An efficient and general enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives

Article abstract of DOI:10.1021/ol802379b

A general and efficient protocol for the enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives was established. These compounds were obtained from a common intermediate prepared from butadiene monoepoxide by a synthet

Full text of DOI:10.1021/ol802379b

ORGANIC
LETTERS
2009
Vol. 11, No. 1
205-208
An Efficient and General
Enantioselective Synthesis of
Sphingosine, Phythosphingosine, and
4-Substituted Derivatives†
Josep Llaveria, Yolanda D´ıaz, M. Isabel Matheu,* and Sergio Castillo´n*
Departament de Qu´ımica Anal´ıtica i Qu´ımica Orga`nica, Facultat de Qu´ımica,
UniVersitat RoVira i Virgili, C/ Marcel.l´ı Domingo s/n, 43007 Tarragona, Spain
sergio.castillon@urV.cat; maribel.matheu@urV.cat
Received October 15, 2008
ABSTRACT
A general and efficient protocol for the enantioselective synthesis of sphingosine, phythosphingosine, and 4-substituted derivatives was
established. These compounds were obtained from a common intermediate prepared from butadiene monoepoxide by a synthetic sequence
involving enantioselective allylic substitution, cross-metathesis, and dihydroxylation.
Sphingolipids are important structural and functional com-
ponents of the plasma membranes of essentially all eukary-
otic cells. They play critical roles in many physiological
processes, including immune response, cell recognition,
adhesion, and apoptosis.1 Recent studies implicate sphin-
golipids in many of the most common human diseases,
including diabetes,2 cancers,3 infection by microorganisms,4
Alzheimer’s disease,5 heart disease, and an array of neuro-
logical syndromes.6 The most important sphingolipids are
sphingosine and phytosphingosine, which when acylated with
a fatty acid and glycosylated with galactose produce galac-
tosylceramide (GalCer) and R-GalCer (KRN7000), respec-
tively (Figure 1). Recently, structurally modified sphin-
† Dedicated to Professor Josep Font on occasion of his 70th birthday.
(1) (a) Riethmu¨ller, J.; Riehle, A.; Grassme´, H.; Gulbins, E. Biochim.
Biophys. Acta 2006, 1758, 2139–2147. (b) Snook, C. F.; Jones, J. A.;
Hannun, Y. A. Biochim. Biophys. Acta 2006, 1761, 927–946.
(2) Summers, S. A.; Nelson, D. H. Diabetes 2005, 54, 591–602.
(3) Modrak, D. E.; Gold, D. V.; Goldenberg, D. M. Mol. Cancer Ther.
2006, 5, 200–208.
Figure 1. Glycolipids GalCer and R-GalCer and sphingolipids.
(4) Heung, L. J.; Luberto, C.; Del Poeta, M. Infect. Immun. 2006, 74,
28–39.
gosines7 and phytosphingosines8,9 have attracted more
attention because some of their analogues have been observed
to introduce morphological changes in neuronal cells10 and
behave as enzyme inhibitors.11
(5) Zhou, S.; Zhou, H.; Walian, P. J.; Jap, B. K. Biochemistry 2007,
46, 2553–2563.
(6) Kolter, T.; Sandhoff, K. Biochim. Biophys. Acta 2006, 1758, 2057–
2079.
10.1021/ol802379b CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

Since sphingosine and its derivatives are available only
in limited amounts from natural sources and because of purity
requirements for biological testing, there is a growing interest
in developing efficient methods for their synthesis.12 These
compounds have been synthesized by various routes, but
primarily from compounds of the chiral pool, particularly
amino acids (L-serine)13 and carbohydrates.14 Asymmetric
syntheses based on the use of chiral auxiliaries, such as
sulfoxides,15 chiral aziridines,16 or chiral sulfur17 and nitro-
gen18 ylides, or on catalytic procedures, such as Sharpless
asymmetric epoxidation19 and dihydroxylation reactions,16,20
the aldol reaction,21 and organocatalytic procedures, have
also been described.22
a new and efficient enantioselective method for synthesizing
sphingosine (1), phytosphingosine (2), and new 4-substituted
derivatives (3, 4) (Scheme 1) partially protected. In the
Scheme 1. Retrosynthesis
Recently, we reported efficient procedures for the glyco-
sylation of ceramides that facilitated the synthesis of GalCer23
and KRN 7000.24 New analogues of these compounds
containing structural modifications in the sphingolipid moiety
have been reported very recently.25 In this work, we describe
proposed retrosynthesis, compounds 1-4 can be obtained from
a common intermediate 5 (Scheme 1). Nucleophilic substitution
at position 4 in 5 must allow the introduction of different
substituents, affording the natural product and derivatives.
Compound 5 can be obtained by the dihydroxylation of
compound 6, which in turn can be synthesized from compound
7 by a cross-metathesis reaction. The main advantage of this
strategy is its high versatility, allowing the synthesis of not only
sphingosine and phytosphingosine but also a range of structural
analogues from a common precursor.
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natural product. Kim, S.; Lee, N.; Lee, S.; Lee, T.; Lee, Y. M. J. Org.
Chem. 2008, 73, 1379–1385.
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Chiral synthon 7 (NR2 ) phthalimido) was obtained by a
palladium-catalyzed dynamic kinetic asymmetric transforma-
tion (DYKAT) from the racemic butadiene monoepoxide
(8)26 (Scheme 2).
Scheme 2. Synthesis of Alkene 6
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Tetrahedron: Asymmetry 1994, 5, 2195–2208. (h) Fan, G.-T.; Pan, Y.-S.;
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Initially we explored the cross metathesis reaction using
the second generation Grubbs catalyst, which is compatible
with a wide range of functionalities.13e,14b,17,19b In prelimi-
nary screening experiments, compound 7 was reacted with
a 2-fold excess of 1-hexadecene (9) in refluxing dichlo-
romethane to afford 6 at a 82% yield and an E/Z ratio of
18:1 (Scheme 2). Since the metathesis reaction proceeds
under thermodynamic control, both the yield and stereose-
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S. Org. Biomol. Chem. 2008, doi 10.1039/b814882a.
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206
Org. Lett., Vol. 11, No. 1, 2009

lectivity can be improved by increasing the 9/7 ratio and
the reaction time. In this way, using 4 equiv of 9 and
maintaining the reaction for 12 h, compound 6 was obtained
in an quantitative yield, and the E isomer was exclusively
detected by NMR.
tetramethylethylenediamine (TMEDA) was used, the ste-
roselectivity was similar to that reported in entry 1 (entry
3). The use of tetraethylethylenediamine (TEEDA) slightly
increased the 5/10 ratio to 3.8:1, in an 93% yield (entry 4).
It has been reported that the asymmetric dihydroxylation
reactions of related substrates afforded excellent yields and
stereoselectivities of the L-lyxo and D-xylo phytosphingosines,
using AD-MIX R and ꢀ, respectively;27,28 however, when
compound 6 was treated with commercial AD-MIX mix-
tures,27 no reaction was observed (entries 5, 6, Table 1). The
reaction was attempted using a freshly prepared mixture of
[K2OsO2(OH)4] and [K3Fe(CN)6] in the presence of ligands
(DHQD)2-PHAL or (DHQ)2-PHAL, in tBuOH/H2O (1:1), but
unfortunately, the starting material was again exclusively
recovered. Finally, in the presence of K2OsO2(OH)4]/
[K3Fe(CN)6]/(DHQ)2PYR, compounds 5/10 were obtained
in a quantitative yield with a ratio of 5.1:1 (Entry 7).
With compound 5 in hand, the next step involved the
selective protection of the hydroxyl groups at positions 1
and 3 and the activation of the 4-OH as a leaving group.
We initially attempted the simultaneous protection of 1- and
Compound 6 was then reacted with OsO4/NMO to obtain
a mixture of compounds 5 and 10 in an almost quantitative
yield in a ratio of 3.3:1 (Scheme 3) (entry 1, Table 1).
Scheme 3. Dihydroxylation of Alkene 6
t
3-OH by reaction with Bu2Si(OTf)2 and further activation
of the 4-OH as a triflate. However, the subsequent elimination
provided a very poor yield of the sphingosine derivative.
Alternatively, 5 was reacted with TBDPSCl, affording
compound 11 in an 89% yield, which was then treated with
thionyl chloride and RuO4/NaIO4, affording sulfate 12 in a
quantitative yield (Scheme 4).8
Table 1. Dihydroxylation of Alkene 6
entry
reagent
temp (°C) yield (%) ratio 5:10
1
2
OsO4/NMO
OsO4/NMO
OsO4/NMO
OsO4/NMO
AD-MIX Rc
AD-MIX ꢀd
[Os]/(DHQ)2PYRe
rt
0
-78
-78
rt
99
57
95
93
3.3:1
3.4:1
3.4:1
3.8:1
3a
4b
5
Scheme 4. Synthesis of Key Intermediate 12 and Sphingosine
6
7
rt
rt
99
5.1:1
a OsO4 (1 equiv) and TMDA (1.1 equiv) were used. b TEEDA was used
astheligand.c Ligand(DHQ)2PHAL.d Ligand(DHQD)2PHAL.e K2OsO2(OH)4
(0.02 equiv), (DHQ)2PYR (0.03 equiv), CH3SO2NH2 (1.2 equiv), K2CO3
(0.03 equiv), NaHCO3 (0.03 equiv), K3Fe(CN)6, (0.03 equiv).
Decreasing the temperature had a negative effect on the yield
and no effect on the stereoselectivity (entry 2). An attempt
was made to increase the stereoselectivity by carrying out
the reaction at -78 °C and using stoichiometric amounts of
OsO4 in the presence of different diamine ligands. When
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Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 9192–9193.
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Compound 12 was then reacted with DBU in the presence
of tetrabutylammonium iodide to obtain compound 13 in an
82% yield.8 Further deprotection of 13 by reaction with
TBAF in THF at room temperature and treatment with
hydrazine afforded sphingosine (1) in an 82% yield.
Similarly, 12 was also reacted with benzoic acid and
Cs2CO3, to produce compound 14 in a 91% yield (Scheme
5). This excellent regioselectivity was also observed for other
nucleophiles and was atributed to the steric and electronic
interactions between neighboring sustituents and nucleo-
philes.8 Compound 14 was also deprotected by reacting it
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Org. Lett., Vol. 11, No. 1, 2009
207

In conclusion, D-erythro-sphingosine (1), N-phtalimido-
D-lyxo- (5), D-ribo-phytosphingosine (2), and 4-mercapto (15)
and 4-azido (16) analogs were prepared by a highly efficient
and enantioselective procedure (Scheme 7). This procedure
Scheme 5. Synthesis of Phytosphingosine (2)
Scheme 7. Synthesis of Compounds 1, 2, 5, 15 and 16 from 7
with TBAF and hydrazine to furnish phytosphingosine (2)
in an 89% yield. NMR spectra and optical rotation of
compounds 119b and 229 match the reported values for the
natural products.
The possibility to obtain analogues of phytosphingosine
modified at position 4 was illustrated by synthesizing the
new 4-mercapto and the 4-azido derivatives (Scheme 6).
starts from butadiene monoepoxide and uses a Pd-catalyzed
DYKAT process, a cross-metathesis using a second genera-
tion Grubbs catalysis and a dihydroxylation reaction to
produce the key intermediate 5. From this intermediate, the
target compounds were obtained by protection, substitution,
or elimination of 4-OH and deprotection. This procedure is
the most efficient for preparing 1 and 2 using asymmetric
synthesis procedures and opens the way for preparing a large
variety of 4-phytosphingosine derivatives.
Scheme 6. Synthesis of Phytosphingosine Derivatives 15 and 16
Acknowledgment. The authors acknowledge the financial
support of DGESIC, CTQ2005-03124 and Consolider Inge-
nio 2010, CSD2006-0003 (Ministerio de Educacio´n, Spain).
We thank Servei de Recursos Cient´ıfics (URV) for technical
assistance. Fellowships from DURSI (Generalitat de Cata-
lunya) and Fons Social Europeu to J.L. are also acknowl-
edged. We also thank Dr. Christopher Cobley (Dow Pharma)
for the generous gift of a sample of the starting material.
Thus, compound 12 was reacted with BzSH and Cs2CO3 to
render compound 15 in an 87% yield. In a parallel experi-
ment, compound 12 was reacted with sodium azide in the
presence of catalytic 15-crown-5 to afford compound 16 in
an 89% yield.
Supporting Information Available: General experimental
methods, experimental procedures, compound characteriza-
tion data, and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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