Efficient stereodivergent synthesis of erythro- and threo-sphingosines: Unprecedented reversal of the stereochemistry in the addition

Article abstract of DOI:10.1016/S0040-4020(02)01190-0

A convenient diastereoselective synthesis of D-erythro- and L-threo-sphingosine derivatives is described. L-Serine-derived aldehyde (Garner's aldehyde) (2) was treated with 1-alkenyl-zirconocene chlorides (3) in the presence of ZnBr₂ in THF to give the natural erythro-(anti-) isomers with high diastereoselectivity (anti/syn=12-20:1). In contrast, reaction of 2 with 1-alkenyl-ethyl-zinc, prepared from 3 and Et₂Zn, in CH₂Cl₂ gave the unnatural threo-(syn-) isomers predominantly (anti/syn=1:12-15).

Full text of DOI:10.1016/S0040-4020(02)01190-0

Tetrahedron 58 (2002) 9257–9263
Efficient stereodivergent synthesis of erythro- and
threo-sphingosines: unprecedented reversal of the stereochemistry
in the addition
*
Teiichi Murakami and Kiyotaka Furusawa
National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, Tsukuba, Ibaraki 305-8565, Japan
Received 8 August 2002; accepted 12 September 2002
Abstract—A convenient diastereoselective synthesis of D-erythro- and L-threo-sphingosine derivatives is described. L-Serine-derived
aldehyde (Garner’s aldehyde) (2) was treated with 1-alkenyl-zirconocene chlorides (3) in the presence of ZnBr2 in THF to give the natural
erythro-(anti-) isomers with high diastereoselectivity (anti/syn¼12–20:1). In contrast, reaction of 2 with 1-alkenyl-ethyl-zinc, prepared from
3 and Et2Zn, in CH2Cl2 gave the unnatural threo-(syn-) isomers predominantly (anti/syn¼1:12–15). q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
synthetic studies of sphingolipids and a number of synthetic
methods of 1 have been reported since 1950’s.5
Sphingolipids, e.g. sphingomyelin, cerebrosides, and
gangliosides, are ubiquitous membrane components of
eukaryotic cells and are involved in many essential
biological processes such as cell growth, cell differentiation,
and adhesion.1 Common to this diverse group of natural
products is a sphingoid base bearing a long aliphatic chain
and a polar 2-amino-1,3-diol head group. The most
abundant sphingoid base in nature is D-erythro-C18-
sphingosine [(2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol,
1]. Sphingolipid metabolites such as sphingosine and
ceramide are emerging as a novel class of lipid second
messengers.2 Sphingosine is a potent inhibitor of protein
kinase C,3 and ceramide has been found to play a crucial
role in cell regulation and in programmed cell death
(apoptosis) (Fig. 1).4
Conceptually, one of the most straightforward strategies for
the enantioselective synthesis of D-erythro-sphingosine 1
would be the addition of a 1-alkenyl nucleophile to a
suitably protected L-serine-derived aldehyde (serinal).
Earlier syntheses6 based on this strategy, however, met
with serious problems such as low yield,6a poor diastereo-
selectivity,6b and/or loss of enantiomeric purity during the
addition reaction, presumably due to the instability of the
serinal derivatives as well as the modest nucleophilicity of
the alkenylating agent (alkenyl-aluminum). In 1984, Garner
succeeded in preparing a configurationally stable serinal 2
(N-Boc-N,O-isopropylidene-L-serinal¼Garner’s aldehyde)
from L-serine7 (Scheme 1). This aldehyde and the closely
related ones have been widely employed as chiral building
blocks for the synthesis of natural products bearing 1,2-
amino-alcohol or 2-amino-1,3-diol subunit.8 In 1988, four
research groups independently reported9 efficient syntheses
of sphingosine 1 from the aldehyde 2 via addition of
1-pentadecynyllithium to 2 with high anti-diastereo-
selectivity (anti/syn¼8:19b to 15:19d). Herold9a further
investigated the effect of additives and found that the anti-
selectivity increased to 20:1 in the presence of HMPA, a
Because of their biological significance as well as the
difficulty of isolation from natural sources in homogeneous
form, considerable efforts have been devoted to the
Figure 1. D-erythro-C18-sphingosine.
Keywords: sphingosine; addition reactions; diastereoselection; zirconium
and compounds.
*
Corresponding author. Fax: þ81-298-61-4421;
e-mail: t-murakami@aist.go.jp
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01190-0

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T. Murakami, K. Furusawa / Tetrahedron 58 (2002) 9257–9263
M¼B(OH)2] to 2 gives the adducts in 78% yield with anti-
selectivity (anti/syn¼82:18).15c Therefore, improvements in
both the stereoselectivity16 and the yield are still necessary
for practical synthesis.
Here we disclose our results on the stereoselective additions
of 1-alkenyl metals, most of which were prepared via
hydrozirconation of 1-alkynes, to Garner’s aldehyde to
develop an efficient direct synthesis of erythro- and threo-
sphingosines.17–19
Scheme 2. Addition of (E)-1-alkenyl metals 3 to Garner’s aldehyde 2.
cation complexing agent, whereas the selectivity was
reversed to syn-selective (anti/syn¼1:20) by adding
1 equiv. of ZnBr2 in Et2O. These methods have been widely
applied to the synthesis of natural and unnatural sphingo-
lipid derivatives.10 For the sphingosine synthesis, however,
this type of alkyne-addition method requires an additional
step, that is, reduction of the triple bond to an (E)-olefin with
Red-Al9a or lithium/liq. NH3.9d
2. Results and discussion
We focused our attention on 1-(E)-alkenylzirconocene
species, since they are readily formed by hydrozirconation20
of terminal alkynes 6 with zirconocene chloride hydride
(Schwartz reagent) 7 in a regio and stereo-specific manner
(Scheme 3). In general, hydrozirconation of 1-alkynes with
Cp2Zr(H)Cl proceeds more rapidly than hydroalumination
with DIBAL-H, and more importantly, the former reaction
tolerates the presence of certain functional groups such as
ethers, silyl ethers, and t-butyl esters. Although addition of
alkenylzirconocenes to aldehydes is sluggish, the reaction is
accelerated either by adding a catalyst (Ag-salts,15b,21a
ZnBr221b) or by transmetalation with dialkylzinc21c to afford
(E)-allylic alcohols in fair to high yields. Besides,
methyllithium has been reported to promote the addition
by generating a reactive alkyne–zirconocene complex.21d
Compared with the alkynylation mentioned above, less
attention has been paid to the alkenylation of Garner’s
aldehyde 2 (Scheme 2). Coleman et al. investigated the
addition reactions of simple vinyl metals (3, R¼H, M¼Li,
MgBr, ZnCl) to 2 and found that the anti/syn ratio of the
adducts (4/5) ranged from 5:1 to 1:6 depending on the
metals, additives, and solvents.11 However, 1-(E)-alkenyl-
lithiums (R–H) or the Grignard counterparts12 have rarely
been employed for the sphingosine synthesis because, in
addition to their tedious preparations,13 the yield and the
stereoselectivity in the addition are usually lower14 than
those of 1-alkynyl-lithiums. To our knowledge, addition
reactions using other alkenyl-metals have been reported
from four laboratories. Garner et al. observed that the
reaction of 2 with 1-pentadecenyl-alane (3a, M¼Al(i-Bu)2)
gave the adducts with modest syn-selectivity (4a/5a¼1:2).9b
Soai et al. reported that the reaction of 1-pentadecenyl-
ethyl-zinc (3a, M¼ZnEt) with 2 in the presence of
2-(dibutylamino)ethanol afforded 4a/5a in 50% combined
yield in a ratio of 7.3:1, the highest anti-selectivity to
date.15a Suzuki et al. reported that the reaction of 1-octenyl-
zirconocene chloride (3, R¼n-C6H13, M¼ZrCp2Cl) with 2
in the presence of AgAsF6 gave the corresponding allylic
alcohols in 70% yield as a 1:1 diastereomeric mixture.15b
Very recently, Fu¨rstner et al. found that the rhodium-
catalyzed addition of 1-octenylboronic acid [3, R¼n-C6H13,
The aldehyde 2 was prepared from N-Boc-L-serine in three
steps according to an improved procedure by Taylor et al.,22
or was obtained from a commercial source. The results of
the reaction of 2 with 1-pentadecenyl metals 3a are
summarized in Table 1. We first examined the addition of
1-pentadecenyl-lithium (3a, M¼Li), prepared from 8a13
with butyllithium, to 2 at low temperatures in THF (entry 1).
Although the syn-isomer 5a was slightly more polar than the
anti-isomer 4a on TLC as reported by Garner,9b it was
difficult to separate these isomers by silica gel chromatog-
raphy. In addition, the starting aldehyde 2 had a similar Rf
value to the adducts 4a/5a. In the work-up procedure, the
crude extraction mixture was treated with NaBH4 to reduce
the unreacted aldehyde to the more polar primary alcohol.
1
The H NMR spectrum of the product mixture 4a/5a in
Scheme 3. Preparation of 1-alkenyl metals from 1-alkynes.

T. Murakami, K. Furusawa / Tetrahedron 58 (2002) 9257–9263
Table 1. Addition of (E)-1-pentadecenyl metals 3a to Garner’s aldehyde 2
9259
Entry
Ma
Additive (mol%b)
Solvent
Conditions
Yieldc (%)
Ratiod
4a/5a
2e
1
2
3
4
5
6
7
8
Li
THF
270 to 2408C
08C to rt, 6 h
41
30
74
70
73
81
48
78
84
67
77
28
5:1
1:1
12:1
20:1
5:1
5:1
1.1:1
2:1
1:15
12:1
1:1.5
1.8:1
30
40
11
8
Cp2Zr(Cl)
Cp2Zr(Cl)
Cp2Zr(Cl)
Cp2Zr(Cl)
Cp2Zr(Cl)
Cp2Zr(Cl)
Cp2Zr(Cl)
EtZn
AgOTf (15)
ZnBr2 (50)
ZnBr2 (25)
ZnBr2 (100)
ZnBr2 (50)
CH2Cl2
THF
THF
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF
CH2Cl2
THF
08C to rt, 24 h
08C to rt, 24 h
08C to rt, 20 h
08C to rt, 20 h
08C to rt, 24 h
08C to rt, 24 h
230 to 08C, 1 h
2208C to rt, 18 h
2208C to rt
5
Zn(OTf)2 (50)
Zn(OTf)2 (45)
33
9
10
11
12
EtZn
Me2Al
Cp2Zr(Me)
19
42
2308C to rt, 2 h
a
Alkenyl-metals used were 1.8–2.0 equiv. to 2.
Relative to 2.
Isolated yield after chromatography.
Ratio determined by H NMR.
The yield of reduced primary alcohol.
b
c
d
e
1
C6D6 at 758C† revealed the anti/syn ratio to be¼5:1 from the
integration of the diastereotopic (C-10) protons [4a: d 4.31
(br s) vs 5a: d 4.41 (t, J¼7 Hz)].15a This anti/syn ratio is in
accordance with those reported for the addition of
vinyllithium,11 vinylmagnesium bromide,23a and aryl-
lithiums,23b,c indicating that the addition would occur
mainly via a non-chelated Felkin–Anh transition state.
high syn-selectivity (anti/syn¼1:15). When this Et2Zn-
mediated reaction was carried out in THF, the anti/syn ratio
was entirely reversed to anti-selective (entry 10). In the case
of transmetalation with Me2AlCl25 in CH2Cl2, both isomers
were obtained with modest syn-selectivity (entry 11). When
MeLi was used for replacing the chloride with methyl group
following the protocol of Maier,21d the adducts were
obtained in low yield with modest anti-selectivity (entry
12).
We then investigated the reaction of 1-(E)-pentadecenyl-
zirconocene chloride (3a-Zr), prepared from 1-pentadecyne
6a and Cp2Zr(H)Cl 7,24 with 2. Following the protocol of
Suzuki,21a a catalytic amount of silver trifluoromethane-
sulfonate (AgOTf) was added to a mixture of 2 and 3a-Zr
(2 equiv. to 2) in CH2Cl2 (entry 2). This reaction provided a
1:1 mixture of 4a/5a in low yield (not optimized). The lack
of stereoselectivity is consistent with the precedent15b
mentioned above. Next, according to the protocol of
Srebnik,21b ZnBr2 (50 mol% to 2) was added to a mixture
of 2 and 3a-Zr in THF (entry 3). The addition reaction was
very slow at 08C, but gradually proceeded at room
temperature to afford the adducts in 74% yield along with
the primary alcohol (11%) after treatment with NaBH4. The
1H NMR analysis showed that anti-4a was the major
product with high diastereoselectivity (12:1). The anti-
selectivity increased to 20:1 by using a reduced amount
(25 mol%) of ZnBr2, whereas it decreased to 5:1 with
100 mol% of ZnBr2. When the reaction was carried out in
CH2Cl2 instead of THF, the addition proceeded more
rapidly to give the adducts in better yield, albeit with a
slightly diminished selectivity (entry 6). We found the
addition was promoted by Zn(OTf)2, but the stereo-
selectivities were low (entries 7 and 8).
The enantiomeric purities of the anti-rich (entry 4) and the
syn-rich (entry 9) products were determined by their optical
rotations, which agreed well with those reported,9b as well
as by NMR analysis of their Mosher esters26 prepared by
condensation with (S)-a-methoxy-a-(trifluoromethyl)-
1
phenylacetic acid (S-MTPA). The H NMR spectrum of
the each Mosher ester showed no diastereomeric peak from
the antipode,‡ indicating that essentially no racemization
occurred during the reaction.
We then examined the reaction of 2 with (E)-b-styryl-
metals 3b derived from phenylacetylene 6b and Schwartz
reagent 7. The addition products 4b/5b17h,27 were easily
detected on TLC by their UV absorption at 254 nm, but they
were also inseparable by silica gel chromatography. The
structures and the ratio of the adducts were determined by
NMR analyses.§ The results are summarized in Table 2.
ZnBr2 catalyzed addition of 3b-Zr in THF predominantly
gave the anti-isomer 4b (entry 1), whereas syn-isomer 5b
was major in CH2Cl2 (entry 2). Addition of b-styryl-ethyl-
zinc (3b-Zn), generated in situ from 3b-Zr with Et2Zn, to 2
in CH2Cl2 predominantly afforded the syn-isomer 5b (entry
3). However, Et2Zn-mediated reaction carried out in THF
gave a complex mixture, which contained the adducts 4b/5b
in only ca. 5% yield (entry 4). Thus, the stereochemical
Then according to the protocol of Wipf,21c an equimolar
amount of Et2Zn (1.0 M solution in hexane) was added to a
solution of 3a-Zr in CH2Cl2 at 2408C to generate
1-pentadecenyl-ethyl-zinc (3a-Zn) via transmetalation,
then 2 was added (entry 9). The reaction proceeded
smoothly below 08C giving the adducts in high yield with
‡
Racemic anti- and syn-adducts were prepared from racemic Garner’s
aldehyde, which was prepared by treatment of 2 with DBU in CH2Cl2, by
the same procedures as above, and they were treated with (S)-MTPA to
give the 1:1 diastereomeric Mosher esters, respectively.
†
§
This type of oxazolidine-carbamate exists as a pair of rotamers that
interconvert slowly at 258C, thereby the 1H NMR spectrum shows
doubling and line broadening of certain resonances.
Distinguishable proton signals: C10 –H: 4b d 4.40 (s-like) vs 5b d 4.60 (t);
C30 –H: 4b d 6.72 (d) vs 5b d 6.62 (d); t-Bu (9H): 4b d 1.32 (s) vs 5b d
1.39 (s).

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T. Murakami, K. Furusawa / Tetrahedron 58 (2002) 9257–9263
Table 2. Addition of (E)-b-styryl-metals 3b to Garner’s aldehyde 2
Entry
Ma
Additive (mol%b)
Solvent
Conditions
Yieldc (%)
Ratiod
4b/5b
2e
1
2
3
4
Cp2Zr(Cl)
Cp2Zr(Cl)
EtZn
ZnBr2 (50)
ZnBr2 (25)
THF
08C to rt, 24 h
08C to rt, 3 h
230 to 08C, 1 h
2208C to rt, 16 h
58
87
86
ca. 5f
15:1
1:4.5
1:12
3:1
14
CH2Cl2
CH2Cl2
THF
EtZn
a
Alkenyl-metals used were 1.8–2.0 equiv. to 2.
Relative to 2.
Isolated yield after chromatography.
Ratio determined by 1H NMR.
The yield of reduced primary alcohol.
Contaminated with byproducts.
b
c
d
e
f
results of entries 1 and 3 are consistent with those observed
for the additions of 3a-Zr and 3a-Zn under otherwise
identical conditions, respectively. (Scheme 4)
indicated that the stereoselectivity in the additions of
alkenylzirconocene-zinc reagents (for both ZnBr2 and
Et2Zn) to 2 is strongly dependent on the solvent employed.
The high selectivities observed here may be attributed to the
steric bulk of the zirconocene moiety.
There have been a number of studies8,28 on the addition of
organometallic reagents to the aldehyde 2. The stereo-
chemical outcome of these reactions has been generally
rationalized that the anti-isomers are formed via the Felkin–
Anh transition state, whereas the syn-isomers are formed via
a cyclic chelate between the aldehyde carbonyl and the Boc
carbonyl groups. However, the stereoselectivity has been
shown to be rather reagent dependent, and both chelated and
non-chelated processes can occur concomitantly. To our
knowledge, the reaction mechanism of the ZnBr2 catalyzed
addition of alkenylzirconocenes remains unclear,21b,29 and
no precedent exists for the addition to a-chiral aldehydes. In
our cases, ZnBr2 catalyzed additions in THF afforded the
non-chelation controlled anti-adducts 4a,b predominantly
and the anti-selectivity slightly decreased with the increase
of ZnBr2. These results suggest that zinc bromide in THF
would interact preferably with 3-Zr rather than with the
serinal 2 and excess ZnBr2 may form a chelate with 2. The
syn-selective addition of 3a,b-Zn in CH2Cl2 can be
explained by a chelated transition model of 2 with zinc or
by a coordinated delivery model.11 However, high anti-
selectivity is also observed in the addition of 3a-Zn in THF
(entry 10) or in toluene.15a Therefore it has been clearly
The N,O-isopropylidene acetal of 4a,b and 5a,b was
selectively cleaved with aqueous acetic acid to give the
known N-Boc sphingosines 9a,b and 10a,b in good to
high yields (Scheme 4). These N-Boc derivatives except 9b
were recrystallized to remove the minor diastereomer and
showed spectral and physical data identical with those
reported.9a,10b,30
3. Conclusion
We have developed a practical, highly diastereoselective
synthesis of both D-erythro- and L-threo-sphingosines from
Garner’s aldehyde 2 with 1-alkenyl nucleophiles prepared
via hydrozirconation. The enantiomeric L-erythro- and
D-threo-sphingosines should be accessible from D-serine
by the same procedures. This diastereodivergent approach
has been applied to the synthesis of phenyl-substituted
sphingosine analogues. Since hydrozirconation is com-
patible with some functional groups, this protocol would
also be applicable to the synthesis of sphingosine analogues
Scheme 4. Diastereodivergent synthesis of N-Boc sphingosine derivatives from 2 and alkenyl-zirconocenes (3-Zr).

T. Murakami, K. Furusawa / Tetrahedron 58 (2002) 9257–9263
9261
bearing a functionalized hydrophobic backbone. Syntheses
of other sphingoid bases using this protocol are in progress
and will be reported in due course.
hexane–AcOEt (2:1!1:1) gave the primary alcohol
(13 mg, 11%).
4.1.2. tert-Butyl (4S)-4-[(1R,2E)-1-hydroxy-3-phenyl-2-
propenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(4b). This compound was prepared as described for 4a,
using phenylacetylene 6b (82 mg, 0.80 mmol), 7 (210 mg,
0.81 mmol), 2 (93 mg, 0.40 mmol), and ZnBr2 (46 mg,
4. Experimental
4.1. General
0.2 mmol).
Column
chromatographic
purification
(hexane/AcOEt¼3:1) gave 77 mg (58%) of 4b containing
a small amount of 5b (15:1 ratio by 1H NMR) as a colorless
oil: [a]2D4¼247.0 (c 2.40, CHCl3); 1H NMR (C6D6, 758C) d
1.32 (s, 9H), 1.42 (s, 3H), 1.58 (s, 3H), 3.67 (dd, J¼6.6,
9.0 Hz, 1H), 3.81 (d-like, J¼9.0 Hz, 1H), 4.01 (br s, 1H),
4.40 (br s, 1H), 6.23 (dd, J¼5.6, 15.9 Hz, 1H), 6.72
(d, J¼15.9 Hz, 1H), 7.01 (m, 1H), 7.11 (m, 2H), 7.29
(m, 2H); 13C NMR (C6D6, 758C)31 d 24.4, 26.9, 28.4 (3C),
62.8, 65.1, 74.1, 80.4, 94.7, 126.9 (2C), 128.6, 128.7
(2C), 130.1, 131.3, 137.8; HRMS calcd for C19H28NO4
(MþH)þ 334.2020, found 334.1990. Further elution with
hexane–AcOEt (2:1!1:1) gave the primary alcohol
(13 mg, 14%).
Melting points were determined with a Yanaco melting
point apparatus MP-500D and are uncorrected. Optical
rotations were measured with a JASCO DIP-1000 polari-
1
meter and [a]D values are given in 1021 deg. cm2 g21. H
NMR spectra were recorded at 270 MHz on a JEOL JNM-
GSX-270 spectrometer for solutions in CDCl3 or C6D6, and
chemical shifts (d) are reported in ppm relative to internal
tetramethylsilane (d 0.00), residual CHCl3 (d 7.26), or
C6HD5 (d 7.15). 13C NMR spectra were recorded at
67.8 MHz and chemical shifts (d) are reported in ppm
relative to CDCl3 (d 77.0), or C6D6 (d 128.0). Elemental
analyses and high-resolution mass spectrometry (HRMS)
were performed in the analytical section in this Institute
(AIST). Thin layer chromatography (TLC) and column
chromatography were performed on Merck pre-coated silica
gel 60F254 plates and silica gel (Kanto Chemicals, neutral,
100–210 mm), respectively. Schwartz reagent 7 and Et2Zn
(1.0 M in hexane) were purchased from Fluka, and Garner’s
aldehyde 2 and 1-pentadecyne 6a were purchased from
Tokyo Kasei (TCI).
4.1.3. tert-Butyl (4S)-4-[(1S,2E)-1-hydroxy-2-hexa-
decenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(5a). To an ice-cooled stirred suspension of Cp2Zr(H)Cl 7
(260 mg, 1.0 mmol) in CH2Cl2 (1 mL) under argon was
added 1-pentadecyne 6a (210 mg, 1.0 mmol) in CH2Cl2
(1.4 mL), and the mixture was stirred at room temperature
for 1 h, and then cooled to 2408C. To the resulting yellow
solution was added 1.0 M solution in hexane Et2Zn (1 mL,
1.0 mmol) followed by the aldehyde 2 (116 mg, 0.5 mmol)
in CH2Cl2 (1.4 mL), and the mixture was allowed to warm
to 08C. The mixture was diluted with AcOEt (10 mL) and
aq. sodium potassium tartrate (10 mL). The products were
purified as described for 4a to give 185 mg (84%) of 5a
containing a small amount of 4a (15:1 ratio by 1H NMR) as
a colorless oil: [a]2D4¼237.8 (c 0.84, CHCl3) [lit.9b
4.1.1. tert-Butyl (4S)-4-[(1R,2E)-1-hydroxy-2-hexa-
decenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(4a). To an ice-cooled stirred suspension of Cp2Zr(H)Cl 7
(260 mg, 1.0 mmol) in THF (1 mL) under argon was added
1-pentadecyne 6a (210 mg, 1.0 mmol) in THF (1.4 mL),
and the mixture was stirred at room temperature for 1 h, and
then cooled to 08C. To the resulting orange solution was
added the aldehyde 2 (116 mg, 0.5 mmol) in THF (1.4 mL)
followed by ZnBr2 (60 mg, 0.25 mmol, dried under vacuum
for 1 h before use), and the mixture was stirred for 24 h at
room temperature. The mixture was diluted with AcOEt
(10 mL) and aq. potassium sodium (þ)-tartrate (10 mL),
and stirred for 10 min. The resulting suspension was filtered
off and washed thoroughly with AcOEt (10 mL). The
combined filtrate and washings were transferred into a
separatory funnel, and successively washed with H2O and
brine. The aqueous phase was extracted with AcOEt
(2£20 mL), and the combined organic layers were dried
over Na2SO4. After filtration and removal of the solvent
under reduced pressure, the residue was dissolved in THF
(3 mL) and methanol (1 mL), and treated with NaBH4
(10 mg, 0.25 mmol). After 30 min, AcOH (20 mg,
0.33 mmol) was added, and the mixture was concentrated
and purified by silica gel chromatography (eluting with
hexane–AcOEt mixture, 7:1!5:1!4:1) to afford 163 mg
(74%) of 4a containing a small amount of 5a (12:1 ratio by
1H NMR) as a colorless oil: [a]D24¼228.7 (c 0.84, CHCl3)
1
[a]D¼239 (c 0.25, CHCl3); H NMR data (C6D6, 758C)
were fully consistent with those reported;9b 13C NMR
(C6D6, 758C)31 d 14.1, 23.0, 24.3, 27.2, 28.5, 29.5, 29.6,
29.7, 29.9, 30.00, 30.03, 30.1, 32.3, 32.7, 62.4, 64.7, 74.6,
80.3, 94.5, 130.5, 134.0; HRMS calcd for C26H50NO4
(MþH)þ: 440.3742, found 440.3652.
4.1.4. tert-Butyl (4S)-4-[(1S,2E)-1-hydroxy-3-phenyl-2-
propenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(5b).27b This compound was prepared as described for 4b,
using phenylacetylene 6b (103 mg, 1.0 mmol), 7 (265 mg,
1.0 mmol), 1.0 M Et2Zn solution (1.0 mL, 1.0 mmol), and 2
(135 mg, 0.60 mmol). Column chromatographic puri-
fication (hexane/AcOEt¼3:1) gave 177 mg (86%) of 5b
containing a small amount of 4b (12:1 ratio by 1H NMR) as
1
a colorless oil: [a]D24¼289.1 (c 1.48, CHCl3); H NMR
(C6D6, 758C) d 1.39 (s, 9H), 1.42 (s, 3H), 1.59 (s, 3H), 3.67
(dd, J¼6.3, 9.3 Hz, 1H), 3.94 (dd, J¼2.0, 9.3 Hz, 1H), 4.02
(dt, J¼2.0, 6.4 Hz, 1H), 4.60 (t, J¼6.7 Hz, 1H), 6.22
(dd, J¼7.1, 15.9 Hz, 1H), 6.62 (d, J¼15.9 Hz, 1H),
7.00–7.15 (m, 3H), 7.26 (m, 2H); 13C NMR (C6D6,
758C)31 d 24.3, 27.1, 28.5 (3C), 62.5, 64.5, 74.4, 80.4,
94.6, 127.0 (2C), 127.1, 128.8 (2C), 128.9, 129.9, 132.7;
HRMS calcd for C19H28NO4 (MþH)þ 334.2020, found
334.1962.
1
[lit.9b [a]D¼228 (c 0.65, CHCl3)]; H NMR data (C6D6,
758C) were fully consistent with those reported;9b 13C NMR
(C6D6, 758C)31 d 14.1, 23.0, 24.4, 26.8, 28.4, 29.6, 29.7,
29.9, 30.0, 30.1, 32.3, 32.8, 62.8, 64.9, 73.7, 80.1, 94.6,
130.2, 132.6; HRMS (CI) calcd for C22H40NO3 (M2t-
BuO)þ 366.3008, found 366.2982. Further elution with

9262
T. Murakami, K. Furusawa / Tetrahedron 58 (2002) 9257–9263
Lipid Research. Sphingolipid Biochemistry; Plenum: New
York, 1983; Vol. 3. (b) Hannun, Y. A.; Bell, R. M. Science
1989, 243, 500–507. (c) Merrill, A. H.; Sweely, C. C.
Biochemistry of Lipids, Lipoproteins and Membranes;
Elsevier: Amsterdam, 1996; Chapter 12. (d) Kolter, T.;
Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532–1568.
2. (a) Hannun, Y. A. Science 1996, 274, 1855–1859. (b) Hannun,
Y. A. Sphingolipid-Mediated Signal Transduction; Chapman
and Hall: New York, 1997.
4.1.5. tert-Butyl (1S,2R,3E)-N-[2-hydroxy-1-(hydroxy-
methyl)-3-heptadecenyl]carbamate (9a). The alcohol 4a
(145 mg, 0.33 mmol) was dissolved in acetic acid (0.9 mL)
and water (0.1 mL), and the mixture was stirred at 508C for
5 h. The mixture was concentrated and co-evaporated with
heptane (2£1 mL). The residue was purified by silica gel
chromatography (eluting with hexane–AcOEt mixture,
2:1!1:1) to afford the N-Boc sphingosine 9a (110 mg,
83%) as a colorless solid: mp 65–678C, [a]2D4¼21.4 (c 1.25,
CHCl3) [lit.9a mp 64–658C, [a]D25¼21.4 (c 1.1, CHCl3)]; 1H
and 13C NMR data (CDCl3) were fully consistent with those
reported;9d Anal. Calcd for C23H45NO4: C, 69.13; H, 11.35;
N, 3.51. Found: C, 69.27; H, 11.38; N, 3.49.
3. Hannun, Y. A.; Loomis, C. R.; Merill, Jr. A. H.; Bell, R. M.
J. Biol. Chem. 1986, 261, 12604.
4. (a) Hannun, Y. A.; Obeid, L. M. Trends Biochem. Sci. 1995,
20, 73–77. (b) Mathias, S.; Pena, L. A.; Kolesnick, R. N.
Biochem. J. 1998, 335, 465–480. (c) Birbes, H.; Bawab, S. E.;
Obeid, L. M.; Hannun, Y. A. Adv. Enzyme Regul. 2002, 42,
113–129.
4.1.6. tert-Butyl (1S,2S,3E)-N-[2-hydroxy-1-(hydroxy-
methyl)-3-heptadecenyl]carbamate (10a). In a manner
similar to that described for 9a, compound 10a was obtained
from 5a in 93% yield as a colorless oil, which was
recrystallized from hexane to afford a colorless solid: mp
58–608C; [a]2D4¼20.7 (c 1.6, CHCl3) [lit.9a mp 58–598C;
5. For recent reviews, see: (a) Koskinen, P. M.; Koskinen, A. M.
P. Synthesis 1998, 1075–1091. (b) Curfman, C.; Liotta, D.
Methods Enzymol. 2000, 311, 391–457.
6. (a) Newman, H. J. Am. Chem. Soc. 1973, 95, 4098–4099.
(b) Tkaczuk, P.; Thornton, E. R. J. Org. Chem. 1981, 46,
4393–4398.
1
[a]2D4¼20.4 (c 1.0, CHCl3)]; H NMR (CDCl3) d 0.88 (t,
J¼6.6 Hz, 3H), 1.26 (s, 20H), 1.35 (m, 2H), 1.45 (s, 9H),
2.04 (q, J¼6.7 Hz, 2H), 2.61 (d, J¼3.2 Hz, 1H), 2.68, (br,
1H), 3.62 (dq, J¼4.2, 8.3 Hz, 1H), 3.79 (t-like, J¼5.0 Hz,
2H), 4.34 (m, 1H), 5.17 (d, J¼7.8 Hz, 1H), 5.51 (tdd, J¼1.2,
6.6, 15.5 Hz, 1H), 5.75 (dtd, J¼1.0, 6.7, 15.5 Hz, 1H); 13C
NMR (CDCl3) d 14.1, 22.7, 28.3 (3C), 29.1, 29.2, 29.3,
29.5, 29.58, 29.63, 29.7 (3C), 31.9, 32.3, 55.5, 64.4, 73.5,
79.7, 128.9, 134.1, 156.6; Anal. Calcd for C23H45NO4: C,
69.13; H, 11.35; N, 3.51. Found: C, 69.43; H, 11.41; N, 3.40.
7. (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855–5858.
(b) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52,
2361–2364. (c) Garner, P.; Park, J. M. Org. Synth. 1991, 70,
18–28.
8. For a review, see: Liang, X.; Andersch, J.; Bols, M. J. Chem.
Soc., Perkin Trans. 1 2001, 2136–2157.
9. (a) Herold, P. Helv. Chim. Acta 1988, 71, 354–362. (b) Garner,
P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53,
4395–4398. (c) Nimkar, S.; Menaldino, D.; Merill, A. H.;
Liotta, D. Tetrahedron Lett. 1988, 29, 3037–3040. (d) Radunz,
H.-E.; Devant, R. M.; Eiermann, V. Liebigs Ann. Chem. 1988,
1103–1105.
4.1.7. tert-Butyl (1S,2R,3E)-N-[2-hydroxy-1-(hydroxy-
methyl)-4-phenyl-3-butenyl]carbamate (9b). In a manner
similar to that described for 9a, compound 9b was obtained
from 4b in 75% yield as a colorless semi-solid: [a]2D4¼þ6.5
10. (a) Miura, T.; Kajimoto, T.; Jimbo, M.; Yamagishi, K.;
Inokuchi, J.-C.; Wong, C.-H. Bioorg. Med. Chem. 1998, 6,
1481–1489. (b) Van Overmeire, I.; Boldin, S. A.; Dumont, F.;
Van Calenbergh, S.; Slegers, G.; De Keukeleire, D.; Futerman,
A. H.; Herdewijn, P. J. Med. Chem. 1999, 42, 2697–2705.
(c) Seki, M.; Kayo, A.; Mori, K. Tetrahedron Lett. 2001, 42,
2357–2360.
1
(c 1.05, CHCl3) [lit.10b [a]D¼þ5.12 (c 1.23, CHCl3)]; H
NMR (CDCl3) d 1.40 (s, 9H), 3.50 (br, 2H), 3.72 (dd, J¼3.5,
12.0 Hz, 1H), 3.75 (m, 1H), 3.95 (dd, J¼4.4, 12.0 Hz, 1H),
4.49 (m, 1H), 5.46 (d, J¼7.1 Hz, 1H), 6.24 (dd, J¼6.1,
16.1 Hz, 1H), 6.66 (d, J¼16.1 Hz, 1H), 7.20–7.40 (m, 5H);
13C NMR (CDCl3) d 28.3 (3C), 55.5, 62.3, 74.2, 79.9, 126.5
(2C), 127.7, 128.5 (3C), 131.7, 136.3, 156.3; HRMS calcd
for C16H24NO4 (MþH)þ 294.1705, found 294.1645.
11. Coleman, R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 33,
1697–1700.
12. For addition of an alkenyl-MgBr to cysteine-derived hetero-
cyclic aldehyde, see: Takikawa, H.; Nozawa, D.; Kayo, A.;
Muto, S.; Mori, K. J. Chem. Soc., Perkin Trans. 1 1999,
2467–2477.
4.1.8. tert-Butyl (1S,2S,3E)-N-[2-hydroxy-1-(hydroxy-
methyl)-4-phenyl-3-butenyl]carbamate (10b). In a man-
ner similar to that described for 9a, compound 10b was
obtained from 5b in 83% yield as a colorless solid: mp 112–
1148C; [a]2D4¼þ11.3 (c 1.32, CHCl3) [lit.10b [a]D¼þ8.61 (c
13. Peterson, M. A.; Polt, R. Synth. Commun. 1992, 22, 477–480.
14. For an unsuccessful attempt (data not shown): Duffin, G. R.;
Ellames, G. J.; Hartmann, S.; Herbert, J. M.; Smith, D. I.
J. Chem. Soc., Perkin Trans. 1 2000, 2237–2242.
15. (a) Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1
1994, 1257–1258. (b) Suzuki, K.; Hasegawa, T.; Imai, T.;
Maeta, H.; Ohba, S. Tetrahedron 1995, 51, 4483–4494.
(c) Fu¨rstner, A.; Krause, H. Adv. Synth. Catal. 2001, 343,
343–350.
1
1.37, CHCl3)]; H NMR (CDCl3) d 1.40 (s, 9H), 2.80 (br,
1H), 3.06 (d, J¼3.4 Hz, 1H), 3.75 (m, 1H), 3.85 (t-like, 2H),
4.60 (m, 1H), 5.24 (d, J¼8.3 Hz, 1H), 6.27 (dd, J¼6.1,
15.9 Hz, 1H), 6.67 (d, J¼15.9 Hz, 1H), 7.20–7.40 (m, 5H);
13C NMR (CDCl3) d 28.3 (3C), 55.5, 64.1, 73.3, 79.9, 126.6
(2C), 127.8, 128.5 (2C), 128.7, 131.6, 136.4, 156.5; Anal.
Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C,
65.41; H, 7.66; N, 4.75.
16. Highly syn-selective (.20:1) alkenylation of another serinal
derivative was reported: Polt, R.; Peterson, M. A.; DeYoung,
L. J. Org. Chem. 1992, 57, 5469–5480.
17. Recent syntheses of sphingosine derivatives from serine:
(a) Hoffman, R. V.; Tao, J. J. Org. Chem. 1998, 63,
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