Novel, efficient and stereospecific synthesis of xylo-(2R,3S,4S)-phytosphingosine and threo-(2R,3R)-sphingosine

Article abstract of DOI:10.1016/S0957-4166(03)00427-0

The stereo- and regioselective elaboration of a bromohydrin from an olefinic precursor and Pummerer ene reaction for carbon-carbon bond formation are the key steps in a novel and flexible synthesis of xylo-phytosphingosine and threo-sphingosine.

Full text of DOI:10.1016/S0957-4166(03)00427-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2093–2099
Novel, efficient and stereospecific synthesis of
xylo-(2R,3S,4S)-phytosphingosine and
threo-(2R,3R)-sphingosineꢀ
Sadagopan Raghavan,* A. Rajender and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 April 2003; revised 9 May 2003; accepted 14 May 2003
Abstract—The stereo- and regioselective elaboration of a bromohydrin from an olefinic precursor and Pummerer ene reaction for
carbonꢀcarbon bond formation are the key steps in a novel and flexible synthesis of xylo-phytosphingosine and threo-sphingosine.
© 2003 Elsevier Ltd. All rights reserved.
cell signaling.1 The phytosphingosines2a and their
derivatives2b also exhibit important physiological activi-
ties. The majority of phytosphingosines have eighteen
carbons, minor amounts of other chain lengths; espe-
cially C20, are also present depending on the sources of
origin. Phytosphingosine was first isolated from mush-
rooms in 19113 and was subsequently shown to be
widely distributed in yeast,4 fungi,5 plants,6 marine
organisms7 and mammalian tissues.8 Since it is not
1. Introduction
Sphingosines, dihydrosphingosines and phytosphingosi-
nes (Fig. 1) are long-chain bases that form the back-
bone of sphingolipids, which are important membrane
components. Sphingolipids are involved in a number of
cellular events including cell growth, differentiation,
adhesion and neuronal repair. They have also been
shown to play a critical role as secondary messengers in
Figure 1.
ꢀ IICT Communication No. 030106.
* Corresponding author. E-mail: purush101@yahoo.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00427-0

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S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
possible to obtain homogenous material from natural
sources and it is expensive to isolate these lipids, a great
deal of synthetic effort has been made to obtain
homogenous compounds for biological studies. Most
syntheses have focused on the preparation of ribo-
(2S,3S,4R)-phytosphingosine starting with compounds
from a chiral pool9,10 or approaches involving asym-
metric induction.11 It is therefore of great interest to
synthesize other phytosphingosine diastereomers to
learn about the precise function of individual sphin-
golipids in vivo. The design of an efficient and
improved route to phytosphingosines therefore contin-
ues to be important.
group and bromine at C3 and C4 respectively, is
expected from a overall anti addition across the double
bond. The observed stereo- and regioselectivity can be
rationalized through the intermediacy of a sulfoxonium
salt 7 (Scheme 2).
The 5-exo nucleophilic attack by the sulfinyl group
onto the olefin p-complexed to the bromonium ion
results in the formation of the sulfoxonium salt 7,
which upon hydrolysis by attack of water on sulfur in
an SN2 fashion, yields the bromohydrin 8, with inver-
sion of the sulfur configuration.17 The acetonide 9, was
converted readily to the azido sulfoxide 10 by treatment
with sodium azide in DMSO. The C13 hydrocarbon
chain was introduced by the Pummerer ene reaction.18
Thus treatment of the sulfoxide 10 with TFAA in
DCM, afforded the Pummerer intermediate 11 which
was then reacted in the same pot with 1-tridecene and
2. Results and discussion
A general synthesis that would allow syntheses of phy-
tosphingosine diastereomers in high purity and incorpo-
ration of different hydrocarbon chain lengths is
required. We recently disclosed stereoselective bromo-
hydration of b-hydroxy-g,d-unsaturated sulfoxides p-
complexed to a bromonium ion via intramolecular
nucleophilic attack by the sulfinyl moiety.12 The poten-
tial of this methodology is illustrated by the enantiose-
lective synthesis of xylo-(2R,3S,4S)-C18-phytoshin-
gosine13a,b and threo-(2R,3R)-C18-sphingosine.13c The
retrosynthetic analysis is illustrated in Scheme 1. The
phytosphingosine 1, can be elaborated from the sulfide
2, which in turn can be obtained eventually by a ene
reaction from the bromohydrin 3. The bromohydrin 3
can be readily obtained from the olefin 4 by the
methodology disclosed by us.
1
SnCl4 to afford the sulfide 12. The H NMR and 13C
spectrum of 12 revealed the presence of only one isomer
although four isomers are theoretically expected; two
that differ due to the configuration at the newly created
stereogenic center and two geometrical isomers. The
structure of the sulfide 12, was not rigorously estab-
lished since the configuration at the newly created
stereogenic center was of no consequence for the syn-
thesis of the target molecule. The synthesis of the target
was accomplished as depicted in Scheme 3.
Five transformations were effected in a one pot opera-
tion, by treatment of the sulfide 12, with Ra-Ni in
methanol in the presence of di-tert-butyl dicarbonate
under an atmosphere of hydrogen to yield the acetonide
13. The double bond and the azide were reduced with
the resulting amine transformed into a urethane and the
toluene thio group and benzyl ether hydrogenolysed
under the reaction conditions. The acetonide 13 was
then deprotected to give the triol 14, which when
acetylated, afforded the tetraacetate 15 with physical
characteristics identical (except for the sign of rotation)
to that reported in the literature.13d
2.1. Synthesis of xylo-(2R,3S,4S)-C18-phytosphingosine
On the basis of the retrosynthetic analysis (Scheme 1),
the first target for the synthesis is the b-hydroxy-g,d-
unsaturated sulfoxide 6, which was prepared by the
reduction of the keto sulfoxide 514 with DIBAL-H/
ZnCl2.15 Treatment of the olefin 6, with NBS in toluene
in the presence of water, afforded the bromohydrin 8 as
the sole product. The syn-disposition of the two
hydroxy groups at C2 and C3 was proven by acetonide
formation 9 and the 13C NMR16 spectrum, which
revealed signals at l 27.0 and 27.4 for the methyl
groups. The orientation, as indicated for the hydroxy
2.2. Synthesis of threo-(2R,3R)-C18-sphingosine
threo-Sphingosine and their derivatives are reversible
inhibitors of protein kinase C.19 Herein we report the
synthesis of threo-(2R,3R)-sphingosine from the azido
Scheme 1.

S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
2095
Scheme 2. Reagents and conditions: (a) DIBAL, THF, −78°C, 91%; (b) NBS, H2O, toluene, rt, 88%; (c) 2,2-DMP, acetone, CSA
(cat.), rt, 86%.
Scheme 3. Reagents and conditions: (a) NaN3, DMSO, 85°C, 75%; (b) TFAA, CH2Cl2, 0°C; (c) C13H26, SnCl4, 0°C, 65% for the
two steps; (d) Ra-Ni, H2, (Boc)2O, MeOH, rt–reflux, 68%; (e) TFA:H2O, 0°C; (f) Ac2O, DMAP (cat.), pyridine, rt, 78%.
In conclusion, we have described a flexible (use of
different olefins in the Pummerer ene reaction permits
the introduction of variable carbon chains), stereoselec-
tive synthesis of xylo-(2R,3S,4S)-C18-phytosphingosine
and threo-(2R,3R)-C18-sphingosine. The key steps of
the syntheses are i) asymmetric induction from sulfur to
C2 in the transformation of 5 to 6, ii) asymmetric
induction from C2 to C3 and C4 in the transformation
of 6 to 8, iii) ene reaction for the introduction of the
hydrocarbon chain (of varying lengths if desired), iv)
sulfide 12 (Scheme 4). Oxidation of the sulfide 12, with
oxone20 afforded the sulfone 16, which was transformed
into the urethane 17, in a one pot, four step transfor-
mation by treatment with Pd(OH)2/C in methanol
under an atmosphere of hydrogen. Treatment of the
sulfone 17, with Na/Hg21 in methanol yielded the threo-
sphingosine derivative 18 (Scheme 4) with physical
characteristics identical to that reported in the litera-
1
ture.22 The crude H NMR spectrum of 18 revealed the
presence of the trans-olefin only.

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S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
Scheme 4. Reagents and conditions: (a) 2KHSO5·KHSO4·K2SO4, MeOH:H2O:THF, 0°C–rt, 82%; (b) Pd(OH)2/C, (Boc)2O, H2,
EtOH, rt, 71%; (c) Na-Hg, Na2HPO4, MeOH, 20°C, rt, 65%.
followed by N-bromosuccinimide (850 mg, 4.8 mmol)
one pot multi step transformation of 12 to 13 and 16 to
and the reaction mixture stirred at room temperature
for 15 min. The reaction mixture was quenched by the
addition of an aq. saturated NaHCO3 solution. The
layers were separated and the aqueous layer extracted
17, v) transformation of the sulfone 17 into sphingosine
18 cleanly using Na-Hg. It is pertinent to mention that
starting from the C2 diastereomer of alcohol 6, the
xylo-(2S,3R,4R)-phytosphingosine and threo-(2S,3S)-
sphingosine can be synthesized, essentially following an
with ethylacetate. The combined organic layers were
successively washed with water, brine and dried over
identical reaction sequence.
Na2SO4. Evaporation of the solvent afforded the crude
product, which was purified by column chromatography
using AcOEt/petroleum ether (2:3) as the eluent to yield
3. Experimental
the bromohydrin 8 (1.5 g, 3.52 mmol) in 88% yield as a
white solid. Mp 136–137°C, Rf=0.26 (60% petroleum
3.1. 5-Benzyloxy-1-(SR)-(4-methylphenylsulfinyl)-
(2R,3E)-penten-2-ol 6
ether/AcOEt), [h]D25=−129.5 (c 1.0, CHCl3), LSIMS
1
m/z: 427 [M+H]+, H NMR (300 MHz, CDCl3): l 7.53
(d, J=8.2 Hz, 2H), 7.35–7.27 (m, 7H), 4.64–4.56 (m,
3H), 4.17 (dt, J=7.6, 4.8 Hz, 1H), 3.98 (dd, J=10.3, 4.8
Hz, 1H), 3.85 (dd, J=10.3, 4.8 Hz, 1H), 3.61 (dt,
The b-ketosulfoxide 5 (1.56 g, 4.76 mmol) was stirred
for 15 min with ZnCl2 (935 mg, 5.7 mmol) in THF (48
mL). The reaction mixture was cooled to −78°C, and
DIBAL (2M solution in toluene, 3.6 mL, 7.2 mmol)
added dropwise over a period of 10 min. After 30 min
while stirring at the same temperature, methanol (48
mL) was added and the reaction mixture allowed to
J=7.6, 4.8 Hz, 1H), 3.38–3.17 (m, 2H), 2.66 (dd,
J=13.4, 1.88 Hz, 1H), 2.43 (s, 3H), 13C NMR (50 MHz,
CDCl3): l=21.3, 51.2, 61.0, 65.9, 71.6, 73.3, 75.1, 124.0,
127.6, 127.7, 128.4, 130.0, 137.5, 139.6, 141.6.
return to rt. The solvent was evaporated under reduced
pressure. The residue was diluted with 5% aq. HCl
solution and extracted into CH2Cl2. The organic layer
was washed with 5% aq. NaOH solution, brine and
dried over Na2SO4. The crude product was purified by
column chromatography using 50% EtOAc/petroleum
ether as the eluent to afford the hydroxysulfoxide 6
(1.41 g, 4.3 mmol) as a single diastereomer in 91% yield.
Pale yellow liquid. Rf=0.27 (50% petroleum ether/
AcOEt), [h]2D5=118.9 (c 0.75, CHCl3), LSIMS m/z: 331
[M+H]+, 1H NMR (200 MHz, CDCl3): l=7.53 (d,
J=8.2 Hz, 2H), 7.36–7.22 (m, 7H), 5.87 (dt, J=14.9, 5.9
Hz, 1H), 5.72 (dd, J=14.9, 4.6 Hz, 1H), 4.79 (m, 1H),
4.52 (s, 2H), 4.06 (d, J=4.6 Hz, 2H), 2.94 (dd, J=13.4,
9.6 Hz, 1H), 2.76 (dd, J=13.4, 3.0 Hz, 1H), 2.43 (s, 3H).
3.3. 4-[2-Benzyloxy-1-bromo-(1S)-ethyl]-2,2-dimethyl-5-
(SS)-(4-methylphenylsulfinylmethyl)-(4R,5R)-1,3-diox-
olane 9
To a solution of the diol 8 (1.45 g, 3.4 mmol) in a
mixture of 2,2-dimethoxypropane and acetone (1:3, 13
mL) was added CSA (32 mg, 0.14 mmol) and the
reaction mixture stirred at ambient temperature for 2 h.
The organic layer was evaporated under reduced pres-
sure to afford the crude product which was purified by
column chromatography using 20% AcOEt/petroleum
ether as the eluent to yield the acetonide 9 (1.35 g, 2.92
mmol) as colourless crystalline solid in 86% yield. Mp
147–149°C, Rf=0.64 (50% petroleum ether/AcOEt),
[h]2D5=−152.4 (c 1.0, CHCl3), LSIMS m/z: 467 [M+H]+,
1H NMR (200 MHz, CDCl3): l=7.56 (d, J=8.2 Hz,
2H), 7.37–7.27 (m, 7H), 4.65–4.53 (m, 3H), 4.12–3.96
(m, 2H), 3.80–3.70 (m, 2H), 3.35 (dd, J=13.2, 2.9 Hz,
1H), 2.84 (dd, J=13.2, 10.3 Hz, 1H), 2.41 (s, 3H), 1.40
3.2. 5-Benzyloxy-4-bromo-1-(SS)-(4-methylphenylsulfi-
nyl)-(2R,3R,4S)-pentane-2,3-diol 8
To a solution of the sulfoxide 6 (1.32 g, 4 mmol) in dry
toluene, (16 mL) water (144 mg, 8 mmol) was added,

S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
2097
(s, 6H), 13C NMR (75 MHz, CDCl3): l=21.3, 27.0,
27.4, 51.9, 63.6, 71.1, 73.3, 74.9, 79.8, 110.5, 123.9,
127.6, 127.7, 128.3, 130.0, 137.6, 141.4, 141.5.
added. The reaction mixture was stirred under H2
pressure for 2 h at room temperature. The reaction
mixture was then refluxed for 6 h upon which TLC
revealed the completion of reaction. The reaction mix-
ture was allowed to return to room temperature and
then filtered through a small pad of Celite. The Celite
pad was repeatedly washed with methanol (10×5).
Evaporation of the solvent under reduced pressure fol-
lowed by purificaion by column chromatography using
20% AcOEt/petroleum ether afforded the N-Boc
aminoalcohol 13 (62 mg, 0.14 mmol) as a pale yellow
liquid in 68% yield. Rf=0.26 (20% petroleum ether/
AcOEt), [h]2D5=−9.1 (c 0.6, CHCl3), LSIMS m/z: 458
[M+H]+, 1H NMR (200 MHz, CDCl3): l=5.04 (d,
J=6.9 Hz, 1H, NH), 3.82–3.55 (m, 5H), 1.95 (bs, 1H,
OH), 1.60–1.43 (m, 2H), 1.41–1.10 (m, 39H), 0.86 (t,
J=6.7 Hz, 3H), 13C NMR (75 MHz, CDCl3): l=14.0,
22.6, 25.6, 26.1, 26.7, 27.2, 28.2, 29.3, 29.6, 30.8, 31.8,
32.4, 33.2, 52.9, 63.0, 71.3, 80.0, 81.2, 108.7, 156.4.
3.4. 4-[1-Azido-2-benzyloxy-(1R)-ethyl]-2,2-dimethyl-5-
(SS)-(4-methylphenylsulfinylmethyl)-(4S,5R)-1,3-diox-
olane 10
To a solution of acetonide 9 (1.33 g, 2.85 mmol) in
DMSO, (12 mL) NaN3 (925 mg, 14.2 mmol) was
added. The reaction mixture was stirred at 85°C for 8 h.
Once the reaction mixture returned to room tempera-
ture, it was diluted with ether. The organic layer was
washed successively with water, brine and dried over
Na2SO4. Evaporation of the solvent under reduced
pressure followed by purification of the crude product
by column chromatography using 20% AcOEt/
petroleum ether as the eluent afforded azido acetonide
10 (915 mg, 2.14 mmol) in 75% yield. White solid. Mp
82–84°C, Rf=0.66 (50% petroleum ether/AcOEt),
[h]2D5=−49.5 (c 0.65, CHCl3), LSIMS m/z: 430 [M+H]+,
1H NMR (200 MHz, CDCl3): l=7.52 (d, J=8.2 Hz,
2H), 7.33–7.26 (m, 7H), 4.60–4.50 (m, 3H), 3.88 (dd,
J=7.4, 4.6 Hz, 1H), 3.74–3.61 (m, 2H), 3.56 (m, 1H),
2.95 (dd, J=13.4, 3.7 Hz, 1H), 2.81 (dd, J=13.4, 8.2
Hz, 1H), 2.43 (s, 3H), 1.48 (s, 3H), 1.42 (s, 3H), 13C
NMR (50MHz, CDCl3): l=21.4, 26.6, 27.2, 60.1, 62.2,
69.6, 72.0, 73.4, 80.0, 110.4, 123.8, 127.7, 127.8, 128.9,
130.0, 137.4, 141.1, 141.7.
3.7. 3,4-Di(methylcarbonyloxy)-2-methylcarboxamido-
(2R,3S,4S)-octadecylacetate 15
To the protected aminoalcohol 13 (40 mg, 0.09 mmol)
in dichloromethane (0.1 mL) a 20:1 solution of TFA/
Water (0.4 mL) was added and stirred at 0°C for 3 h.
The solvent was evaporated under reduced pressure and
then azeotroped with benzene. The aminotriol was
directly taken to the step without further purification.
Pyridine (0.9 mL), and acetic anhydride (0.1 mL) were
added to the reaction vessel. The resulting mixture was
stirred overnight at rt. The reaction mixture was then
concentrated, and the residue chromatographed on a
silica gel column using 30% EtOAc/petroleum ether
system as the eluent to give the tetraacetylderivative 15
(34 mg, 0.07 mmol) in 78% yield as a viscous liquid.
Rf=0.23 (30% petroleum ether/AcOEt), [h]2D5=−6.9 (c
0.9, CHCl3) (Lit. [h]D21=+7.0 (c 0.86, CHCl3) for the
enantiomer),13d LSIMS m/z: 485 [M+H]+, 1H
NMR(300 MHz, CDCl3): l=5.73 (d, J=9.5 Hz, 1H,
NH), 5.11 (dd, J=6.5, 4.3 Hz, 1H), 5.03 (dd, J=12.7,
6.5 Hz, 1H), 4.49 (m, 1H), 4.03 (dd, J=11.3, 6.0 Hz,
1H), 3.97 (dd, J=11.3, 5.9 Hz, 1H), 2.08 (s, 3H), 2.06
(s, 6H), 2.01 (s, 3H), 1.67–1.51 (m, 2H), 1.39–1.15 (m,
24H), 0.88 (t, J=6.7 Hz, 3H), 13C NMR (75 MHz,
CDCl3): l=14.1, 20.6, 20.7, 20.9, 22.7, 23.2, 24.8, 29.2,
29.3, 29.5, 29.6, 30.5, 31.9, 48.0, 62.9, 71.9, 72.2, 169.9.
3.5. 2-Azido-2-[2,2-dimethyl-5-[1-(4-methylphenylsul-
fanyl)-(E)-3-tetradecenyl]-(4S,5R)-1,3-dioxolan-4-
yl]ethylbenzylether 12
Trifluoroacetic anhydride (1.3 g, 6.15 mmol) was added
dropwise over 5 min to a mixture of the acetonide 10
(880 mg, 2.05 mmol) and 1-tridecene (560 mg, 3.08
mmol) in dichloromethane (16 mL) cooled at 0°C and
stirred for 1 h at the same temperature. SnCl4 (550 mg,
2.05 mmol) was then added and after 10 min at 0°C,
the reaction mixture was quenched by the slow addition
of aq. saturated Na2CO3 solution. Extraction into
diethylether followed by purification by column chro-
matography using 2% AcOEt/petroleum ether afforded
12 (790 mg, 1.33 mmol) in 65% yield as a pale yellow
liquid. Rf=0.51 (10% petroleum ether/AcOEt), [h]2D5=
13.1 (c 0.2, CHCl3), LSIMS m/z: 594 [M+H]+, 1H
NMR (200 MHz, CDCl3): l=7.31–7.16 (m, 7H), 6.95
(d, J=8.2 Hz, 2H), 5.50–5.20 (m, 2H), 4.50 (s, 2H),
4.25–4.10 (m, 2H), 3.7–3.45 (m, 3H), 2.90 (td, J=7.4,
2.2 Hz, 1H), 2.56–2.24 (m, 2H), 2.22 (s, 3H), 1.96–1.82
(m, 2H), 1.36 (s, 3H), 1.32 (s, 3H), 1.24–1.11 (m, 16H),
0.78 (t, J=6.7 Hz, 3H), 13C NMR (75 MHz, CDCl3):
l=14.1, 21.0 22.6, 26.7, 27.1, 29.1, 29.3, 29.5, 29.6,
31.9, 32.5, 35.6, 60.8, 70.4, 73.5, 76.7, 77.0, 77.3, 109.7,
126.4, 127.7, 127.8, 128.3, 128.4, 129, 129.7, 132.2,
132.4, 133.0, 137.0.
3.8. 1-[5-[1-Azido-2-benzyloxy-(1R)-ethyl]-2,2-dimethyl-
5-[1-(4-methylphenylsulfonyl)-(E)-3-tetradecenyl]-
(4S,5R)-1,3-dioxolane 16
To a solution of sulfide 12 (296 mg, 0.5 mmol) in a
mixture of MeOH:water:tetrahydrofuran (1:1:2, 0.5
mL) Oxone® (153 mg, 1.0 mmol) was added at 0°C for
30 min after which the mixture was allowed to return to
room temperature. After complete conversion to the
sulfone, which was revealed by TLC examination (ca. 4
h), the solvent was evaporated under reduced pressure
and the residue extracted into ethylacetate. Column
3.6. 2-(N-tert-Butoxycarbonyl)amino-2-(2,2-dimethyl-5-
tetradecyl-(4S,5R)-1,3-dioxalan-4-yl)-1-ethanol 13
To a mixture of 12 (118 mg, 0.2 mmol), (Boc)2O (87
mg, 1 mmol) in methanol (2 mL) Ra-Ni (1 g) was

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S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
chromatography using 15% AcOEt/petroleum ether
afforded sulfone 16 (250 mg, 0.4 mmol) in 82% yield.
Viscous liquid. Rf=0.52 (20% petroleum ether/AcOEt),
[h]2D5=−12.7 (c 1.6, CHCl3), LSIMS m/z: 626 [M+H]+,
1H NMR (200 MHz, CDCl3): l=7.74 (d, J=8.2 Hz,
2H), 7.39–7.22 (m, 7H), 5.35 (dt, J=13.4, 6.7 Hz, 1H),
5.16 (dt, J=13.4, 6.7 Hz, 1H), 4.58 (s, 2H), 4.50 (dd,
J=8.2, 3.7 Hz, 1H), 4.28 (dd, J=8.2, 2.2 Hz, 1H),
3.85–3.68 (m, 3H), 3.28 (m, 1H), 2.60–2.40 (m, 5H),
1.96–1.76 (m, 2H), 1.55–1.15 (m, 22H), 0.88 (t, J=6.7
Hz, 3H), 13C NMR (75 MHz, CDCl3): l=14.1, 21.6,
22.6, 26.5, 26.9, 28.8, 29.1, 29.2, 29.3, 29.5, 29.6, 31.9,
32.3, 59.6, 65.4, 70.5, 73.3, 74.4, 77.2, 109.5, 124.8,
127.7, 127.8, 128.4, 128.9, 129.5, 134.7, 136.4, 137.7,
144.7, 144.8.
1H), 2.08–1.88 (m, 2H), 1.44–1.12 (m, 31H), 0.85 (t,
J=6.5 Hz, 3H), 13C NMR (75 MHz, CDCl3): 14.1,
22.7, 28.3, 29.1, 29.2, 29.3, 29.5, 29.7, 31.9, 32.3, 55.6,
64.5, 73.6, 79.8, 129.0, 134.2, 156.4.
Acknowledgements
S.R. wishes to thank Dr. A. C. Kunwar for the NMR
spectra. A.R. wishes to thank CSIR (New Delhi) for
the senior research fellowship. Financial assistance
from DST is also gratefully acknowledged.
References
3.9. 2-(N-tert-Butoxycarbonyl)amino-2-{2,2-dimethyl-5-
[1-(4-methylphenylsulfonyl)tetracetyl]-(4S,5S)-1,3-diox-
alan-4-yl}-1-ethanol 17
1. (a) Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500; (b)
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2. (a) Scneiter, R. Bioassays 1999, 21, 1004; (b) Kobayashi,
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3. Zellner, J. Monatsch. Chem. 1911, 32, 133.
To a mixture of sulfone 16 (188 mg, 0.3 mmol) and
(Boc)2O (130 mg, 0.60 mmol) in abs. ethanol (0.6 mL),
Pd(OH)2/C (200 mg, 0.03 mmol, 10 mol%) was added.
After evacuating, the reaction mixture was then stirred
under H2 atmosphere for 16 h. The reaction mixture
was then filtered through a small pad of Celite and
repeatedly washed with ethanol. Evaporation of the
solvent afforded the crude product which was purified
by column chromatography using 30% AcOEt/
petroleum ether as the eluent to give 17 (134 mg, 0.22
mmol) in 71%. Low melting oily solid. Rf=0.16 (20%
petroleum ether/AcOEt), [h]2D5=−3.4 (c 2.4, CHCl3),
LSIMS m/z: 612 [M+H]+, 1H NMR (200 MHz,
CDCl3): l=7.78 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz,
2H), 5.09 (d, J=8.9 Hz, NH, 1H), 4.7 (d, J=8.3 Hz,
1H), 4.04 (dd, J=8.3, 3.8 Hz, 1H), 3.93 (dd, J=9.7, 4.5
Hz, 1H), 3.83 (m, 1H), 3.69 (dd, J=11.1, 4.5 Hz, 1H),
3.29 (m, 1H), 2.45 (s, 3H), 1.76–1.63 (m, 2H), 1.44–1.16
(m, 37H), 0.88 (t, J=6.7 Hz, 3H), 13C NMR (50 MHz,
CDCl3): l=14.2, 21.7, 22.7, 26.8, 28.4, 29.2, 29.4, 29.7,
32.0, 50.1, 65.0, 75.2, 78.7, 79.9, 109.1, 129.1, 129.5,
136.9, 144.4, 155.9.
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3.10. 2-(N-tert-Butoxycarbonyl)amino-(2R,3R,4E)-4-
octadecene-1,3-diol 18
6% Na-Hg (250 mg) was added to a solution of 17 (100
mg, 0.16 mmol) and Na2HPO4 (29 mg, 0.32 mmol) in
methanol (3.2 mL) at −20°C for 30 min after which the
reaction mixture was allowed to return to room temper-
ature. After stirring for another 2 h, the reaction mix-
ture was diluted with water (3.2 mL) and evaporated
under reduced pressure. The residue was extracted with
ethylacetate to afford the crude product mixture. Purifi-
cation by column chromatography using 25% AcOEt/
petroleum ether afforded the sphingosine 18 (41 mg,
0.104 mmol) in 65% yield. Low melting solid. [h]2D5=
+0.4 (c 0.9, CHCl3) (Lit. [h]2D5=−0.4 (c 1.0, CHCl3) for
1
the enantiomer),22 LSIMS m/z: 400 [M+H]+, H NMR
(200 MHz, CDCl3): l=5.71 (dt, J=15.6, 6.7 Hz, 1H),
5.46 (dd, J=15.6, 6.7 Hz, 1H), 5.1 (bs, 1H, NH), 4.29
(dd, J=5.9, 3.7 Hz, 1H), 3.80–3.71 (m, 2H), 3.58 (m,

S. Ragha6an et al. / Tetrahedron: Asymmetry 14 (2003) 2093–2099
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