Synthesis of an orthogonally protected d-(+)-erythro-sphingosine

Article abstract of DOI:10.1016/S0040-4039(01)01152-2

The synthesis presented provides rapid access to an orthogonally protected d-(+)-erythro-sphingosine: 1-methoxymethyl, 2-azido, 3-benzoyl. After selective deprotection the resulting sphingosine derivative is suitable for coupling to a wide variety of saccharides or other molecules at either the 1- or 3-position.

Full text of DOI:10.1016/S0040-4039(01)01152-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5845–5847
Synthesis of an orthogonally protected
D-(+)-erythro-sphingosine
Joseph M. Gargano and Watson J. Lees*
1-014 CST, Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
Received 6 June 2001; accepted 28 June 2001
Abstract—The synthesis presented provides rapid access to an orthogonally protected
D-(+)-erythro-sphingosine: 1-
methoxymethyl, 2-azido, 3-benzoyl. After selective deprotection the resulting sphingosine derivative is suitable for coupling to a
wide variety of saccharides or other molecules at either the 1- or 3-position. © 2001 Elsevier Science Ltd. All rights reserved.
Glycosphingolipids are involved in many essential bio-
logical processes such as cellular recognition and cell
growth.1–4 They inhibit protein kinase C and are lig-
ands for numerous receptor proteins (lectins, toxins and
antibodies). Glycosphingolipids consist of a carbohy-
drate attached to a sphingosine lipid through a glyco-
sidic bond. While the saccharide varies from system to
cases dramatically lower coupling yields.5 Over 65 syn-
theses of sphingosine have been reported previously
and the advantages and disadvantages of each have
recently been reviewed.6–8 However, most of these syn-
theses do not proceed via an azide and do not produce
a differentially protected sphingosine. Scheme 2 repre-
sents our overall synthetic sequence which, although
different from those previously reported, combines
advantageous elements of former studies.
system the most common lipid moiety is
D
-(+)-erythro-
sphingosine, with 2S,3R,E olefin configuration
a
(Scheme 1). We sought to develop a synthetic route
generating ample amounts of orthogonally protected
Sphingosine consists of a polar head portion connected
to a long-chain alkane by an E olefin. Following the
precedent of Yamanoi et al. the polar head portion was
D
-(+)-erythro-sphingosine suitable for coupling to car-
bohydrates. In order to enhance coupling yields we
desired an azide group at the 2-position of sphingosine
instead of an amine or amide as NH protons in many
synthesized from
D-mannitol in multigram quantities
and then coupled to tetradecyl aldehyde via a Horner–
Wadsworth–Emmons (HWE) reaction.9
D-Mannitol
was protected as the 1,2,5,6 diacetonide,10 which was
then in one-pot oxidatively cleaved and esterified pro-
ducing the commercially available 1.11 Compound 1
was treated with the lithium anion of dimethyl methyl
phosphonate generating the HWE reagent 2.9 Com-
Scheme 1. Sphingosine.
Scheme 2. (a) LiCH2PO(OMe)2, THF, −77°C; (b) (i) tetradecyl aldehyde, CH3CN, K2CO3, (ii) L-Selectride®, THF, −100°C, (iii)
BzCl, pyr., 62% yield from 1; (c) (i) H+/H2O, (ii) TBSCl, pyr., (iii) MsCl, pyr., (iv) HF·pyr., THF, (v) MOMCl, pyr., 69% yield
from 3; (d) LiN3, DMF, 15-crown-5, 90°C, 90% yield.
* Corresponding author. Tel.: 1-315-443-5803; fax: 1-315-443-4070; e-mail: wjlees@syr.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01152-2

5846
J. M. Gargano, W. J. Lees / Tetrahedron Letters 42 (2001) 5845–5847
pound 2 was then coupled to commercially available
tetradecyl aldehyde giving exclusively the trans isomer.9
The main advantage of the HWE procedure is the
exclusive formation of the trans isomer. The ketone was
then reduced with L-Selectride® (11:1, syn:anti ),9 fol-
lowed by protection of the 3-OH as the benzoyl ester to
give 3 (62% over four steps from 1). We observed no
loss in selectivity or yield with the omission of labor
intensive chromatographic separation after each step,
and thus only compound 3 was purified.
In summary, we have demonstrated the synthesis of a
protected -(+)-erythro-sphingosine in 39% overall
D
yield from commercially available 1 with three chro-
matographic steps. The synthesis provides rapid access
to an orthogonally protected precursor suitable for
coupling to a wide variety of saccharides or other
molecules at either the 1- or 3-positions. The route is
rapid, high yielding and results in pure material without
the need for numerous purification steps.
Protection of the 3-OH as the benzoyl ester was essen-
tial for orthogonal protection and also proved impor-
tant during subsequent steps. Removal of the acetonide
with aqueous acid from material containing the unpro-
tected 3-OH yielded an appreciable amount of a side
product, most likely via an allylic transposition. Previ-
ous synthetic routes in general did not protect the 3-OH
but removed the acetonide with aqueous acid and then
protected the 1,3-OH groups as a benzyl acetal in
approximately 45% yield for the two steps.9 Subsequent
mesylation of the benzyl acetal, displacement of the
mesylate with azide, and removal of the acetal also
proceeded in low yield.9,12 Due to these low yielding
reactions we chose an alternative route to an orthogo-
nally protected azide.
Acknowledgements
Financial support was provided by the National Sci-
ence Foundation and by the Petroleum Research Fund.
References
1. Advances in Lipid Research: Sphingolipids and Their
Metabolism; Bell, R. M.; Hannun, Y. A.; Merrill, A. H.,
Eds.; Academic Press: Orlando, FL, 1993; Vol. 25, p. 26.
2. Kanfer, J. N.; Hakomori, S. Handbook of Lipid Research,
Vol. 3 Sphingolipid Biochemistry; Plenum Press: New
York, 1983.
3. Hannun, Y. A. J. Biol. Chem. 1994, 269, 3125–3128.
4. Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500–507.
5. Nicolaou, K. C.; Caulfield, T. J.; Katoaka, H. Carbohydr.
Res. 1990, 202, 177–191.
6. Devant, R. M. Kontakte 1992, 11–28.
7. Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998,
1075–1091.
8. Curfman, C.; Liotta, D. Methods Enzymol. 2000, 311,
391–440.
9. Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.;
Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335–336.
10. Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6–13.
11. Lichtenthaler, F. W.; Jarglis, P.; Lorenz, K. Synthesis
1988, 790–792.
12. Schmidt, R. R.; Zimmermann, P. Tetrahedron Lett. 1986,
27, 481–484.
13. Schmidt, R. R.; Zimmermann, P. Angew. Chem. 1986, 98,
722–723.
The acetonide was then removed from compound 3 by
aqueous acid and the 1° alcohol was protected selec-
tively as the TBS ether.13 The 2° alcohol was then
activated for SN2 displacement as the mesylate and the
protecting group on the 1° alcohol was exchanged from
a TBS group to a MOM group thereby providing 4 in
69% yield over five steps.14 The circular route was
necessitated by the requirements for high 1° versus 2°
alcohol selectivity of the initial protecting group and a
sterically small protecting group at the 1° alcohol for
−
subsequent N3 displacement. The robust OTBS group
sterically blocked the C-2 OMs preventing any −N3
displacement at the site later in the synthesis. The extra
steps were offset by very high yields and omission of
chromatographic separation. As in the earlier portions
of the synthesis all the intermediates were thoroughly
characterized but we obtained higher yields when only
one final purification step was performed on 4. The
final azido displacement goes smoothly in 90% yield
producing compound 5.15 To verify the structure and to
demonstrate selective deprotection, compound 5 was
quantitatively deprotected at C1 to known compound 6
which is the most commonly used sphingosine deriva-
tives for carbohydrate coupling reactions (Scheme 3).13
14. All compounds described have been fully characterized
by H and 13C NMR spectroscopy, and microanalysis.
1
Procedure and characterization data for compound 4: To
a solution of 3 (2.36 g, 5.30 mmol) in CH3CN (40 mL)
was added 6N HCl (10 mL). The reaction was followed
by TLC (hexanes:EtOAc 5:1) until the complete con-
sumption of 3, about 2 h. The solution was then poured
into an EtOAc/H2O partition and the organic layer
removed. The organic portion was further washed with
saturated NaHCO3 and brine, dried (MgSO4), filtered,
and concentrated. The residue was then dried by a single
azeotropic distillation with toluene and dissolved in
CHCl3 (20 mL). To the solution was added TBSCl (1.00
g, 6.90 mmol) and pyridine (1.00 g, 12.70 mmol). After 4
h the solution was diluted with CHCl3 (100 mL) and
washed twice with brine, dried (MgSO4), filtered and
concentrated. The residue was dissolved in CHCl3 (20
mL). Pyridine (1.00 g, 12.70 mmol) and MsCl (1.80 g,
15.70 mmol) were then added. The solution was stirred at
Scheme 3. Selective deprotection at C1.

J. M. Gargano, W. J. Lees / Tetrahedron Letters 42 (2001) 5845–5847
5847
room temperature for 12 h then diluted with CHCl3 (100
mL), washed one time with 5% HCl, twice with brine,
dried (MgSO4), filtered and concentrated. The residue
was dissolved in THF (25 mL) and HF·pyridine was
added (5 mL). After 1 h the reaction was neutralized with
2N NaOH, and diluted with EtOAc. The mixture was
extracted once with brine, dried and concentrated. The
resulting syrup was dried by a single azeotropic distilla-
tion with toluene and used without further purification.
The crude syrup was dissolved in CHCl3 (10 mL) to
which was then added pyridine (1.00 mL, 12.70 mmol)
and MOMCl (1.00 g, 12.70 mmol). The solution was
stirred for 12 h then diluted with 100 mL CHCl3 and
washed once with 5% HCl and once with brine, dried
(MgSO4), filtered and concentrated. The residue was sub-
jected to column chromatography on silica gel (hex-
138.42, 133.25, 129.78, 128.47, 122.71, 96.64, 81.38, 73.11,
66.44, 55.51, 38.81, 32.33, 31.92, 29.64, 29.39, 29.15,
28.60, 22.68, 14.11. Anal. calcd for C28H46O7S: C, 63.85;
H, 8.80. Found: C, 63.79; H, 8.71%.
15. Procedure and characterization data for compound 5: To
a solution of 4 (0.100 g, 0.190 mmol) in DMF (25 mL)
was added 15-crown-5 (0.140 g, 0.630 mmol) and LiN3
(0.031 g, 0.630 mmol). The mixture was stirred at 90°C
for 1 day, cooled and diluted with Et2O (100 mL). The
mixture was washed once with 5% HCl and once brine,
dried (MgSO4), filtered and concentrated. The residue
was subjected to column chromatography on silica gel
1
(hexanes:EtOAc 7:1) to give 5 (0.081 g, 90%); H NMR
(300 MHz, CDCl3): l 8.07 (d, J=7.0 Hz, 2H), 7.51 (t,
J=7.4 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H), 5.94 (dt, J=13.5,
6.6 Hz, 1H), 5.66–5.54 (m, 2H), 4.66 (s, 2H), 3.95 (dt,
J=7.4, 4.3 Hz, 1H), 3.67 (dd, J=10.5, 4.7 Hz, 1H), 3.59
(dd, J=10.4, 7.6 Hz, 1H), 3.37 (s, 3H), 2.05 (broad q,
J=7.1 Hz, 2H), 1.50–1.16 (m, 22H), 0.91 (t, J=7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3): l 165.22, 138.77,
133.21, 129.76, 128.44, 122.94, 96.72, 74.82, 66.88, 64.09,
55.51, 32.34, 31.90, 29.64, 29.57, 29.41, 29.34, 29.12,
28.68, 22.68, 14.12. Anal. calcd for C27H43N3O4: C,
68.47; H, 9.15; N, 8.87. Found: C, 68.45; H, 9.21; N,
8.84%.
1
anes:EtOAc 3:1) to give 4 (1.92 g, 69% in five steps); H
NMR (300 MHz, CDCl3): l 8.07 (d, J=7.0 Hz, 2H), 7.51
(t, J=7.4 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H), 6.00 (dt,
J=15.4, 6.7 Hz, 1H), 5.74 (t, J=7.4 Hz, 1H), 5.51 (dd,
J=15.4, 7.6 Hz, 1H), 5.00 (td, J=6.6, 3.3 Hz, 1H), 4.66
(s, 2H), 3.85 (dd, J=11.4, 3.3 Hz, 1H), 3.76 (dd, J=11.4,
6.4 Hz, 1H), 3.37 (s, 3H), 3.01 (s, 3H), 2.05 (broad q,
J=7.1 Hz, 2H), 1.50–1.16 (m, 22H), 0.91 (t, J=7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3): l 165.22, 138.89,
.