Efficient synthesis of d-xylo and d-ribo-phytosphingosines from methyl 2-amino-2-deoxy-β-d-hexopyranosides

Article abstract of DOI:10.1016/j.carres.2009.07.007

A general and flexible synthetic approach to biologically important 5,6-unsaturated C₁₈-phytosphingosines was developed via olefin cross-metathesis employing truncated C₆-phytosphingosines as the key intermediates. These were efficie

Full text of DOI:10.1016/j.carres.2009.07.007

Carbohydrate Research 344 (2009) 2120–2126
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Efficient synthesis of D-xylo and D-ribo-phytosphingosines from methyl
2-amino-2-deoxy-b-D-hexopyranosides
*
Ye Cai, Chang-Chun Ling , David R. Bundle
Alberta Ingenuity Center for Carbohydrate Science, Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2009
Received in revised form 20 July 2009
Accepted 21 July 2009
Available online 25 July 2009
A general and flexible synthetic approach to biologically important 5,6-unsaturated C18-phytosphingo-
sines was developed via olefin cross-metathesis employing truncated C6-phytosphingosines as the key
intermediates. These were efficiently prepared in high yields by zinc-mediated reductive opening of
methyl 2-amino-2-deoxy-b-hexopyranosides.
NHP OH
I
NHP OH
Keywords:
Phytosphingosines
Synthesis
Olefin cross-metathesis
Grubbs’ catalyst
Zn powder
OCM
HO
HO
O
*
*
OH
*
*
OH
C12H25
HO
OMe
NHP
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
and their analogs.8 However, many reported syntheses suffer from
inefficiency and lack the flexibility to access other stereoisomers or
alkyl chain lengths.9 Recently, a number of groups have synthe-
sized bioactive sphingosines via olefin cross-metathesis (OCM)
using different truncated precursors,10,11 and in the case of phy-
tosphingosines, three similar approaches were also reported.12
Here we report our strategy to synthesize some truncated C6-phy-
tosphingosines and their subsequent transformation to 5,6-unsat-
urated C18-phytosphingosines using Grubbs’ catalyst-mediated
OCM. The success of our approach is demonstrated by the synthe-
Phytosphingosines are important structural constituents of cell
membranes (Fig. 1).1 Unlike sphingosines which are abundant in
animals, phytosphingosines are mainly found in plants but are also
present in some bacteria, fungi, and marine organisms.2 Although
the majority of phytosphingosines have a C18 lipid chain, C20-phy-
tosphingosines may also exist depending on the source of origin;
all possess a saturated lipid chain. Interestingly, an unsaturated
analog, Amphicerebroside F (2, Fig. 1), which has a trans double
bond at C-5 and a terminal isopropyl group, was isolated from
the marine organism Amphimedon viridis.3 Studies have shown that
phytosphingosines play important structural and regulatory roles
in living organisms, and some glycolipids containing unsaturated
phytosphingosine analogs exhibit antifungal activity.2,3 For exam-
sis of two families of phytosphingosines with either
D-xylo or D-ribo
configurations. All C6-phytosphingosines have a terminal alkene
NH2 OH
NH2 OH
ple, D-ribo-phytosphingosine was reported to be a potential heat-
HO
HO
stress signal in yeast cells,4 and some of its glycosylated forms,
such as KRN7000,5 exhibit potent immunostimulatory properties
capable of activating natural killer T (NKT) cells to produce a spec-
C14H29
11
OH
OH
1
2
(2S,3S,4R)-D-ribo-
Unsaturated D-ribo
trum of cytokines. KRN7000 is a synthetic analog containing a D-
phytosphingosine
phytosphingosine
ribo-C18-phytosphingosine and is related to agelasphin, which
was isolated from a marine sponge.6,7
OH
OH
HO
HO
HO
The biological significance of phytosphingosines has prompted
considerable interest in the synthesis of this class of compounds
O
C
25H51
NH OH
C14H29
O
C20H41
O
O
HO
NH OH
HO
AcHN
O
O
11
OH
OH
* Corresponding author. Tel.: +1 403 492 8808; fax: +1 403 492 8231.
E-mail address: dave.bundle@ualberta.ca (D.R. Bundle).
Present address: Department of Chemistry, University of Calgary, Calgary, AB,
Canada T2N 1N4.
α-GalCer (KRN7000)
Amphimedon viridis
Figure 1. Phytosphingosines and their glycoceramides.
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.07.007

Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
2121
PPh3 (2 equiv)
CI4 (1 equiv)
functional group which permits further chemical derivatization
OH
I
and conjugation to provide bioconjugates of the type that we have
O
O
HO
R1
HO
R1
OMe
NHAc
OMe
NHAc
previously reported.13
Pyr, 50 oC
R2
1 = OH, R2 = H
R2
1 = OH, R2 = H; 74%
4a
5a
R
2. Results and discussion
R
4b R1 = H, R2 = OH
5b R1 = H, R2 = OH; 71%
The retrosynthesis is illustrated in Scheme 1. The 5,6-unsatu-
rated C18-phytosphingosines were prepared from truncated C6-
amino alcohols I with a terminal double bond that can be used
for OCM reaction with a suitable alkene. The backbone of I can
be obtained from the parent 6-halogenated 2-acetamido-2-
deoxy-hexoside via zinc-mediated reductive ring-opening;14 the
double bond of structure I originates from the C-5 and C-6 carbon
atoms, while the primary hydroxymethyl group is generated from
the aldehyde at C-1. The stereocenters of I that define different
truncated phytosphingosines are directly inherited from the parent
gluco-, galacto-, allo-, or gulo-aminohexoses, all of which can be
obtained on large scales after 1–3-step transformations from the
Scheme 2. One-step synthesis of 6-iodo derivatives 5a and 5b.
anhydrous pyridine afforded the corresponding 6-mesylates, and
after removing the solvent, crude mesylates were reacted with so-
dium iodide in refluxing acetone to afford the 6-iodides 5a and 5b,
respectively, in 78% and 86% yields over two steps and on a 5-g
scale. Next, the zinc-mediated reductive ring-opening was investi-
gated. The reactions of 5a or 5b with pre-activated zinc powder un-
der sonication conditions20 at 40 °C for 1–2 h afforded the desired
aldehydes, which exist as the furanoses 6a and 6b. Direct reduction
with NaBH4 in MeOH afforded the corresponding
D-xylo- (7a) and
inexpensive methyl 2-acetamido-2-deoxy-b-D-glucopyranoside,
D
-ribo-C6-phytosphingosines (7b) in excellent yields (91% for 7a
which was in turn prepared from the key oxazoline 3 on a 30-g
and 89% for 7b over two steps). The procedure was successfully
scaled to multigram quantities without complications. To facilitate
the subsequent OCM reactions, both 7a and 7b were quantitatively
converted to their peracetates 8a and 8b, which have better solu-
bilities in dichloromethane, the common solvent used in OCM
reactions.
scale, as reported by our group.15 Although there are two published
syntheses of D-ribo-C18-phytosphingosine from D-glucosamine via
a Wittig olefination8a,16 or a stereocontrolled alkylation;17 both
suffered from long reaction sequences and required separation of
diastereoisomers. In principle, both
a- and b-glycosides of amino
sugars can be used to obtain the desired intermediates I; however,
our initial investigation18 indicated that the use of b-glycosides
should be a preferred choice because of their higher reactivity in
the zinc-mediated elimination step compared to the reactivity of
the corresponding a-anomers. We attributed the higher reactivity
of b-anomers to the favorable antiperiplanar orientation of the C-
With fully protected truncated phytosphingosines 8a and 8b in
hand, their subsequent chain elongation was investigated (Scheme
4). The limited literature reporting the preparation of phytosp-
hingosines revealed a drastic discrepancy in yields for the OCM
reactions, ranging from 20% to 90%.12 It is also known that the
OCM reactions depend on the nature of the substrates, their pro-
tecting groups, and catalyst as well as reaction conditions.21 We
studied various conditions to enhance the efficiency in the elonga-
tion of the alkyl chain of substrates 8a and 8b. The results are sum-
marized in Table 1. The metathesis was conducted in
dichloromethane under refluxing conditions in the presence of
5 equiv of 1-tetradecene using Grubbs’ second-generation catalyst
5–O-5 and C-1-OMe bonds (the higher reactivity of b-glycosides
in reductive elimination was observed when treating an
ture of GlcNAc glycosides with preactivated Zn powder).
a/b-mix-
The synthesis of truncated
sines began with the selective halogenation (Scheme 2) of the
methyl b-glycosides of
-GlcNAc (4a)15b and -AllNAc (4b),15a
D-xylo- and D-ribo-C6-phytosphingo-
D
D
respectively. When following a published procedure19 by treating
either triol 4a or 4b with triphenylphosphine (2 equiv) and carbon
tetraiodide (1 equiv) in pyridine at room temperature, it was found
that the reactions proceeded very sluggishly. After we raised the
temperature to 50 °C, the reactions proceeded smoothly, and both
reactions were complete within 5–6 h. The desired 6-iodo deriva-
tives 5a and 5b were obtained in 74% and 71% yields, respectively.
However, due to the difficulty encountered in the separation of
by-product (Ph3PO), as well as the high cost associated with carbon
tetraiodide, we concluded that the PPh3/CI4 iodination method was
not suitable for multigram-scale syntheses. Alternatively, a two-
step route, better suited to large-scale syntheses was pursued,
and the transformations were carried out in a one-pot manner
(Scheme 3). Thus treatment of 4a and 4b with an essentially
stoichiometric amount of mesyl chloride at low temperature in
i) MsCl/ Pyr, -10 o
ii) NaI,acetone, reflux
C
OH
O
I
O
HO
R1
HO
R1
OMe
OMe
NHAc
NHAc
R2
R2
5a R1 = OH, R2 = H; 78%
4a R1 = OH, R2 = H
1
R = H, R2 = OH; 86%
1
= H, R2 = OH
5b
4b
R
Zn, THF/H2O,
40 oC, sonication
O
AcHN
OH
R1
OH
R1
NaBH4, MeOH
HO
R2 NHAc
R2
NH2 OH
*
AcHN
HO
OH
*
OCM
1
7a
7b
R
= OH, R2 = H; 91%
6a R1 = OH, R2 = H
6b R1 = H, R2 = OH
HO
*
R = H, R2 = OH; 89%
1
C12H25
*
*
*
OH
OH
I
Ac2O/Pyr
Zn-mediated
reductive
elimination
AcHN
AcO
OAc
R1
O
O
O
OMe
Ref 14
XZn
HO
O
HO
R2
*
*
*
NHAc
O
1
8a
R
= OAc, R2 = H
N
OH
multigrams
8b R1 = H, R2 = OAc
3
Scheme 1. Retrosynthetic plan of phytosphingosines.
Scheme 3. Synthesis of truncated phytosphingosines 8a and 8b.

2122
Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
1-tetradecene
DCM, 40 oC
AcHN
AcO
OAc
AcHN
AcO
OAc
C14H29
AcHN
HO
OBz
AcHN
HO
OBz
i
ii
8a
8b
91%
C12H25
E/Z = ~14:1
C12H25
OCM
quant.
R1
10a R1 = OAc, R2 = H
20% catalyst B,
R1
R2
R2
9a R1 = OAc, R2 = H; 73%
9b
OBz
12
OBz
11
R
1 = H, R2 = OAc; 86%
1 = H, R2 = OAc
10b
R
1-tetradecene
AcHN
HO
O
AcHN
HO
O
O
O
DCM, 40 o
C
i) 1-tetradecene, DCM, 40 oC, Grubbs' 2nd generation; ii) H2, Pd(OH)2, EtOAc
82%
C12H25
E/Z = ~16:1
20% catalyst B,
O
O
O
O
Scheme 4. OCM reactions with 8a and 8b.
13
14
1-tetradecene
DCM, 40 oC
BocHN
HO
O
BocHN
HO
77%
(catalyst B). It was found that, for substrate 8a, only moderate
yields (30–40%) were obtained by either prolonging the reaction
time (5 days, entry 2) or even increasing the catalyst amount up
to a 40% molar ratio (entry 3). After numerous trials, it was found
that the manner of catalyst addition played a critical role in the
outcome of the OCM reactions; for example, if the catalyst was
added in one portion (protocol A, entries 1–3), the reaction never
went to completion, and at least half of the starting material was
recovered each time, leading to low yields. However, a dramatic
improvement was observed when we added the catalyst in a por-
tionwise manner (protocol B, entries 4–6). If the same amount of
catalyst (20% molar ratios) was added in five portions at 2-h inter-
vals, the yield of the desired product 9a was improved to 86% as
shown in entry 4; the reaction was quite clean, and only trace
amounts of the starting material remained. Furthermore, by
decreasing the amounts of catalyst to 10% molar ratio, the desired
9a was still obtained in 78% yield (entry 5). Our results could be ex-
plained by the fact that only a small amount of catalyst was in-
volved in the OCM reaction as most of the catalyst was quickly
decomposed during the reaction;22 therefore, a constant supply
of catalyst to the reaction is the key to the success of OCM reac-
C12H25 E/Z = ~12:1
20% catalyst B,
O
15
16
1-tetradecene
TFAHN
HO
O
TFAHN
HO
DCM, 40 o
C
83%
only E-isomer
12H25
C
20% catalyst B,
O
17
18
Scheme 5. Chain elongation of truncated compounds 11, 13, 15, and 17 by OCM
reaction.
of the chain elongation was unaffected with good to excellent
yields of the OCM products (12, 14, 16, and 18) and in all cases
with excellent E/Z-ratios (>12:1). In the case of the TFA-protected
phytosphingosine (17), the E-isomer was obtained exclusively in
83% yield.
In summary, a general and flexible approach to C6-phytosp-
hingosines containing a terminal double bond was established
using amino sugars as convenient starting materials. The alkyl
chains of these truncated amino alcohols can be extended to de-
sired lengths via a OCM reaction to afford 5,6-unsaturated phy-
tosphingosines, which can also be converted to the saturated
homologs by hydrogenation.
tions. Using protocol B, truncated D-ribo-C6-phytosphingosine 8b
was also smoothly reacted with 1-tetradecene to give 9b in 73%
yield (entry 6). Both 5,6-unstaturated C18-phytosphingosines 9a
and 9b were obtained with excellent E/Z selectivity, as only a trace
amount of the Z-isomer was observed by 1H NMR spectroscopy in
the case of 9a (E/Z = 19:1), and no Z-isomer was observed in the
case of 9b. The presence of the trans double bond at C-5/C-6 was
unambiguously confirmed by the large 1H NMR coupling constant
(>15 Hz) between H-5 and H-6. The flexibility of our synthetic
route is illustrated by converting the unsaturated phytosphingo-
sines 9a and 9b to the saturated forms 10a and 10b in quantitative
yields after a catalytic hydrogenation step. The spectroscopic and
optical data of both 10a and 10b were in full agreement with those
reported in the literature.23
3. Experimental
3.1. General methods
Allchemicalreagentswereusedassuppliedunlessindicated. Sol-
vents used in organic reactions were either distilled under an inert
atmosphere, or purified by a solvent purification system by Innova-
tive Technology, Inc. Unless otherwise noted, all reactions were car-
ried out at rt, and non-hydrolytic reactions were performed under a
positive pressure of argon. Solvents were removed between 20 and
40 °C (bath temperature) unless indicated. Molecular sieves were
stored in an oven (>170 °C) and cooled in vacuo prior to use. Amber-
lite IR-120 resin (H+) was used where acidic ion-exchange resin is
indicated. Amberlite IR-400(ClÀ)wastreatedwithM NaOH(3Â), fol-
lowed by washing with MeOH (3 Â) to afford the basic ion-exchange
resin. Analytical TLC was performed on Silica Gel 60-F254 with detec-
tion by quenching of fluorescence and/or by charring with 5% etha-
nolic sulfuric acid or with a cerium ammonium molybdate dip.
Grubbs’ second-generation catalyst employed in all olefin cross-
metathesis has the following chemical structure.
The applicability of protocol B to other truncated structures24
appears to be quite robust (11, 13, 15, and 17, Scheme 5) and is
compatible with substrates that contain protecting groups such
as acetyl, benzoyl, acetonide, Boc, and TFA groups. The efficiency
Table 1
Studies on OCM chain elongationsa
Entry
Substrates
Catalyst
B (mol %)
Addition
times (h)
Reaction
protocolb
Yieldc
(%)
1
2
3
4
5
6
8a
8a
8a
8a
8a
8b
20
40
20
20
10
20
18
72
A
A
A
B
B
B
36d
41d
32d
86
78
73
120
18
18
18
N
N
Cl
Cl
a
All reactions were heated to 40 °C with 1-tetradecene (5 equiv) added.
Protocol A: catalyst B was added in one portion at the beginning of reactions;
Ru
b
Ph
PCy3
Protocol B: catalyst B was added in 5 portions every 2 h during the reactions.
c
Isolated yields.
Starting materials (49–55%) were recovered.
Grubbs' second generation
catalyst
d

Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
2123
sively added in portions. The mixture was warmed to 40 °C and
stirred for 5–6 h (the reaction was monitored by TLC). MeOH
(2 mL) was added to quench the reaction. After concentration,
the precipitate was filtered off, and the solvent was removed under
reduced pressure. The resulting residue was purified by chroma-
tography on silica gel using 3% MeOH in CH2Cl2 as eluent to give
a pale-yellow solid residue that was dissolved in MeOH (5 mL)
and treated with Dowex MR-3 mixed-bed ion-exchange resin
(2 g). The mixture was stirred at rt for 20 min, and the resin was
filtered off. Subsequent concentration of the filtrate gave the de-
sired compound 5b as a white amorphous solid (245 mg, 71%).
3.2. Characterization
1H NMR spectra were recorded at 400, 500, or 600 MHz, and 13
C
NMR spectra were recorded at 125 MHz. First-order 1H NMR chemi-
calshiftsarereportedind(ppm)unitsusingsignalsfromresidualsol-
vents as reference or to internal acetone at d 2.225 in the case of D2O.
13C NMR chemical shifts are referenced to internal solvent (dC 77.00,
CDCl3) or to external acetone at d 31.07 in the case of D2O. 1H and 13
C
NMR spectra were assigned with the assistance of COSY, HMQC,
HMBC, TOCSY, and TROESY spectra as necessary. Electrospray-ioni-
zation mass spectra (ESIMS) were recorded on a TOF mass spectrom-
eter. For high-resolution mass determination, spectra were obtained
by voltage scan over a narrow range at a resolution of approximately
104. Optical rotations were determined for samples in a 10-cm cell at
3.4.2. Method B
Methanesulfonyl chloride (1.23 mL, 16.2 mmol) was added
dropwise to a solution of methyl 2-acetamido-2-deoxy-b-D-allo-
22 2 °C, and are reported in units of deg mL gÀ1 dmÀ1
.
pyranoside 4b (3.47 g, 14.8 mmol) in dry pyridine (100 mL) at
À30 °C. The mixture was stirred at À30 °C for 18 h to form the
intermediate 6-mesylate (Rf: 0.31, 5:1 CH2Cl2–MeOH). After con-
centration, the residue was dissolved in dry acetone (120 mL). To
the above solution, NaI (6.75 g, 45 mmol) was added, and the mix-
ture was stirred at reflux for 18 h. After filtration, the solvent was
removed. The residue was purified by silica gel chromatography
using 3% MeOH in CH2Cl2 as eluent to give a solid residue which
was dissolved in MeOH (20 mL) and treated with Dowex MR-3
mixed-bed ion-exchange resin (10 g) as above to afford the desired
compound 5b as a white amorphous solid (4.39 g, 86%): Rf 0.48
3.3. Methyl2-acetamido-2,6-dideoxy-6-iodo-b-D-glucopyranoside
(5a)
3.3.1. Method A
To a solution of methyl 2-acetamido-2-deoxy-b-D-glucopyrano-
side15b 4a (1.175 g, 5 mmol) and PPh3 (3.93 g, 15 mmol) in anhyd
pyridine (55 mL) was added portionwise CI4 (3.9 g, 7.5 mmol) at
0 °C. The mixture was warmed to 40 °C and stirred for 5–6 h (mon-
itored by TLC). The reaction was quenched by addition of MeOH
(10 mL), and the mixture was concentrated and filtered. The filtrate
was concentrated, and the mixture was separated by chromatogra-
phy on silica gel using 3% MeOH in CH2Cl2 as eluent to give a pale-
yellow solid residue. This residue was dissolved in MeOH (20 mL)
and Dowex MR-3 mixed-bed ion-exchange resin (10 g) was added.
The mixture was stirred at rt for 20 min, and the resin was filtered
off. Subsequent concentration of the filtrate gave the desired com-
pound 5a as a white amorphous solid (1.24 g, 74%).
(10:1 CH2Cl2–MeOH);
[a
]
D
À47.2 (c 1.12, MeOH); 1H NMR
(500 MHz, CD3OD): d 4.60 (d, 1H, J1.2 = 8.6 Hz, H-1), 3.93 (dd, 1H,
J3,4 = 2.9 Hz, H-3), 3.77 (dd, 1H, J2,3 = 2.8 Hz, H-2), 3.59 (dd, 1H,
J6a,6b = 10.5 Hz, H-6a), 3.55 (ddd, 1H, J5,6b = 7.7 Hz, J5,6a = 2.4 Hz,
H-5), 3.47 (s, 3H, OMe), 3.36 (dd, 1H, J4,5 = 9.3 Hz, H-4), 3.27 (dd,
1H, H-6b), 1.98 (s, 3H, NHCOCH3); 13C NMR (125 MHz, CD3OD): d
173.0, 101.2, 74.4, 72.6, 71.4, 56.9, 55.0, 22.6, 7.5; HRESIMS: calcd
for C9H17NO5I (M+H+) m/z 346.0146; found, m/z 346.0146. Anal.
Calcd for C9H16INO5: C, 31.32; H, 4.67; N, 4.06. Found: C, 31.85;
H, 5.01; N, 4.00.
3.3.2. Method B
Methanesulfonyl chloride (1.6 mL, 20.6 mmol) was added drop-
wise to a solution of methyl 2-acetamido-2-deoxy-b-D-glucopyran-
3.5. (2S,3R,4R)-2-Acetamidohex-5-ene-1,3,4-triol (7a)
oside 4a (4.7 g, 20 mmol) in dry pyridine (150 mL) at À10 °C. The
mixture was stirred at À10 °C for 18 h to form the intermediate 6-
mesylate (Rf: 0.37, 5:1 CH2Cl2–MeOH). After concentration, the res-
iduewasredissolvedindryacetone(160 mL), andNaI(9 g, 60 mmol)
was added. The mixture was stirred at reflux for 18 h. Filtration, fol-
lowed by evaporation, gave a residue, which was subjected to silica
gel chromatography using 3% MeOH in CH2Cl2 as eluent to afford
crude 4a, which was dissolved in MeOH (30 mL) and treated with
Dowex MR-3 mixed-bed ion-exchange resin (10 g). After stirring at
rt for 20 min, the resin was filtered off. Subsequent concentration
of the filtrate afforded the desired compound 5a as a white amor-
To a solution of compound 5a (2.40 g, 7 mmol) in a mixture of
4:1 THF–water (30 mL) was added freshly activated zinc powder
(4.57 g, 70 mmol). The mixture was sonicated at 40–50 °C for 2 h
and passed through a short silica gel pad and eluted with acetone.
After concentration, the residue was dissolved in dry MeOH
(20 mL), and NaBH4 (1.32 g, 35 mmol) was added in portions at
0 °C. The reaction was allowed to continue from 0 °C to rt over
18 h, at the end of which time it was quenched by addition of HOAc
(1 mL). After filtration through a short silica gel pad and concentra-
tion of the filtrate, the residue was purified by chromatography on
silica gel using a gradient of 10–15% MeOH in CH2Cl2, affording the
desired product 7a as a white amorphous solid (1.2 g, 91%): Rf 0.46
phous solid (5.4 g, 78%): Rf 0.59 (5:1 CH2Cl2–MeOH); [
a
]
À2.2 (c
D
0.68, MeOH); 1H NMR (500 MHz, CD3OD):
d
4.34 (d, 1H,
J1,2 = 8.5 Hz, H-1), 3.63 (d, 1H, J2,3 = 10.3 Hz, H-2), 3.61 (dd, 1H,
J6a,6b = 10.7 Hz, H-6a), 3.46 (s, 3H, OCH3), 3.44 (dd, 1H, J3,4 = 8.6 Hz,
H-3), 3.32 (dd, 1H, H-6b), 3.18 (dd, 1H, J4,5 = 9.2 Hz, H-4), 3.10
(ddd, 1H, J5,6b = 7.4 Hz, J5,6a = 2.4 Hz, H-5), 1.98 (s, 3H, NHCOCH3);
13C NMR (125 MHz, CD3OD): d 173.8, 103.3, 76.6, 75.9, 75.7, 57.4,
57.0, 22.9, 6.4; HRESIMS: calcd for C9H16INO5Na (M+Na+) m/z
367.9966; found, m/z 367.9970.
(5:1 CH2Cl2–MeOH); [
a]
D À5.5 (c 0.62, MeOH); 1H NMR (500 MHz,
CD3OD): d 5.90 (ddd, 1H, J5,6t = 17.1 Hz, J5,6c = 10.5 Hz, H-5), 5.29
(ddd, 1H, J6t,6c = 1.6 Hz, H-6t), 5.16 (ddd, 1H, H-6c), 4.02 (ddd, 1H,
J2,3 = 2.7 Hz, H-2), 3.96 (ddd, 1H, J4,5 = 6.9 Hz, J4,6 = 1.2 Hz, H-4),
3.67 (dd, 1H, J3,4 = 7.1 Hz, H-3), 3.60 (dd, 1H, J1a,1b = 10.8 Hz,
J1a,2 = 6.9 Hz, H-1a), 3.52 (dd, 1H, J1b,2 = 6.0 Hz, H-1b), 1.96 (s, 3H,
NHCOCH3); 13C NMR (125 MHz, CD3OD): d 173.3, 138.9, 117.1,
74.8, 73.7, 62.8, 52.2, 22.9; HRESIMS: calcd for C8H15NO4Na
(M+Na+) m/z 212.0893; found, m/z 212.0895.
3.4. Methyl 2-acetamido-2,6-dideoxy-6-iodo-b-D-allopyranoside
(5b)
3.4.1. Method A
3.6. (2S,3S,4R)-2-Acetamidohex-5-ene-1,3,4-triol (7b)
To a solution of methyl 2-acetamido-2-deoxy-b-D-allopyrano-
side15a 4b (235 mg, 1 mmol) in anhyd pyridine (10 mL) at 0 °C,
To a solution of allopyranoside 5b (345 mg, 1 mmol) in a mix-
PPh3 (786 mg, 3 mmol) and CI4 (780 mg, 2.5 mmol) were succes-
ture of 4:1 THF–water (5 mL) was added freshly activated zinc

2124
Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
powder (653 mg, 10 mmol). The mixture was sonicated at 40–
50 °C for 2 h and then passed through a short silica gel pad, which
was then washed with acetone. After concentration of the filtrate,
the resulting residue was dissolved in dry MeOH (3 mL), and
NaBH4 (190 mg, 5 mmol) was added in portions at 0 °C. The mix-
ture was stirred and allowed to warm to room temperature over
18 h. Then the reaction was quenched by addition of HOAc
(0.5 mL). After filtration through a short silica gel pad and concen-
tration of the filtrate, the residue was purified by silica gel chroma-
tography using a gradient of 10–15% MeOH in CH2Cl2, affording the
desired product 7b as a white amorphous solid (168 mg, 89%): Rf
3.9. (2S,3S,4R,5E)-2-Acetamido-1,3,4-tri-O-acetyloctadec-5-ene-
1,3,4-triol (9b)
Triol 7b (28 mg, 0.148 mmol) was dissolved in dry pyridine
(2 mL), and Ac2O (0.15 mL) was added dropwise. The mixture
was stirred at rt for 18 h. Then the solution was diluted with
CH2Cl2, and the organic phase was washed with water and brine
and dried over anhyd Na2SO4. Removal of solvent gave a colorless
syrup 8b that was redissolved in dry CH2Cl2 (3 mL) followed by
addition of 1-tetradecene (0.184 mL, 0.73 mmol). To the resulting
mixture, Grubbs’ second-generation catalyst (20%, 25 mg) was
added in four portions (protocol B) under reflux. The reaction
was continued for 18 h at gentle reflux. The mixture was concen-
trated and purified by chromatography on silica gel using 1:1 to
1:2 hexane–EtOAc as eluent to yield the desired compound 9b as
a white amorphous solid (52 mg, 73%): Rf 0.53 (1:5 hexane–
0.17 (10:1 CH2Cl2–MeOH); [
a]
D
+8.4 (c 0.63, MeOH); 1H NMR
(500 MHz, CD3OD): d 5.98 (ddd, 1H, J5,6t = 17.2 Hz, J5,6c = 10.5 Hz,
H-5), 5.27 (ddd, 1H, J6t,6c = 1.7 Hz, H-6t), 5.17 (ddd, 1H, H-6c),
4.08 (ddd, 1H, J4,5 = 5.5 Hz, J4,6 = 1.4 Hz, H-4), 4.02 (ddd, 1H,
J2,3 = 6.0 Hz, H-2), 3.76 (dd, 1H, J1a,1b = 11.3 Hz, J1a,2 = 4.3 Hz,
H-1a), 3.71 (dd, 1H, J1b,2 = 5.7 Hz, H-1b), 3.64 (dd, 1H,
J3,4 = 5.2 Hz, H-3), 1.96 (s, 3H, NHCOCH3); 13C NMR (125 MHz,
CD3OD): d 173.2 138.7, 116.5, 75.4, 74.8, 62.0, 53.8, 49.5, 22.8;
HRESIMS: calcd for C8H15NO4Na (M+Na+) m/z 212.0893; found,
m/z 212.0891.
EtOAc); [
a]
+11.4 (c 0.44, CHCl3); 1H NMR (400 Hz, CDCl3): d
D
6.05 (d, 1H, JNH, H-2 = 9.5 Hz, NH), 5.83 (ddd, 1 H, J6,7 = 6.8 Hz,
6.8 Hz, H-6), 5.45 (dd, 1H, J5,6 = 15.7 Hz, H-5), 5.34 (dd, 1H,
J4,5 = 8.0 Hz, H-4), 5.14 (dd, 1H, J3,4 = 3.4 Hz, H-3), 4.45 (dddd, 1H,
JNH,H-2 = 10.8 Hz, J2,3 = 8.0 Hz, H-2), 4.30 (dd, 1H, J1a,1b = 11.6 Hz,
J1a,2 = 4.6 Hz, H-1a), 3.99 (dd, 1H, J1b,2 = 3.3 Hz, H-1b), 2.08 (s, 3H,
COCH3), 2.05 (s, 3H, COCH3), 2.05 (s, 3H, COCH3), 2.03 (s, 3H, NHC-
OCH3), 2.02 (m, 2H, alkane CH2), 1.34–1.42 (d, 2H, J = 6.1 Hz, alkane
CH2), 1.20–1.34 (m, 18H, alkane CH2), 0.88 (t, 3H, J = 6.7 Hz, alkyl
CH3); 13C NMR (125 MHz, CDCl3): d 170.7, 170.3, 170.0, 169.4,
138.9, 121.8, 74.0, 72.1, 62.8, 47.8, 32.4, 31.9, 29.7, 29.6, 29.6,
29.6, 29.4, 29.3, 29.2, 28.8, 23.4, 22.7, 21.1, 20.8, 20.7, 14.1; HRE-
SIMS: calcd for C26H45NO7Na (M+Na+) m/z 506.3088; found, m/z
506.3088.
3.7. (2S,3R,4R)-2-Acetamido-1,3,4-tri-O-acetylhex-5-ene-1,3,4-
triol (8a)
To a solution of compound 7a (190 mg, 1 mmol) in dry pyridine
(2 mL), Ac2O (0.15 mL) was added dropwise. The mixture was stir-
red at rt for 18 h and diluted with CH2Cl2, washed with water and
brine, and dried over anhyd Na2SO4. Removal of solvent provided
the pure target product 8a as a colorless syrup (306 mg, 97%): Rf
0.18 (1:4 hexane–EtOAc); [
a
]
D
À19.2 (c 2.4, CHCl3); 1H NMR
(600 MHz, CDCl3): d 5.78 (ddd, 1H, J5,6t = 17.1 Hz, J5,6c = 10.5 Hz,
H-5), 5.69 (d, 1H, JNH,2 = 9.5 Hz), 5.39 (ddd, 1H, J4,5 = 6.3 Hz,
J4,6 = 1.1 Hz, H-4), 5.37 (d, 1H, H-6t), 5.34 (d, 1H, H-6c), 5.19 (dd,
1H, J3,4 = 7.3 Hz, H-3), 4.55 (ddd, 1H, J2,3 = 3.5 Hz, H-2), 4.01 (dd,
1H, J1a,1b = 11.3 Hz, J1a,2 = 6.3 Hz, H-1a), 3.97 (dd, 1H, J1b,2 = 5.9 Hz,
H-1b), 2.10 (s, 3H, COCH3), 2.07 (s, 3H, COCH3), 2.05 (s, 3H, COCH3),
2.02 (s, 3H, NHCOCH3); 13C NMR (125 MHz, CDCl3): d 170.5, 169.8,
169.7, 169.6, 131.3, 120.6, 73.0, 72.0, 62.9, 47.5, 23.3, 20.9, 20.7,
20.6; HRESIMS: calcd for C14H21NO7Na (M+Na+) m/z 338.1210;
found, m/z 338.1208.
3.10. (2S,3R,4R)-2-Acetamido-1,3,4-tri-O-acetyloctadecane-
1,3,4-triol (D-xylo-phytosphingosine tetraacetate) (10a)
To a solution of compound 9a (20 mg, 0.04 mmol) in EtOAc
(2 mL) was added a catalytic amount of palladium hydroxide-on-
charcoal (15 mg). The mixture was stirred at rt under an atmo-
sphere of hydrogen for 18 h. After filtration, the filtrate was con-
centrated, and the residue was dried under vacuum to provide
the desired product 10a as a white amorphous solid in quantitative
yield: Rf 0.45 (1:4 hexane–EtOAc); [
[a]
a]
D +6.0 (c 0.62, CHCl3); {lit.23b
D +6.3 (c 0.86, CHCl3)}; 1H NMR (500 MHz, CDCl3): d 5.71 (d, 1H,
3.8. (2S,3R,4R,5E)-2-Acetamido-1,3,4-tri-O-acetyloctadec-5-ene-
1,3,4-triol (9a)
JNH,H-2 = 9.5 Hz, NH), 5.16 (dd, 1H, J3,4 = 6.5 Hz, H-3), 5.06 (ddd, 1H,
J4.5 = 6.6 Hz, H-4), 4.53 (dddd, J2,3 = 4.4 Hz, H-2), 4.05 (dd, 1H,
J1a,1b = 11.4 Hz, J1a,2 = 6.0 Hz, H-1a), 4.01 (dd, 1H, J1b,2 = 5.7 Hz, H-
1b), 2.09 (s, 3H, COCH3), 2.06 (s, 6H, COCH3), 2.02 (s, 3H, NHC-
OCH3), 1.55–1.64 (m, 2H, alkane CH2), 1.20–1.35 (m, 24H, alkane
CH2), 0.88 (t, 3H, J = 6.7 Hz, alkyl CH3); 13C NMR (125 MHz, CDCl3):
d 170.5, 170.5, 170.1, 169.8, 72.3, 71.9, 62.9, 48.0, 31.9, 30.5, 29.7,
29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 24.8, 23.2, 22.7, 20.9, 20.7,
20.6, 14.1; HRESIMS: calcd for C26H47NO7Na (M+Na+) m/z
508.3245; found, m/z 508.3246.
To a solution of compound 8a (28 mg, 0.09 mmol) and 1-
tetradecene (0.112 mL, 0.445 mmol) in dry CH2Cl2 (2 mL), Grubbs’
second-generation catalyst (20%, 15.3 mg) was added portionwise
(protocol B) at reflux. The reaction was continued for 18 h under
gentle reflux. After concentration, the residue was chromato-
graphed on silica gel using 1:1 to 1:2 hexane–EtOAc as eluent
to yield the desired compound 9a as a white amorphous solid
(37 mg, 86%, E/Z = 19:1): Rf 0.41 (1:5 hexane–EtOAc); 1H NMR
(500 Hz, CDCl3): d 5.82 (ddd, 1H, J6,7a = 6.7 Hz, J6,7b = 4.1 Hz, H-
6), 5.69 (d, 1H, JNH,H-2 = 9.5 Hz, NH), 5.32–5.38 (m, 2H,
J5,6 = 14.7 Hz, H-5 and H-4), 5.17 (dd, 1H, J = 7.4 Hz, J = 3.4 Hz,
H-3), 4.52 (dddd, 1H, J = 7.8 Hz, J = 3.2 Hz, H-2), 3.94–4.02 (dd,
2H, J1a,1b = 11.3 Hz, J = 6.4 Hz, H-1a and H1b), 2.09 (s, 3H, COCH3),
2.05 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.02 (s, 3H, NHCOCH3),
2.02 (m, 2H, alkane CH2), 1.32–1.40 (d, 2H, J = 6.1 Hz, alkane
CH2), 1.20–1.32 (m, 18H, alkane CH2), 0.88 (t, 3H, J = 6.7 Hz, alkyl
CH3); 13C NMR (125 MHz, CDCl3): d 170.7, 169.8, 169.8, 169.5,
138.9, 122.6, 73.2, 72.3, 62.9, 47.5, 32.3, 31.9, 29.7, 29.6, 29.6,
29.6, 29.4, 29.3, 29.2, 28.6, 23.2, 22.7, 21.0, 20.7, 20.6, 14.1; HRE-
SIMS: calcd for C26H45NO7Na (M+Na+) m/z 506.3088; found, m/z
506.3089.
3.11. (2S,3S,4R)-2-Acetamido-1,3,4-tri-O-acetyloctadecane-
1,3,4-triol (D-ribo-phytosphingosine tetraacetate, 10b)
To a solution of compound 9b (15 mg, 0.03 mmol) in EtOAc
(2 mL) was added a catalytic amount of palladium hydroxide-on-
charcoal (12 mg). The mixture was stirred under an atmosphere
of hydrogen at rt for several hours. After filtration, the filtrate
was concentrated, and the residue was dried under vacuum to af-
ford the desired product 10b as a white amorphous solid (13.8 mg,
92%): Rf 0.58 (1:5 hexane–EtOAc); [a]
D +25.8 (c 1.4, CHCl3); {lit.23a
[a] [a] [a]
+27.8 (c 0.8, CHCl3), lit.8f +26.5 (c 0.84, CHCl3), lit.25
D D D
+26.2 (c 2.0, CHCl3)}; 1H NMR (500 MHz, CDCl3): d 5.91 (d, 1H,
JNH,H-2 = 9.4 Hz, NH), 5.10 (dd, 1H, J3,4 = 3.1 Hz, H-3), 4.94 (dt, 1H,

Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
2125
J4,5a = 3.2 Hz, J4,5b = 9.9 Hz, H-4), 4.48 (dddd, 1H, J2,3 = 8.2 Hz, H-2),
4.29 (dd, 1H, J1a,1b = 11.7 Hz, J1a,2 = 5.0 Hz, H-1a), 4.01 (dd, 1H,
J1b,2 = 3.1 Hz, H-1b), 2.08 (s, 3H, COCH3), 2.05 (s, 6H, COCH3), 2.03
(s, 3H, NHCOCH3), 1.55–1.64 (m, 2H, alkyl CH2), 1.20–1.35 (m,
24H, alkyl CH2), 0.88 (t, 3H, J = 6.7 Hz, alkyl CH3); 13C NMR
(125 MHz, CDCl3): d 171.1, 170.8, 170.0, 169.7, 73.0, 72.1, 62.8,
47.7, 31.9, 29.7, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 28.2, 25.5, 23.3,
22.7, 21.0, 20.7, 20.7, 14.1; HRESIMS: calcd for C26H47NO7Na
(M+Na+) m/z 508.3245; found, m/z 508.3247.
second-generation catalyst (20%, 41.4 mg) was added in four por-
tions (protocol B) under reflux. The reaction was continued for
18 h under gentle reflux. After concentration, the residue was puri-
fied by chromatography on silica using 4:1 hexane–EtOAc as eluent
to afford the target product 16 as a white amorphous solid (85 mg,
77%, E/Z = ꢀ12:1): Rf 0.34 (2:1 hexane–EtOAc). 1H NMR (600 MHz,
CDCl3): d 5.83 (dt, 1H, J6,7 = 6.8 Hz, H-6), 5.50 (dd, 1H, J5,6 = 15.3 Hz,
H-5), 4.93 (s, br, 1H, NH), 4.65 (dd, 1H, J4,5 = 7.2 Hz, H-4), 4.19 (dd,
1H, J2,3 = J3,4 = 6.3 Hz, H-3), 3.86 (dd, 1H, J1a,1b = 11.0 Hz, J1a,2
=
3.0 Hz, H1a), 3.70 (dd, 2H, J = 9.3 Hz, J = 3.2 Hz, H-2 and H1b),
2.06 (t, 2H, J = 7.0 Hz, @CHCH2), 1.49 (s, 3H, C(CH3)2), 1.36 (s, 3H,
C(CH3)2), 1.44 (s, 9H, C(CH3)3), 1.20–1.40 (m, 20H, alkane CH2),
0.88 (t, 3H, J = 6.9 Hz, CH3); 13C NMR (125 MHz, CDCl3): d 155.4,
136.9, 124.2, 108.5, 78.9, 78.7, 63.5, 51.6, 32.5, 31.9, 29.7, 29.6,
29.6, 29.6, 29.5, 29.5, 29.3, 29.3, 29.0, 28.4, 27.4, 25.0, 22.7, 14.1;
HRESIMS: calcd for C26H49NO5Na (M+Na+) m/z 478.3503; found,
m/z 478.3507.
3.12. (2S,3S,4R,5E)-2-Acetamido-3,4-di-O-benzoyloctadec-5-
ene-1,3,4-triol (12)
To a solution of compound 11 (50 mg, 0.126 mmol) and 1-
tetradecene (0.16 mL, 0.63 mmol) in dry CH2Cl2 (5 mL), Grubbs’
second-generation catalyst (20%, 26.7 mg) was added in four por-
tions (protocol B) under reflux. The reaction was continued under
gentle reflux for 18 h (TLC showed that almost all starting material
was consumed). Concentration and chromatography of the residue
on silica gel using 1:5 hexane–EtOAc as eluent gave the target
3.15. (2S,3S,4R,5E)-3,4-O-Isopropylidene-2-trifluoroacetamido-
octadec-5-ene-1,3,4-triol (18)
product 12 as
a white amorphous solid (65 mg, 91%, E/
Z = ꢀ14:1): Rf 0.48 (1:5 hexane–EtOAc). 1H NMR (600 MHz, CDCl3):
d 8.07 (d, 2H, J = 7.2 Hz, ArH), 7.96 (d, 2H, J = 10.8 Hz, ArH), 7.64 (t,
1H, J = 7.4 Hz, ArH), 7.48–7.54 (m, 3H, ArH), 7.38 (t, 2H, J = 7.7 Hz,
ArH), 6.30 (d, 1H, JNH,H-2 = 9.2 Hz, NH), 6.03 (ddd, 1H, J5,6 = 14.3 Hz,
J6,7 = 6.9 Hz, 7.4 Hz, H-6), 5.74–5.82 (m, 2H, H-5 and H-4), 5.41 (dd,
1H, J = 9.1 Hz, 2.5 Hz, H-3), 4.39 (m, 1H, H-2), 3.69 (dd, 1H,
J1a,1b = 12.3 Hz, J1a,2 = 2,5 Hz, H-1a), 3.64 (dd, 1H, J1b,2 = 2.9 Hz, H-
1b), 2.15 (q, 2H, J = 7.2 Hz, H-7 or @CHCH2), 2.1 (s, 3H, NHCOCH3),
1.38–1.44 (m, 2H, alkane CH2), 1.20–1.32 (m, 18H, alkane CH2),
0.88 (t, 3H, J = 7.1 Hz, alkyl CH3); 13C NMR (125 MHz, CDCl3): d
170.0, 167.2, 165.5, 138.6, 133.9, 133.1, 130.0, 129.9, 129.7,
129.7, 129.0, 128.7, 128.6, 128.4, 122.0, 61.4, 50.3, 32.6, 31.9,
29.7, 29.6, 29.6, 29.4, 29.3, 29.3, 29.2, 28.9, 23.5, 22.7, 14.1; HRE-
SIMS: calcd for C34H47NO6Na (M+Na+) m/z 588.3296; found, m/z
588.3297.
To a solution of compound 17 (40 mg, 0.14 mmol) and 1-
tetradecene (0.18 mL, 0.7 mmol) in dry CH2Cl2 (5 mL), Grubbs’ sec-
ond-generation catalyst (20%, 23.7 mg) was added in four portions
(protocol B) under reflux. The reaction was continued for 18 h un-
der gentle reflux. Concentration, followed by chromatography of
the residue on silica gel (4:1 hexane–EtOAc), afforded the target
product 18 as a white amorphous solid (53 mg, 83%): Rf = 0.33
(2:1 hexane–EtOAc);
[
a]
D
À4.06 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): d 6.79 (d, 1H, JNH,H-2 = 8.2 Hz, NH), 5.85 (dt,
1H, J6,7 = 6.7 Hz, H-6), 5.44 (dd, 1H, J5,6 = 15.3 Hz, H-5), 4.70 (dd,
1H, J4,5 = 7.3 Hz, H-4), 4.27 (dd, 1H, J3,4 = 6.5 Hz, H-3), 4.09 (ddd,
1H, J2,3 = 6.0 Hz, H-2), 4.00 (dd, J1a,1b = 11.5 Hz, J1a,2 = 2.7 Hz, H-
1a), 3.70 (dd, 1H, J1b,2 = 3.4 Hz, H-1b), 2.04 (q, 2H, J = 7.1 Hz,
@CCH2), 1.51 (s, 3H, C(CH3)2), 1.38 (s, 3H, C(CH3)2), 1.20–1.40 (m,
20H, alkane CH2), 0.88 (t, 3H, J = 6.8 Hz, alkyl CH3); 13C NMR
(125 MHz, CDCl3): d 156.5, 137.8, 123.3, 115.6, 108.9, 78.6, 77.7,
62.0, 50.8, 32.3, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.3, 28.8, 27.3,
24.8, 22.7, 14.1; HRESIMS: calcd for C23H40F3NO4Na (M+Na+) m/z
474.2802; found, m/z 474.2804. Anal. Calcd for C23H40F3NO4: C,
61.18; H, 8.93; N, 3.10. Found: C, 61.42; H, 8.72; N, 3.28.
3.13. (2S,3S,4R,5E)-2-Acetamido-3,4-O-isopropylideneoctadec-
5-ene-1,3,4-triol (14)
To a solution of compound 13 (60 mg, 0.26 mmol) and 1-
tetradecene (0.33 mL, 1.3 mmol) in dry CH2Cl2 (9 mL), Grubbs’ sec-
ond-generation catalyst (20%, 44 mg) was added in four portions
(protocol B) under reflux. The reaction was continued for 18 h un-
der gentle reflux (TLC showed that almost all starting material had
disappeared). Concentration, followed by chromatography of the
residue on silica gel using 1:5 hexane–EtOAc as eluent provided
the target product 14 as a white amorphous solid (85 mg, 82%, E/
Z = ꢀ16:1): Rf 0.22 (1:5 hexane–EtOAc). 1H NMR (500 MHz, CDCl3):
d 5.96 (d, 1H, JNH,H-2 = 8.2 Hz, NH), 5.84 (dt, 1H, J6,7 = 6.8 Hz, H-6),
5.50 (ddd, 1H, J5,6 = 15.3 Hz, H-5), 4.67 (dd, 1H, J4,5 = 7.3 Hz, H-4),
4.24 (dd, 1H, J3,4 = 6.0 Hz, H-3), 4.03 (dddd, 1H, J2,3 = 6.3 Hz, H-2),
3.90 (dd, 1H, J1a,1b = 11.5 Hz, J1a,2 = 3.5 Hz, H-1a) 3.68 (dd, 1H,
J1b,2 = 3.5 Hz, H-1b), 2.02–2.08 (m, 2H, H-7 or @CHCH2), 1.98 (s,
3H, NHCOCH3), 1.50 (s, 3H, C(CH3)2), 1.36 (s, 3H, C(CH3)2), 1.20–
1.40 (m, 20H, alkane CH2), 0.88 (t, 3H, J = 6.8 Hz, alkyl CH3); 13C
NMR (125 MHz, CDCl3): d 169.8 (C@O), 139.1, 124.2, 108.5, 78.8,
63.1, 50.7, 32.4, 31.9, 29.7, 29.6, 29.6, 29.6, 29.5, 29.3, 29.3, 29.0,
27.3, 24.8, 23.4, 22.7, 14.1; HRESIMS: calcd for C23H43NO4Na
(M+Na+) m/z 420.3084; found, m/z 420.3085.
Acknowledgments
Financial support was provided by research grants to D.R. Bun-
dle from the Natural Science and Engineering Research Council
(NSERC) and the University of Alberta.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2009.07.007.
References
1. Merrill, A. H.; Sweeley, C. C. In Biochemistry of Lipids, Lipoproteins and Membranes;
Vance, D. E., Vance, J., Eds.; Elsevier: Amsterdam, 1996; pp 309–339.
2. Holst, O., 1st ed.. In Glycoscience: Chemistry and Chemical Biology; Fraser-Reid,
B., Tatsuta, K., Thiem, J., Eds.; Springer: New York, 2001; Vol. 3, pp 2083–2106.
3. (a) Shier, W. T.; Shier, A. C. J. Toxicol.-Toxin Rev. 2000, 19, 189–246; (b) Hirsch,
S.; Kashman, Y. Tetrahedron 1989, 45, 3897–3906.
4. Dickson, R. C.; Nagiec, E. E.; Skrzypek, M.; Tillman, P.; Wells, G. B.; Lester, R. L. J.
Biol. Chem. 1997, 272, 30196–30200.
5. (a) Sharif, S.; Arreaza, G. A.; Zucker, P.; Mi, Q.-S.; Sondhi, J.; Naidenko, O. V.;
Kronenberg, M.; Koezuka, Y.; Delovitch, T. L. Nat. Med. 2001, 7, 1057–1062; (b)
Luc Van Kaer Nat. Rev. Immunol. 2004, 5, 31–42.
3.14. (2S,3S,4R,5E)-2-N-(tert-Butoxycarbonyl)amino-3,4-O-
isopropylideneoctadec-5-ene-1,3,4-triol (16)
6. (a) Natori, T.; Yasuhiko, K.; Higa, T. Tetrahedron Lett. 1993, 34, 5591–5592; (b)
Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Tetrahedron 1994, 50, 2771–
2784.
To a solution of compound 15 (70 mg, 0.244 mmol) and 1-
tetradecene (0.32 mL, 12.6 mmol) in dry CH2Cl2 (10 mL), Grubbs’

2126
Y. Cai et al. / Carbohydrate Research 344 (2009) 2120–2126
7. (a) Motoki, K.; Kobayashi, E.; Uchida, T.; Fukushima, H.; Koezuka, Y. Bioorg.
Med. Chem. Lett. 1995, 5, 705–710; (b) Morita, M.; Motoki, K.; Akimoto, K.;
Natori, T.; Sakai, T.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.; Fukushima, H. J. Med.
Chem. 1995, 38, 2176–2187; (c) Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.;
Kaneko, Y.; Motoki, K.; Ueno, H.; Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.;
Taniguchi, M. Science 1997, 278, 1626–1629; (d) Koezuka, Y.; Kazuhiro, M.;
Sakai, T.; Takenori, N. Rec. Res. Dev. Cancer 1999, 1, 341–354.
Rosenbeiger, D.; Hogenauer, K. Chem. Commun. (Cambridge) 2005, 5086–5087;
(f) Peters, C.; Billich, A.; Ghobrial, M.; Hogenauer, K.; Ullrich, T.; Nussbaumer, P.
J. Org. Chem. 2007, 72, 1842–1845.
12. For the syntheses of phytosphingosine via OCM, see: (a) Singh, O. V.; Kampf, D.
J.; Han, H. Tetrahedron Lett. 2004, 45, 7239–7242; (b) Lomardo, M.; Capdevilla,
M. G.; Pasi, F.; Trombini, C. Org. Lett. 2006, 8, 3303–3305; (c) Chang, C.-W.;
Chen, Y.-N.; Adak, A. K.; Lin, K.-H.; Tzou, D. M.; Lin, C.-C. Tetrahedron 2007, 63,
4310–4318.
13. Jacques, S. Ph.D. Thesis, University of Alberta, September, 2008.
14. (a) Bernet, B.; Vassela, A. Helv. Chim. Acta 1979, 62, 1990–2016; (b) Bernet, B.;
Vassela, A. Helv. Chim. Acta 1979, 62, 2400–2410.
15. (a) Cai, Y.; Ling, C.-C.; Bunlde, D. R. J. Org. Chem. 2009, 74, 580–589; (b) Cai, Y.;
Ling, C.-C.; Bundle, D. R. Org. Lett. 2005, 7, 4021–4024.
16. Luo, S.-Y.; Kulkarin, S. S.; Chou, C.-H.; Liao, W.-M.; Hung, S.-C. J. Org. Chem.
2006, 71, 1226–1229.
17. (a) Murakami, T.; Taguchi, K. Tetrahedron 1999, 55, 989–1004; (b) Murakami,
T.; Minamikawa, H.; Hato, M. Tetrahedron Lett. 1994, 35, 745–747.
18. Cai, Y.; Bundle, D. R., unpublished work.
19. Kashem, A.; Anisuzzaman, M.; Whistler, R. L. Carbohydr. Res. 1978, 61,
511–518.
20. (a) Hyldtoft, L.; Madsen, R. J. Am. Chem. Soc 2000, 122, 8444–8452; (b)
Skaanderup, P. R.; Hyldtoft, L.; Madsen, R. Monatsh. Chem. 2002, 133, 467–472.
21. Jorgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.; Wrodnigg, T. M. Curr. Org.
Chem. 2000, 4, 565–588.
22. Sanford, M.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543–6554.
23. (a) He, L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7618–7626; (b)
Ndakala, J.; Hashemzadeh, M.; So, R. C.; Howell, A. R. Org. Lett. 2002, 4, 1719–
1722.
8. For recent examples of syntheses of phytosphingosine and derivatives, see: (a)
Luo, S.-Y.; Thorpate, S. R.; Hsu, C.-Y.; Hung, S.-C. Tetrahedron Lett. 2002, 43,
4889–4892. and references cited therein; (b) Raghavan, S.; Rajender, A. J. Org.
Chem. 2003, 68, 7094–7097; (c) Lu, X.; Bittman, R. Tetrahedron Lett. 2005, 46,
3165–3168; (d) Cai, Y.; Ling, C.-C.; Bundle, D. R. Org. Biomol. Chem. 2006, 4,
1140–1146; (e) Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;
Nicholson, R. L.; Roberts, P. M.; Rusell, A. J.; Smith, A. D.; Thomson, J. E.
Tetrahedron: Asymmetry 2007, 18, 2510–2513; (f) Jeon, J.; Shin, M.; Yoo, J. W.;
Oh, J. S.; Bae, J. G.; Jung, S. H.; Kim, Y. G. Tetrahedron Lett. 2007, 48, 1105–1108;
(g) Kim, S.; Lee, N.; Lee, S.; Lee, T.; Lee, Y. M. J. Org. Chem. 2008, 73, 1379–1385.
9. For reviews, see: (a) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075–
1091; (b) Vankar, Y. D.; Schmidt, R. R. Chem. Soc. Rev. 2000, 29, 201–216.
10. (a) For examples of truncated sphingosine and its applications in our group,
see: Bundle, D. R.; Ling, C.-C.; Zhang, P. Patent WO 03/101937; Chem. Abstr.
2003, 140, 16928.; (b) Rich, J. R.; Bundle, D. R. Org. Lett. 2004, 6, 897; (c)
Jacques, S.; Rich, J. R.; Ling, C.-C.; Bundle, D. R. Org. Biomol. Chem. 2006, 4, 142–
154; (d) Bundle, D. R.; Rich, J. R.; Jacques, S.; Yu, H. N.; Nitz, M.; Ling, C.-C.
Angew. Chem., Int. Ed. 2005, 44, 7725–7729; (e) Rich, J. R.; Bundle, D. R. Chem.
Eur. J. 2006, 12, 845–858.
11. For the syntheses of E-sphingosine via OCM, see: (a) Torssell, S.; Somfai, P. Org.
Biomol. Chem. 2004, 2, 1643–1646; (b) Rai, A. N.; Basu, A. Org. Lett. 2004, 6,
2861–2863; (c) Chaudhari, V. D.; Ajish Kumar, K. S.; Dhavale, D. D. Org. Lett.
2005, 7, 5805–5807; (d) Yamamoto, T.; Hasegawa, H.; Hakogi, T.; Katsumura, S.
Org. Lett. 2006, 8, 5569–5572; (e) Nussbaumer, P.; Ettmayer, P.; Peters, C.;
24. Compounds 11, 13, 15, and 17 were prepared from truncated 7b. Cai, Y., Ph.D.
thesis, University of Alberta, 2008.
25. Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000, 65, 3538–3541.