Efficient and versatile synthesis of (2S,3R)-sphingosine and its 2-azido-3-O-benzylsphingosine analogue

Article abstract of DOI:10.1016/j.tetlet.2005.01.104

The title compounds (1, 2) were synthesized from (2R,3S)-2-O-benzyl-3,4-O- (3′-pentylidene)-2,3,4-trihydroxybutanal (5). Installation of the E-double bond and aliphatic chain into the sphingosine base was effected by a sequence of Horner-Wadsworth-Emmons olefination of 5, conversion to allylic acetate 8, and copper-mediated Grignard coupling. The method is versatile, allowing a broad variety of aliphatic chains to be introduced in the organocuprate coupling step.

Full text of DOI:10.1016/j.tetlet.2005.01.104

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1873–1875
Efficient and versatile synthesis of (2S,3R)-sphingosine and its
2-azido-3-O-benzylsphingosine analogue
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 1 November 2004; accepted 20 January 2005
Abstract—The title compounds (1, 2) were synthesized from (2R,3S)-2-O-benzyl-3,4-O-(30-pentylidene)-2,3,4-trihydroxybutanal (5).
Installation of the E-double bond and aliphatic chain into the sphingosine base was effected by a sequence of Horner–Wadsworth–
Emmons olefination of 5, conversion to allylic acetate 8, and copper-mediated Grignard coupling. The method is versatile, allowing
a broad variety of aliphatic chains to be introduced in the organocuprate coupling step.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Sphingolipids are structural components of eukaryotic
cell membranes, are the key contributors to the stability
of Ôlipid raftÕ microdomains, and are a source of lipid
messengers that regulate a wide variety of biological
processes ranging from inflammation to cell prolifera-
tion and apoptosis.1 Sphingoid bases, which form the
backbone of sphingolipids, are aliphatic 2-amino-1,3-
diols. The most prevalent base is (2S,3R)-2-amino-4E-
1,3-octadecenediol, known as D-erythro-sphingosine (1).
OH
NH2
OBn
N3
HO
C13H27
HO
C13H27
2
1
logue 2, which has been used as a glycosyl acceptor in
glycosphingolipid synthesis.6,7 We recently reported
the utility of D-threose synthon 4, which is derived from
D-tartaric acid (3),8 as a convenient synthon of a phos-
phonate of phytosphingosine.9 The Horner–Wads-
worth–Emmons (HWE) reaction, followed by coupling
of an allylic acetate with dodecylorganocuprate to intro-
duce the 4,5-trans double bond and the long chain, com-
pleted the synthesis of 1 in nine steps from 4.
Facile synthetic routes to sphingosine and its analogues
are needed. Indeed, a great dealof effort has been de-
voted toward the synthesis of 1 and its derivatives for
use in biological and pharmacological studies.2 Many
synthetic efforts have utilized starting materials derived
from the chiral pool, in particular, carbohydrate, serine,
and tartaric acid precursors,3 whereas other syntheses
have employed asymmetric induction, including Sharp-
less asymmetric epoxidation, asymmetric aldol, and
other stereoselective reactions, to achieve high diastereo-
selectivity.4 When chiralsubstrates are used as the
starting materials, the characteristic trans double bond
of sphingosine is often generated by Wittig reaction4e
or Julia olefination.5 When an E,Z mixture is obtained,
photoisomerization has been used to convert the Z
unsaturation to the desired E configuration.4e
Scheme 1 illustrates the synthesis of sphingosine 1 from
4.9 The
pentylidene-protected D-threitolderivative
advantage of pentylidene acetal 4 is that it is less acid
sensitive and thus more stable than the corresponding
isopropylidene acetal. Alcohol 4 was oxidized with
PCC to afford aldehyde 5, which was used directly in
the next step without further purification. After the trans
double bond was formed with diisopropyl (ethoxycar-
bonylmethyl)phosphonate in the presence of lithium
bromide and triethylamine, the resulting ester 610 was
converted via alcohol 711 to allylic acetate 8.12
In this communication, we describe an efficient method
for the preparation of 1 and its 2-azido-3-O-benzylana-
In our initial attempt to install the aliphatic chain, allylic
alcohol 7 was activated by mesylation and then sub-
jected to copper-mediated Grignard reaction. Unfortu-
nately, the coupling reaction with mesylate 1213 was
*
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.2005.01.104

1874
X. Lu, R. Bittman / Tetrahedron Letters 46 (2005) 1873–1875
prepared (six steps from 5, 23% overall yield). The
OBn
OBn
OBn
O
OH
OEt
b
a
advantage of the method described here lies in its versa-
tility, since many (2S,3R)-sphingosine derivatives can be
readily prepared with the desired 4E stereochemistry. In
addition, if the enantiomer of 4 is prepared from L-tar-
taric acid, this method would provide a convenient route
to the enantiomer of 1.
O
O
O
Et
O
Et
O
O
Et
4
O
Et
Et
R
Et
6 (77%)
5 (91%)
OBn
OBn
f
c
O
e
O
C13H27
O
O
Et
Et
d
Et
Et
Acknowledgements
7 (83%) R = OH
9
8 (92%) R = OAc
This work was supported in part by USPHS Grant
HL16660.
OBn
R
g
h
HO
C13H27
HO
2 (61%)
C13H27
NH2
OH
References and notes
11 (90%) R = OBn
1 (85%) R = OH
10 (63%)
i
1. (a) Menaldino, D. S.; Bushnev, A.; Sun, A.; Liotta, D. C.;
Symolon, H.; Desai, K.; Dillehay, D. L.; Peng, Q.; Wang,
E.; Allegood, J.; Trotman-Pruett, S.; Sullards, M. C.;
Merrill, A. H., Jr. Pharmacol Res. 2003, 47, 373–381; (b)
Futerman, A. H.; Hannun, Y. A. EMBO Reports 2004, 5,
777–782.
2. For reviews of the synthesis of sphingosine, see: (a) Byun,
H.-S.; Bittman, R. In Phospholipids Handbook; Cevc, G.,
Ed.; Dekker: New York, 1993; pp 97–140; (b) Koskinen,
P. M.; Koskinen, A. M. P. Synthesis 1998, 8, 1075–1091;
(c) Curfman, C.; Liotta, D. Methods Enzymol. 1999, 311,
391–440; (d) Jung, K.-H.; Schmidt, R. R. In Lipid
Synthesis and Manufacture; Gunstone, F. D., Ed.; Shef-
field Academic: Sheffield UK, 1999; pp 208–249; (e)
Koskinen, P. M.; Koskinen, A. M. P. Methods Enzymol.
1999, 311, 458–479.
3. (a) Zimmermann, P.; Schmidt, R. R. Liebigs Ann. Chem.
1988, 663–667; (b) Garner, P.; Park, J. M.; Malecki, E. J.
Org. Chem. 1988, 53, 4395–4398; (c) Herold, P. Helv.
Chim. Acta 1988, 71, 354–362; (d) Somfai, P.; Olsson, R.
Tetrahedron 1993, 49, 6645–6650; (e) Murakami, T.; Hato,
M. J. Chem. Soc., Perkin Trans. 1 1996, 823–827.
4. (a) Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. Helv.
Chim. Acta 1986, 69, 368–373; (b) Boutin, R. H.;
Rapoport, H. J. Org. Chem. 1986, 51, 5320–5327; (c)
Scheme 1. Synthesis of (2S,3R)-sphingosine (1) and intermediate 2.
Reagents and conditions: (a) PCC, NaOAc, CH2Cl2, MS; (b) (i-
PrO)2P(O)CH2CO2Et, NEt3, LiBr, THF, rt; (c) DIBAL-H, À78 ꢁC,
CH2Cl2; (d) AcCl, i-Pr2NEt, CH2Cl2, À40 ꢁC–rt; (e) C12H25MgBr,
Li2CuCl4, Et2O, À78 ꢁC–rt; (f) 5% H2SO4, MeOH; (g) (i) PPh3, DIAD,
CH2Cl2, 0 ꢁC, (ii) TMSN3, 0 ꢁC–rt, (iii) TBAF, THF; (h) PPh3, THF/
H2O 9:1; and (i) Na, NH3, THF, À78 ꢁC, 30 min.
not regioselective, giving a 1:2 mixture of the desired
coupling product 9 (via a attack) and product 13 (via
c attack).14 Therefore, allylic alcohol 7 was converted
to acetate derivative 8 by treatment with acetylchol ride
in the presence of i-Pr2NEt. Coupling of acetate 8 with
freshly prepared C12H25MgBr in the presence of cata-
lytic Li2CuCl4 in Et2O at À78 ꢁC was regioselective,
affording intermediate 9 exclusively.
Deprotection of acetal 9 with 5% H2SO4 in methanol
provided diol 10 (65% yield for the two steps).15 The sec-
ondary hydroxy group of 10 was converted to an azido
group in a one-pot reaction,16 which was accomplished
by adding diol 10 to a mixture of diisopropylazodicarb-
oxylate (DIAD) and Ph3P at 0 ꢁC. After 3 h, TMSN3
was added to give the azide substitution product with
concomitant transfer of the silyl group to the primary
hydroxyl group. Hydrolysis of the silyl ether and purifi-
cation by column chromatography provided azidosp-
hingosine derivative 2 in 61% yield.17 Although Birch
reduction would reduce the azido group and cleave the
O-benzylgroup of 2 in one-pot, it was reported that
the yield is low for this conversion.18 Therefore, the
azide was first reduced to an amino group by the Stau-
dinger reaction (PPh3, THF/H2O (9:1))19 to afford a-
amino alcohol 11 in high yield,20 and then the benzyl
group was removed by Birch reduction (À78 ꢁC,
30 min) to give sphingosine 1 in 85% yield. The structure
of 1 was confirmed by the identity of its physicaldata
´
Solladie-Cavallo, A.; Koessler, J. L. J. Org. Chem. 1994,
59, 3240–3242; (d) Nugent, T. C.; Hudlicky, T. J. Org.
Chem. 1998, 63, 510–520; (e) He, L.; Byun, H.-S.; Bittman,
R. J. Org. Chem. 2000, 65, 7627–7633; (f) van den Berg, R.
J. B. H. N.; Korevaar, C. G. N.; Overkleeft, H. S.; van der
Marel, G. A.; van Boom, J. H. J. Org. Chem. 2004, 69,
5699–5704; (g) Torsell, S.; Somfai, P. Org. Biomol. Chem.
2004, 2, 1643–1646.
5. Compostella, F.; Franchini, L.; Panza, L.; Prosperi, D.;
Ronchetti, F. Tetrahedron 2002, 58, 4425–4428.
6. Tsunoda, H.; Ogawa, S. Liebigs Ann. Chem. 1995, 2, 267–
277.
7. For uses of 2 as a glycosyl acceptor, see: (a) Park, T. K.;
Lim, I. J.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36,
9089–9092; (b) Park, T. K.; Kim, I. J.; Hu, S.; Bilodeau,
M. T.; Randolph, J. T.; Kwon, O.; Danishefsky, S. J. J.
Am. Chem. Soc. 1996, 118, 11488–11500; (c) Kwon, O.;
Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1588–
1599; (d) Deshpande, P. P.; Kim, H. M.; Zatorski, A.;
Park, T.-K.; Ragupathi, G.; Livingston, P. O.; Live, D.;
Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1600–
1614.
25
D
13
(1H and C NMR, ½aꢀ , mp)21 with those reported in
the literature.3,4
In summary, a facile synthesis of sphingosine (1) via
aldehyde 5 in eight steps in 17% overall yield has been
described. 2-Azido-3-O-benzylsphingosine 2 was also
8. For reviews of the uses of 3 and its derivatives as synthons
´
of naturalproducts, see: (a) Gawron ski, J.; Gawronska,
K. Tartaric and Malic Acids in Synthesis; John Wiley &
´

X. Lu, R. Bittman / Tetrahedron Letters 46 (2005) 1873–1875
1875
Sons: New York; (b) Ghosh, A. K.; Koltun, E. S.; Bilcer,
G. Synthesis 2001, 1281–1301.
mixture was stirred overnight, 5 g of K2CO3 was added,
the mixture was filtered, and the filtrate was removed.
Column chromatography (hexane/EtOAc 2:1) gave 1.23 g
of 10 (63% for two steps) as a colorless oil; Rf 0.15
9. Lu, X.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2004, 69,
5433–5438.
25
25
10. Data for (À)-6: Rf 0.72 (EtOAc/hexane 1:3); ½aꢀD À11.0 (c
(hexane/EtOAc 3:1); ½aꢀD À23.7 (c 4.35, CHCl3); 1H NMR
1
2.7, CHCl3); H NMR (CDCl3) d 0.84–0.92 (m, 6H), 1.32
(CDCl3) d 0.88 (t, 3H, J = 6.8 Hz), 1.25–1.41 (m, 22H),
2.10 (m, 2H), 3.54 (m, 1H), 3.65 (m, 2H), 3.77 (m, 1H),
4.30 (d, 1H, J = 11.6 Hz), 4.60 (d, 1H, J = 11.6 Hz), 5.38
(m, 1H), 5.76 (m, 1H), 7.27–7.35 (m, 5H); 13C NMR
(CDCl3) 14.2, 19.5, 29.0, 29.3, 29.5, 29.8, 29.9, 30.0, 30.1,
31.9, 32.3, 63.3, 70.0, 74.1, 81.1, 126.3, 127.9, 128.0, 128.6,
138.0, 138.2. MS (ESI) m/z 408.3 (MNH4+).
(t, 3H, J = 6.8 Hz), 1.58–1.66 (m, 4H), 3.68 (t, 1H,
J = 7.6 Hz), 3.98 (t, 1H, J = 6.8 Hz), 4.13 (m, 1H), 4.22
(m, 3H), 4.52 (d, 1H, J = 12.0 Hz), 4.70 (d, 1H,
J = 12.0 Hz), 6.10 (d, 1H, J = 16.0 Hz), 6.85 (dd, 1H,
J = 6.0, 7.6 Hz), 7.25–7.40 (m, 5H); 13C NMR (CDCl3) d
8.1, 8.2, 14.2, 28.9, 29.4, 60.6, 65.9, 71.5, 77.2, 79.0, 83.1,
113.8, 124.4, 127.8, 128.4, 137.7, 143.4, 165.8.
16. (a) He, L.; Wanunu, M.; Byun, H.-S.; Bittman, R. J. Org.
Chem. 1999, 64, 6049–6055; (b) For a postulated mech-
anism to account for the conversion of a 1,2-diolto a 2-
azido-1-olwith inversion, see: Scheme 1 of Ref. 16a and
Mathieu-Pelta, I.; Evans, S. A., Jr. J. Org. Chem. 1992, 57,
3409–3413.
11. Reduction of ester 6 to allylic alcohol 7 with DIBAL-H
was carried out at À78 ꢁC because it was found that the
acetalwas reduced to reelase the primary hydroxy group
when the temperature was raised to 0 ꢁC. Data for ((À)-7):
25
Rf 0.21 (EtOAc/hexane 1:3); ½aꢀD À18.6 (c 2.8, CHCl3); 1H
25
NMR (CDCl3) d 0.84–0.92 (m, 6H), 1.70–1.86 (m, 4H),
3.77 (t, 1H, J = 8.0 Hz), 3.92 (m, 4H), 4.28 (m, 1H), 4.48
(d, 1H, J = 12.4 Hz), 4.70 (d, 1H, J = 12.0 Hz), 5.73 (m,
2H), 7.20 (m, 1H), 7.25–7.47 (m, 4H); 13C NMR (CDCl3)
d 8.4, 8.5, 29.6, 30.1, 62.5, 66.5, 70.6, 78.7, 80.9, 113.6,
126.7, 134.8, 139.2.
17. Data for (À)-2: Rf 0.51 (hexane/EtOAc 3:1); ½aꢀD À55.2 (c
1.34, CHCl3); 1H NMR (CDCl3)
d 0.88 (t, 3H,
J = 6.8 Hz), 1.25–1.41 (m, 22H), 2.10 (m, 2H), 3.50 (m,
1H), 3.71 (m, 2H), 3.90 (m, 1H), 4.34 (d, 1H, J = 11.6 Hz),
4.62 (d, 1H, J = 11.6 Hz), 5.48 (m, 1H), 5.80 (m, 1H),
7.27–7.35 (m, 5H); 13C NMR (CDCl3) 14.1, 22.7, 28.9,
29.2, 29.3, 29.6, 31.9, 32.4, 62.7, 66.0, 70.1, 80.7, 126.3,
127.7, 128.5, 137.8, 138.4. MS (ESI) m/z 433.4
25
12. Data for (À)-8: Rf 0.64 (EtOAc/hexane 1:3); ½aꢀD À13.5 (c
4.0, CHCl3); 1H NMR (CDCl3) d 0.84–0.91 (m, 6H), 1.60–
1.65 (m, 4H), 2.07 (s, 3H), 3.65 (t, 1H, J = 8.0 Hz), 3.92
(m, 2H), 4.20 (dd, 1H, J = 6.8, 13.6 Hz), 4.48 (d, 1H,
J = 12.4 Hz), 4.59 (m, 1H), 4.70 (d, 1H, J = 12.4 Hz), 5.66
(dd, 1H, J = 7.2, 15.6 Hz), 5.85 (dt, 1H, J = 5.6, 15.6 Hz),
7.25–7.37 (m, 5H); 13C NMR (CDCl3) d 8.0, 8.2, 20.9,
29.1, 29.6, 63.9, 66.2, 70.6, 77.8, 79.7, 113.4, 127.6, 128.0,
128.4, 129.4, 129.9, 138.1, 170.7.
+
(MNH4 ).18
18. Wang, X.-Z.; Wu, Y.-L.; Jiang, S.; Singh, G. Tetrahedron
Lett. 1999, 40, 8911–8914.
19. For a review of the Staudinger reaction, see: Gololobov,
Yu. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353–
1406.
25
20. Data for (À)-11: Rf 0.38 (CHCl3/MeOH 9:1); ½aꢀD À35.3 (c
25
13. Data for (À)-12: Rf 0.70 (hexane/EtOAc 3:1); ½aꢀD À16.4
0.75, CHCl3); 1H NMR (CDCl3)
d 0.88 (t, 3H,
1
(c 1.35, CHCl3); H NMR (CDCl3) d 0.84–0.92 (m, 6H),
J = 6.8 Hz), 1.25–1.41 (m, 22H), 2.10 (m, 2H), 3.10 (m,
4H), 3.71 (m, 3H), 4.31 (d, 1H, J = 12.0 Hz), 4.65 (d, 1H,
J = 12.0 Hz), 5.38 (m, 1H), 5.76 (m, 1H), 7.27–7.35 (m,
5H); 13C NMR (CDCl3) 14.1, 22.7, 29.2, 29.3, 29.5, 29.8,
32.8, 32.9, 55.9, 63.0, 70.1, 74.1, 81.2, 126.6, 127.7, 127.8,
128.4, 138.1. MS (ESI) m/z 390.3 (MH+).
1.70–1.86 (m, 4H), 3.77 (t, 1H, J = 8.0 Hz), 3.92 (m, 4H),
4.28 (m, 1H), 4.48 (d, 1H, J = 12.4 Hz), 4.70 (d, 1H,
J = 12.0 Hz), 5.73 (m, 2H), 7.20(m, 1H), 7.25–7.47 (m,
4H); 13C NMR (CDCl3) (8.4, 8.5, 29.6, 30.1, 62.5, 66.5,
70.6, 78.7, 80.9, 113.6, 126.7, 134.8, 139.2.
14. Copper-mediated Grignard reaction of allylic mesylate 12
gave a mixture of 9 and 13:
21. Data for (À)-1: Rf 0.35 (CHCl3/MeOH/NH4OH 135:25:4);
mp 81.0–82.3 ꢁC [lit.4b mp 72–75 ꢁC, lit.4c mp 76–77 ꢁC,
OBn
OBn
C12H25
MsCl, i-Pr2NEt
OMs
C
12H25MgBr, Li2CuCl4
O
O
+
9
7
O
O
Et
CH2Cl2, -40 °C - rt
Et2O, -78 °C - rt
Et
Et
Et
12 (92%)
13
9:13 = 1:2 (75%)
25
lit.4e mp 80.7–82.1 ꢁC]; ½aꢀD À2.9 (c 1.0, CHCl3) [lit.3a
15. Preparation of (À)-10. To a solution of acetate 8 (1.74 g,
5.0 mmol) and Li2CuCl4 (0.1 mmol, 1 mL of a 0.1 M
solution) in 50 mL of Et2O at À78 ꢁC was quickly added
freshly prepared C12H25MgBr (15 mmol) in 50 mL of
Et2O. The solution was stirred at À78 ꢁC for 3 h, then
warmed to room temperature and stirred overnight. After
the reaction was quenched with water, the organic phase
was separated, the aqueous phase was extracted with Et2O
(3 · 20 mL), the organic layer was dried (Na2SO4), and the
solvent was removed. To the residue was added 100 mL of
MeOH, followed by 10 mL of 5% aqueous H2SO4. The
22
21
½aꢀD À2.5ꢁ(c 6, CHCl3), lit.4b ½aꢀD À1.3ꢁ (c 3.5,
25
20
CHCl3), lit.4e ½aꢀD À2.7 (c 1.2, CHCl3), lit.4f ½aꢀD À1.4
20
(c 0.42, CHCl3), lit.4g ½aꢀD À1.6 (c 1.0, CHCl3)]; 1H NMR
(CDCl3) d 0.85 (t, 3H, J = 7.0 Hz), 1.23 (m, 20H), 1.35 (m,
2H), 2.02 (q, 2H, J = 7.0 Hz), 2.64 (br s, 4H), 2.84 (q, 1H,
J = 5.2 Hz), 3.64 (m, 2H), 4.04 (t, 1H, J = 6.0 Hz), 5.44
(dd, 1H, J = 15.4, 7.2 Hz), 5.71 (dt, 1H, J = 15.4, 7.2 Hz);
13C NMR (CDCl3) d 14.1, 22.7, 29.2, 29.3, 29.4, 29.5,
29.62, 29.65, 29.68, 31.9, 32.4, 56.2, 63.7, 75.1, 129.1,
134.7. MS (ESI) m/z 300.3 (MH+).