Tejero, T. J. Org. Chem. 2006, 71, 4685-4688.
(7) van den Berg, R. J. B. H. N.; Korevaar, C. G. N.; van der Marel, G.
A.; Overkleeft, H. S.; van Boom, J. H. Tetrahedron Lett. 2002, 43, 8409-
8412.
* To whom correspondence should be addressed. Tel: 82-2-740-8913. Fax:
82-2-762-8322.
† College of Pharmacy.
‡ Natural Products Research Institute.
(1) Merrill, A. H., Jr.; Sandhoff, K. Sphingolipids: Metabolism and Cell
Signaling. In Biochemistry of Lipids, Lipoprotein, and Membranes; Vance,
D. E., Vance, J. E., Eds.; Elsevier: New York, 2002; pp 373-407.
(2) For a good review with citations, see: (a) Kester, M.; Kolesnick, R.
Pharmacol. Res. 2003, 47, 365-371. (b) Rosen, H.; Liao, J. Curr. Opin.
Chem. Biol. 2003, 7, 461-468.
(8) van den Berg, R. J. B. H. N.; Korevaar, C. G. N.; Overkleeft, H. S.;
van der Marel, G. A.; van Boom, J. H. J. Org. Chem. 2004, 69, 5699-
5704.
10.1021/jo0614543 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/04/2006
J. Org. Chem. 2006, 71, 8661-8664
8661

SCHEME 1. Synthesis of Azidosphingosine 3
2-azidosphingosine 37,9 from inexpensive phytosphingosine 2.
Our strategy is based on the use of a cyclic sulfate10 for the
regio- and stereoselective transformation of the C-4 hydroxyl
group of phytosphingosine into the characteristic 4,5-trans
double bond of sphingosine. One of the advantages of the cyclic
sulfate in this approach is that it eliminates the need for selective
activation of only one vicinal hydroxyl group.
sulfate in an acyclic system has not been explored.15 To our
delight, we found that the elimination reaction of cyclic sulfate
6 was feasible even in an inactivated acyclic system. The
reaction of cyclic sulfate 6 with DBU in refluxing toluene14
led, after hydrolysis of the resulting sulfate ester intermediate
with aqueous sulfuric acid, to the formation of the desired allylic
alcohol 7 with the trans selectivity. No cis olefin was detected
1
in the crude H NMR spectra. Unfortunately, however, the
Our approach commenced with the protection of the amino
function and primary hydroxyl group of phytosphingosine. The
azide was chosen as an amino protecting group. Thus, the known
azido-phytosphingosine 4 was prepared without column chro-
matographic purification in high yield (90-99%) according to
the published procedure.7,9a,11 The primary alcohol was protected
selectively as its silyl ether 5 (87%). Conversion of 3,4-vicinal
diol 5 to its cyclic sulfite with thionyl chloride in the presence
chemical yield was too low (39%) to utilize this condition on
a preparative scale. The reason for this unsatisfactory yield was
partially due to the nucleophilic substitution of cyclic sulfate
with DBU.16 We were unable to fully characterize the DBU
adduct and could not prevent the formation of this byproduct
by modification of the solvent, reaction temperature and
stoichiometry. The employment of other so-called nonnucleo-
philic bases, such as LHMDS and t-BuOK, did not improve
the yield.
12
of triethylamine followed by oxidation with RuCl3/NaIO4
provided cyclic sulfate 613 in high yield (90%) (Scheme 1).
To utilize the facile nucleophilic substitution of cyclic sulfate
in this transformation, we decided to employ the ring opening
of cyclic sulfate by the iodide and subsequent dehydrohaloge-
nation reaction. A similar strategy was employed previously
by Shing17 for the transformation of a cyclic sulfate into an
allylic alcohol in a carbocyclic ring system. To accomplish this,
we first needed to examine the regioselectivity of nucleophilic
ring opening of cyclic sulfate by the iodide. We found that the
treatment of cyclic sulfate 6 with Bu4NI in THF followed by
acidic hydrolysis of the intermediate O-sulfate provided the iodo
alcohol 8 as the only identifiable regioisomer in 94% yield
(Scheme 1). The regiochemistry of 8 was determined by the
1H NMR chemical shifts and splitting patterns of the protons
at C-3 and C-4. Although more systematic studies are needed
to elucidate the origin of this excellent regioselectivity, one
possible reason may be due to the steric and electronic
interactions between the neighboring substituents and nucleo-
phile.
With multigram quantities of cyclic sulfate 6 in hand, we
explored the possibility of a base-mediated direct transformation
of cyclic sulfate into allylic alcohol by the regioselective
abstraction of a â-hydrogen. A limited number of applications
of this transformation have been made by us and others to install
the cis double bond in the carbocyclic ring system.14 However,
to our knowledge, the scope of the elimination reaction of cyclic
(9) (a) Du, W.; Gervay-Hague, J. Org. Lett. 2005, 7, 2063-2065. (b)
Duclos, R. I., Jr. Chem. Phys. Lipids 2001, 111, 111-138. (c) Nugent, T.
C.; Hudlicky, T. J. Org. Chem. 1998, 63, 510-520. (d) Kumar, P.; Schmidt,
R. R. Synthesis 1998, 510-520. (e) Somfai, P.; Olsson, R. Tetrahedron
1993, 49, 6645-6650. (f) Zimmermann, P.; Schmidt, R. R. Liebigs Ann.
Chem. 1988, 663-668.
(10) For a review of cyclic sulfates, see: (a) Byun, H.-S.; He, L.; Bittman,
R. Tetrahedron 2000, 56, 7051-7091. (b) Lohray, B. B. Synthesis 1992,
1035-1052.
(11) van den Berg, R. J. B. H. N.; Boltje, T. J.; Verhagen, C. P.; Litjens,
R. E. J. N.; Van der Marel, G. A.; Overkleeft, H. S. J. Org. Chem. 2006,
71, 836-839.
(12) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-
7539.
(15) Elimination reactions of the less reactive cyclic sulfites in an acyclic
system have been reported to afford the trans-allylic alcohol if the â-position
of cyclic sulfites is activated by an electron-withdrawing group. See (a)
Kang, S.-K.; Lee, D.-H.; Kim, Y.-S.; Kang, S.-C. Synth. Commun. 1992,
22, 1109-1113. (b) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett.
1993, 34, 2083-2086.
(16) For a previous example of a nucleophilic substitution of cyclic sulfate
with DBU, see Gourlain, T.; Wadouachi, A.; Beaupe`re, D. Tetrahedron
Lett. 2000, 41, 659-662.
(17) Shing, T. K. M.; Tai, V. W. F. J. Chem. Soc., Perkin Trans. 1 1994,
2017-2025.
(13) Cyclic sulfate 6 is stable enough to be stored in the refrigerator for
weeks without significative decomposition.
(14) (a) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg,
P. M. J. Am. Chem. Soc. 1999, 121, 296-300. (b) Kim, C. U.; Lew, W.;
Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P. A.; Mendel, D.
B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451-2460. (c)
Schaub, C.; Mu¨ller, B.; Schmidt, R. R. Eur. J. Org. Chem. 2000, 1745-
1758. (d) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343-
1345. (e) Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J. Org. Chem.
2004, 69, 112-121.
8662 J. Org. Chem., Vol. 71, No. 22, 2006

SCHEME 2. Synthesis of D-erythro-Sphingosine (1)
modest isolated yield in our hands. The analytical and spectro-
scopic data of both the synthetic 1 and its triacetate derivative
1021 were identical to those reported.6,8,22
In conclusion, these studies provide a practical preparative
route to D-erythro-sphingosine (1) from the low cost phytos-
phingosine 2 in high overall yield (ca 60%). An important
feature of this synthesis is the selective transformation of the
3,4-vicinal diol of phytosphingosine into the characteristic E-
allylic alcohol of sphingosine via a cyclic sulfate. The treatment
of cyclic sulfate 6 with Bu4NI/ DBU led to the exclusive for-
mation of trans olefin in high yield. This transformation is com-
plementary to the eliminative epoxide opening. Further studies
will be forthcoming which will elucidate the scope and limi-
tations of the elimination reaction of cyclic sulfate in an acyclic
system.
Pleased with this result, we studied the direct one-pot ring
opening/ dehydrohalogenation sequence. After the nucleophilic
ring opening reaction in THF was completed as judged by TLC
analysis, DBU was added and the reaction temperature was
raised to reflux. This treatment followed by acidic hydrolysis
successfully furnished the desired E-allylic alcohol 7 as the only
isomer in much higher yield (84%) compared to that of the direct
elimination reaction of the cyclic sulfate (39%). When the
solvent of one-pot process was replaced with toluene, the yield
of 7 was slightly improved to 88%. Alternatively and more
conveniently, 7 could be obtained in similar yield (87%) by
simultaneous addition of both Bu4NI and DBU to a toluene
solution of cyclic sulfate 6 and refluxing for 2 h. At this stage,
it is of interest to note that diol 5 could be converted to allylic
alcohol 7 even without column chromatographic purification
of cyclic sulfate intermediate 6 in similar overall yield (80%)
(Scheme 1).
With a facile route to the large-scale preparation of the desired
compound 7, efforts were next directed toward the deprotection
steps. The silyl group was removed by treatment with Bu4NF
in THF, affording the known 2-azidosphingosine 3 in 99% yield.
The analytical and spectroscopic data of 3 were in good
agreement with literature data.7,9
Alternatively, when the known diol 9,9a,18 containing an acid-
labile trityl ether protecting group, was employed as a 1,2-
amino-alcohol protected phytosphingosine, the application of
the above sequence also successfully afforded 2-azidosphin-
gosine 3 in high overall yield (Scheme 2). The diol 9 was
converted to a cyclic sulfate, which was submitted directly to
one-pot ring opening/dehydrohalogenation conditions (Bu4NI
and DBU in refluxing toluene) without column chromatography.
Exposure of the resulting reaction mixture to HCl/THF resulted
in simultaneous hydrolysis of the sulfate ester intermediate and
removal of the trityl protecting group to give the 2-azidos-
phingosine 3 in 80% overall yield.
Experimental Section
(2S,4S,5R)-[2-Azido-2-(2,2-dioxo-5-tetradecyl-2λ6-[1,3,2]diox-
athiolan-4-yl)ethoxy]-tert-butyldiphenylsilane (6). To a solution
of diol 5 (1.10 g, 1.88 mmol) in CH2Cl2 (10 mL) were added
triethylamine (786 µL, 5.64 mmol) and thionyl chloride (160 µL,
2.26 mmol) at 0 °C. After 30 min, this reaction mixture was poured
into brine and extracted with EtOAc. The organic layer was dried
over Na2SO4 and concentrated. This crude cyclic sulfite was dried
in vacuo for 3 h and dissolved in CCl4/CH3CN/H2O (12 mL, 1:1:
1). To the resulting solution were added RuCl3‚3H2O (19 mg, 0.09
mmol) and NaIO4 (1.21 g, 5.64 mmol). After this reaction mixture
was stirred at room temperature for 2 h, it was diluted with EtOAc
and washed with saturated NaHSO3 solution. The organic layer
was dried over Na2SO4, concentrated, and purified by column
chromatography on silica gel (hexane/EtOAc, 10:1) to give cyclic
sulfate 6 (1.09 g, 90%) as a colorless oil: [R]25 +53.8 (c 1.0,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 0.90 (t, J ) 6.6 Hz, 3H),
1.11 (s, 9H), 1.29 (s, 22H), 1.47-1.63 (m, 2H), 1.71-1.80 (m,
1H), 1.88-2.00 (m 1H), 3.70 (ddd, J ) 2.4, 5.1, 9.9 Hz, 1H), 3.91
(dd, J ) 5.1, 11.4 Hz, 1H), 4.05 (dd, J ) 2.4, 11.4 Hz, 1H), 4.91-
5.03 (m, 2H), 7.41-7.51 (m, 6H), 7.68-7.72 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 19.1, 22.6, 25.1, 26.6, 28.0, 28.9, 29.2,
29.3, 29.4, 29.5, 29.59, 29.61, 29.63, 31.9, 59.1, 63.5, 79.8, 86.4,
127.90, 127.92, 130.1, 131.9, 132.1, 135.47, 135.50; IR (CHCl3)
υmax 2108, 1392 (cm-1); HRMS (FAB) calcd for C34H52O5N3SiS
642.3397 ([M-H]-), found 642.3378.
(2S,3R)-(E)-2-Azido-1-(tert-butyldiphenylsilyoxy)octadec-4-en-
3-ol (7). To a solution of cyclic sulfate 6 (534 mg, 0.83 mmol) in
toluene (8 mL) were added Bu4NI (336 mg, 0.91 mmol) and DBU
(187 µL, 1.25 mmol). This reaction mixture was heated to reflux
for 2 h. The reaction was cooled to room temperature, and to it
were added concentrated H2SO4 (14 µL), H2O (17 µL), and THF
(217 µL). The mixture was stirred for 1 h at room temperature and
then diluted with EtOAc. It was washed with saturated aqueous
NaHCO3 solution and brine. The organic layer was dried over Na2-
SO4 and concentrated. The crude product was purified by silica
gel column chromatography (hexane/EtOAc, 10:1) to give 7 (408
mg, 87%) as a colorless oil: [R]25D +2.54 (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 0.89 (t, J ) 6.9 Hz, 3H), 1.08 (s, 9H), 1.26
(s, 20H), 1.31-1.33 (m, 2H), 1.98-2.05 (m, 2H), 3.51 (td, J )
1.2, 5.1 Hz, 1H), 3.77 (dd, J ) 4.5, 11.1 Hz, 1H), 3.82 (dd, J )
6.6, 11.1 Hz, 1H), 4.23 (app. t, J ) 6.0 Hz, 1H), 5.43 (tdd, J )
1.2, 6.9, 15.3 Hz, 1H), 5.74 (dtd, J ) 0.9, 7.8, 15.3 Hz, 1H), 7.37-
7.48 (m, 6H), 7.67-7.70 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ
14.1, 19.0, 22.6, 26.7, 28.9, 29.1, 29.3, 29.4, 29.5, 29.6, 31.9, 32.2,
A final reduction of the azide to an amino group was achieved
by treatment of 3 with NaBH4 in refluxing 2-propanol19 to give
D-erythro-sphingosine (1) as waxy solid in 87% isolated yield
(Scheme 2). Other literature conditions,6c,20 such as Staudinger
reaction, LiAlH4, and Zn/NH4Cl, gave several products and
(18) (a) Fan, G.-T.; Pan, Y.-s.; Lu, K.-C.; Cheng, Y.-P.; Lin, W.-C.;
Lin, S.; Lin, C.-H.; Wong, C.-H.; Fang, J.-M.; Lin, C.-C. Tetrahedron 2005,
61, 1855-1862. (b) Kratzer, B.; Mayer, T. G.; Schmidt, R. R. Eur. J. Org.
Chem. 1998, 291-298. (c) Morita, M.; Sawa, E.; Yamaji, K.; Sakai, T.;
Natori, T. Biosci., Biotechnol., Biochem. 1996, 60, 288-292.
(19) Kiso, M.; Nakamura, A.; Tomita, Y.; Hasegawa, A. Carbohydr.
Res. 1986, 158, 101-111.
(20) (a) Yadav, J. S.; Vidyanand, D.; Rajagopal, D. Tetrahedron Lett.
1993, 34, 1191-1194. (b) Milne, J. E.; Jarowicki, K.; Kocienski, P. J.;
Alonso, J. Chem. Commun. 2002, 426-427.
(21) Owing to the reported instability of 1, it was also characterized as
the triacetate derivative 10.
(22) (a) Lee, J.-M.; Lim, H.-S.; Chung, S.-K. Tetrahedron: Asymmetry
2002, 13, 343-347. (b) Ohashi, K.; Kosai, S.; Arizuka, M.; Watanabe, T.;
Yamagiwa, Y.; Kamikawa, T. Tetrahedron 1989, 45, 2557-2570 and
references therein.
J. Org. Chem, Vol. 71, No. 22, 2006 8663

64.1, 66.9, 72.7, 127.75, 127.84, 129.8, 132.7, 135.2, 135.5; IR
(CHCl3) υmax 3420, 2101, 1642 (cm-1); HRMS (FAB) calcd for
C34H52O2N3Si 562.3829 ([M-H]-), found 562.3838.
oil: [R]24 -37.7 (c 1.0, CHCl3) (Optical rotation values of
D
azidosphingosine 3 range from -29.1 to -34.1. See: refs 7, 9b-
1
f, and 19); H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.6 Hz,
(2S,3S,4S)-2-Azido-1-(tert-butyldiphenylsilyloxy)-4-iodoocta-
decan-3-ol (8). To a solution of cyclic sulfate 6 (104 mg, 0.16
mmol) in THF (3 mL) was added Bu4NI (65.0 mg, 0.176 mmol).
This reaction mixture was heated for 1 h at 40 °C. The reaction
was cooled to room temperature, and to it were added concentrated
H2SO4 (14 µL), H2O (17 µL), and THF (212 µL). The mixture
was stirred for 1 h at room temperature and then diluted with
EtOAc. It was washed with saturated aqueous NaHCO3 solution
and brine. The organic layer was dried over Na2SO4 and concen-
trated. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 10:1) to give iodo alcohol 8 (104
mg, 94%) as a colorless oil: [R]25D +7.0 (c 1.0, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 0.88 (t, J ) 6.9 Hz, 3H), 1.09 (s, 9H), 1.26
(s, 22H), 1.72-1.82 (m, 1H), 1.86 (d, J ) 9.6 Hz, 1H), 2.01-2.13
(m, 1H), 2.55 (dt, J ) 1.5, 9.3 Hz, 1H), 3.45 (ddd, J ) 3.3, 6.3,
9.6 Hz, 1H), 3.93 (dd, J ) 6.0, 11.1 Hz, 1H), 4.06 (dd, J ) 3.3,
11.1 Hz, 1H), 4.53 (ddd, J ) 1.5, 6.0, 9.0 Hz, 1H), 7.38-7.49 (m,
6H), 7.68-7.73 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.1,
22.7, 26.7, 28.7, 29.3, 29.4, 29.5, 29.59, 29.63, 29.7, 31.9, 38.0,
46.3, 64.3, 68.1, 72.0, 127.83, 127.85, 129.92, 129.94, 132.66,
132.70, 135.6; IR (CHCl3) υmax 3449, 2926, 2854, 2101, 1113
(cm-1); HRMS (CI) calcd for C34H55N3IO2Si 692.3108 ([M+H]+),
found 692.3108.
3H), 1.26 (s, 20H), 1.36-1.41 (m, 2H), 2.04-2.10 (m, 2H), 3.51
(dd, J ) 5.7, 10.2 Hz, 1H), 3.76 (dd, J ) 5.7, 11.7 Hz, 1H), 3.81
(dd, J ) 4.8, 11.7 Hz, 1H), 4.25 (app. t, J ) 6.3 Hz, 1H), 5.54
(tdd, J ) 1.2, 7.5, 15.3 Hz, 1H), 5.82 (dtd, J ) 0.6, 7.8, 14.7 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 22.6, 28.9, 29.2, 29.3,
29.4, 29.55, 29.59, 29.61, 31.9, 32.3, 62.3, 66.7, 73.4, 128.0, 135.8;
IR (CHCl3) υmax 3382, 2101, 1642 (cm-1); HRMS (FAB) calcd
for C18H34O2N3 324.2651 ([M - H]-), found 324.2661.
(2S,3R)-(E)-2-Aminooctadec-4-ene-1,4-diol (D-erythro-sphin-
gosine) (1). To a solution of azidosphingosine 3 (98 mg, 0.30 mmol)
in 2-propanol (3 mL) was added NaBH4 (68 mg, 1.8 mmol). This
reaction mixture was heated to reflux for 24 h and cooled to room
temperature. Acetone (1 mL) was added to destroy unreacted
NaBH4, and the resulting mixture was stirred for 10 min and
concentrated. It was diluted with Et2O and centrifuged (1000 rpm)
for 10 min twice. The supernatant was concentrated and purified
by silica gel column chromatography (CHCl3/ MeOH/NH4OH, 135:
25:4) to give a white solid. The obtained solid was dissolved in
CHCl3 and passed through a pad of Celite to remove residual silica
gel. The filtrate was concentrated to give sphingosine 1 (77 mg,
87%) as a white waxy solid: Rf ) 0.15 (CHCl3/MeOH/NH4OH,
135:25:4); (mp 76-77 °C (lit.6d mp 72-75 °C, lit.6e mp 73-75
°C, lit.9b mp 75-80 °C, lit.22a mp 79-82 °C); [R]24 -3.0 (c 1.0,
D
(2S,3R)-(E)-2-Azidooctadec-4-ene-1,3-diol (3). From 7: To a
solution of 7 (138 mg, 0.24 mmol) in THF (1.2 mL) was added
TBAF (480 µL, 0.48 mmol, 1.0 M solution in THF) at room
temperature. The reaction mixture was stirred for 1 h and then
diluted with water and extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, concentrated. The crude
product was purified by column chromatography on silica gel
(hexane/EtOAc, 3:1) to give azidosphingosine 3 (80 mg, 99%) as
CHCl3) (Optical rotation values of sphingosine 1 range from -1.4
1
to -2.9. See: refs 6-8 and 22a); H NMR (CDCl3, 300 MHz) δ
0.88 (t, J ) 6.6 Hz, 3H), 1.25 (s, 20H), 1.37 (m, 2H), 2.05 (q, J )
6.6 Hz, 2H), 2.34 (br s, 4H), 2.88 (br s, 1H), 3.66 (br s, 2H), 4.06
(br s, 1H), 5.47 (dd, J ) 6.9, 15.3 Hz, 1H), 5.76 (td, J ) 6.6, 15.3
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 22.7, 29.2, 29.25,
29.34, 29.5, 29.7, 31.9, 32.3, 56.2, 63.7, 75.1, 129.0, 134.7; IR
(CHCl3) υmax 3240, 2919, 2851, 1467, 1032, 970 (cm-1); HRMS
(FAB) calcd for C18H38O2N 300.2903 ([M + H]+), found 300.2907.
Compound 1 was also characterized as the triacetate derivative 10
(see Supporting Information).
a colorless oil: [R]25 -37.3 (c 0.7, CHCl3).
D
From 9: Following the same procedure as for 6, the crude cyclic
sulfate was obtained from diol 9 (856 mg, 1.46 mmol). To a solution
of crude cyclic sulfate in toluene (15 mL) were added Bu4NI (595
mg, 1.61 mmol) and DBU (296 µL, 1.98 mmol). This reaction
mixture was heated to reflux for 2 h. After the reaction mixture
was cooled to room temperature, 5.0 N HCl (7 mL) and toluene (5
mL) were added. The resulting mixture was stirred for 2 h at room
temperature and then diluted with EtOAc. It was washed with
saturated aqueous NaHCO3 solution and brine. The organic layer
was dried over Na2SO4 and concentrated. The crude product was
purified by silica gel column chromatography (hexane/EtOAc, 4:1)
to give azidosphingosine 3 (381 mg, 80% from 9) as a colorless
Acknowledgment. This study was supported by the National
Research Laboratory Program (2005-01319), NRDP, Ministry
of Science and Technology, Republic of Korea.
Supporting Information Available: Experimental procedures
for the synthesis of 5, 9, and 10; copies of 1H NMR and 13C NMR
spectra of compounds 1, 3, 5, 6, 7, 8, and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0614543
8664 J. Org. Chem., Vol. 71, No. 22, 2006