Chemoenzymatic stereoconvergent synthesis of 3-O-benzoyl azidosphingosine

Article abstract of DOI:10.1016/S0957-4166(02)00201-X

The synthesis of 3-O-benzoyl azidosphingosine 1 through a stereoconvergent approach is described. Nucleophilic addition of the Grignard reagent of 1-pentadecyne to cyclohexylidene-D-glyceraldehyde results in a mixture of diastereoisomeric propargylic alco

Full text of DOI:10.1016/S0957-4166(02)00201-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 867–872
Chemoenzymatic stereoconvergent synthesis of 3-O-benzoyl
azidosphingosine
Federica Compostella,a Laura Franchini,a Giovanni Battista Giovenzana,b Luigi Panza,b,*
Davide Prosperib and Fiamma Ronchettia
aDipartimento di Chimica e Biochimica Medica, Universita` di Milano, Via Saldini 50, 20133 Milano, Italy
bDipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita` del Piemonte Orientale,
Viale Ferrucci 33, 28100 Novara, Italy
Received 20 March 2002; accepted 23 April 2002
Abstract—The synthesis of 3-O-benzoyl azidosphingosine 1 through a stereoconvergent approach is described. Nucleophilic
addition of the Grignard reagent of 1-pentadecyne to cyclohexylidene-D-glyceraldehyde results in a mixture of diastereoisomeric
propargylic alcohols. Subsequent enzymatic separation of these diastereoisomers, mediated by lipase from Candida antarctica,
Mitsunobu inversion on the wrong diastereoisomer and extremely efficient introduction of azide using a chloromesylate leaving
group affords the title compound in 30% overall yield. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
many glycosphingolipid derivatives. As a part of our
project toward the synthesis of sulfated glycosphin-
golipid antigens we became interested in the develop-
ment of a new synthetic approach to 3-O-benzoyl
azidosphingosine 1 (Fig. 1).
Glycosphingolipids are important membrane compo-
nents of all eukaryotic cells, as they are involved in
molecular recognition phenomena such as cell–cell
interaction and interaction between the cell and other
biological agents.1
Syntheses of azidosphingosine have been reported by
two main approaches: the chiral pool approach and the
asymmetric induction approach.1 We focused our atten-
tion on the first one, planning a stereoselective nucle-
Most natural glycosphingolipids contain the basic
amino alcohol
D-erythro-sphingosine [(2S,3R,4E)-2-
amino-3-hydroxyoctadec-4-en-1-ol], which is linked to a
fatty acid chain through an amide bond (ceramide unit)
and to a hydrophilic carbohydrate portion through a
glycosidic linkage.
ophilic addition to
derived from -mannitol.
a
protected
D-glyceraldehyde,
D
The synthesis of glycosphingolipids involves the linkage
among these three fragments and it has been observed
that the coupling of the preformed ceramide unit to the
carbohydrate part usually gives lower yield than the
glycosylation of a sphingosine precursor, such as azi-
dosphingosine,2 followed by azido group reduction and
N-acylation with suitable fatty acid derivative to gener-
ate the desired ceramide moiety. In particular 3-O-ben-
zoyl azidosphingosine has been employed successfully
in the so called azidosphingosine glycosylation proce-
dure,2,3 as a versatile synthon for the preparation of
2. Results and discussion
Nucleophilic additions to 2,3-O-alkylidene-
aldehyde for the stereoselective synthesis of chiral alco-
hols are reported to proceed with moderate
stereoselectivity and the resulting diastereoisomeric
D
-glycer-
N3
3
HO
2
OBz
1
* Corresponding author. Tel.: +39-0321-657616; fax: +39-0321-
657621; e-mail: panza@pharm.unipmn.it
Figure 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00201-X

868
F. Compostella et al. / Tetrahedron: Asymmetry 13 (2002) 867–872
Treatment of the 4:6 diastereoisomeric mixture of 3 and
4 with lipase from Candida antarctica (LCA) and vinyl
acetate in cyclohexane furnished, after chromato-
graphic separation, the anti acetyl derivative 4a (57%
yield), while the syn alcohol 3 was recovered as unre-
acted starting material (38% yield); both compounds
alcohols are not easily separable through conventional
procedures.4 Among the commonly used acetals, the
cyclohexylidene acetal has been exploited as a protect-
ing group for
D-glyceraldehyde as an alternative to the
isopropylidene analogue, as it gives better results in
terms of stability and usually allows more efficient
separation of the mixture of diastereoisomeric alcohols
generated from the addition reaction.4,5 Following these
1
were found to be diastereoisomerically pure by H and
13C NMR analysis (Scheme 2). The presence of the syn
acetylated derivative was never observed. The acylation
reaction was reproducible up to at least 8 g scale and
the enzyme was recycled up to three times without any
significant loss of activity.
considerations 2,3-O-cyclohexylidene-
appeared a suitable chiral building block for the initial
task of construction of the C18 precursor of -erythro-
azidosphingosine. 2,3-O-Cyclohexylidene- -glycerale-
hyde 2 was easily synthesized by periodate cleavage of
D-glyceraldehyde
D
D
Following a convergent synthetic approach, the unde-
sired anti-4a was recycled through Zemple`n deacetyla-
tion followed by Mitsunobu inversion with acetic acid10
that furnished the acetyl derivative 3a, with the desired
syn configuration of hydroxyl groups at positions 2 and
3, giving an overall yield from 4a to 3a of 72%. The
trans-allylic alcohol 5 was obtained in quantitative yield
from 3 and 3a, which were reacted independently with
LiAlH4 in THF. In this way the lack of stereoselectivity
of the addition step was overcome since both the
diastereoisomeric alcohols 3 and 4 were converted into
5. The crude 5 was then subjected to conventional
benzoylation to yield the fully protected derivative 6;
the yield of the two step reduction–benzoylation pro-
cess was 80% starting from either 3 or 3a. Benzoyl
derivative 6 was then subjected to acidic deketalization.
Attempts to perform the cleavage of the cyclohexyli-
dene acetal with acid catalysis using PTSA or pyri-
dinium tosylate gave mainly benzoyl group migration
on position 1. To avoid this side reaction deketalization
of 6 was carried out with aqueous trifluoroacetic acid
giving compound 7 in quantitative yield, a small
amount of which was purified and confirmed to be the
known 3-O-benzoyloctadec-4-en-1,2,3-triol.8 However,
during the synthesis, compound 7 was used in the next
step without purification, since it was observed that
column chromatography on silica gel also promotes
partial benzoyl group migration on position 1.
1,2:5,6-di-O-cyclohexylidene-D-mannitol according to a
literature procedure.5
Treatment of aldehyde 2 with preformed Grignard
reagent from 1-pentadecyne furnished the mixture of
diastereoisomeric propargylic alcohols 3 and 4 (Scheme
1) in a syn/anti ratio of 4:6 and 90% yield.
1
The diastereomeric ratio was established by H NMR
analysis of the mixture of compounds 3 and 4. Their
syn and anti configurations were assigned by comparing
1
the H NMR resonance of the H-COH protons with
those for analogous propargylic alcohols reported in
literature.6,7,†
The stereochemistry was later confirmed by chemical
correlation when the syn derivative 3 was transformed
into the known 3-O-benzoyloctadec-4-en-1,2,3-triol.8
The low stereoselectivity of the addition, together with
the almost impossible separation of the mixture of
propargylic alcohols 3 and 4 by column chromatogra-
phy prompted us to investigate an enzymatic approach
for their separation. In fact it is known that lipases are
useful tools for synthetic applications due to their abil-
ity to catalyze transesterification reactions in organic
solvents with high regio- and stereoselectivities. For
example, racemic mixtures of propargylic and allylic
alcohols were resolved with excellent enantioselectivities
via enzymatic transesterification promoted by various
lipases in organic solvent.9
The synthesis of 1 was accomplished employing a series
of high-yielding protecting group manipulations in
order to introduce nitrogen at position 2 with the
O
O
O
C13H27
C13H27
i
O
O
O
+
CHO
OH
OH
4
3
2
ratio, 3:4 = 4:6
Scheme 1. (i) 1-Pentadecynyl magnesium bromide, Et2O, THF, −40°C.
† During the assignment of the syn/anti configuration of compounds 3 and 4 it was found that the 1H NMR spectra of the related compounds
described in Ref. 6 (compounds 7b and 8b in Table 3 of page 107) had been exchanged.

F. Compostella et al. / Tetrahedron: Asymmetry 13 (2002) 867–872
869
desired (S)-configuration, by means of nucleophilic
substitution with azide. A selective protecting orthogo-
nal to benzoate for the primary hydroxyl group at
position 3 is required to allow selectively deblocking for
glycosylation. Although thexyldimethylsilyl ether pro-
tection fulfills these requirements it could hamper the
alternative to the above procedure; however when
applied to the mesylate derivative, obtained from 8
according to literature,12 this method gave only a disap-
pointing 56% yield. The attention turned to a more
active leaving group, such as chloromesylate, which was
demonstrated to give better results in comparison with
mesylate and triflate, in the inversion of secondary
alcohols with different nucleophiles, including
NaN3.13,14 Therefore, chloromesylate 9 was obtained
from compound 8 by treatment with chloromethanesul-
fonyl chloride in pyridine in 86% yield.15 Chloromesyl-
ate 9 was then treated with NaN3 in DMF at 85°C
without crown ether affording a very satisfactory 85%
yield of the fully protected azidosphingosine 10 in only
2 h. The choice of chloromesylate as the leaving group
allowed us to avoid protecting group manipulation at
position 1.11
−
leaving group displacement at position 2 by the N3
nucleophile as was recently observed with a TBS
ether.11 The proposed solution to this problem had
been the change of the protecting group at position 1
before the substitution reaction.11 Possible alternatives
to avoid extra steps would be the enhancement either of
−
the nucleophilicity of the N3 nucleophile or of the
leaving group ability.
Selective 1-O-silylation was performed on the crude 7
according to a procedure by Ohlsson and Magnusson,12
giving the TDS ether 8 with a yield of 80% from
compound 6. Hydroxyl group at position 2 is usually
activated for nucleophilic displacement as the mesylate
derivative, but the nucleophilic substitution carried out
with NaN3 requires harsh conditions and the use of
To prevent benzoyl group migration, hydrolysis of the
thexyldimethylsilyl ether of compound 10 under mild
conditions was carried out with 2% HF solution in
CH3CN/THF,16 affording the target compound 1 in
85% yield.
crown ether.12 The use of the good N3 donor, tetra-
−
butylammonium azide, was expected to be a good
O
O
O
C13H27
C13H27
C13H27
a
O
O
O
+
OAc
OH
OH
3
3,4
4a
b
c,d
OH
O
O
C13H27
b
f
RO
O
O
C13H27
C13H27
OBz
OR
OAc
3a
7 : R=H
8 : R=TDS
5 : R=H
6 : R=Bz
e
g
h
OMc
N3
N3
j
i
C13H27
C13H27
TDSO
HO
TDSO
C13H27
OBz
10
OBz
1
OBz
9
Scheme 2. (a) LCA, vinyl acetate, cyclohexane, 40°C, 95%; (b) LiAlH4, THF, 40°C; (c) MeONa, MeOH; (d) AcOH, PPh3, DIAD,
pyridine, THF, 0°C then rt, 72% (from 4a); (e) BzCl, pyridine, CH2Cl2, 80% (two steps either from 3 or 3a); (f) 60% aq.
trifluoroacetic acid, 0°C; (g) TDSCl (TDS=thexyldimethylsilyl), pyridine, 0°C then rt, 80% (from 6); (h) McCl (Mc=
chloromethanesulfonyl), pyridine, 0°C then rt, 86%; (i) NaN3, DMF, 85°C, 85%; (j) 2% aq. HF, THF, CH3CN, 85%.

870
F. Compostella et al. / Tetrahedron: Asymmetry 13 (2002) 867–872
3. Conclusions
tion was heated under reflux for 1 h, cooled to −40°C,
and a solution of 2 (6.96 g, 41 mmol) in THF (30 mL)
was added dropwise. The mixture was stirred at −40°C
for 1 h and then at rt overnight. The reaction was
quenched by addition of satd aq. NH4Cl solution and
extracted with diethyl ether (3×100 mL). The combined
organic layers were washed with water and brine, dried
and concentrated. The residue was purified by flash
chromatography (hexane/ethyl acetate, 9:1), affording
the mixture of diastereoisomeric propargylic alcohols 3
and 4 (20.4 g, 90%) in a syn:anti ratio of 4:6. The
diastereoisomeric ratio was determined by the 1H NMR
through the integral ratio of the signals due to H-C-
OH, which resonates at 4.48 (anti diastereoisomer) and
4.25 ppm (syn diastereoisomer). Full characterizations
of compounds 3 and 4 are reported after enzymatic
separation.
In conclusion, we have developed a new synthesis of
3-O-benzoyl azidosphingosine following a chemoenzy-
matic stereoconvergent approach, which is based on an
enzymatic resolution mediated by C. antarctica lipase,
Mitsunobu inversion and very smooth introduction of
azide through the use of chloromesylate as a leaving
group, with an overall yield of 30% from this ten step
synthesis; this work also confirms the effectiveness of
chloromesylate as a leaving group.
4. Experimental
4.1. General methods
Dry solvents and liquid reagents were distilled prior to
use: THF and diethyl ether were distilled from sodium,
dichloromethane and pyridine were distilled from cal-
4.3. Enzymatic resolution of propargylic alcohols 3 and
4 to (2R,3S)-3-O-acetyl-1,2-O-cyclohexylidene-4-octa-
decyn-1,2,3-triol 4a and (2R,3R)-1,2-O-cyclohexylidene-
4-octadecyn-1,2,3-triol 3
,
cium hydride, DMF was dried over 4 A molecular
sieves; all reaction vessels, after being dried were kept
under argon. Organic solutions were dried over anhy-
drous sodium sulfate, and the solvent was evaporated
at reduced pressure below 40°C. TLC was performed
on glass plates coated with silica gel 60 F-254 Merck,
spots being developed with 5% sulfuric acid in
methanol/water (1:1), or with phosphomolybdate based
reagent. Silica gel Merck 60 (230–400 mesh) was used
for flash chromatography.
To a solution of 3 and 4 (1.45 g, 3.83 mmol) in
cyclohexane (30 mL), lipase from C. antarctica (4.50 g)
and vinyl acetate (1.41 mL, 15.3 mmol) were added.
The mixture was shaken at 40°C for 8 h, at rt overnight
and finally for 5 h at 40°C. The enzyme was filtered off
and washed with cyclohexane. After evaporation of the
solvent the residue was submitted to flash chromatogra-
phy (petroleum ether/ethyl acetate, 9:1) affording the
anti acetyl derivative 4a (0.92 g, 57%) and the syn
alcohol 3 (0.55 g, 38%) as unconverted starting mate-
rial, both as colorless oils.
Optical rotation measurements were obtained for
CHCl3 solutions with a 241 Perkin–Elmer polarimeter
1
at 20°C. H and 13C NMR spectra were recorded in
CDCl3 solutions with a Bruker AM-500 spectrometer.
Chemical shifts are given in ppm (l), relative to SiMe4
as internal standard; coupling constant (J)-values are
given in Hz. Diastereoisomeric ratios were determined
by integration of well-separated signals in 1H NMR
spectra. IR spectra were measured neat by a Perkin–
Elmer 1420 Spectrophotometer (NaCl crystal win-
4.3.1.
(2R,3R)-1,2-O-Cyclohexylidene-4-octadecyn-
1
1,2,3-triol 3. [h]D=+16.9 (c 1); H NMR l 0.85 (t, 3H,
J=7.0 Hz, CH3), 1.20–1.65 (m, 32H, CH2), 2.16 (td,
2H, J=6.5 Hz, J=1.5 Hz, ꢀCH-CH2), 2.39 (d, 1H,
J=3.5 Hz, OH), 3.84 (dd, 1H, J=8.5 Hz, J=5.0 Hz,
OCHaHb), 4.04 (dd, 1H, J=8.5 Hz, J=6.5 Hz,
OCHaHb), 4.10 (m, 1H, OCHCH2), 4.25 (m, 1H,
CHOH); 13C NMR l 14.7, 19.3, 23.3, 24.4, 24.7, 25.7,
29.1, 29.5, 29.7, 30.0, 30.1–30.3 (5C), 32.6, 35.5, 37.3,
65.6, 66.6, 77.9, 79.6, 88.0, 111.6; IR: 3430, 2940, 2860,
1460, 1380, 1170, 1100, 1050, 940 cm−1; MS (EI): m/e
378 [M+]. Anal. calcd for C24H42O3: C, 76.14; H, 11.18.
Found: C, 76.30; H, 11.02%.
dows). Mass spectrometry was performed on
a
Hewlett–Packard HP-5988-A spectrometer. Mass spec-
tra were recorded by electronic impact (LC-EI) or
chemical ionization (LC-CI) techniques as described in
Ref. 17. 2,3-O-Cyclohexylidene-
prepared from 1,2:5,6-di-O-cyclohexylidene-
D
-glyceradehyde 2 was
-mannitol
D
according to a literature procedure4 and subjected to
azeotropic distillation with toluene just before the use.
C. antarctica lipase SP 435L, immobilized on a macro-
porous acrylic resin (Novozym® 435, LCA, specific
activity 9.5 PL units/mg solid), was a generous gift
from Novo Nordisk A/S; 1-pentadecyne was purchased
from Fluka; chloromethanesulfonyl chloride was pur-
chased from Alfa Aesar.
4.3.2.
(2R,3S)-3-O-Acetyl-1,2-O-cyclohexylidene-4-
1
octadecyn-1,2,3-triol 4a. [h]D=+57.5 (c 0.68); H NMR
l 0.86 (t, 3H, J=7.0 Hz, CH3), 1.20–1.65 (m, 32H,
CH2), 2.09 (s, 3H, COCH3), 2.17 (td, 2H, J=7.0 Hz,
J=2.0 Hz, ꢀCH-CH2), 3.94 (dd, 1H, J=8.5 Hz, J=6.5
Hz, OCHaHb), 4.07 (dd, 1H, J=8.5 Hz, J=6.5 Hz,
OCHaHb), 4.26 (td, 1H, J=6.5 Hz, J=4.0 Hz,
OCHCH2), 5.51 (m, 1H, CHOCOCH3); 13C NMR l
14.7, 19.4, 21.6, 23.3, 24.4, 24.5, 25.8, 29.0–30.3 (9C),
32.6, 35.7, 36.5, 64.5, 65.9, 75.0, 77.1, 88.5, 111.6, 170.4;
IR: 2980, 2900, 1770, 1460, 1380, 1250, 1170, 1060, 950
cm−1; MS (EI): m/e 420 [M+]. Anal. calcd for C26H44O4:
C, 74.24; H, 10.54. Found: C, 74.48; H, 10.21%.
4.2. Addition of 1-pentadecynyl magnesium bromide to
2,3-O-cyclohexylidene-D-glyceraldehyde 2
To a stirred solution of 1-pentadecyne (16.4 mL, 62.0
mmol) in THF (30 mL) at 0°C was added dropwise
freshly prepared ethylmagnesium bromide (16.4 mL,
41.0 mmol, 2.5 M solution in diethyl ether). The solu-

F. Compostella et al. / Tetrahedron: Asymmetry 13 (2002) 867–872
871
From 3: Following the same procedure described above
crude 5 (0.43 g) was obtained starting from 3 (0.46 g,
1.23 mmol). The two crudes were combined (0.78 g)
and used in the next step without purification. A sam-
ple was purified by flash chromatography (hexane/ethyl
acetate, 9:1) to afford (2R,3R,4E)-1,2-O-cyclohexyli-
dene-4-octadecen-1,2,3-triol 5 as a colorless oil. [h]D=
4.4. (2R,3R)-3-O-Acetyl-1,2-O-cyclohexylidene-4-octa-
decyn-1,2,3-triol 3a
A solution of MeONa in MeOH (0.2 mL, 0.1 M) was
added to 4a (0.84 g, 1.99 mmol) in anhydrous MeOH (5
mL), and the mixture was stirred for 1 h at rt. Subse-
quently it was neutralized with ion-exchange resin
Dowex H+ (50W-X8). The resin was filtered off and
washed with MeOH. The filtrate was concentrated,
affording crude 4 (0.74 g), which was used in the next
step without further purification. A sample was purified
by flash chromatography (hexane/ethyl acetate, 9:1) to
1
−1.0 (c 1); H NMR l 0.86 (t, 3H, J=6.5 Hz, CH3),
1.20–1.68 (m, 32H, CH2), 2.02 (m, 2H, ꢀCHCH2), 2.34
(d, 1H, J=2.0 Hz, OH), 3.69 (dd, 1H, J=8.0 Hz,
J=5.0 Hz, OCHCH2), 3.90–4.00 (m, 3H, CHOH,
OCH2), 5.35 (dd, 1H, J=15.0 Hz, J=7.0 Hz,
CHꢀCHCH2), 5.76 (m, 1H, CHꢀCHCH2); 13C NMR l
14.7, 23.3, 24.4, 24.7, 25.8, 29.6–30.3 (9C), 32.6, 33.0,
35.6, 37.3, 66.3, 75.4, 79.4, 111.1, 128.4, 136.3; IR:
2900, 2840, 1450, 1360, 1270, 1150, 1100, 1040, 960
cm−1; MS (CI): m/e 398 [M+NH4]+. Anal. calcd for
C24H44O3: C, 75.74; H, 11.65. Found: C, 75.48; H,
11.92%.
afford
(2R,3S)-1,2-O-cyclohexylidene-4-octadecyn-
1,2,3-triol 4 as a colorless oil. [h]D=+20.0 (c 1); 1H
NMR l 0.85 (t, 3H, J=7.0 Hz, CH3), 1.20–1.75 (m,
32H, CH2), 2.14 (d, 1H, J=4.0 Hz, OH), 2.18 (td, 2H,
J=7.0 Hz, J=2.0 Hz, ꢀCHCH2), 4.03 (m, 2H, OCH2),
4.19 (m, 1H, OCHCH2), 4.48 (m, 1H, CHOH); 13C
NMR l 14.8, 19.4, 23.4, 24.4, 24.6, 25.8, 29.1, 29.5,
29.8, 30.0, 30.2–30.3 (5C), 32.6, 35.4, 36.6, 63.1, 65.4,
77.7, 78.4, 88.0, 111.2; IR: 3450, 2960, 2890, 1450, 1370,
1170, 1120, 1040, 940 cm−1; MS (EI): m/e 378 [M+].
Anal. calcd for C24H42O3: C, 76.14; H, 11.18. Found:
C, 76.35; H, 10.95%.
To
a stirred solution of crude 5 (0.78 g) in
dichloromethane (10 mL) pyridine (1.00 mL, 12.3
mmol) and benzoyl chloride (0.72 mL, 6.21 mmol) were
added. The solution was stirred at rt for 2 h then water
was added, after separation, the organic layer was
washed with satd aq. NaHCO3 solution (10 mL); then
dried and concentrated. The residue was purified by
flash chromatography, (petroleum ether/ethyl acetate,
99:1) to give 6 as a colorless oil (0.84 g, 80%). [h]D=
To a solution of the crude 4 (0.74 g) in anhydrous THF
(24 mL) at 0°C were added PPh3 (2.06 g, 7.85 mmol),
glacial acetic acid (0.56 mL, 9.80 mmol) and pyridine
(0.32 mL, 7.85 mmol). The mixture was cooled to
−40°C and DIAD (1.50 mL, 7.85 mmol) was added
dropwise. After being stirred at 0°C for 5 h the solution
was taken up in ether (50 mL) and washed with satd
aq. NaHCO3, 5% aq. HCl solution, and brine. The
organic layer was dried and concentrated. The residue
was purified by flash chromatography, (hexane/ethyl
acetate, 9:1) to give 3a as a colorless oil (0.59 g, 72%).
1
+16.7 (c 1); H NMR l 0.87 (t, 3H, J=9.5 Hz, CH3),
1.20–1.68 (m, 32H, CH2), 2.03 (m, 2H, ꢀCHCH2), 3.81
(dd, 1H, J=8.5 Hz, J=6.0 Hz, OCHaHb), 4.01 (dd, 1H,
J=8.5 Hz, J=6.5 Hz, OCHaHb), 4.30 (m, 1H,
OCHCH2),
5.43–5.52
(m,
2H,
CHꢀCHCH2,
CHOCOPh), 5.90 (dt, 1H, J=15.0 Hz, 7.0 Hz,
CHꢀCHCH2), 7.42 (m, 2H, Ph), 7.53 (m, 1H, Ph), 8.04
(m, 2H, Ph); 13C NMR l 14.0, 22.6, 23.8 (2C), 25.0,
28.7–29.5 (9C), 31.8, 32.3, 34.9, 36.0, 65.4, 75.8, 76.3,
110.5, 123.8, 128.2 (2C), 129.6 (2C), 129.9, 132.8, 137.6,
165.6; IR: 2890, 2810, 1700, 1450, 1430, 1250, 1240,
1230, 1170, 1150, 1100, 1050, 1010, 950, 690 cm−1; MS
(EI), m/e 484 [M+]. Anal. calcd for C31H48O4: C, 76.82;
H, 9.98. Found: C, 76.70; H, 9.92%.
1
[h]D=−25.8 (c 1); H NMR l 0.85 (t, 3H, J=7.0 Hz,
CH3), 1.20–1.65 (m, 32H, CH2), 2.08 (s, 3H, COCH3),
2.15 (dt, 2H, J=7.0 Hz, J=2.0 Hz, ꢀCHCH2), 3.94
(dd, 1H, J=9.0 Hz, J=5.5 Hz, OCHaHb), 4.06 (dd, 1H,
J=9.0 Hz, J=7.0 Hz, OCHaHb), 4.19 (m, 1H,
OCHCH2), 5.38 (dt, 1H, J=7.5 Hz, CHOCOCH3); 13C
NMR l 14.8, 19.3, 21.7, 23.4, 24.5, 24.6, 25.7, 29.0,
29.5, 29.8, 30.0, 30.2–30.3 (5C), 32.6, 35.7, 36.9, 66.7
(2C), 75.1, 77.0, 88.6, 111.9, 170.5; IR: 2960, 2880,
1750, 1460, 1380, 1240, 1170, 1110, 940 cm−1; MS (EI):
m/e 420 [M+]. Anal. calcd for C26H44O4: C, 74.24; H,
10.54. Found: C, 74.45; H, 10.32%.
4.6. (2R,3R,4E)-1-O-Thexyldimethylsilyl-3-O-benzoyl-
4-octadecen-1,2,3-triol 8
Compound 6 (0.84 g, 1.73 mmol) was diluted with 60%
aq. trifluoroacetic acid (6 mL) and stirred for 3 h at
0°C; satd aq. NaHCO3 solution mixed with ice was
added until neutralization and the suspension was
extracted with ethyl acetate (3×50 mL), the combined
organic layers were dried and concentrated. The crude
7 (0.82 g), was used in the next step without purifica-
tion. A sample was purified by flash chromatography
(petroleum ether/ethyl acetate, 8:2) to afford
(2R,3R,4E)-3-O-benzoyl-4-octadecen-1,2,3-triol 7 as a
4.5. (2R,3R,4E)-3-O-Benzoyl-1,2-O-cyclohexylidene-4-
octadecen-1,2,3-triol 6
From 3a: To a stirred solution of 3a (0.39 g, 0.93 mmol)
in THF (8 mL) LiAlH4 (0.08 g, 2.20 mmol) was added
in small portions; the suspension was stirred at 40°C for
5 h. After destroying the excess of LiAlH4 with 2-
propanol, water (1 mL) and silica gel (2 g) were added.
The mixture was stirred for 1 h at 0°C, then MgSO4
was added, the insoluble material was removed by
filtration through Celite and the filtrate was concen-
trated affording crude 5 (0.35 g).
1
colorless oil; H NMR and [h]D were in agreement with
those reported in Ref. 8. 13C NMR l 14.8, 23.4, 29.5,
29.8, 30.1–30.3 (7C), 32.6, 33.0, 63.8, 74.3, 76.8, 124.6,
129.1 (2C), 130.4 (2C), 130.7, 133.9, 138.4, 166.9.

872
F. Compostella et al. / Tetrahedron: Asymmetry 13 (2002) 867–872
4.9. (2S,3R,4E)-2-Azido-3-O-benzoyl-4-octadecen-1,2,3-
To a solution of the crude 7 (0.82 g) in pyridine (10
mL) at 0°C was added thexyldimethylsilyl chloride
(0.51 mL, 2.60 mmol). The solution was stirred
overnight at rt, then diluted with dichloromethane (30
mL) and washed with satd aq. NaHCO3 solution (20
mL). The aq. layer was extracted with dichloro-
methane (3×20 mL) and the combined organic layers
were dried and concentrated. The crude was submit-
ted to flash chromatography (petroleum ether/ethyl
acetate, 10:1) to give 8 (0.76 g, 80%) as a colorless
oil. Physical data were in agreement with those
reported in Ref. 11.
triol 1
Compound 10 (0.12 g, 0.22 mmol) was dissolved in
HF solution (2%, 4.4 mL), prepared by adding 40%
aq. HF to a solution of CH3CN:THF (9:1). The solu-
tion was stirred at rt overnight, then diluted with
dichloromethane (100 mL) and washed with satd aq.
NaHCO3 solution (100 mL). The aq. layer was
extracted with dichloromethane (3×30 mL) and the
combined organic layers were dried. The crude was
purified by flash chromatography (hexane/ethyl ace-
tate, 10:1.5) to afford 1 as a colorless oil (0.08 g,
85%). Physical data were in agreement with those
reported in Refs. 3 and 18.
4.7. (2R,3R,4E)-3-O-Benzoyl-2-O-chloromethylsulfonyl-
1-O-thexyldimethylsilyl-4-octadecen-1,2,3-triol 9
To a solution of 8 (0.46 g, 0.84 mmol) in pyridine (10
mL) at 0°C methanesulfonyl chloride was added (0.11
mL, 1.26 mmol). The solution was stirred for 2 h at
rt, then it was diluted with water and extracted with
ethyl acetate (3×30 mL). The combined organic layers
were washed with 1 M aq. HCl solution and brine,
dried and purified by flash chromatography (hexane/
ethyl acetate, 10:1) to give 9 (0.48 g, 86%) as a color-
less oil.
Acknowledgements
The authors thank the MIUR, the University of
Piemonte Orientale and the University of Milano for
financial support.
References
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1
[h]D=−1.6 (c 1); H NMR l 0.09 (s, 3H, (CH3)2Si),
0.10 (s, 3H, (CH3)2Si), 0.82–0.94 (m, 15H, 5CH3),
1.20–1.40 (m, 22H, CH2), 1.60 (heptet, 1H, J=6.0
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(m, 1H, Ph), 8.10 (m, 2H, Ph); 13C NMR l −2.9
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To a stirred solution of 9 (0.47 g, 0.71 mmol) in dry
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