A practical and cost-effective synthesis of d-erythro-sphingosine from d-ribo-phytosphingosine via a cyclic sulfate intermediate

Article abstract of DOI:10.1055/s-0030-1258437

The practical and efficient synthesis of d-erythro-sphingosine 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 that contains a non-nucleophilic trifluoroacetamide protecting group. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258437

PAPER
867
A Practical and Cost-Effective Synthesis of D-erythro-Sphingosine from
D-ribo-Phytosphingosine via a Cyclic Sulfate Intermediate
Yun Mi Lee, Seokwoo Lee, Hongjun Jeon, Dong Jae Baek, Jae Hong Seo, Deukjoon Kim, Sanghee Kim*
College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea
Fax +82(2)8880649; E-mail: pennkim@snu.ac.kr
Received 4 January 2011; revised 19 January 2011
relatively inexpensive phytosphingosine 2 has been also
employed as a starting material for the facile synthesis of
sphingosine 1.6,7 The key requirement of this synthetic ap-
proach is the selective transformation of the C-4 hydroxy
Abstract: The practical and efficient synthesis of D-erythro-sphin-
gosine 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 group of phytosphingosine into the characteristic 4,5-
intermediate that contains a non-nucleophilic trifluoroacetamide
protecting group.
trans double bond of sphingosine.
We have previously reported a convenient synthetic route
Key words: cyclic sulfates, protecting groups, reactive intermedi-
to sphingosine 1 from phytosphingosine 2.7 The key step
ates, sphingolipids, synthetic methods
in the reaction sequence, as depicted in Scheme 1, com-
prises the selective elimination reaction of cyclic sulfate 3
for the transformation of the 3,4-vicinal diol of phyto-
Sphingolipids are a structurally diverse class of lipids that
sphingosine into the E-allylic alcohol of sphingosine. The
contain long-chain aliphatic amino alcohols. They are im-
advantage of the use of a cyclic sulfate is that it eliminates
portant structural components of the plasma membranes
the need for selective activation of only one vicinal hy-
of essentially all eukaryotic cells and play critical roles in
droxy group. The non-nucleophilic azide was chosen as
many biological processes.1 Growing interest in the bio-
the amino protecting group because a nucleophilic pro-
logical functions of sphingolipids has generated a desire
tecting group might react with the cyclic sulfate in an
to develop efficient methods for their synthesis. One of
intramolecular manner. Regrettably, the possibility of
the important factors for the successful synthesis of natu-
scaling up the process is limited due to the explosive po-
ral and non-natural sphingolipids is the acquisition of the
tential of organic azide8 and the cost-ineffective transfor-
appropriate sphingoid bases, which are the principal back-
bone of sphingolipids.
mation of the amino group of phytosphingosine into an
azide. Thus, we sought to identify an alternative amino
Among the naturally occurring sphingoid bases, D-erythro- protecting group that is compatible with the reactive cy-
sphingosine (1; Figure 1) and D-ribo-phytosphingosine clic sulfate functional group. Herein, we wish to report
(2) are the most important and common species.2 While D- our studies on this subject and to describe a cost-effective,
ribo-phytosphingosine is readily obtainable on an indus- efficient synthetic route to sphingosine 1.
trial scale from a yeast fermentation process,3,4 D-erythro-
sphingosine is rather expensive and available only from
laborious animal tissue extraction or chemical synthesis.
NH2 OH
NH2
HO
C13H27
HO
C13H27
OH
OH
sphingosine 1
NH2
NH2 OH
phytosphingosine 2
HO
C13H27
HO
C13H27
N3
OH
D-erythro-sphingosine (1)
OH
RO
C13H27
D-ribo-phytosphingosine (2)
O
O
O
S
Figure 1 Chemical structures of compounds 1 and 2
O
3
A great deal of effort has been devoted to the synthesis of
D-erythro-sphingosine.5,6 To install the absolute stereo-
chemistry of sphingosine 1, many synthetic approaches
have involved asymmetric induction such as Sharpless
asymmetric epoxidation and asymmetric aldol reaction. A
second popular approach involves the use of chiral start-
ing materials, such as carbohydrates and amino acids. The
Scheme 1 Synthesis of sphingosine 1 via azido-phytosphingosine 3
A great many protecting groups have been used to protect
amino groups, including carbamates, sulfonamides, and
amides.9 Amino protecting groups for our synthetic needs
should be non-nucleophilic and stable during both cyclic
sulfate formation and under the cyclic sulfate-mediated
elimination conditions. In addition, these protecting
groups should be readily cleaved under mild conditions
SYNTHESIS 2011, No. 6, pp 0867–0872
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x
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Advanced online publication: 10.02.2011
DOI: 10.1055/s-0030-1258437; Art ID: F09111SS
© Georg Thieme Verlag Stuttgart · New York

868
Y. M. Lee et al.
PAPER
because sphingosine is not very stable due to the presence ble enough at room temperature to allow proper use for
of the reactive allylic alcohol functional group.
several days.
Sulfonamide is one of the most stable nitrogen protecting
groups, and the oxygen atoms of sulfonamide are poor in-
tramolecular nucleophiles.10 However, cleavage of sul-
fonamide generally requires harsh conditions. Although
some sulfonamide protecting groups, such as 2- or 4-ni-
tro- and 2,4-dinitrobenzenesulfonamides can be removed
under relatively mild conditions,11 they are somewhat ex-
pensive. Thus, sulfonamides were not considered to be the
protecting group of choice. Carbamates and amides have
been used widely as protecting groups for amines, howev-
er, due to the high nucleophilicity of the oxygen atoms,
the electron-rich carbamates and amides would not be
suitable nitrogen protecting groups for our synthetic
needs. These protecting groups have been utilized in the
intramolecular inversion of activated hydroxy groups.12
The cyclic sulfates derived from N-Boc or N-acetyl pro-
tected ribo-phytosphingosine (Scheme 2), in our hands,
were rather unstable and decomposed into the polar sul-
fate esters upon standing in solution at room temperature,
as a result of nucleophilic substitution of the cyclic sulfate
functional group by the oxygen atom of the protecting
group.13
O
NH2 OH
HO
F3C
HO
NH OH
CF3CO2Et
C13H27
C13H27
EtOH, r.t.
12 h, 92%
OH
2
OH
4
TBDPSCl, Et3N
DMAP, CH2Cl2–DMF
r.t., 1 d
TrCl, DMAP
CH2Cl2–pyridine
r.t., 1 d
or
O
1. SOCl2, Et3N
CH2Cl2, 0 °C, 0.5 h
F3C
NH OH
OH
RO
C13H27
2. RuCl3•3H2O, NaIO4
CCl4–MeCN–H2O
r.t., 2 h
5a R = TBDPS (88%)
5b R = Tr (85%)
O
F3C
RO
NH
C13H27
O
O
S
O
O
6a R = TBDPS (96% from 5a)
6b R = Tr (94% from 5b)
Scheme 3 Synthesis of cyclic sulfate 6
R
R
+
HN
O
NH
O
r.t.
With multigram quantities of cyclic sulfate 6 available,
we attempted to apply our previous reaction process7 for
the transformation of a cyclic sulfate into an allylic alco-
hol, which involves the regioselective ring opening of the
cyclic sulfate by iodide and a subsequent dehydrohaloge-
nation reaction. Thus, we first examined the regioselectiv-
ity of the nucleophilic ring opening of cyclic sulfate by
iodide (Scheme 4).
PO
PO
C13H27
C13H27
–O
O
O
O
O
O
P = TBDPS
R = t-BuO, Me
S
S
O
O
R = Me
R = t-BuO
O
O
NH
O
N
O
PO
PO
C13H27
C13H27
F3C
NH
–
–
TBDPSO
OSO3
OSO3
3
4
2
C13H27
O
O
O
Scheme 2 Thermolysis of the cyclic sulfate
S
O
6a
It occurred to us that protection of the 2-amino function-
ality of ribo-phytosphingosine (2) with electron-deficient
amides would present an attractive alternative to our ini-
tial azide approach. Among electron-deficient amide pro-
tecting groups, trifluoroacetamide was chosen due to its
low cost, efficient introduction, and convenient removal
under mild conditions. Thus, known trifluoroacetamide
derivative 414 was prepared in high yield (92%) by treat-
ment of 2 with CF3CO2Et in ethanol at room temperature
(Scheme 3). The primary alcohol of 4 was protected selec-
tively either as its silyl or trityl ether to produce 5a (88%)
or 5b (85%), respectively. Conversion of 3,4-vicinal diol
5 into its cyclic sulfite with thionyl chloride in the pres-
ence of triethylamine followed by oxidation with RuCl3/
NaIO4, provided cyclic sulfate 6 in high yield (96% for 6a
and 94% for 6b). Both cyclic sulfates 6a and 6b were sta-
i) Bu4NI, THF
ii) H2SO4–H2O–THF, r.t., 1 h
O
O
F3C
NH
I
F3C
NH OH
TBDPSO
C13H27
+
TBDPSO
C13H27
OH
I
7
8
40 °C, 2 h
30 °C, 24 h
7/8 = 13:1
7/8 = 20:1
75%
76%
Scheme 4 Nucleophilic ring opening of cyclic sulfate 6a
We found that the treatment of cyclic sulfate 6a with tet-
rabutylammonium iodide (Bu4NI) in tetrahydrofuran at
40 °C for two hours, followed by acidic hydrolysis of the
Synthesis 2011, No. 6, 867–872 © Thieme Stuttgart · New York

PAPER
D-erythro-Sphingosine from D-ribo-Phytosphingosine
869
intermediate O-sulfate, afforded a 13:1 mixture of iodo al- group was easily removed under alkaline conditions to af-
cohols 7 and 8 in 75% combined yield. The regioselectiv- ford the desired D-erythro-sphingosine 1 in 96% yield.
ity could be improved to 20:1 when the reactions were The analytical and spectroscopic data of both the synthetic
carried out at lower temperature (30 °C) for one day 1 and its triacetate derivative 1116 were in good agreement
(76%). When the solvent was changed from tetrahydrofu- with literature data.5,6b,17
ran to toluene, similar regioselectivities and yields were
observed. The regioselectivity attained was high enough,
but slightly lower than, that for the azide-protected cyclic
sulfate 3 (Scheme 1).
The above sequence could be also successfully applied to
the cyclic sulfate 6b (Scheme 5), which contains the less
expensive trityl group as the protecting group of the pri-
mary hydroxy group. The cyclic sulfate 6b was submitted
After studying the ring opening of cyclic sulfate 6a by io- to the aforementioned one-pot ring opening/dehydrohalo-
dide, we examined the direct one-pot ring opening/dehy- genation conditions. Exposure of the resulting reaction
drohalogenation sequence (Scheme 5). The treatment of mixture to hydrochloric acid in tetrahydrofuran resulted in
cyclic sulfate 6a with Bu4NI in toluene at 40 °C led to the simultaneous hydrolysis of the sulfate ester intermediate
disappearance of the starting material and to the formation and removal of the trityl protecting group to give the 2-
of polar material in two hours. Then, 1,8-diazabicyc- acyl-protected sphingosine 10 with a 69% overall yield. It
lo[5.4.0]undec-7-ene (DBU) was added and the reaction is worth noting that it was possible to prepare compound
temperature was raised to reflux, where it was held for one 10 from phytosphingosine 2 through this sequence with a
hour. This treatment, followed by acidic hydrolysis of the similar overall yield without the need for column chro-
resulting sulfate ester intermediate with aqueous sulfuric matographic purification of the intermediates.
acid, successfully furnished the desired E-allylic alcohol
9 in high yield (74%). When the reaction was carried out
in tetrahydrofuran, the yield was slightly decreased
(70%).
In summary, we have developed an efficient and practical
route for the synthesis of D-erythro-sphingosine (1) from
the low cost phytosphingosine 2 with a high overall yield
(ca. 55%). The 3,4-vicinal diol of phytosphingosine was
transformed into the characteristic E-allylic alcohol of
sphingosine via a cyclic sulfate. An important feature of
this synthesis is the use of the non-nucleophilic trifluoro-
O
O
F3C
RO
NH
acetamide protecting group for the 2-amino functionality
in phytosphingosine to avoid complications caused by the
participation of the neighboring group in the cyclic sul-
fate-mediated elimination reactions. The process is highly
selective and seems to be readily amenable to large-scale
synthesis.
F3C
NH
I
i) Bu4NI
C13H27
TBDPSO
C13H27
toluene
40 °C
O
O
O
S
–
OSO3
O
6a R = TBDPS
6b R = Tr
74%
from 6a
ii) DBU, reflux
iii) H2SO4–H2O–THF
O
i) Bu4NI, toluene, 40 °C
ii) DBU, reflux
iii) 5 M HCl, THF
69%
from 6b
All chemicals were reagent grade and used as purchased. All reac-
tions were performed in an inert atmosphere of anhydrous argon or
nitrogen using distilled anhydrous solvents. Reactions were moni-
tored by TLC analysis using silica gel 60 F-254 TLC plates. Melting
points are uncorrected. Flash column chromatography was carried
out with silica gel (230–400 mesh). Optical rotations were mea-
sured using sodium light (D line at 589.3 nm). 1H NMR (400 or 300
MHz) and 13C NMR (100 or 75 MHz) spectra were recorded in d
units relative to the non-deuterated solvent as an internal reference.
IR spectra were measured with a Fourier transform infrared spec-
trometer. High-resolution mass spectra (HRMS) were recorded us-
ing fast atom bombardment (FAB).
F3C
NH
TBDPSO
C13H27
OH
O
9
F3C
HO
NH
Bu4NF, THF
r.t., 1 h
99%
C13H27
OH
10
2 M NaOH
96%
NH2
EtOH, r.t., 2 h
C13H27
NHAc
Ac2O
2,2,2-Trifluoro-N-[(2S,3S,4R)-1,3,4-trihydroxyoctadecan-2-
yl]acetamide (4)
pyridine
AcO
C13H27
HO
r.t., 5 h
90%
To a solution of phytosphingosine 2 (4.00 g, 12.6 mmol) in EtOH
(25 mL), was slowly added ethyl trifluoroacetate (2.30 mL, 19.3
mmol). After stirring for 12 h at r.t., the reaction mixture was poured
into brine (80 mL) and extracted with EtOAc (2 × 80 mL). The
combined organic layers were dried over MgSO4 and concentrated.
The crude product was purified by column chromatography on sili-
ca gel (hexane–EtOAc, 1:1) to give trifluoroacetamide 4.
Yield: 4.79 g (92%); white solid; mp 98–102 °C; [a]D25 –1.7 (c 0.9,
EtOH).
IR (neat): 3303, 2918, 2850, 1700 cm–1.
OAc
11
OH
1
Scheme 5 Synthesis of D-erythro-sphingosine (1)
With a facile route to the large-scale preparation of 1,2-
protected D-erythro-sphingosine 9 established, efforts
were then directed toward the deprotection steps. Remov-
al of the silyl protecting group in 9 with Bu4NF in tetrahy-
drofuran furnished the known 2-acyl-protected
sphingosine 1015 in high yield. Finally, the trifluoroacetyl 1H NMR (300 MHz, CD3OD): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.27 (s,
24 H), 1.48–1.70 (m, 2 H), 3.45–3.54 (m, 1 H), 3.59 (t, J = 5.7 Hz,
Synthesis 2011, No. 6, 867–872 © Thieme Stuttgart · New York

870
Y. M. Lee et al.
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1 H), 3.72 (dd, J = 7.2, 11.7 Hz, 1 H), 3.86 (dd, J = 4.2, 11.7 Hz,
1 H), 4.16–4.24 (m, 1 H).
RuCl3·3H2O (26.0 mg, 0.13 mmol) and NaIO4 (1.60 g, 7.48 mmol),
and the reaction mixture was stirred at r.t. for 2 h, diluted with
EtOAc (100 mL) and washed with saturated NaHSO3 (2 × 80 mL).
The organic layer was dried over Na2SO4, concentrated, and puri-
fied by column chromatography on silica gel (hexane–EtOAc, 10:1)
to give cyclic sulfate 6.
13C NMR (75 MHz, CD3OD): d = 15.3, 24.5, 27.6, 31.3, 31.52,
1
31.56, 31.6, 33.9, 34.2, 55.6, 62.0, 73.9, 76.2, 120.2 (q, JC–F
=
285.2 Hz, CF3), 159.8 (q, 2JC–F = 36.8 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C20H39F3NO4: 414.2831;
found: 414.2828.
(2S,3S,4S)-1-(tert-Butyldiphenylsilyloxy)-2-[N-(trifluoro-
acetyl)amino]octadecan-3,4-cyclic Sulfate (6a)
Yield: 1.71 g (96% from 5a); colorless oil; [a]D +4.0 (c 0.6,
CHCl3).
25
N-[(2S,3S,4R)-1-(tert-Butyldiphenylsilyloxy)-3,4-dihydroxy-
octadecan-2-yl]-2,2,2-trifluoroacetamide (5a)
To a solution of 4 (2.00 g, 4.84 mmol) in CH2Cl2 (20 mL) and DMF
(7 mL), were added Et3N (1.00 mL, 7.17 mmol), DMAP (58 mg,
0.47 mmol), and TBDPSCl (1.80 mL, 7.03 mmol) at 0 °C. The re-
action mixture was stirred at r.t. for 24 h, and then diluted with
EtOAc (100 mL). The organic layer was washed with brine (2 × 80
mL), dried over MgSO4, and concentrated. Purification of the crude
product by silica gel column chromatography (hexane–EtOAc, 6:1)
afforded diol 5a.
IR (neat): 3420, 2926, 2855, 1789, 1216 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.4 Hz, 3 H), 1.07 (s,
9 H), 1.15–1.44 (m, 22 H), 1.45–1.60 (m, 1 H), 1.61–1.74 (m, 2 H),
1.78–1.92 (m, 1 H), 3.73 (dd, J = 2.8, 10.9 Hz, 1 H), 4.00 (dd,
J = 3.2, 10.9 Hz, 1 H), 4.35–4.43 (m, 1 H), 4.92–4.99 (m, 1 H), 5.10
(dd, J = 5.1, 8.9 Hz, 1 H), 6.76 (d, J = 9.1 Hz, 1 H), 7.31–7.50 (m,
6 H), 7.56–7.67 (m, 4 H).
Yield: 2.78 g (88%); colorless oil; [a]D25 +30.3 (c 0.7, CHCl3).
IR (neat): 3423, 2926, 2855, 1714 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.06 (s,
9 H), 1.25 (s, 23 H), 1.38–1.55 (m, 2 H), 1.68–1.78 (m, 1 H), 2.10
(br s, 1 H), 3.11 (br s, 1 H), 3.58–3.68 (m, 2 H), 3.83 (dd, J = 4.2,
10.9 Hz, 1 H), 4.04 (dd, J = 3.1, 11.0 Hz, 1 H), 4.18–4.26 (m, 1 H),
7.08 (d, J = 8.4 Hz, 1 H), 7.35–7.48 (m, 6 H), 7.51–7.66 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 19.2, 22.7, 25.1, 26.5, 26.7,
27.7, 28.7, 29.1, 29.3, 29.4, 29.5, 29.60, 29.63, 29.7, 31.9, 49.2,
1
62.1, 80.9, 86.0, 117.4 (q, JC–F = 286.3 Hz), 127.7, 128.1, 129.6,
2
130.3, 131.5, 131.9, 134.8, 135.3, 135.4, 135.5, 157.2 (q, JC–F
=
37.8 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C36H55F3NO4SSi: 714.3471;
found: 714.3470.
13C NMR (100 MHz, CDCl3): d = 14.1, 19.0, 22.6, 25.6, 26.7, 29.3,
(2S,3S,4S)-1-(Trityloxy)-2-[N-(trifluoroacetyl)amino]octa-
29.5, 29.56, 29.6, 29.64, 29.7, 31.9, 33.3, 51.3, 63.1, 73.0, 75.2,
decan-3,4-cyclic Sulfate (6b)
Yield: 1.69 g (94% from 5b); colorless oil; [a]D –15.1 (c 0.9,
CHCl3).
1
25
117.2 (q, JC–F = 286.3 Hz), 128.0, 130.27, 130.3, 131.77, 131.8,
135.39, 135.5, 156.9 (q, 2JC–F = 37.0 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C36H57F3NO4Si: 652.4009;
found: 652.4003.
IR (neat): 3476, 2918, 2849, 1445, 1158 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 6.0 Hz, 3 H), 1.16–
1.44 (m, 23 H), 1.46–1.74 (m, 2 H), 1.78–1.94 (m, 1 H), 3.28 (dd,
J = 2.7, 10.2 Hz, 1 H), 3.64 (dd, J = 3.9, 10.2 Hz, 1 H), 4.34–4.46
(m, 1 H), 4.92–5.00 (m, 1 H), 5.16 (dd, J = 5.4, 8.7 Hz, 1 H), 6.52
(d, J = 9.0 Hz, 1 H), 7.22–7.40 (m, 15 H).
N-[(2S,3S,4R)-3,4-Dihydroxy-1-(trityloxy)octadecan-2-yl]-
2,2,2-trifluoroacetamide (5b)
To a solution of 4 (1.70 g, 4.11 mmol) in pyridine (8 mL) and
CH2Cl2 (15 mL), were added DMAP (50 mg, 0.41 mmol) and tri-
phenyl methyl chloride (1.40 g, 5.02 mmol). This reaction mixture
was stirred for 24 h at r.t., then quenched with 0.5 M HCl (10 mL)
and extracted with EtOAc (2 × 80 mL). The combined organic lay-
ers were washed with brine (2 × 80 mL), dried over MgSO4, and
concentrated. Purification of the crude product by silica gel column
chromatography (hexane–EtOAc, 4:1) afforded diol 5b.
13C NMR (75 MHz, CDCl3): d = 14.1, 22.6, 25.2, 27.7, 28.7, 29.1,
29.3, 29.4, 29.5, 29.61, 29.64, 31.9, 48.4, 61.4, 81.6, 85.9, 87.6,
1
117.3 (q, JC–F = 286.3 Hz), 127.2, 127.6, 127.9, 128.2, 128.3,
142.7, 146.8, 157.2 (q, 2JC–F = 37.8 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C39H51F3NO6S: 718.3389;
found: 718.3387.
Yield: 2.30 g (85%); colorless oil; [a]D25 +39.7 (c 0.7, CHCl3).
IR (neat): 3420, 2924, 2853, 1712 cm–1.
Synthesis of Iodo Alcohols 7 and 8
To a solution of cyclic sulfate 6a (200 mg, 0.26 mmol) in THF (3
mL) was added Bu4NI (140 mg, 0.38 mmol). The reaction mixture
was heated for 2 h at 40 °C, then cooled to r.t. and concentrated
H2SO4 (5 mL), H2O (6 mL), and THF (80 mL) were added. The mix-
ture was stirred for 1 h at r.t. and then diluted with EtOAc (20 mL),
washed with sat. aq NaHCO3 (2 × 20 mL) and brine (2 × 20 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo
to provide a mixture of iodo alcohols 7 and 8 in a ratio of 13:1 ac-
cording to 1H NMR analysis in CDCl3. Purification of the crude ma-
terial by column chromatography on silica gel (hexane–EtOAc,
15:1) gave iodo alcohols 7 and 8.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 6.9 Hz, 3 H), 1.22–
1.54 (m, 26 H), 1.62–1.74 (m 1 H), 2.44 (br s, 1 H), 3.26 (br s, 1 H),
3.34–3.42 (m, 1 H), 3.46–3.56 (m, 2 H), 3.63 (br s, 1 H), 4.32–4.40
(m, 1 H), 7.26–7.37 (m, 10 H), 7.40–7.47 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 25.5, 29.3, 29.4, 29.5,
29.6, 29.64, 31.9, 33.0, 50.7, 62.1, 72.5, 74.9, 87.8, 117.7 (q, 1JC–F
286.3 Hz), 127.4, 127.8, 128.1, 128.3, 142.8, 157.0 (q, JC–F
=
=
2
37.0 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C39H53F3NO4: 656.3927;
found: 656.3921.
N-[(2S,3S,4S)-1-(tert-Butyldiphenylsilyloxy)-3-hydroxy-4-iodo-
octadecan-2-yl]-2,2,2-trifluoroacetamide (7)
Synthesis of Cyclic Sulfates 6a and 6b; General Procedure
To a solution of diol 5 (2.50 mmol) in CH2Cl2 (20 mL) were added
Et3N (1.20 mL, 8.61 mmol) and thionyl chloride (0.24 mL, 2.77
mmol) at 0 °C. After 30 min, this reaction mixture was poured into
brine (50 mL) and extracted with EtOAc (2 × 80 mL). The organic
layer was dried over MgSO4 and concentrated. This crude cyclic
sulfite was dried in vacuo for 3 h, then dissolved in CCl4–MeCN–
H2O (1:1:1, 21 mL). To the resulting solution were added
Yield: 138 mg (69%); colorless oil; [a]D25 +2.1 (c 0.7, CHCl3).
IR (neat): 3419, 2926, 2855, 1709, 1169 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.4 Hz, 3 H), 1.06 (s,
9 H), 1.16–1.40 (m, 23 H), 1.45–1.56 (m, 1 H), 1.62–1.73 (m, 1 H),
1.87–1.98 (m, 1 H), 2.35 (d, J = 8.0 Hz, 1 H), 3.24–3.31 (m, 1 H),
Synthesis 2011, No. 6, 867–872 © Thieme Stuttgart · New York

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D-erythro-Sphingosine from D-ribo-Phytosphingosine
871
3.74 (dd, J = 3.8, 10.7 Hz, 1 H), 4.03 (dd, J = 3.9, 10.7 Hz, 1 H),
4.12–4.19 (m, 1 H), 4.22 (dt, J = 4.6, 9.3 Hz, 1 H), 6.8 (d,
J = 8.9 Hz, 1 H), 7.34–7.48 (m, 6 H), 7.58–7.67 (m, 4 H).
with brine (2 × 100 mL), dried over Na2SO4, and concentrated. Pu-
rification of the crude product by silica gel column chromatography
(hexane–EtOAc, 3:1) afforded 10 (681 mg, 99%) as a white solid.
13C NMR (100 MHz, CDCl3): d = 14.1, 19.2, 22.7, 26.5, 26.8, 28.7,
29.3, 29.4, 29.5, 29.6, 29.64, 29.67, 29.68, 29.7, 31.9, 37.3, 44.6,
54.2, 61.6, 73.8, 117.2 (q, 1JC–F = 286.5 Hz), 127.7, 127.98, 128.0,
129.6, 130.17, 130.2, 132.2, 134.8, 135.2, 135.4, 135.5, 157.0 (q,
2JC–F = 37.1 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C36H56F3INO3Si: 762.3026;
found: 762.3022.
From 6b: To a solution of crude cyclic sulfate 6b (3.00 g, 4.18
mmol) in toluene (60 mL) was added Bu4NI (1.71 g, 4.62 mmol).
The reaction mixture was heated for 3 h at 40 °C. After the reaction
was complete, DBU (0.90 mL, 6.00 mmol) was added and the reac-
tion mixture was heated to reflux for 2 h. The reaction mixture was
then cooled to r.t. and 5.0 M HCl (40 mL) and toluene (30 mL) were
added. The resulting mixture was stirred for 2 h at r.t. and then di-
luted with EtOAc (100 mL) and washed with sat. aq NaHCO3
(2 × 100 mL) and brine (2 × 100 mL). The organic layer was dried
over Na2SO4 and concentrated. Purification of the crude product by
silica gel column chromatography (hexane–EtOAc, 3:1) afforded
10 (1.14 g, 69% from 6b) as a white solid.
N-[(2S,3R,4R)-1-(tert-Butyldiphenylsilyloxy)-4-hydroxy-
3-iodooctadecan-2-yl]-2,2,2-trifluoroacetamide (8)
Yield: 11 mg (6%); colorless oil.
IR (neat): 3421, 2926, 2855, 1726, 1169 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.3 Hz, 3 H), 1.08 (s,
9 H), 1.20–1.41 (m, 22 H), 1.74–1.90 (m, 1 H), 1.90–2.24 (m, 1 H),
3.18 (d, J = 8.4 Hz, 1 H), 3.87 (dd, J = 2.4, 11.1 Hz, 1 H), 3.90–4.0
(m, 1 H), 4.01–4.09 (m, 1 H), 4.12 (dd, J = 2.1, 11.1 Hz, 1 H), 4.42–
4.50 (m, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.36–7.50 (m, 6 H), 7.54–
7.66 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 14.1, 19.2, 22.7, 26.8, 26.9, 28.7,
29.36, 29.4, 29.5, 29.6, 29.62, 29.68, 31.9, 34.5, 38.5, 52.1, 63.1,
76.3, 117.2, 128.0, 128.1, 128.2, 130.2, 130.4, 131.5, 131.7, 135.3,
135.4, 156.8.
Mp 89–91 °C; [a]D25 –28.7 (c 0.8, CHCl3).
IR (CHCl3): 3280, 2916, 2850, 1699, 1181 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.5 Hz, 3 H), 1.24 (s,
20 H), 1.30–1.41 (m, 2 H), 2.04 (dd, J = 6.8, 13.9 Hz, 2 H), 3.71
(dd, J = 3.4, 11.6 Hz, 1 H), 3.87–3.94 (m, 1 H), 4.07 (dd, J = 2.7,
8.7 Hz, 1 H), 4.35 (t, J = 5.2 Hz, 1 H), 5.50 (dd, J = 6.5, 15.4 Hz,
1 H), 5.80 (app. dt, J = 6.7, 14.7 Hz, 1 H), 7.16 (d, J = 7.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 22.7, 29.0, 29.2, 29.3, 29.4,
29.6, 29.7, 31.9, 32.2, 54.1, 61.1, 74.0, 117.7 (q, 1JC–F = 286.0 Hz),
127.9, 135.3, 157.4 (q, 2JC–F = 36.8 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C36H56F3INO3Si: 762.3026;
HRMS (FAB): m/z [M + H]+ calcd for C20H37F3NO3: 396.2726;
found: 762.3030.
found: 396.2724.
N-[(2S,3R,E)-1-(tert-Butyldiphenylsilyloxy)-3-hydroxyoctadec-
4-en-2-yl]-2,2,2-trifluoroacetamide (9)
(2S,3R)-(E)-2-Aminooctadec-4-ene-1,4-diol (D-erythro-Sphin-
gosine) (1)
To a solution of cyclic sulfate 6a (1.70 g, 2.38 mmol) in toluene (25
mL) was added Bu4NI (1.00 g, 2.71 mmol). The reaction mixture
was heated for 3 h at 40 °C. After the reaction was complete, DBU
(0.50 mL, 3.40 mmol) was added and the reaction mixture was heat-
ed to reflux for 2 h. The reaction was cooled to r.t. and concentrated
H2SO4 (34 mL), H2O (30 mL), and THF (546 mL) were added. The
mixture was stirred for 1 h at r.t., then diluted with EtOAc (80 mL)
and washed with sat. aq NaHCO3 (2 × 100 mL) and brine (2 × 100
mL). The organic layer was dried over Na2SO4 and concentrated.
Purification of the crude product by silica gel column chromatogra-
phy (hexane–EtOAc, 25:1) afforded 9.
Yield: 1.11 g (74%); colorless oil; [a]D25 +26.0 (c 0.7, CHCl3).
IR (neat): 3427, 2926, 2855, 1722, 1168 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.4 Hz, 3 H), 1.06 (s,
9 H), 1.15–1.40 (m, 24 H), 2.03 (dd, J = 6.6, 13.6 Hz, 2 H), 2.69 (d,
J = 7.4 Hz, 1 H), 3.76 (dd, J = 3.0, 10.7 Hz, 1 H), 3.90–3.98 (m,
1 H), 4.01 (dd, J = 2.9, 10.7 Hz, 1 H), 4.23–4.30 (m, 1 H), 5.46 (dd,
J = 6.0, 15.4 Hz, 1 H), 5.81 (app. dt, J = 6.6, 14.6 Hz, 1 H), 6.98 (d,
J = 8.0 Hz, 1 H), 7.33–7.47 (m, 6 H), 7.55–7.65 (m, 4 H).
To a solution of 10 (1.53 g, 4.68 mmol) in EtOH (90 mL) was added
2 M NaOH (75 mL) at r.t. The reaction mixture was stirred for 2 h
and then diluted with H2O (80 mL) and extracted with EtOAc
(2 × 100 mL). The organic layer was washed with brine (2 × 100
mL), dried over Na2SO4, and concentrated. The crude product was
purified by column chromatography on silica gel (CHCl3–MeOH–
NH4OH, 135:25:4) to give sphingosine 1.
Yield: 1.33 g (96%); white waxy solid; mp 76–77 °C (Lit.17a 79–
25
82 °C); [a]D –3.0 (c 1.0, CHCl3) (Optical rotation values5–7,17a of
sphingosine 1 range from –1.4 to –2.9); Rf = 0.15 (CHCl3–MeOH–
NH4OH, 135:25:4).
IR (neat): 3240, 2919, 2851, 1467, 1032, 970 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 6.5 Hz, 3 H), 1.24 (s,
20 H), 1.33–1.38 (m, 2 H), 2.05 (q, J = 6.6 Hz, 2 H), 2.56–2.58 (m,
1 H), 3.60 (dd, J = 6.0, 10.8 Hz, 1 H), 3.67 (dd, J = 4.6, 10.8 Hz,
1 H), 4.06 (t, J = 6.4 Hz, 1 H), 5.47 (dd, J = 7.2, 15.4 Hz, 1 H), 5.76
(td, J = 6.7, 14.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 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.
HRMS (FAB): m/z [M + H]+ calcd for C18H38O2N: 300.2903;
found: 300.2907.
13C NMR (75 MHz, CDCl3): d = 14.1, 19.1, 22.7, 26.8, 29.0, 29.2,
29.4, 29.5, 29.6, 29.7, 31.9, 32.2, 54.0, 62.7, 71.5, 73.3, 117.8 (q,
1JC–F = 286.3 Hz), 127.6, 127.7, 127.8, 127.97, 128.0, 128.1, 130.2,
130.24, 131.9, 132.1, 134.7, 135.4, 135.42, 135.6, 157.0 (q, 2JC–F
=
(2S,3R)-(E)-2-Acetamidooctadec-4-ene-1,3-diyl Diacetate (11)
To a solution of sphingosine 1 (300 mg, 1.00 mmol) in pyridine (9
mL) was added Ac2O (578 mL, 6.12 mmol) at 0 °C. After stirring at
r.t. for 5 h, the reaction mixture was poured into H2O (30 mL) and
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers
were washed with brine (2 × 50 mL), dried over MgSO4 and con-
centrated. The crude product was purified by silica gel column chro-
matography (hexane–EtOAc, 1:1) to give sphingosine triacetate 11.
37 Hz).
HRMS (FAB): m/z [M + H]+ calcd for C36H55F3INO3Si: 634.3903;
found: 634.3902.
N-[(2S,3R,E)-1,3-Dihydroxyoctadec-4-en-2-yl]-2,2,2-trifluoro-
acetamide (10)
From 9: To a solution of 9 (1.10 g, 1.74 mmol) in THF (25 mL) was
added Bu4NF (2.60 mL, 2.60 mmol, 1.0 M in THF) at r.t. The reac-
tion mixture was stirred for 1 h, then diluted with H2O (80 mL) and
extracted with EtOAc (2 × 100 mL). The organic layer was washed
Yield: 386 mg (90%); white solid; mp 102–104 °C (Lit. 100–
25
102 °C,5g 101–102 °C,17a 104.6–106.0 °C17b); [a]D –14.4 (c 1.2,
Synthesis 2011, No. 6, 867–872 © Thieme Stuttgart · New York

872
Y. M. Lee et al.
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CHCl3) (Optical rotation values5g,6b,17a of sphingosine triacetate 11
range from –13.0 to –13.2).
IR (neat): 3290, 1736, 1657, 1552 cm–1.
71, 4685. (g) Disadee, W.; Ishikawa, T. J. Org. Chem. 2005,
70, 9399. (h) Chaudhari, V. D.; Kumar, K. S. A.; Dhavale,
D. D. Org. Lett. 2005, 7, 5805. (i) Lu, X.; Bittman, R.
Tetrahedron Lett. 2005, 46, 1873.
1H NMR (300 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.25 (s,
22 H), 1.98 (s, 3 H), 2.01–2.04 (m, 2 H), 2.056 (s, 3 H), 2.062 (s,
3 H), 4.03 (dd, J = 3.9, 11.4 Hz, 1 H), 4.29 (dd, J = 6.0, 11.4 Hz,
1 H), 4.39–4.46 (m, 1 H), 5.27 (app. t, J = 6.5 Hz, 1 H), 5.38 (dd,
J = 7.5, 15.3 Hz, 1 H), 5.66 (br d, J = 9.0 Hz, 1 H), 5.78 (td, J = 6.9,
15.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 20.8, 21.1, 22.7, 23.3, 28.9,
29.1, 29.3, 29.4, 29.57, 29.64, 31.9, 32.3, 50.7, 62.6, 73.8, 124.1,
137.4, 169.6, 170.0, 170.9.
(6) (a) Ha, H.-J.; Yoon, D.-H.; Kang, L.-S.; Hong, M. C.; Lee,
W. K. Bull. Korean Chem. Soc. 2009, 30, 535.
(b) 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. (c) 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; See
also ref. 7.
(7) Kim, S.; Lee, S.; Lee, T.; Ko, H.; Kim, D. J. Org. Chem.
2006, 71, 8661.
(8) (a) Conrow, R. E.; Dean, W. D. Org. Process Res. Dev.
2008, 12, 1285. (b) Banert, K.; Joo, Y. H.; Rüffer, T.;
Walfort, B.; Lang, H. Angew. Chem. Int. Ed. 2007, 46,
1168. (c) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V.
Angew. Chem. Int. Ed. 2005, 44, 5188.
HRMS (FAB): m/z [M + H]+ calcd for C24H44O5N: 426.3219;
found: 426.3230.
Acknowledgment
This work was supported by the World Class University Program
(R32-2008-000-10098-0) and the MarineBio Research Program
(NRF-C1ABA001-2010-0020428) of the National Research Foun-
dation of Korea (NRF) grant funded by the Korea government
(MEST).
(9) Wuts, P. G. M.; Green, T. W. Protective Groups in Organic
Synthesis, 4th ed.; Wiley-Interscience: New York, 2006.
(10) Menger, F. M.; Mandell, L. J. Am. Chem. Soc. 1967, 89,
4424.
(11) (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831.
(12) (a) Kemp, S. J.; Bao, J.; Pedersen, S. F. J. Org. Chem. 1996,
61, 7162. (b) Kempf, D. J.; Sowin, T. J.; Doherty, E. M.;
Hannick, S. M.; Codavoci, L.; Henry, R. F.; Green, B. E.;
Spanton, S. G.; Norbeck, D. W. J. Org. Chem. 1992, 57,
5692. (c) Sakaitanti, M.; Ohfune, Y. J. Am. Chem. Soc.
1990, 112, 1150. (d) Sakaitanti, M.; Ohfune, Y. J. Org.
Chem. 1990, 55, 870. (e) Kano, S.; Yokomatsu, T.;
Iwasawa, H.; Shibuya, S. Tetrahedron Lett. 1987, 28, 6331.
(f) Baker, B. R.; Hullar, T. L. J. Org. Chem. 1965, 30, 4049.
(13) Lee, Y. M.; Baek, D. J.; Lee, S.; Kim, D.; Kim, S. J. Org.
Chem. 2011, 76, 408.
(14) Jo, S. Y.; Kim, H. C.; Jeon, D. J.; Kim, H. R. Heterocycles
2001, 55, 1127.
(15) (a) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37,
4349. (b) Mori, K.; Nishio, H. Liebigs Ann. Chem. 1991,
253.
(16) Owing to the reported instability of 1, it was also
characterized as the triacetate derivative 11.
(17) (a) Lee, J.-M.; Lim, H.-S.; Chung, S.-K. Tetrahedron:
Asymmetry 2002, 13, 343. (b) Ohashi, K.; Kosai, S.;
Arizuka, M.; Watanabe, T.; Yamagiwa, Y.; Kamikawa, T.
Tetrahedron 1989, 45, 2557; and references therein.
References
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and Cell Signaling in Biochemistry of Lipids, Lipoprotein,
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(4) Phytosphingosine from fermentation can be purchased at
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(5) For selected publications on recent syntheses of D-erythro-
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Matheu, M. I.; Castillón, S. Org. Lett. 2009, 11, 205.
(b) Morales-Serna, J. A.; Díaz, Y.; Matheu, M. I.; Castillón,
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Synthesis 2011, No. 6, 867–872 © Thieme Stuttgart · New York