A rapid and efficient synthesis of D-erythro-sphingosine from D-ribo-phytosphingosine

Article abstract of DOI:10.1002/ejoc.201100911

In this paper we describe the concise synthesis of D-erythro-sphingosine starting from the readily available chiral building block D-ribo- phytosphingosine. The title compound is the ubiquitous sphingolipid from which most mammalian ceramides are derived. Our work is based on the existing literature in which the same sphingoid base is used as a starting point and culminates in what we believe is the most efficient synthesis of D-erythro-sphingosine reported to date.

Full text of DOI:10.1002/ejoc.201100911

FULL PAPER
DOI: 10.1002/ejoc.201100911
A Rapid and Efficient Synthesis of
D
-erythro-Sphingosine from -ribo-
D
Phytosphingosine
Richard J. B. H. N. van den Berg,[a] Hans van den Elst,[a] Cornelius G. N. Korevaar,[b]
Johannes M. F. G. Aerts,[c] Gijsbert A. van der Marel,[a] and Herman S. Overkleeft*[a]
Keywords: Sphingolipids / Chirality / Stereoselectivity / Protecting groups / Cyclic sulfate
In this paper we describe the concise synthesis of
sphingosine starting from the readily available chiral build-
ing block -ribo-phytosphingosine. The title compound is the
D
-erythro-
ides are derived. Our work is based on the existing literature
in which the same sphingoid base is used as a starting point
and culminates in what we believe is the most efficient syn-
D
ubiquitous sphingolipid from which most mammalian ceram-
thesis of D-erythro-sphingosine reported to date.
accessible from natural sources and is commonly prepared
through synthetic organic chemistry.[2–17]
Introduction
Sphingolipids and their derivatives such as glycosphingo-
lipids and sphingomyelins are important components of the
cell membrane and are present throughout all kingdoms of
life. The importance of sphingolipids and their metabolism
to human health is underscored by the existence of numer-
ous inherited metabolic disorders, all characterized by mal-
functioning of a specific lysosomal enzyme caused by alter-
ations (deletions, duplications, point mutations) in the gene
encoding for the enzyme. As a result, the sphingolipid sub-
strate accumulates, which eventually leads to clinical mani-
festation of the disease.[1] In order to study particulars of
these lysosomal storage disorders, and more in general to
study the role of sphingolipids and their derivatives in fun-
damental physiological processes, suitable quantities of
well-defined and pure compounds are needed. The large
majority of sphingolipids in man are derived from d-
erythro-sphingosine 2 (Scheme 1) as the core sphingoid
base. Variation is found in the nature (size, number of un-
saturations) of the N-acyl group in the d-erythro-sphingo-
sine-derived lipids called ceramides, and in the nature
(phosphate, phosphodiester, carbohydrate) of the polar
head group attached to the primary alcohol group in 2. d-
erythro-Sphingolipid 2 in its various protective forms there-
fore often features in synthetic schemes towards sphingoli-
pid compounds.[2] This sphingoid base is however not easily
Results and Discussion
Among the various synthetic strategies we, as well as the
group of Kim, have recognized the potential of using the
closely related sphingoid base d-ribo-phytosphingosine 1
(Scheme 1) as a starting point.[18–21] In contrast to 2, com-
pound 1 is readily available in large quantities and in highly
pure form through fermentation processes.[22] It thus consti-
tutes a cheap and highly accessible chiral pool starting ma-
terial, and both our group and the group of Kim have re-
ported two synthetic schemes in the past decade, increasing
each time the efficiency in terms of yield and ease of execu-
tion.[20,21] Our first approach (Scheme 1) was based on enol
triflate 3 as the key intermediate derived from 1 by using
standard protecting group and functional group manipula-
tions.[18] Reductive elimination of the triflate in 3 followed
by global deprotection led to the isolation of 2 in 57% yield
on a 0.8-mmol scale (final product) in eight steps starting
from 1. In a later contribution, we improved on our syn-
thetic scheme by both minimizing the number of protecting
group manipulations and avoiding the somewhat cumber-
some formation and reduction of the enol triflate moiety.[19]
The key intermediate in our second synthetic scheme was
epoxide 4, which was β-eliminated to install the E-allylic
alcohol moiety. In this work, we were able to transform 1
into 2 in seven steps and in 52% overall yield. Kim and
co-workers in evaluating our synthetic scheme noted that
selective tosylation of the least-hindered alcohol in 1 after
installment of the oxazoline bifunctional protecting group,
required for the formation of the epoxide with the required
stereochemistry, did not proceed as the exclusive event and
that considerable amounts of the ditosylate was formed as
an unwanted side product. In two consecutive reports they
[a] Leiden Institute of Chemistry, Gorlaeus Laboratories,
Einsteinweg 55, 2333 CC Leiden, The Netherlands
Fax: +31-71-5274307
E-mail: h.s.overkleeft@chem.leidenuniv.nl
[b] Evonik BU CS, Cosmoferm BV,
Delft, The Netherlands
[c] Department of Medical Biochemistry,
Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100911.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. S. Overkleeft et al.
FULL PAPER
Scheme 1. Synthetic approaches towards 2 starting from 1.
improved on our synthetic scheme by making use of cyclic ually. To investigate the merits of this reasoning, we set out
sulfate chemistry.[20,21] In their first report, they prepared to prepare key intermediate 7 from 1 and to explore its
cyclic sulfate 5 as the key intermediate.[20] In a one-pot pro- transformation into the title compound.
cedure, the cyclic sulfate was first opened with iodide (treat-
Our straightforward route of synthesis is depicted in
ment with tetrabutylammonium iodide) and the transiently Scheme 2 and commences with protection of the amino
formed iodine was β-eliminated by addition of the base 1,9- alcohol moiety. According to our previously reported pro-
diazabicycloundecene (DBU). In this scheme, d-ribo-phyto-
sphingosine is transformed into d-erythro-sphingosine in
nine steps and in 53% overall yield. In a very recent paper,
Kim and co-workers finally reported an additional im-
provement, which lies in the nature of the protecting groups
employed to protect the functionalities in 1 that do not par-
take in the desired transformation (diol to allylic
alcohol).[21] Whereas initially the secondary amine was pro-
tected as the azide (as in 5), the authors realized that this
protecting group might not be the optimal choice when
aiming for bulk-scale synthesis. They also had experienced
in prior work that relatively electron-rich N-acyl protecting
groups are incompatible with the cyclic sulfate moiety due
to intramolecular attack of the carbonyl as the nucleo-
phile.[23,24] They therefore opted to use the highly electron-
deficient trifluoroacetate protecting group, leading to cyclic
sulfate 6 as the key intermediate. In this recent publication,
1 was transformed into 2 in nine steps and in 55% overall
yield. The work of Kim and co-workers prompted us to
reinvestigate our synthetic strategy. Obviously, the cyclic
sulfate chemistry is superior to our epoxide chemistry, yet
we felt that our simple one-step protection of the amino
alcohol bystander moiety is the more efficient strategy com-
pared to a protecting group scheme in which both a pri-
mary alcohol and a secondary amine are protected individ- Scheme 2. Synthesis of d-erythro-sphingosine 2.
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Synthesis of d-erythro-Sphingosine from d-ribo-Phytosphingosine
Figure 1. HPLC traces, visualization at 254 nm, of the conversion of 7 into 10. A: t = 0 min, initiating the reaction by treating 7 with
TBAI and DBU in toluene at 70 °C, tR = 4.42 min (toluene), tR = 9.42 min compound 7; B: t = 60 min, T = 70 °C, tR = 4.48 min
(toluene), tR = 6.13 min (3-O-sulfate 10), tR = 6.64 min (3-O-sulfate-4-iodate 7); C: t = 240, 180 min at T = 110 °C, tR = 4.58 min
(toluene), tR = 6.06 min (3-O-sulfate 10); D: t = 240 min, T = 22 °C, reaction mixture was cooled, filtered, and concentrated, the residue
dissolved in a mixture of THF/MeOH (25:1) and H2SO4 (2.5 equiv.) and H2O (2.5 equiv.) were added, tR = 6.05 min (3-O-sulfate 10); E:
t = 420, 180 min at T = 22 °C, tR = 8.60 min (compound 10).
cedure,[18] d-ribo-phytosphingosine is readily transformed in into a tetrahydrofuran/methanol mixture (15:1) and concen-
95% yield into oxazoline derivative 8 by treatment with trated sulfuric acid (2.5 equiv.) and water (2.5 equiv.) were
ethyl benzimidate and triethylamine in dichloromethane. added.[25] LCMS analysis using a diphenyl reverse-phase
Installment of the cyclic sulfate is effected by following es- column and buffered ammonium acetate as the mobile
sentially the protocol advocated by Kim and co-workers. In phase revealed completion of the reaction after 3 h, at
the first step, compound 8 is treated with thionyl chloride which point the reaction mixture was neutralized by ti-
and triethylamine in dichloromethane. The reaction mixture tration with triethylamine and concentrated. Silica gel
containing intermediate cyclic sulfite 9 is diluted by ad- chromatography delivered d-erythro-sphingosine 10 in 90%
dition of an equal amount of acetonitrile and a half amount yield starting from 7. Final deprotection afforded the title
of water (relative to dichloromethane), upon which a cata- compound in 85% yield.[26] The total yield of this synthetic
lytic amount of ruthenium trichloride and sodium periodate scheme is 67% in seven steps starting from 1.
(excess) are added to effect oxidation to cyclic sulfate 7.
Elimination of the cyclic sulfate to give partially protected
d-erythro-sphingosine 10 was accomplished in an optimized
procedure as follows (Figure 1). To a solution of 7 in tolu-
Conclusions
ene was added tetrabutylammonium iodide (1.2 equiv.) and
In summary, we have considerably improved our synthe-
1,9-diazabicycloundecene (DBU, 1.5 equiv.), and the reac- sis of d-erythro-sphingosine 2 starting from the cheap and
tion mixture was left for 1 h at 70 °C. Subsequently, the readily available d-ribo-phytosphingosine. To accomplish
reaction mixture was brought to reflux for 3 h and then this, we have effectively taken the best of the two synthetic
cooled to room temperature, during which tetrabutylammo- strategies known to date, that is, the oxazoline protecting
nium iodide precipitated. Filtration of the reaction mixture group put forward by us in combination with the cyclic sul-
led to removal of about 70% of this salt, and the filtrate fate chemistry as advocated by Kim and co-workers. We
was concentrated. Removal of the salt facilitates the latter feel that our route compares well to the existing routes of
silica gel column purification of 10. The residue was taken synthesis of d-erythro-sphingosine, both those based on d-
Eur. J. Org. Chem. 2011, 6685–6689
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H. S. Overkleeft et al.
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3317, 2916, 2846, 1643, 1465, 1365, 1095, 948 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.88 (t, 3 H), 1.25 (s, 24 H), 1.52 (m, 2 H),
2.17 (d, 1 H), 3.27 (d, 1 H), 3.71 (m, 1 H), 3.81 (m, 1 H), 4.40–
4.61 (m, 3 H), 7.26–7.92 (m, 5 H, Ph) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.9, 22.5, 25.4, 29.1, 29.5, 31.7, 32.9, 68.4, 69.3, 73.5,
74.9, 126.9–132.9, 165.4 ppm. MS (ESI): m/z = 404.3 [M + H]+,
ribo-sphingosine as the starting material and those using
other chiral pool materials as a starting point and/or em-
ploying synthetic strategies unrelated to ours.
426.1 [M
+
Na]+. HRMS (QTOF): calcd. for C25H42NO3
Experimental Section
[M + H]+ 404.3159; found 404.3139.
General: Commercially available reagents and solvents (Acros,
Fluka, or Merck) were used as received. Reactions were executed at
ambient temperature unless stated otherwise. All moisture-sensitive
reactions were performed under an argon atmosphere. All solvents
were removed by evaporation under reduced pressure. Reactions
were monitored by TLC analysis with the use of silica gel coated
plates (0.2 mm thickness) and detection by 254 nm UV light or by
spraying with either a solution of 20% H2SO4 in ethanol or a solu-
tion of (NH4)6Mo7O24·4H2O (25 gL–1), (NH4)4Ce(SO4)4·2H2O
(10 gL–1) in 10% sulfuric acid followed by charring at ≈150 °C or
by spraying with potassium permanganate (5 gL–1) and potassium
carbonate (25 gL–1) in water. Liquid column chromatography puri-
fication was performed using forced flow of the indicated solvent
systems on silica gel 60 (40–63 μm mesh). Conversion of compound
7 into compound 10 was monitored by HPLC–MS analysis. An
HPLC system (detection simultaneously at 214, 254 nm and ELSD)
was equipped with an analytical TP diphenyl column (300 A, 3 μm
particle size, length 50 mm, ID 4.6 mm) in combination with buff-
ers A: H2O, B: MeCN, and C: 0.1 m NH4Ac (method gradient, t
in min; buffers A/B/C, v/v/v: t = 0, 80:10:10; t = 0.5, 80:10:10; t =
10.5, 0:90:10; t = 12.5, 0:90:10; t = 14.0, 80:10:10, flow in mL/min)
and coupled to a mass instrument with an electrospray interface
(ESI) was used. HPLC sample preparation: 20 μL of reaction mix-
ture was diluted with 980 μL of a stock solution of tBuOH/ACN/
H2O/AcOH, 3:3:3:1, v/v/v/v, from the HPLC sample stock solution
10 μL was injected in the HPLC system. IR spectra were recorded
with a Shimadzu FTIR-8300 fitted with a single bounce diamond
crystal ATR-element. Optical rotations were measured with a Pro-
pol automatic polarimeter (sodium D line, λ = 589 nm). Melting
points were measured with a melting point apparatus with a heat-
ing rate of 0.5 °C/minute. The 1H and 13C-APT NMR spectra, 1H–
1H COSY, and 1H–13C HSQC experiments were recorded with a
400/100 MHz spectrometer. Chemical shifts are given in ppm (δ)
relative to tetramethylsilane as internal standard. NMR peak as-
signments were made using COSY and HSQC experiments. All
presented 13C-APT spectra are proton decoupled. LC–MS analyses
were performed with a LCQ Advantage Max (Thermo Finnigan)
equipped with a Gemini C18 column (Phenomenex, 50ϫ4.6 mm,
3 μ), utilizing the following buffers: A: H2O, B: acetonitrile, and C:
1.0% TFA (aq.). High-resolution mass spectra were recorded with
a mass spectrometer equipped with an electrospray ion source in
positive mode (source voltage 3.5 kV, sheath gas flow 10%, capil-
lary temperature 275 °C) with resolution R = 100000 at m/z = 400.
The high-resolution mass spectrometer was calibrated prior to
measurements with a calibration solution (caffeine, MRFA, Ultra-
mark 1621).
2-Phenyl-4-(S)-[(4S,5S)-4-(tetradecyl)-1,3,2-dioxathiolane-2,2-di-
oxide-5-yl]-1,3-oxazoline (7): To a cooled (ice bath) and stirred sus-
pension of 8 (11.67 g, 28.94 mmol) in DCM (200 mL) was added
TEA (12.0 mL, 86.6 mmol) and thionyl chloride (3.15 mL,
43.4 mmol). The mixture was stirred for 1 h at room temperature,
after which (TLC, silica gel; petroleum ether/EtOAc, 9:1; Rf = 0.55
and 0.56 cyclic sulfite 9) acetonitrile (200 mL), water (100 mL), and
a mixture of NaIO4 (18.58 g, 86.9 mmol) and RuCl3 (0.30 g,
1.4 mmol) were added. Stirring of the mixture was continued for
another 2 h. The mixture was concentrated to approximately
200 mL, diluted with EtOAc (250 mL), and washed with aqueous
saturated NaHSO4 (2ϫ50 mL), dried (Na2SO4), and concentrated.
Flash column chromatography of the residue (silica gel; petroleum
ether/EtOAc, 19:1 Ǟ 7:3) gave 7 (12.35 g, 26.52 mmol, 92%) as a
green yellow oil, which upon standing solidified. TLC (silica gel;
petroleum ether/EtOAc, 9:1): Rf = 0.45. [α]2D0 = 57.2 (c = 1.00,
CHCl ). IR (thin film): ν = 2924, 2852, 1641, 1386, 1209, 958,
˜
3
906 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, 3 H, CH3),
1.27 (s, 24 H, 12 CH2), 2.09 (m, 2 H, CH2-5), 4.40 (d, J1a1b
9.2 Hz, J1a,2 = 6.8 Hz, 1 H, H-1a), 4.53 (t, J1a1b = 9.2 Hz, J1b,2
=
=
9.2 Hz, 1 H, H-1b), 4.63 (ddd, J1a,2 = 6.8 Hz, J1b,2 = 9.2 Hz, J2,3
= 9.0 Hz, 1 H, H-2), 4.75 (dd, J2,3 = 9.0 Hz, J3,4 = 5.2 Hz, 1 H, H-
3), 5.05 (ddd, J4,5 = 4.6 Hz, J3,4 = 5.2 Hz, J4,5 = 9.8 Hz, H-4), 7.38–
7.92 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0
(CH3), 22.6, 25.2, 28.3, 28.9, 29.1, 29.3, 29.4, 29.5, 29.6, 31.8 (CH2),
64.6 (C-2), 69.9 (C-1), 85.2 (C-3), 86.5 (C-4), 126.5 (Cq Ph), 128.3,
128.4, 132.0 (CH Ph), 166.7 (C=N) ppm. MS (ESI): m/z = 466.3
[M + H]+ , 931.5 [2M + H]+ . HRMS (QTOF): calcd. for
C25H40NO5S [M + H]+ 466.26217; found 466.26183.
2-Phenyl-4-(S)-[(1S,2E)-1-hydroxyhexadec-2-enyl]-1,3-oxazoline
(10): To a stirred solution (70 °C) of 7 (1.11 g, 2.38 mmol) in tolu-
ene (24 mL) was added TBAI (1.06 g, 2.87 mmol) and DBU
(0.54 mL, 3.56 mmol). After 1 h (HPLC analysis showed completed
consumption of starting material), the temperature was raised to
reflux, HPLC analysis showed after 4 h the sole formation of sul-
fated 10. The mixture was cooled to room temperature, TBAI salts
were filtered off, and the volatiles were evaporated. The residue was
dissolved in a mixture of THF/MeOH (15:1, 24 mL) and a solution
of H2SO4 and water in THF (6.0 mL, 1 mmol H2SO4, 1 mmol H2O
in 1 mL of THF) was added. After 3 h, HPLC analysis showed the
complete and sole formation of 10. The mixture was neutralized
with TEA (1 mL) and concentrated, and the residue was purified
by silica gel column chromatography (petroleum ether/EtOAc, 9:1
Ǟ 6:4) to give 10 (0.83 g, 2.15 mmol, 90%) as a white crystalline
solid. TLC (silica gel; petroleum ether/EtOAc, 9:1): Rf = 0.20.
2-Phenyl-4-(S)-[(1S,2R)-1,2-dihydroxyhexadecyl]-1,3-oxazoline (8):
To a stirred suspension of phytosphingosine (1; 11.4 g, 35.9 mmol)
and ethyl benzimidate hydrochloride (8.0 g, 43.1 mmol) in DCM
(200 mL) was added TEA (6.0 mL, 43.1 mmol), and the mixture
was stirred for 48 h at 40 °C. The solvent was evaporated, and the
residue was dissolved in hot ethyl acetate (250 mL), washed with
aqueous HCl (1 n, 2ϫ50 mL), and concentrated. Crystallization
of the residue from MeOH gave 8 as white crystals (13.8 g, 95%).
TLC (silica gel; DCM/MeOH, 9:1): Rf = 0.60. M.p. 137–138 °C.
[α]2D0 = –1.4 (c = 1.00, CHCl ). M.p. 87–88 °C. IR (thin film): ν =
˜
3
3155, 2916, 2848, 1645, 1463, 1363, 1099, 966 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.88 (t, 3 H, CH3), 1.27 (br. s, 20 H, 10
CH2), 1.38 (br. s, 2 H, CH2), 2.04 (m, 2 H, CH2-6), 4.28–4.41 (3, 3
H, H-1a, H-1b, H-2), 4.67 (d, J = 4.4 Hz, 1 H, H-3), 4.91 (br. s, 1
H, OH-3), 5.42 (dd, J4,5 = 15.2 Hz, J3,4 = 5.2 Hz, 1 H, H-4), 5.85
(ddd, J4,5 = 15.2 Hz, J5,6a = J5,6b = 6.8 Hz, 1 H, H-5), 7.19–7.68
(m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3),
22.6, 29.1, 29.3, 29.4, 29.5, 29.6, 29.8, 31.8 (CH2), 32.4 (C-6), 67.3
(C-1), 71.1 (C-3), 71.2 (C-2), 126.8 (Cq Ph), 127.9 (C-4), 128.1,
[α]2D0 = 24.8 (c = 1.60, CHCl /methanol, 5:1). IR (thin film): ν =
˜
3
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Synthesis of d-erythro-Sphingosine from d-ribo-Phytosphingosine
128.2, 131.1 (CH Ph), 132.8 (C-5), 165.4 (C=N) ppm. MS (ESI):
m/z = 386.3 [M + H]+, 771.8 [2M + H]+. HRMS (QTOF): calcd.
for C25H40NO2 [M + H]+ 386.30536; found 386.30594.
NMR, 13C NMR, COSY, and HSQC spectra of compounds 8, 7,
10, 2, and acetylated 2.
Acknowledgments
(2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol (D-erythro-sphingosine 2):
To a solution of 10 (2.05 g, 5.31 mmol) in THF (50 mL) was added
aqueous HCl (2 n, 12.5 mL). The mixture was stirred for 3 h, after
which water was added (50 mL), and the mixture was extracted
with chloroform/MeOH (87:13, 3ϫ50 mL). The combined organic
phase was dried (MgSO4), filtered, and concentrated. The residue
was dissolved in MeOH (60 mL), aqueous NaOH (12.5 m, 25 mL)
was added, and the mixture was heated at reflux for 1 h. The cooled
reaction mixture was diluted with water (50 mL) and extracted with
diethyl ether (3ϫ50 mL). The organic layer was dried (MgSO4)
filtered, and concentrated. Column chromatography of the residue
(silica gel; EtOAc/MeOH/NH4OH, 90:10:0 Ǟ 40:10:1) gave 2
(1.35 g, 85%) as a pale white solid. TLC silica gel (diethyl ether/
EtOH/NH4OH, 6:3:1): Rf = 0.80. [α]2D0 = –0.9 (c = 0.8, CHCl3).
The research described was funded by The Netherlands Organiza-
tion for Scientific Research (NWO) and Leiden University
[1] T. Wennekes, R. J. B. H. N. van den Berg, R. G. Boot, G. A.
van der Marel, H. S. Overkleeft, J. M. F. G. Aerts, Angew.
Chem. 2009, 121, 9006; Angew. Chem. Int. Ed. 2009, 48, 8848–
8870.
[2] J. A. Morales-Serna, J. Llaveria, Y. Díaz, M. I. Matheu, S. Cas-
tillón, Curr. Org. Chem. 2010, 14, 2483–2521.
[3] H.-J. Ha, D.-J. Yoon, L.-S. Kang, M. C. Hong, W. K. Lee, Bull.
Korean Chem. Soc. 2009, 30, 535–536.
[4] K. Sa-Ei, J. Montgomery, Tetrahedron 2009, 65, 6707–6711.
[5] R. Sridhar, B. Srinivas, K. Rama Rao, Tetrahedron 2009, 65,
10701–10708.
M.p. 74–78 °C. IR (thin film): ν = 3234, 2914, 2846, 1583, 1467,
˜
[6] J. Llaveria, Y. Díaz, M. I. Matheu, S. Castillón, Org. Lett. 2009,
1
1046, 1029, 968 cm–1. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J
11, 205–208.
= 6.8 Hz, 3 H, CH3), 1.26 (br. s, 20 H, 10 CH2), 1.35–1.37 (br. s, 2
H, CH2), 2.04 (q, J = 6.8 Hz, 2 H, 6-H2), 2.77 (m, 1 H, 2-H), 3.29
(br. s, 4 H, NH2, 2 OH), 3.64 (d, 2 H, 1-H2), 4.02 (dd, J = 6.8,
5.6 Hz, 1 H, 3-H), 5.43 (dd, J4,5 = 15.2 Hz, J3,4 = 6.8 Hz, 1 H, 4-
H), 5.72 (ddd, J4,5 = 15.2 Hz, J5,6a = J5,6b = 6.8 Hz, 1 H, 5-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3-18), 22.6, 29.2,
29.3, 29.5, 29.6, 31.8 (CH2), 32.3 (C-6), 56.2 (C-2), 63.2 (C-1), 74.5
(C-3), 129.4 (C-4), 134.2 (C-5) ppm. MS (ESI): m/z = 300.3 [M +
H]+. HRMS (QTOF): calcd. for C18H38NO2 [M + H]+ 300.28971;
found 300.28978.
[7] E. Abraham, S. G. Davies, N. L. Millican, R. L. Nicholson,
P. M. Roberts, A. D. Smith, Org. Biomol. Chem. 2008, 6, 1655–
1664.
[8] H. Yang, L. S. Liebeskind, Org. Lett. 2007, 9, 2993–2995.
[9] X. Lu, R. Bittman, Tetrahedron Lett. 2005, 46, 1873–1876.
[10] W. Disadee, T. Ishikawa, J. Org. Chem. 2005, 70, 9399–9406.
[11] V. D. Chaudhari, K. S. A. Kumar, D. D. Dhavale, Org. Lett.
2005, 7, 5805–5808.
[12] S. Torssell, P. Somfai, Org. Biomol. Chem. 2004, 2, 1643–1646.
[13] B. Olofsson, P. Somfai, J. Org. Chem. 2003, 68, 2514–2517.
[14] J.-M. Lee, H.-S. Lim, S.-K. Chung, Tetrahedron: Asymmetry
2002, 13, 343–347.
[15] J. E. Milne, K. Jarowicki, P. J. Kocienski, P. J. J. Alonso, Chem.
Commun. 2002, 426–427.
[16] R. I. Duclos, Chem. Phys. Lipids 2001, 111, 111–138.
[17] L. He, H.-S. Byun, R. Bittman, J. Org. Chem. 2000, 65, 7627–
7633.
[18] R. J. B. H. N. van den Berg, C. G. N. Korevaar, G. A.
van der Marel, H. S. Overkleeft, J. H. van Boom, Tetrahedron
Lett. 2002, 43, 8409–8412.
[19] R. J. B. H. N. van den Berg, C. G. N. Korevaar, H. S. Overk-
leeft, G. A. van der Marel, J. H. van Boom, J. Org. Chem. 2004,
69, 5699–5704.
(2S,3R,4E)-2-Acetamido-1,3-diacetyl-octadec-4-ene-1,3-diol: To
a
solution of 2 (0.289 g, 0.96 mmol) in pyridine (10 mL) was added
acetic anhydride (0.36 mL, 3.84 mmol) at 0 °C. After stirring for
18 h at room temperature, the mixture was concentrated. The resi-
due was dissolved in EtOAc and washed with aqueous HCl (1 n),
saturated aqueous NaHCO3, and brine. The organic layer was
dried (MgSO4), filtered, and concentrated. The residue was purified
by silica gel column chromatography (petroleum ether/EtOAc, 1:1
Ǟ 0:1) to give the title compound (0.40 g, 0.95 mmol, 99%) as a
white crystalline solid oil. TLC (silica gel; petroleum ether/EtOAc,
3:1): Rf = 0.40. [α]2D0 = –12.6 (c = 0.54, CHCl3). M.p. 102–104 °C.
[20] S. Kim, S. Lee, T. Lee, H. Ko, D. Kim, J. Org. Chem. 2006, 71,
IR (thin film): ν = 3282, 2918, 2848, 1732, 1653, 1550, 1371, 1265,
˜
8661–8664.
1230, 1028 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J =
6.4 Hz, 3 H, CH3), 1.26 (br. s, 22 H, 11 CH2), 1.97 (s, 3 H, CH3
Ac), 2.01 (m, 2 H, 6-H2), 2.05 (s, 6 H, 2 CH3 Ac), 4.07 (dd, J =
3.6, 11.6 Hz, 1 H, 1a-H), 4.26 (dd, J = 6.4, 11.6 Hz, 1 H, 1b-H),
4.43 (m, 1 H, 2-H), 5.31 (t, J = 6.8 Hz, 1 H, 3-H), 5.41 (dd, J =
15.2, 7.2 Hz, 1 H, 4-H), 5.79 (ddd, J = 15.2, 6.8 Hz, 1 H, 5-H),
6.42 (d, J = 9.2 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 13.8 (CH3-18), 20.4, 20.7 (2 CH3 Ac), 22.3 (CH2), 22.8 (CH3
Ac), 28.6, 28.8, 29.0, 29.1, 29.2, 29.3, 31.6 (CH2), 32.0 (C-6), 50.3
(C-2), 62.3 (C-1), 73.4 (C-3), 124.0 (C-4), 136.8 (C-5), 169.6, 169.7,
170.5 (3 C=O Ac) ppm. MS (ESI): m/z = 448.3 [M + Na]+, 873.5
[2M + Na]+. HRMS (QTOF): calcd. for C24H44NO5 [M + H]+
426.32140; found 426.32149.
[21] Y. M. Lee, S. Lee, H. Jeon, D. J. Baek, J. H. Seo, D. Kim, S.
Kim, Synthesis 2011, 867–872.
[22] d-ribo-Phytosphingosine can be purchased from Evonik
Goldschmidt GmbH Germany.
[23] Y. M. Lee, D. J. Baek, S. Lee, D. Kim, S. Kim, J. Org. Chem.
2011, 76, 408–416.
[24] S. J. Kemp, J. Bao, S. F. Pedersen, J. Org. Chem. 1996, 61, 7162–
7167.
[25] G. Chi, V. Nair, Nucleosides Nucleotides Nucleic Acids 2005,
24, 1449–1468.
[26] For proper analysis, sphingosine 1 was peracetylated towards
(2S,3R,4E)-2-acetamido-1,3-diacetyl-octadec-4-ene-1,3-diol in
near quantitative yield. The analytical data (see the Experimen-
tal Section), were in full accordance with those reported in the
literature.
Supporting Information (see footnote on the first page of this arti-
Received: June 22, 2011
Published Online: September 22, 2011
1
cle): Copies of the HPLC traces for the conversion of 7 Ǟ 10; H
Eur. J. Org. Chem. 2011, 6685–6689
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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