Synthesis of D-ribo-C18-phytosphingosine from D-glucosamine via the D-allosamine derivatives as key intermediates

Article abstract of DOI:10.1016/S0040-4039(02)00919-X

A straightforward synthesis of D-ribo-C₁₈-phytosphingosine from D-glucosamine hydrochloride in ten steps in 18.4% overall yield via the D-allosamine derivatives as key intermediates is described here.

Full text of DOI:10.1016/S0040-4039(02)00919-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4889–4892
Synthesis of
D
-ribo-C18-phytosphingosine from
D
-glucosamine via
the
D-allosamine derivatives as key intermediates
Shun-Yuan Luo,a Shankar R. Thopate,a Ching-Yun Hsub and Shang-Cheng Hunga,*
aInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan
bDepartment of Chemical Engineering, Cheng-Shiu Institute of Technology, 840 Cheng-Ching Road, Kaohsiung County 833,
Taiwan
Received 22 March 2002; accepted 3 April 2002
Abstract—A straightforward synthesis of
overall yield via the
reserved.
D
-ribo-C18-phytosphingosine from
D-glucosamine hydrochloride in ten steps in 18.4%
D-allosamine derivatives as key intermediates is described here. © 2002 Elsevier Science Ltd. All rights
D
-ribo-C18-Phytosphingosine 1, (2S,3S,4R)-2-aminooc-
mers in their syntheses which need to be separated or
require lengthy routes to reach the target molecule.8
There is an ongoing demand to develop more efficient
and improved methodologies for the preparation of
phytosphingosine.
tadecane-1,3,4-triol, is a key backbone component of
sphingolipids ubiquitously distributed in many mam-
malian tissues,1 plants,2 fungi,3 as well as marine organ-
isms.4 It is a bioactive lipid that has potential heat
stress signal in yeast cell.5 Its derived a-galactosyl-
ceramide 2, exhibiting significant immunostimulatory
and antitumor properties,6 can be used as a ligand for
mouse and human natural killer T cells to enhance their
activities.7 Due to the difficulty in obtaining homoge-
neous material from natural sources, the synthetic
methods have acquired immense importance. As a
result, the literature documents many asymmetric syn-
thetic strategies to prepare phytosphingosine. Most
Due to the striking similarity between phytosphingosine
1 and the -allosamine derivative 6, with respect to the
D
configuration at three asymmetric centers, the C2, C3,
and C4, it was obvious for us to involve 6 as a key
intermediate. Our retro-synthetic plan, as illustrated in
Scheme 1, is to carry out the hydride reduction at the
anomeric center of 6 to generate a triol 5, which may
undergo oxidative cleavage of the C5ꢀC6 bond with
sodium periodate to provide the aldehyde 4 and further
approaches, that utilize
L-serine and various carbohy-
drates as the starting materials, often have diastereoiso-
5
O
P4O
1
Ph3P=CHC12H25
+
OH
1
H2N
OH
NP1P2
P3O
3
3
18
HO
4
1
5
OH
OH
1 : D-ribo-C18-phytosphingosine
OH
5
OH
O
P4O
P4O
OH
OH
NP1P2
O
NP1P2
P3O
P3O
OH
HO
5
6
HN
C25H51
OH
O
HO
HO
O
OH
O
OH
NH3+Cl-
C14H29
OH
2 : α-galactosyl ceramide
HO
HO
3
7
* Corresponding author. Fax: 886-2-2783-1237; e-mail: schung@
chem.sinica.edu.tw
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00919-X

4890
S.-Y. Luo et al. / Tetrahedron Letters 43 (2002) 4889–4892
1. TfN3, CuSO4
Ph
O
Ph
O
Ag2O, BnBr
81%
O
O
O
O
7
11
OBz
HO
OH
2. cat. CSA,
PhCH(OMe)2
N3
N3
BnO
8
12
75% in two steps
OH
TMSOTf,
BH3/THF
BzOBT, Et3N;
then Tf2O
Ph
O
NaBH4
O
NaNO2
O
N3
BnO
O
OBz
OBz
RO
oC, 87%
0 oC, 76%
0
N3
79%
15-crown-5,
HMPA, 74%
BnO
9 : R = H
13
10 : R = Tf
OH
O
OH
NaIO4
94%
Ph
O
O
OH
N3
O
BnO
OH
OBz
OBn
N3
N3
BnO
HO
OBn
14
11
15
Scheme 2.
[Ph3PCH2C12H25]+Br-,
LiN(SiMe3)2
N3 OBn C12H25
coupling with the Wittig reagent 3 to form the skeleton
of phytosphingosine. The -allosamine derivative 6 can
in turn be obtained from commercially available and
cheap -glucosamine hydrochloride 7 via regioselective
epimerization of hydroxyl group at the C3 position.
HO
D
THF, -84 oC, 87%
OBn
16
D
Ac2O, Pyr.
86%
10% Pd/C, H2
96%
Our efficient synthesis of the D-allosamine derivatives is
1
outlined in Scheme 2. Transformation of 7 into the diol
8 was executed in two steps in 75% overall yield
through a combination of amino–azido conversion9 and
4,6-O-benzylidenation.10 A highly regioselective ben-
AcHN
AcO
OAc
C
zoylation of
8
with 1-(benzoyloxy)benzotriazole
14H29
(BzOBT)11 affording the b-anomeric ester 9 in excellent
yield was recently developed by us.12 We proceeded to
study the one-pot benzoylation–triflation of 8 and the
product 10 was successfully isolated in 79% yield.
Nucleophilic substitution of 10 with sodium nitrite led
to the alcohol 11 (74%). The absolute configuration of
OAc
17
Scheme 3.
conditions (Ag2O, BnBr) provided the ether 12 in 81%
yield. Regioselective ring opening of the benzylidene
acetal at O6 with borane/tetrahydrofuran complex in
the presence of trimethylsilyl trifluoromethane-
sulfonate14 furnished the primary alcohol 1315
(87%), which was subjected to hydride reduction
to produce the triol 14 in 76% yield. Oxidative cleavage
of CꢀC single bond between the vicinal dihydroxyl
groups of 14 with sodium periodate gave the cyclic
hemi-acetal 15 in 94% yield. Wittig reaction of 15
the
D
-allosamine derivative 11 was determined by its
X-ray single-crystal analysis.13 Its ORTEP drawing is
presented in Fig. 1, indicating that the hydroxyl and
benzoyloxy groups at the C3 and C1 positions orient
toward the axial and equatorial directions, respectively.
With the key synthon 11 in hand, the total synthesis of
phytosphingosine was carried out in a straightforward
manner (Scheme 3). Benzylation of 11 under neutral
Figure 1. ORTEP drawing of compound 11.

S.-Y. Luo et al. / Tetrahedron Letters 43 (2002) 4889–4892
4891
with Ph3PꢁCHC12H25 3 yielded the (Z)-olefin 16 (87%),
which was further reduced under hydrogenation condi-
tions to afford the expected target molecule 1 in 96%
yield. Comparison of our data of its per-acetylated
derivative 17 with the literature report8e revealed iden-
1529; (d) Brossay, L.; Chioda, M. C.; Burdin, N.;
Koezuka, Y.; Casorati, G.; Dellabona, P.; Kronenberg,
M. J. Exp. Med. 1998, 188, 1521; (e) Couedel, C.; Reyrat,
M.-A.; Brossay, L.; Koezuka, Y.; Porcelli, S.; Davodeau,
F.; Bonneville, M. Eur. J. Immunol. 1998, 28, 4391.
8. (a) He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000,
65, 7618; (b) Azuma, H.; Tamagaki, S.; Ogino, K. J. Org.
Chem. 2000, 65, 3538; (c) Graziani, A.; Passacantilli, P.;
Piancatelli, P.; Tani, S. Tetrahedron: Asymmetry 2000, 11,
3921; (d) Santiago, F.-P.; Schmidt, R. R. Carbohydr. Res.
2000, 328, 95; (e) Murakami, T.; Taguchi, K. Tetrahedron
1999, 55, 989; (f) Imashiro, R.; Sakurai, O.; Yamashita,
T.; Horikawa, H. Tetrahedron 1998, 54, 10657; (g)
Shimizu, M.; Wakioka, I.; Fujisawa, T. Tetrahedron Lett.
1997, 38, 6027; (h) Yoda, H.; Oguchi, T.; Takabe, K.
Tetrahedron: Asymmetry 1996, 7, 2113; (i) Murakami,
M.; Ito, H.; Ito, Y. Chem. Lett. 1996, 185; (j) Lin, G.;
Shi, Z. Tetrahedron 1996, 52, 2187; (k) Bettelli, E.; Chin-
zari, P.; D’Andrea, P.; Passacantilli, P.; Piancatelli, G.;
Topai, A. Korean J. Med. Chem. 1996, 6, 339; (l) Li,
Y.-L.; Wu, Y.-L. Tetrahedron Lett. 1995, 36, 3875; (m)
Li, Y.-L.; Mao, X.-H.; Wu, Y.-L. J. Chem. Soc., Perkin
Trans. 1 1995, 1559; (n) Matsumoto, K.; Ebata, T.;
Matsushita, H. Carbohydr. Res. 1995, 279, 93; (o)
Murakami, T.; Minamikawa, H.; Hato, M. Tetrahedron
Lett. 1994, 35, 745; (p) Kobayashi, S.; Hayashi, T.;
Kawasuji, T. Tetrahedron Lett. 1994, 35, 9573; (q) Wild,
R.; Schmidt, R. R. Liebigs Ann. Chem. 1995, 755; (r)
Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J.
Org. Chem. 1990, 55, 1439; (s) Sugiyama, S.; Honda, M.;
Komori, T. Liebigs Ann. Chem. 1990, 1069; (t) Schmidt,
R. R.; Maier, T. Carbohydr. Res. 1988, 174, 169; (u)
Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann.
Chem. 1988, 619; (v) Mulzer, J.; Brand, C. Tetrahedron
1986, 42, 5961.
1
tity with respect to H and 13C spectra.
In conclusion, we have successfully developed
straightforward route to synthesize -ribo-C18-phyto-
sphingosine 1 from -glucosamine hydrochloride 7 in
ten steps in 18.4% overall yield. Conversion of 7 into
-allopyranosyl
a
D
D
2-azido-4,6-O-benzylidene-2-deoxy-b-
D
benzoate 11 was efficiently achieved in four steps. A
three-stepped functional group transformation of 11 led
to 5-azido-5-deoxy-3,4-di-O-benzyl- -allitol 14, which
L
underwent oxidative cleavage of C1ꢀC2 single bond,
coupling with Wittig reagent 3, and one-pot reduction
of azido group, (Z)-double bond as well as two benzyl
groups under hydrogenation conditions to give the
target compound 1.
Acknowledgements
We dedicate this paper to Professor Chun-Chen Liao
on the occasion of his 60th birthday. This work was
supported by the National Science Council of Republic
of China (NSC 90-2323-B-001-008).
References
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13. Colorless crystals from chloroform/hexane, C20H17N3O6,
fw=395.37, crystal dimensions: 0.38×0.31×0.13 mm3,
crystal system: orthorhombic, space group: P21, unit cell
dimensions: a=6.1725(7), b=8.6279(17), c=18.2294(22)
3
A, V=965.83(25) A , Z=2, Dcalcd=1.360 g cm−3, wave-
,
,
length=0.71073 A, F(000)=412, v=0.10 mm−1
2q(max)=50.0. The deposition number at the Cambridge
Crystallographic Data Centre is CCDC 173067.
,
,
6. (a) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.;
Sakai, T.; Sawa, E.; Yamaji, K.; Kobayashi, E.;
Fukushima, H.; Koezuka, Y. J. Med. Chem. 1995, 38,
2176; (b) Nakagawa, R.; Motoki, K.; Ueno, H.; Iijima,
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F.; Koezuka, Y.; Porcelli, S. A. J. Exp. Med. 1998, 188,
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15. The selected physical data of new compounds is listed.
1
Compound 13: H NMR (400 MHz, CDCl3) l 8.07–8.05
(m, 2H, ArH), 7.59–7.55 (m, 1H, ArH), 7.45–7.25 (m,
12H, ArH), 6.28 (d, J=8.4 Hz, 1H, H-1), 4.88 (d, J=11.2
Hz, 1H, PhCH2), 4.80 (d, J=11.2 Hz, 1H, PhCH2), 4.62
(d, J=11.6 Hz, 1H, PhCH2), 4.54 (d, J=11.6 Hz, 1H,
PhCH2), 4.22 (t, J=2.4 Hz, 1H, H-3), 4.18 (ddd, J=9.6,
6.0, 3.0 Hz, 1H, H-5), 3.90 (ddd, J=12.2, 5.1, 3.0 Hz, 1H,
H-6a), 3.75 (ddd, J=12.2, 8.0, 6.0 Hz, 1H, H-6b), 3.62
(dd, J=9.6, 2.4 Hz, 1H, H-4), 3.49 (dd, J=8.4, 2.4 Hz,
1H, H-2), 1.71 (dd, J=8.0, 5.1 Hz, 1H, OH); 13C NMR
(100 MHz, CDCl3) l 164.64 (C), 137.89 (C), 137.35 (C),

4892
S.-Y. Luo et al. / Tetrahedron Letters 43 (2002) 4889–4892
133.72 (CH), 130.04 (CH), 128.91 (C), 128.59 (CH),
NMR (100 MHz, CDCl3) l 137.30 (C), 136.80 (C),
128.56 (CH), 128.47 (CH), 128.30 (CH), 128.07 (CH),
127.89 (CH), 127.81 (CH), 127.73 (CH), 91.81 (CH),
77.83 (CH), 75.76 (CH2), 74.36 (CH), 71.02 (CH2), 61.72
(CH2), 56.72 (CH); HRMS (FAB, MH+) calcd for
C19H22N3O4 356.1610, found 356.1619. Compound 16:
1H NMR (400 MHz, CDCl3) l 7.36–7.25 (m, 10H, ArH),
5.78 (td, J=7.2, 11.2 Hz, 1H, H-6), 5.45 (dd, J=11.2, 9.4
Hz, 1H, H-5), 4.73 (d, J=11.2 Hz, 1H, PhCH2), 4.62 (d,
J=11.2 Hz, 1H, PhCH2), 4.61 (d, J=11.2 Hz, 1H,
PhCH2), 4.41 (dd, J=9.4, 5.0 Hz, 1H, H-4), 4.33 (d,
J=11.2 Hz, 1H, PhCH2), 3.86 (dd, J=11.6, 5.0 Hz, 1H,
H-1a), 3.79 (dd, J=11.6, 5.0 Hz, 1H, H-1b), 3.68 (t,
J=5.0 Hz, 1H, H-3), 3.56 (t, J=5.0 Hz, 1H, H-2),
2.02–1.97 (m, 2H, H-7), 1.30 (bs, 20H, 10CH2), 0.86 (t,
J=6.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) l
138.06 (C), 137.77 (C), 137.011 (CH), 128.40 (CH),
128.14 (CH), 127.77 (CH), 127.71 (CH), 125.73 (CH),
81.35 (CH), 74.40 (CH), 74.12 (CH2), 70.21 (CH2), 62.95
(CH), 62.69 (CH2), 31.91 (CH2), 29.65 (CH2), 29.50
(CH2), 29.37 (CH2), 29.35 (CH2), 28.02 (CH2), 22.68
(CH2), 14.10 (CH3); HRMS (FAB, MH+−N2) calcd for
C32H48NO3 494.3634, found 494.3639.
128.49 (CH), 128.29 (CH), 128.14 (CH), 127.97 (CH),
127.92 (CH), 127.75 (CH), 92.30 (CH), 74.94 (CH2),
74.86 (CH), 74.72 (CH), 73.94 (CH2), 72.05 (CH), 62.35
(CH), 61.46 (CH2); HRMS (FAB, M+−H) calcd for
C27H26N3O6 488.1822, found 488.1826. Compound 14:
1H NMR (400 MHz, CDCl3) l 7.37–7.29 (m, 10H, ArH),
4.72 (d, J=11.2 Hz, 2H, PhCH2), 4.66 (d, J=11.2 Hz,
1H, PhCH2), 4.60 (d, J=11.2 Hz, 1H, PhCH2), 3.91–3.81
(m, 4H), 3.78–3.74 (m, 3H), 3.68–3.65 (m, 1H), 2.67 (d,
J=3.9 Hz, 1H, OH), 2.07 (s, 1H, OH), 1.90 (s, 1H, OH);
13C NMR (100 MHz, CDCl3) l 137.42 (C), 137.20 (C),
128.60 (CH), 128.56 (CH), 128.22 (CH), 128.15 (CH),
128.10 (CH), 79.07 (CH), 78.82 (CH), 73.72 (CH2), 73.66
(CH2), 71.52 (CH), 63.82 (CH2), 63.52 (CH), 62.36
(CH2); HRMS (FAB, MH+) calcd for C20H26N3O5
1
388.1872, found 388.1871. Compound 15: H NMR (400
MHz, CDCl3) l 7.38–7.25 (m, 10H, ArH), 5.15 (dd,
J=5.5, 4.4 Hz, 1H, H-1), 4.84 (d, J=11.2 Hz, 1H,
PhCH2), 4.80 (d, J=12.0 Hz, 1H, PhCH2), 4.72 (d,
J=12.0 Hz, 1H, PhCH2), 4.71 (d, J=11.2 Hz, 1H,
PhCH2), 4.06 (t, J=2.8 Hz, 1H, H-3), 3.86 (d, J=6.4 Hz,
2H, H-5), 3.45 (dt, J=2.8, 6.4 Hz, 1H, H-4), 3.36 (dd,
J=5.5, 2.8 Hz, H-2), 2.99 (d, J=4.4 Hz 1H, OH); 13C