An efficient synthesis of D-ribo- and L-lyxo-phytosphingosine from D-tartaric acid

Article abstract of DOI:10.1016/j.tetlet.2005.03.063

The preparations of D-ribo- and L-lyxo-phytosphingosines (1, 2) are described. Chelation-controlled addition of tetradecylmagnesium bromide to pentylidene-protected D-threitol aldehyde 6 afforded the key intermediate tetrol 7, providing the desired L-lyxo stereochemistry of phytosphingosine. Inversion at C4 of intermediate 7 provided the D-ribo stereochemistry.

Full text of DOI:10.1016/j.tetlet.2005.03.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3165–3168
An efficient synthesis of D-ribo- and L-lyxo-phytosphingosine
from D-tartaric acid
Xuequan Lu and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing,
NY 11367-1597, USA
Received 14 February 2005; revised 9 March 2005; accepted 11 March 2005
Available online 26 March 2005
Abstract—The preparations of D-ribo- and L-lyxo-phytosphingosines (1, 2) are described. Chelation-controlled addition of tetradec-
ylmagnesium bromide to pentylidene-protected D-threitol aldehyde 6 afforded the key intermediate tetrol 7, providing the desired
L-lyxo stereochemistry of phytosphingosine. Inversion at C4 of intermediate 7 provided the D-ribo stereochemistry.
ꢀ 2005 Elsevier Ltd. All rights reserved.
D-ribo-Phytosphingosine (4D-hydroxysphinganine, PHS,
1, Fig. 1) consists of a long-chain base (an aliphatic
chain, predominantly octadecyl) with a 2-amino-1,3,4-
triol head group. It is broadly distributed in fungal,
plant, and animal sphingolipids, where it forms the back-
bone of various glycosphingolipids.1 In addition to its
structural role in membranes, D-ribo-PHS (1) has been
implicated in the regulation of cellular growth; for exam-
ple, PHS is involved in the heat stress response of yeast
cells2 and induction of apoptosis in some cancer cells.3
Amide-linked derivatives of PHS, which constitute
ꢀ30% of the total ceramide content of the outer layer
Figure 1. Structures of D-ribo-PHS (1), L-lyxo-PHS (2), and their
and 4,
of the epidermis (stratum corneum), are important com-
ponents of the lipid architecture that make up the water
permeability barrier of human skin.4 PHS also forms the
backbone of (a) the marine glycolipid KRN7000, a li-
gand of natural killer cells (a unique class of T lympho-
cytes that produce cytokines and have many potential
therapeutic applications in disease settings),5 and (b)
the glycosylphosphatidylinositol (GPI) of the mem-
brane-anchored proteins in yeast.6
corresponding 2-azido-3,4-O-dibenzyl intermediates
respectively.
3
2-azido-3,4-O-dibenzyl intermediates 3 and 4, which
are useful galactosyl acceptors in the preparation of
galactosylphytoceramides.9
Scheme 1 illustrates the retrosynthetic analysis for our
syntheses of D-ribo- and L-lyxo-PHS (1 and 2, respec-
tively) starting with readily available D-(ꢁ)-tartaric acid
(5). The key step is the addition of the long aliphatic
chain to aldehyde 6 under stereocontrolled conditions,
which was accomplished by a chelation-controlled Grig-
nard reaction. After the 4S-hydroxy group was pro-
tected as a benzyl ether, the acetal of the tetrol was
released to form a 1,2-diol. Regioselective azidation at
C2 was accomplished with inversion of configuration,
affording azido alcohol 4. Reduction of the azido group
and removal of the O-benzyl groups of 4 in a one-pot
The biological significance of PHS has intensified the
interest in this lipid as a synthetic target.7 We report
here the preparation of 1 and one of its diastereomers,
L-lyxo-PHS (2), from D-threose synthon 68 via reaction
with tetradecylmagnesium bromide. The route also
provides a convenient access to the corresponding
Keywords: Sphingolipid; Lipid synthesis; Phytosphingosine.
*
Corresponding author. Tel.: +1 718 997 3279; fax: +1 718 997
3349; e-mail: robert_bittman@qc.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.063

3166
X. Lu, R. Bittman / Tetrahedron Letters 46 (2005) 3165–3168
Scheme 1. Retrosynthetic plan.
reaction gave target 2, which was characterized as its N-
Boc derivative 11. For the synthesis of 1, the requisite R
configuration at C4 was obtained by inversion of inter-
mediate 7 using the Mitsunobu reaction.
yield. Simultaneous reduction of the azido group and
hydrogenolysis of the benzyl groups in the presence of
PearlmanÕs catalyst (Pd(OH)2/C) gave 2, whose amino
group was protected as carbamate 11 for ease of isola-
tion14 (78% yield for the two steps).
Scheme 2 outlines the synthesis of 2 from D-tartaric acid
(5). Aldehyde 6 was prepared from D-tartaric acid as re-
ported previously.8 Reaction of aldehyde 6 with tetradec-
ylmagnesium bromide in Et2O at 0 ꢁC gave a 9:1
mixture of compounds 7 and 8.10 The diastereoselecti-
vity of the Grignard addition is markedly higher than
that of the reaction between aldehyde 6 and tetra-
decynyllithium in Et2O at ꢁ20 ꢁC in the presence of ZnBr2,
which (as we reported previously) furnished the
2R,3R,4S and 2R,3R,4R diastereomers in a 3:1 ratio.8
Thus Grignard addition afforded the chelation-con-
trolled product 7,11 which was obtained in 68% yield
after purification by column chromatography (elution
with hexane/EtOAc 3:1). The configuration at C4 was
confirmed when 7 was finally converted to L-lyxo-PHS
(2). After the hydroxy group of 7 was protected as a benzyl
ether (BnBr, NaH, catalytic n-Bu4NBr (TBAB)), selec-
tive deprotection of 9 with 5% H2SO4 provided 1,2-diol
1012 in 82% yield for the two steps. Diol 10 was con-
verted to azido alcohol 4 in a one-pot reaction.13 This
was accomplished by adding the diol to a mixture of
diisopropyl azodicarboxylate (DIAD) and Ph3P at
0 ꢁC. After 3 h, TMSN3 was added to accomplish the
azide substitution reaction together with silylation of
the primary hydroxyl group. Hydrolysis of the silyl ether
with n-Bu4NF (TBAF) provided azido alcohol 4 in 61%
Scheme 3 outlines the synthesis of 1 from alcohol 7. The
configuration at C4 of compound 7 was inverted by
Mitsunobu reaction (p-nitrobenzoic acid, DIAD,
PPh3). Hydrolysis of benzoate ester 1215 with NaOMe
in methanol gave alcohol 8 (80% overall yield for the
two steps). As in the preparation of 2 (Scheme 2), the
C4 hydroxy group was protected as a benzyl ether and
the acetonide was opened by treatment with H2SO4.
After the secondary hydroxy group of diol 1416 was con-
verted to an azido group,17 the azido group was reduced
and the O-benzyl groups were deprotected to give prod-
uct 1. The amino group of 1 was protected as a N-Boc
group to give 1518 (78% yield for two steps).
In summary, short routes to L-lyxo-PHS (2) and D-ribo-
PHS (1) via D-threitol acetal derivative 6 are reported
here. Coupling of tetradecylmagnesium bromide with
aldehyde 6 gave a mixture of alcohols 7 and 8 in a 9:1
ratio. After protection of the 4-hydroxy group and
deprotection of the 1,2-hydroxy groups, the 2-hydroxy
group was converted to an azido group with inversion
of configuration. Hydrogenolysis gave L-lyxo-PHS (2).
For the synthesis of D-ribo-PHS (1), a Mitsunobu reac-
tion was used to invert the requisite configuration of the
third chiral center.
Scheme 2. Synthesis of N-Boc-L-lyxo-phytosphingosine (11). Reagents
and conditions: (a) Ref. 8; (b) C14H29Br, Mg, BrCH2CH2Br, Et2O; (c)
BnBr, NaH, THF; (d) 5% H2SO4, MeOH; (e) (i) PPh3, DIAD, CH2Cl2,
0 ꢁC, (ii) TMSN3, 0 ꢁC–rt, (iii) TBAF, THF; (f) Pd(OH)2/C, H2,
MeOH; (g) Boc2O, Et3N, dioxane/H2O.
Scheme 3. Synthesis of N-Boc-D-ribo-phytosphingosine (15). Reagents
and conditions: (a) DIAD, PPh3, p-nitrobenzoic acid, CH2Cl2; (b)
NaOMe, MeOH; (c) BnBr, NaH, THF; (d) 5% H2SO4, MeOH; (e) (i)
PPh3, DIAD, CH2Cl2, 0 ꢁC, (ii) TMSN3, 0 ꢁC–rt, (iii) TBAF, THF; (f)
Pd(OH)2/C, H2, MeOH; (g) Boc2O, Et3N, dioxane/H2O.

X. Lu, R. Bittman / Tetrahedron Letters 46 (2005) 3165–3168
3167
(CDCl3) d 0.86–0.95 (m, 9H), 1.25–1.35 (m, 24H), 1.62–
1.72 (m, 6H), 1.82 (s, 1H), 3.31 (m, 1H), 3.39 (m, 1H), 3.62
(dd, 1H, J = 8.0, 0.4 Hz), 4.08 (dd, 1H, J = 8.0, 6.4 Hz),
4.40 (m, 1H), 4.67 (d, 1H, J = 11.2 Hz), 4.92 (d, 1H,
J = 11.2 Hz), 7.26–7.37 (m, 5H); 13C NMR (CDCl3) d
8.12, 8.31, 14.1, 22.7, 25.9, 29.3, 29.6, 29.7, 31.9, 34.8, 68.2,
72.1, 74.1, 78.3, 81.2, 113.2, 127.8, 128.3, 128.4, 138.4.
Also obtained was 168 mg of 8 (7%): Rf 0.58 (hexane/
Acknowledgements
This work was supported in part by USPHS Grant
HL16660.
References and notes
25
EtOAc 3:1); ½aꢂD +17.0 (c 0.37, CHCl3); 1H NMR
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1.70 (m, 6H), 2.48 (m, 1H), 3.42 (m, 1H), 3.65 (m, 1H),
3.75 (m, 1H), 3.99 (m, 1H), 4.30 (m, 1H), 4.66 (d, 1H,
J = 11.2 Hz), 4.76 (d, 1H, J = 11.2 Hz), 7.25–7.37 (m, 5H);
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29.7, 31.9, 33.1, 66.4, 72.1, 74.1, 78.3, 81.3, 113.1, 127.4,
127.8, 128.3, 138.4.
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25
12. Data for (ꢁ)-10: Rf 0.24 (hexane/EtOAc 3:1); ½aꢂD ꢁ11.6
(c 1.08, CHCl3); 1H NMR (CDCl3) d 0.88 (t, 3H,
J = 6.8 Hz), 1.33–1.71 (m, 26H), 2.60 (s, 2H), 3.49 (m,
1H), 3.60 (m, 3H), 3.78 (m, 1H), 4.56 (m, 3H), 4.71 (d, 1H,
J = 11.2 Hz), 7.28–7.36 (m, 10H); 13C NMR (CDCl3) d
14.2, 22.7, 26.0, 29.4, 29.6, 30.4, 32.0, 64.3, 71.3, 72.9, 74.2,
77.3, 79.6, 127.8, 128.0, 128.1, 128.2, 128.5, 128.6, 137.9,
138.0.
5. (a) Rogers, P. R.; Matsumoto, A.; Naidenko, O.; Kro-
nenberg, M.; Mikayama, T.; Kato, S. J. Immunol. Meth-
ods 2004, 285, 197–214; (b) Lin, H.; Nieda, M.; Nicol, A.
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6. (a) Lester, R. L.; Dickson, R. C. Adv. Lipid Res. 1993, 26,
253–274; (b) Fankhauser, C.; Homans, S. W.; Thomas-
Oates, J. E.; McConville, M. J.; Desponds, C.; Conzel-
mann, A.; Ferguson, M. A. J. Biol. Chem. 1993, 268,
26365–26374; (c) Fontaine, T.; Magnin, T.; Melhert, A.;
Lamont, D.; Latge, J.-P.; Ferguson, M. A. Glycobiology
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13. (a) He, L.; Wanunu, M.; Byun, H. S.; Bittman, R. J.
Org. Chem. 1999, 64, 6049–6055; (b) For a postulated
mechanism to account for the conversion of a 1,2-diol to
a 2-azido-1-ol with inversion, see: Scheme 1 of Ref. 13a
and Mathieu-Pelta, I.; Evans, S. A., Jr. J. Org. Chem.
1992, 57, 3409–3413; (c) Data for (ꢁ)-4: Rf 0.58 (hexane/
25
EtOAc 3:1); ½aꢂD ꢁ2.4 (c 1.15, CHCl3); Rf 0.70 (hexane/
1
EtOAc 3:1); H NMR (CDCl3) d 0.88 (t, 3H, J = 6.4 Hz),
1.33–1.51 (m, 24H), 1.62 (m, 2H), 1.91 (br s, 1H), 3.56
(m, 1H), 3.68 (m, 2H), 3.87 (m, 2H), 4.59 (m, 2H), 4.65
(m, 2H), 7.28–7.36 (m, 10H); 13C NMR (CDCl3) d 14.2,
22.7, 25.9, 29.4, 29.6, 30.4, 32.0, 62.5, 63.3, 72.6, 74.4,
79.2, 79.8, 127.8, 128.0, 128.1, 128.2, 128.5, 128.6, 137.7,
138.2.
7. For a recent review of syntheses of phytosphingosine, see:
Howell, A. R.; Ndakala, A. J. Curr. Org. Chem. 2002, 6,
365–391.
8. Lu, X.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2004, 69,
5433–5438.
14. Data for (ꢁ)-11: Rf 0.29 (hexane/EtOAc 1:1); mp 129.5–
25
131.2 ꢁC; ½aꢂD ꢁ7.9 (c 0.35, CHCl3), 1H NMR (CDCl3)
9. For the use of 2-azido-3,4-O-dibenzyl PHS (4) in the
preparation of galactosylphytoceramides, see: (a) Bernd,
K.; Thomas, G. M.; Richard, R. S. Eur. J. Org. Chem.
1998, 291–298; (b) Valeria, C.; Ernesto, F.; Concetta, I.;
Alfonso, M. Tetrahedron 2002, 58, 369–375; (c) Lucia, B.;
Valeria, C.; Ernesto, F.; Alfonso, M.; Elisabetta, A.;
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(d) Fan, G. T.; Pan, Y. S.; Lu, K. C.; Cheng, Y. P.; Lin,
W. C.; Lin, S.; Lin, C. H.; Wong, C. H.; Fang, J. M.; Lin,
C. C. Tetrahedron 2005, 61, 1855–1862.
d 0.88 (t, 3H, J = 6.4 Hz), 1.33–1.71 (m, 33H), 1.62 (m,
2H), 3.32 (m, 1H), 3.51 (m, 1H), 3.72 (m, 1H), 4.06 (m,
1H), 5.21 (m, 1H); 13C NMR (CDCl3) d 14.1, 22.7, 28.3,
29.4, 29.6, 32.0, 53.5, 61.9, 69.7, 72.8, 80.4, 157.3.
25
15. Data for (ꢁ)-12: Rf 0.69 (hexane/EtOAc 3:1); ½aꢂD ꢁ15.0
1
(c 1.33, CHCl3); H NMR (CDCl3) d 0.86–0.93 (m, 9H),
1.23–1.55 (m, 24H), 1.60–1.69 (m, 6H), 3.67 (m, 1H), 3.77
(m, 1H), 4.01 (m, 1H), 4.25 (m, 1H), 4.75 (d, 1H,
J = 11.2 Hz), 4.79 (d, 1H, J = 11.2 Hz), 5.04 (m, 1H),
7.26–7.37 (m, 5H), 8.14 (d, 2H, J = 7.2 Hz), 8.29 (d, 2H,
J = 7.2 Hz); 13C NMR (CDCl3) d 8.14, 8.23, 14.1, 22.7,
25.7, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 66.7, 73.9, 76.2, 77.6,
80.7, 113.4, 123.5, 127.7, 128.1, 128.3, 130.8, 135.5, 138.2,
150.6, 164.2.
10. Experimental details for the addition of aldehyde 6 to
C14H29MgBr and the isolation of 7 and 8: To a solution of
aldehyde 6 (1.39 g, 5.0 mmol) in 50 mL of Et2O at 0 ꢁC
was quickly added freshly prepared C14H29MgBr
(15 mmol) in 50 mL of Et2O. The reaction mixture was
stirred at 0 ꢁC for 3 h, then warmed to room temperature
and stirred overnight. The reaction mixture was quenched
by adding 50 mL of water, the organic phase was
separated, and the aqueous phase was extracted with
Et2O (3 · 20 mL). The organic layer was dried (Na2SO4),
and the solvent was removed by vacuum evaporation. The
residue was purified by chromatography (hexane/EtOAc
3:1) to give 1.61 g of 7 (68%) as a colorless oil: Rf 0.54
25
16. Data for (ꢁ)-14: Rf 0.24 (hexane/EtOAc 3:1); ½aꢂD ꢁ9.8 (c
1.39, CHCl3); 1H NMR (CDCl3)
d 0.88 (t, 3H,
J = 6.8 Hz), 1.33–1.71 (m, 26H), 2.51 (s, 1H), 3.34 (m,
1H), 3.53 (m, 1H), 3.65 (m, 3H), 3.87 (m, 1H), 4.54 (m,
2H), 4.63 (d, 1H, J = 11.2 Hz), 4.71 (d, 1H, J = 11.2 Hz),
7.28–7.36 (m, 10H); 13C NMR (CDCl3) d 14.1, 22.5, 25.6,
29.4, 29.6, 30.8, 31.9, 63.7, 71.4, 72.7, 73.6, 77.4, 79.7,
127.8, 128.0, 128.1, 128.2, 128.5, 128.6, 137.9, 138.0.
17. Data for azido alcohol (ꢁ)-3: Rf 0.58 (hexane/EtOAc 3:1);
25
25
½aꢂD ꢁ3.71 (c 4.15, CHCl3); Rf 0.70 (hexane/EtOAc 3:1);
(hexane/EtOAc 3:1); ½aꢂD +18.6 (c 2.36, CHCl3); 1H NMR

3168
X. Lu, R. Bittman / Tetrahedron Letters 46 (2005) 3165–3168
1H NMR (CDCl3) d 0.88 (t, 3H, J = 6.4 Hz), 1.33–1.51 (m,
18. Data for (+)-15: Rf 0.29 (hexane/EtOAc 1:1); mp
25
24H), 1.60 (m, 2H), 2.61 (m, 1H), 3.63 (m, 3H), 3.78 (m,
1H), 3.87 (m, 1H), 4.59 (m, 2H), 4.67 (m, 2H), 7.28–7.36
(m, 10H); 13C NMR (CDCl3) d 14.1, 22.7, 25.5, 29.4, 29.6,
30.2, 31.9, 62.2, 63.1, 72.5, 73.6, 79.1, 80.4, 127.8, 128.0,
128.1, 128.2, 128.4, 128.5, 137.7, 138.2.
89.2–90.4 ꢁC; ½aꢂD +7.5 (c 0.51, CHCl3); 1H NMR (CDCl3)
d 0.88 (t, 3H, J = 6.4 Hz), 1.16–1.78 (m, 35H), 3.64 (m,
3H), 3.82 (m, 2H), 4.09 (m, 1H), 4.16 (m, 1H), 4.44 (m,
1H), 5.62 (m, 1H); 13C NMR (CDCl3) d 14.1, 22.7, 28.3,
29.4, 29.6, 29.7, 31.9, 52.6, 61.7, 73.0, 75.6, 79.9, 156.3.