An efficient synthesis of D-ribo-C18-phytosphingosine and L-arabino-C18-phytosphingosine from D-fructose

Article abstract of DOI:10.1016/j.tet.2011.10.003

D-ribo-C₁₈-phytosphingosine and L-arabino-C₁₈- phytosphingosine were synthesised starting from commercially inexpensive D-fructose. Metal-mediated fragmentation and stereoselective reduction were used as key steps to provide the hydrophilic portion of D-ribo and L-arabino phytosphingosines. Grubbs' cross-metathesis and hydrogenation allowed the incorporation of hydrophobic tail.

Full text of DOI:10.1016/j.tet.2011.10.003

Tetrahedron 67 (2011) 9283e9290
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An efficient synthesis of
D-ribo-C18-phytosphingosine and
L
-arabino-C18-phytosphingosine from
D-fructose
*
Ramu Sridhar Perali , Suresh Mandava, Sudharani Chalapala
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2011
Received in revised form 8 September 2011
Accepted 3 October 2011
Available online 6 October 2011
D
-ribo-C18-phytosphingosine and
mercially inexpensive -fructose. Metal-mediated fragmentation and stereoselective reduction were
used as key steps to provide the hydrophilic portion of -ribo and -arabino phytosphingosines. Grubbs’
cross-metathesis and hydrogenation allowed the incorporation of hydrophobic tail.
Ó 2011 Elsevier Ltd. All rights reserved.
L-arabino-C18-phytosphingosine were synthesised starting from com-
D
D
L
Keywords:
Phytosphingosines
Sphingolipids
Olefin cross-metathesis
D
-Fructose
1. Introduction
still in demand. Thus, in addition to the existing methods, herein
we report a convenient enantioselective synthesis of -ribo-C18
phytosphingosine and -arabino-C18-phytosphingosine starting
D
-
Sphingolipids are ubiquitous structural motifs influencing
several biological machineries.1 They play important roles in cel-
lular adhesion, molecular recognition, signal transduction, im-
mune response and apoptosis.2 The significant involvement of
sphingolipids in physiological process makes them critical for the
diagnosis of most common human diseases like diabetes,3 cancer,4
Alzheimer’s,5 infectious6 and several neurological syndromes.7
Recent studies revealed that some of the sphingosine analogues
are capable of bringing about morphological changes in neuronal
cells8 and behaving as like enzyme inhibitors.9 Due to their mul-
tiple biological activities, a great deal of effort has been made
towards the asymmetric synthesis of aminodiol sphingoid bases
(sphingosines)10 in the last decade and several methods for their
preparations have been reported. However enantioselective
methods for the synthesis of aminotriol sphingoid bases (phytos-
phingosines)11 have increased in the recent years due to their
growing biological relevance. It is also evident that a majority of
phytosphingolipids has 18-carbon long-chain base. Out of several
synthetic methods for phytosphingosines, the chiral-pool ap-
L
from grape sugar, fructose.
2. Results and discussion
D
-Fructose 1 was converted to the known diacetonide 2 in an
overall yield of 39% over four steps.14 Compound 2 was treated with
I2/Ph3P/imidazole under reflux in toluene to provide iodo diac-
etonide 3 in 95% yield. Zinc-mediated fragmentation of 3 gave al-
cohol that was protected with TBDMSCl without isolation of the
a
-hydroxy ketone to produce ketone 415 in good yield (85%, over
two steps). Reduction of ketone 4 with NaBH4 at ꢀ78 ꢁC in etha-
nol16 provided 2,3-syn alcohol 517 and 2,3-anti alcohol 618 in a ratio
16
of 1:24, respectively. Interestingly, when LiAlH(O-tBu)3 was
employed for the reduction the ratio of 5 and 6 was 7:3, re-
spectively with 70% combined yield. The 2,3-syn relationship in
compound
5 was assigned based on the coupling constant
J3,2¼3.2 Hz where as in the case of compound 6 the 2,3-anti re-
lationship was assigned by observing the coupling constant
J3,2¼8.8 Hz. The stereochemistry at 2-position was further con-
firmed by comparing the NMR spectral data with the reported
values.17,18 Both the diastereomers can be isolated in pure form by
conventional silica gel column chromatography. It is noteworthy
that key intermediates 5 and 6 can be synthesised on gram scale
proaches particularly from
L
-serine12 and carbohydrates13 are
noteworthy. Novel methods for the enantioselective synthesis of
sphingolipids and phytosphingosine analogues involving fewer
synthetic steps and commercially inexpensive raw materials are
from
D-fructose in a series of eight steps involving only three col-
* Corresponding author. Tel.: þ91 40 6679 4823; fax: þ91 40 2301 2460; e-mail
address: prssc@uohyd.ernet.in (R.S. Perali).
umn chromatographic purifications (Scheme 1).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.003

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R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
chain via a cross-metathesis have been reported,21 to the best of
our knowledge, very few reports were observed for the synthesis
of phytosphingosines.22 Activation of the secondary alcohol in 11
or 12 using CH3SO2Cl/pyridine in CH2Cl2 provided sulfonates
1320 and 14. A one-pot deprotection of TBDMS and acetonide
protective groups using p-TsOH/MeOH/20% aqueous HCl pro-
vided the C-2-O-methanesulfonated triols 1513g,23 and 16
(Scheme 2).
Substitution of mesylate 15 with NaN3 provided the azido-
ribo-phytosphingosine 1724 that was further hydrogenated to give
pure
-ribo-C18-phytosphingosine 1822 in good yield. However,
under similar reaction conditions mesylate 16 provided an in-
separable 1:1 mixture of azido- -ribo-phytosphingosine 17 and
azido- -arabino-phytosphingosine 19 (Scheme 3). The structure of
19 was confirmed by comparing the 13C NMR with the reported
enantiomer of 19, i.e., azido-
-arabino-phytosphingosine.25
D-
D
D
L
D
Scheme 1. Preparation of key intermediates 5 and 6.
Attempts to incorporate the amino group in the form of
phthalimide, to resemble the phytosphingosine skeleton, via
a Mitsunobu reaction provided compounds 7 and 8. The un-
expected formation of the rearranged products 7 and 8 can be vi-
Scheme 3. Stereoselective synthesis of D-ribo-C18-phytosphingosine.
sualized through
a 1,4 O/O silyl migration followed by
The formation of only 17 from 15 and a mixture of 17 and 19
from 16 could be justified by considering the energy-minimised
conformation of 15, which adopts like a chair conformation and
16 adopting like a twist-boat conformation. As shown in Fig. 1 both
the conformations possess an intramolecular hydrogen-bond be-
tween C1eOH and C3eOH forming a six-membered ring. Presence
of an axial methanesulfonate in compound 15 facilitates an SN2
type substitution reaction with azide. However, compound 16 to
undergo SN2 substitution reaction suffers with steric hindrance due
to the ring oxygen as well as axial substituent at C3. Probably due to
this reason compound 16 will undergo SN1 type substitution re-
action that leads to the formation of 17 and 19.
substitution at C-1 (Scheme 2).19 Activation of alcohol function in 5
or 6 by reacting with CH3SO2Cl/pyridine in CH2Cl2 followed by SN2
substitution with NaN3/DMF was not successful. We reasoned that
the steric bulk present on both sides of the alcohol probably hinders
the incoming nucleophile for substitution. To overcome this prob-
lem the substitution reaction was postponed to a later stage in
which the activated alcohol will be less hindered.
Fig. 1. Energy-minimised conformation for 15 and 16.
Towards the enantioselective synthesis of L-arabino-phytos-
phingosine, the alcohol derived from Zn-mediated fragmentation
of 3 was protected in situ with methoxymethyl (MOM) protective
group using MOMCl/DIPEA to give ketone 20. Interestingly, treat-
ment of ketone with LiAlH(O-tBu)3 in EtOH at ꢀ78 ꢁC provided an
inseparable mixture of syn and anti alcohols 21 and 22 in 3:7 ratio,
respectively. Treatment of this diastereomeric alcohol mixture with
Ph3P/DIAD/phthalimide in dry THF at 0 ꢁC followed by warming it
to 25 ꢁC provided Mitsunobu inversion products 23 and 24 again in
3:7 ratio in good yield (Scheme 4). The stereochemistry for 24 was
found to be 2,3-syn configuration by observing the coupling con-
stant J3,2¼4.4 Hz and based on this the other diastereomer was
assigned to be 2,3-anti compound 23.
Scheme 2. Synthesis of 2-O-methanesulfonyl D-ribo- and L-arabino-C18-phytosphin-
gosine.
Towards this, cross-metathesis of alcohols 5 and 6 with tet-
radec-1-ene using Grubbs’ II generation catalyst provided the
alkenols 9 and 10, which were further hydrogenated with 10%
Pd/C under hydrogen to give alcohols 1120 and 12, respectively,
in good yield. Even though quite a few methods for the prepa-
ration of sphingosines through the incorporation of the lipid

R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
9285
4. Experimental section
4.1. General
All the reactions were carried out under an inert atmosphere
with dry solvents under anhydrous conditions unless otherwise
mentioned. Acetone was distilled from potassium permanganate,
CH2Cl2 was distilled from calcium hydride, ethanol was distilled
from sodium ethoxide followed by distillation from magnesium
ethoxide, pyridine was distilled from KOH and toluene was distilled
from sodium. TLC was run on Silica Gel 60 F254 (Merck) and the
spots were detected by staining with H2SO4 in methanol (5%, v/v) or
phosphomolybdic acid in ethanol (5%, w/v) and heat. Silica gel
(100e200 mesh) was used as a stationary phase for column chro-
matography. NMR spectra were recorded at 25 ꢁC on a Bruker
Avance III 400 (400 MHz for 1H and 100 MHz for 13C) or 500
(500 MHz for 1H and 125 MHz for 13C) instrument with CDCl3 or
CD3OD or DMSO-d6 as solvent and residual CHCl3 (dH 7.26 ppm) or
CH3OH (dH 3.31 ppm) or (CH3)2SO (dH 2.50 ppm) as internal stan-
Scheme 4. Preparation of key intermediate for the synthesis of L-arabino-
phytosphingosine.
Cross-metathesis of olefin 24 with tetradec-1-ene using Grubbs’
II generation catalyst provided olefin 25, which upon hydrogena-
tion using 10% Pd/C/H2 provided compound 26. A one-pot depro-
tection of acid-sensitive MOM and acetonide protective groups by
heating the reaction mixture in 80% aqueous CH3COOH at 80 ꢁC
provided the triol 27 in excellent yield. Final deprotection of
phthalimide was achieved by stirring the reaction mixture in
dard for 1H and CDCl3
DMSO-d6 (
C 39.5 ppm) as internal standard for 13C. Chemical shifts
are given in (ppm) and coupling constants (J) in hertz. IR spectra
(dC 77.0 ppm) or CD3OD (dC 49.0 ppm) or
d
d
were recorded on JASCO FT/IR-5300. Elemental analyses were
recorded on a Thermo Finnigan Flash EA 1112 analyzer. Mass
spectra were recorded on
spectrometer.
a
Shimadzu-LCMS-2010A mass
H2NNH2$H2O/MeOH provided the expected
L-arabino-C18-phytos-
phingosine22b,26 28 as a white solid (Scheme 5). A similar procedure
4.2. (4S,5R)-1-(2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
(tert-butyldimethylsilyloxy)-1(R)-ethan-1-ol (5)17 and (4S,5R)-
1-(2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-(tert-
butyldimethylsilyloxy)-1(S)-ethan-1-ol (6)18
can also be applied to compound 23 to synthesise
tosphingosine 18.
D-ribo-C18-phy-
Reduction with NaBH4:
A solution of ketone 4 (4.0 g,
13.3 mmol) in EtOH (40 mL) was added dropwise for a period of
1 h to a solution of NaBH4 (1.0 g, 26.6 mmol) in EtOH (80 mL) at
ꢀ78 ꢁC. After 2 h the reaction was quenched with saturated NH4Cl
solution (10 mL) and allowed it to warm to 25 ꢁC. The reaction
mixture was concentrated under reduced pressure to give a thick
semi solid. EtOAc (150 mL) and water (50 mL) were added and
the organic layer was separated and the aqueous layer was
extracted with EtOAc (3ꢂ50 mL). The combined organic layers
were dried over anhydrous Na2SO4, filtered and the solvent was
concentrated under reduced pressure. The crude product was
purified by column chromatography using EtOAc/hexane (3:97) to
give alcohol 6 (3.4 g, 85%) as a colourless liquid. Rf (10% EtOAc/
hexane) 0.58; IR (neat): 3562, 2986, 2934, 2858, 1645, 1464,
1371 cmꢀ1
. dH (400 MHz, CDCl3): 6.01e6.09 (m, H-5, 1H), 5.41 (dt,
J¼1.6, 17.2 Hz, H-6a, 1H), 5.28 (d, J¼10.4 Hz, H-6b, 1H), 4.68 (t,
J¼6.4 Hz, H-4, 1H), 4.05 (dd, J¼6.4, 8.8 Hz, H-3, 1H), 3.80 (dd,
J¼2.8, 9.6 Hz, H-1a, 1H), 3.61e3.70 (m, H-1b, H-2, 2H), 2.51 (d,
J¼5.2 Hz, 2-OH, 1H), 1.46 (s, CH3 (isopropylidine), 3H), 1.35 (s, CH3
(isopropylidine), 3H), 0.91 (s, SietBu, 9H), 0.08 (br s, Sie(CH3)2,
6H). dC (100 MHz, CDCl3): 134.1, 117.5, 108.7, 78.7, 77.4, 69.5, 64.3,
27.8, 25.8, 25.4, 18.3, ꢀ5.4, ꢀ5.5. Low-resolution MS (EI): m/z: 303
(Mþþ1). Anal. Calcd for C15H30O4Si: C, 59.56; H, 10.00. Found: C,
59.38, 10.12.
Scheme 5. Stereoselective synthesis of L-arabino-C18-phytosphingosine.
3. Conclusion
In conclusion, an efficient method for the stereoselective syn-
thesis of -ribo-C18-phytosphingosine involving a total of 13 steps
with an overall yield 6% and -arabino-C18-phytosphingosine in-
volving a total of 11 steps with an overall yield of 4.4% has been
developed starting from commercially inexpensive -fructose.
Further, the present methodology will also provide an access to the
synthesis of phytosphingosine analogues with variable alkyl chain
lengths. Further application of the key intermediates 5, 6, 23 and 24
in the total synthesis of biologically active natural products is under
progress.
Reduction with LiAlH(O-tBu)3: A solution of ketone 4 (1.5 g,
5.0 mmol) in EtOH (30 mL) was added dropwise for a period of
1 h to a solution of LiAlH(O-tBu)3 (3.2 g, 12.5 mmol) in EtOH
(40 mL) at ꢀ78 ꢁC. After stirring for 2 h at same temperature, the
reaction was quenched with 5% aqueous NaOH solution (1 mL)
and water (15 mL). After allowing the reaction mixture to warm
to 25 ꢁC it was filtered through a pad of Celite and the filter cake
was washed with MeOH/EtOAc (1:1, 400 mL). Evaporation of the
solvents under reduced pressure gave a thick syrup to which
EtOAc (100 mL) and water (40 mL) were added. The organic
D
L
D

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R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
layer was separated and the aqueous layer was extracted with
EtOAc (3ꢂ50 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure to give a 7:3 mixture of 5 and 6, respectively. The crude
product was purified by column chromatography using EtOAc/
hexane (3:97) to give alcohol 5 (735 mg) and 6 (315 mg) as
colourless liquids. Yield 70% (combined yield): 5: Rf (10% EtOAc/
hexane) 0.53; IR (neat): 3564, 2928, 2856, 1647, 1464,
4.5. (R)-2-(tert-Butyldimethylsilyloxy)-1-((4S,5S)-2,2-
dimethyl-5-((E)-tetradec-1-enyl)-1,3-dioxolan-4-yl)ethanol (9)
Compound 5 (0.35 g, 1.2 mmol) and 1-tetradecene (0.91 g,
4.6 mmol) were dissolved in CH2Cl2 (25 mL) at room temperature.
Grubbs’ II generation catalyst (4 mol %) was added to the solution
and then the reaction mixture was refluxed under nitrogen for 24 h.
After completion of reaction it was allowed to warm to 25 ꢁC and
the solvent was evaporated. Purification of the residue by column
chromatography with EtOAc/hexane: (4:96) afforded compound 9
(310 mg, 57%) as a colourless liquid. Rf (10% EtOAc/hexane) 0.63; IR
1379 cmꢀ1
. dH (400 MHz, CDCl3): 6.00e6.09 (m, H-5, 1H), 5.35
(d, J¼17.2 Hz, H-6a, 1H), 5.30 (d, J¼10.4 Hz, H-6b, 1H), 4.59 (t,
J¼7.2 Hz, H-4, 1H), 4.24 (dd, J¼3.2, 6.8 Hz, H-3, 1H), 3.59e3.63
(br s, H-1a, H-1b, H-2, 3H), 2.35 (d, J¼5.6 Hz, 2-OH, 1H), 1.53 (s,
CH3 (isopropylidine), 3H), 1.39 (s, CH3 (isopropylidine), 3H), 0.89
(s, SietBu, 9H), 0.06 (br s, Sie(CH3)2, 6H). dC (100 MHz, CDCl3):
134.4, 119.3, 108.6, 79.1, 77.3, 69.9, 64.1, 27.2, 25.8, 24.9, 18.3,
ꢀ5.4, ꢀ5.4. Low-resolution MS (EI): m/z: 303 (Mþþ1). Anal.
Calcd for C15H30O4Si: C, 59.56; H, 10.00. Found: C, 59.41; H,
10.22.
(neat): 3562, 2926, 2854, 1464, 1379 cmꢀ1
. dH (400 MHz, CDCl3):
5.75 (dt, J¼6.4, 15.2 Hz, H-6, 1H), 5.64 (dd, J¼8.4, 15.2 Hz, H-5, 1H),
4.55 (dd, J¼7.2, 8.4 Hz, H-4, 1H), 4.15 (dd, J¼3.2, 6.8 Hz, H-3, 1H),
3.57 (br s, H-2, H-1a, H-1b, 3H), 2.36 (d, J¼4.8 Hz, 2-OH, 1H),
2.01e2.05 (m, 7-CH2, 2H), 1.48 (s, CH3 (isopropylidine), 3H), 1.35 (s,
CH3 (isopropylidine), 3H), 1.22 (br s, 8 to 17-(CH2)10, 20H), 0.86 (s,
SietBu, 9H), 0.84 (t, J¼6.8 Hz,18-CH3, 3H), 0.03 (s, Sie(CH3)2, 6H). dC
(100 MHz, CDCl3): 137.2,125.6,108.1, 78.9, 76.9, 70.1, 64.1, 32.2, 31.8,
29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 28.9, 27.1, 25.8, 24.8, 22.6, 18.2, 14.0,
ꢀ5.4. Low-resolution MS (EI): m/z: 471 (Mþþ1). Anal. Calcd for
C27H54O4Si: C, 68.88; H, 11.56. Found: C, 68.75; H, 11.48.
4.3. 2-((R)-2-(tert-Butyldimethylsilyloxy)-2-((4R,5R)-2,2-
dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethyl)isoindoline-1,3-
dione (7)19
To a stirred solution of alcohol 5 (300 mg, 1.0 mmol), Ph3P
(782 mg, 3.0 mmol) and phthalimide (176 mg, 1.2 mmol) in dry THF
(8 mL) at 0 ꢁC was injected DIAD (602 mg, 3.0 mmol) dropwise for
a period of 10 min. The reaction mixture was allowed to stir at 25 ꢁC
for 6 h. After completion of reaction (by TLC) the mixture was
concentrated and the product was purified by column chroma-
tography using EtOAc/hexane (1:9) to give compound 7 (322 mg,
75%) as colourless needles. Rf (10% EtOAc/hexane) 0.39; IR (KBr):
4.6. (S)-2-(tert-Butyldimethylsilyloxy)-1-((4S,5S)-2,2-
dimethyl-5-((E)-tetradec-1-enyl)-1,3-dioxolan-4-yl)ethanol
(10)
Compound 10 was synthesised following the procedure de-
scribed for compound 9. Yield 60%. Rf (10% EtOAc/hexane) 0.67; IR
(neat): 3560, 2928, 2856, 1464, 1369 cmꢀ1
. dH (400 MHz, CDCl3):
5.80 (dt, J¼6.8, 15.2 Hz, H-6, 1H), 5.60 (tdd, J¼1.5, 7.6, 16.0 Hz, H-5,
1H), 4.63 (t, J¼6.8 Hz, H-4, 1H), 4.00 (dd, J¼6.4, 8.8 Hz, H-3, 1H),
3.78e3.82 (m, H-1a, 1H), 3.67e3.70 (m, H-2, H-1b, 2H), 2.46 (d,
J¼4.4 Hz, 2-OH, 1H), 2.03e2.10 (m, 7-CH2, 2H), 1.44 (s, CH3 (iso-
propylidine), 3H), 1.36e1.40 (m, 8-CH2, 2H), 1.33 (s, CH3 (iso-
propylidine), 3H),1.24e1.29 (m, 9 to 17-(CH2)9,18H), 0.90 (s, SietBu,
9H), 0.87 (t, J¼7.2 Hz, 18-CH3, 3H), 0.98 (s, Sie(CH3)2, 6H). dC
(100 MHz, CDCl3): 135.5, 125.3, 108.3, 78.9, 77.5, 69.6, 64.4, 32.3,
31.9, 29.7, 29.6, 29.5, 29.3, 29.2, 29.0, 27.9, 25.8, 25.4, 22.7, 18.3, 14.1,
ꢀ5.3, ꢀ5.4. Low-resolution MS (EI): m/z: 471 (Mþþ1). Anal. Calcd
for C27H54O4Si: C, 68.59; H, 11.94. Found: C, 68.71; H, 11.68.
2984, 2932, 2854, 1772, 1718, 1616, 1469, 1394 cmꢀ1
. dH (400 MHz,
CDCl3): 7.83 (dd, J¼3.6, 5.6 Hz, phthalimide AreH, 2H), 7.70 (dd,
J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 5.99e6.08 (m, H-5, 1H), 5.33
(d, J¼16.0 Hz, H-6a, 1H), 5.32 (d, J¼11.6 Hz, H-6b, 1H), 4.58 (dd,
J¼6.0, 8.4 Hz, H-4, 1H), 4.14e4.20 (m, H-2, 1H), 4.08 (dd, J¼5.6,
8.0 Hz, H-3, 1H), 3.78 (dd, J¼3.2, 14.0 Hz, H-1a, 1H), 3.71 (dd, J¼3.6,
14.0 Hz, H-1b, 1H), 1.49 (s, CH3 (isopropylidine), 3H), 1.34 (s, CH3
(isopropylidine), 3H), 0.76 (s, SietBu, 9H), 0.04 (s, SieCH3, 3H),
ꢀ0.13 (s, SieCH3, 3H). dC (100 MHz, CDCl3): 168.3, 134.3, 133.9,
132.1, 123.1, 119.3, 108.5, 80.1, 78.7, 69.0, 40.1, 27.9, 25.6, 25.4, 18.1,
ꢀ4.4, ꢀ4.8. Low-resolution MS (EI): m/z: 432 (Mþþ1). Anal. Calcd
for C23H33NO5Si: C, 64.01; H, 7.71; N, 3.25. Found: C, 64.12; H, 7.62;
N, 3.36.
4.7. (R)-2-(tert-Butyldimethylsilyloxy)-1-((4S,5S)-2,2-
dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)ethanol (11)20
4.4. 2-((S)-2-(tert-Butyldimethylsilyloxy)-2-((4R,5R)-2,2-
dimethyl-5-vinyl-1,3-dioxolan-4-yl)ethyl)isoindoline-1,3-
dione (8)19
To a stirred solution of compound 9 (140 mg, 0.3 mmol) in EtOAc
(5 mL) was added 10% palladium on charcoal (30 mg). Then the
mixture was degassed and stirred under the hydrogen atmosphere
at 25 ꢁC overnight. After completion of the reaction (by TLC) the
suspension was filtered through a pad of Celite and concentrated.
The crude product was purified by column chromatography using
hexane/EtOAc (19:1) to afford compound 11 (120 mg, 85%) as
a colourless liquid. Rf (5% EtOAc/hexane) 0.54; IR (neat): 3468, 2924,
Compound 8 was synthesised following the procedure de-
scribed for compound 7 as a colourless liquid. Yield 75%. Rf (10%
EtOAc/hexane) 0.43; IR (neat): 2986, 2932, 2858, 1774, 1718, 1616,
1469, 1394 cmꢀ1
.
dH (400 MHz, CDCl3): 7.82 (dd, J¼3.2, 5.6 Hz,
phthalimide AreH, 2H), 7.70 (dd, J¼3.2, 5.6 Hz, phthalimide AreH,
2H), 6.06e6.15 (m, H-5, 1H), 5.38 (d, J¼16.8 Hz, H-6a, 1H), 5.31 (d,
J¼10.4 Hz, H-6b, 1H), 4.64 (t, J¼7.2 Hz, H-4, 1H), 4.18e4.23, (m, H-2,
1H), 4.13 (dd, J¼4.8, 6.4 Hz, H-3, 1H), 3.87 (dd, J¼6.8, 14.4 Hz, H-1a,
1H), 3.76 (dd, J¼6.8, 14.4 Hz, H-1b, 1H), 1.27 (s, CH3 (isopropylidine),
3H), 1.25 (s, CH3 (isopropylidine), 3H), 0.83 (s, SietBu, 9H), 0.03 (s,
SieCH3, 3H), ꢀ0.02 (s, SieCH3, 3H). dC (100 MHz, CDCl3): 168.3,
134.5,133.8,132.1,123.0,119.0,108.3, 80.3, 79.1, 68.2, 41.4, 27.0, 25.7,
24.6, 17.8, ꢀ4.3, ꢀ4.5. Low-resolution MS (EI): m/z: 432 (Mþþ1).
Anal. Calcd for C23H33NO5Si: C, 64.01; H, 7.71; N, 3.25. Found: C,
64.12; H, 7.68; N, 3.36.
2854, 1464, 1379 cmꢀ1
. dH (500 MHz, CDCl3): 4.14e4.18 (m, H-4,
1H), 4.10 (dd, J¼3.0, 6.5 Hz, H-3, 1H), 3.65 (dd, J¼3.0, 6.0 Hz, H-2,
1H), 3.62 (dd, J¼6.0, 9.5 Hz, H-1a, 1H), 3.57 (dd, J¼6.0, 9.5 Hz, H-1b,
1H), 2.31 (d, J¼5.5 Hz, 2-OH, 1H), 1.73e1.77 (m, 5-CHa, 1H),
1.53e1.54 (m, 5-CHb, 1H), 1.48 (s, CH3 (isopropylidine), 3H), 1.36 (s,
CH3 (isopropylidine), 3H), 1.25 (br m, 6 to 17-(CH2)9, 24H), 0.89 (s,
SietBu, 9H), 0.87 (t, J¼5.6 Hz, 18-CH3, 3H), 0.06 (s, Sie(CH3)2, 6H). dC
(125 MHz, CDCl3): 107.6, 77.5, 76.4, 69.9, 64.5, 31.9, 29.9, 29.7, 29.6,
29.6, 29.5, 29.5, 29.3, 27.2, 26.7, 25.8, 25.1, 22.6, 18.3, 14.0, ꢀ5.3.
Low-resolution MS (EI): m/z: 473 (Mþþ1). Anal. Calcd for
C27H56O4Si: C, 68.59; H, 11.94. Found: C, 68.51; H, 11.89.

R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
9287
4.8. (S)-2-(tert-Butyldimethylsilyloxy)-1-((4S,5S)-2,2-
dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)ethanol (12)
HCI (3 mL) was added to the mixture and stirred at 25 ꢁC for an-
other 2 h. Removal of the solvents under reduced pressure provided
a viscous residue. To the residue were added EtOAc (20 mL) and
water (10 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (3ꢂ20 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated. Col-
umn chromatography of the crude product using CH2Cl2/MeOH
(19:1) provided compound 15 (74 mg, 85%) as a white solid. Rf
(hexane/EtOAc/MeOH 10:10:1) 0.44; IR (KBr): 3504, 3383, 3225,
Compound 12 was synthesised following the procedure de-
scribed for compound 11. Yield 87%. Rf (5% EtOAc/hexane) 0.61; IR
(neat): 3562, 2926, 2854, 1464, 1379 cmꢀ1
. dH (400 MHz, CDCl3):
4.13e4.17 (m, H-4, 1H), 3.89 (dd, J¼5.6, 8.8 Hz, H-3, 1H), 3.81 (dd,
J¼5.6, 12.4 Hz, H-1a, 1H), 3.62e3.69 (m, H-2, H-1b, 2H), 2.57 (d,
J¼4.8 Hz, 2-OH, 1H), 1.68e1.75 (m, 6-CHa, 1H), 1.49e1.58 (m, 5-CH2,
2H), 1.38 (s, CH3 (isopropylidine), 3H), 1.30 (s, CH3 (isopropylidine),
3H),1.24 (br s, 7 to 17-(CH2)11, 6-CHb, 23H), 0.90 (s, SietBu, 9H), 0.86
(t, J¼6.4 Hz, 18-CH3, 3H), 0.08 (s, Sie(CH3)2, 6H). dC (100 MHz,
CDCl3): 107.8, 78.2, 77.1, 69.2, 64.6, 31.9, 29.9, 29.7, 29.6, 29.6, 29.6,
29.5, 29.3, 28.3, 26.4, 25.8, 25.7, 22.6, 18.3, 14.1, ꢀ5.3, ꢀ5.4. Low-
resolution MS (EI): m/z: 473 (Mþþ1). Anal. Calcd for C27H56O4Si:
C, 68.88; H, 11.56. Found: C, 68.45; H, 11.89.
2918, 2851, 1471, 1439, 1359 cmꢀ1
. dH (500 MHz, DMSO-d6): 5.03 (t,
J¼5.5 Hz, 1-OH, 1H), 4.93 (d, J¼7.0 Hz, 3-OH, 1H), 4.73 (dt, J¼1.5,
6.5 Hz, H-2, 1H), 4.49 (d, J¼6.5 Hz, 4-OH, 1H), 3.59e3.67 (m, H-1a,
1H), 3.33e3.36 (m, H-1b, H-3, H-4, 3H), 3.17 (s, eSO2CH3, 3H),
1.65e1.69 (m, H-5a, 1H), 1.43e1.45 (m, H-5b, 1H), 1.24 (br s, 6 to 17-
(CH2)12, 24H), 0.85 (t, J¼7 Hz, 18-CH3, 3H). dC (125 MHz, DMSO-d6):
83.1, 71.9, 69.6, 60.6, 38.3, 33.9, 31.7, 29.7, 29.6, 29.5, 29.4, 29.1, 25.2,
22.5, 14.4. Low-resolution MS (EI): m/z: 397 (Mþþ1). Anal. Calcd for
C19H40O6S: C, 57.54; H, 10.17. Found: C, 57.71; H, 10.08.
4.9. (R)-2-(tert-Butyldimethylsilyloxy)-1-((4R,5S)-2,2-
dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)ethyl
methanesulfonate (13)20
4.12. (2S,3R,4R)-1,3,4-Trihydroxyoctadecan-2-yl
methanesulfonate (16)
To a stirred solution of compound 11 (90 mg, 0.2 mmol) in
CH2Cl2 (2.5 mL) were added pyridine (0.57 mL) and meth-
Compound 16 was synthesised following the procedure de-
scribed for compound 15. Yield 87%. White solid. Rf (hexane/EtOAc/
MeOH 10:10:1) 0.39; IR (KBr): 3526, 3402, 2920, 2851, 1473, 1431,
anesulfonyl chloride (38 m
L, 0.5 mmol), respectively, at 25 ꢁC. The
resultant mixture was stirred for 4 h, then was diluted with CH2Cl2
(40 mL). The solution was washed with saturated aqueous CuSO4
solution (2ꢂ10 mL) to remove the pyridine. CH2Cl2 was dried under
anhydrous Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (EtOAc/hexane (1:40)) of crude afforded
compound 13 (95 mg, 90%) as a viscous oil. Rf (5% EtOAc/hexane)
1350 cmꢀ1
.
dH (400 MHz, CDCl3): 4.90 (dt, J¼4.5, 8.5 Hz, H-2, 1H),
4.06e4.09 (m, H-3,1H), 3.91e3.97 (m, H-1a and H1b, 2H), 3.74e3.77
(m, H-4, 1H), 3.13 (s, eSO2CH3, 3H), 2.98e3.02 (m, eOH, 2H), 2.43
(br s, eOH, 1H), 1.47e1.51 (m, 5-CH2, 2H), 1.25e1.30 (br m, 6 to 17-
(CH2)12, 24H), 0.87 (t, J¼7.0 Hz, 18-CH3, 3H). dC (100 MHz, CDCl3):
82.5, 74.9, 72.4, 61.2, 38.6, 32.7, 31.9, 29.7, 29.6, 29.5, 29.5, 29.5, 29.3,
25.6, 22.6, 14.1. Low-resolution MS (EI): m/z: 397 (Mþþ1). Anal.
Calcd for C19H40O6S: C, 57.54; H, 10.17. Found: C, 57.45; H, 10.21.
0.37; IR (neat): 2926, 2858, 1647, 1460, 1363, 1255 cmꢀ1
. dH
(500 MHz, CDCl3): 4.67 (dt, J¼5.5, 6.5 Hz, H-2, 1H), 4.25 (t, J¼6.0 Hz,
H-3, 1H), 4.10e4.14 (m, H-4, 1H), 3.88 (dd, J¼5.5, 11.0 Hz, H-1a, 1H),
3.82 (dd, J¼5.5, 11.5 Hz, H-1b, 1H), 3.08 (s, 3H), 1.48e1.56 (m, 5-CH2,
2H), 1.45 (s, CH3 (isopropylidine), 3H), 1.34 (s, CH3 (isopropylidine),
3H), 1.24 (br s, 6 to 17-(CH2)12, 24H), 0.88 (s, SietBu, 9H), 0.87 (t,
J¼7.0 Hz, 18-CH3, 3H), 0.08 (s, SieCH3, 3H), 0.07 (s, SieCH3, 3H). dC
(125 MHz, CDCl3): 108.2, 80.7, 77.1, 75.9, 63.0, 38.9, 31.9, 29.7, 29.6,
29.6, 29.6, 29.5, 29.5, 29.5, 29.3, 27.7, 26.1, 25.9, 25.8, 22.6, 18.2, 14.1,
ꢀ5.4, ꢀ5.5. Low-resolution MS (EI): m/z: 551 (Mþþ1). Anal. Calcd
for C28H58O6SSi: C, 61.04; H, 10.61. Found: C, 61.15; H, 10.52.
4.13. (2S,3S,4R)-2-Azidooctadecane-1,3,4-triol (17)13g,23
To a stirred solution of compound 15 (60 mg, 0.15 mmol) in dry
DMF, sodium azide (50 mg, 0.75 mmol) was added. The resultant
mixture was stirred for 48 h at 90 ꢁC. The reaction mixture was
brought to 25 ꢁC and CH2Cl2 (5 mL) was added. The excess amount
of sodium azide was filtered and the filtrate was concentrated to
give a thick gummy residue, which was purified by column chro-
matography using CH2Cl2/MeOH (19:1) to afford compound 17
(42 mg, 80%) as a white solid. Rf (hexane/EtOAc/MeOH 10:10:1)
4.10. (S)-2-(tert-Butyldimethylsilyloxy)-1-((4R,5S)-2,2-
dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)ethyl
methanesulfonate (14)
0.62; IR (KBr): 3396, 2918, 2849, 2118, 1738, 1464 cmꢀ1
. dH
(500 MHz, CDCl3): 3.99 (dd, J¼5.5, 11.5 Hz, H-1a, 1H), 3.87e3.89 (m,
H-1b, 1H), 3.76e3.81 (m, H-3, H-4, 2H), 3.66 (dd, J¼5.0,10.0 Hz, H-2,
1H), 2.84 (br s, eOH, 1H), 2.67 (br s, eOH, 1H), 2.35 (br s, eOH, 1H),
1.48e1.57 (m, 5-CH2, 2H), 1.25e1.33 (br m, 6 to 17-(CH2)12, 24H),
0.87 (t, J¼7 Hz, 18-CH3, 3H). dC (125 MHz, CDCl3): 74.7, 72.5, 63.1,
61.7, 32.0, 31.9, 29.7, 29.6, 29.5, 29.3, 25.7, 22.6, 14.0. Low-resolution
MS (EI): m/z: 344 (Mþþ1). Anal. Calcd for C18H37N3O3: C, 62.94; H,
10.86; N, 12.23. Found: C, 62.85; H, 10.76; N, 12.31.
Compound 14 was synthesised following the procedure de-
scribed for compound 13. Yield 88%. Rf (5% EtOAc/hexane) 0.39; IR
(neat): 2926, 2854, 1464, 1361, 1255, 1179, 1109 cmꢀ1
. dH (500 MHz,
CDCl3): 4.66 (td, J¼2.0, 6.0 Hz, H-2, 1H), 4.24 (t, J¼6.0 Hz, H-3, 1H),
4.17e4.21 (m, H-4, 1H), 3.96 (dd, J¼2.0, 12.0 Hz, H-1a, 1H), 3.87 (dd,
J¼6.0, 12.0 Hz, H-1b, 1H), 3.09 (s, SO2CH3, 3H), 1.55e1.65 (m, 5-CH2,
2H), 1.40 (s, CH3 (isopropylidine), 3H), 1.31 (s, CH3 (isopropylidine),
3H), 1.24 (br s, 6 to 17-(CH2)12, 24H), 0.89 (s, SietBu, 9H), 0.86 (t,
J¼7.0 Hz, 18-CH3, 3H), 0.08 (s, SieCH3, 3H), 0.07 (s, SieCH3, 3H). dC
(125 MHz, CDCl3): 108.1, 82.6, 77.2, 76.1, 62.9, 39.1, 29.7, 29.6, 29.6,
29.5, 29.4, 29.4, 29.3, 27.3, 26.6, 25.8, 25.1, 22.6, 18.3, 14.1, ꢀ5.4,
ꢀ5.5. Low-resolution MS (EI): m/z: 551 (Mþþ1). Anal. Calcd for
C28H58O6SSi: C, 61.04; H, 10.61. Found: C, 61.15; H, 10.58.
4.14. (2S,3S,4R)-2-Aminooctadecane-1,3,4-triol (D-ribo-C18-
Phytosphingosine) (18)22
To a stirred solution of compound 17 (40 mg, 0.1 mmol) in
MeOH (3 mL) was added 10% palladium on charcoal (15 mg). Then
the mixture was degassed and stirred under the hydrogen atmo-
sphere at 25 ꢁC for 3 h. After completion of the reaction (by TLC) the
suspension was filtered through a pad of Celite and concentrated.
The crude product was purified by flash column chromatography
using CH2Cl2/MeOH/NH4OH (80:20:1) to afford compound 18
(32 mg, 87%) as a white solid. Rf (CH2Cl2/MeOH/NH4OH 85:15:1)
4.11. (2R,3R,4R)-1,3,4-Trihydroxyoctadecan-2-yl
methanesulfonate (15)13g,23
To a stirred solution of 13 (120 mg, 0.2 mmol) in methanol
(2 mL) was added p-toluenesulfonic acid (63 mg, 0.3 mmol). The
resultant mixture was stirred at 25 ꢁC for 2 h. Then 20% aqueous
0.15; IR (KBr): 3369, 2918, 2851, 1469 cmꢀ1
. dH (500 MHz, CD3OD):

9288
R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
3.79 (dd, J¼4.0, 11.0 Hz, H-1a, 1H), 3.59 (dd, J¼7.0, 11.0 Hz, H-1b, 1H),
3.51e3.54 (m, H-4, 1H), 3.37 (dd, J¼5.5, 8.0 Hz, H-3, 1H), 3.00e3.03
(m, H-2, 1H), 1.74e1.78 (m, 5-CHa, 1H), 1.56e1.58 (m, 5-CHb, 1H),
1.30e1.37 (br m, 6 to 17-(CH2)12, 24H), 0.91 (t, J¼7.0 Hz,18-CH3, 3H).
dC (125 MHz, CD3OD): 74.8, 73.0, 62.3, 54.5, 33.4, 31.6, 29.5, 29.4,
29.3, 29.0, 25.1, 22.3,13.0. Low-resolution MS (EI): m/z: 318 (Mþþ1).
Anal. Calcd for C18H39NO3: C, 68.09; H, 12.38; N, 4.41. Found: C,
68.15; H, 12.31; N, 4.38.
4.18. 2-((S)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)-2-(methoxymethyloxy)ethyl)isoindoline-1,3-dione (23)
and 2-((R)-1-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
2-(methoxymethyloxy)ethyl)isoindoline-1,3-dione (24)
To a stirred solution of diastereomeric alcohol mixture 21 and 22
(390 mg, 1.7 mmol), Ph3P (1.3 g, 5.0 mmol) and phthalimide
(296 mg, 2.0 mmol) in dry THF (25 mL) at 0 ꢁC was injected DIAD
(1.0 g, 5.0 mmol) dropwise for a period of 20 min. The reaction
mixture was allowed to stir at 25 ꢁC for 6 h. After completion of
reaction (by TLC) the mixture was concentrated and the product
was purified by column chromatography using EtOAc/hexane to
give compounds 23 (110 mg) and 24 (256 mg) as semisolids in 60%
combined yield. Compound 23: Rf (20% EtOAc/hexane) 0.58; IR
4.15. (2S,3S,4R)-2-Azidooctadecane-1,3,4-triol (17) and
(2R,3S,4R)-2-azido-1,3,4-octadecane triol (19) (mixture)
Compounds 17 and 19 were synthesised following the pro-
cedure described for compound 17. Yield 81% (1:1). White solid. Rf
(hexane/EtOAc/MeOH 10:10:1) 0.62; IR (KBr): 3354, 2918, 2851,
(neat): 2988, 2934, 1776, 1714, 1614, 1467, 1383 cmꢀ1
. dH (400 MHz,
2139, 2104, 1471, 1354 cmꢀ1
.
dC (100 MHz, CDCl3): 74.6, 74.3, 72.6,
CDCl3): 7.84 (dd, J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 7.71 (dd,
J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 5.84e5.92 (m, H-5, 1H), 5.48
(d, J¼16.8 Hz, H-6a, 1H), 5.33 (d, J¼10.4 Hz, H-6b, 1H), 4.51e4.59 (m,
H-2, eOCH2Oe, 3H), 4.32 (dd, H-3, J¼7.2, 9.6 Hz, 1H), 4.27e4.34 (m,
H-3, H-4, 2H), 4.14 (dd, J¼9.6, 10.4 Hz, H-1a, 1H), 3.80 (dd, J¼5.2,
10.4 Hz, H-1b, 1H), 3.24 (s, eOCH3, 3H), 1.35 (s, CH3 (isopropylidine),
3H), 1.32 (s, CH3 (isopropylidine), 3H). dC (100 MHz, CDCl3): 168.3,
135.2, 133.9, 131.9, 123.5, 119.8, 109.6, 96.4, 80.8, 78.1, 64.3, 55.4,
53.6, 27.0, 26.8. Low-resolution MS (EI): m/z: 362 (Mþþ1). Anal.
Calcd for C19H23NO6: C, 63.15; H, 6.41; N, 3.88. Found: C, 63.25; H,
6.37; N, 3.81. Compound 24: Rf (20% EtOAc/hexane) 0.52; IR (neat):
72.5, 63.8, 63.1, 62.8, 61.7, 33.4, 31.9, 29.7, 29.6, 29.3, 25.7, 25.5, 22.7,
14.1, 14.0. Low-resolution MS (EI): m/z: 344 (Mþþ1). Anal. Calcd for
C18H37N3O3: C, 68.09; H, 12.38; N, 12.23. Found: C, 68.12; H, 12.47;
N, 12.45.
4.16. 1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
(methoxymethoxy)ethanone (20)
The crude oily residue (800 mg, 4.3 mmol) obtained after zinc-
mediated fragmentation reaction of iodide 3 was dissolved in
dichloromethane (30 mL) and cooled to 0 ꢁC. To this N,N-diiso-
propylethylamine (5.5 g, 43.0 mmol) was added followed by
methoxymethylchloride (3.5 g, 43.0 mmol) dropwise over 30 min.
The mixture was allowed to warm to 25 ꢁC and stirred for 24 h. The
solvent was evaporated and the residue was diluted with EtOAc
(50 mL). The resultant solution was washed with water (30 mL) and
the aqueous layer was extracted with EtOAc (2ꢂ30 mL). The or-
ganic layers were combined, dried over anhydrous Na2SO4, and
concentrated. The crude residue was purified by flash column
chromatography using EtOAc/hexane (1:24) to afford pure ketone
20 (485 mg, 13.8 mmol) as a pale yellow liquid. Yield (49% from 3).
Rf (20% EtOAc/hexane) 0.52; IR (neat): 3086, 2989, 2895, 1738, 1614,
2988, 2935, 2891, 1776, 1714 cmꢀ1
; dH (400 MHz, CDCl3): 7.81 (dd,
J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 7.71 (dd, J¼3.2, 5.6 Hz,
phthalimide AreH, 2H), 5.57e5.65 (m, H-5, 1H), 4.96 (d, J¼16.8 Hz,
H-6a, 1H), 4.76 (d, J¼10.4 Hz, H-6b, 1H), 4.50e4.57 (m, H-2,
eOCH2Oe, 3H), 4.31 (dd, J¼4.4, 9.6 Hz, H-3, 1H), 4.29 (dd, J¼8.0,
9.6 Hz, H-1a, 1H), 4.18 (t, J¼8.4 Hz, H-4, 1H), 4.00 (dd, J¼4.0, 10.4 Hz,
H-1b, 1H), 3.22 (s, OeCH3, 3H), 1.43 (s, CH3 (isopropylidine), 3H),
1.41 (s, CH3 (isopropylidine), 3H). dC (100 MHz, CDCl3): 168.4, 134.9,
134.0, 131.5, 123.3, 119.1, 109.8, 96.4, 82.1, 76.2, 64.9, 55.3, 53.6, 27.0,
26.9. Low-resolution MS (EI): m/z: 362 (Mþþ1). Anal. Calcd for
C19H23NO6: C, 63.15; H, 6.41; N, 3.81. Found: C, 63.31; H, 6.38; N,
3.82.
1456, 1377 cmꢀ1
. dH (400 MHz, CDCl3): 5.79e5.88 (m, H-5, 1H), 5.35
(d, J¼17.2 Hz, H-6a, 1H), 5.23 (d, J¼10.4 Hz, H-6b, 1H), 4.62 (s,
eOCH2Oe, 2H), 4.44 (m, carbonyleCH2Oe, 2H), 4.39 (t, J¼7.6 Hz, H-
4, 1H), 4.13 (d, J¼8.0 Hz, H-2, 1H), 3.31 (s, eOCH3, 3H), 1.39 (s, CH3
(isopropylidine), 3H), 1.38 (s, CH3 (isopropylidine), 3H). dC
(100 MHz, CDCl3): 204.4, 134.3, 118.7, 111.0, 96.4, 83.5, 79.1, 69.6,
55.7, 26.7, 26.2. Low-resolution MS (EI): m/z: 231 (Mþþ1). Anal.
Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.19; H, 7.91.
4.19. 2-((R)-1-((4S,5S)-2,2-Dimethyl-5-((E)-tetradec-1-enyl)-
1,3-dioxolan-4-yl)-2-(methoxymethyloxy)ethyl)isoindoline-
1,3-dione (25)
Compound 24 (200 mg, 0.55 mmol) and 1-tetradecene (430 mg,
2.2 mmol) were dissolved in CH2Cl2 (20 mL) at room temperature.
Grubbs’ II generation catalyst (4 mol %) was added to the solution
and then the reaction mixture was refluxed under nitrogen for 24 h.
After cooling the reaction mixture was concentrated and purified
by column chromatography with EtOAc/hexane (1:9) to afford
compound 25 (220 mg, 75%) as a colourless liquid. Rf (20% EtOAc/
hexane) 0.64; IR (neat): 3053, 2926, 2847, 1776, 1714, 1614, 1467,
4.17. (R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
(methoxymethyloxy)ethanol (21) and (S)-1-((4S,5S)-2,2-
dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-(methoxymethyloxy)
ethanol (22)
To a solution of LiAlH(O-tBu)3 (1.2 g, 4.7 mmol) in EtOH (18 mL)
at ꢀ78 ꢁC was added a solution of ketone 20 (540 mg, 2.3 mmol) in
EtOH (18 mL) dropwise for a period of 45 min. After stirring for 2 h
at same temperature, the reaction was quenched with 5% aqueous
NaOH solution (0.5 mL) and water (5 mL). After allowing the re-
action mixture to warm to 25 ꢁC it was filtered through a pad of
Celite and filter cake was washed with MeOH/EtOAc (1:1, 200 mL).
Evaporation of the solvents under reduced pressure gave thick
syrup to which EtOAc (50 mL) and water (25 mL) were added. The
organic layer was separated and the aqueous layer was extracted
with EtOAc (3ꢂ30 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, concentrated under reduced
pressure to give compounds 21 and 22 (450 mg, 83%) as a 7:3 di-
astereomeric mixture, respectively.
1385 cmꢀ1
.
dH (400 MHz, CDCl3): 7.81 (dd, J¼3.2, 5.6 Hz, phthali-
mide AreH, 2H), 7.70 (dd, J¼3.2, 5.6 Hz, phthalimide AreH, 2H),
5.43 (dt, J¼6.4, 15.6 Hz, H-6, 1H), 5.23 (dd, J¼7.6, 15.6 Hz, H-5, 1H),
4.58 (d, J¼6.4 Hz, eOCHaOe, 1H), 4.54 (dd, J¼3.6, 10.8 Hz, H-2, 1H),
4.52 (d, J¼6.4 Hz, eOCHbOe, 1H), 4.31 (t, J¼10.8 Hz, H-1a, 1H), 4.25
(dd, J¼8.4, 10.0 Hz, H-3, 1H), 4.15 (t, J¼8.4 Hz, H-4, 1H), 4.01 (dd,
J¼4.0, 10.4 Hz, H-1b, 1H), 3.22 (s, eOCH3, 3H), 1.43 (s, CH3 (iso-
propylidine), 3H), 1.40 (s, CH3 (isopropylidine), 3H), 0.92e1.33 (br
m, 8 to 17-(CH2)10, 20H), 0.87 (t, J¼5.2 Hz, 18-CH3, 3H), 0.65e0.79
(m, 7-CH2, 2H). dC (100 MHz, CDCl3): 168.3, 137.4, 134.0, 131.7, 125.9,
123.2, 109.3, 96.4, 82.1, 75.7, 65.0, 55.3, 53.6, 31.9, 31.7, 29.6, 29.4,
29.3, 29.3, 29.1, 28.2, 27.1, 26.9, 22.6, 14.1. Low-resolution MS (EI):
m/z: 529 (Mþ). Anal. Calcd for C31H47NO6: C, 70.29; H, 8.94; N, 2.64.
Found: C, 70.15; H, 8.89; N, 2.71.

R.S. Perali et al. / Tetrahedron 67 (2011) 9283e9290
9289
4.20. 2-((R)-1-(4S,5S)-2,2-(Dimethyl-5-tetradecyl-1,3-
dioxolan-4-yl)-2-(methoxymethyloxy)ethyl)isoindoline-1,3-
dione (26)
Anal. Calcd for C18H39NO3: C, 68.09; H, 12.38; N, 4.41. Found: C,
68.15; H, 12.31; N, 4.38.
Acknowledgements
To a stirred solution of compound 25 (200 mg, 0.38 mmol) in
MeOH (6 mL) was added 10% palladium on charcoal (40 mg). Then
the mixture was degassed and stirred under the hydrogen atmo-
sphere at 25 ꢁC for overnight. After completion of the reaction (by
TLC) the suspension was filtered through a pad of Celite and con-
centrated to give compound 26 (190 mg, 95%) as a colourless liquid.
Rf (10% EtOAc/toluene) 0.53; IR (neat): 2926, 2854, 1776, 1716, 1467,
This work was supported by the Department of Science and
Technology (DST) FAST track project grant No. SR/FTP/SC-64/2007.
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.003.
1383 cmꢀ1
.
dH (400 MHz, CDCl3): 7.85 (dd, J¼3.2, 5.6 Hz, phthali-
mide AreH, 2H), 7.73 (dd, J¼3.2, 5.6 Hz, phthalimide AreH, 2H),
4.57 (d, J¼6.8 Hz, eOCHaOe, 1H), 4.53e4.56 (m, H-2, 1H), 4.52 (d,
J¼6.4 Hz, eOCHbOe, 1H), 4.31 (t, J¼10.4 Hz, H-1a, 1H), 4.21 (dd,
J¼7.2, 9.6 Hz, H-3, 1H), 4.02 (dd, J¼4.4, 10.4 Hz, H-1b, 1H), 3.89 (td,
J¼2.8, 7.6 Hz, H-4, 1H), 3.22 (s, eOCH3, 3H), 1.43 (s, CH3 (iso-
propylidine), 3H), 1.40 (s, CH3 (isopropylidine), 3H), 1.09e1.25 (m, 5
to 17-(CH2)13, 26H), 0.89 (t, J¼6.8 Hz, 18-CH3, 3H). dC (100 MHz,
CDCl3): 168.4, 134.2, 131.5, 123.4, 109.2, 96.4, 80.0, 64.7, 55.3, 55.4,
33.7, 31.9, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 27.4, 27.1, 25.4, 22.6,
14.1. Low-resolution MS (EI): m/z: 531 (Mþ). Anal. Calcd for
C31H49NO6: C, 70.02; H, 9.29; N, 2.63. Found: C, 70.12; H, 9.23; N,
2.55.
References and notes
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CDCl3): 7.88 (dd, J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 7.78 (dd,
J¼3.2, 5.6 Hz, phthalimide AreH, 2H), 4.48e4.52 (m, H-2, 1H), 4.24
(dd, J¼4.4, 12.0 Hz, H-1a, 1H), 4.14 (dd, J¼6.0, 12.0 Hz, H-1b, 1H),
4.06 (d, J¼7.2 Hz, H-3, 1H), 3.50e3.5 (m, H-4, 1H), 1.62e1.65 (m, 5-
Ha, 1H), 1.50e1.54 (m, 5-Hb, 1H), 1.27 (br s, 6 to 17-(CH2)12, 24H),
0.89 (t, J¼6.8 Hz, 18-CH3, 3H). dC (100 MHz, CDCl3): 169.2, 134.5,
131.5, 123.7, 72.3, 71.0, 61.5, 54.9, 33.6, 31.9, 29.7, 29.6, 29.6, 29.5,
29.5, 29.3, 25.8, 22.7, 14.1. Low-resolution MS (EI): m/z: 448
(Mþþ1). Anal. Calcd for C26H41NO5: C, 69.77; H, 9.23, N; 3.13.
Found: C, 69.85; H, 9.18; N, 3.25.
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-
lyxose: (n) Morita, M.; Sawa, E.; Yamaji, K.; Sakai, T.; Natori, T.; Koezuka, Y.;
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4.22. (2R,3S,4R)-2-Aminooctadecane-1,3,4-triol (L-arabino-
C18-phytosphingosine) (28)
To a stirred solution of compound 27 (40 mg, 0.10 mmol) in dry
CH3OH (3 mL) was added hydrazine hydrate (9.0 mg, 0.18 mmol)
at 25 ꢁC. The resulting mixture was stirred for 24 h. After com-
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pressure. The obtained residue was purified by flash column
chromatography using CHCl3/MeOH/NH4OH (85:15:1) to give
compound 28 (23 mg, 81%) as a white solid. Rf (CHCl3/MeOH/
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NH4OH (80:20:1)) 0.48; IR (KBr): 3462, 2924, 2854, 1466 cmꢀ1
. dH
(400 MHz, CD3OD): 3.80 (dd, J¼4.0, 10.8 Hz, H-1a, 1H), 3.67e3.71
(m, H-4, 1H), 3.55 (dd, J¼5.2, 10.8 Hz, H-1b, 1H), 3.36 (dd, J¼2.4,
6.8 Hz, H-3, 1H), 2.94e2.99 (m, H-2, 1H), 1.50e1.60 (m, 2H), 1.31
(br s, 6 to 17-(CH2)12, 24H), 0.92 (t, J¼6.8 Hz, 18-CH3, 3H). dC
(100 MHz, CD3OD): 73.7, 70.8, 63.1, 54.2, 33.2, 31.6, 29.5, 29.4, 29.3,
29.0, 25.6, 22.3, 13.0. Low-resolution MS (EI): m/z: 318 (Mþþ1).

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