Synthesis of D/L-erythro-Sphingosine Using a Tethered Aminohydroxylation Reaction as the Key Step

Article abstract of DOI:10.1055/s-0028-1083367

A diastereoselective synthesis of racemic D/L-erythro- sphingosine is described. The approach involves employing tethered aminohydroxylation (TA) to introduce the 2-amino and 3- hydroxy functions with required stereochemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083367

710
SHORT PAPER
Synthesis of D/L-erythro-Sphingosine Using a Tethered Aminohydroxylation
Reaction as the Key Step
S
ynthesis
o
of
D
/
L
-
erythr
s
o
-Sphing
é
osine
U
sing a Tet
A
hered Aminohydro
n
xylation tonio Morales-Serna, Yolanda Díaz, M. Isabel Matheu, Sergio Castillón*
Departamento de Química Analítica y Química Orgánica, Universitat Rovira I Virgili, C/Marcel.li Domingo s/n, 43007 Tarragona, Spain
Fax +34(977)558446; E-mail: sergio.castillon@urv.net
Received 14 July 2008; revised 18 November 2008
gosine,14 which can be classified into four categories: (i)
Abstract: A diastereoselective synthesis of racemic D/L-erythro-
first, carbohydrates are used as the source of chirality; (ii)
second, the Sharpless asymmetric epoxidation is used to
generate the stereogenic centers; (iii) the third relies on
the aldol reaction with a chiral auxiliary and finally (iv)
the amino acid serine is used as the source of chirality.
sphingosine is described. The approach involves employing
tethered aminohydroxylation (TA) to introduce the 2-amino and 3-
hydroxy functions with required stereochemistry.
Key words: sphingolipids, sphingosine, ceramide, amino alcohols,
diasteroselectivity
Here, we wish to enrich this diverse range of strategies for
sphingosine synthesis. In this paper, we report an efficient
method for the synthesis of racemic D/L-erythro-sphin-
gosine employing an aminohydroxylation reaction as the
key step. Unfortunately, this reaction is not compatible
with the use of cinchona alkaloid-derived chiral ligands,
which therefore precludes an enantioselective version.
Our choice of starting material was dictated by the type of
reaction that we planned to employ to generate the asym-
metric centers. The chiral aminohydroxylic functions
were introduced in the last step by an aminohydroxylation
of diene 3, which has the appropriate E,Z-configuration in
the aminohydroxylation reaction. This diene can be pre-
pared by reduction of 4, which in turn can be obtained
from aldehydes 5 through a Wittig reaction (Scheme 1).
In 1881, when Johann Thudichum first described a com-
pound that would later be fully characterized as sphin-
gosine, he named it after the Greek mythological
character, the Sphinx, ‘in commemoration of the many
enigmas which it has presented to the inquirer’.1 Sphin-
golipids have emerged over the last decades as a family of
key signaling molecules, which include sphingosine and
ceramide.2 These compounds, together with glycerophos-
pholipids and cholesterol, are building blocks3 that play
essential roles as structural cell membrane components4
and participate in higher order physiological processes in-
cluding inflammation5 and vasculogenesis.6 Recent stud-
ies demonstrated the involvement of sphingolipids in
many of the most common human diseases, including in-
fection by microorganisms,7 diabetes,8 a range of can-
cers,9 Alzheimer’s,10 and many others.11
HO
NH2
aminohydroxylation
C13H27
HO
3
OH
1
O
C13H27
NH2
C13H27
HO
C15H31
C13H27
HN
HO
Lindlar reduction
OH
1
OH
ceramide
2
D-erythro-sphingosine
Wittig reaction
O
H
C13H27
Figure 1 The prevalent backbone in sphingolipids
RO
HO
5
+
4
Structurally, the prevalent backbone in sphingolipids is
sphingosine which, when bearing a long-chain fatty acid
into the amino function, is called ceramide (Figure 1).
There are four sphingosine stereoisomers with a wide
range of biological activities.12,13 The D-erythro-isomer is
the most common metabolite and has been widely studied.
Since, sphingosine and its derivatives are only available in
limited amounts from natural sources, there is growing in-
terest in developing efficient methods for their synthesis.
There are many reported methods for synthesizing sphin-
Br
Ph3PC14H29
6
Scheme 1 Retrosynthetic analysis of D-erythro-sphingosine
The synthesis of the diene 315 started from acetylenic al-
cohol 7 which, under oxidation conditions, gave aldehyde
5. Reaction of 5 with the phosphonium salt 6, followed by
deprotection of the hydroxy group under acidic condi-
tions, afforded the E-enyne 4. The desired E,Z-diene 3
was obtained in 80% yield by Lindlar reduction of 4
(Scheme 2).
SYNTHESIS 2009, No. 5, pp 0710–0712
x
x
.
x
x
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0
0
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Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083367; Art ID: T11308SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of D/L-erythro-Sphingosine Using a Tethered Aminohydroxylation
711
The Sharpless asymmetric aminohydroxylation16 (AA) All reactions were conducted under a dried argon stream. Solvents
and tethered aminohydroxylation17 (TA) allows the cata-
(CH2Cl2, 99.9%; benzene, 99.9%) were purchased in capped Pure
Solv System-4® bottles, stored under argon and used without further
lytic and diastereoselective synthesis of amino alcohols.
purification. All other solvents and reagents were used without fur-
However, in AA the drawbacks of regioselectivity persist
during the oxidation of unsymmetrical alkenes. This in-
ther purification. All glassware utilized was flame-dried before use.
Reactions were monitored by TLC carried out using silica gel plates
convenience can be avoided through the use of TA. At this
(0.25 mm, E. Merck). Developed TLC plates were visualized under
point of the synthesis, we were interested in extending the
TA methodology18 as a general strategy in order to amino-
hydroxylate the double bond. Thus, the E,Z-diene 3 was
reacted with N,N¢-carbonyldiimidazole (CDI) in the pres-
ence of pyridine, followed by the addition of hydroxyl-
amine hydrochloride, to give the hydroxycarbamate 8.
The latter was treated with pentafluorobenzoyl chloride
(C6F5COCl) to yield the hydroxycarbamate 9. When 9
was treated under TA conditions, oxazolidinone 10 was
obtained in 85% yield with complete control of the regio-
and relative stereoselectivity. Alkaline hydrolysis of 10
afforded racemic sphingosine 1 in quantitative yield.
a short-wave UV lamp and by heating plates that were dipped in
EtOH–H2SO4 (15:1). Flash column chromatography was performed
using flash silica gel (32–63 mm) and employed a solvent polarity
correlated with TLC mobility. NMR experiments were conducted
on a Varian 400 MHz instrument using CDCl3 (99.9% D) as sol-
vent, with chemical shifts (d) referenced to internal standards
1
CDCl3 (d = 7.26 ppm for H, 77.23 ppm for 13C) or TMS (0.00
ppm). Chemical shifts are given in parts per million (ppm) relative
to the deuterated solvent peak.
Hydroxycarbamate 9
CDI (182 mg, 1.12 mmol) was added to alcohol 3 (200 mg, 0.75
mmol) in pyridine (20 mL) at 40 °C. When the adduct between the
alcohol and the CDI was totally formed, NH2OH·HCl (130 mg, 1.87
mmol) was added. The resulting reaction mixture was stirred for 24
h at 40 °C, then quenched with HCl (1 M, 10 mL), and EtOAc (10
mL) was added. After separation of the organic phase, the aqueous
phase was extracted with EtOAc (2 × 10 mL). The combined organ-
ic layers were washed sequentially with H2O (10 mL) and brine
(3 × 10 mL), dried (NaSO4), filtered and the solvent was azeotropi-
cally removed with toluene. The crude product was purified by flash
column chromatography on silica gel (hexane–EtOAc, 85:15) to
give 8, which was used directly in the next step.
O
H
OH
BaMnO4
CH2Cl2
r.t., 4 h
94%
TBDMSO
TBDMSO
5
7
1) 6, n-BuLi, hexanes
THF, –30 °C, 1.5 h
2) HCl (3.5 N)
r.t., 22 h
74% (2 steps)
A solution of 8 (243 mg, 0.75 mmol) and Et3N (83 mg, 0.82 mmol)
in anhydrous Et2O (20 mL) was cooled to 0 °C. The acid chloride
C6F5COCl (172 mg, 0.75 mmol) in anhydrous Et2O (10 mL) was
added dropwise over 1 h at 0 °C, then the reaction was stirred under
argon at r.t. for 12 h. The reaction was quenched with aq HCl (1 M,
10 mL) and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were washed sequentially with aq HCl
(10%, 10 mL), aq NaHCO3 (7%, 10 mL), and brine (3 × 10 mL).
The organic layer was dried over MgSO4 and concentrated under
vacuum. The residue was purified by flash column chromatography
on silica gel (hexane–EtOAc, 85:15) to give 9.
HO
C13H27
Lindlar catalyst
toluene, r.t., 3 h
80%
HO
3
4
C13H27
CDI, then
NH2OH•HCl,
pyridine, 40 °C, 24 h
F
F
O
F
H
N
H
N
F
O
O
O
C6F5COCl
Yield: 270 mg (70%); clear oil.
HO
1H NMR (400 MHz, CDCl3): d = 8.36 (s, 1 H), 6.3 (dd, J = 13.8,
11.1 Hz, 1 H), 6.15 (dd, J = 11.1, 10.6 Hz, 1 H), 5.8 (dq, J = 13.8,
6.6 Hz, 1 H), 5.4 (dt, J = 10.6, 7.1 Hz, 1 H), 4.73 (d, J = 7.1 Hz,
2 H), 2.12 (q, J = 7.0 Hz, 2 H), 1.37–1.2 (m, 22 H), 0.85 (t, J = 6
Hz, 3 H).
O
Et2O, Et3N,
0 °C, 12 h
70% (2 steps)
O
F
H27C13
9
H27C13
8
K2OsO2⋅2H2O (1 mol%)
t-BuOH–H2O (3:1), r.t., 12 h
85%
13C NMR (100 MHz, CDCl3): d = 158.5, 155.7, 148.9, 147.2, 145.6,
143.0, 138.4, 133.1, 124.5, 121.9, 61.1, 32.8, 31.9, 29.6, 29.5, 29.4,
29.3, 29.2, 29.1, 22.6, 14.0.
O
NH2
HRMS (FAB+): m/z [M + H] calcd for C26H35F5NO4: 520.2486;
found: 520.2494.
NH
KOH, EtOH–H2O
C13H27
HO
O
C13H27
reflux, 2.5 h
100%
Anal. Calcd for C26H34F5NO4: C, 60.11; H, 6.60; N, 2.70. Found: C,
60.13; H, 6.59; N, 2.72.
OH
1
OH
10
Scheme 2 Synthesis of sphingosine 1
Oxazolidinone 10
To a solution of 9 (250 mg, 0.48 mmol) in t-BuOH–H2O (3:1, 10
mL/mmol), was added dropwise a solution of K2OsO2·2H2O (1.8
mg, 1 mol%) in H2O (0.25 mL). The resulting reaction mixture was
then stirred at r.t. for 12 h. The reaction was quenched by addition
of Na2SO3 (100 mg, mmol), allowed to stir for 30 min, then the sol-
vent was azeotropically removed with toluene. The crude product
was purified by flash column chromatography on silica gel (hex-
ane–EtOAc, 85:15) to give 10.
In conclusion, D/L-erythro-sphingosine (1) has been syn-
thesized in eight steps and 33% overall yield from alcohol
7 using a tethered aminohydroxylation (TA) as key step.
This approach allowed the introduction of the 2-amino
and 3-hydroxy groups with complete regio- and stereo-
selectivity.
Yield: 132 mg (85%); white solid.19
Synthesis 2009, No. 5, 710–712 © Thieme Stuttgart · New York

712
J. A. Morales-Serna et al.
SHORT PAPER
1H NMR (400 MHz, CDCl3): d = 6.10 (s, 1 H), 5.83 (ddt, J = 15.4,
6.8, 0.8 Hz, 1 H), 5.37 (ddt, J = 15.4, 6.8, 1.2 Hz, 1 H), 4.39 (dd,
J = 8.8, 8.5 Hz, 1 H), 4.33 (dd, J = 8.8, 5.2 Hz, 1 H), 4.12 (m, 1 H),
3.86 (m, 1 H), 2.92 (br s, 1 H), 2.04 (q, J = 7.0 Hz, 2 H), 1.37–1.2
(m, 22 H), 0.81 (t, J = 6.8 Hz, 3 H).
(2) Tani, M.; Ito, M.; Igarashi, Y. Cell. Signal. 2007, 19, 229.
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Biochim. Biophys. Acta 2006, 1758, 2139.
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13C NMR (100 MHz, CDCl3): d = 160.5, 136.6, 126.6, 73.3, 66.4,
56.4, 32.5, 32.1, 29.81, 29.79, 29.74, 29.6, 29.5, 29.4, 29.1, 22.8,
14.2.
HRMS (FAB+): m/z [M + H] calcd for C19H36NO3: 326.2695;
found: 326.2699.
Anal. Calcd for C19H35NO3: C, 70.11; H, 10.84; N, 4.30. Found: C,
70.19; H, 10.80; N, 4.32.
Sphingosine (1)
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Oxazolidinone 10 (100 mg, 0.30 mmol) in 1 M KOH (H2O–EtOH,
1:1; 5 mL) was heated to reflux for 2.5 h, then cooled to r.t. and aq
HCl (2 M, 2.5 mL) was added.19 The mixture was extracted with
EtOAc (3 × 10 mL) and the combined organic layers were dried
over MgSO4 and concentrated under vacuum to give 1.
Yield: 89 mg (100%); white solid.20
1H NMR (400 MHz, CDCl3): d = 5.76 (dt, J = 15.4, 6.7 Hz, 1 H),
5.47 (dd, J = 15.4, 7 Hz, 1 H), 4.11 (m, 1 H), 3.70 (dd, J = 11, 3 Hz,
1 H), 3.65 (dd, J = 11, 5.8 Hz, 1 H), 2.92 (m, 1 H), 2.05 (dt, J = 6.7,
7.3 Hz, 2 H), 1.37 (m, 2 H), 1.20–1.40 (m, 20 H), 0.88 (t, J = 6.9
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 134.7, 128.8, 74.7, 63.3, 56.3,
32.5, 31.9, 29.7–29.2, 22.7, 14.1.
HRMS (FAB+): m/z [M + H] calcd for C18H38NO2: 300.2903;
found: 300.2909.
(16) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 451. (b) For a review, see: Bodkin, J. A.;
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(17) (a) Donohoe, T. J.; Helliwell, M.; Johnson, P. D.; Keenan,
M. Chem. Commun. 2001, 2078. (b) Donohoe, T. J.;
Cowley, A.; Johnson, P. D.; Keenan, M. J. Am. Chem. Soc.
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2583. (e) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.;
Griffin, D.; Campbell, A. D. J. Am. Chem. Soc. 2006, 128,
2514.
Anal. Calcd for C18H37NO2: C, 72.19; H, 12.45; N, 4.68. Found: C,
72.21; H, 12.41; N, 4.70.
Acknowledgment
Financial support from DGESIC CTQ-2005-03124/BQU (Ministe-
rio de Educación y Ciencia, Spain) is acknowledged. We are also
grateful to the Servei de Recursos Cientifics (URV) for its technical
assistance. Fellowship from DURSI (Generalitat de Catalunya to
J.A.M.S. is gratefully acknowledged).
(18) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.;
Rossignol, E. Org. Lett. 2007, 9, 1725.
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Synthesis 2009, No. 5, 710–712 © Thieme Stuttgart · New York