Effective, high-yielding, and stereospecific total synthesis of D-erythro-(2R,3S)-sphingosine from D-ribo-(2S,3S,4R)-phytosphingosine

Article abstract of DOI:10.1021/jo049277y

The synthesis of naturally occurring D-erythro-(2R,3S,4E)-sphingosine from commercially available D-ribo-(2S,3S,4R)-phytosphingosine is described. The key step in the reaction sequence comprises TMSI/DBN promoted regio- and stereoselective oxirane opening of intermediate 2-phenyl-4-(S)-[(1S,2S)-1,2- epoxyhexadecyl]-1,3-oxazoline followed by the in situ trans-elimination of 2-phenyl-4-(S)-[(1S,2R)-1,2-dideoxy-2-iodo-1-trimethylsilyloxyhexadecyl]-1, 3-oxazoline.

Full text of DOI:10.1021/jo049277y

Effective, High -Yield in g, a n d Ster eosp ecific Tota l Syn th esis of
D-er yth r o-(2R,3S)-Sp h in gosin e fr om
D-r ibo-(2S,3S,4R)-P h ytosp h in gosin e
Richard J . B. H. N. van den Berg,† Cornelius G. N. Korevaar,† Herman S. Overkleeft,‡
Gijsbert A. van der Marel,‡ and J acques H. van Boom*,‡
Cosmoferm B.V., P.O. Box 386, 2600 AJ Delft, The Netherlands, and Leiden Institute of Chemistry,
Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
j.boom@chem.leidenuniv.nl
Received April 29, 2004
The synthesis of naturally occurring D-erythro-(2R,3S,4E)-sphingosine from commercially available
D-ribo-(2S,3S,4R)-phytosphingosine is described. The key step in the reaction sequence comprises
TMSI/DBN promoted regio- and stereoselective oxirane opening of intermediate 2-phenyl-4-(S)-
[(1S,2S)-1,2-epoxyhexadecyl]-1,3-oxazoline followed by the in situ trans-elimination of 2-phenyl-
4-(S)-[(1S,2R)-1,2-dideoxy-2-iodo-1-trimethylsilyloxyhexadecyl]-1,3-oxazoline.
In tr od u ction
ment of synthetic strategies to obtain 1 in useful quan-
tities. Despite these efforts, an efficient and straightfor-
ward synthesis of 1 on a large scale has not been achieved
yet. Most reported approaches are hampered by lengthy
and expensive routes, lack of stereochemical control, and/
or moderate yielding steps. A crucial requirement for an
efficient and cost-effective synthesis of 1 is the avail-
ability of a starting material that not only requires
minimal protecting-group manipulations but also enables
highly stereoselective transformations. We here report
that commercially available and cheap D-ribo-phyto-
sphingosine 28 fulfils most of the requirements mentioned
previously.
Glycosphingolipids (GSL), such as ceramides, cerebro-
sides, and gangliosides, are ubiquitous components of
plasma membranes1 and are involved in a plethora of
biological processes, including cellular recognition, signal
transduction, and apoptosis.2 Furthermore, recent stud-
ies3 indicate that ceramides from skin tissue, or their
synthetic analogues, show promise as therapeutics for
the treatment of pathogenesis in which skin barrier
impairment is involved, such as in atopic skin, psoriasis,
ichthyosis, and contact dermatitis. As such, GSL are of
increasing interest for cosmetic4 and therapeutic5 ap-
plication. Unfortunately, GSL in homogeneous form are
not readily available from natural sources. The most
common key-backbone component of GSL is D-erythro-
sphingosine [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-
ene-1-ol (1)], of which the primary hydroxyl function is
glycosylated while the amino function is acylated by a
fatty acid. In this respect, ever since the 50 year-old
report6 describing the preparation of racemic 1, consider-
able research efforts7 have been devoted to the develop-
Resu lts a n d Discu ssion
Recently, we published a convenient route to 1 starting
from 2.9 The key event in this approach, as briefly
portrayed in Scheme 1, is the regiospecific and stereo-
selective transformation of fully protected ketone 3 into
the corresponding Z-enol triflate 410 followed by pal-
ladium-assisted regiospecific reduction.11 According to
* To whom correspondence should be addressed. Phone: +31-71-
5274274. Fax: +31-71-5274307.
(7) Selected publications on recent syntheses of D-erythro-sphin-
gosine (a) He, L. L.; Byun, H. S.; Bittman, R. J . Org. Chem. 2000, 65,
7627-7633. (b) Corey, E. J .; Choi, S. Y. 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.; J arowicki, 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. (g) Murakami, T.; Furusawa, K. Tetrahedron 2002, 58, 9257-
9263. (h) Lee, H. K.; Kim, E. K.; Pak, C. S. Tetrahedron Lett. 2002,
43, 9641-9644. (i) Raghavan, S.; Rajender, A. J . Org. Chem. 2003,
68, 7094-7097. (j) Olofsson, B.; Somfai, P. J . Org. Chem. 2002, 67,
8574-8583. 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. Synthesis 1998, 8, 1075-1091. (c) J ung, K. H.;
Schmidt, R. R. In Lipid Synthesis and Manufacture; Gunstone, F. D.,
Ed.; Sheffield Academic Press: Sheffield, U.K.; CRC Press: Boca
Raton, FL, 1999; pp 208-249. (d) Curfman, C.; Liotta, D. Methods
Enzymol. 2000, 311, 391-440.
† Cosmoferm B. V.
‡ Leiden Institute of Chemistry, Leiden University.
(1) Sweely, C. C. In Biochemistry of Lipids, Lipoproteins, and
Membranes; Vance D. E., Vance, J . E., Eds.; Elsevier: Amsterdam,
1991.
(2) (a) Cinque, B.; Di Marzio, L.; Centi, C.; Di Rocco, C.; Riccardi,
C.; Cifone, M. G. Pharmacol. Res. 2003, 47, 421-437. (b) Angel, I.;
Bar, A.; Haring, R. Curr. Opin. Drug Disc. Dev. 2002, 5, 728-740. (c)
Liu, G. L.; Kleine, L.; Hebert, R. L. Crit. Rev. Clin. Lab. Sci. 1999, 36,
511-573. (d) Spiegel, S.; Foster, D.; Kolesnick, R. Curr. Opin. Cell Biol.
1996, 8, 159-167. (e) Merrill, A. H.; Schmelz, E. M.; Dillehay, D. L.;
Spiegel, S.; Shayman, J . A.; Schroeder, J . J .; Riley, R. T.; Voss, K. A.;
Wang, E. Toxicol. Appl. Pharm. 1997, 142, 208-225.
(3) (a) Loden, M. Am. J . Clin. Dermatol. 2003, 4, 771-788. (b)
Coderch, L.; Lopez, O.; De La Maza, A.; Parra, J . L. Am. J . Clin.
Dermatol. 2003, 4, 107-129.
(4) Shigeki, I.; Makoto, I.; Ikuo, H.; Yasutaka, S. J P2003040728.
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10.1021/jo049277y CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/17/2004
J . Org. Chem. 2004, 69, 5699-5704
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van den Berg et al.
SCHEME 1. Syn th esis of Sp h in gosin e (1) via
En oltr ifla te Ap p r oa ch Sta r tin g fr om
P h ytosp h in gosin e (2)
ring-opening, and concomitant â-elimination under the
influence of iodotrimethylsilane15 and 1,5-diazabicyclo-
[5.4.0]undec-5-ene (DBN) would eventually lead to target
compound 1 as a mixture of E- and Z-isomers.
In the first instance, we examined (see Scheme 3)
whether N-benzoylation and subsequent tosylation would
offer 2-phenyl-oxazoline derivative 5. Accordingly, treat-
ment of an emulsion of 2 in THF with benzoyl chloride
and triethylamine gave the benzamide derivative 716 in
near-quantitative yield. Unfortunately, treatment of 7
with p-toluenesulfonyl chloride17 in pyridine led to the
exclusive isolation of furan species 8, the physical data
of which were in full accord with those reported ear-
lier.18,19 Alternatively, tritylation of 7 with triphenylm-
ethyl chloride at elevated temperature afforded diol 9.
Subsequent benzoylation of 9 gave the fully protected
phytosphingosine 10, detritylation of which proceeded
uneventfully under the agency of borontrifluoride in
methanol and toluene, affording alcohol 11 in a near-
quantitative yield over the three steps. Methanesulfony-
lation of 11 in the presence of excess triethylamine
resulted in the isolation of 2-phenyl-1,3-oxazoline 12 in
a gratifying yield of 86%. Saponification of the benzoyl
esters in 12 with potassium carbonate in methanol and
methylene chloride afforded crystalline diol 5 in 82% yield
over the seven steps. At this stage, it is of interest to note
that 2 can be converted in a seven-step one-pot event into
5 on a multigram scale.20 Despite the successful synthesis
of 5, we were intrigued by the possibility whether 5 could
be obtained in a single step by treatment of 2 with ethyl
benzimidate hydrochloride. Although literature prece-
dents did not augur well for the regioselective formation
of the requested isomer 5 (see Scheme 3), treatment of
phytosphingosine 2 with ethyl benzimidate hydrochloride
in refluxing DCM proceeded smoothly to give exclusively
regioisomer 5 in an excellent yield.
this protocol, 1.5 mmol of phytosphingosine 2 was readily
converted in an eight-step process into sphingosine 1 in
an overall yield of 58% (0.8 mmol). Unfortunately, the
possibility to upscale the process is limited due to the
following drawbacks. First of all, the strategy relies on
the use of rather expensive reagents such as di-tert-butyl
dicarbonate [Boc2O] and di-tert-butylsilyl bis(trifluoro-
methanesulfonate) [(tBu)2Si(OTf)2] for the protection of
the amine- and 1,3-diol functionalities in 2 and N-phenyl-
bis(trifluoromethanesulfonate) [PhN(Tf)2] for the chemi-
cal transformation of 3 into 4. Apart from this, the
mandatory low temperature for the latter conversion
prevents the execution of this reaction on a large scale.
It occurred to us that protection of the 1,2-â-amino-
alcohol functionality in 2 would present an attractive
alternative to our initial approach. It has been reported
that protection of the 1,2-â-amino-alcohol function in an
amino poly-ol system as the 2-phenyl-1,3-oxazoline unit12
can in principle be effected by N-benzoylation of 2
followed by regioselective sulfonylation of the primary
hydroxyl group provides, after cyclization, the 2-phenyl-
1,3-oxazoline derivative 5 (see Scheme 2). On the other
hand, treatment of 2 with ethyl benzimidate hydrochlo-
ride13 may also lead, despite the poor observed regio-
selectivity14 in the case of several amino poly-ol systems,
to the corresponding phenyl oxazoline derivative 5 in one
step. Transformation of 5 into threo-epoxide 6, selective
Having achieved the facile synthesis of phenyl-oxazo-
line 5, attention was turned to the stereospecific oxirane
formation to gain key intermediate 6. To this end, several
methods were screened for the stereospecific transforma-
tion of the vicinal diol system of 5 into the oxirane
derivative 6. The strategy for the stereospecific conver-
sion of vicinal diols into epoxides as reviewed by Kolb
and Sharpless21 was in our case not successful and led
to decomposition of the starting material. On the other
hand, epoxidation of diol 5 under phase-transfer condi-
tions using p-toluenesulfonyl chloride and aqueous so-
(8) Phytosphingosine [(2S,3S,4R)-2-amino-1,3,4-octadecanetriol] is
now readily available from a yeast fermentation process. For informa-
tion, contact Cosmoferm B. V. Wateringseweg 1, P.O. Box 386, 2600
AJ Delft, The Netherlands, Fax +31(15)2794120; e-mail: info@
cosmoferm.com.
(14) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567-576.
(15) Laaziri, A.; Uziel, J .; J uge´, S. Tetrahedron Asymmetry 1998, 9,
437-447.
(9) van den Berg, R. J . B. H. N.; Korevaar, C. G. N.; van der Marel,
G. A.; Overkleeft, H. S.; Van Boom, J . H. Tetrahedron Lett. 2002, 43,
8409-8412.
(10) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979-
(16) Carter, H. E.; Celmer, W. D.; Lands, W. E. M.; Mueller, K. L.;
Tomizawa, H. H. J . Biol. Chem. 1954, 206, 613-623.
(17) Murakami, T.; Masakatsu, H. J . Chem. Soc. Perkin Trans. 1
1996, 823-828.
982.
(11) Cacchi, S.; Morera. A.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821-4824.
(12) Giordano, C.; Cavicchioli, S.; Levi, S.; Villa, M. Tetrahedron Lett.
1988, 29, 5561-5564. (b) Poelert, M. A.; Hulshof, L. A.; Kellogg, R.
M.; Recl. Trav. Chim. Pays-Bas 1994, 113, 355-364. (c) Murakami,
T.; Hato, M. J . Chem. Soc. Perkin Trans 1 1996, 823-828. (d) Hou, D.
R.; Reibenspies, J . H.; Burgess, K. J . Org. Chem. 2001, 66, 206-215.
(e) Zhang, X. M.; Lin, W. Q.; Gong, L. Z.; Mi, A. Q.; Cui, X.; J iang, Y.
Z.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1535-
1537. (f) Perry, M. C.; Cui, X. H.; Powell, M. T.; Hou, D. R.; Reibenspies,
J . H.; Burgess, K. J . Am. Chem. Soc. 2003, 125, 113-123. (g) Zhang,
X. M.; Zhang, H. L.; Lin, W. Q.; Gong, L.-Z.; Mi, A. Q.; Cui, X.; J iang,
Y. Z.; Yu, K. B. J . Org. Chem. 2003, 38, 4322-4329.
(13) Slack, R. U.S. patent office 1955, US 2718520.
(18) Apsimon, J . W.; Hannafor, A. J .; Whalley, W. B. J . Chem. Soc.
1965, 4164-4168.
(19) Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem. 1990,
1069-1078.
(20) Conversion of phytosphingosine 2 into diol 5 has been performed
on multigram scale (226
g starting material 2) without column
chromatographic purification. This seven-step one-pot event was
performed with minor adjustments of the here-described method in
an overall yield of 58% and high chemical purity. For the detailed
experimental protocol, see Supporting Information.
(21) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-
10530.
5700 J . Org. Chem., Vol. 69, No. 17, 2004

Short Stereospecific Synthesis of D-erythro-Sphingosine
SCHEME 2. Retr o Syn th etic An a lysis of th e Con str u ction of er yth r o-Sp h in gosin e (1) Sta r tin g fr om 2
SCHEME 3. P r ep a r a tion of D-er yth o-Sp h in gosin e 1a
a
Reagents and conditions: (a) BzCl, TEA, THF, rt, 30 min, 99%; (b) TsCl, pyridine, 0 f 20 °C, 18 h, 80%; (c) TrtCl, TEA, EtOAc, 80
°C, 2.5 h, 99%; (d) BzCl, TEA, EtOAc, rt, 16 h, 99%; (e) BF3‚OEt2, MeOH/toluene (1:1, v/v), rt, 1.5 h, 99%; (f) MsCl, TEA, DCM, 0 f 20
°C, 18 h, 86%; (g) K2CO3, MeOH, DCM, 40 °C, 18 h, 99%; (h) ethyl benzimidate hydrochloride, DCM, 40 °C, 48 h, 95%; (i) MsCl or TsCl,
pyridine/DCM (3:2, v/v), DMAP (5%), 69% (13b), 75% (13d ); (j) tBuOK, THF, 0 °C, 1 h, 99%; (k) TMSI, DBN, acetonitrile, 40 f 86 °C,
94%; (l) (i) 2N HCl, THF, rt, 18 h and (ii) NaOH, MeOH, 100 °C, 2 h, 79%; (m) Ac2O, pyridine, rt, 2 h, 99%.
dium hydroxide as described by Szeja22 led to the near-
quantitative formation of expoxide 6, which was isolated
as an inseparable diastereomeric mixture in a ratio of
4:1 [(6-1S,2R)/(6-1R,2R)], as was ascertained by proton
NMR spectroscopy. Alternatively, treatment of 5 with one
equivalent of methanesulfonyl chloride in pyridine23 gave
a mixture of the 1-mesylate 13a , 2-mesylate 13b, as well
as 1,2-di-mesylate 13c. Nonetheless, tedious column
chromatographic purification of the mesylated com-
pounds 13a -13c led to isolation of the regioselective
mesylate 13b in a moderate yield of 69%. It turned out
that tosylation of 5 in a mixture of pyridine and meth-
ylene chloride in the presence of a catalytic amount of
DMAP afforded 13d in 75%. The sole side product, the
1,2-di-tosylate 13e, was readily removed by column
chromatography. The synthesis of key intermediate 6 was
finally realized by treatment of 2-tolenesulfonyl deriva-
tive 13d with potassium tert-butylate in methanol to
afford crystalline oxirane 6.
A crucial event in our strategy is the regiospecific and
stereoselective transformation of the oxirane functional-
ity into the characteristic E-allylic hydroxyl functionality
(22) Szeja, W. Synthesis 1985, 983-985.
(23) Knapp, S.; Dong, Y. H. Tetrahedron Lett. 1997, 38, 3813-3816.
J . Org. Chem, Vol. 69, No. 17, 2004 5701

van den Berg et al.
of sphingosine 1. Unfortunately, the number of literature
examples discussing specific chemical conversions of
inactivated open chain aliphatic oxiranes to the corre-
sponding E-olefins are limited.24 Interestingly, in their
total synthesis of (-)-Elaeokanine C, Mori and co-
workers25 reported a procedure in which a diastereomeric
mixture of a 1,2-epoxybutyl-indolizidine derivative was
transformed into the corresponding 1-hydroxy-2-E-
butenyl indolizidine derivative using iodotrimethylsilane
and 1,5-diazobicyclo-[5.4.0]undec-5-ene, a methodology
developed by Kraus and Frazier.26 Consequently, we
examined whether the TMSI/DBN methodology could be
adopted to the synthesis of sphingosine 1. To our delight,
stereospecific and regioselective eliminative epoxide open-
ing of oxirane 6 led to the exclusive isolation of E-allyl
silyl ether 14 (J 4,5 ) 15.2 Hz) in high yield. Having the
desired compound at the penultimate stage, attention
was focused on the final deprotection step. Application
of an one-pot two-step deblocking procedure27 of the
trimethylsilyl and phenyloxazoline protecting groups of
14 using aqueous hydrochloric acid followed by aqueous
base treatment of the in situ formed 1-O-benzoate sph-
ingosine furnished target compound D-erythro-sphin-
gosine 1 in an overall yield of 70% (seven steps).28 For
analytical reasons, 1 was acetylated with acetic anhy-
dride in pyridine to gain tri-acetate 15 in good yield. The
analytical and spectroscopical data of both 1 and 15 were
in full accordance with those reported in the literature,
thereby providing unambiguous proof of their structural
and stereochemical integrity.7,29
Exp er im en ta l P r oced u r es
(2S,3S,4R)-2-N-Ben zoyla m in o-1,3,4-octa deca n etr iol (7).
To a stirred suspension of 2 (10.0 g, 31.5 mmol) in THF (250
mL) containing TEA (5.27 mL, 37.8 mmol) was added benzoyl
chloride (3.84 mL, 33.1 mmol), and the mixture was stirred
for 30 min. The solvent was evaporated, and the residue was
dissolved in hot ethyl acetate (250 mL) and washed with
aqueous HCl (1 N, 2 × 50 mL). Upon cooling of the organic
layer to 0 °C, white crystals precipitated. Yield 13.1 g (99%):
TLC (silica gel, diethyl ether/ethanol/ammoniumhydroxide,
6:3:1) Rf ) 0.75; Mp 114 °C; [R]20D 13.6° (c ) 1.07 CHCl3/MeOH,
5:1, v/v); IR (neat) ν 3317, 2916, 2846, 1612, 1542, 1465, 1334,
1
1056; H NMR (CDCl3 HH-COSY) δ 0.88 (t, 3H, CH3), 1.25
(s, 24H, 12 × CH2), 1.51-1.77 (m, 2H, CH2), 2.66 (bs, 1H, OH),
3.51 (bs, 1H, OH), 3.74 (m, 2H, H-4, OH), 3.76 (m, 1H, H-3),
3.87 (b s, 1H, H-1a), 4.04 (dd, 1H, H-1b), 4.35 (m, 1H, H-2),
7.05 (d, 1H, NH, J ) 7.3 Hz), 7.40-7.80 (m, 5H, CH-arom
benzoyl); 13C{1H}-NMR (CDCl3) δ 14.0, 22.6, 25.6, 29.3, 29.6,
31.9, 33.5, 53.7, 62.1, 73.0, 76.7, 127.1, 128.6, 133.1, 131.8,
168.3; ES-MS: m/z 422.3 [M + H]+, 444.6 [M + Na]+, 865.9
[2M + Na]+. HR-MS [QTOF, MH+]: m/z calcd for C25H44NO4
422.3270, found 422.3294.
(2R,3S,4S)-4-N-Ben zoyla m in o-3-h yd r oxy-2-tetr a d ecyl-
tetr a h yd r ofu r a n (8). To a cooled (0 °C) and stirred solution
of 7 (5.0 g, 11.9 mmol) in pyridine (75 mL) was added solution
of p-toluenesulfonyl chloride (2.62 g, 13.7 mmol) in pyridine
(25 mL). Stirring was continued overnight at ambient tem-
perature. The solvent was evaporated, and the residue was
dissolved in hot ethyl acetate (250 mL) and washed with
aqueous HCl (1 N, 2 × 50 mL). Upon cooling of the organic
layer to 0 °C, white crystals were obtained. Yield 3.9 g (80%):
TLC (silica gel, MeOH/DCM, 1:9) Rf ) 0.70; IR (neat) ν 3371,
2916, 2846, 1635, 1535, 1488, 1334, 1172, 1118, 1033; 1H NMR
(CDCl3) δ 0.89 (t, 3H), 1.26 (s, 24H), 1.60 (dd, 2H), 2.59 (bs,
1H), 3.64 (dd, 1H, J ) 8.8 Hz, J ) 7.3 Hz), 3.78 (dd, 1H, J )
10.2 Hz, J ) 6.6 Hz), 4.18 (dd, 1H, J ) 10.2 Hz, J ) 6.6 Hz),
4.30 (d, 1H, J ) 8.8 Hz, J ) 6.6 Hz), 4.58 (quin, 1H, J ) 6.6
Hz, J ) 7.3 Hz, J ) 6.6 Hz, J ) 7.3 Hz), 6.73 (d, 1H, J ) 7.3
Hz), 7.38-7.80 (m, 5H); 13C{1H}-NMR (CDCl3) δ 14.0, 22.6,
25.8, 29.6, 31.8, 33.3, 52.0, 70.6, 74.7, 85.2, 126.9, 128.5, 131.7,
133.7, 168.0; HR-MS [QTOF, MH+]: m/z calcd for C25H41NO3
404.3165, found 404.3156.
In summary, in this paper, the high yielding (seven
steps, 70%) and high diastereoselective synthesis of
naturally occurring sphingosine (1) is presented. The
results clearly show that the multigram synthesis of
sphingosine (1) is now feasible using D-ribo-phytosphin-
gosine (2) as the starting material. The straightforward
approach to 1 focused on the stereo- and regioselective
eliminative oxirane opening of 6 to afford the completely
protected sphingosine 14. In addition, the synthetic
methodology allowed the application of two-pot multistep
conversions of phytosphingosine 2 into sphingosine 1
with a minimal number of column chromatographic
purification steps.
(2S,3S,4R)-2-N-Ben zoyla m in o-1-O-t r it yl-1,3,4-oct a d e-
ca n etr iol (9). To a stirred suspension of 7 (58.9 g, 140 mmol)
in EtOAc (700 mL) containing TEA (23 mL, 165 mmol),
maintained at 80 °C, was added neat triphenylmethyl chloride
(42.9 g, 138 mmol). The suspension was stirred at 80 °C for
2.5 h. The solvent was washed successively with aqueous HCl
(1 N, 3 × 200 mL) and aqueous NaHCO3 (10%, 1 × 200 mL)
and was concentrated. Column chromatography of the residue
over silica gel with toluene/EtOAc (1:0 f 3:2, v/v) gave 9 (92.8
g, 99%) as a yellow oil: Rf ) 0.80 (MeOH/EtOAc, 1:9); [R]20
(24) (a) Magnus, A.; Bertilsson, S. K.; Andersson, P. G. Chem. Soc.
Rev. 2002, 31, 223-229. (b) O’Brien, P. J . Chem. Soc. Perkin Trans. 1
1998, 1439-1457. (c) Mordini, A.; Rayana, E. B.; Margot, C.; Schlosser,
M. Tetrahedron 1990, 46, 2401-2410. (d) Mosset, P.; Manna, S.; Viala,
J .; Falck, J . R. Tetrahedron Lett. 1986, 27, 299-302. (e) Gorzynski
Smit, J . Synthesis 1984, 629-656. (f) Crandall, J . K.; Apparu, M. Org.
React. 1983, 29, 345-443. (g) Murata, S.; Suzuki, M.; Noyori, R. Bull.
Chem. Soc. J pn. 1982, 55, 247-254. (h) Detty, M. R. J . Org. Chem.
1980, 45, 924-926.
D
11.2° (c ) 1.04 CHCl3); 1H NMR (CD3OD/ CDCl3) δ 0.87 (t,
3H), 1.25 (s, 24H), 1.44 (m, 2H), 2.57 (bt, 1H), 3.35 (dd, 1H, J
) 8.0 Hz, J ) 8.4 Hz), 3.47 (dd, 2H, J ) 9.9 Hz, J ) 4.4 Hz),
3.60 (dd, 1H, J ) 9.9 Hz, J ) 3.3 Hz), 3.69 (m, 1H), 4.47 (m,
1H, J ) 8.0 Hz, J ) 4.4 Hz, J ) 3.3 Hz), 6.90 (d, 1H, J ) 8.0
Hz), 7.16-7.75 (m, 20H); 13C{1H}-NMR (CDCl3) δ 14.0, 22.5,
25.6, 29.2, 29.5, 31.7, 50.9, 62.9, 72.8, 75.5, 87.3, 126.9-131.4,
134.0, 143.1, 167.2; ES-MS: m/z 686.7 [M + Na]+.
(25) (a) Sato, Y.; Saito, N.; Mori, M. Tetrahedron Lett. 1997, 38,
3931-3934. (b) Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998, 54,
1153-1168.
(2S ,3S ,4R )-2-N -Be n zoyla m in o-3,4-O-d ib e n zoyl-1-O-
tr ityl-1,3,4-octa d eca n etr iol (10). To a stirred solution of 9
(17.5 g, 26 mmol) in EtOAc (50 mL) containing TEA (8.0 mL,
57 mmol) was added dropwise benzoyl chloride (6.6 mL, 57
mmol). Stirring was continued overnight. Excess of benzoyl
chloride was quenched by the addition MeOH (5 mL). The
mixture was diluted with EtOAc (50 mL) and successively
washed with aqueous HCl (1 N, 3 × 100 mL), aqueous
NaHCO3 (10%, 2 × 50 mL), and dried (MgSO4) and was
concentrated. Column chromatography of the residue over
silica gel with petroleum ether/EtOAc (95:5 f 80:20, v/v) gave
10 (24.0 g, 99%) as a colorless oil: TLC (silica gel, petroleum
(26) Kraus, G. A.; Frazier, K. J . Org. Chem. 1980, 45, 2579-2581.
(27) Hertweck, C.; Sebek, P.; Svatos, A. Synlett 2001, 1965-1967;
Tkaczuk, P.; Thornton, E. R. J . Org. Chem. 1981, 46, 4393-4398.
(28) With slight modifications of the here-described procedure,
p-toluenesulfonyl derivative 13 can be transformed into sphingosine
1 on a multigram scale (65 g starting material of 13) via a one-pot
six-step methodology in high overall yield (60%), requiring only singly
column chromatography purification step. For the detailed experimen-
tal protocol see Supporting Information.
(29) (a) Shapiro, D.; Segal, H.; Flowers, H. M. J . Am. Chem. Soc.
1958, 80, 1194-1197. (b) Reist, E. J .; Christie, P. H. J . Org. Chem.
1970, 35, 4127-4130. (c) Lee, J . M.; Lim, H. S.; Chung, S. K.
Tetrahedron Asymmetry 2002, 13, 343-347.
5702 J . Org. Chem., Vol. 69, No. 17, 2004

Short Stereospecific Synthesis of D-erythro-Sphingosine
ether/EtOAc, 2:1) Rf ) 0.90; [R]20 -6.6° (c ) 1.03 CHCl3); 1H
mmol). The mixture was stirred for 32 h at ambient temper-
ature. Methanol (5 mL) was added, and the solvent was
evaporated in vacuo. The residue was dissolved in EtOAc (50
mL), and the solution was washed successively with aqueous
HCl (1 N, 2 × 25 mL), aqueous NaHCO3 (10%, 50 mL), brine
(50 mL), and dried (MgSO4) and was concentrated. Column
chromatography of the residue over silica gel with toluene/
EtOAc (1:0 f 9:1, v/v) gave 13d (10.4 g, 75%) as a colorless
oil. TLC (silica gel, toluene/EtOAc, 3:1) Rf ) 0.60: [R]20D 36.2°
(c ) 1.06 CHCl3). IR (neat) ν 2923, 2854, 1643, 1458, 1357,
D
NMR (CDCl3) δ 0.88 (t, 3H), 1.26 (s, 24H), 1.93 (m, 2H), 3.41
(bm, 2H), 4.80 (bt, 1H), 5.44 (dd, 1H), 5.96 (dd, 1H), 6.92 (d,
1H), 7.02-8.00 (m, 30H); 13C{1H}-NMR (CDCl3) δ 13.9, 22.4,
25.4, 28.3, 29.4, 31.6, 33.1, 49.3, 61.6, 72.6, 74.0, 86.6, 126.7-
134.0, 143.0, 164.9, 166.3, 168.8; ES-MS: m/z 894.9 [M + Na]+.
(2S,3S,4R)-2-N-Ben zoyla m in o-3,4-O-d iben zoyl-1,3,4-oc-
ta d eca n etr iol (11). To a solution of 10 (52.4 g, 60.2 mmol) in
MeOH/toluene (400 mL, 1:1, v/v) was added BF3‚OEt2 (11.3
mL, 90.3 mmol). The mixture was stirred for 1.5 h. The
mixture was diluted with EtOAc (100 mL) and washed with
aqueous NaHCO3 (10%, 3 × 100 mL) and dried (MgSO4) and
was concentrated. Column chromatography of the residue over
silica gel with petroleum ether/EtOAc (95:5 f 33:66, v/v) gave
1
1265, 1172, 1095, 1026, 894; H NMR (CDCl3) δ 0.88 (t, 3H),
1.26 (s, 24H), 1.71 (m, 2H), 2.39 (s, 3H), 399 (t, 1H), 4.36 (m,
3H), 4.71 (dt, 1H), 7.23-7.81 (m, 9H); 13C{1H}-NMR (CDCl3)
δ 13.8, 21.2, 22.4, 24.1, 29.2, 29.5, 30.1, 31.7, 67.1, 67.8, 71.6,
83.5, 126.5, 127.6-131.9, 133.9, 144.3, 165.2; ES-MS: m/z
558.4 [M + H]+, 580.5 [M + Na]+. HR-MS [QTOF, MH+]: m/z
calcd for C32H48NO5S 558.3253, found 558.3193.
11 (94 g, 99%) as a yellow oil: TLC (silica gel, petroleum ether/
1
EtOAc, 2:1) Rf ) 0.40; [R]20 50.6° (c ) 1.14 CHCl3); H NMR
D
(CDCl3) δ 0.87 (t, 3H), 1.21 (s, 24H), 2.06 (bs, 2H), 3.00 (t, 1H),
3.75 (m, 2H), 4.60 (m, 1H), 5.47 (m, 1H), 5.60 (dd, 1H), 7.21
(d, 1H), 7.33-8.08 (m, 15H); 13C{1H}-NMR (CDCl3) δ 14.0,
22.6, 25.6, 28.3, 29.5, 31.8, 50.7, 61.3, 73.1, 74.0, 127.1-133.9,
166.5, 167.5; ES-MS: m/z 630.5 [M + H]+, 652.4 [M + Na]+.
2-P h en yl-4-(S)-[(1S,2S)-1,2-ep oxyh exa d ecyl]-1,3-oxa zo-
lin e (6). To a solution of 13d (7.24 g, 15.0 mmol) in THF (150
mL), maintained at 0 °C, was added potassium tert-butylate
(1.85 g, 16.5 mmol), and the mixture was stirred for 1 h. The
mixture was diluted with EtOAc (150 mL) and successively
washed with water (2 × 100 mL), brine (100 mL), and dried
(MgSO4) and was concentrated. Column chromatography of
the residue over silica gel with toluene/EtOAc (95:5 f 80:20,
v/ v) gave 6 (5.72 g, 99%) as a crystalline solid: TLC (silica
2-P h en yl-4-(S)-[(1S,2R)-1,2-O-diben zoyloxyh exadecyl)]-
1,3-oxa zolin e (12). To solution of 11 (32.0 g, 50.8 mmol) in
DCM (250 mL) containing TEA (75 mL, 531 mmol), main-
tained at 0 °C, was added methanesulfonyl chloride (8.22 mL,
106.2 mmol). After 1 h, the reaction mixture was allowed to
rise to ambient temperature and was stirred for 18 h. The
reaction was washed with aqueous HCl (1 N, 3 × 200 mL),
aqueous NaHCO3 (10%, 200 mL), and dried (MgSO4) and was
concentrated. Column chromatography of the residue over
silica gel with petroleum ether/EtOAc (95:5 f 85:15, v/v) gave
12 (26.7 g, 86%) as a colorless oil: TLC (silica gel, petroleum
ether/EtOAc, 3:1, v/v) Rf ) 0.80; [R]20D -50.0° (c ) 1.42 CHCl3);
IR (neat) ν 3440, 3317, 2916, 2846, 1612, 1542, 1465, 1334,
gel, petroleum ether/EtOAc, 4:1) Rf ) 0.70; Mp 63-64 °C; [R]20
D
24.8° (c ) 1.60 CHCl3/MeOH 5:1, v/v); IR (neat) ν 3325, 2916,
2854, 1735, 1643, 1527, 1465, 1365, 1180, 1049, 910; 1H NMR
(CDCl3) δ 0.88 (t, 3H), 1.25 (s, 24H), 1.55 (m, 2H), 2.95 (dd,
1H), 3.05 (dt, 1H), 4.27 (m, 1H), 4.41-4.56 (m, 2H), 7.35-7.97
(m, 5H); 13C{1H}-NMR (CDCl3) δ 14.0, 22.7, 25.9, 29.4, 29.6,
31.6, 33.4, 55.8, 59.1, 66.4, 68.9, 128.3-131.5, 165.2; ES-MS:
m/z 386.3 [M + H]+, 408.2 [M + Na]+. HR-MS [QTOF, MH+]:
m/z calcd for C25H40NO2 386.3053, found 386.3038.
1
1056; H NMR (CDCl3) δ 0.88 (t, 3H), 1.24 (s, 24H), 1.91 (dd,
2H), 4.53 (dd, 1H, J ) 8.8 Hz, J ) 10.2 Hz), 4.62 (dd, 1H, J )
8.4 Hz, J ) 6.9 Hz), 4.77 (ddd, 1H, J ) 10.2 Hz, J ) 6.6 Hz, J
) 3.7 Hz), 5.62 (m, 2H), 7.26-8.04 (m, 15H); 13C{1H}-NMR
(CDCl3) δ 14.0, 22.6, 25.3, 29.3, 29.6, 30.6, 31.8, 66.6, 69.1,
73.4, 75.4, 127.2-133.1, 165.3, 165.5, 165.7; ES-MS: m/z 612.5
[M + H]+, 634.7 [M + Na]+.
2-P h en yl-4-(S)-[(1S,2E)-1-tr im eth ylsila n yloxyh exa d ec-
2-en yl]-1,3-oxa zolin e (14). To a solution of 6 (5.07, 13.2
mmol) in acetonitrile (66 mL), maintained at 40 °C, was added
TMSI (2.15 mL, 15.8 mmol), and the mixture was stirred for
45 min at 40 °C. DBN (5.20 mL, 43.6 mmol) was added, and
the mixture was refluxed for 1.0 h. Subsequently, the solvent
was concentrated, and column chromatography of the residue
using petroleum ether/EtOAc (1:0 f 4:1) gave 6 (5.60, 94%)
as a colorless oil: TLC (silica gel, petroleum ether/EtOAc, 4:1)
2-P h en yl-4-(S)-[(1S,2R)-1,2-d ih yd r oxyh exa d ecyl]-1,3-
oxa zolin e (5). Method 1 (12 f 5): potassium carbonate (15.0
g, 108 mmol) was added to a mixture of 12 (13.4 g, 21.8 mmol)
in DCM and MeOH (100 mL, 3:1, v/v) maintained at 40 °C.
The mixture was stirred for 18 h. After the solvents were
evaporated, the residue was dissolved in EtOAc (500 mL) and
washed with water (3 × 100 mL), after which the organic layer
was concentrated. Crystallization of the residue from pentane
gave 5 as white crystals (8.8 g, 99%). Method 2 (2 f 5): to a
stirred suspension of 2 (11.4 g, 35.9 mmol) and ethyl benz-
imidate hydrochloride (8.0 g, 43.1 mmol) in DCM (200 mL)
was added TEA (6.0 mL, 43.1 mmol), and the mixture was
stirred for 48 h at 40 °C. The solvent was evaporated, and the
residue was dissolved in hot ethyl acetate (250 mL), washed
with aqueous HCl (1 N, 2 × 50 mL), and concentrated.
Crystallization of the residue from MeOH gave 5 as white
crystals (13.8 g, 95%): TLC (silica gel, DCM/MeOH, 9:1, v/v)
Rf ) 0.90; [R]20 6.2° (c ) 1.28 CHCl3); IR (neat) ν 2923, 2854,
D
1651, 1458, 1357, 1249, 1085, 1056, 1026, 972; 1H NMR
(CDCl3, HH-COSY) δ 0.04 (s, 9H, TMS), 0.87 (t, 3H, CH3),
1.26 (s, 22H, 11 × CH2), 1.37 (bt, 2H, CH2), 2.05 (dd, 2H, CH2),
4.27 (bt, 1H, H-5a), 4.28 (m, 1H, H-4), 4.39 (m, 1H, H-1′), 4.42
(dd, 1H, H-5b, J ) 1.7 Hz, J ) 2.7 Hz), 5.45 (ddt, 1H, H-2′,
J 2′,3′ ) 15.2 Hz, J 1′,2′ ) 6.6 Hz), 5.71 (ddt, 1H, H-3′, J 2′,3′ ) 15.2
Hz, J 3′,4′ ) 6.9 Hz), 7.37-7.95 (m, 5H, CH-arom phenyloxazole);
13C{1H}-NMR (CDCl3, CH-COSY): δ ) 0.3 (CH3 TMS), 14.1
(CH3), 22.6, 29.1, 29.2, 29.3, 29.4, 29.6, 31.9, 32.2 (×CH2), 67.9
(C-5), 71.7 (C-4), 73.8 (C-1′), 127.9 (Cq phenyloxazole), 128.2,
131.1 (CH-arom phenyloxazole), 129.9 (C-2′), 132.1 (C-3′), 164.4
(CdN phenyloxazole); ES-MS: m/z 458.4 [M + H]+, 480.4 [M
+ Na]+. HR-MS [QTOF, MH+]: m/z calcd for C28H48NO2Si
458.3448, found 458.3392.
Rf ) 0.60; Mp 137-138 °C; [R]20 24.8° (c ) 1.60 CHCl3/
D
methanol, 5:1, v/v); IR (neat) ν 3317, 2916, 2846, 1643, 1465,
1365, 1095, 948; 1H NMR (CDCl3) δ 0.88 (t, 3H), 1.25 (s, 24H),
1.52 (m, 2H), 2.17 (d, 1H), 3.27 (d, 1H), 3.71 (m, 1H), 3.81 (m,
1H), 4.40-4.61 (m, 3H), 7.26-7.92 (m, 5H); 13C{1H}-NMR
(CDCl3) δ 13.9, 22.5, 25.4, 29.1, 29.5, 31.7, 32.9, 68.4, 69.3,
73.5, 74.9, 126.9-132.9, 165.4; ES-MS: m/z 404.3 [M + H]+,
426.1 [M + Na]+, 444.5 [M + K]+, 807.6 [2M + H]+, 829.5 [2M
+ Na]+, 847.9 [2M + K]+. HR-MS [QTOF, MH+]: m/z calcd
for C25H42NO3 404.3159, found 404.3139.
2-P h en yl-4-(S)-[(1S,2R)-1-h yd r oxy-2-O-t osyloxyh exa -
d ecyl]-1,3-oxa zolin e (13d ). To a mixture of 5 (10.0 g, 24.8
mmol) and TEA (3.6 mL, 26.0 mmol) in DCM/pyridine (250
mL, 2:3, v/v) was added p-toluenesulfonyl chloride (9.92 g, 49.6
(2S,3S,4E)-2-Am in o-octa d ec-4-en e-1,3-d iol (1). To a so-
lution of 14 (4.98, 10.8 mmol) in THF (100 mL) was added
aqueous HCl (2 N, 25 mL). The mixture was stirred for 18 h.
The mixture was diluted with chloroform/MeOH (50 mL, 87:
13 v/v) and water (25 mL). The organic phase was separated,
and the aqueous phase was extracted with a chloroform/
methanol mixture (3 × 75 mL, 87:13 v/v). The combined
organic layers were dried (MgSO4) and concentrated. The
residue was dissolved in MeOH (60 mL), aqueous NaOH (12.5
M, 25 mL) was added, and the mixture refluxed for 40 min.
The cooled reaction mixture was diluted with water (50 mL)
and extracted with diethyl ether (3 × 100 mL). The organic
layer was dried (MgSO4) and was concentrated. Column
J . Org. Chem, Vol. 69, No. 17, 2004 5703

van den Berg et al.
chromatography of the residue over silica gel with EtOAc/
MeOH/NH4OH (90:10:0 f 40:10:1) gave 1 (2.58 g, 79%) as a
white solid: TLC (silica gel, diethyl ether/EtOH/NH4OH,
6:3:1) Rf ) 0.50; [R]20D -1.4° (c ) 0.42 CHCl3); IR (neat) ν 3240,
Column chromatography of the residue over silica gel with
petroleum ether/EtOAc (50:50 f 0:100) gave 15 (0.240 g, 80%)
as a white solid: TLC (silica gel, petroleum ether/EtOAc, 1:1)
Rf ) 0.20; [R]20 -13.2° (c ) 1.00 CHCl3); IR (neat) ν 3286,
D
1
2916, 2846, 1735, 1651, 1550, 1465, 1373, 1226, 1026, 972; 1H
NMR (CDCl3) δ 0.88 (t, 3H), 1.25 (s, 22H), 1.98 (s, 3H), 2.03
(m, 2H), 2.06 (s, 3H), 2.07 (s, 3H), 4.03 (dd, 1H, J ) 11.3 Hz,
J ) 3.7 Hz), 4.42 (m, 1H), 5.29 (dd, 1H, J ) 13.1 Hz, J ) 7.3
Hz), 5.39 (dd, 1H, J ) 7.3 Hz, J ) 15.0 Hz), 5.71 (d, 1H, J )
9.1 Hz), 5.77, (ddd, 1H, J ) 15.0 Hz, J ) 6.6 Hz); 13C{1H}-
NMR (CDCl3) δ 13.9, 20.5, 20.8, 22.9, 22.4, 28.6, 28.9, 29.1,
29.2, 29.4, 31.7, 32.0, 50.4, 62.4, 73.5, 124.0, 137.0, 169.7, 169.7,
170.7; ES-MS: m/z 426.4 [M + H]+, 448.3 [M + Na]+. HR-MS
[QTOF, MH+]: m/z calcd for C24H44NO5 426.3214, found
426.3174.
2916, 2846, 1581, 1465, 1380, 1249, 1033, 972, 933; H NMR
(CDCl3, HH-COSY) δ 0.88 (t, 3H, CH3), 1.24 (s, 22H, 11 ×
CH2), 1.97 (bs, 4H, NH2, 2 × OH), 2.05 (q, 2H, CH2-6), 2.88
(m, 1H, H-2), 3.62 (dd, 1H, H-1, J 1,1 ) 10.8 Hz, J 1,2 ) 5.9 Hz),
3.69 (dd, 1H, H-1, J 1,1 ) 10.8 Hz, J 1,2 ) 4.5 Hz), 4.05 (t, 1H,
H-3, J ) 6.3 Hz), 5.47 (dd, 1H, H-4, J 4,5 ) 15.4 Hz, J 3,4 ) 7.1
Hz), 5.71 (dt, 1H, H-5, J 4,5 ) 15.4 Hz, J 5,6 ) 6.6 Hz); ES-MS:
m/z 300.4 [M + H]+, 322.4 [M + Na]+. HR-MS [QTOF, MH+]:
m/z calcd for C18H38NO2 300.2897, found 300.2873.
(2S,3S,4E)-2-Aceta m id o-1,3-d ia cetyl-octa d ec-4-en e-1,3-
d iol (15). To a solution of 14 (0.322, 0.70 mmol) in THF (6.5
mL) was added aqueous HCl (2 N, 1.5 mL). The mixture was
stirred for 18 h. The mixture was diluted with chloroform/
MeOH (20 mL, 87:13 v/v) and water (10 mL). The organic
phase was separated, and the aqueous phase was extracted
with a chloroform/methanol mixture (2 × 20 mL, 87:13 v/v).
The combined organic layers were dried (MgSO4) and were
concentrated. The residue was dissolved in MeOH (40 mL) and
aqueous NaOH (12.5 M, 1.6 mL) and refluxed for 2 h. The
cooled mixture was diluted with water (10 mL) and extracted
with diethyl ether (3 × 20 mL). The organic layer was dried
(MgSO4) and was concentrated. The residue was dissolved in
pyridine (2 mL), acetic anhydride (2 mL) was added, and the
mixture was stirred for 4 h. The mixture was concentrated.
Ack n ow led gm en t . The authors thank the Dutch
Ministry of Economic Affairs for financial support (BTS
99182). The authors acknowledge Piet Weber for his
assistance and scientific contribution on the large-scale
syntheses.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O049277Y
5704 J . Org. Chem., Vol. 69, No. 17, 2004