A simple and low cost synthesis of D-erythro-sphingosine and D-erythro-azidosphingosine from D-ribo-phytosphingosine: Glycosphingolipid precursors

Article abstract of DOI:10.1016/S0040-4039(02)01807-5

D-erythro-Sphingosine (1) and D-erythro-2-azidosphingosine (2) are both prepared from commercially available and cheap D-ribo-phytosphingosine (3) in a yield of 58% and 70%, respectively. A key transformation in the synthesis of D-erythro-sphingosine (1) is the palladium catalyzed regiospecific reduction of the Z-enol triflate 9. A crucial step in the synthesis of azidosphingosine 2 comprises a regio- and stereoselective in situ trans-elimination of the 4-O-triflate of azidophytosphingosine 13.

Full text of DOI:10.1016/S0040-4039(02)01807-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8409–8412
A simple and low cost synthesis of
-erythro-azidosphingosine from
glycosphingolipid precursors
D
-erythro-sphingosine and
D
D-ribo-phytosphingosine:
Richard J. B. H. N. van den Berg,a Cornelis G. N. Korevaar,a Gijsbert A. van der Marel,b
Herman S. Overkleeftb and Jacques H. van Boomb,*
aCosmoferm B.V., PO Box 386, 2600 AJ Delft, Netherlands
bLeiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, Netherlands
Received 9 July 2002; accepted 23 August 2002
Abstract—
cheap -ribo-phytosphingosine (3) in a yield of 58% and 70%, respectively. A key transformation in the synthesis of
-erythro-sphingosine (1) is the palladium catalyzed regiospecific reduction of the Z-enol triflate 9. A crucial step in the synthesis
D-erythro-Sphingosine (1) and D-erythro-2-azidosphingosine (2) are both prepared from commercially available and
D
D
of azidosphingosine 2 comprises a regio- and stereoselective in situ trans-elimination of the 4-O-triflate of azidophytosphingosine
13. © 2002 Elsevier Science Ltd. All rights reserved.
Glycosphingolipids (GLS) are common elements of
plasma membranes1 and important factors in various
biological processes, including cellular recognition
events and several signal transduction pathways.2 Many
It was envisaged that both target compounds 1 and 2
could in principle be prepared from phytosphingosine
(3) taking into account the following literature prece-
dents dealing with the introduction of the requisite
E-alkene moiety. Shiozaki et al. showed10 that the
properly protected 4-ketone derivative 4 (Scheme 1),
natural GLS are characterized by the presence of D-ery-
thro-sphingosine [(2S,3R,4E)-2-amino-3-hydroxyocta-
dec-4-en-1-ol], the primary hydroxyl group of which is
glycosylated while the amino function is acylated by a
fatty acid (ceramide unit). At present, GLS are gaining
interest for cosmetic and therapeutic applications.3,4
Unfortunately, GLS are not readily available from
natural sources in a homogeneous form. In order to
meet the growing demand for GLS, many different
methods, starting with the first racemic one in 1954,5
have been devised6,7 for the chemical synthesis of
(2S,3R,4E)-sphingosine (1) in sufficient amounts and
high chiral purity. It is also well recognized8 that the
use of 2-azidosphingosine 2 (see Fig. 1) is in several
aspects superior to sphingosine 1 in the synthesis of
GLS.
obtained from
D-tartaric acid, could be transformed
with a high degree of stereoselectivity into sphingosine
(1). A key event in this approach is the regiospecific and
stereoselective transformation of 4 into the correspond-
ing Z-enol triflate followed by a palladium assisted
regiospecific reduction. On the other hand, Schmidt et
al. reported11 that the properly protected 2-azido-4-
nitrophenylsulfonate derivative 5 (Scheme 1), prepared
from
D-galactose, could be converted into azidosphin-
We here report a convenient and concise route for the
synthesis of sphingosine 1 as well as 2-azidosphingosine
2 from commercially available and cheap9 phytosphin-
gosine 3.
* Corresponding author. Tel.: +31-(0)71-5274274; fax: +31-(0)71-
5274307; e-mail: j.boom@chem.leidenuniv.nl
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01807-5

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R. J. B. H. N. 6an den Berg et al. / Tetrahedron Letters 43 (2002) 8409–8412
silylation with di-tert-butylsilyl ditriflate13 to afford the
2-N-Boc-1,3-di-tert-butyl silylene derivative 7. Oxida-
tion of the 4-hydroxyl group in 7 with acetic anhydride
in dimethyl sulfoxide14 provided ketone 8 in a yield of
88% over the three steps. Treatment of 8 with potas-
sium bis(trimethylsilyl)amide followed by sulfonylation
of the in situ formed enolate with N-phenyl trifl-
uoromethanesulfonimide furnished E-enol triflate 9 in a
yield of 89%. Ensuing stereospecific reductive elimina-
tion of the enol triflate function with formic acid/tri-
15
ethylamine under the agency of Pd(OAc)2(PPh3)2 led
to the exclusive isolation of 10 (J4,5=15.4 Hz) in a yield
of 81% based on the 4-ketone derivative 8. Unmasking
of 10 proceeded uneventfully by the following two-step
procedure. Thus, desilyation of 10 with tetra-
butylammonium fluoride in the presence of acetic acid
afforded diol 11 in near quantitative yield. Acidolysis of
the N-Boc protecting group in 11 with trifluoroacetic
acid furnished target compound 1, analytical data of
which are in full accord with those reported16 for the
same compound.
Scheme 1.
gosine 2 either via a regio- and stereoselective trans-
elimination or a regio- and stereoselective cis-elimina-
tion of the corresponding 4-phenylselenoxide.12
At this stage, attention was focused on the synthesis of
2-azidosphingosine (2) from phytosphingosine (3) fol-
lowing the Schmidt11 procedure for the introduction of
the 4,5 E-double bond. In the first step 3 was subjected,
as outlined in Scheme 3, to Wong’s17 diazo transfer to
furnish the azido derivative 12. Regioselective protec-
tion of the 1,3-diol in 12 with the di-tert-butyl silylene
protective group afforded alcohol 13 in a yield of 93%
over the two steps. Surprisingly, nitrophenylsulfonyla-
tion of 13 under standard conditions11 led to an
intractable mixture of products. In contrast, nosylation
Consequently, we first examined whether the enol tri-
flate methodology could be readily adopted to the
synthesis of sphingosine (1) starting from phytosphin-
gosine (3). The synthetic route we followed is depicted
in Scheme 2 and commences with the protection of the
amino function of phytosphingosine (3). Thus, treat-
ment of sphingoide 3 with di-tert-butyl dicarbonate
gave the N-Boc protected derivative 6. Attempts to
mask the 1,3-diol in 6 with the benzylidene group led to
an inseparable mixture of products. However, regiose-
lective protection of 6 was readily accomplished by
18
Scheme 2.
(a) Boc2O, TEA, THF, rt, 30 min, 92%; (b)
18
(tBu)2Si(OTf)2, DMF, pyridine, −40°C, 30 min, 97%; (c)
DMSO, Ac2O, rt, 16 h, 99%; (d) KHMDS, phenylbistri-
fluoromethanesulfonimide, THF/toluene, −68°C“−20°C, 3 h,
89%; (e) Pd(OAc)2(triphenylphosphine)2, HCO2H, TEA,
DMF, 60°C, 4 h, 91%; (f) TBAF, AcOH, THF, 0°C, 1 h,
quantitative; (g) TFA, DCM, 0°C, 15 min, 81%.
Scheme 3.
(a) N3Tf, K2CO3, CuSO4, DCM, MeOH, H2O,
rt, 16 h, 93%; (b) (tBu)2Si(OTf)2, DMF, pyridine, −40°C, 30
min, quantitative; (c) AgOTf, pNsCl, pyridine, rt, 1 h, 96%;
(d) DBU, toluene, 80°C, 96 h, 38%; (e) Tf2O, DCE/pyridine,
0°C, 15 min; 77%; (f) TBAF, AcOH, THF, 0°C, 2 h, 99%; (g)
Me3P, H2O, THF, 0“55°C, 16 h, 84%; (g) as (f), 98%.

R. J. B. H. N. 6an den Berg et al. / Tetrahedron Letters 43 (2002) 8409–8412
8411
with the mixed anhydride, prepared in situ from silver
triflate and 4-nitrophenylsulfonyl chloride, gave the
nitrophenylsulfonyl derivative 14 in a yield of 96%.
Subjection of 14 (R3=pNs) to elimination using 1,8-
diazabicyclo[5.4.0]undec-7-ene as a base led to the iso-
lation of the E-olefin 15 in a comparable unsatisfactory
yield (38%) as reported11 earlier starting from the differ-
ently protected nitrophenylsulfonyl derivative 5 (see
Scheme 1). It turned out that a twofold increase in yield
of the crucial elimination step could be attained by the
following one-pot two-step procedure. Thus, triflation
of 13 with triflic anhydride in the presence of pyridine
gave after work-up and purification, the E-olefin 15
(J4,5=15.4 Hz), instead of expected triflated 13 (R3=
Tf), in a gratifying yield of 77%. Interestingly, triflation
of 13 in the absence of base led to the isolation of a
mixture of the E- and Z-olefins 15. Ensuing deblocking
of the di-tert-butyl silylene protecting group in 15
afforded 2-azidosphingosine (2) in an overall yield of
70% over the four steps. At this stage, it is also worth-
while mentioning that 2-azidosphingosine could be
readily transformed in two high yielding steps (i.e.
Staudinger reduction followed by desilylation; see
Scheme 3 steps g and h, respectively) into sphingosine
(1).
6. (a) He, L.; Byun, H. S.; Bittman, R. J. Org. Chem. 2000,
65, 7627–7633; (b) Corey, E. J.; Choi, S. Tetrahedron
Lett. 2000, 41, 2765–2768; (c) Ohlsson, J.; Magnusson, G.
Carbohydr. Res. 2001, 331, 91–94; (d) Gargano, J. M.;
Lees, W. J. Tetrahedron Lett. 2001, 42, 5845–5847; (e)
Milne, J. E.; Jarowicki, K.; Kocienski, P. J.; Alonso, J.
Chem. Commun. 2002, 426–427; (f) Compostella, F.;
Franchini, L.; Panza, L.; Prosperi, D.; Ronchetti, H.
Tetrahedron 2002, 58, 4425–4428.
7. For reviews on
D-erythro-sphingosine synthesis, see: (a)
Byun, H. S.; Bittman, R. In Phospholipids Handbook;
Cevc, G., Ed.; Marcel Dekker: New York, 1993; pp.
97–140; (b) Koskinen, P. M.; Koskinen, A. M. P. Synthe-
sis 1998, 8, 1075–1091; (c) Jung, K. H.; Smidt, R. R. In
Lipid Synthesis and Manufacture; Gunstone, F. D., Ed.;
Sheffield Academic Press: Sheffield, UK; CRC Press:
Boca Raton, FL, 1999; pp. 208–249; (d) Curfman, C.;
Liotta, D. Methods Enzymol. 1999, 311, 458–479.
8. (a) Zimmerman, P.; Bommer, R.; Schmidt, R. R. J.
Carbohydr. Chem. 1988, 7, 435–452; (b) Ito, Y.; Kiso, M.;
Hasegawa, A. J. Carbohydr. Chem. 1989, 8, 285–294; (c)
Compostella, F.; Franchini, L.; Giovenzana, G. B.;
Panza, L.; Prosperi, D.; Ronchetti, H. Tetrahedron:
Asymmetry 2002, 13, 867–872.
9. Phytosphingosine
[(2S,3S,4R)-2-amino-1,3,4-octade-
canetriol] is now readily available from a yeast fermenta-
tion process. For information, contact; Cosmoferm B.V.,
Wateringseweg 1, PO Box 386, 2600 AJ Delft, The
Netherlands, Fax: +31(15)2794120; e-mail: info@
cosmoferm.com.
The results presented in this paper clearly show that
D
-ribo-phytosphingosine (3) can be transformed into
-erythro-sphingosine (1) and its 2-azido analog 2 in an
D
overall yield of 58% and 70%, respectively. It was also
established that sphingosine (1) can be prepared in the
same overall yield (58%) following the azido route,
which invokes a one-pot procedure, instead of a more
costly two-step process (cf. conversion of 8“10), in
generating the requisite E-olefin function. It may there-
fore be concluded that the azido route not only presents
an economic route to sphingosine (1) but also to 2-azi-
dosphingosine (2), which is a valuable starting com-
pound in the synthesis of GLS. The application of the
azido route in a large-scale synthesis of several GLS is
currently under investigation.
10. (a) Nakamura, T.; Shiozaki, M. Tetrahedron 2001, 57,
9089–9092; (b) Nakamura, T.; Shiozaki, M. Tetrahedron
Lett. 1999, 40, 9063–9064.
11. Wild, R.; Schmidt, R. R. Tetrahedron: Asymmetry 1994,
5, 2195–2208.
12. The cis-elimination of the 4-phenylselenoxide, obtained
by a two-step conversion of 5 (Scheme 1), proceeded with
an overall yield of 50%. A similar yield was obtained in
the trans-elimination of 5.
13. Hoberg, J. O. Carbohydr. Res. 1997, 300, 365–367.
14. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89,
2416–2419.
15. Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984,
25, 4821–4824.
Acknowledgements
16. Duclos, R. I., Jr. Chem. Phys. Lipids 2001, 111, 111–138
and references cited therein.
The authors thank the Dutch Ministry of Economic
Affairs for financial support (BTS 99182).
17. Alper, P. B.; Hung, S. C.; Wong, C. H. Tetrahedron Lett.
1996, 37, 6029–6032.
1
18. All compounds were fully characterized by H, 13C NMR
and MS. Relevant data of the key compounds, 8: [h]2D0 4.1
1
References
(c 1.00, CHCl3). H NMR (200 MHz, CDCl3): l 0.88 (t,
t
t
3H, CH3), 1.03 (s, 9H, Bu), 1.07 (s, 9H, Bu), 1.25 (br. s,
t
1. Sweely, C. C. In Biochemistry of Lipids, Lipoproteins, and
Membranes; Vance, D. E.; Vance, J. E., Eds.; Elsevier:
Amsterdam, 1991; pp. 327–361.
2. Dickson, R. C. Annu. Rev. Biochem. 1998, 67, 27–48.
3. Sakai, T.; Koezuka, Y. Expert Opin. Ther. Pat. 1999, 9,
917–930.
4. Selzner, M.; Bielawska, A.; Morse, M. A.; Rudiger, H.
A.; Sindram, D.; Hannun, Y. A.; Clavien, P. A. Cancer
Res. 2001, 61, 1233–1240.
5. Shapiro, D.; Segal, K. J. Am. Chem. Soc. 1954, 76,
5894–5895.
2H, CH2), 1.39 (s, 9H, Bu Boc), 1.55 (m, 2H, CH2), 2.73
(m, 2H, CH2-5), 3.75 (dd, 1H, H-1ax, J1ax,1eq=9.5 Hz,
J
J
1ax,2=10.2 Hz), 3.93 (m, 1H, H-2, J1eq,2=4.4 Hz,
1ax,2=10.2 Hz, J2,3=9.5 Hz, J2,NH=8.8 Hz), 4.13 (d,
1H, H-3, J2,3=9.5 Hz), 4.14 (dd, 1H, H-1eq, J1ax,1eq=9.5
Hz, J1eq,2=4.4 Hz), 4.43 (br. d, 1H, NH, J2,NH=8.0 Hz).
13C{1H} NMR (50.1 MHz, CDCl3): l 14.0 (CH3), 20.1
t
(Cq Bu), 22.6, 25.5 (CH2), 27.0, 27.3, 28.1 (3×tBu), 29.1,
29.6, 30.9, 31.9, 36.8 (CH2), 49.8 (C-2), 67.4 (C-1), 79.9
(Cq Boc), 82.8 (C-3), 154.9 (CꢀO Boc), 210.6 (C-4). ES
(ESI): m/z=578.7 [M+Na]+. 10: [h]D20 23.4 (c 1.64,

8412
R. J. B. H. N. 6an den Berg et al. / Tetrahedron Letters 43 (2002) 8409–8412
t
CHCl3). 1H NMR (200 MHz, CDCl3): l 0.88 (t, 3H,
(s, 9H, Bu), 1.26 (s, 22H, 11×CH2), 2.09 (m, 2H, CH2),
CH3), 1.01 (s, 9H, tBu), 1.03 (s, 9H, tBu), 1.25 (br. s, 24H,
3.30 (m, 1H, H-2, J1eq,2=4.4 Hz, J1ax,2=11.0 Hz, J2,3
9.5 Hz), 3.81 (t, 1H, H-1ax, J1ax,1eq=11.0 Hz, J1ax,2=11.1
Hz), 4.10–4.28 (m, 2H, H-1eq, H-3, J1ax,1eq=11.0 Hz,
=
t
12×CH2), 1.41 (s, 9H, Bu Boc), 2.02 (m, 2H, CH2-6),
3.69–4.17 (m, 5H, H2-1, H-2, H-3, NH), 5.48 (dd, 1H,
H-4, J4,5=15.4 Hz, J3,4=6.6 Hz), 5.71 (dt, 1H, H-5,
J
1eq,2=4.4 Hz, J2,3=9.5 Hz, J3,4=5.9 Hz), 5.51 (dd, 1H,
J
4,5=15.4 Hz, J5,6a=J5,6b=6.6 Hz). 13C{1H} NMR (50.1
H-4, J3,4=6.6 Hz, J4,5=15.4 Hz), 5.87 (ddd, 1H, H-5,
t
MHz, CDCl3): l 14.0 (CH3), 20.0 (Cq Bu), 22.6 (CH2),
27.1, 27.4, 28.3 (3×tBu), 29.1, 29.3, 29.6, 31.9, 32.2 (CH2),
52.2 (C-2), 67.2 (C-1), 79.0 (C-3), 79.6 (Cq Boc), 129.5
(C-5), 133.8 (C-4), 155.0 (CꢀO Boc). ES (ESI): m/z=
540.6 [M+H]+, 562.3 [M+Na]+, 578.8 [M+K]+. 12: mp
97–98°C. [h]2D0 15.1 (c 1.00, CHCl3). IR: 2120 (broad
J
5,6a=6.6 Hz, J5,6b=6.5 Hz, J4,5=15.4 Hz). 13C{1H}
t
NMR (50.1 MHz, CDCl3): l 14.1 (CH3), 20.0 (Cq Bu),
22.7 (CH2), 27.0, 27.4 (2×tBu), 28.9, 29.4, 29.7, 31.9, 32.3
(CH2), 62.5 (C-2), 66.4 (C-1), 78.1 (C-3), 129.1 (C-5),
134.7 (C-4). ES (ESI): m/z=488.5 [M+Na]+, 931.8 [2M+
H]+, 954.0 [2M+Na]+. 1: mp: 70°C. [h]2D0 −1.2 (c 1.74,
CHCl3). 1H NMR (200 MHz, CDCl3): l 0.88 (t, 3H,
CH3), 1.26 (br. s, 22H, 11×CH2), 2.05 (q, 2H, CH2-6),
2.28 (br. s, 3H, OH/NH2/H2O), 2.86 (br. s, 1H, H-2), 3.66
(br. s, 2H, H2-1), 4.05 (br. s, 1H, H-3), 5.46, (dd, 1H,
H-4, J4,5=15.4 Hz, J3,4=6.6 Hz), 5.73 (dt, 1H, H-5,
1
azido peak). H NMR (200 MHz, CDCl3): l 0.88 (t, 3H,
CH3), 1.25 (s, H, CH2), 1.56 (br. s, 4H, CH2), 3.68 (m,
1H, H-2,), 3.80 (m, 2H, H-3, H-4), 3.87 (dd, 1H, H-1a,
J
J
1a,1b=11.7 Hz, J1a,2=4.4 Hz), 4.01 (dd, 1H, H-1b,
1a,1b=11.7 Hz, J1b,2=5.9 Hz). ES (ESI): m/z=366.5
[M+Na]+, 709.6 [2M+Na]+. 14: [h]D20 67.6 (c 1.40, CHCl3).
J
4,5=15.4 Hz, J5,6a=J5,6b 6.6 Hz). 13C{1H} NMR (50.1
MHz, CDCl3): l 14.0 (CH3), 22.6, 29.3, 29.6, 31.8, 32.3
(CH2), 56.2 (C-2), 63.1 (C-1), 74.5 (C-3), 129.1 (C-5),
134.4 (C-4). ES (ESI): m/z=300.5 [M+H]+. 2: [h]D20 −29.8
1H NMR (200 MHz, CDCl3): l 0.88 (t, 3H, CH3), 0.96
t
t
(s, 9H, Bu), 0.97 (s, 9H, Bu), 1.26 (s, 22H, 11×CH2),
1.54 (m, 2H, CH2), 1.90 (dd, 2H, CH2), 3.51 (dt, 1H, H-2,
J1eq,2=5.1 Hz, J1ax,2=J2,3=10.2 Hz), 3.88 (dd, 1H, H-
1
(c 1.04, CHCl3). H NMR (200 MHz, CDCl3): l 0.88 (t,
1ax, J1ax,1eq=10.9 Hz, J1ax,2=10.2 Hz), 4.09 (dd, 1H,
H-3, J3,4=2.2 Hz, J2,3=10.2 Hz), 4.23 (dd, 1H, H-1eq,
3H, CH3), 1.26 (s, 22H, 11×CH2), 2.07 (m, 2H, CH2),
2.21 (s, 2H, 2×OH), 3.50 (dd, 1H, H-2, J1eq,2=J2,3=5.1
Hz, J1ax,2=11.0 Hz), 3.78 (d, 1H, H-2), 4.25 (t, 1H, H-3,
2,3=5.9 Hz, J3,4=6.6 Hz), 5.54 (dd, 1H, H-4, J3,4=6.6
Hz, J4,5=15.4 Hz), 5.82 (dt, 1H, H-5, J5,6a=6.6 Hz,
5,6b=6.5 Hz, J4,5=15.4 Hz). 13C{1H} NMR (50.1 MHz,
CDCl3): l 14.0 (CH3), 22.6, 28.9, 29.6, 31.8, 32.2 (CH2),
62.4 (C-1), 66.7 (C-2), 73.5 (C-3), 128.0 (C-5), 135.9
(C-4). ES (ESI): m/z=348.1 [M+Na]+, 673.6 [2M+Na]+.
J
1ax,1eq=10.9 Hz, J1eq,2=5.1 Hz), 4.92 (dt, 1H, H-4),
8.12–8.42 (m, 4H, CHarm Ns). 13C{1H} NMR (50.1 MHz,
t
J
CDCl3): l 14.0 (CH3), 20.1 (Cq Bu), 22.5, 24.9 (CH2),
26.7, 27.2 (2×tBu), 27.7, 29.0, 29.3, 29.6, 31.8 (CH2), 57.9
(C-2), 66.1 (C-1), 77.0 (C-3), 85.1 (C-4), 124.3, 129.0
(CHarm Ns), 142.9, 150.5 (Cq Ns). ES (ESI): m/z=691.4
[M+Na]+. 15: [h]D20 6.0 (c 1.55, CHCl3). 1H NMR (200
MHz, CDCl3): l 0.88 (t, 3H, CH3), 1.01 (s, 9H, tBu), 1.04
J