Synthesis of sphingadienine-type glucocerebrosides

Article abstract of DOI:10.1016/S0040-4020(99)01018-2

Sphinga-4,8-dienine derivatives were synthesized from a vinyl-epoxide 5 via three routes. First, reaction of 5 with 2-dodecenyl cyanocuprate afforded a 1:1 mixture of (4E,8E)- and (4E,8Z)-sphingadienine derivatives in high yield. Second, the (4E,8E)-isome

Full text of DOI:10.1016/S0040-4020(99)01018-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 533–545
Synthesis of Sphingadienine-type Glucocerebrosides1
*
Teiichi Murakami, Toshimi Shimizu and Kazuhiro Taguchi
National Institute of Materials and Chemical Research, 1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
Received 12 October 1999; accepted 15 November 1999
Abstract—Sphinga-4,8-dienine derivatives were synthesized from a vinyl-epoxide 5 via three routes. First, reaction of 5 with 2-dodecenyl
cyanocuprate afforded a 1:1 mixture of (4E,8E)- and (4E,8Z)-sphingadienine derivatives in high yield. Second, the (4E,8E)-isomer was
selectively synthesized via allylic bromide-allylic sulfone coupling followed by desulfonylation. Third, the (4E,8Z)-isomer was selectively
synthesized via SN20-type addition of di(cyanomethyl)copper-lithium followed by Wittig olefination. These synthetic intermediates were
converted to sphingadienine-type glucocerebrosides 1a and 1b which have calcium ionophoretic activity. ᭧ 2000 Elsevier Science Ltd. All
rights reserved.
Introduction
Sphingolipids, e.g. ceramides, sphingomyelin, cerebrosides
and gangliosides, are important constituents of cellular
membranes. The principal component of sphingolipids is
the long-chain base, sphingosine.2 In nature, the most
widely occurring of sphingoid bases is d-erythro-sphingo-
sine [4(E)-sphingenine], which has one (E)-double bond
between C-4 and C-5. Sphingadienines, which have two
double bonds in the hydrocarbon chain, are minor sphingoid
bases obtained from fungi,3 plants,4 marine organisms5 and
In this paper, we report a regio- and stereocontrolled
synthesis of glucocerebrosides 1a and 1b, employing a
mammalian tissues.6 In recent years, it has been reported
that simple mono-glucocerebrosides containing sphinga-
4,8-dienine in the hydrophobic moiety exhibit significant
activities. In 1983, Yamazaki et al. reported that gluco-
cerebrosides from Tetragonia tetragonides showed anti-
ulcerogenic activity.7 In 1990, Kitagawa et al. reported8
that soya-cerebrosides from soybean, the seeds of Glycine
max Merrill, showed ionophoretic activity for Ca2ϩ ion.
Also Ina et al. reported9 that cerebrosides from the bark of
Prunus jamasakura showed repellent activity against the
Blue Mussel, Mytilus edulis. The major constituents of all
these cerebrosides were determined to be (2S,3R,4E,8E,
20R)-1-O-b-d-glucopyranosyl-2-(20-hydroxypalmitoyl)-
amino-4,8-octadecadien-1,3-diol (1a) and its (8Z)-isomer
(1b). For the ionophoretic property, the (8Z)-isomer showed
higher Ca2ϩ ion binding activity than the (8E)-isomer,
whereas usual (4E)-sphingenine-type cerebroside showed
little activity.8 Several syntheses10 of 1a and/or 1b have
been reported. The scarcity in nature as well as the interest-
ing properties, especially the ionophoretic activity, of 1
prompted us to investigate their synthesis.
vinyl-epoxide derived from d-glucosamine as a key
intermediate of the sphingadienine moiety.
Results and Discussion
Stereocontrolled syntheses of sphingadienines
Cross-coupling reaction with allylic cuprates. Our retro-
synthetic analysis of 1 is shown in Fig. 1. Glucocerebrosides
1 consist of three segments, that is, sphinga-4,8-dienine,
d-glucose, and (2R)-hydroxypalmitic acid. The glucose
residue and the optically active fatty acid can be introduced
by using a suitably protected glycosyl donor 3 and a recently
reported acyl donor 4, respectively. Thus the analysis is
focused on the synthetic strategy for the sphingadienine
moiety. We already reported11 a stereocontrolled synthesis
of d-erythro-C18-sphingosine,12 utilizing SN20-type reac-
tion13 of dodecylmagnesium bromide with a vinyl-epoxide
5, which was prepared from N-benzoyl-d-glucosamine 6 in
six steps,14 in the presence of a catalytic amount of copper(I)
cyanide (CuCN). According to this approach, sphinga-4,8-
dienine derivatives would be obtained by employing
2-dodecenylmagnesium halide instead of n-C12H25MgBr.
Keywords: glycolipids; dienes; vinyl-epoxide; coupling reactions.
* Corresponding author. E-mail: tmurakami@home.nimc.go.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01018-2

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T. Murakami et al. / Tetrahedron 56 (2000) 533–545
Figure 1. Retrosynthetic analysis of glucocerebrosides 1a,b.
Scheme 1. Reagents and conditions: (a) CH2yCHCH2MgBr (2 equiv.), CuCN (10 mol%), THF,Ϫ70 to Ϫ20ЊC; (b) n-Bu3SnLi (1.0 equiv.), THF,Ϫ70 to
Ϫ20ЊC; (c) MeLi (1.0 equiv.), THF,Ϫ70 to Ϫ10ЊC, then CuCN (0.5 equiv), LiCl (1.0 equiv.), THF Ϫ70ЊC; (d) vinyl-epoxide 5 (0.25 equiv. to 10), THF, Ϫ70
to Ϫ20ЊC, 2 h; (e) 2M-HCl, THF room temperature 15 h; then 4 (1.5 equiv.), Et3N, DMF, 60ЊC, 6 h; (f) 1-methyltetrazol-5-yl disulfide (0.5 equiv.), AIBN,
toluene, 100ЊC, 4 h, then recrystallization from hexane.

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
535
Thus installation of the 1,5-diene part in the sphingadienine
would be achieved by using 2-dodecenyl metal derivatives
7a as allylic nucleophiles15 and the vinyl-epoxide 5 as an
allylic electrophile. However, regiocontrol of the reaction is
a serious problem associated with this allyl–allyl cross-
coupling approach to 1,5-dienes. Control of the olefin
geometry is also a problem when g-substituted allylic
metals are used. For example, 2-butenylmagnesium
bromide is known to isomerize rapidly between the (Z)-
and (E)-isomers even at Ϫ80ЊC.16 However, this isomeriza-
tion is favorable for our case since both (E)- and (Z)-isomers
can be formed from an (E)-allylic halide.
small peaks around d 27 ppm and those around d 32 ppm
are assigned to methylene carbons adjacent to (Z)-olefinic
carbons and those to (E)-olefinic carbons, respectively.7,8,25
Therefore, the product consists of (4E,8E)-diene 12a and
(4E,8Z)-diene 12b in ca. 1:1 ratio. This result was consistent
with that reported by Normant et al.18 mentioned above.
Unfortunately, separation of the isomers was found to be
difficult not only at this stage but also at later stages of the
synthesis.26
For the synthesis of (4E,8E)-diene-type ceramide from the
mixture, olefin-isomerization was then examined. Acid
catalyzed ring opening of the oxazoline in 12 gave 1-O-
benzoyl-sphingadienine hydrochloride, which upon treat-
ment with (2R)-acetoxypalmitoyl imide 4 (Fig. 1) as
previously reported1 afforded the amide 13. Treatment of
13 with 1-methyltetrazol-5-yl disulfide in the presence of
2,20-azobis(isobutyronitrile) (AIBN)27 at 100ЊC gave an
equilibrium mixture of (4E,8E)- and (4E,8Z)-dienes in a
ratio of 5:1 as determined by NMR. Recrystallization of
the major product from hexane afforded the pure (4E,8E)-
diene 13a in ca. 60% yield from 13. The physical data of
13a were identical with those reported.10b
There have been several reports on the allyl–allyl cross-
coupling reactions. Yamamoto et al. reported17a that
g-substituted allylic Grignard reagents reacted regio-
selectively with allylic 1-diphenylphosphates to give g-a0
coupling products bearing one terminal olefin. In
contrast, they also reported17b that, in the presence of
CuCN, similar coupling reactions afforded mixtures of
regio- and geometrical-isomers, in which a-g0 coupling
products predominated. Normant et al. reported18 that the
reaction of g-substituted allylic Grignard reagents with
vinyl-epoxides in the presence of CuBr occurred regio-
selectively to afford 2,6-dien-1-ols bearing two internal
olefins in high yields. In general, g-substituted allylic
cuprates tend to react at the less-substituted terminus to
give the coupling products with predominantly internal
olefin.19,20
This cross-coupling approach appeared to be attractive since
both (4E,8E)- and (4E,8Z)-sphingadienine derivatives were
obtained from the common precursor in one step for carbon
chain elongation. However, the difficulty in separating the
isomers and the toxicity of organotin compounds and CuCN
led us to search for an alternative route.
Encouraged by these precedents, we investigated the reac-
tion of the vinyl-epoxide 5 with allylic cuprates. (Scheme 1)
At first, as a model experiment, allylmagnesium bromide
was employed in the presence of CuCN (10 mol%). This
reaction provided the desired SN20-type reaction product 8
having an (E)-olefin in 68% yield. Next we tried to prepare
2-dodecenyl metal derivatives (7a in Fig. 1) from 2(E)-
dodecenyl chloride 9, which was readily prepared from
commercially available 2(E)-dodecen-1-ol21 with LiCl,
methanesulfonyl chloride, and 2,6-lutidine.22 In our hands,
however, attempts to prepare 2-dodecenylmagnesium
chloride using activated Mg,23 to avoid homo-coupling,
were unsuccessful. We then turned our attention to allylic
higher-order cyanocuprates developed by Lipshutz.24 The
required 2-dodecenyllithium could be formed via tin–
lithium exchange reaction. Thus 2-dodecenyl chloride 9
was treated with tributyltinlithium to give 1-tributyl-
stannyl-2-dodecene 10. Treatment of 10 with methyllithium
(1 equiv.) in THF gave 2-dodecenyllithium, which was
treated in situ with CuCN (0.5 equiv.) and LiCl to generate
the higher-order cyanocuprate 11. Reaction of 11 with the
vinyl-epoxide (0.25 equiv. to 10) was rapid at Ϫ70ЊC,
affording the cross-coupled product in high yield based on
5. Its 1H NMR spectrum showed the presence of four
internal olefinic protons at d 5.3–5.9 ppm and the absence
of terminal olefin, indicating that the reaction took place at
the desired position. The large coupling constant (15.5 Hz)
between the protons at lower field indicated the (E)-
geometry of the olefin adjacent to hydroxy group. However,
the geometry of the C8–C9 olefin (sphingosine numbering)
could not be determined by 1H NMR. Its 13C NMR spectrum
showed 12 sp2 carbon signals at d 127–133 ppm and rela-
tively small peaks at d 26.8, 27.2, 32.1 and 32.6 ppm. The
Selective synthesis of (4E,8E)-sphingadienine. For the
synthesis of the (4E,8E)-diene, our attention was focused
on allylic sulfones as stabilized allylic nucleophiles (7b in
Fig. 1). Grieco et al.28 reported the preparation of geo-
metrically pure 1,5-dienes via coupling of allylic aromatic
sulfones with allylic halides followed by reductive
desulfonylation with lithium in ethylamine. Later a regio-
selective desulfonylation under milder reaction conditions
was developed by using lithium triethylborohydride with a
palladium catalyst.29a The latter method has been applied to
the syntheses of natural products.30 Thus we tried the
coupling reaction of 5 with 2-dodecenyl phenyl sulfone
14, which was readily prepared from 9 and sodium benzene-
sulfinate. (Scheme 2) Treatment of 14 with n-butyllithium
gave the yellow-colored anion 140, which was treated with 5
to give a product. 1H NMR indicated that the major product
resulted from equimolar coupling, but it was neither the
expected SN20 product nor SN2 reaction product. In the
presence of CuCN, the coupling reaction did not take place.
A recent paper reported31 that lithiated methyl (phenyl-
sulfonyl)acetate reacted predominantly with a primary
bromide in the presence of vinyl-epoxide moiety. This and
our results led us to examine the conversion of the vinyl-
epoxide moiety in 5 to allylic halide, which would be more
reactive toward sulfone anion, by opening the epoxy-ring
with a hydrogen halide (HX) equivalent. Although we could
not predict the regioselectivity (SN2 or SN20) of the epoxy-
ring opening with HX equivalent, we anticipated that,
regardless of the halogen position, the bulky sulfone reagent
140 would attack at the less-substituted site to give the
coupling product with internal diene. We employed

536
T. Murakami et al. / Tetrahedron 56 (2000) 533–545
Scheme 2. Reagents and conditions: (a) PhSO2Na (2 equiv.), DMF, 50ЊC, 5 h; (b) BuLi (1.0 equiv.), THF, Ϫ40ЊC; (c) Me3SiCl (4 equiv.), CH3CN, 0ЊC to room
temperature, then Et3N (4 equiv.); (c0) Me3SiCl (3.6 equiv.), LiBr (4 equiv.), CH3CN, 0–10ЊC, 3 h, then Et3N (4 equiv.), 5–10ЊC; (d) LiBEt3H (3 equiv.),
Pd(OAc)2 (10 mol%), dppp (10 mol%), THF, 0–5ЊC, 2 h; (e) 2M-HCl, THF, room temperature, 15 h, then 4 (1.5 equiv.), Et3N, DMF, 60ЊC, 5 h, then
recrystallization from hexane.
trimethylsilyl halide (TMSX) as a HX equivalent since the
reaction would give O-TMS protected vicinal halohydrin,32
which should not revert to the epoxide under basic reaction
conditions. Treatment of 5 with TMSCl and LiCl in aceto-
and regioisomeric (4E,7E)-diene 1833 resulting from SN20
reduction. Alternatively, in view of the coordination effect
of the hydroxy group, we examined a desulfonylation reac-
tion after desilylation of 16 with Bu4NF. However, the ratio
of the regioisomers was similar. Separation of the isomers
was achieved in a similar manner as mentioned above. Thus
ring opening of the oxazoline followed by N-acylation with
4 gave the 1-O-benzoyl-ceramide, from which the pure
(4E,8E)-ceramide 13a was obtained by recrystallization in
41% overall yield from 16.
1
nitrile gave allylic chloride 15a in 70% yield. Its H NMR
spectrum showed the presence of terminal olefin, indicating
that the chloride was introduced at the a position of the
epoxide regioselectively. Similarly, 5 was treated with
premixed TMSCl and LiBr to give the allylic bromide
15b, which was not contaminated with the chloride as deter-
mined by NMR. Treatment of the chloride 15a with the
lithiated 2-dodecenyl phenyl sulfone 140 at 50ЊC gave
the desired SN20 reaction product with (E,E)-diene 16, but
the yield was only 35%. In contrast, reaction of the bromide
15b with 140 proceeded smoothly at 0–10ЊC to afford 16 in
71% yield as a 1:1 diastereomeric mixture. Desulfonylation
of 16 was achieved with LiBEt3H in the presence of
palladium acetate29b and 1,3-bis(diphenylphosphino)-
Selective synthesis of (4E,8Z)-sphingadienine. Next we
investigated a selective synthesis of the (8Z)-olefin. We
adopted a two-stage chain-elongation strategy, i.e. addition
of an acetaldehyde equivalent to 5 and subsequent Wittig
olefination. (Scheme 3) Thus 5 was treated with di(cyano-
methyl)copper-lithium34 prepared from lithiated acetonitrile
and CuI to give the SN20-type product 19 having (E)-olefin
in high yield. The nitrile was reduced by diisobutyl-
aluminum hydride (DIBAL-H) at Ϫ70 to Ϫ50ЊC to give
the aldehyde 20. At higher temperatures, the CyN bond of
1
propane (dppp) to give the product in 75% yield. Its H
and 13C NMR spectra indicated that the product was an
inseparable 4:1 mixture of the desired (4E,8E)-diene 17

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
537
Scheme 3. Reagents and conditions: (a) LiCH2CN (4 equiv.), Cul (2 equiv.), THF, Ϫ70 to Ϫ10ЊC, 5 h; (b) i-Bu2AlH (2.4 equiv.), toluene, Ϫ70 to Ϫ50ЊC; (c)
Ph3PyCH–(CH2)8CH3 (2.8 equiv.), THF Ϫ70–0ЊC; (d) 2M-HCl, THF, room temperature, 15 h then 4 (1.5 equiv.), Et3N. DMF., 60ЊC, 6 h.
the oxazoline should be reduced. Without purification, the
aldehyde 20 was subjected to Wittig olefination with
decylidene triphenylphosphorane to afford the (4E,8Z)-
sphingadienine derivative 12b in 78% yield. When
potassium t-butoxide was used as a base in the olefination,
no (8E)-isomer was detected by 13C NMR. Ring opening of
the oxazoline in 12 followed by N-acylation with the
imide 4 gave the 1-O-benzoyl-ceramide 13b in 80%
yield. The physical data of 13b were identical with those
reported.10b
Scheme 4. Reagents and conditions: (a) NaOMe, MeOH–CH2Cl2, 0–5ЊC, 1 h; (b) t-BuPh2SiCl (1.5 equiv.), imidazole (5 equiv.), DMF, CH2Cl2, 0–5ЊC, 0.5 h;
(c) Ao2O (4 equiv.), pyridine, DMAP (cat.), THF, 0–10ЊC; (d) Bu4NF (2 equiv.), AcOH, THF, room temperature, 3 h; (e) 2,3,4,6-tetra-O-benzoyl-a-d-
glucopyranosyl bromide (1.8 equiv.), AgOTf (1.8 equiv.), M.S. 4A, CH2Cl2, Ϫ20–0ЊC, 2 h; (f) NaOMe (1 equiv.), MeOH–THF, 0–10ЊC, 2 h.

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T. Murakami et al. / Tetrahedron 56 (2000) 533–545
Since the (8Z)-isomer 12b has been efficiently synthesized,
the (8E)-isomer can be obtained by the olefin inversion
reaction as shown in Scheme 1. However, the reaction
usually gives an equilibrium mixture of (E)- and (Z)-olefins
and isolation of the pure (E)-isomer is sometimes tedious.
The (8E)-olefin would be selectively obtained from 20 by
Julia olefination.35 However, Julia olefin synthesis usually
requires 3 steps from aldehydes ((1) addition of sulfone
reagent; (2) activation of the resultant alcohol; (3) reductive
elimination to olefin). In addition, our substrate has an
allylic alcohol and an oxazoline, both of which may be
incompatible with the reaction conditions. Thus we did
not examine this approach to the (8E)-isomer.
efficiently converted to sphingadienine-type glucocerebro-
sides 1a and 1b, respectively.
Experimental
Air- and moisture-sensitive reactions were carried out under
argon or nitrogen atmosphere. Melting points were deter-
mined with a Yanaco melting point apparatus MP-500D and
are uncorrected. Optical rotations were measured with a
JASCO DIP-1000 polarimeter and [a]D values are given
in 10Ϫ1 deg cm2 gϪ1 1H and 13C NMR spectra were
.
recorded at 270 and 67.8 MHz on a JEOL JNM-GSX-270
spectrometer for solutions in CDCl3 unless otherwise noted.
Tetramethylsilane (TMS) was used as internal standard
(dHˆ0) for 1H NMR and CDCl3 served as internal standard
(dCˆ77.0) for 13C NMR. When pyridine-d5 was used,
pyridine-d5 served as internal standard (dHˆ7.19,
dCˆ123.5). Infrared (IR) spectra were measured with a
JASCO FT-IR 620 spectrophotometer. Elemental analyses
were performed by the analytical center in this Institute
(NIMC). High-resolution mass spectra (HRMS) and FAB
mass spectra (FAB-MS) were obtained on a Hitachi M-80B
and a JEOL DX-303 mass spectrometers, respectively. Thin
layer chromatography (TLC) was performed on Merck pre-
coated silica gel 60F254 plates. Column chromatography was
performed on silica gel (Wako gel C-200 or C-300). Organic
solutions after extractive work-up were dried over Na2SO4,
filtered through a cotton plug, and concentrated under
reduced pressure.
Improved synthesis of glucocerebrosides
Since Mori et al. already reported10b the synthesis of the
glucocerebrosides from the protected sphingadienine
derivatives 13a,b, a formal synthesis of 1a,b has been
finished. However, we found the first step, protection of
the secondary hydroxy group of 13 with t-butyldiphenylsilyl
(TBDPS) chloride, to be somewhat capricious and poorly
reproducible. An alternative route was explored via usual
protecting group manipulations.36 (Scheme 4) Deacylation
of 13a with NaOMe in methanol–CH2Cl2 gave the
unprotected ceramide 21a. Selective protection of the
primary hydroxy group with TBDPS-Cl gave the 1-O-
TBDPS ether 22a in 82% yield. Acetylation of the second-
ary hydroxy groups followed by desilylation afforded the
protected ceramide 24a. The ceramide 24a was treated
with 2,3,4,6-tetra-O-benzoyl-a-d-glucopyranosyl bromide
[Fig. 1, 3 (Rˆbenzoyl, XˆBr)] in the presence of silver
trifluoromethanesulfonate (AgOTf) at Ϫ20–0ЊC to afford
the desired b-glucoside 25a in 78% yield. This glycosyl-
ation method37 seems to be more efficient than those used in
the previous syntheses10a,b,e,f since the glycosyl donor
(perbenzoylated glucosyl bromide) is readily available38
and rather stable, and the reaction products were free from
glycosyl orthoester derivative39 and 1-O-benzoylated 24a.40
Finally 25a was deacylated with NaOMe in methanol–THF
to afford the glycolipid 1a. In a similar manner, the (4E,8Z)-
glucocerebroside 1b was synthesized from 13b. The physi-
cal data of 1a and 1b were in good agreement with those
reported.10 Thus this route provided 1 in 6 steps from 13
with better overall yields (49–56%) than the previous one
(14–37% yields).10b
(1R,2E,40S)-1-(20-Phenyl-40,50-dihydrooxazol-40-yl)-
hepta-2,6-dien-1-ol (8). To a stirred suspension of the
vinyl-epoxide 5 (108 mg, 0.50 mmol) and CuCN (5 mg,
50 mmol) in THF (5 ml) at Ϫ70ЊC was added dropwise a
1.0 M solution of allylmagnesium bromide in Et2O (1.0 ml,
1.0 mmol), and the mixture was allowed to warm to Ϫ20ЊC.
The reaction was quenched by addition of saturated aq.
NH4Cl (2 ml), and the mixture was diluted with AcOEt
(15 ml) and H2O (5 ml). The layers were separated and
the aqueous phase was extracted with AcOEt ꢀ2×15 ml†:
The combined organic layers were successively washed
with H2O and brine (10 ml each), dried and concentrated.
The residue was purified by silica gel chromatography elut-
ing with hexane–AcOEt (5:2) to afford the diene 8 (87 mg,
68% yield) as a colorless solid: mp 80–82ЊC; Rf 0.30
25
(hexane–AcOEt, 2:1); [a]D Ϫ5.1Њ (c 0.55, CHCl3); dH
(270 MHz, CDCl3) 2.17 (4H, t-like, Jˆ3.0 Hz, 4-H2,
5-H2), 4.10 (1H, br, OH), 4.37 (3H, m, 40-H and 50-H2),
4.63 (1H, br d, Jˆ5.6 Hz, 1-H), 4.98 (1H, dt, Jˆ1.0,
10.2 Hz, 7-Hcis), 5.03 (1H, dt, Jˆ1.0, 17.5 Hz, 7-Htrans),
5.47 (1H, dd, Jˆ5.5, 15.5 Hz, 2-H), 5.74–5.92 (2H, m,
3-H, 6-H), 7.29 (2H, m, Ph), 7.41 (1H, m, Ph), 7.75 (2H,
m, Ph); dC (67.8 MHz, CDCl3) 31.7, 33.2, 67.4, 71.1, 71.4,
114.8, 127.0, 128.1 (2C), 128.2 (2C), 128.6, 131.3, 132.1,
138.0, 165.5; nmax (KBr) 3162 (broad), 2914, 2841, 1649,
1450, 1365, 1273, 1099, 971, 910, 693 cmϪ1; Anal. Calcd
for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.55;
H, 7.50; N, 5.39.
Conclusion
We have achieved stereoselective syntheses of sphinga-4,8-
dienines by using the vinyl-epoxide 5 as a key chiral
building block. The protected (4E,8E)-ceramide 13a was
synthesized from 5 via 2-dodecenyl cuprate coupling
followed by olefin-isomerization in 43% overall yield, or
via dodecenyl sulfone coupling in 26% overall yield. The
(4E,8Z)-ceramide 13b was also synthesized via two-stage
chain-elongation including Wittig olefination in 57% over-
all yield from 5. Despite some technical difficulties, the first
cross-coupling approach with dodecenyl cuprate seems to
be still attractive and promising from a viewpoint of
synthetic chemistry. These ceramides 13a and 13b were
1-Tributylstannyl-2-dodecene (10). To a stirred solution
of diisopropylamine (0.30 ml, 2.1 mmol) in THF (10 ml)
under argon at Ϫ30ЊC was added a 1.5 M solution of

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
539
n-butyllithium in hexane (1.4 ml, 2.1 mmol), and the solu-
tion was stirred for 20 min. To this solution was added
dropwise tributyltin hydride (0.6 ml, 2.0 mmol), and the
mixture was stirred for 20 min at Ϫ30ЊC before being
cooled to Ϫ70ЊC. To this solution was added a solution of
2(E)-dodecenyl chloride (405 mg, 2.0 mmol) in THF (4 ml),
and the mixture was allowed to warm to Ϫ20ЊC. The
solution was diluted with hexane (20 ml) and aq. NH4Cl
(20 ml), and the layers were separated. The aqueous phase
was extracted with hexane ꢀ2×20 ml† and the combined
organic layers were successively washed with H2O and
brine, and then dried. Removal of the solvent gave a color-
less oil, which was passed through a short pad of silica gel
eluting with hexane to give the allylic stannane 10
(940 mg, 103%) as a colorless oil: dH 0.77–0.95 (6H,
m), 0.88 (3H, t, Jˆ6.8 Hz, 12-CH3), 0.89 (9H, t,
Jˆ7.2 Hz), 1.26 (14H, s), 1.23–1.37 (6H, m), 1.41–
1.54 (6H, m), 1.68 (2H, d, Jˆ8.2 Hz, 1-H2), 1.94 (2H,
q, Jˆ6.9 Hz, 4-H2), 5.21 (1H, dt, Jˆ6.9, 14.8 Hz, 4-H),
5.51 (1H, dt, Jˆ8.2, 15.2 Hz, 2-H); nmax (neat) 2956,
solution of 12ab (77 mg, 0. 20 mmol) in THF (2.7 ml) was
added a 2.0 M aq. HCl (0.3 ml), and the mixture was stirred
for 16 h at room temperature. To this solution were added
CHCl3–MeOH (8:1) (10 ml) and H2O (10 ml). The layers
were separated and the aqueous phase was extracted with
CHCl3–MeOH
(8:1)
ꢀ2×10 ml†:
The
combined
organic extracts were dried and concentrated under reduced
pressure to give crude 1-O-benzoyl-4,8-sphingadienine
hydrochloride (82 mg) as a colorless foam. This foam and
(R)-acetoxy-palmitoyl imide 4 (150 mg, 0.30 mmol) were
dissolved in N,N-dimethylformamide (2 ml). To this solu-
tion was added triethylamine (40 ml, 0.29 mmol), and the
mixture was stirred at 60ЊC for 6 h. The reaction mixture
was diluted with AcOEt and H2O (10 ml), and extracted
with AcOEt ꢀ3×10 ml†: The combined organic layers
were dried and concentrated to give a yellow oil, which
was purified by chromatography with hexane–AcOEt
(3:1) to give 13ab (115 mg, 82%) as a colorless solid: Rf
0.27 (hexane–AcOEt, 3:1); dH 0.88 (6H, t, Jˆ6.6 Hz), 1.25
(38H, s-like), 1.79 (2H, m), 1.97 (2H, m), 2.09 (4H, m), 2.12
(3H, s), 2.86 (1H, br s), 4.30 (1H, m), 4.38 (2H, m), 4.65
(1H, dd, Jˆ8.6, 12.5 Hz), 5.08 (1H, dd, Jˆ5.1, 7.1 Hz), 5.38
(2H, m), 5.54 (0.5H, dd, Jˆ6.4, 15.3 Hz), 5.56 (0.5H, dd,
Jˆ6.4, 15.3 Hz), 5.81 (1H, dt-like, Jˆ6.5, 15.5 Hz), 6.64
(1H, d, Jˆ7.9 Hz), 7.45 (2H, m), 7.58 (1H, m), 8.00 (2H,
m); dC 14.1, 20.8, 22.7, 24.8, 26.6, 27.3, 29.2, 29.3, 29.4,
29.5, 29.68, 29.70, 31.9, 31.98, 32.02, 32.3, 32.6, 53.7, 63.0,
73.1, 74.1, 128.2, 128.3, 128.3, 128.4, 129.5, 128.9, 129.4,
129.7, 130.8, 131.3, 133.4, 134.0, 134.1, 167.1, 169.8, 170.9.
2922, 2853, 1463, 1376, 1071, 959, 873, 717, 686 cmϪ1
;
HRMS (EI) Calcd for C24H50Sn (Mϩ): 456.2935. Found:
456.2913. Although this oil contains small amounts of 9
and Bu3SnH, it was used in the next step without
further purification.
1-O,2-N-Protected (4E,8E)-sphingadienine (12a) and
(4E,8Z)-sphingadienine (12b). To a stirred solution of the
stannane 10 (400 mg, 0.86 mmol) in THF (4 ml) was added
dropwise a 1.0 M solution of methyllithium in Et2O (0.8 ml,
0.8 mmol) over 5 min at Ϫ70ЊC. The resulting pale yellow
solution was allowed to warm to Ϫ10ЊC, and was then
cooled to Ϫ70ЊC. To this solution was added a solution of
CuCN (36 mg, 0.40 mmol) and LiCl (34 mg, 0.8 mmol) in
THF (1 ml), and the resulting orange-brown solution was
stirred for 20 min at Ϫ70ЊC. To this solution was added a
solution of vinyl-epoxide 5 (43 mg, 0.20 mmol) in THF
(1 ml), and the mixture was allowed to warm to Ϫ20ЊC.
The mixture was treated with saturated aq. NH4Cl (2 ml),
followed by AcOEt (15 ml) and H2O (5 ml). The layers
were separated and the aqueous phase was extracted with
AcOEt ꢀ2×15 ml†: The organic layer was successively
washed with H2O and brine, dried, and concentrated. The
residue was chromatographed on a column with hexane–
AcOEt (4:1!5:2) as eluent to afford 1:1 mixture of the
(4E,8E)- and (4E,8Z)-dienes 12ab (68 mg, 89% yield) as a
colorless solid: Rf 0.28 (hexane–AcOEt, 3:1); dH (sphingo-
sine numbering) 0.88 (3H, t, Jˆ6.6 Hz, 18-CH3), 1.26 (14H,
s-like, 11–17-CH2), 2.00 (2H, m, 10-H2) 2.12 (4H, m, 6-H2,
7-H2), 4.02 (1H, br s, OH), 4.37 (3H, m, 1-H2 and 2-H), 4.63
(1H, br d, Jˆ5.0 Hz, 3-H), 5.35–5.51 (3H, m, 4-H, 8-H,
9-H), 5.85 (1H, br d, Jˆ15.5 Hz, 5-H), 7.29 (2H, m, Ph),
7.41 (1H, m, Ph), 7.76 (2H, m, Ph); dC 14.1, 22.6, 26.8 (b),
27.2 (b), 29.1, 29.3, 29.47, 29.54, 29.6, 31.8, 32.1
(a), 32.5, 32.6 (a), 67.4, 71.2, 71.5, 127.0, 128.1 (2C),
128.2 (2C), 128.3, 128.4, 128.6, 129.1, 130.5, 131.0,
131.2, 132.4, 132.5, 165.5; nmax (KBr) 3190 (broad),
2922, 2851, 1648, 1468, 1450, 1364, 1274, 1098, 969,
692 cmϪ1; HRMS Calcd for C25H37NO2 (Mϩ): 383.2824.
Found: 383.2824.
(2S,3R,4E,8E,20R)-2-(20-Acetoxyhexadecanoyl)amino-1-
O-benzoyl-4,8-octadecadiene-1,3-diol (13a). A mixture of
13ab (70 mg, 0.10 mmol), 1-methylterazol-5-yl disulfide
(12 mg, 0.05 mmol), 2,20-azobis(isobutyronitrile) (8 mg,
50 mmol) in toluene (4 ml) under argon was heated at
100ЊC for 4 h. Removal of the solvent gave a pale-yellow
solid, which was purified by preparative TLC eluting with
hexane–AcOEt to give the ceramide 13a (63 mg, 90%) as a
colorless solid. Recrystallization from hexane gave pure 13a
(42 mg, 60% from 13ab) as a colorless solid: mp 75–77ЊC;
([a]D24ϩ9.5Њ (c 1.0, CHCl3) {lit.10b mp 77.0–78.0ЊC;
([a]D21ϩ9.0Њ (c 0.66, CHCl3)}; dH 0.88 (6H, t, Jˆ6.6 Hz,
18- and 160-CH3), 1.25 (38H, s-like, 19×CH2†; 1.78 (2H,
m, 30-H2), 1.96 (2H, q, Jˆ6.6 Hz, 10-H2), 2.08 (4H, m, 6-H2,
7-H2), 2.11 (3H, s, CH3CO), 2.80 (1H, d, Jˆ5.1 Hz, OH),
4.28 (1H, m, 3-H), 4.36 (1H, m, 2-H), 4.37 (1H, dd, Jˆ3.9,
12.5 Hz, 1-Ha), 4.64 (1H, dd, Jˆ8.5, 12.7 Hz, 1-Hb), 5.07
(1H, dd, Jˆ5.1, 7.1 Hz, 20-H), 5.38 (2H, m, 8-H, 9-H), 5.54
(1H, dd, Jˆ6.3, 15.6 Hz, 4-H), 5.80 (1H, dt, Jˆ6.6, 15.4 Hz,
5-H), 6.63 (1H, d, Jˆ7.6 Hz, NH), 7.44 (2H, m, Ph), 7.58
(1H, m, Ph), 8.00 (2H, m, Ph); dC 14.1, 20.8, 22.7, 24.8,
29.2, 29.32, 29.35, 29.36, 29.51, 29.55, 29.58, 29.59, 29.64,
29.68, 31.9, 31.96, 32.00, 32.3, 32.6, 53.7, 63.0, 73.1, 74.1,
128.2, 128.5, 128.9, 129.4, 129.7, 131.3, 133.4, 134.1,
167.1, 169.7, 170.8; nmax (KBr) 3287 (broad), 2919, 2850,
1745, 1727, 1655, 1550, 1468, 1452, 1381, 1278, 1232,
1029, 964, 705 cmϪ1; Anal. Calcd for C43H71NO6: C,
73.99; H, 10.25; N, 2.01. Found: C, 73.88; H, 10.43; N, 1.98.
2-Dodecenyl phenyl sulfone (14). To a stirred solution of 9
(507 mg, 2.5 mmol) in DMF (6 ml) was added sodium
phenylsulfinate dihydrate (1.00 g, 5.0 mmol) at room
temp., and the resulting suspension was stirred at 50ЊC for
(2S,3R,4E,8EZ,20R)-2-(20-Acetoxyhexadecanoyl)amino-
1-O-benzoyl-4,8-octadecadiene-1,3-diol (13ab). To a stirred

540
T. Murakami et al. / Tetrahedron 56 (2000) 533–545
5 h. The mixture was diluted with H2O and extracted with
AcOEt. The combined extracts were successively washed
with H2O and brine, dried and concentrated in vacuo. The
residue was purified by chromatography eluting with hex-
ane–AcOEt (9:1!7:1) to give the allylic sulfone 14
(693 mg, 90%) as a colorless oil: Rf 0.33 (hexane–AcOEt,
6:1); dH 0.88 (3H, t, Jˆ6.6 Hz), 1.25 (14H, br s), 1.98 (2H,
q, Jˆ6.5 Hz), 3.75 (2H, d, Jˆ6.9 Hz), 5.38 (1H, dt, Jˆ6.9,
15.5 Hz, 4-H), 5.50 (1H, dt, Jˆ6.2, 15.5 Hz, 1-Ha), 7.54
(2H, m), 7.64 (1H, m), 7.85 (2H, m); dC 14.1, 22.6, 28.6,
29.0, 29.3, 29.4, 29.5, 31.8, 32.5, 60.1, 115.8, 128.5, 128.9,
133.5, 138.3, 141.9; nmax (neat) 2956, 2925, 2854, 1466,
Ϫ0.02 (9H, s), 0.87 (3H, t, Jˆ6.5 Hz), 1.15–1.30 (14H, br
s), 1.93 (2H, q, Jˆ6.3 Hz), 2.43 (1H, m), 2.90 (1H, m), 3.49
(1H, ddd, Jˆ3.2, 9.0, 11.0 Hz), 4.20–4.40 (4H, m), 5.20
(0.5H, dd, Jˆ9.0, 15.4 Hz), 5.21 (0.5H, dd, Jˆ9.0,
15.4 Hz), 5.36 (0.5H, dt, Jˆ6.6, 15.4 Hz), 5.37 (0.5H, dt,
Jˆ6.6, 15.4 Hz), 5.59 (2H, m), 7.39 (2H, m), 7.47 (1H, m),
7.52 (2H, m), 7.63 (1H, m), 7.82 (2H, m), 7.91 (2H, m); dC
0.21, 0.22, 14.1, 22.7, 28.70, 28.74, 29.09, 29.12, 29.3, 29.4,
29.5, 30.17, 30.20, 31.9, 32.5, 32.6, 67.7, 67.8, 68.86, 68.93,
71.4, 71.5, 73.3, 73.4, 121.25, 121.31, 125.8, 125.9, 127.8,
128.2, 128.3, 128.8, 129.2, 131.2, 133.5, 133.9, 137.4,
141.01, 141.05, 164.57, 164.60; HRMS Calcd for
C34H50NO4SSi (MϩH)ϩ: 596.3229. Found: 596.3127.
1447, 1320, 1308, 1146, 1087, 971, 733, 689 cmϪ1
;
HRMS Calcd for C18H29O2S (MϩH)ϩ: 309.1888. Found:
309.1871.
N,O,O-Protected (4E,8E)-sphingadienine (17). A mixture
of 16 (84 mg, 0.18 mmol), Pd(OAc)2 (3 mg, 13 mmol), and
1,3-bis(diphenylphosphino)propane (6 mg, 14 mmol) in
THF (4 ml) was stirred at room temperature for 30 min.
To this mixture was added a 1.0 M solution of lithium
triethylborohydride in THF (0.4 ml, 0.4 mmol) at 0ЊC, and
the resulting orange-brown solution was stirred for 1 h. The
mixture was treated with acetone (50 ml), and diluted with
AcOEt (10 ml) and H2O (10 ml), and the layers were sepa-
rated. The organic layer was washed with brine (10 ml) and
the combined aqueous layers were extracted with AcOEt
ꢀ2×10 ml†: The combined organic extracts were dried,
concentrated and purified by chromatography eluting with
hexane–AcOEt (6:1) to give a 4:1 mixture of 17 and 18
(48 mg, 75%; 17: 60% yield) as a colorless oil: Rf 0.43
(4S,10S,20S)-2-Phenyl-4-(20-bromo-10-trimethylsilyloxy-
30-butenyl)-4,5-dihydrooxazole (15b). To a solution of
LiBr (175 mg, 2.0 mmol) in acetonitrile (6 ml) under nitro-
gen was added chlorotrimethylsilane (0.22 ml, 1.8 mmol),
and the mixture was stirred for 30 min at room temperature
before being cooled by an ice-water bath. To this solution
was added vinyl-epoxide 5 (112 mg, 0.52 mmol), and the
mixture was stirred for 3 h at 5–10ЊC. To this mixture was
added triethylamine (0.3 ml, 2.0 mmol), and the stirring was
continued for 1 h at 5–10ЊC. The mixture was diluted with
AcOEt (15 ml) and aq. NaHCO3 (10 ml). The layers were
separated and the aqueous phase was extracted with AcOEt
ꢀ2×15 ml†: The combined organic extracts were dried and
concentrated to give an orange oil, which was purified by
chromatography eluting with hexane–AcOEt (5:1) to give
the allylic bromide 15b (136 mg, 71%; 89% yield based on
recovered 5: 23 mg, 20.5%) as a colorless solid: mp
70–71ЊC; [a]D23 Ϫ15.2Њ (c 1.28, CHCl3); Rf 0.42 (hexane–
AcOEt, 6:1); dH 0.07 (9H, s), 4.23 (1H, dd, Jˆ2.1, 5.7 Hz,
10-H), 4.35 (1H, m), 4.48 (1H, dd, Jˆ5.7, 9.7 Hz, 20-H),
4.50–4.58 (2H, m), 5.15 (1H, dd, Jˆ0.7, 10.0 Hz, 40-Hcis),
5.27 (1H, dt, Jˆ0.9, 16.8 Hz, 40-Htrans), 6.01 (1H, dt, Jˆ9.9,
16.8 Hz, 30-H), 7.40 (2H, m, Ph), 7.47 (1H, m, Ph), 7.93
(2H, m, Ph); dC 0.6, 58.4, 67.2, 69.6, 77.2, 118.1, 127.6,
128.2, 128.3, 131.3, 135.9, 164.6; nmax (KBr) 2961, 2895,
23
(hexane–AcOEt, 6:1); [a]D ϩ0.16Њ (c 2.4, CHCl3); 17:
dH (sphingosine numbering) 0.03 (9H, s), 0.88 (3H, t,
Jˆ6.5 Hz, 18-CH3), 1.26 (14H, s, 11–17-CH2), 1.92-2.16
(6H, m, 6-, 7-, 10-CH2), 4.28 (2H, m, 2-H, 3-H), 4.36-4.44
(2H, m, 1-H2), 5.40 (2H, m, 8-H, 9-H), 5.47 (1H, dd,Jˆ5.0,
15.5 Hz, 4-H), 5.72 (1H, dt, Jˆ6.3, 15.5 Hz, 5-H), 7.40 (2H,
m, Ph), 7.47 (1H, m, Ph), 7.94 (2H, m, Ph); dC 0.3, 14.1,
22.7, 29.2, 29.3, 29.5, 29.6, 31.9, 32.3, 32.4, 32.6, 67.9,
71.7, 73.8, 127.9, 128.2 (4C), 129.2, 130.2, 131.07,
131.10, 131.4, 164.4; nmax (KBr) 2925, 2854, 1651, 1468,
1451, 1358, 1251, 1088, 1026, 968, 842, 694 cmϪ1; HRMS
Calcd for C28H45NO2Si (MϩH)ϩ: 455.3219. Found:
455.3163.
1649, 1463, 1362, 1249, 1024, 938, 879, 840, 697 cmϪ1
;
HRMS Calcd for C16H23NO2SiBr (MϩH)ϩ: 368.0681.
Found: 368.0591.
(2S,3R,4E,8E,20R)-2-(20-Acetoxyhexadecanoyl)amino-1-
O-benzoyl-4,8-octadecadiene-1,3-diol (13a). In the same
manner as described for the synthesis of 13ab from 12ab,
a 4:1 mixture of 17 and 18 (52 mg, 0.11 mmol) gave the
20-O-acetyl-1-O-benzoyl-ceramide (69 mg, 86%) as a
colorless solid. Recrystallization from hexane afforded
pure 13a (44 mg, 41% from 16).
(4S,10R,20E,50RS,60E)-2-Phenyl-4-(50-phenylsulfonyl-10-
trimethylsilyloxyhexadeca-20,60-dienyl)-4,5-dihydro-
oxazole (16). To a stirred solution of 2-dodecenyl phenyl
sulfone 14 (200 mg, 0.65 mmol) in THF (5 ml) under argon
was added a 1.5 M solution of n-butyllithium in hexane
(0.4 ml, 0.65 mmol) at Ϫ70ЊC, and the resulting orange
solution was allowed to warm to Ϫ40ЊC. To this solution
was added a solution of the bromide 15b (108 mg,
0.29 mmol) in THF (2 ml), and the mixture was allowed
to warm to ϩ10ЊC. The mixture was treated with saturated
aq. NH4Cl (2 ml), and diluted with AcOEt (15 ml) and H2O
(5 ml). The layers were separated and the aqueous phase
was extracted with AcOEt ꢀ2 × 15 ml†: The organic layer
was successively washed with H2O and brine, dried and
concentrated. The residue was chromatographed on a
column with hexane–AcOEt (5:1!3:1) as eluent to afford
(E,E)-diene 16 diastereomeric mixture; 125 mg, 71% yield)
as a colorless oil: Rf 0.41 and 0.36 (hexane–AcOEt, 2:1); dH
(1R,2E,40S)-5-Cyano-1-(20-phenyl-40,50-dihydrooxazol-
40-yl)-2-penten-1-ol (19). To a stirred solution of diiso-
propylamine (0.56 ml, 4.0 mmol) in THF (8 ml) under
argon was added a 1.5 M solution of butyllithium in hexane
(2.6 ml, 3.9 mmol) at Ϫ40ЊC, and the solution was stirred
for 20 min before being cooled to Ϫ70ЊC. To this solution
was added a solution of CH3CN (165 mg, 4.0 mmol) in THF
(1 ml), and the mixture was allowed to warm. At Ϫ40ЊC,
CuI (381 mg, 2.0 mmol) was added in one portion, and the
resulting yellowish-brown suspension was stirred for
10 min at Ϫ70ЊC. To the mixture was added a solution of
vinyl-epoxide 5 (198 mg, 0.92 mmol) in THF (4.0 ml), and

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
541
the mixture was allowed to warm to Ϫ10ЊC. The mixture
was treated with saturated aq. NH4Cl (2 ml), and diluted
with AcOEt (15 ml) and H2O (5 ml). The layers were sepa-
rated and the aqueous phase was extracted with AcOEt
ꢀ2×15 ml†: The organic layer was successively washed
with H2O and brine (10 ml each), dried and concentrated.
The residue was purified by chromatography eluting with
hexane–AcOEt (1:3) to give the nitrile 19 (218 mg, 92%) as
(2H, m, 8-H, 9-H), 5.47 (1H, dd, Jˆ5.6, 15.5 Hz, 4-H), 5.84
(1H, m, 5-H), 7.36 (2H, m, Ph), 7.46 (1H, m, Ph), 7.86 (2H,
m, Ph); dC 14.1, 22.6, 26.8, 27.3, 29.3, 29.5, 29.6, 29.7, 31.9,
32.5, 67.4, 71.2, 71.4, 127.0, 128.1 (2C), 128.2 (2C), 128.5,
128.6, 130.5, 131.2, 132.4, 165.6; nmax (KBr) 3175 (broad),
2919, 2850, 1651, 1469, 1449, 1360, 1270, 1107, 1093, 971,
690 cmϪ1; Anal. Calcd for C25H37NO2: C, 78.28; H, 9.72; N,
3.65. Found: C, 78.16; H, 9.81; N, 3.56.
25
a colorless solid: mp 121–122ЊC; [a]D Ϫ1.58Њ (c 1.0,
CHCl3); Rf 0.30 (hexane–AcOEt, 1:2); dH 2.43 (4H, s,
4-H2, 5-H2), 4.38 (3H, m, 40-H and 50-H2), 4.67 (1H, br d,
Jˆ4.3 Hz, 1-H), 5.64 (1H, dd, Jˆ4.6, 15.5 Hz, 2-H), 5.89
(1H, ddt, Jˆ1.7, 6.6, 15.5 Hz, 3-H), 7.30 (2H, m, Ph), 7.42
(1H, m, Ph), 7.76 (2H, m, Ph); dC 17.4, 28.1, 67.4, 70.7,
70.9, 126.9, 127.6, 128.1, 128.2, 131.4, 132.0, 165.9; nmax
(KBr) 3171 (broad), 2251 (CN), 1646, 1366, 1273, 1124,
1101, 967, 696 cmϪ1; Anal. Calcd for C15H16N2O2: C,
70.29; H, 6.29; N, 10.93. Found: C, 70.37; H, 6.26; N, 11.01.
(2S,3R,4E,8Z,20R)-2-(20-Acetoxyhexadecanoyl)amino-1-
O-benzoyl-4,8-octadecadiene-1,3-diol (13b). To a stirred
solution of 12b (135 mg, 0.35 mmol) in THF (4.5 ml) was
added a 2.0 M aq. HCl (0.5 ml) and the mixture was stirred
for 16 h at room temperature. To this solution were added
CHCl3–MeOH (8:1) (10 ml) and H2O (10 ml). The layers
were separated and the aqueous phase was extracted with
CHCl3–MeOH (8:1) ꢀ2×10 ml†: The combined organic
extracts were dried and concentrated in vacuo to give
crude 1-O-benzoyl-sphingadienine hydrochloride (145 mg)
as a colorless foam. This foam (145 mg) and (R)-acetoxy-
palmitoyl imide 4 (260 mg, 0.53 mmol) were dissolved in
N,N-dimethylformamide (3 ml). To this solution was added
triethylamine (70 ml, 0.50 mmol), and the mixture was stir-
red at 60ЊC for 6 h. The reaction mixture was diluted with
AcOEt and H2O (10 ml), and extracted with AcOEt
ꢀ3×10 ml†: The combined organic layers were dried and
concentrated to give a yellow oil, which was purified by
chromatography with hexane–AcOEt (3:1) to give 13b
(1R,2E,40S)-5-Formyl-1-(20-phenyl-40,50-dihydrooxazol-
40-yl)-2-penten-1-ol (20). To a stirred suspension of the
nitrile 19 (128 mg, 0.50 mmol) in toluene (5 ml) was
added a 1.5 M solution of diisobutylaluminum hydride in
toluene (0.8 ml, 1.2 mmol) at Ϫ70ЊC over a period of 5 min,
and the mixture was stirred for 50 min at between Ϫ70 and
Ϫ50ЊC. The mixture was treated with acetone (50 ml) and
diluted with AcOEt (10 ml) and 5% aq. tartaric acid (10 ml).
The layers were separated and the organic layer was washed
with brine. The combined aqueous layers were neutralized
with aq. NaHCO3 and extracted with AcOEt ꢀ2×10 ml†: The
combined organic layers were dried and concentrated to
give crude aldehyde 20 (118 mg, 91%) as a colorless
solid: Rf 0.30 (hexane–AcOEt, 1:2); dH 2.42 (2H, m),
2.55 (2H, m), 2.63 (1H, br, OH), 4.37 (3H, m), 4.55 (1H,
d, Jˆ5.2 Hz), 5.53 (1H, dd, Jˆ5.3, 15.5 Hz), 5.85 (1H, ddt,
Jˆ1.5, 6.4, 15.5 Hz), 7.34 (2H, m), 7.47 (1H, m), 7.80 (2H,
m), 9.77 (1H, t, Jˆ1.4 Hz, CHO); dC 24.8, 43.0, 67.3, 71.0,
71.2, 126.9, 128.1, 128.2, 129.6, 130.3, 131.3, 165.7, 201.7;
nmax (KBr) 3189 (broad), 2907, 1724 (CHO), 1647, 1450,
1364, 1273, 1098, 967, 696 cmϪ1. This solid was used in the
next step without further purification.
23
(198 mg, 80%) as a colorless solid: mp 60–62ЊC; [a]D23
ϩ5.0Њ (c 2.7, CHCl3) {lit.10b mp 58.5–59.5ЊC; [a]D
ϩ6.17Њ (c 0.55, CHCl3)}; dH 0.88 (6H, t, Jˆ6.6 Hz, 18-
and 160-CH3), 1.25 (38H, s-like, 19×CH2†; 1.79 (2H, m,
30-H2), 2.01 (2H, 10-H2), 2.12 (7H, m, CH3CO, 6-H2, 7-H2),
2.90 (1H, br s, OH), 4.31 (1H, m, 3-H), 4.38 (1H, m, 2-H),
4.38 (1H, dd, Jˆ3.6, 12.5 Hz, 1-Ha), 4.65 (1H, dd, Jˆ8.6,
12.5 Hz, 1-Hb), 5.08 (1H, dd, Jˆ5.1, 7.1 Hz, 20-H), 5.37
(2H, m, 8-H, 9-H), 5.56 (1H, dd, Jˆ6.4, 15.3 Hz, 4-H),
5.81 (1H, br d, Jˆ15.5 Hz, 5-H), 6.65 (1H, d, Jˆ7.6 Hz,
NH), 7.44 (2H, m, Ph), 7.58 (1H, m, Ph), 8.00 (2H, m, Ph);
dC 14.1, 20.8, 22.4, 24.7, 26.6, 27.3, 29.2, 29.3, 29.56,
29.64, 31.86, 31.92, 32.3, 53.7, 62.9, 73.0, 74.0, 128.3,
128.36, 128.44, 129.4, 129.6, 130.7, 133.4, 134.0, 167.0,
169.7, 170.8; nmax (KBr) 3174 (broad), 3106, 2921, 2852,
1751, 1727, 1661, 1573, 1468, 1452, 1375, 1274, 1229,
1099, 1071, 706 cmϪ1; Anal. Calcd for C43H71NO6: C,
73.99; H, 10.25; N, 2.01. Found: C, 74.27; H, 10.29; N, 1.94.
1-O,2-N-Protected (4E,8Z)-sphingadienine (12b). To a
stirred solution of decyltriphenylphosphonium bromide
(550 mg, 1.1 mmol) in THF (7.5 ml) was added potassium
t-butoxide (112 mg, 1.0 mmol) in three portions at Ϫ40ЊC.
The resulting red-orange solution was allowed to warm to
Ϫ20ЊC, and was then cooled to Ϫ70ЊC. To this solution was
added a solution of the aldehyde 20 (105 mg, 0.40 mmol) in
THF (1.5 ml) and the mixture was allowed to warm to 0ЊC.
The mixture was treated with saturated aq. NH4Cl (2 ml)
and diluted with AcOEt (15 ml) and H2O (10 ml). The
layers were separated and the aqueous phase was extracted
with AcOEt ꢀ2×15 ml†: The organic layer was successively
washed with H2O and brine, dried and concentrated. The
residue was chromatographed on a column with hexane–
AcOEt (5:2) as eluent to afford (E,Z)-diene 12b (120 mg,
78%) as a colorless solid: mp 57–59ЊC; [a]D25 Ϫ3.7Њ (c 2.4,
(2S,3R,4E,8E,20R)-2-(20-Hydroxyhexadecanoyl)amino-
4,8-octadecadiene-1,3-diol (21a). To an ice-cooled solu-
tion of 13a (108 mg, 0.15 mmol) in CH2Cl2 (2 ml) and
MeOH (1 ml) was added a 1.0 M solution of NaOMe in
MeOH (0.1 ml, 0.1 mmol), and the mixture was stirred for
1 h at this temperature. Acetic acid (10 mg) was added and
the solvent was removed. Residual white solid was washed
successively with MeOH, H2O, and haxane–AcOEt (2:1) to
give 21a (60 mg) as a colorless solid. The filtrate was
extracted with AcOEt as usual to give a pale-yellow
solid, which was purified by chromatography eluting
with CH2Cl2–MeOH (15:1!10:1) to give the additional
21a (20 mg; total 80 mg, 94%) as white granules: mp 97–
CHCl3) {lit.10b mp 58.0–58.5ЊC; [a]D Ϫ4.23Њ (c 0.39,
23
CHCl3)}; dH (sphingosine numbering) 0.88 (3H, t,
Jˆ6.6 Hz, 18-CH3), 1.26 (14H, s-like, 11–17-CH2), 2.01
(2H, q, Jˆ6.5 Hz, 10-H2), 2.13 (4H, m, 6-H2, 7-H2), 4.38
(3H, m, 1-H2 and 2-H), 4.56 (1H, br d, Jˆ5.3 Hz, 3-H), 5.36
23
100ЊC;[a]D ϩ5.6Њ (c 1.0, CHCl3) {lit.10b mp 104–105ЊC;
[a]D23 ϩ7.84Њ (c 0.25, CHCl3)}; dH (CDCl3–CD3OD) 0.88
(6H, t, Jˆ6.6 Hz, 18- and 160-CH3), 1.26 (38H, s-like,

542
T. Murakami et al. / Tetrahedron 56 (2000) 533–545
19×CH2), 1.54 (1H, m, 30-Ha), 1.77 (1H, m, 30-Hb), 1.96
(2H, m, 10-H2), 2.08 (4H, m, 6-H2, 7-H2), 3.69 (1H, dd,
Jˆ3.3, 11.2 Hz, 1-Ha), 3.80 (1H, dd, Jˆ4.6, 11.5 Hz,
1-Hb), 3.85 (1H, m, 2-H), 4.04 (1H, dd, Jˆ3.5, 8.0 Hz,
2-H), 4.14 (1H, t, Jˆ5.8 Hz, 3-H), 5.40 (2H, m, 8-H,
9-H), 5.48 (1H, dd, Jˆ6.4, 15.4 Hz, 4-H), 5.76 (1H, dt,
Jˆ6.3, 15.2 Hz, 5-H); nmax (KBr) 3359, 3278, 2919, 2849,
1631, 1535, 1468, 1433, 1315, 1080, 963, 721 cmϪ1; Anal.
Calcd for C34H65NO4: C, 74.00; H, 11.87; N, 2.54. Found:
C, 73.98; H, 11.85; N, 2.42.
and the combined aqueous layers were extracted with
AcOEt. The combined organic extracts were dried and
concentrated to give a residue, which was purified by chro-
matography eluting with hexane–AcOEt (3:1!3:2) to give
24a (53 mg, 88%) as a colorless solid: mp 69–71ЊC; Rf 0.27
(hexane–AcOEt, 3:2); [a]D26 Ϫ1.6Њ (c 2.6, CHCl3); dH 0.88
(3H, t, Jˆ6.6 Hz, 18- and 160-CH3), 1.25 (38H, s-like,
19×CH2), 1.81 (2H, m, 30-H2), 1.96 (2H, q, Jˆ6.3 Hz,
10-H2), 2.09 (3H, s, CH3CO), 2.09 (4H, m, 6-H2, 7-H2),
2.15 (3H, s, CH3CO), 2.75 (1H, br, OH), 3.64 (2H, m,
1-H2), 4.09 (1H, m, 2-H), 5.14 (1H, dd, Jˆ4.9, 7.1 Hz, 20-
H), 5.32 (1H, t, Jˆ7.2 Hz, 3-H), 5.39 (2H, m, 8-H, 9-H),
5.49 (1H, dd, Jˆ7.4, 15.3 Hz, 4-H), 5.81 (1H, dt, Jˆ6.0,
15.4 Hz, 5-H), 6.65 (1H, d, Jˆ8.5 Hz, NH); dC 14.1, 20.9,
21.1, 22.6, 24.8, 29.19, 29.27, 29.32, 29.41, 29.50, 29.57,
29.63, 29.66, 31.8, 31.9, 32.3, 32.6, 53.1, 61.3, 73.9, 74.2,
124.8, 128.7, 131.4, 136.5, 169.8, 170.1, 171.0; nmax (KBr)
3320 (broad), 2955, 2921, 2851, 1733, 1659, 1543,
1469, 1374, 1227, 1028, 968 cmϪ1; Anal. Calcd for
C38H69NO6: C, 71.77; H, 10.94; N, 2.20. Found: C, 72.14;
H, 10.97; N, 2.08.
(2S,3R,4E,8E,20R)-1-(t-Butyldiphenylsilyl)oxy-2-(20-
hydroxyhexadecanoyl)amino-4,8-octadecadien-3-ol
(22a). To an ice-cooled solution of 21a (72 mg, 0.13 mmol)
and imidazole (45 mg, 0.65 mmol) in CH2Cl2 (2 ml) and
DMF (1 ml) was added t-butyldiphenylchlorosilane
(55 mg, 0.20 mmol), and the mixture was stirred for
30 min at this temperature. The reaction was quenched
with MeOH (50 ml) and the mixture was diluted with
AcOEt and H2O, and the layers were separated. The organic
layer was washed with brine and the combined aqueous
layers were extracted with AcOEt. The combined organic
extracts were dried and concentrated to give a residue,
which was purified by chromatography eluting with
hexane–AcOEt (3:1) to afford the ceramide 22a (84 mg,
82%) as a waxy solid: Rf 0.35 (hexane–AcOEt, 3:1);
(2S,3R,4E,8E,20R)-2-(20-Acetoxyhexadecanoyl)amino-3-
O-acetyl-1-O-(200,300,400,600-tetra-O-benzoyl-b-d-gluco-
pyranosyl)-4,8-octadecadien-1,3-diol (25a). A solution of
24a (42 mg, 0.66 mmol), 2,3,4,6-tetra-O-benzoyl-a-d-
glucosyl bromide (80 mg, 0.12 mmol), oven-dried molecu-
lar sieves 4A (50 mg) in dichloromethane (2.5 ml) was stir-
red under argon at room temperature for 30 min before
being cooled to Ϫ20ЊC. To this suspension was added
AgOTf (31 mg, 0.12 mmol) in toluene (0.5 ml), and the
mixture was stirred at Ϫ20–0ЊC for 2 h. The resulting
suspension was diluted with AcOEt (10 ml), and the
insoluble material was filtered off and washed thoroughly
with AcOEt (15 ml). The filtrate was washed with aq.
NaHCO3, H2O and brine (10 ml each). The combined
aqueous layers were extracted with AcOEt ꢀ2×20 ml†;
and the organic extracts were dried and concentrated. The
residue was purified by chromatography eluting with
hexane–AcOEt (3:1!5:2) to afford the glycoside 25a
(63 mg, 78%) as a colorless solid: Rf 0.30 (hexane–
25
[a]D ϩ10.0Њ (c 1.7, CHCl3); dH 0.88 (6H, t, Jˆ6.6 Hz),
1.07 (9H, s, t-Bu), 1.26 (38H, s-like), 1.60 (1H, m), 1.78
(1H, m), 1.95 (2H, q, Jˆ6.2 Hz), 2.06 (4H, m), 2.35 (1H, br,
OH), 3.44 (1H, br d, Jˆ8.1 Hz, OH), 3.75 (1H, dd, Jˆ4.9,
11.5 Hz), 3.97 (2H, m), 4.05 (1H, m), 4.21 (1H, m), 5.39
(2H, m), 5.48 (1H, dd, Jˆ6.2, 15.5 Hz), 5.77 (1H, dt, Jˆ6.4,
15.6 Hz), 7.09 (1H, d, Jˆ7.8 Hz), 7.40 (6H, m, Ph), 7.63
(4H, m, Ph); dC 14.1, 19.1, 22.7, 25.1, 26.82, 26.84, 29.2,
29.3, 29.4, 29.5, 29.60, 29.65, 29.69, 31.90, 31.91, 32.2,
32.4, 32.6, 35.1, 54.0, 63.7, 72.3, 73.9, 127.9, 129.1,
129.2, 130.1, 131.1, 132.46, 132.51, 133.0, 135.5, 135.6,
173.9; FAB-MS (positive) m/z (relative intensity %) 790
(MϩϩH, 22), 772 (MϪOH, 49), 732 (MϪC4H9, 10), 712
(MϪC6H5, 14).
26
(2S,3R,4E,8E,20R)-3-Acetoxy-2-(20-acetoxyhexadeca-
noyl)amino-4,8-octadecadien-1-ol (24a). To an ice-cooled
solution of 22a (75 mg, 0.095 mmol) and 4-(dimethyl-
amino)pyridine (2 mg) in CH2Cl2 (2 ml) were added
pyridine (0.2 ml) and acetic anhydride (0.15 ml) and the
mixture was stirred at 5–10ЊC for 2 h. The mixture was
treated with MeOH (0.1 ml), and then diluted with AcOEt
and H2O. After extractive work-up, the organic layer was
dried and concentrated to give crude diacetate 23a (90 mg),
which was used in the next step without further purification:
dH 0.88 (6H, t, Jˆ6.6 Hz), 1.07 (9H, s), 1.26 (38H, s-like),
1.80 (2H, m), 1.94 (2H, m), 1.96 (3H, s), 2.00 (3H, s), 2.05
(4H, m), 3.63 (1H, dd, Jˆ3.9, 10.5 Hz), 3.78 (1H, dd,
Jˆ2.2, 10.5 Hz), 4.25 (1H, m), 5.23 (1H, dd, Jˆ4.9,
6.8 Hz), 5.32–5.48 (4H, m), 5.83 (1H, br d, Jˆ15 Hz),
6.57 (1H, d, Jˆ8.3 Hz), 7.39 (6H, m), 7.59 (4H, m). To a
solution of the crude diacetate 23a in THF (2 ml) were
added acetic acid (12 ml, 0.2 mmol) and a 1.0 M solution
of tetrabutylammonium fluoride in THF (0.2 ml, 0.2 mmol),
and the mixture was stirred at room temperature for 3 h. The
mixture was diluted with AcOEt and H2O and the layers
were separated. The organic layer was washed with brine
AcOEt, 5:2); [a]D ϩ8.8Њ (c 1.2, CHCl3); dH 0.88 (6H, t,
Jˆ6.6 Hz, 18- and 160-CH3), 1.25 (38H, s-like, 19×CH2†;
1.66 (2H, m, 30-H2), 1.93 (2H, m, 10-H2), 1.95 (3H, s,
CH3CO), 1.96 (3H, s, CH3CO), 1.99 (4H, m, 6-H2, 7-H2),
3.64 (1H, dd, Jˆ4.4, 10.0 Hz, 1-Ha), 4.04 (1H, dd, Jˆ3.7,
10.2 Hz, 1-Hb), 4.17 (1H, m, 500-H), 4.31 (1H, m, 2-H), 4.49
(1H, dd, Jˆ5.0, 12.1 Hz, 600-Ha), 4.65 (1H, dd, Jˆ3.2,
12.2 Hz, 600-Hb), 4.85 (1H, d, Jˆ7.8 Hz, 100-H), 4.95 (1H,
dd, Jˆ5.4, 6.3 Hz, 20-H), 5.28–5.43 (4H, m, 3-, 4-, 8- and
9-H), 5.48 (1H, dd, Jˆ7.8, 9.8 Hz, 200-H), 5.67 (1H, t,
Jˆ9.6 Hz, 400-H), 5.73 (1H, m, 5-H), 5.89 (1H, t,
Jˆ9.6 Hz, 300-H), 6.31 (1H, d, Jˆ9.0 Hz, NH), 7.22–7.58
(12H, m), 7.80 (2H, m), 7.90 (2H, m), 7.93 (2H, m), 8.02
(2H, m); dC 14.1, 20.7, 21.0, 22.7, 24.6, 29.2, 29.3, 29.45,
29.53, 29.60, 29.63, 29.7, 31.7, 31.9, 32.3, 32.6, 50.6, 63.0,
67.4, 69.5, 72.0, 72.4, 72.8, 73.1, 73.9, 100.8, 124.6, 128.3,
128.4, 128.7, 128.9, 129.0, 129.5, 129.8, 131.1, 133.1,
133.2, 133.4, 136.5, 165.0, 165.1, 165.7, 166.1, 169.56,
169.58, 169.7; nmax (KBr) 2925, 2853, 1732, 1690,
1519, 1452, 1371, 1265, 1094, 1069, 1027, 710 cmϪ1
;
FAB-MS (positive) m/z (%) 1214 (MϩϩH, 3), 1154
(MϪCH3CO2, 26), 579 (18).

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
543
(2S,3R,4E,8E,20R)-1-O-(b-d-Glucopyranosyl)-2-(20-
hydroxyhexadecanoyl)amino-4,8-octadecadiene-1,3-diol
(1a). To a stirred solution of 25a (55 mg, 45 mmol) in
MeOH (1 ml) and THF (1 ml) was added 1.0 M solution
of NaOMe in MeOH (50 ml, 50 mmol), and the mixture
was stirred for 2 h at 5–10ЊC. Acetic acid (10 mg) was
added and the solvent was removed. The residue was puri-
fied by silica gel column chromatography eluting with
CH2Cl2–MeOH (9:1!7:1) to afford the cerebroside 1a
(30 mg, 93%) as a colorless solid: mp 180ЊC (125ЊC- liquid
crystal-like) {lit.10a 184–186ЊC; lit.10b 184–185ЊC; lit.10c
30-Hb), 2.00 (2H, q, Jˆ6.2 Hz, 10-H2), 2.09 (4H, m, 6-H2,
7-H2), 2.33 (1H, br d, Jˆ4.6 Hz, OH), 3.40 (1H, br d,
Jˆ7.3 Hz, OH), 3.75 (1H, dd, Jˆ4.9, 11.5 Hz, 1-Ha), 3.97
(2H, m, 1-Ha, 2-H), 4.05 (1H, m, 20-H), 4.21 (1H, m, 3-H),
5.34 (2H, m, 8-H, 9-H), 5.49 (1H, dd, Jˆ6.1, 15.4 Hz, 4-H),
5.77 (1H, br d, Jˆ15.4 Hz, 5-H), 7.08 (1H, d, Jˆ7.6 Hz,
NH), 7.40 (6H, m, Ph), 7.63 (4H, m, Ph); dC 14.1, 19.1, 22.7,
25.1, 26.8, 26.9, 27.3, 29.3, 29.5, 29.6, 29.7, 31.9, 32.4,
35.1, 54.1, 63.6, 72.3, 73.9, 127.9, 128.6, 129.3, 130.0,
130.7, 132.48, 132.52, 133.0, 135.5, 135.6, 173.9; Anal.
Calcd for C50H83NO4Si: C, 75.99; H, 10.59; N, 1.77.
Found: C, 76.10; H, 10.71; N, 1.74.
24
184ЊC}; Rf 0.33 (CH2Cl2–MeOH, 7:1); [a]D ϩ4.0Њ (c
0.95, CHCl3–MeOH, 1:1) {lit.7 [a]D15.5 ϩ5.4Њ (c 0.648,
CHCl3–MeOH, 2:3); lit.10b [a]D ϩ10.5Њ (c 0.30, CHCl3–
(2S,3R,4E,8Z,20R)-3-Acetoxy-2-(20-acetoxyhexadecanoyl)-
amino-4,8-octadecadien-1-ol (24b). In the same manner as
described for the synthesis of 22a, 22b (120 mg, 0.15 mmol)
gave crude full-protected ceramide 23b (140 mg) as a color-
less oil: Rf 0.46 (hexane–AcOEt, 5:1); dH 0.88 (6H, t,
Jˆ6.6 Hz), 1.07 (9H, s), 1.26 (38H, s-like), 1.77 (2H, m),
1.96 (3H, s), 2.00 (3H, s), 2.00 (2H, q, Jˆ6.2 Hz), 2.08 (4H,
m), 3.64 (1H, dd, Jˆ3.8, 10.4 Hz), 3.77 (1H, dd, Jˆ2.2,
10.5 Hz), 4.25 (1H, m), 5.23 (1H, dd, Jˆ4.9, 6.8 Hz),
5.27–5.50 (4H, m), 5.84 (1H, br d, Jˆ15 Hz), 6.57 (1H, d,
Jˆ9.5 Hz), 7.40 (6H, m), 7.59 (4H, m). In the same manner
as described for the synthesis of 24a, the crude 23b
(140 mg) gave the di-O-acetyl-ceramide 24b (91 mg, 94%
from 22b) as a colorless solid: mp 70–72ЊC; Rf 0.34
24
MeOH, 2:3); lit.10c [a]D ϩ5.4Њ (c 0.4, MeOH)}; dH
20
(pyridine-d5) 0.85 (6H, t, Jˆ6.3 Hz, 18- and 160-CH3),
1.24 (38H, s-like, 19×CH2†; 1.74 (2H, br, 30-H2), 2.00
(2H, m, 10-H2), 2.13 (4H, m, 6-H2, 7-H2), 3.89 (1H, m,
500-H), 4.01 (1H, m, 200-H), 4.20 (3H, m, 1-Ha, 300-H,
400-H), 4.33 (1H, dd, Jˆ5.0, 11.8 Hz, 600-Ha), 4.49 (1H, br
d, Jˆ11.5 Hz, 600-Hb), 4.57 (1H, m, 20-H), 4.69 (1H, dd,
Jˆ5.4, 10.7 Hz, 1-Hb), 4.76 (m, 2H, 2-H, 3-H), 4.91 (1H,
d, Jˆ7.5 Hz, 100-H), 5.48 (2H, m, 8-H, 9-H), 5.95 (2H, m,
4-H, 5-H), 8.33 (1H, d, Jˆ8.3 Hz, NH); dC (pyridine-d5)
14.1, 22.8, 25.7, 29.4, 29.5, 29.67, 29.73, 29.8, 29.9, 32.0,
32.6, 32.8, 35.4, 54.2, 62.3, 69.7, 71.2, 72.0, 72.2, 74.8,
78.0, 78.2, 105.2, 129.8, 131.0, 131.6, 132.2, 175.7; nmax
(KBr) 3370 (broad), 2956, 2920, 2850, 1645, 1537, 1469,
1082, 1046, 963 cmϪ1; FAB-MS (positive) m/z (%) 714
(MϩϩH, 19), 697 (MϪOHϩH, 20), 534 (22).
26
(hexane–AcOEt, 1:1); [a]D Ϫ0.6Њ (c 1.2, CHCl3); dH
0.88 (6H, t, Jˆ6.6 Hz), 1.25 (38H, s-like), 1.78 (2H, m),
2.00 (2H, q, Jˆ6.3 Hz), 2.10 (3H, s), 2.11 (4H, m), 2.16
(3H, s), 2.72 (1H, br), 3.65 (2H, m), 4.10 (1H, m), 5.14 (1H,
dd, Jˆ4.8, 7.2 Hz), 5.26–5.45 (3H, m), 5.51 (1H, dd, Jˆ7.3,
15.1 Hz), 5.81 (1H, dt, Jˆ5.9, 15.4 Hz), 6.66 (1H, d,
Jˆ8.5 Hz); dC 14.1, 20.9, 21.1, 22.6, 24.8, 26.4, 27.3,
29.26, 29.32, 29.4, 29.56, 29.58, 29.63, 29.66, 31.8, 31.9,
32.3, 53.2, 61.4, 74.0, 74.1, 124.9, 128.2, 130.9, 136.4,
169.8, 170.2, 171.0; nmax (KBr) 3275 (broad), 2955, 2921,
2852, 1747, 1667, 1567, 1468, 1372, 1245, 1229, 1073,
979 cmϪ1; HRMS Calcd for C38H69NO6 (Mϩ): 635.5125.
Found: 635.5132.
(2S,3R,4E,8Z,20R)-2-(20-Hydroxyhexadecanoyl)amino-
4,8-octadecadiene-1,3-diol (21b). In a similar manner as
described for the synthesis of 21a, 13b (160 mg,
0.23 mmol) in CH2Cl2 (2 ml) and MeOH (1 ml) was treated
with a 1.0 M solution of NaOMe in MeOH (0.1 ml,
0.1 mmol) at 0ЊC, and the mixture was stirred for 1 h. Acetic
acid was added and the solvent was removed. The residue
was purified by chromatography eluting with CH2Cl2–
MeOH (20:1!15:1) to give 21b as a colorless solid
24
(120 mg, 94%); mp 72–75ЊC; [a]D ϩ6.1Њ (c 2.4, CHCl3)
{lit.10b mp 78.0–79.5ЊC; [a]D ϩ6.29Њ (c 0.18, CHCl3)};
(2S,3R,4E,8Z,20R)-2-(20-Acetoxyhexadecanoyl)amino-3-
O-acetyl-1-O-(200,300,400,600-tetra-O-benzoyl-b-d-gluco-
pyranosyl)-4,8-octadecadien-1,3-diol (25b). In the same
manner as described for the synthesis of 25a, 24b (62 mg,
0.097 mmol) afforded the glucoside 25b (91 mg, 77, 88%
yield based on recovered 24b: 8 mg, 13%) as a colorless oil:
Rf 0.30 (hexane–AcOEt, 5:2); [a]D26 ϩ13.1Њ (c 1.2, CHCl3);
dH 0.88 (6H, t, Jˆ6.8 Hz, 18- and 160-CH3), 1.25 (38H,
s-like, 19×CH2), 1.65 (2H, m, 30-H2), 1.93 (2H, m,
10-H2), 1.95 (3H, s, CH3CO), 1.97 (3H, s, CH3CO), 2.01
(4H, m, 6-H2, 7-H2), 3.65 (1H, dd, Jˆ4.2, 10.3 Hz, 1-Ha),
4.04 (1H, dd, Jˆ3.7, 10.3 Hz, 1-Hb), 4.17 (1H, m, 500-H),
4.31 (1H, m, 2-H), 4.50 (1H, dd, Jˆ4.8, 12.1 Hz, 600-Ha),
4.65 (1H, dd, Jˆ2.6, 12.0 Hz, 600-Hb), 4.85 (1H, d,
Jˆ7.8 Hz, 100-H), 4.94 (1H, dd, Jˆ5.4, 6.3 Hz, 20-H),
5.22–5.45 (4H, m, 3-, 4-, 8- and 9-H), 5.48 (1H, dd,
Jˆ7.8, 9.8 Hz, 200-H), 5.67 (1H, t, Jˆ9.6 Hz, 400-H), 5.74
(1H, m, 5-H), 5.89 (1H, t, Jˆ9.6 Hz, 300-H), 6.31 (1H, d,
Jˆ9.0 Hz, NH), 7.20–7.60 (12H, m), 7.80 (2H, m), 7.90
(2H, m), 7.93 (2H, m), 8.02 (2H, m); dC 14.1, 20.6, 21.0,
22.7, 24.6, 26.5, 27.3, 29.3, 29.5, 29.60, 29.64, 29.7, 31.7,
31.9, 32.3, 50.5, 63.0, 67.4, 69.5, 72.0, 72.4, 72.8, 73.1,
22
dH 0.88 (6H, t, Jˆ6.7 Hz), 1.25 (38H, s-like), 1.60 (1H, m),
1.78 (1H, m), 2.01 (2H, q, Jˆ6.6 Hz), 2.12 (4H, m), 3.75
(1H, dd, Jˆ3.3, 11.2 Hz), 3.80–3.96 (2H, m), 4.10 (1H, dd,
Jˆ3.8, 8.0 Hz), 4.25 (1H, m), 5.36 (2H, m), 5.56 (1H, dd,
Jˆ6.2, 15.5 Hz), 5.79 (1H, br d, Jˆ15.0 Hz), 6.65 (1H, d,
Jˆ7.6 Hz); dC 14.1, 22.7, 25.3, 26.7, 27.3, 29.3, 29.4, 29.5,
29.6, 29.67, 29.69, 29.73, 29.74, 31.88, 31.90, 32.4, 34.5,
54.6, 61.6, 72.4, 73.5, 128.4, 128.8, 130.7, 133.7, 176.1;
nmax 3465, 3351, 3271, 2917, 2849, 1618, 1556, 1469,
1377, 1319, 1070, 965, 718 cmϪ1; Anal. Calcd for
C34H65NO4: C, 74.00; H, 11.87; N, 2.54. Found: C, 74.10;
H, 11.91; N, 2.45.
(2S,3R,4E,8Z,20R)-1-(t-Butyldiphenylsilyl)oxy-2-(20-
hydroxyhexadecanoyl)amino-4,8-octadecadien-3-ol
(22b). In the same manner as described for the synthesis of
22a, 21b (111 mg, 0.20 mmol) gave 1-O-TBDPS ceramide
22b (144 mg, 91%) as a waxy solid: Rf 0.35 (hexane–
25
AcOEt, 3:1); [a]D ϩ10.5Њ (c 2.0, CHCl3); dH 0.88 (6H,
t, Jˆ6.6 Hz, 18- and 160-CH3), 1.07 (9H, s, t-Bu), 1.26
(38H, s-like, 19×CH2†; 1.60 (1H, m, 30-Ha), 1.78 (1H, m,

544
T. Murakami et al. / Tetrahedron 56 (2000) 533–545
Minagawa, K.; Katayama, S.; Kitagawa, I. Chem. Pharm. Bull.
1993, 41, 1534.
11. Murakami, T.; Hato, M. J. Chem. Soc., Perkin Trans. 1, 1996,
823.
12. For a review on recent sphingosine synthesis: Koskinen, P. M.;
Koskinen, A. M. P. Synthesis 1998, 1075.
13. Other (4E)-sphingenine syntheses using SN20-reaction, see: (a)
Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1991, 820. (b) Li, Y.-L.; Wu, Y.-L. Liebigs Ann.
Chem. 1996, 2079. (c) Hertweck, C.; Goerls, H.; Boland, W.
Chem. Commun. 1998, 1955.
14. Murakami, T.; Shimizu, T. Synth. Commun. 1997, 27, 4255.
15. For a review on allylic metals, see: Yamamoto, Y.; Asao, N.
Chem. Rev. 1993, 93, 2207.
16. Huchinson, D. A.; Beck, K. R.; Benkeser, R. A.; Grutzner, J. B.
J. Am. Chem. Soc. 1973, 95, 7075.
74.0, 100.8, 124.8, 128.3, 128.4, 128.7, 129.0, 129.5, 129.7,
130.7, 133.1, 133.2, 133.4, 136.4, 165.0, 165.1, 165.7,
166.1, 169.6, 169.7; nmax (KBr) 2925, 2854, 1731, 1691,
1518, 1452, 1371, 1265, 1094, 1069, 1027, 710 cmϪ1
;
FAB-MS (positive) m/z (%) 1237 (MϩϩNa, 69), 1155
(93), 579 (100).
(2S,3R,4E,8Z,20R)-1-O-(b-d-Glucopyranosyl)-2-(20-
hydroxyhexadecanoyl)amino-4,8-octadecadiene-1,3-diol
(1b). In the same manner as described for the synthesis of
1a, 25b (72 mg, 59 mmol) afforded the cerebroside 1b
(38 mg, 90%) as a colorless solid: mp 173ЊC (115ЊC- liquid
crystal-like) {lit.10a 183ЊC; lit.10b 192–194ЊC; lit.10d 183ЊC};
26
Rf 0.33 (CH2Cl2–MeOH, 7:1); [a]D ϩ4.4Њ (c 1.30,
CHCl3–MeOH, 1:1) {lit.10a [a]D ϩ4.6Њ (c 1.76, CHCl3–
20
MeOH, 1:1); lit.10b [a]D ϩ13.4Њ (c 0.43, CHCl3–MeOH,
24
2:3); lit.10d [a]D20 ϩ4Њ (c 0.2, MeOH); lit.10f [a]D24 ϩ5.6Њ (c
0.1, MeOH)}; dH (pyridine-d5) 0.85 (6H, t, Jˆ6.3 Hz, 18-
and 160-CH3), 1.25 (38H, s-like, 19 × CH2†; 1.75 (2H, br,
30-H2), 2.03 (2H, q, Jˆ5.7 Hz, 10-H2), 2.17 (4H, m, 6-H2,
7-H2), 3.89 (1H, m, Jˆ2.6, 4.6, 9.9 Hz, 500-H), 4.01 (1H, m,
200-H), 4.19 (2H, m, 300-H, 400-H), 4.23 (1H, dd, Jˆ2.4,
10.3 Hz, 1-Ha), 4.33 (1H, dd, Jˆ5.0, 11.8 Hz, 600-Ha),
4.49 (1H, br d, Jˆ12.4 Hz, 600-Hb), 4.57 (1H, m, 20-H),
4.69 (1H, dd, Jˆ5.4, 10.7 Hz, 1-Hb), 4.76 (m, 2H, 2- and
3-H), 4.90 (1H, d, Jˆ7.8 Hz, 100-H), 5.47 (2H, m, 8-H, 9-H),
5.90 (1H, br d, Jˆ15.4 Hz, 5-H), 6.00 (1H, dd, Jˆ5.1,
15.4 Hz, 4-H), 8.34 (1H, d, Jˆ8.1 Hz, NH); dC (CDCl3–
CD3OD) 13.7, 22.4, 25.0, 26.4, 27.0, 29.1, 29.3, 29.4,
29.5, 31.6, 32.2, 34.2, 52.8, 60.9, 68.3, 69.4, 71.6, 71.8,
73.1, 75.9, 102.7, 128.3, 128.9, 130.4, 133.6, 175.8; nmax
(KBr) 3365 (broad), 2957, 2920, 2850, 1644, 1536, 1469,
1082, 960 cmϪ1; Anal. Calcd for C40H75NO9. H2O: C, 65.63;
H, 10.60; N, 1.91. Found: C, 65.85; H, 10.44; N, 1.88.
17. (a) Yanagisawa, A.; Hibino, H.; Nomura, N.; Yamamoto, H.
J. Am. Chem. Soc. 1993, 115, 5879. (b) Yanagisawa, A.; Nomura,
N.; Yamamoto, H. Synlett 1993, 689.
18. Cahiez, C.; Alexakis, A.; Normant, J. F. Synthesis 1978, 528.
19. (a) Derguini-Boumechal, F.; Lorne, R.; Linstrumelle, G.
Tetrahedron Lett. 1977, 1181. (b) Linstrumelle, G.; Lorne, R.;
Dang, H. P. Tetrahedron Lett. 1978, 4069.
20. For a review on organocuprates, see: Lipshutz, B. H.,
Sengupta, S. Org. React. (NY) 1992, 41, 135.
21. 2(E)-dodecen-1-ol was purchased from Tokyo Kasei Co.
Inexpensive 2(E)-dodecenal is also available.
22. Collington, E. W.; Meyers, A. I. J. Org. Chem. 1971, 36,
3044.
23. Oppolzer, W.; Schneider, P. Tetrahedron Lett. 1984, 25,
3305.
24. (a) Lipshutz, B. H.; Crow, R.; Dimock, S. H.; Ellsworth, E. L.;
Smith, R. A. J.; Behling, J. R. J. Am. Chem. Soc. 1990, 112, 4063.
(b) Lipshutz, B. H.; Ung, C.; Elworthy, T. R.; Reuter, D. C.
Tetrahedron Lett. 1990, 31, 4539.
25. Stothers, J. B. Carbon-13 NMR spectroscopy; Academic
Press: New York, 1972; p 406.
References
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ceramides stage; Rf values of TLC: 21a: 0.32; 21b: 0.36
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¨
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39. Formation of the orthoester often complicates the reaction

T. Murakami et al. / Tetrahedron 56 (2000) 533–545
545
and lowers the yield of the desired glycoside, see: (a) Kunz,
H; Harreus, A. Liebigs Ann. Chem. 1982, 41. (b) Sato, S.;
Nunomura, S.; Nakano, T.; Ito, Y.; Ogawa, T. Tetrahedron
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40. When O-(2,3,4,6-tetra-O-acetyl-a-d-glucopyranosyl) trichloro-
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formed in 10–20% yields; See Ref. 10e and Sugiyama, S.;
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