An efficient and stereoselective route to 1-deoxy-5-hydroxy sphingosine analogues

Article abstract of DOI:10.1016/j.tetlet.2009.01.024

A short and efficient synthesis of 1-deoxy-5-hydroxy sphingolipid is described. The key steps involved are a Jacobsen hydrolytic kinetic resolution (HKR) and Shibasaki's asymmetric Henry reaction.

Full text of DOI:10.1016/j.tetlet.2009.01.024

Tetrahedron Letters 50 (2009) 1328–1330
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Tetrahedron Letters
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An efficient and stereoselective route to 1-deoxy-5-hydroxy
sphingosine analogues
*
Partha Pratim Saikia, Abhishek Goswami, Gakul Baishya, Nabin C. Barua
Natural Products Chemistry Division, North East Institute of Science and Technology, Jorhat 785 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient synthesis of 1-deoxy-5-hydroxy sphingolipid is described. The key steps involved are
a Jacobsen hydrolytic kinetic resolution (HKR) and Shibasaki’s asymmetric Henry reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 20 November 2008
Revised 1 January 2009
Accepted 9 January 2009
Available online 13 January 2009
Keywords:
Sphingolipids
Asymmetric synthesis
Asymmetric Henry reaction
Hydrolytic kinetic resolution
Regioselective ring opening
Sphingolipids are ubiquitous components of cell membranes
that play critical roles in many physiological processes including
cell recognition, adhesion and signalling.1 Over the past decade,
significant strides have been made in the elucidation of the biolog-
ical function of sphingolipids. One remarkable finding is the iden-
tification of sphingolipid metabolites as second messengers, which
provides the basis for the emerging concept of sphingolipid metab-
olites as therapeutics with clinical potential.2 While the interest in
investigating the biological functions of sphingolipids grows, ef-
forts for the effective preparation of natural and nonnatural sphin-
golipids have generated much attention.3
activity against colon cancer. Similar aminodiol stereochemistry
is also found in the substructure of fungal toxin fumonisin B1 5.
So far, only one synthesis of 2 has been reported in the literature.5
Over the past few years, investigations in our laboratory have
demonstrated the utility of nitroaliphatics in the synthesis of phar-
macologically important natural products.6 In this context, we re-
port herein our successful exercise towards the synthesis of 1-
deoxy-5-hydroxy sphingolipid 2.
OH
OH OH
This family of biomolecules has been shown to play a variety of
important roles in the chemistry of cellular membranes as well as
in cell growth, differentiation and apoptosis. For instance, the anti-
C
13H27
OH
C13H27
NH2
NH2
2
Sphingosine (1)
cancer activity of the parent D-erythro-(2S,3R)-sphingosine 1 and
other sphingolipids has been demonstrated both in vitro and
in vivo against colon cancer cell lines. However, it was observed
that sphingosine 1-phosphate produced in vivo from sphingosine
1 possessed promitotic and antiapoptotic properties. In order to
overcome this problem, Liotta et al.4 have developed 1-deoxy-5-
hydroxysphingosine analogues 2 and 3 with C-2, C-3 amino alcohol
stereochemistry of safingol 4. The primary hydroxyl group of
sphingosine has been moved to the C-5 position to maintain simi-
lar lipophilicity while further decreasing the opportunity for phos-
phorylation of hydroxyl substituents ( Fig. 1). The resulting 1-
deoxy-5-hydroxysphingosine analogue 2 has exhibited excellent
OH OH
OH
C13H27
C13H27
Safingol (4)
OH OH
OH
NH2
NH2
3
OR
C4H9
CH3
CH3 OR CH3 OH
NH2
Fumonisin B1 (5) R = C(O)CH2CH(CO2H)CH2CO2H
* Corresponding author.
Figure 1. 1-Deoxy-5-hydroxysphingolipid analogues and an aminodiol substruc-
E-mail address: ncbarua12@rediffmail.com (N.C. Barua).
ture containing natural products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.024

P. P. Saikia et al. / Tetrahedron Letters 50 (2009) 1328–1330
1329
The retrosynthetic analysis envisioned for 2 is depicted in
Scheme 1. As indicated in the scheme, the nitro alcohol 15 could
serve as the key intermediate, which can be traced back to the pro-
tected alcohol 11, which in turn could be obtained from the epox-
ide 6a. We reasoned that the stereochemistry at C-5 could be
secured by the regioselective ring opening of the epoxide. For the
installation of the stereochemistry of the C-2 and C-3 stereocen-
tres, we relied on Shibasaki’s asymmetric Henry reaction.
The synthesis of the 1-deoxy-5-hydroxy sphingolipid analogue
(2) started from racemic 2-(2-benzyloxyethyl)-oxirane (6). Thus,
racemic 2-(2-benzyloxyethyl)-oxirane (6) was subjected to Jacob-
sen’s HKR7 using (S,S)-(salen)CoIIIꢀOAc complex to give (S)-2-(2-
benzyloxyethyl)-oxirane8 (6a) as the optically pure isomer
(Scheme 2).
tion of 7 with acetic anhydride in the presence of pyridine
furnished 8 in a quantitative yield. Compound 8 was then sub-
jected to Pd–C-catalysed hydrogenation to afford 9 in 92% yield.
Our next aim was to carry out the two-carbon homologation of
9 with the generation of the desired stereocentres by means of
Shibasaki’s asymmetric Henry reaction.10 To this end, compound
9 was oxidised to the aldehyde 10 with DMP in 94% yield. Then,
the aldehyde 10 was treated with nitroethane in the presence of
La-(R)-BINOL catalyst at ꢁ40 °C, but under these reaction condi-
tions 10 was not stable and slowly decomposed without yielding
the nitroaldol product. Therefore, we decided to change the pro-
tecting group of the alcohol 7. Accordingly, treatment of 7 with
TBS triflate in the presence of 2,6-lutidine afforded 11 in 95% yield.
Removal of the benzyl protecting group in 11 released the terminal
hydroxyl group to furnish 12 in 85% yield. Oxidation of 12 with
DMP smoothly proceeded to produce the aldehyde 13. The alde-
hyde 13 without further purification was subjected to Shibasaki’s
asymmetric nitroaldol reaction with nitroethane under the influ-
ence of La-(R)-BINOL catalyst in THF at ꢁ40 °C to deliver the nitro
alcohol 14 in 68% yield over two steps with a satisfactory diaste-
reomeric ratio (10:1; syn:anti).11 Desilylation of 14 with 3 N HCl
gave 15 in 73% yield. Finally, reduction of the nitro group in 15
with H2/Pd–C afforded the target compound 2 in 82% yield, the
spectral and physical data of which were identical to those
reported.5
With enantiomerically pure 2-(2-benzyloxyethyl)-oxirane (6a)
in hand, we then subjected it to Li2CuCl4-catalysed9 regioselective
ring opening with dodecyl magnesium bromide to give the corre-
sponding alcohol 7 in 88% yield (Scheme 3). The hydroxyl protec-
OH OH
OH OH
C13H27
C13H27
NH2
NO2
15
2
In conclusion, we have demonstrated a new and flexible syn-
thetic sequence for the preparation of 1-deoxy-5-hydroxy sphingo-
lipid analogues in 29% overall yield from chiral oxirane 6a. The
synthetic route detailed herein is potentially useful for the synthe-
sis of other natural products bearing similar aminodiol substruc-
tures. Moreover, this synthetic strategy is perceptibly efficient for
tuning the stereochemistry at the C-2, C-3 and C-5 positions to ob-
tain different sphingolipid analogues.
OTBS
O
OBn
C13H27
OBn
11
6a
Scheme 1. Retrosynthetic analysis.
Spectral data of selected compounds: Compound 6a: ½a D20
ꢁ15.6 (c
ꢂ
1.26, CHCl3). IR (CHCl3):
m = 3031, 2860, 1601, 1492, 1255,
1098 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.36–7.24 (m, 5H),
.
OH
i
O
4.52 (s, 2H), 3.62 (t, 2H, J = 7.2 Hz), 3.07–3.01 (m, 1H), 2.79–2.76
(m, 1H), 2.53–2.52 (m, 1H), 1.96–1.86 (m, 1H), 1.82–1.76 (m,
1H). 13C NMR (75 MHz, CDCl3): d = 137.9, 128.1, 127.8, 127.3,
66.7, 49.8, 46.8, 32.6. MS (ESI): m/z = 179.0 (M++1). Compound 7:
O
+
HO
OBn
OBn
OBn
6
6a
6b
a 2D0 = 3413, 2924, 2853 cmꢁ1 1H
+6.2 (c 0.8, CHCl3). IR (CHCl3): m .
ꢂ
Scheme 2. Reagents and conditions: (i) (S,S)-(salen)CoIIIꢀOAc (0.5 mol %), distd. H2O
(0.55 equiv), 0 °C, 14 h, (44% for 6a, 46% for 6b).
½
NMR (300 MHz, CDCl3): d = 7.33–7.26 (m, 5H), 4.52 (s, 2H), 3.79–
3.75 (m, 1H), 3.68–3.63 (m, 2H), 2.92 (br s, 1H), 1.75–1.73 (m,
2H), 1.49–1.42 (m, 2H), 1.25 (br s, 20H), 0.90 (t, 3H, J = 5.7 Hz).
13C NMR (75 MHz, CDCl3): d = 137.6, 128.1, 127.4, 127.3, 73.0,
71.2, 69.0, 37.1, 36.0, 31.6, 29.4, 29.0, 25.3, 22.4, 13.8. MS (ESI):
OH
OAc
b
O
a
OBn
m/z = 372.0 (M++Na); Compound 11: ½a 2D0
ꢂ
ꢁ7.1 (c 1.0, CHCl3). IR
C13H27
OBn
C13H27
OBn
7
8
= 2953, 2926, 2854, 1463 cmꢁ1 1H NMR (300 MHz,
6a
(CHCl3):
m .
CDCl3): d = 7.31–7.25 (m, 5H), 4.46–4.45 (d, 2H, J = 3.0 Hz), 3.80–
3.78 (m, 1H), 3.50 (t, 2H, J = 6.0 Hz), 1.75–1.68 (m, 2H), 1.38–1.36
(m, 2H), 1.22 (br s, 22H), 0.86–0.84 (m, 12H), 0.01 (s, 3H), 0.00
(s, 3H). 13C NMR (75 MHz, CDCl3): d = 138.6, 128.3, 127.6, 127.5,
72.9, 69.4, 67.2, 37.6, 36.9, 31.9, 29.8, 29.74, 29.72, 29.6, 29.4,
25.9, 25.0, 22.7, 18.1, 14.1, ꢁ4.3, ꢁ4.5. MS (ESI): m/z = 485.1
OAc
e
c
Decomposition
C13H27
OH
d
9
10
OTBS
OTBS
c
e
(M++Na); Compound 12: ½a 2D0
ꢂ
ꢁ14.6 (c 1.2, CHCl3). IR (CHCl3):
f
7
C13H27
OH
= 3351, 2926, 2855, 1463, 1255 cmꢁ1. 1H NMR (300 MHz, CDCl3):
C13H27
OBn
m
12
13
11
d
d = 3.82–3.80 (m, 2H), 3.63 (m, 1H), 2.45 (br s, 1H), 1.80–1.65 (m,
1H), 1.43–1.41 (m, 2H), 1.16 (br s, 24H), 0.80–0. 76 (m, 12H),
0.00 (s, 3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 72.1,
60.3, 37.5, 36.7, 31.9, 29.8, 29.7, 29.67, 29.63, 29.61, 29.4, 25.8,
25.3, 22.7, 17.9, 14.1, ꢁ4.4, ꢁ4.7. MS (ESI): m/z = 374.2 (M++2);
TBS
OH
O
OH OH
g
h
2
C13H27
C
13H27
NO2
Compound 14: ½a 2D0
ꢂ
ꢁ16.1 (c 1.04, CHCl3). IR (CHCl3):
m = 3428,
NO2
14
15
2926, 2854, 1551 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d = 4.43–4.39
Scheme 3. Reagents and conditions: (a) C12H25MgBr, Li2CuCl4, THF, 0 °C; (b) Ac2O,
pyridine, rt; (c) H2, Pd–C, ethyl acetate; (d) Dess–Martin periodinane, CH2Cl2, 0 °C;
(e) nitroethane, La-(R)-BINOL, THF, ꢁ40 °C: (f) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (g)
3 N HCl, THF, rt; (h) H2, Pd–C, EtOH.
(m, 1H), 4.21–4.19 (m, 1H), 3.85–3.81 (m, 1H), 1.55–1.45 (m,
4H), 1.43 (d, 3H, J = 6.6 Hz), 1.17 (br s, 22H), 0.80–0.77 (m, 12H),
ꢁ0.03 (s, 3H), ꢁ0.08 (s, 3H). 13C NMR (75 MHz, CDCl3): d = 87.8,

1330
P. P. Saikia et al. / Tetrahedron Letters 50 (2009) 1328–1330
70.1, 44.7, 37.8, 35.9, 31.9, 29.6, 29.5, 29.3, 25.7, 22.7, 17.9, 15.5,
References and notes
14.1, 11.1, ꢁ3.9, ꢁ4.5. MS (ESI): m/z = 446.5 (M++1); Compound
15: mp 54–56 °C. ½a D20
ꢂ
ꢁ6.7 (c 0.9, CHCl3). IR (CHCl3):
m = 3401,
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2924, 2853, 1552 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 4.60–4.57
.
(m, 1H), 4.30–4.25 (m, 1H), 3.94–3.90 (m, 1H), 3.37 (br s, 2H),
1.69–1.58 (m, 4H), 1.55 (d, 3H, J = 6.3 Hz), 1.25 (br s, 22H), 0.90
(t, 3H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3): d = 70.4, 68.7, 37.5,
31.9, 29.6, 29.5, 29.3, 25.6, 22.7, 16.1, 14.1. MS (ESI): m/z = 354.2
(M++Na); Compound 2: mp 64–65 °C. ½a 2D0
ꢂ
+2.9 (c 0.8, CHCl3). IR
m .
(CHCl3):
= 3400, 2920, 2848, 1474 cmꢁ1 1H NMR (300 MHz,
CDCl3): d = 3.8 (m, 1H), 3.74 (m, 1H), 3.24 (br s, 4H), 2.81 (m,
1H), 1.6 (m, 1H), 1.45 (m, 3H), 1.25 (br s, 22H), 1.00 (d, 3H,
J = 6.2 Hz), 0.87 (t, 3H, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3):
d = 76.5, 70.1, 52.3, 41.2, 35.5, 32.2, 29.82, 29.76, 29.6, 29.5, 25.8,
22.9, 17.4, 14.2. MS (ESI): m/z = 324.4 (M++Na).
Acknowledgements
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(b) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 851–854.
11. The diastereomeric ratio was determined from its NMR spectrum.
The authors thank the Director, NEIST, Jorhat, for providing
facilities to carry out this work. P.P.S. and A.G. also thank CSIR
and UGC, New Delhi, respectively, for the award of fellowships.