Enantioselective access to a versatile 4-oxazolidinonecarbaldehyde and application to the synthesis of a cytotoxic jaspine B truncated analogue

Article abstract of DOI:10.1016/j.tetasy.2007.03.029

The preparation of the versatile aldehyde 15 via a concise route based on a formal anti-asymmetric aminohydroxylation and its use in a 5-step synthesis of a cytotoxic C₁₂ analogue of the natural anhydrophytosphingosine jaspine B is presented.

Full text of DOI:10.1016/j.tetasy.2007.03.029

Tetrahedron: Asymmetry 18 (2007) 857–864
Enantioselective access to a versatile 4-oxazolidinonecarbaldehyde
and application to the synthesis of a cytotoxic jaspine B
truncated analogue
a,
a
a,b
Yves Genisson, Lydia Lamande, Yahya Salma, Nathalie Andrieu-Abadie,b
*
´
´
a
a
´
Chantal Andre and Michel Baltas
aLSPCMIB, UMR 5068, Universite´ Paul Sabatier, 31062 Toulouse Cedex 9, France
bINSERM U858, Institut de Me´decine Mole´culaire de Rangueil, BP 84225, 31432 Toulouse Cedex 4, France
Received 21 February 2007; accepted 29 March 2007
Abstract—The preparation of the versatile aldehyde 15 via a concise route based on a formal anti-asymmetric aminohydroxylation and
its use in a 5-step synthesis of a cytotoxic C12 analogue of the natural anhydrophytosphingosine jaspine B is presented.
ꢀ 2007 Elsevier Ltd. All rights reserved.
NH2
1. Introduction
HO
HO
Me
Me
Sphingoid bases are long-chain (typically C18) aminopoly-
ols that constitute the backbone of sphingolipids, ubiqui-
tous components of eukaryotic cell membranes.1 Once
N-acylated with a fatty acid they give rise to ceramides,
precursors of sphingomyelin and glycosphingolipid
through C-1 functionalisation. Most sphingoid bases are
of the D-erythro-sphingosine type but the less prevalent
D-ribo-phytosphingosine subclass has attracted great inter-
est (Fig. 1).2 Notably, the participation of simpler sphingo-
lipids in signal transduction and cell growth regulation has
been established. Ceramide is recognised as a second
messenger causing various antimitogenic effects, including
apoptosis.3 In contrast, sphingosine-1-phosphate has
emerged as a key mitogenic regulator.4 These observations
suggest that the pharmacological manipulation of the
sphingolipid metabolism represents a promising approach
for the development of novel anticancer therapies.5
1
OH
D-erythro-sphingosine
NH2 OH
2
OH
OH
D-ribo-phytosphingosine
H2N
Me
O
3
jaspine B (pachastrissamine)
Figure 1. Sphingoid derivatives.
type 6, which represents an ideal four carbon electrophilic
synthon (Scheme 1). The synthetic usefulness of a similar
entity for the synthesis of D-ribo-phytosphingosine has
We recently developed an access to the D-ribo-phytosphin-
gosine backbone from a trans-2,3-epoxyaldehyde precur-
sor.6 However, the flexibility of this route is hampered by
the sensitivity of the oxirane functionality. Thus, we turned
our attention towards a 4-oxazolidinonecarbaldehyde of
O
OH
O
O
P'N
PO
OH
H
OH
PO
PO
P'N
H
O
4
5
6
*
Corresponding author. Tel.: +33 05 61 55 62 99; fax: +33 05 61 55 60
11; e-mail: genisson@chimie.ups-tlse.fr
Scheme 1. Retrosynthetic approach to aldehydes of type 6.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.029

858
Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
already been demonstrated by Wee7 who attained such a 4-
oxazolidinonecarbaldehyde intermediate via a nine-step
chemical route starting from a non-commercial D-man-
nose-derived phenylsulfide.
corresponding acetonides (1.2 equiv PTSA, dimethoxypro-
pane, RT, several days) in order to confirm their identity:
11 yielded a 1,3-dioxolane displaying a characteristic
13C NMR signal at dC 108.9 ppm for the quaternary ketal
carbon. On the other hand, 12 was transformed into the
isomeric 1,3-dioxane (dC 98.7 ppm for the corresponding
quaternary carbon).9 The use of p-methoxybenzylamine
as a nucleophile in the epoxide opening gave a comparable
result (65% yield of a 60:40 mixture). Notably, the regio-
selectivity was reversed in favour of the C-2 opening
product, using an aluminium-based catalyst (3.5 equiv
AlMe3, 2.5 equiv BnNH2, CH2Cl2, reflux, 65% yield of a
58:42 mixture). Interestingly, the same result was obtained
by gentle heating of 10 in aqueous medium (3 equiv
BnNH2, methoxyethanol/water, 65 ꢁC).
2. Results and discussion
Our synthetic plan was centred on the ring opening of a
chiral trans-2,3-epoxyalcohol 4 by a primary amine
(Scheme 1). The resulting aminodiol 5 could in turn be
readily transformed into the targeted aldehyde through
oxazolidinone ring formation and primary alcohol
oxidation.
2.1. Preparation of the 4-oxazolidinonecarbaldehyde
intermediate
An attractive feature of the titanium-catalysed process is
the possibility of combining it with Sharpless epoxidation
in an overall formal anti-asymmetric aminohydroxylation.
This one-pot procedure was successfully applied to allylic
alcohol 9. After consumption of the starting olefin, the
excess hydroperoxide was reduced with Me2S. The latter
was preferred to the equally efficient, but far more expen-
sive, polymer-bound triphenylphosphine. The addition of
an excess amount of Ti(Oi-Pr)4 and BnNH2 to the reaction
medium then smoothly allowed the formation of the
desired aminodiols 11 and 12 after 1.5 days at room tem-
perature (60% isolated yield from allylic alcohol 9) as a
70:30 mixture. Preliminary experiments aimed at the
formation of the oxazolidinone moiety showed that the
treatment of 11 with trichloromethyl chloroformate
(0.5 equiv, CH2Cl2/Et3N 1:1, ꢀ 20 ꢁC) exclusively afforded
the undesired cyclic carbonate, as indicated, for example,
by the infrared data (mC@O 1796 cmꢀ1).10 The formation of
the expected cyclic carbamate was, however, accomplished
through a convenient two-step procedure: treatment of
the aminodiol with methyl chloroformate in excess fol-
lowed by selective saponification of the carbonate function-
alities and spontaneous intramolecular cyclisation. This
sequence could be equally applied to major compound 11
or the mixture of regioisomers 11 and 12. In the latter case,
The starting allylic alcohol 9 was readily obtained by
monobenzylation of butyne-1,4-diol followed by LAH
reduction (Scheme 2). This was then subjected to Sharpless’
asymmetric epoxidation to yield 10. We then focused on
the regio- and stereoselective Ti(Oi-Pr)4-catalysed ring-
8
`
opening process developed by Pericas and Riera. When
treated with benzylamine under these conditions, 2,3-
epoxyalcohol 10 afforded the expected aminodiols 11 and
12 in 75% yield and in a 70:30 ratio, in favour of C-3 open-
ing. The two regioisomers were separated for full charac-
terisation. These were independently cyclised into the
RO
b
7: R = OH
8: R = OBn
OH
a
O
c
OH
OH
BnO
BnO
9
10
e
d
OH
BnNH
OH
OH
+
+
BnO
BnO
11
12
BnNH
O
OH
f
O
O
BnN
BnN
OH
O
BnO
13
14
OH
BnO
g
O
O
BnN
BnO
H
O
15
Scheme 2. Reagents and conditions: (a) BnBr, KOH, H2O, rt, 2 days, 70%
based on the bromide; (b) LiAlH4, THF, ꢀ20 ꢁC to rt, 6 h, 60%; (c) Ti(Oi-
˚
Pr)4, (ꢀ)-DET, t-BuOOH, 4 A MS, CH2Cl2, ꢀ23 ꢁC, 3.5 days, 90%; (d)
˚
Ti(Oi-Pr)4, (ꢀ)-DET, t-BuO2H, 4 A MS, CH2Cl2, ꢀ23 ꢁC, 3 days, then
Me2S, rt, 3 h, then Ti(Oi-Pr)4, BnNH2, rt, 1.5 days, 60% of a 70:30 mixture
of 11 and 12; (e) Ti(Oi-Pr)4, BnNH2, CH2Cl2, reflux, 24 h, 75% of a 70:30
mixture of 11 and 12; (f) (i) K2CO3, MeOCOCl, THF, rt, 18 h; (ii) 80%
KOH in MeOH, rt, 5 h, 60% overall yield of 13, 23% overall yield of 14;
(g) DMP, CH2Cl2, rt, 3 h, 90%.
Figure 2. X-ray structure of oxazolidinone 13.

Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
859
this led to oxazolidinones 13 and 14 in 83% combined yield.
Separation of the regioisomers proved trivial at that stage.
X-ray diffraction analysis confirmed the structure of the
major product 13 (Fig. 2).11 The final oxidation procedure
had to be carefully chosen to diminish the risk of epimeri-
sation into a trans-oxazolidinone ring, as observed, for
example, using Swern conditions. The Dess–Martin period-
inane proved to be the most suitable, allowing isolation of
the expected aldehyde 15 in 90% yield. The latter was thus
obtained in a most efficient manner and was fully
characterised.
magnesium bromide resulted in a completely diastereo-
selective addition (Scheme 3). The same procedure was also
carried out using n-heptyne lithium, giving adduct 17 as
the sole diastereoisomer. The latter represents an interest-
ing precursor for original 5,6-unsaturated phytosphingo-
sine analogues. Elaboration of the all-cis-trisubstituted
tetrahydrofuran moiety of jaspine B required configuration
inversion at C-4. The hydroxyl group was thus activated by
conversion to the corresponding mesylate 18. Pleasingly,
we found that the cyclisation occurred spontaneously dur-
ing the hydrogenolysis of the C-1 benzylic ether, cleanly
providing the bicyclic intermediate 19 in 75% yield. Despite
the high hydrogen pressure required for the reaction to
proceed, the N-benzyl carbamate fragment remained unaf-
fected. In fact, this group proved particularly reluctant to
cleavage. Pushing the hydrogenation reaction resulted,
for example, in saturating the phenyl ring instead of the
expected hydrogenolysis reaction. We felt that the highly
constrained bicyclic structure of 19 might explain this
behaviour. Therefore the carbamate function was hydro-
lysed and deprotection of the resulting N-benzyl amine 21
was attempted.23 Hydrogenolysis under forcing conditions
(10 bars H2, 10% Pd/C, 12 M HCl, MeOH, 4 days) left the
starting material unchanged. A Birch reduction (Na/NH3,
THF, ꢀ78 ꢁC, 1 h) resulted in the partial reduction of the
aromatic nucleus into a cyclohexadiene ring. We thus
reconsidered the reaction sequence and applied a Birch
reduction to the oxazolidinone precursor 19. Gratifyingly
the expected debenzylated product 20 was isolated in good
yield. The final saponification under standard conditions
led smoothly to the targeted truncated jaspine B analogue
22. Spectral data for the latter were in agreement with that
2.2. Synthesis of the truncated jaspine B analogue
Access to 15 constitutes a formal synthesis of natural
D-ribo-phytosphingosine.7 In order to further illustrate
the synthetic potential of aldehyde 15, we targeted a
biologically relevant analogue of sphingosine, jaspine B
(pachastrissamine) (Fig. 1). This anhydrophytosphingosine,
isolated from a marine sponge, has been independently
described by Higa14 and Debitus.15 Either the free base
or the hydrochloride displayed a pronounced cytotoxicity
towards several cell lines with IC50 values in the submicro-
molar range. Several total syntheses of jaspine B have
been reported from a chiral pool derived precursor. Rao16
and Datta17 made use of serine while Linhart18 and Du19
employed D-xylose. Lately, Falomir and Marco20 made use
of the (R)-glycidol as a starting material whereas Chandra-
sekhar21 prepared a truncated pachastrissamine from
D-xylose. The C-4 epimer of jaspine B is known and no
biological activity has been attributed to this D-ribo ana-
logue.22 However, the absence of a proper structure–activ-
ity relationship in this series prompted us to develop direct
access to the jaspine B skeleton from aldehyde 15. In
particular, the incidence of the aliphatic chain length on
cytotoxicity seemed interesting to evaluate. Indeed the high
lipophilicity of jaspine B appears disadvantageous for
further development.
1
of the natural product.18 In particular, H NMR of the
tetrahydrofuran region allowed confirmation of the all-cis
configuration.
2.3. Biological evaluation
The biological activity of 22 was then tested on melanoma
cell lines. Melanoma is indeed considered as a radiation-
and chemotherapy-refractory neoplasm of increasing
incidence. As illustrated in Figure 3, the truncated jaspine
B analogue 22 gratifyingly exhibited dose-dependent
With regards to the introduction of the lipophilic side
chain, we took advantage of the syn-selective organocerium
nucleophilic addition developed by Wee.7 Treatment of 15
with the in situ-generated reagent derived from n-octyl
O
O
O
O
O
O
R'N
BnN
BnN
H
R
R
a
c
O
O
OR'
BnO
BnO
15
16: R = C8H17, R' = H
17: R =C5H11 C, R' = H
18: R = C8H17, R' = Ms
19: R = C8H17, R' = Bn
d
b
20: R = C8H17, R' = H
C
HO
OH
5
3
BnHN
H2N
R
e
f
2
Me
12
4
1
O
O
22
21: R = C8H17, from 19
Scheme 3. Reagents and conditions: (a) C8H17MgBr/CeCl3, THF, ꢀ78 ꢁC, 5 h, then 0 ꢁC, 1 h, 56% in 16, or C5H11CCLi/CeCl3, THF, ꢀ78 ꢁC, 6 h, 75% in
17; (b) MsCl, Et3N, CH2Cl2, 0 ꢁC to rt, 1.5 h, 90%; (c) 10 bar H2, Pd(OH)2, EtOH, 2 days, 75%; (d) Na/NH3, THF, ꢀ78 ꢁC, 4 h, 83%; (e) LiOH, p-
dioxane/H2O, reflux, 2.5 days, 97% br sm at 70% conversion, from 19; (f) KOH, EtOH/H2O, 85 ꢁC, 7 h, 95%.

860
Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
Perkin–Elmer FT-IR 1725X spectrometer. High resolution
100
80
60
40
20
0
A375
B16
mass spectra (HRMS) were performed on a ThermoFinni-
gan MAT 95 XL spectrometer (DCI). Optical rotations
were measured on a Perkin–Elmer model 141 polarimeter.
4.1.1. 4-Benzyloxy-2-propyn-1-ol 8. To a solution of
KOH (18.8 g, 335.0 mmol) in H2O (250 mL) was added
butyne 1,4-diol 7 (28.9 g, 336.0 mmol) and benzyl bromide
(10.0 mL, 84.1 mmol). The mixture was stirred at room
temperature for 48 h. Most of the water was then evapo-
rated off and the mixture was extracted three times with
CH2Cl2. The combined organic layers were washed with
water and brine, then dried over MgSO4 and concentrated
in vacuo. The crude material was purified by column chro-
matography on SiO2 eluted with PE/ether (70:30 to 60:40)
to give 8 (10.4 g, 70% based on the bromide) as a colourless
0
1
2.5
5
10
Compound 22 (µM)
Figure 3. Sensitivity of melanoma cells to compound 22.
cytotoxicity towards B16 murine and A375 human
melanoma cell lines, reaching 50% activity at 2.5 lM.
oil. IR (film) mOH 3392, mCC 2237 cmꢀ1
;
1H NMR
(250 MHz, CDCl3) d 7.45–7.15 (m, 5H, Ph), 4.59 (s, 2H,
CH2Ph), 4.31 (s, 2H, H1), 4.21 (s, 2H, H4), 2.10 (s, 1H,
OH); 13C NMR (63 MHz, CDCl3) d 137.9 (Cq, Ph),
129.2, 128.9 and 128.7 (CH, Ph), 86.0, 81.7 (C2 and C3),
72.4 (CH2Ph), 58.1 (C1), 51.2 (C4); MS (DCI/NH3) m/z
194 (M+NH4)+.
3. Conclusion
In conclusion, we have developed a practical enantioselec-
tive access to 4-oxazolidinonecarbaldehyde 15, obtained in
four steps and in 30% yield from the readily available
allylic alcohol 9. The latter was further transformed into
an original C12 analogue of jaspine B 22 through a concise
five-step sequence. Notably, this truncated anhydrophyto-
sphingosine retains potent cytotoxicity on murine and
human melanoma cell lines. The preparation of other var-
ious chain-modified jaspine B derivatives potentially active
against this typically chemoresistant tumour as well as
studies aiming at a better understanding their mode of
action are currently in progress.
4.1.2. 4-Benzyloxy-2-propen-1-ol 9. To a suspension of
LiAlH4 (1.95 g, 85.0 mmol) in anhydrous THF (100 mL)
at ꢀ20 ꢁC and under nitrogen atmosphere was added
dropwise a solution of propargylic alcohol 8 (17.6 g,
100.0 mmol) in THF (40 mL). The mixture was stirred at
ꢀ20 ꢁC for 3 h and at room temperature for 3 h, after
which H2O (4.2 mL) was added, followed by a 10% aque-
ous NaOH solution (4.2 mL) and water (12.4 mL). The
reaction mixture was then filtered over Celite and the cake
was rinsed with THF. The resulting solution was concen-
trated in vacuo and the crude material purified by column
chromatography on SiO2 eluted with PE/AcOEt (70:30 to
60:40) to give allylic alcohol 9 (10.7 g, 60%) as a colour
4. Experimental
4.1. General
1
less liquid. IR (film) mOH 3408 cmꢀ1; H NMR (250 MHz,
Reactions were performed in flame-dried glass, sealed with
a rubber septum and stirred with a magnetic stirring bar,
under argon or nitrogen if required. Materials were ob-
tained from commercial suppliers and were used without
purification, unless otherwise stated. The following sol-
vents were dried prior to use: CH2Cl2 (freshly distilled from
calcium hydride), Et2O and THF (distilled from sodium/
benzophenone). Thin layer chromatography (TLC) reac-
tion monitoring was carried out with Macherey-Nagel
ALUGRAMꢂ SIL G/UV254 (0.2 mm) plates visualised
with 10% phosphomolybdic acid in ethanol or Dragendorff
reagent24 as dipping solutions. Standard column chroma-
tography was performed with SDS 70–200 lm silica gel.
Flash column chromatography was carried out with SDS
35–70 lm silica gel. Medium-pressure liquid chromatogra-
phy was performed with a Jobin–Yvon apparatus using
Merck 15-40 lm silica gel. NMR spectroscopic data were
obtained with Bruker AC 250, Avance 300, ARX 400
CDCl3) d 7.40–7.20 (m, 5H, Ph), 5.89–5.78 (m, 2H, H2,
H3), 4.53 (s, 2H, OCH2Ph), 4.20–4.10 (m, 2H, H1), 4.05
3
(d, 2H, H4, JH –H ¼ 7:0 Hz), 1.80–1.70 (m, 1H, OH);
4
3
13C NMR (63 MHz, CDCl3) d 138.8 (Cq, Ph), 133.4,
129.1, 128.4, 128.3, 127.8 (CH, Ph, C2 and C3), 72.8
(OCH2Ph), 70.8 (C1), 63.0 (C4); MS (DCI/NH3) m/z 196
(M+NH4)+.
4.1.3. Aminodiols 11 and 12. To a solution of Ti(Oi-Pr)4
(1.67 mL, 5.64 mmol) in anhydrous CH2Cl2 (10 mL) con-
˚
taining 4 A molecular sieves (1.2 g) at ꢀ23 ꢁC and under
nitrogen atmosphere was added (ꢀ)-diethyl tartrate
(1.4 mL, 8.15 mmol). The mixture was stirred for 10 min
and a solution of allylic alcohol 9 (4.0 g, 22.5 mmol) in
anhydrous CH2Cl2 (35 mL) was added. After 30 min of
stirring, t-butyl hydroperoxide (8.2 mL of a 5.5 M solution
in decane, 45.0 mmol) was added. The mixture was then
stirred at ꢀ23 ꢁC for 72 h, after which anhydrous dimethyl
sulfide (2.4 mL, 33.7 mmol) was added and the stirring con-
tinued for 3 h at ꢀ23 ꢁC. Anhydrous benzylamine (7.4 mL,
67.4 mmol) was added followed by Ti(Oi-Pr)4 (10.0 mL,
33.7 mmol) and the mixture then allowed to stir at room
temperature for 36 h. The reaction was quenched by the
addition of a 10% aqueous NaOH solution saturated in
1
and Avance 500 instruments operating for H NMR spec-
tra at 250, 300, 400 and 500 MHz, respectively, and for 13C
NMR spectra at 63, 75, 100 and 125 MHz, respectively.
Chemical shifts are quoted in parts per million (ppm)
downfield from tetramethylsilane and coupling constants
are in Hertz. Infrared (IR) spectra were recorded on a

Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
861
NaCl (22 mL) and stirring at room temperature for 5 h.
The mixture was filtered over Celite, the cake rinsed with
CH2Cl2 and the solution concentrated in vacuo. The crude
material was purified by column chromatography on SiO2
eluted with PE/i-PrOH/Et3N (79.85:20:0.15 to 69.85:30:
0.15) to give a 70:30 mixture of 11 and 12 (4.1 g, 60%).
Compounds 11 and 12 were separated by MPLC column
chromatography on SiO2 eluted with PE/i-PrOH/Et3N
(79.85:20:0.15 to 69.85:30:0.15). A 90% ee was assigned
to compounds 11 and 12 on the basis of that of the epoxide
intermediate measured by chiral HPLC (CHIRALCEL
OD, hexane/i-PrOH, 85:15, 1 mL/min).
washed with brine, dried over Na2SO4 and concentrated
in vacuo. The crude material was purified by column chro-
matography on SiO2 eluted with CH2Cl2/AcOEt (80:20) to
give 13 (893 mg, 60%) and 14 (342 mg, 23%).
4.1.4.1. (4S,5S)-3-Benzyl-4-(benzyloxymethyl)-5-(hydroxy-
methyl)-2-oxazolidinone 13. White solid; mp: 64–65 ꢁC;
20
½aꢁD ¼ þ27:5 (c 1.3, CHCl3); IR (film) mOH 3435, mC@O
1
1736 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.40–7.21 (m,
3
3
10H, Ph), 4.58 (dt,1H, H2, JH –H ¼ 5:4 Hz, JH –H
¼
2
1
2
2
3
8:3 Hz), 4.47 (ABq, 2H, OCH2Ph, Jgem = 11.8 Hz, Dd =
16,6 Hz), 4.42 (ABq, 2H, Jgem = 15.2 Hz, Dd = 269 Hz,
2
2
NCH2Ph), 3.89 (AB of an ABX, 2H, 2 · H1, Jgem
=
3
4.1.3.1. (2S,3S)-3-Benzylamino-4-(benzyloxy)propan-1,2-
12.5 Hz, JH –H ¼ 3JH
¼ 5:4 Hz), 3.84–3.81 (m, 1H,
–H
0
1
2
2
1
20
2
diol 11. White solid; mp: 74 ꢁC; ½aꢁD ¼ þ28:0 (c 1.4,
H3), 3.60 (AB of an ABX, 2H, 2 · H4, Jgem = 10.3 Hz,
CHCl3); IR (film) mOH,NH 3405 cmꢀ1
;
1H NMR
3JH –H ¼ 6:0 Hz, 3JH
¼ 4:0 Hz, Dd = 21.3 Hz); 13C
–H
0
4
3
3
4
(400 MHz, CDCl3 + D2O) d 7.40–7.28 (m, 10H, Ph), 4.53
NMR (100 MHz, CDCl3) d 158.0 (C@O) 136.8 (Cq,
OCH2Ph), 136.2 (Cq, NCH2Ph), 129.0, 128.9, 128.5,
128.3, 128.2, 128.1 (CH, Ph), 76.4 (C2), 73.9 (OCH2Ph),
65.7 (C4), 60.0 (C1), 56.0 (C3), 46.8 (NCH2Ph); MS
(DCI/NH3) m/z 328 (M+H)+; HRMS (CI) m/z calcd for
C19H22NO4: 328.1549; found, 328.1551. Anal. Calcd for
C19H21NO4: C, 69.71; H, 6.47; N, 4.28; Found: C, 69.69;
H, 6.49; H, 4.08.
2
(ABq, 2H, OCH2Ph, Jgem = 11.9 Hz, Dd = 17.0 Hz), 3.79
(pseudoq, 1H, JH –H ¼ JH –H ¼ 5:5 Hz, H2), 3.80 (ABq,
2
1
2
3
2
2H, NCH2Ph, Jgem = 13.0 Hz, Dd = 23.5 Hz), 3.68–3.62
(m, 4H, 2 · H1 and 2 · H4), 2.89 (dt, 1H, H3,
3JH –H ¼ 5:9 Hz, JH –H ¼ 4:8 Hz); 13C NMR (100 MHz,
3
3
2
3
4
CDCl3 + D2O)
d 139.9 (Cq, NCH2Ph), 137.9 (Cq,
OCH2Ph), 128.9, 128.5, 128.2, 128.0, 127.5 (CH, Ph),
73.6 (OCH2Ph), 70.7 (C2), 68.3 (C1 or C4), 65.3 (C4 or
C1), 59.9 (C3), 51.8 (NCH2Ph); MS (DCI/NH3) m/z 302
(M+H)+; HRMS (CI) m/z calcd for C18H24NO3:
302.1756; found, 302.1755. Anal. Calcd for C18H23NO3:
C, 71.73; H, 7.69; N, 4.65. Found: C, 71.25; H, 7.64; N,
4.54.
4.1.4.2. (4S)-3-Benzyl-4-[(1S)-2-benzyloxy-1-(hydroxy-
20
methyl)]-2-oxazolidinone 14. Colourless oil; ½aꢁD ¼ þ4:0
1
(c 1.2, CHCl3); IR (film) mOH 3420, mC@O 1735 cmꢀ1; H
NMR (400 MHz, CDCl3) d 7.38–7.25 (m, 10H, Ph), 4.51
2
(ABq, 2H, NCH2Ph, Jgem = 15.3 Hz, Dd = 198 Hz), 4.49
(s, 2H, OCH2Ph), 4.30 (AB of an ABX, 2H, 2 · H1,
4.1.3.2. (2S,3S)-2-Benzylamino-4-(benzyloxy)propan-1,3-
2Jgem = 8.9 Hz,
3JH –H ¼ 8:9 Hz,
3JH
¼ 6:5 Hz,
–H
0
1
2
2
1
20
diol 12. Colourless oil; ½aꢁD ¼ þ6:7 (c 1.3, CHCl3); IR
Dd = 82.4 Hz), 4.04–4.01 (m, 1H, H3), 3.77 (ddd, 1H, H2,
1
(film) mOH,NH 3401 cmꢀ1; H NMR (400 MHz, CDCl3 +
JH –H ¼ 9:0 Hz, JH –H ¼ 6:5 Hz, JH –H ¼ 2:3 Hz), 3.45
0
2
1
2
2
3
1
2
3
D2O) d 7.40–7.28 (m, 10H, Ph), 4.55 (s, 2H, OCH2Ph),
(AB of an ABX, 2H, 2 · H4, Jgem = 9.9 Hz, JH –H
¼
4
3
3.95 (dt, 1H, 3JH –H ¼ 3JH –H ¼ 4:9 Hz; JH –H
¼
5:7 Hz, 3JH
¼ 4:8 Hz, Dd = 15.0 Hz); 13C NMR
3
–H
0
0
3
4
3
2
3
3
4
6:4 Hz, H3), 3.81 (ABq, 2H, NCH2Ph, Jgem = 13.0 4Hz,
(100 MHz, CDCl3) d 159.3 (C@O) 137.5 (Cq, OCH2Ph),
136.3 (Cq, NCH2Ph), 129.2, 128.8, 128.3, 128.2, 128.0
(CH, Ph), 73.9 (OCH2Ph), 70.5 (C4), 67.4 (C3), 62.9 (C1),
57.1 (C2), 46.7 (NCH2Ph); SM (DCI/NH3) m/z 345
(M+NH4)+; HRMS (CI) m/z calcd for C19H22NO4:
328.1549; found, 328.1549.
2
3
Dd = 21.9 Hz) 3.69 (d, 2H, 2 · H1 JH –H ¼ 4:6 Hz),
1
2
2
3.58 (AB of an ABX, 2H, 2 · H4, Jgem = 9.7 Hz,
3
3JH
¼ 6:4 Hz, JH –H ¼ 4:9 Hz, Dd = 22.3 Hz), 2.74
2 3 2 1
–H
0
3
4
3
4
(dt, 1H, H2, JH –H ¼ 4:9 Hz, JH –H ¼ 4:5 Hz); 13C
3
3
NMR (100 MHz, CDCl3 + D2O) d 140.1 (Cq, NCH2Ph),
137.9 (Cq, OCH2Ph), 128.8, 128.7, 128.5, 128.2, 128.1,
127.4 (CH, Ph), 73.8 (OCH2Ph), 72.1 (C4), 70.6 (C3), 60.4
(C1), 59.5 (C2), 51.5 (NCH2Ph); MS (DCI/NH3) m/z 302
(M+H)+; HRMS (CI) m/z calcd for C18H24NO3:
302.1756; found, 302.1758.
4.1.5. (4S,5S)-3-Benzyl-4-(benzyloxymethyl)-5-(formyl)-2-
oxazolidinone 15. To a solution of alcohol 13 (210 mg,
0.64 mmol) in anhydrous CH2Cl2 (4 mL) at room temper-
ature and under a nitrogen atmosphere was added Dess–
Martin periodinane (351 mg, 0.83 mmol). The mixture
was stirred for 3 h after which it was diluted with diethyl
ether and Na2S2O3 (950 mg, 6.0 mmol) in a saturated aque-
ous NaHCO3 (12 mL) solution was added. The mixture
was extracted three times with diethyl ether and the com-
bined extracts were washed with brine and dried over
Na2SO4. Most of the solvent was then gently evaporated
off in vacuo and the resulting concentrated solution was di-
rectly filtered over Florisil eluted with diethyl ether. Gentle
evaporation of the solvent in vacuo gave aldehyde 15
(188 mg, 90%). A sample was further purified by column
4.1.4. Oxazolidinones 13 and 14. To a solution of a
mixture of regioisomers 11 and 12 (1.37 g, 4.55 mmol) in
anhydrous THF (34 mL) at room temperature and under
a nitrogen atmosphere was added anhydrous K2CO3
(5.1 g, 37.0 mmol) and methyl chloroformate (1.8 mL,
23.2 mmol). The mixture was stirred at room temperature
for 18 h after which it was filtered over Celite. The cake
was rinsed with THF, and the filtrate concentrated in
vacuo. The crude material was then taken up in a 10% solu-
tion of KOH in methanol (31 mL) and the mixture stirred
at room temperature for 5 h. The solution was acidified by
the addition of a 1.2 M aqueous solution of HCl, the meth-
anol was evaporated off and the mixture was extracted
three times with CH2Cl2. The combined extracts were
chromatography on SiO2 eluted with CH2Cl2/AcOEt
20
(80:20) for complete characterisation. ½aꢁD ¼ þ11:0 (c 2.2,
1
CHCl3); IR (neat) mC@O 1744 cmꢀ1; H NMR (400 MHz,
3
CDCl3) 9.72 (d, 1H, Hald., JH
¼ 1:5 Hz), 7.42–7.18
ald:–H2

862
Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
3
(m, 10H, Ph), 4.68 (dd, 1H, H2, JH –H ¼ 10:0 Hz,
tion mixture stirred at ꢀ78 ꢁC for 1 h. Aldehyde 15
(184 mg, 0.57 mmol) in solution in anhydrous THF
(1 mL) was added and the mixture stirred at ꢀ78 ꢁC for
6 h. The reaction was then quenched by the addition of a
saturated aqueous solution of NH4Cl (15 mL) and stirring
at 0 ꢁC for 30 min. The mixture was diluted by the addition
of THF, vigorously stirred at room temperature and dec-
anted. The organic layer was separated and the extraction
repeated with AcOEt (3 · 30 mL). The combined extracts
were washed with brine, died over Na2SO4 and concen-
trated to dryness. The crude material was purified by col-
umn chromatography on SiO2 eluted with PE/AcOEt
2
3
3JH –H ¼ 1:5 Hz),
4.32
(ABq,
2H,
OCH2Ph,
2
ald:
2Jgem = 11.8 Hz, Dd = 74.8 Hz), 4.40 (ABq, 2H, NCH2Ph,
2Jgem = 15.3 Hz, Dd = 314.0 Hz), 3.96 (dt, 1H, H3,
3JH –H ¼ 10:0 Hz, JH –H ¼ 2:0 Hz), 3.40 (AB of an
3
3
2
3
4
2
3
ABX, 2H, 2 · H4, Jgem = 11.0 Hz, JH –H ¼ 2:0 Hz, Dd =
4
3
108.0 Hz); 13C NMR (100 MHz, CDCl3) 198.7 (C@O,
ald.), 157.2 (C@O, carbamate), 136.8 (Cq, OCH2Ph),
135.5 (Cq, NCH2Ph), 129.1, 128.8, 128.4, 128.3, 128.2,
128.1 (CH, Ph), 76.7 (C2), 73.1 (OCH2Ph), 62.8 (C4), 58.2
(C3), 46.4 (NCH2Ph); SM (DCI, NH3) m/z 343
ðMNH4þÞ; HRMS (ESI) m/z calcd for C19H20NO4:
326.1392; found, 326.1393.
(70:30 to 60:40) to give 17 (180 mg, 75%) as a colourless
20
oil. ½aꢁD ¼ þ22:0 (c 1.32, CHCl3); IR (film) mOH 3400,
1
4.1.6. (4S,5S)-3-Benzyl-4-(benzyloxymethyl)-5-[(1R)-1-(hydr-
oxyoctyl)]-2-oxazolidinone 16. A suspension of anhydrous
CeCl3 (1.5 g, 6.0 mmol) in anhydrous THF (23 mL) under
a nitrogen atmosphere was stirred overnight at room tem-
perature. The mixture was then cooled to ꢀ78 ꢁC. n-Octyl
magnesium bromide (3.0 mL of a 2 M commercial solution
in diethyl ether, 6.0 mmol) was then added dropwise and
the solution was stirred at ꢀ78 ꢁC for 1 h. Aldehyde 15
(465 mg, 1.43 mmol) in solution in anhydrous THF
(2 mL) was added and the mixture stirred at ꢀ78 ꢁC for
5 h and then at 0 ꢁC for 1 h. The reaction was quenched
by addition of a saturated aqueous solution of NH4Cl
(42 mL) and then stirred at 0 ꢁC for 30 min. The mixture
was diluted by the addition of THF, vigorously stirred at
room temperature and decanted. The organic layer was
separated and the extraction repeated with AcOEt
(3 · 50 mL). The combined extracts were washed with
brine, died over Na2SO4 and concentrated to dryness.
The crude material was purified by column chromatogra-
mCC 2228, mC@O 1736 cmꢀ1; H NMR (400 MHz, CDCl3)
d 7.40–7.30 (m, 8H, Ph), 7.21–7.18 (m, 2H, Ph), 4.74–
4.68 (m, 1H, H4), 4.52 (dd, 1H, H3, 3J = 8.0 Hz and
2
5.6 Hz), 4.50 (ABq, 2H, OCH2Ph, Jgem = 11.6 Hz,
2
Dd = 52.0 Hz), 4.41 (ABq, 2H, NCH2Ph, Jgem = 16.4 Hz,
Dd = 303.0 Hz), 3.87–3.82 (m, 2H, H1, H2), 3.74 (dd, 1H,
2
3
H10, Jgem = 11.2 Hz, JH
¼ 6:2 Hz), 2.20 (dt, 2H, H7,
–H
0
2
1
3JH –H ¼ 7:0 Hz, JH –H ¼ 2:0 Hz), 1.55–1.45 (m, 2H,
5
7
8
7
4
H8), 1.40–1.27 (m, 4H, H9, H10), 0.91 (t, 3H, Me,
3J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d 158.4
(C@O), 136.6, 136.1 (Cq, NCH2Ph, OCH2Ph), 129.0,
128.9, 128.6, 128.5, 128.2, 128.1 (CH, Ph), 88.3 (C5 or
C6), 77.8 (C3), 77.1 (C6 or C5), 73.8 (OCH2Ph), 65.2 (C1),
61.4 (C4), 56.1 (C2), 46.7 (NCH2Ph), 31.3 (C9), 28.3 (C8),
22.4 (C10), 18.9 (C7), 14.2 (CH3) MS (DCI/NH3) m/z 439
(M+NH4)+; HRMS (CI) m/z calcd for C26H32NO4:
422.2331; found, 422.2332.
4.1.8.
(4S,5S)-3-Benzyl-4-(benzyloxymethyl)-5-[(1R)-1-
phy on SiO2 eluted with PE/Et2O (60:40 to 50:50) to give
(methanesulfonyloxyoctyl)]-2-oxazolidinone 18. To a solu-
tion of alcohol 16 (168 mg, 0.38 mmol) in anhydrous
CH2Cl2 (6 mL) at 0 ꢁC under a nitrogen atmosphere was
added mesyl chloride (40 lL, 0.52 mmol). After 5 min
Et3N (80 lL, 0.57 mmol) was added and the solution stir-
red for 25 min at 0 ꢁC and 1 h at room temperature. Water
(10 mL) was then added and the reaction mixture extracted
three times with CH2Cl2. The combined extracts were
washed with brine, dried over Na2SO4 and concentrated
in vacuo. The crude material was purified by column chro-
matography on SiO2 eluted with PE/CH2Cl2/AcOEt
20
16 (350 mg, 56%) as a colourless oil. ½aꢁD ¼ þ26:4
(c 1.65, CHCl3); IR (film) mOH 3410, mC@O 1735 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.42–7.27 (m, 8H, Ph),
2
7.25–7.20 (m, 2H, Ph), 4.40 (ABq, 2H, NCH2Ph, Jgem
=
15.4 Hz, Dd = 302.0 Hz), 4.52 (ABq, 2H, OCH2Ph,
2Jgem = 11.6 Hz, Dd = 26.0 Hz), 4.20 (dd, 1H, H3,
3J = 9.4 Hz and 7.0 Hz), 3.81–3.76 (m, 2H, H2, H4), 3.58
2
3
(AB of an ABX, 2H, 2 · H1, Jgem = 10.0 Hz, JH ;H
=
1
2
8.4 Hz, 3JH
= 3.0 Hz Dd = 36.4 Hz), 1.82–1.75 (m,
;H
0
2
1
0
1H, H5), 1.60–1.22 (m, 13H, H5 , H6–H11), 0.91 (t, 3H,
3J = 6.8 Hz, Me), 13C NMR (100 MHz, CDCl3) d 157.7
(C@O), 136.3, 136.2 (Cq, NCH2Ph, OCH2Ph), 129.1,
129.0, 128.8, 128.5, 128.3, 128.1 (CH, Ph), 79.5 (C3), 74.1
(OCH2Ph), 68.2 (C4), 64.7 (C1), 56.3 (C2), 46.7 (NCH2Ph),
33.7, 32.1, 29.8, 29.7, 29.5, 25.0, 22.9 (C5–C11), 14.3 (CH3);
MS (APCI) m/z 440 (M+H)+; HRMS (CI) m/z calcd for
C27H38NO4: 440.2801; found, 440.2804.
(70:24:6 to 60:32:8) to give 18 (178 mg, 90%) as a colourless
20
oil. ½aꢁD ¼ þ26:0 (c 1.0, CHCl3); IR (film) mC@O 1752 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.44–7.26 (m, 8H, Ph),
7.20–7.14 (m, 2H, Ph), 5.14 (pseudoq, 1H, H4,
3JH –H ¼ 3JH –H ¼ 6:8 Hz), 4.60–4.52 (m, 1H, H3), 4.50
4
3
4
5
2
(ABq, 2H, OCH2Ph, Jg2em = 14.1 Hz, Dd = 59.5 Hz), 4.35
(ABq, 2H, NCH2Ph, Jgem = 18.3 Hz, Dd = 261.0 Hz),
2
0
3.73–3.68 (m, 2H, H1, H2), 3.60 (dd, 1H, H1 , Jgem
13.9 Hz, JH
=
3
4.1.7. (4S,5S)-3-Benzyl-4-(benzyloxymethyl)-5-[(1R)-1-hydr-
oxy-2-(heptynyl)]-2-oxazolidinone 17. A suspension of
anhydrous CeCl3 (562 mg, 2.28 mmol) in anhydrous THF
(9 mL) under a nitrogen atmosphere was stirred overnight
at room temperature. Meanwhile a solution of n-heptyne
lithium was prepared by the addition of n-BuLi (1.5 mL
of a 1.6 M commercial solution in hexanes) to n-heptyne
(300 lL, 2.28 mmol) in anhydrous THF (10 mL) at 0 ꢁC.
The suspension of CeCl3 was then cooled to ꢀ78 ꢁC, the
n-heptyne lithium solution added dropwise and the reac-
¼ 4:9 Hz), 2.99 (s, 3H, OSO2CH3), 1.95–
–H
0
2
1
1.80 (m, 2H, H5), 1.55–1.20 (m, 12H, H6–H11), 0.88 (t,
3H, Me, 3J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d
157.3 (C@O), 137.2, 135.8 (Cq, Ph), 128.8, 128.7, 128.6,
128.2, 128.1, 128.0 (CH, Ph), 79.2 (C3), 75.3 (C4), 73.2
(OCH2Ph), 64.5 (C1), 56.3 (C2), 46.3 (NCH2Ph), 39.2
(OSO2CH3), 31.8, 30.9, 29.6, 29.4, 29.2, 23.9, 22.6 (C5–
C11), 14.1 (Me); MS (DCI/NH3) m/z 535 (M+NH4)+;
HRMS (ESI) m/z calcd for C28H39NO6SNa: 540.2396;
found, 540.2394.

Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
863
1
4.1.9. (3aS,6S,6aS)-3-Benzyl-6-octyltetrahydrofuro[3,4-d]-
[1,3]oxazol-2(3H)-one 19. A solution of mesylate 18
(170 mg, 0.33 mmol) in ethanol (3.5 mL) containing
Pd(OH)2 (25 mg) was stirred under H2 atmosphere
(10 bars) for 2 days. The reaction mixture was then filtered
over Celite, the precipitate was rinsed with CH2Cl2 and the
filtrate concentrated in vacuo. The crude material was puri-
fied by column chromatography on SiO2 eluted with PE/
(neat) mOH,NH 3340 cmꢀ1; H NMR (500 MHz, CDCl3) d
2
3
3.93 (dd, 1H, H1, JH –H ¼ 8:6 Hz; JH –H ¼ 7:5 Hz),
0
1
1
2
1
3
3
3.86 (dd, 1H, H3, JH –H ¼ 5:0 Hz; JH –H ¼ 3:6 Hz),
3
2
3
4
3
3.73
(ddd,
1H,
H4,
3JH –H ¼ 7:5 Hz; JH –H
¼
0
4
5
4
5
3
6:3 Hz; JH –H ¼ 3:4 Hz), 3.66 (dpseudot, 1H, H2,
4
3
3
3
0
JH –H ꢂ 7:0 Hz; JH –H ¼ 5:2 Hz), 3.51 (dd, 1H, H1 ,
2
1
2
3
2JH
¼ 8:6 Hz; JH
¼ 6:8 Hz), 1.90–1.60 (m, 5H,
3
–H
–H
0
0
1
2
2 · 1H5, NH2, OH), 1.50–1.20 (m, 12H, 6 · CH2), 0.90 (t,
1
3
CH2Cl2/AcOEt (70:24:6 to 60:32:8) to give 19 (82 mg,
3H, Me, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d 83.2
20
75%) as a white solid. Mp: 179 ꢁC; ½aꢁD ¼ þ69:5 (c 1.0,
(C4), 72.3 (C1), 71.7 (C3), 54.3 (C2), 31.9 (C5), 29.8, 29.7,
29.5, 29.4, 29.3, 26.3, 22.7 (C6–C11), 14.1 (C12); SM
(DCI, NH3) m/z 233 MNH4þ; HRMS (CI) m/z calcd
C12H26NO2: 216.1964; found, 216.1965.
1
CHCl3); IR (film) mC@O 1751 cmꢀ1; H NMR (400 MHz,
CDCl3) d 7.39–7.30 (m, 3H, Ph), 7.29–7.25 (m, 2H, Ph),
3
3
4.78 (dd, 1H, H3, JH –H ¼ 8:0 Hz, JH –H ¼ 4:0 Hz),
4.46 (ABq, 2H, NCH2Ph, 2Jgem = 15.2 Hz, D3d = 130.0 Hz),
3
2
4
4.09 (dd, 1H, H2, 3JH –H ¼ 7:6 Hz; JH –H ¼ 4:0 Hz), 3.96
3
4.1.12. Cell viability experiments. Murine B16 or human
A375 melanoma cell lines were seeded in 24-well plates
and at 70% confluency, compound 22 was added at the
indicated concentrations. After 24 h, cell viability was esti-
mated by assessing the cellular MTT conversion capacity.
Data are expressed as a percentage of the values of un-
treated cells. Shown are the means SE (n = 2–7).
2
3
2
10
2
2
(d, 1H, H1, Jgem = 10.4 Hz), 3.45 (dt, 1H, H4, JH –H
¼
4
5
2
0
6:8 Hz; JH –H ¼ 4:0 Hz), 3.31 (dd, 1H, H1 , Jgem
=
3
3 4
10.6 Hz, JH
¼ 4:2 Hz), 1.80–1.72 (m, 2H, H5), 1.48–
–H
0
2
1
1.22 (m, 12H, H6–H11), 0.88 (t, 3H, Me, J = 6.8 Hz);13C
NMR (100 MHz, CDCl3) d 157 (C@O), 135.6 (Cq, Ph),
129.2, 128.4, 128.3 (CH, Ph), 83.7 (C4), 78.0 (C3), 69.5
(C1), 60.2 (C2), 47.0 (NCH2Ph), 32.1, 29.8, 29.7, 29.4,
28.2, 26.2, 22.9 (C5–C11), 14.3 (Me); MS (DCI/NH3) m/z
349 (M+NH4)+; HRMS (CI) m/z calcd C20H30NO3:
332.222; found, 332.2229.
3
Acknowledgements
`
We thank Professors M. A. Pericas and A. Riera for help-
4.1.10. (3aS,6S,6aS)-6-Octyltetrahydrofuro[3,4-d][1,3]oxa-
zol-2(3H)-one 20. A solution of 19 (20 mg, 0.06 mmol)
in THF (1 mL) was added to a deep blue solution of Na
(100 mg, 4.3 mmol) in liquid NH3 (ca. 5 mL) at ꢀ78 ꢁC
under a nitrogen atmosphere and the mixture was stirred
at ꢀ78 ꢁC for 4 h. The reaction was quenched by the addi-
tion of solid NH4Cl and the ammonia was allowed to evap-
orate at room temperature. AcOEt was then added and the
mixture sonicated before being filtered over Celite. The preci-
pitate was rinsed with AcOEt and the filtrate concentrated
in vacuo. The crude material was purified by column chro-
matography on SiO2 eluted with CH2Cl2/AcOEt (70:30 to
ful personal communication.
References
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Biochim. Biophys. Acta 2000, 1485, 63–99.
2. For synthetic approaches see: Howell, A. R.; Ndakala, A. J.
Curr. Org. Chem. 2002, 6, 365–391; For a-galactosylcera-
mides as immunostimulatory and antitumour agents see:
Hayakawa, Y.; Godfrey, D. I.; Smyth, M. J. Curr. Med.
Chem. 2004, 11, 241–252.
3. Pettus, B. J.; Chalfant, C. E.; Hannun, Y. A. Biochim.
Biophys. Acta 2002, 1585, 114–125.
4. Spiegel, S.; Milstein, S. Nat. Rev. Mol. Cell Biol. 2003, 4, 397–
407.
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Target 2004, 5, 375–382; Padron, J. M. Curr. Med. Chem.
2006, 13, 755–770.
50:50) to give 20 (12 mg, 83%) as a colourless oil.
20
½aꢁD ¼ þ77:7 (c 0.6, CHCl3); IR (film) mC@O 1740 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 5.95 (1s, 1H, NH), 4.88
3
3
(dd, 1H, H3, JH –H ¼ 3:6 Hz, JH –H ¼ 7:5 Hz), 4.30
3
4
3
2
3
3
(dd, 1H, H2, JH –H ¼ 3:9 Hz, JH –H ¼ 7:5 Hz), 3.66
2
1
2
3
2
3
(AB of an ABX, 2H, 2 · H1, Jgem = 10.5 Hz, JH –H
¼
1
2
3
3:9 Hz; JH
¼ 0:0 Hz Dd = 129.0 Hz), 3.48–3.43 (m,
–H
0
2
1
1H, H4), 1.75–1.65 (m, 2H, H5), 1.40–1.15 (m, 12H, H6–
H11), 0.81 (t, 3H, Me, J = 7.0 Hz);13C NMR (75 MHz,
CDCl3) d 159 (C@O), 83.2 (C4), 81.0 (C3), 73.3 (C1), 57.2
(C2), 31.8, 29.6, 29.4, 29.2, 28.1, 26.0, 22.6 (C5–C11), 14.1
(Me); MS (DCI/NH3) m/z 276 (MNH4)+; HRMS (CI)
m/z calcd C13H24NO3: 242.1756; found, 242.1757.
´
6. Ayad, T.; Genisson, Y.; Verdu, A.; Baltas, M.; Gorrichon, L.
Tetrahedron Lett. 2003, 44, 579–582.
7. Wee, A. G. H.; Tang, F. Tetrahedron Lett. 1996, 37, 6677–
6680; Wee, A. G. H.; Tang, F. Can. J. Chem. 1998, 76, 1070–
1081.
`
8. Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Pericas,
M. A.; Riera, A. Tetrahedron Lett. 1991, 32, 6931–6934;
´
`
Alcon, M.; Moyano, A.; Pericas, M. A.; Riera, A. Tetra-
4.1.11. (2S,3S,4S)-4-Amino-2-(octyl)tetrahydrofuran-3-ol
22. KOH (23 mg, 0.41 mmol) was added to a solution
of 20 (10 mg, 0.04 mmol) in EtOH (800 lL) and H2O
(200 lL). The mixture was heated at 85 ꢁC for 7 h before
being diluted with AcOEt and brine. The mixture was ex-
tracted three times with AcOEt and the combined extracts
were concentrated in vacuo. The crude material was puri-
fied by column chromatography on SiO2 eluted with
´
hedron: Asymmetry 1999, 10, 4639–4651; Martin, R.; Alcon,
M.; Pericas, M. A.; Riera, A. J. Org. Chem. 2002, 67, 6896–
`
6901.
9. Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemical Shifts
in Structural and Stereochemical Analysis; VCH: New York,
1994, pp 55–56.
10. Melon, D.; Gravier-Pelletier, C.; Le Merrer, Y.; Depezay, J.
C. Bull. Soc. Fr. Chim. 1992, 129, 585–593.
11. Crystal data for 13: C19H21NO4, M = 327.3, monoclinic, P21,
AcOEt/MeOH/NH4OH (69.2:30:0.8) to give 22 (8.2 mg,
20
˚
˚
˚
95%) as a white solid. ½aꢁD ¼ þ20:0 (c 0.5, CHCl3); IR
a = 4.718(1) A, b = 31.915(8) A, c = 11.238(3) A, b =

864
Y. Ge´nisson et al. / Tetrahedron: Asymmetry 18 (2007) 857–864
3
92.376(5)ꢁ, V = 1690.5(8) A , Z = 4, qcalcd = 1.286 Mg mꢀ3
,
17. Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett.
2005, 7, 875–876.
18. Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2006, 71, 1251–
1253.
19. Liu, J.; Du, Y.; Dong, X.; Meng, S.; Xiao, J.; Cheng, L.
Carbohydrate Res. 2006, 341, 2653–2657.
20. Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron
2006, 62, 5421–5425.
˚
˚
F(000) = 696, k = 0.71073 A, T = 193(2) K, l(MoKa) =
0.090 mmꢀ1, crystal dimensions 0.05 · 0.1 · 0.7 mm3, 8076
reflections (4089 independent, Rint = 0.0684) were collected at
low temperatures using an oil-coated shock-cooled crystal on
a Bruker-AXS CCD 1000 diffractometer. The structure was
solved by direct method (SHELXS-97)12 and 435 parameters
were refined using the least-squares method on F2.13 Largest
electron density residue 0.165 e Aꢀ3, R1 (for I > 2r(I)) =
21. Chandrasekhar, S.; Tiwari, B.; Prakash, S. J. ARKIVOC
2006, xi, 155–161.
˚
P
0.0544 and wR2 (all data) = 0.1049 with R1 = jFojꢀ
P
P
P
2
2 0:5
jFcj/ jFoj and wR2 ¼ wð wðF 2o ꢀ F c2Þ = wðF o2Þ Þ
.
22. For recent synthetic reports from phytosphingosine see: Jo, S.
Y.; Kim, H. C.; Jeon, D. J.; Kim, H. R. Heterocycles 2001,
55, 1127–1132; van den Berg, R. J. B. H. N.; Boltje, T. J.;
Verhagen, C. P.; Litjens, R. E. J. N.; van den Marel, G. A.;
Overkleeft, H. S. J. Org. Chem. 2006, 71, 836–839; Lee, T.;
Lee, S.; Kwak, Y. S.; Kim, D.; Kim, S. Org. Lett. 2007, 9,
429–432.
CCDC 629176 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
12. Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467–
473.
23. Structure of 21 was assigned on the basis of the following
1
13. Sheldrick, G. M. SHELXL-97: Program for Crystal Structure
Refinement; University of Go¨ttingen, 1997.
14. Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.;
Garcia Gravalos, D.; Higa, T. J. Nat. Prod. 2002, 65, 1505–
1506.
data: H NMR (300 MHz, CDCl3) d 7.32–7.17 (m, 5H, Ph),
3.88–3.82 (m, 2H, H1, H3), 3.73 (ABq, 2H, NCH2Ph,
2Jgem = 13.1 Hz, Dd = 24.0 Hz), 3.67–3.58 (m, 1H, H4),
0
3.52–3.45 (m, 1H, H1 ), 3.41–3.32 (m, 1H, H2), 2.55 (1s, 2H,
OH, NH), 1.70–1.54 (m, 2H, H5), 1.38–1.14 (m, 12H, H6–
15. Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetrahe-
dron Lett. 2003, 44, 225–228.
H11), 0.84–0.76 (m, 3H, Me); SM (DCI, NH3) m/z 306
(M+H+).
16. Sudhakar, N.; Kumar, A. R.; Prabhakar, A.; Jagadeesh, B.;
Rao, B. V. Tetrahedron Lett. 2005, 46, 325–327.
24. Skidmore, W. D.; Entenman, C. J. Lipid Res. 1962, 3, 471–
475.