Synthesis of Ceramide Analogues Having the C(4)-C(5) Bond of the Long-Chain Base as Part of an Aromatic or Heteroaromatic System

Article abstract of DOI:10.1021/jo001227f

Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl ceramide analogues 2 and 3. The first route involves the addition of an aryllithium or a heteroaryllithium reagent (7a or 25a, respectively) to the L-serine-derived aldehyde 4, followed by hydrolysis of the oxazolidine, liberation of the amino group, and N-acylation. The second route, which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting with 3-bromobenzaldehyde, utilizes a Heck reaction to afford (E)-α,β-unsaturated ester 16, then osmium-catalyzed asymmetric dihydroxylation for the introduction of the desired chirality at C-2 and C-3. Regioselective α-azidation of α-O-nosyl-β-hydroxyester 18 with sodium azide, followed by LiAlH₄ reduction of the azido and ester groups and N-acylation, complete the synthesis of arylceramide analogue 2.

Full text of DOI:10.1021/jo001227f

7634
J . Org. Chem. 2000, 65, 7634-7640
Syn th esis of Cer a m id e An a logu es Ha vin g th e C(4)-C(5) Bon d of
th e Lon g-Ch a in Ba se a s P a r t of a n Ar om a tic or Heter oa r om a tic
System
J iong Chun, Linli He, Hoe-Sup Byun, and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York,
Flushing, New York 11367-1597
robert_bittman@qc.edu
Received August 10, 2000
Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl
ceramide analogues 2 and 3. The first route involves the addition of an aryllithium or a
heteroaryllithium reagent (7a or 25a , respectively) to the L-serine-derived aldehyde 4, followed by
hydrolysis of the oxazolidine, liberation of the amino group, and N-acylation. The second route,
which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting
with 3-bromobenzaldehyde, utilizes a Heck reaction to afford (E)-R,â-unsaturated ester 16, then
osmium-catalyzed asymmetric dihydroxylation for the introduction of the desired chirality at C-2
and C-3. Regioselective R-azidation of R-O-nosyl-â-hydroxyester 18 with sodium azide, followed by
LiAlH4 reduction of the azido and ester groups and N-acylation, complete the synthesis of
arylceramide analogue 2.
Ch a r t 1
In tr od u ction
Ceramide (N-acylsphingosine, 1) is a long-chain ali-
phatic 2-amido-1,3-diol with a C(4),C(5)-trans double
bond; the predominant long-chain base found in mam-
malian cells has 18 carbons (Chart 1).1 Ceramide is an
important signaling molecule that has been implicated
in a myriad of physiological events, including the regula-
tion of cell growth and differentiation, inflammation, and
apotosis.2 The mechanisms by which ceramide regulates
cellular functions involve its ability to stimulate kinases
and protein phosphatases.2
Ceramide is one of the major lipid components of
human skin. It comprises about 35% of the total lipids
in human stratum corneum (the apical skin layer).3 Its
role in normal skin tissue function includes maintenance
of the permeability barrier and water-binding properties
of the outer layer.4
biological functions.6 Indeed, it was shown very recently
that an unnatural ceramide analogue having a trans
C(5)-C(6) double bond is unable to support fusion of
SFV.7 To obtain more information about viral fusion at
the molecular level, we set out to prepare a series of new
ceramide analogues in which unsaturated functional
groups are incorporated. In the present study, the C(4)-
C(5) double bond of the long-chain base was incorporated
into an aromatic ring such as benzene and pyridine
(Chart 1, compounds 2 and 3). These analogues will allow
us to test whether a C(4)-C(5)-double bond that is part
of an aromatic or heteroaromatic system can substitute
for the aliphatic double bond in the long-chain base of 1
in the activation of fusion of SFV with target membranes.
Ceramides are the minimally required sphingolipids
for activation of membrane fusion of Semliki Forest virus
(SFV).5 The C(4)-C(5) trans double bond in the sphingoid
base of naturally occurring 1 may be crucial for
ceramide’s capacity to modulate various fundamental
* To whom correspondence should be addressed. Tel: (718) 997-
3279. Fax: (718) 997-3349.
(1) Karlsson, K.-A. Chem. Phys. Lipids 1970, 5, 6-43.
(2) (a) Hannun, Y. A. Science 1996, 274, 1855-1859. (b) Ariga, T.;
J arvis, W. D.; Yu, R. K. J . Lipid Res. 1998, 39, 1-16. (c) Mathias, S.;
Pen˜a, L. A.; Kolesnick, R. N. Biochem. J . 1998, 335, 465-480. (d) Perry,
D. K.; Hannun, Y. A. Biochim. Biophys. Acta 1998, 1436, 233-243.
(3) (a) Lampe, M. A.; Burlingame, A. L.; Whitney, J .; Williams, M.
L.; Brown, B. E.; Roitman, E.; Elias, P. M. J . Lipid Res. 1983, 24, 120-
130. (b) Downing, D. T. J . Lipid Res. 1992, 33, 301-313. (c) Wertz, P.
W.; Kremer, M.; Squier, C. A. J . Invest. Dermatol. 1992, 98, 375-378.
(d) Gildenast, T.; Lasch, J . Biochim. Biophys. Acta 1997, 1346, 69-
74.
(4) (a) Scheuplein, R. J .; Blank, I. H. Physiol. Rev. 1971, 51, 702-
747. (b) Long, S. A.; Wertz, P. W.; Strauss, J . S.; Downing, D. T. Arch.
Dermatol. Res. 1985, 277, 284-287.
(5) (a) Nieva, J . L.; Bron, R.; Corver, J .; Wilschut, J . EMBO J . 1994,
13, 2797-2804. (b) Wilschut, J .; Nieva, J . L.; Bron, R.; Moesby, L.;
Reddy, K. C.; Bittman, R. Mol. Membr. Biol. 1995, 12, 143-149.
Resu lts a n d Discu ssion
Syn th esis of Ar ylcer a m id e An a logu e 2. The devel-
opment of new methods for the synthesis of sphingosine
and its stereoisomers has been an active field of re-
search.8 In 1988, Garner and co-workers used L-serine
aldehyde 4 (“Garner aldehyde,” which is prepared from
L-(N-Boc) serine methyl ester) for the synthesis of
(6) Corver, J .; Moesby, L.; Erukulla, R. K.; Reddy, K. C.; Bittman,
R.; Wilschut, J . J . Virol. 1995, 69, 3220-3223.
(7) He, L.; Byun, H.-S.; Smith, J .; Wilschut, J .; Bittman, R. J . Am.
Chem. Soc. 1999, 121, 3897-3903.
10.1021/jo001227f CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

Asymmetric Synthesis of New Ceramide Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7635
Sch em e 1. Syn th esis of Cer a m id e An a logu e 2a
Sch em e 2. Oxid a tion a n d Dia ster eoselective
Red u ction
Ta ble 1. Dia ster eoselective Red u ction of 11
reducing
overall
agent
solvent
T (°C) time (h) yield (%) ratio (8:9)
DIBAL
NaBH4
LiBH4
Red-Al
THF
0
0.5
2
2
94
90
93
92
26:1
MeOH
MeOH
toluene
0 to rt
0 to rt
0
1.0:3.2
1.0:2.9
1.0:2.3
2
2 was obtained by N-acylation of sphingosine 10 with
p-nitrophenyl palmitate.
Dia ster eoselective Red u ction of L-(N-Boc)-oxa zo-
lid in e Keton e 11. Scheme 2 outlines an improved
chirospecific route to 2. For induction of stereochemistry
at C-3 of the target ceramide analogue, ketone 11 was
prepared by PCC oxidation of a mixture of 8 and 9, and
several reducing agents were screened for attempted
diastereoselective reduction. As shown in Table 1, high
erythro selectivity was observed with DIBAL, which gave
erythro-8/threo-9 in a ratio of 26:1. However, the undes-
ired threo diastereomer was formed as the major product
with the other reducing agents we used. LiBH4 and
NaBH4 gave a ∼3:1 ratio of threo/erythro isomers; Red-
Al also resulted in threo selectivity (9:8, 2.3:1.0 ratio),
in agreement with previous studies on the reduction of
a ketone linked to an N-Boc-protected oxazolidine.8e,15
Ster eoch em istr y a t C(3) of Cer a m id e An a logu e 2.
To establish the configurations of 8 and 9, we converted
8 to the corresponding acetonide 13 in two steps (Scheme
3).14,16 First, the oxazolidine group was removed by
treatment with an acidic resin (Amberlyst 15) in metha-
nol, forming 12; then, acetalization (2,2-dimethoxypro-
pane, PPTS, CH2Cl2) afforded 13. Since the protons on
C(4) and C(5) occupy the axial position in the chair
conformation of 13, erythro derivative 13 is expected to
have a larger coupling constant (J 4,5 ∼10 Hz) than threo
derivative 15 (J 4,5 ∼1-3 Hz).14 The configurations of 13
and 15 were confirmed by their coupling constants (J 4,5
) 9.3 Hz in 13 and J 4,5 ) 1.3 Hz in 15).
a
Reagents and conditions: (a) n-C11H23MgBr, THF, 0 °C; (b)
Me3SiCl, NaI, MeCN, hexane, rt; (c) n-BuLi, THF, -42 °C; (d) 1
M HCl, THF, 70 °C; (e) p-O2NC6H4CO2C15H31-n, THF, rt.
sphingosine.9a One of the routes used in the present work
started with Garner aldehyde 4 as the chiral synthon to
prepare the target compounds 2 and 3. In this route, the
stereochemistry at C-2 of the target ceramide analogue
is introduced from the L-serine-derived aldehyde 4. Our
approach to 2, which represents an analogue of natural
ceramide (1) in which the aliphatic trans double bond is
incorporated into a benzene ring, is shown in Scheme 1.
Reaction of 3-bromobenzaldehyde 5 with undecylmagne-
sium bromide in THF at 0 °C gave benzylic alcohol 6,
which was reduced by using chlorotrimethylsilane in the
presence of sodium iodide in acetonitrile-hexane to yield
aryl bromide 7.10 The latter was lithiated (n-BuLi, THF,
-42 °C) and reacted with aldehyde 4 to give a mixture
of erythro-8 and threo-9 in 51% overall yield. The ratio
1
of 8:9 was found to be 5:1 by high-temperature H NMR
spectroscopy.11 Addition of 2 equiv of HMPA12 did not
improve the diastereoselectivity significantly. After dia-
stereomers 8 and 9 were separated chromatographi-
cally,13 acid hydrolysis of 8 (1 M HCl in THF, 70 °C)
provided D-erythro-sphingosine 10. Ceramide analogue
(8) For recent reviews, see: (a) Byun, H.-S.; Bittman, R. In Phos-
pholipids Handbook; Cevc, G., Ed.; Marcel Dekker: New York, 1993;
pp 97-140. (b) Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 8,
1075-1091. (c) J ung, K.-H.; Schmidt, R. R. In Lipid Synthesis and
Manufacture; Gunstone, F. D., Ed.; Sheffield Academic Press: Shef-
field, U.K.; CRC Press: Boca Raton, FL, 1999; pp 208-249. (d)
Curfman, C.; Liotta, D. Methods Enzymol. 2000, 311, 391-457. (e)
Koskinen, P. M.; Koskinen, A. M. P. Methods Enzymol. 2000, 311, 458-
479.
Con ver sion of 3-Br om oben za ld eh yd e (5) to 2.
Scheme 4 outlines our second route to arylceramide
(12) Herold14 found that the reaction of 1-pentadecyllithium with
aldehyde 4 at -78 °C produced high erythro stereoselectivity when
HMPA was used as the cosolvent. HMPA competes effectively with
the N-Boc group for coordination to the metal ion; a nonchelated
Felkin-Ahn model can rationalize attack of the alkynyl anion at the
less-hindered re face of aldehyde 4, leading to D-erythro product.8d
However, we noted only a slight effect on the diastereoselectivity when
HMPA was added as a cosolvent (ratio of 8:9, 5.7:1.0).
(9) (a) Garner, P.; Park, J . M.; Malecki, E. J . Org. Chem. 1988, 53,
4395-4398. (b) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-
2364. (c) Garner, P.; Park, J . M. Org. Synth. 1991, 70, 18-27.
(10) (a) For dehydroxylation with Me3SiCl-NaI-MeCN, see: Sakai,
T.; Miyata, K.; Utaka, M.; Takeda, A. Tetrahedron Lett. 1987, 28,
3817-3818, and references therein. (b) Selective dehydroxylation of 6
was also attempted with: (i) palladium-catalyzed hydrogenolysis (H2/
10% Pd/C in EtOH); (ii) Wolff-Kishner reduction of the corresponding
ketone of 6. However, with H2/10% Pd/C, both the hydroxyl group and
the bromine in 6 were removed. The reproducibility of the Wolff-
Kishner reaction was poor, with a maximum yield of 56%.
(13) TLC analysis (Merck silica gel 60F-254, developed with 1:4
EtOAc/hexane) showed the formation of 8 (Rf 0.54) and 9 (Rf 0.48).
(14) Herold, P. Helv. Chim. Acta 1988, 71, 354-362.
(15) Nishida, A.; Sorimachi, H.; Iwaida, M.; Matsumizu, M.; Kawate,
T.; Nakagawa, M. Synlett 1998, 4, 389-390.
(16) Van Overmeire, I.; Boldin, S. A.; Dumont, F.; Van Calenbergh,
S.; Slegers, G.; De Keukeleire, D.; Futerman, A. H.; Herdewijn, P. J .
Med. Chem. 1999, 42, 2697-2705.
(11) The ratio of 8:9 was determined by 400-MHz 1H NMR (C6D6 at
60 °C): C(1′)-H; δ 5.10 (br s) for 8, δ 4.92 (d, J ) 7.8 Hz) for 9.

7636 J . Org. Chem., Vol. 65, No. 22, 2000
Chun et al.
Sch em e 5. Syn th eses of Ar yl-Su bstitu ted
Sch em e 3. Syn th esis of Aceton id es 13 a n d 15a
Cer a m id e An a logu e 2 a n d th e Cor r esp on d in g
Sp h in gosin e An a logu e 10
a
Reagents and conditions: (a) Amberlyst 15, MeOH, rt; (b)
Me2C(OMe)2, PPTS, CH2Cl2, rt.
Sch em e 4. P r ep a r a tion of r-Azid o Ester 19a
yield, together with a small amount of R,â-unsaturated
byproduct (generated when the R,â-dinosylate intermedi-
ate undergoes elimination).20b No â-mononosylate was
detected by TLC and NMR. Nucleophilic substitution of
nosylate 18 with NaN3 in DMF at 55 °C furnished the
desired azido ester 19 in 75% yield.21
Staudinger reduction22 followed by in situ N-acylation
with p-nitrophenyl palmitate was attempted for the
conversion of azido ester 19 to the corresponding amido
ester 21 (Scheme 5). Unexpectedly, aziridine 20 was
formed as the major product (83% yield) instead of the
desired amido ester 21 (∼10% yield). Aziridine 20 was
also formed (90% yield) when the activated fatty acid was
omitted from the reaction mixture. Therefore, we suggest
that the transformation of 19 to 20 may take place via
an intramolecular Mitsunobu23 reaction; the benzylic
hydroxyl group may undergo nucleophilic displacement
during the reaction, as outlined in Scheme 5. Scheme 5
demonstrates that the conversion of 19 to 2 could also
be achieved in 76% overall yield via the corresponding
sphingosine 10. The latter was obtained in 85% yield by
LiAlH4 reduction of azido ester 19. This eight-step
synthesis starting from commercially available 3-bro-
mobenzaldehyde provided ceramide analogue 2 in 28%
overall yield and should also be applicable to the prepa-
ration of the L-erythro stereoisomer. Alternatively, azide
19 was reduced with Lindlar catalyst and then N-
acylated to give amido ester 21, which afforded product
2 on borohydride reduction (Scheme 5).
a
Reagents and conditions: (a) CH2dCHCO2Et, (Ph3P)4Pd(0),
Et3N, DMF, 120 °C; (b) AD-mix-â, MeSO2NH2, t-BuOH/H2O 1/1,
rt; (c) p-O2NC6H4SO2Cl, Et3N, CH2Cl2, 0 °C; (d) NaN3, DMF, 55
°C.
analogue 2, i.e., via a Heck reaction17 to provide the
desired R,â-unsaturated ester 16. Reaction of m-bromo-
dodecylbenzene 7 with ethyl acrylate in the presence of
a catalytic amount of tetrakis(triphenylphosphine)Pd(0)
at 120 °C afforded cinnamate derivative 16 in high yield
(92%). Sharpless asymmetric dihydroxylation18 of 16
provided diol ester 17 in 90% yield and >99% ee.19
Regioselective R-azidation of diol ester 17 was achieved
via nosylate intermediate 18. The selectivity of the
mononosylation reaction at C-2 of diol 17 may arise
because of intramolecular hydrogen bonding between the
C-3 hydroxy group and the carbonyl group20a or the
difference in acidity of the two hydroxy groups.20b The
desired 3-hydroxy-2-nosylate 18 was obtained in 83%
(17) For reviews of the Heck reaction, see: (a) Shibasaki, M.; Boden,
C. D. J .; Kojima, A. Tetrahedron 1997, 53, 7371-7393. (b) Heck, R. F.
In Palladium Reagents in Organic Synthesis; Academic: New York,
1985. (c) de Meijere, A.; Meger, F. E. Angew. Chem., Intl. Ed. Engl.
1994, 33, 2379-2411. (d) Bra¨se, S.; de Meijere, A. In Metal-catalyzed
Cross-coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley: New
York, 1998; pp 99-166. (e) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000, 100, 3009-3066.
Syn th esis of Heter oa r ylcer a m id e An a logu e 3.
Compound 3 represents an analogue of natural ceramide
in which the trans double bond is incorporated into a
(20) (a) Denis, J .-N.; Correa, A.; Greene, A. E. J . Org. Chem. 1990,
55, 1957-1959. (b) Fleming, P. R.; Sharpless, K. B. J . Org. Chem. 1991,
56, 2869-2875.
(18) For an optimized reaction procedure of an asymmetric dihy-
droxylation reaction, see: Sharpless, K. B.; Amberg, W.; Bennani, Y.
L.; Crispino, G. A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-
2771.
(21) It has been reported that such
a substitution reaction is
stereospecific in DMF but not in DMSO.20b
(22) For a review about the Staudinger reaction, see: Gololobov, Y.
G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437-472.
(23) For a review of the Mitsunobu reaction, see: Hughes, D. L. Org.
React. 1992, 42, 335-656.
(19) The enantiomeric excess (ee) was determined by 1H NMR
analysis of the corresponding bis-Mosher esters derived from diol (-)-
17 and its enantiomer (+)-17.

Asymmetric Synthesis of New Ceramide Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7637
Sch em e 6. Syn th esis of Cer a m id e An a logu e 3a
Sch em e 7. Syn th esis of Aceton id e 31a
a
Reagents and conditions: (a) Amberlyst 15, MeOH, rt; (b)
Me2C(OMe)2, PPTS, CH2Cl2, rt.
by the reaction of palmitic acid with p-nitrophenol in CH2Cl2
in the presence of DCC and DMAP. Tetrakis(triphenylphos-
phine)Pd(0) was prepared according to a reported procedure.27
NMR spectra were recorded in CDCl3 unless otherwise noted.
1-(3′-Br om op h en yl)-1-d od eca n ol (6). A suspension of 0.48
g (20 mmol) of magnesium powder in 15 mL of dry THF was
a
Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C, (ii)
treated dropwise with
a solution of 5.0 g (21 mmol) of
n-C11H23CHO, -78 °C to rt; (b) NBS, Ph3P, CH2Cl2, 0 °C to rt; (c)
NaBH4, DMSO, rt; (d) n-BuLi, THF, -78 °C; (e) 1 M HCl, THF,
70 °C; (f) p-O2NC6H4CO2C3H7-n, THF, rt.
1-bromoundecane in 20 mL of dry THF under argon atmo-
sphere at room temperature. The reaction mixture was stirred
until almost all of the magnesium metal reacted (∼3 h). After
the reaction mixture was chilled to 0 °C, a solution of 1.9 g
(10 mmol) of 3-bromobenzaldehyde in 20 mL of THF was added
dropwise over 10 min. The reaction mixture was stirred at 0
°C for 3 h, and then poured into 20 mL of ice-cold 1 M HCl
solution. The product was extracted with Et2O (3 × 40 mL).
The combined organic phase was washed with brine (2 × 10
mL), dried (MgSO4), and concentrated. Flash chromatography
(hexane/EtOAc 4:1) gave 2.84 g (84%) of the desired alcohol 6
pyridine ring. The synthesis of 3 (Scheme 6) started with
commercially available 2,6-dibromopyridine 22, which
was lithiated at -78 °C and reacted with dodecanal to
give alcohol 23 in 80% yield. The alcohol was converted
to bromide 24 in 93% yield by Mitsunobu reaction.
Reduction of the benzylic bromide with sodium borohy-
dride in DMSO provided 25 in 90% yield. Lithiation of
25 followed by reaction with Garner aldehyde 4 gave a
mixture of erythro-26 and threo-27; the ratio of 26:27 was
1
as a low-melting white solid: IR 3601, 3456 cm-1; H NMR δ
0.86 (t, 3H, J ) 7.0 Hz), 1.12-1.50 (m, 18H), 1.55-1.90 (m,
2H), 2.30 (s, 1H), 4.56 (t, 1H, J ) 5.9 Hz), 7.05-7.24 (m, 2H),
7.30-7.40 (m, 1H), 7.45 (s, 1H); 13C NMR δ 14.08, 22.64, 25.63,
29.30, 29.42, 29.48, 29.54, 29.57, 29.59, 31.87, 39.06, 73.89,
122.47, 124.46, 128.94, 129.90, 130.36, 147.24.
1
estimated to be ∼5:1 by H NMR spectroscopy. Diaste-
reoisomers 26 and 27 could not be separated by column
chromatography. Hydrolysis of 26 and 27 (1 M HCl, THF,
70 °C, 5 h) resulted in the formation of diastereomeric
sphingoid alcohol 28. Since chromatographic separation
of the diastereoisomers at this stage was still difficult,
sphingosine analogue 28 was N-acylated with p-nitro-
phenyl butyrate. Fortunately, the ceramide diastereo-
isomers were separated by column chromatography, and
the desired D-erythro stereoisomer 3 was obtained in 70%
yield.24
1-Br om o-3-d od ecylben zen e (7). To a mixture of Me3SiCl
(1.3 g, 12 mmol), NaI (1.8 g, 12 mmol), and MeCN (0.59 g, 12
mmol) was added a solution of 0.68 g (2.0 mmol) of benzylic
alcohol 6 in 2 mL of hexane at room temperature. The reaction
mixture was stirred at this temperature under nitrogen until
the disappearance of alcohol 6 was noticed by TLC (∼48 h).
The reaction mixture was then diluted with 20 mL of water,
extracted with hexane (3 × 30 mL), and dried (Na2SO4).
Concentration gave a liquid residue that was purified by flash
chromatography (hexane), giving 0.55 g (85%) of product 7 as
a colorless oil: 1H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.10-1.40
(m, 18H), 1.50-1.60 (m, 2H), 2.54 (t, 2H, J ) 7.8 Hz), 7.06-
7.14 (m, 2H), 7.23-7.31 (m, 2H); 13C NMR δ 14.13, 22.69,
29.21, 29.35, 29.45, 29.55, 29.64, 29.66, 31.26, 31.92, 35.63,
122.29, 127.06, 128.65, 129.75, 131.42, 145.29.
N-ter t-Bu toxyca r bon yl (4S)-4-[1′-(3′′-Dod ecylp h en yl)-
h yd r oxym eth yl]-2,2-d im eth yl-1,3-oxa zolid in e (8, 9). To a
solution of 0.39 g (1.2 mmol) of 7 in 10 mL of dry THF at -42
°C was added 0.5 mL (1.25 mmol) of n-BuLi (a 2.5 M solution
in hexane) dropwise under argon atmosphere. After the
mixture was stirred for 1 h, a solution of 0.23 g (1.0 mmol) of
aldehyde 4 in 5 mL of dry THF was added dropwise over a
5-min period. The mixture was stirred at -42 °C for 3 h. The
reaction was quenched by addition of aqueous saturated
NaHCO3 solution (5 mL). The organic phase was separated
and the aqueous phase was extracted with Et2O (3 × 15 mL).
To establish the configuration at C(3) in 29, a mixture
of 26 and 27 was converted to 29 and 30 (Scheme 7).
Careful separation of the diastereomers by column chro-
matography gave 29 in 65% yield. Conversion of 29 to
the corresponding acetonide 31 and NMR analysis (J 4,5
) 9.6 Hz) confirmed the absolute configuration of 29.
Exp er im en ta l Section 25
Rea gen ts. LiAlH4, NaBH4, Lindlar catalyst, AD-mix-R/â,
and p-nitrophenyl butyrate were purchased from Sigma-
Aldrich. Sodium azide and 2,6-dibromopyridine were pur-
chased from Lancaster and Acros, respectively. Garner alde-
hyde 4 was prepared from N-Boc-L-serine methyl ester as
described previously.9b,c Mosher esters were prepared as
described previously.26 p-Nitrophenyl palmitate was prepared
(26) Guivisdalsky, P. N.; Bittman, R. J . Org. Chem. 1989, 54, 4637-
4642.
(27) Coulson, D. R. Inorg. Synth. 1972, 13, 121-124.
(24) The ratio of 3 to its threo diastereoisomer was ∼5: 1.
(25) General experimental details have been described; see ref 7.

7638 J . Org. Chem., Vol. 65, No. 22, 2000
Chun et al.
The combined organic phase was washed twice with brine,
dried (MgSO4), and evaporated. Column chromatography
(hexane/EtOAc 4:1) gave 242 mg (51%) of a mixture of 8 and
9.11 Pure 8 and 9 were obtained by chromatography (hexane/
of silica gel, which was washed with CH2Cl2, and the solvent
was evaporated. Flash chromatography (hexane/EtOAc 9:1) of
the residue afforded 0.41 g (85%) of ketone 11 as a white
solid: mp 60.0-61.0 °C; [R]25 -42.0° (c 3.1, CHCl3); IR 1702,
D
EtOAc 4:1) by gravity on multiple columns.13 8: [R]25 -11.3°
1390, 1243, 1173 cm-1; 1H NMR29 (C6D6) δ 0.90 (t, 3H, J ) 6.5
Hz), 1.10-1.50 (m, 29H), 1.55 and 1.72 (two sets of s, 3H),
1.92 and 2.04 (two sets of s, 3H), 2.36 (m, 2H), 3.66 (two sets
of m, 2H), 5.08 (dd, 0.67H, J ) 7.6, 3.7 Hz), 5.32 (dd, 0.33H, J
) 7.3, 3.0 Hz), 7.06 (m, 2H), 7.50 (d, 0.67H, J ) 7.3 Hz), 7.55
(d, 0.33H, J ) 7.5 Hz), 7.81 (s, 1H); 13C NMR (C6D6) δ 14.34,
23.08, 25.04, 25.21, 25.89, 26.32, 28.29, 28.35, 29.56, 29.62,
29.79, 29.85, 30.00, 30.08, 30.10, 31.62, 31.68, 32.30, 36.01,
62.07, 62.39, 65.75, 66.11, 79.63, 79.99, 94.51, 95.48, 125.86,
126.10, 128.68, 128.83, 133.21, 133.46, 135.91, 135.96, 143.70,
143.92, 151.47, 152.00, 195.15, 195.61.
D
(c 10.9, CHCl3); IR 3613, 3366, 1690 1390, 1167 cm-1; 1H NMR
(C6D6, 60 °C) δ 0.88 (t, 3H, J ) 6.7 Hz), 1.10-1.80 (m, 35H),
2.55 (t, 2H, J ) 7.7 Hz), 3.52 (t, 1H, J ) 8.9 Hz), 3.97 (d, 1H,
J ) 8.9 Hz), 4.11 (br s, 1H), 5.10 (br s, 1H), 6.99 (d, 1H, J )
7.2 Hz), 7.15 (t, 1H, J ) 7.7 Hz), 7.23 (d, 1H, J ) 7.5 Hz), 7.31
(s, 1H). 9: 1H NMR (C6D6, 60 °C) δ 0.90 (t, 3H, J ) 5.5 Hz),
1.10-1.80 (m, 35H), 2.53 (t, 2H, J ) 7.7 Hz), 3.46 (t, 1H, J )
7.8 Hz), 3.74 (d, 1H, J ) 8.9 Hz), 4.19 (br s, 1H), 4.92 (d, 1H,
J ) 7.8 Hz), 7.02 (d, 1H, J ) 7.3 Hz), 7.15 (1H, overlap with
C6H6 peak), 7.22 (d, 1H, J ) 7.5 Hz), 7.30 (s, 1H).
DIBALH Red u ction of Keton e 11. To a solution of 0.10
g (0.21 mmol) of ketone 11 in dry THF (10 mL) was added,
dropwise, ∼0.60 mL (∼0.90 mmol) of DIBALH (a 1.5 M
solution in toluene) at 0 °C under argon atmosphere. The rate
of addition was very slow to maintain the low temperature.
The reaction mixture was stirred for 0.5 h at 0 °C until TLC
analysis showed the reaction to be complete. The reaction was
quenched by slow addition of 0.5 mL of MeOH followed by 5.0
mL of cold 5% aqueous potassium sodium tartrate solution.
The product was extracted with EtOAc (3 × 10 mL), and the
combined organic layers were washed with brine (5 mL), dried
(Na2SO4), and concentrated. Purification of the residue by
column chromatography (hexane/EtOAc 4:1) gave 94 mg (94%)
of 8 and 9 in a ratio of 26:1.
(2S,3R)-3-(3′-Dod ecylp h en yl)-2-a m in op r op a n e-1,3-d i-
ol [(-)-10]. Meth od A (Sch em e 1). A solution of 48 mg (1.0
mmol) of 8 in 3 mL of 1 M HCl and 3 mL of THF was heated
at 70 °C with stirring for 5 h under argon. The reaction
mixture was cooled to room temperature, and neutralized with
1 M NaOH (3 mL). The product was extracted with EtOAc (3
× 10 mL), and the combined organic layers were washed with
brine and dried (Na2SO4). Flash chromatography (CHCl3/
MeOH/concd NH4OH 130:25:4) gave 28 mg (83%) of sphin-
gosine analogue 10 as a white solid: mp 55.2-56.2 °C.
Meth od B (Sch em e 5). To an ice-cooled suspension of 57 mg
(1.5 mmol) of LiAlH4 in 15 mL of dry THF under nitrogen was
injected a solution of 101 mg (0.25 mmol) of azido ester 19 in
4 mL of THF. The reaction mixture was stirred at room
temperature for 2 h and then at 65 °C until the full consump-
tion of the azido ester was noticed by TLC (∼2 h). After being
chilled to 0 °C, the reaction mixture was filtered through a
pad of silica gel in a sintered glass funnel to remove the salt
and the excess LiAlH4.28 The pad was washed with CHCl3/
MeOH/concd NH4OH 130:25:4 to collect the product. After
concentration, the residue was purified by flash chromatog-
raphy (CHCl3/MeOH/concd NH4OH 130:25:4). A solution of the
product in CHCl3 was passed through a Cameo filter (Fisher
Scientific) to remove the dissolved silica gel. Concentration
gave 71 mg (85%) of 10 as a white solid: mp 55.0-56.0 °C;
(2S,3R)-3-(3′-Dodecylph en yl)-2-ter t-bu toxycar bon ylam i-
n op r op a n e-1,3-d iol [(-)-12]. To a solution of 0.10 g (0.21
mmol) of 8 in 5 mL of MeOH was added 0.15 g of Amberlyst
15, and the heterogeneous mixture was stirred at room
temperature for 48 h. The mixture was filtered through a
Celite pad, and the filtrate was concentrated. Flash chroma-
tography (CHCl3/MeOH 9:1) of the residue afforded 73 mg
(80%) of 12 as a white solid: mp 76.5-77.5 °C; [R]25 -5.8° (c
D
5.5, CHCl3); IR 3612, 3436, 1699, 1496 cm-1; H NMR (C6D6)
1
δ 0.86 (t, 3H, J ) 8.0 Hz), 1.10-1.50 (m, 29H), 1.59 (s, 2H),
2.54 (t, 2H, J ) 8.0 Hz), 3.58 (d, 1H, J ) 6.6 Hz), 3.63 (s, 1H),
3.82 (d, 1H, J ) 10.3 Hz), 3.98 (d, 1H, J ) 3.4 Hz), 4.20 (d,
1H, J ) 4.4 Hz), 5.03 (t, 1H, J ) 4.7 Hz), 5.58 (d, 1H, J ) 8.3
Hz), 7.01 (d, 1H, J ) 7.3 Hz), 7.15-7.40 (m, 3H); 13C NMR
(C6D6) δ 14.36, 23.07, 28.45, 29.81, 29.89, 30.02, 30.12, 30.16,
32.09, 32.32, 36.44, 57.32, 62.03, 75.82, 79.38, 124.00, 126.68,
127.89, 128.12, 128.53, 142.01, 143.09, 156.48.
[R]25 -22.0° (c 3.4, CHCl3); IR 3609, 3383, 1604, 1462, 1233,
D
1035, 893 cm-1; 1H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.10-1.32
(m, 18H), 1.56 (m, 2H), 2.56 (t, 2H, J ) 7.9 Hz), 2.79 (br s,
4H), 2.98 (dt, 1H, J ) 6.1, 5.1 Hz), 3.62 (m, 2H), 4.58 (d, 1H,
J ) 6.1 Hz), 7.08 (m, 3H), 7.21 (t, 1H, J ) 7.5 Hz); 13C NMR
δ 14.07, 22.65, 29.32, 29.42, 29.48, 29.59, 29.62, 29.65, 31.52,
31.88, 35.97, 57.22, 63.50, 76.45, 123.66, 126.37, 127.88,
128.38, 141.51, 143.32.
(4R,5S)-5-ter t-Bu toxycar bon ylam in o-4-(3′-dodecylph en -
yl)-2,2-d im eth yl-1,3-d ioxa n e [(+)-13]. To a solution of 43
mg (0.10 mmol) of 12 and 100 mg (1.0 mmol) of 2,2-dimethoxy-
propane in dry 5 mL of CH2Cl2 was added 25 mg (0.10 mmol)
of PPTS. The mixture was stirred for ∼48 h at room temper-
ature, concentrated under reduced pressure, and purified by
flash chromatography (hexane/EtOAc 4:1), yielding 32 mg
(2S,3R)-3-(3′-Dodecylph en yl)-2-palm itoylam idopr opan e-
1,3-d iol [(-)-2]. To a solution of 30 mg (0.09 mmol) of 10 in 3
mL of dry THF was added 68 mg (0.18 mmol) of p-nitrophenyl
palmitate at room temperature. The mixture was stirred for
48 h and then concentrated under reduced pressure. Purifica-
tion by flash chromatography (CHCl3/MeOH 9:1) afforded 45
(67%) of 13 as a white solid: mp 68.2-69.6 °C; [R]25 +10.9°
D
mg (88%) of 2 as a white solid: mp 92.1-92.8 °C; [R]25 -5.4°
D
(c 7.9, CHCl3); IR 3436, 1701, 1496, 1366, 1243, 1161 cm-1
;
(c 1.7, CHCl3); IR 3599, 3429, 1655, 1500 cm-1; 1H NMR δ 0.86
(t, 6H, J ) 7.0 Hz), 1.23 (m, 42H), 1.58 (m, 4H), 2.19 (t, 2H, J
) 7.8 Hz), 2.57 (t, 2H, J ) 7.9 Hz), 2.77 (br s, 1H), 3.57 (dd,
1H, J ) 11.5, 3.5 Hz), 3.79 (dd, 1H, J ) 11.5, 3.3 Hz), 4.04 (m,
1H), 4.99 (d, 1H, J ) 3.6 Hz), 6.32 (d, 1H, J ) 7.8 Hz), 7.08 (d,
1H, J ) 7.4 Hz), 7.17 (s, 1H), 7.17 (d, 1H, J ) 6.6 Hz), 7.24 (t,
1H, J ) 7.5 Hz); 13C NMR δ 14.09, 22.67, 25.71, 29.28, 29.35,
29.37, 29.43, 29.51, 29.61, 29.64, 29.67, 29.69, 31.60, 31.91,
36.01, 36.82, 55.46, 61.74, 76.05, 122.99, 125.83, 127.93,
128.46, 140.79, 143.42, 173.98; HR-MS (DCI, MH+) m/z calcd
for C37H68NO3 574.5199, found 574.5187.
N-ter t-Bu toxyca r bon yl (4S)-4-(3′-Dod ecylben zoyl)-2,2-
d im eth yl-1,3-oxa zolid in e [(-)-11]. To a mixture of 0.48 g
(1.0 mmol) of 8 and 9 in 15 mL of CH2Cl2 was added 0.43 g
(2.0 mmol) of PCC. The reaction mixture was stirred at room
temperature for 5 h. The mixture was filtered through a pad
1H NMR (C6D6) δ 0.88 (m, 3H), 1.10-1.0 (m, 37H), 2.53 (t,
2H, J ) 7.6 Hz), 3.60 (br s, 1H), 3.70-4.00 (m, 2H), 4.90 (d,
1H, J 4,5 ) 9.3 Hz), 7.10-7.50 (m, 4H); 13C NMR (C6D6) δ14.34,
19.45, 23.09, 28.28, 29.37, 29.80, 29.98, 30.06, 30.09, 30.13,
32.05, 32.30, 36.42, 51.48, 63.09, 74.68, 78.82, 99.00, 125.26,
127.89, 128.30, 139.94, 142.91, 154.86.
Eth yl m -Dod ecylcin n a m a te (16). A solution of 1.0 g (3.1
mmol) of bromide 7, 0.60 g (6.0 mmol) of ethyl acrylate, 0.60
g (6.0 mmol) of Et3N, and 30 mg (26 µmol) of (Ph3P)4Pd(0) in
10 mL of DMF was stirred at 120 °C under argon atmosphere
for 6 h. After the reaction mixture was allowed to cool to room
temperature, 15 mL of aqueous 1 M HCl solution was added,
and stirring was continued for 5 min. The product was
extracted with Et2O (3 × 30 mL). The combined organic layer
was washed with brine, dried (MgSO4), and concentrated.
Column chromatography (hexane/EtOAc 9:1) yielded 0.98 g
(28) For a note about this workup method, see: He, L.; Byun, H.-
S.; Bittman, R. J . Org. Chem. 2000, 65, 7618-7626.
(29) The oxazolidine system undergoes a dynamic equilibrium at
ambient temperature.9b,c

Asymmetric Synthesis of New Ceramide Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7639
(92%) of cinnamate derivative 16 as a colorless oil: IR 1704,
1637 cm-1; 1H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.10-1.40 (m,
21H), 1.50-1.70 (m, 2H), 2.59 (t, 2H, J ) 7.8 Hz), 4.25 (q, 2H,
J ) 7.1 Hz), 6.41 (d, 1H, J ) 16.0 Hz), 7.17 (d, 1H, J ) 7.4
Hz), 7.26 (t, 1H, J ) 7.5 Hz), 7.30 (s, 1H), 7.32 (d, 1H, J ) 7.4
Hz), 7.65 (d, 1H, J ) 16.0 Hz); 13C NMR δ 14.14, 14.33, 22.71,
29.29, 29.37, 29.51, 29.59, 29.67, 31.40, 31.93, 35.65, 35.81,
60.44, 117.94, 125.44, 127.51, 128.12, 128.75, 128.88, 130.48,
134.38, 143.60, 144.91, 167.10; HR-MS (DEI, M+) m/z calcd
for C23H36O2 344.2715, found 344.2709.
14.04, 14.11, 22.67, 29.30, 29.34, 29.49, 29.58, 29.62, 29.65,
31.45, 31.90, 35.92, 62.11, 66.69, 74.22, 123.84, 126.59, 128.51,
128.87, 138.81, 143.44, 168.97; HR-MS [DCI, MNH4+] m/z calcd
for C23H41O3N4 421.3179, found 421.3186.
t r a n s-2-E t h oxyca r b on yl-3-(3′-d od e cylp h e n yl)a zir i-
d in e [(-)-20]. A solution of 49 mg (0.12 mmol) of azide 19
and 65 mg (0.25 mmol) of Ph3P in 10 mL of THF/H2O 9:1 was
stirred at room-temperature overnight under nitrogen. The
solvents were removed and the residue was purified by column
chromatography (hexane/EtOAc 4:1) to give 39 mg (90%) of
aziridine 20 as a colorless liquid: [R]25D -141.1° (c 1.4, CHCl3);
IR 3689, 3283, 1715, 1600, 1222, 1200, 1025 cm-1; 1H NMR δ
0.86 (t, 3H, J ) 7.0 Hz), 1.23 (m, 18H), 1.30 (t, 3H, J ) 7.6
Hz), 1.56 (m, 2H), 1.89 (br s, 1H), 2.55 (t, 2H, J ) 7.7 Hz),
2.58 (s, 1H), 3.20 (d, 1H, J ) 2.0 Hz), 4.23 (m, 2H), 7.06 (s,
1H), 7.06 (d, 2H, J ) 6.4 Hz), 7.20 (t, 1H, J ) 7.6 Hz); 13C
NMR δ 14.11, 14.15, 22.67, 29.33, 29.36, 29.48, 29.56, 29.62,
29.64, 31.49, 31.90, 35.88, 39.41, 40.45, 61.73, 123.49, 125.93,
127.88, 128.29, 137.65, 143.30, 171.75.
Eth yl (2R,3R)-3-(3′-Dod ecylp h en yl)-3-h yd r oxy-2-p a lm i-
toyla m id op r op ion a te [(-)-21]. To a solution of 49 mg (0.12
mmol) of azido ester 19 in 20 mL of absolute EtOH was added
15 mg of Lindlar catalyst (Pd-CaCO3).30 The apparatus was
evacuated, then flushed with hydrogen from a H2-filled balloon.
The reaction mixture was stirred at room temperature until
all of the starting azido ester 19 was consumed (TLC). After
the solvent was removed, the residue was further dried under
high vacuum (0.7 Torr, 1 h). The residue was dissolved in 10
mL of freshly distilled THF, and 98 mg (0.26 mmol) of
p-nitrophenyl palmitate was added. The reaction mixture was
stirred at room temperature for 60 h under nitrogen. The
solvent was removed, and the residue was purified with
chromatography (elution first with 100 mL of hexane/EtOAc
20:1, then with hexane/EtOAc 5:1), providing 41 mg (55%) of
the desired product 21 as a white solid: mp 69.5-70.4 °C;
[R]25D -25.2° (c 1.6, CHCl3); IR 3521, 1728, 1666 cm-1; 1H NMR
δ 0.86 (t, 6H, J ) 7.0 Hz), 1.18-1.51 (m, 45H), 1.56 (m, 4H),
2.18 (dt, 2H, J ) 7.4, 2.7 Hz), 2.54 (t, 2H, J ) 7.6 Hz), 4.17 (q,
2H, J ) 7.2 Hz), 4.97 (dd, 1H, J ) 6.7, 3.2 Hz), 5.24 (d, 1H, J
) 3.1 Hz), 6.19 (d, 1H, J ) 6.7 Hz), 6.97 (d, 1H, J ) 7.7 Hz),
7.01 (s, 1H), 7.06 (d, 1H, J ) 7.6 Hz), 7.19 (t, 1H, J ) 7.6 Hz);
13C NMR δ 14.03, 14.11, 22.67, 25.60, 29.20, 29.35, 29.38,
29.45, 29.54, 29.62, 29.65, 29.68, 31.56, 31.91, 36.00, 36.31,
59.29, 62.02, 75.41, 123.12, 125.93, 128.06, 138.97, 142.90,
169.45, 174.92; HR-MS (FAB, MH+) calcd for m/z C39H70NO4
616.5305, found 616.5305.
2-Br om o-6-(1′-h yd r oxyd od ecyl)p yr id in e (23). To a solu-
tion of 1.0 g (4.2 mmol) of 2,6-dibromopyridine (22) in 10 mL
of dry THF at -78 °C was added 1.9 mL (4.75 mmol) of n-BuLi
(2.5 M solution in hexane) under argon atmosphere. After the
mixture was stirred for 30 min, a solution of 0.80 g (4.3 mmol)
of dodecanal in 8 mL of dry THF was added. The mixture was
stirred at -78 °C for 1 h, then at room temperature for 1 h.
Saturated aqueous NaHCO3 solution (10 mL) was added, and
vigorous stirring was maintained for 10 min. The product was
extracted with Et2O (3 × 15 mL), the combined extracts were
dried (MgSO4), and concentrated. The residue was purified by
column chromatography (hexane/EtOAc 7:3) to give 1.15 g
(80%) of 23 as a white solid: mp 39.0-40.0 °C; IR 3613, 3460,
1584, 1554, 1437, 1161, 1125 cm-1; 1H NMR δ 0.82 (t, 3H, J )
7.0 Hz), 0.90-1.50 (m, 18H), 1.50-1.90 (m, 2H), 3.58 (br s,
1H), 4.63 (dd, 1H, J ) 8.0, 4.5 Hz), 7.21 (d, 1H, J ) 7.6 Hz),
7.29 (d, 1H, J ) 4.8 Hz), 7.47 (t, 1H, J ) 7.7 Hz);13C NMR δ
14.01, 22.57, 25.26, 29.24, 29.43, 29.48, 29.51, 29.54, 31.80,
38.24, 73.10, 118.96, 126.35, 138.83, 140.99, 164.75.
Eth yl (2S,3R)-3-(3′-Dod ecylp h en yl)-2,3-d ih yd r oxyp r o-
p ion a te [(-)-17]. After a solution of 1.4 g of AD-mix-â and
95 mg (1.0 mmol) of MeSO2NH2 in 30 mL of t-BuOH/H2O 1/1
was stirred vigorously at room temperature for 30 min, 0.35 g
(1.0 mmol) of R,â-unsaturated ester 16 was added. The reaction
mixture was stirred vigorously until the disappearance of the
R,â-unsaturated ester was noted. Sodium sulfite (1.50 g, 1.46
mmol) was added to quench the reaction. Stirring was con-
tinued for another 30 min. The product was extracted with
EtOAc (3 × 20 mL). The combined extracts were dried (Na2-
SO4) and concentrated to give a yellow solid residue, which
was dissolved in minimum volume of EtOAc and passed
through a pad of silica gel in a sintered glass funnel to remove
the ligand. The pad was washed with hexane/EtOAc 2:1 to
collect the product. Concentration of the filtrate provided an
almost pure product, which was purified by column chroma-
tography (hexane/EtOAc 2:1), giving 0.34 g (90%) of diol 17
as a white solid: mp 49.0-49.5 °C. Compound (-)-17 was
1
formed in >99% ee, as estimated by H NMR analysis of the
Mosher esters26 derived from both enantiomers; (+)-17 was
prepared by reaction of 16 with AD-mix-R: [R]25D -4.4° (c 2.3,
1
CHCl3); IR 3549, 1725 cm-1; H NMR δ 0.86 (t, 3H, J ) 7.0
Hz), 1.16-1.31 (m, 21H), 1.58 (m, 2H), 2.58 (t, 2H, J ) 8.0
Hz), 2.83 (br s, 2H), 4.21 (dq, 2H, J ) 7.3, 1.3 Hz), 4.31 (d, 1H,
J ) 3.1 Hz), 4.94 (d, 1H, J ) 3.1 Hz), 7.10 (d, 1H, J ) 7.4 Hz),
7.18 (m, 2H), 7.23 (m, 1H); 13C NMR δ 14.02, 14.09, 22.65,
29.32, 29.37, 29.48, 29.57, 29.61, 29.64, 31.50, 31.88, 35.97,
62.06, 74.62, 74.74, 123.46, 126.26, 128.07, 128.26, 139.79,
143.13, 172.76; HR-MS [DCI, MNH4+] m/z calcd for C23H42
NO4 396.3114, found 396.3120.
-
E t h yl (2S,3R)-3-(3′-Dod ecylp h en yl)-2-n osyloxy-3-h y-
d r oxyp r op ion a te [(-)-18]. To an ice-cooled solution of 0.38
g (1.0 mmol) of diol ester 17 in 25 mL of CH2Cl2 was added
0.51 g (5.0 mmol) of Et3N, followed by 0.26 g (1.2 mmol) of
4-nitrobenzenesulfonyl chloride. The yellow solution was
stirred at 0 °C under argon until the full consumption of diol
ester 17 was observed (TLC). Methanol (0.5 mL) was added
to quench the reaction. After the solvents were removed under
reduced pressure, the yellow residue was purified by column
chromatography (hexane/EtOAc 3:1), giving 0.47 g (83%) of
R-nosylate ester 18 as a pale yellow oil: [R]25 -37.8° (c 1.93,
D
CHCl3); IR 3606, 1745, 1536 cm-1; 1H NMR δ 0.85 (t, 3H, J )
7.5 Hz), 1.17 (t, 3H, J ) 7.2 Hz), 1.24 (m, 19H), 1.49 (m, 2H),
2.45 (t, 2H, J ) 8.0 Hz), 4.16 (t, 2H, J ) 7.2 Hz), 4.98 (d, 1H,
J ) 3.8 Hz), 5.16 (d, 1H, J ) 3.8 Hz), 6.95-7.20 (m, 5H), 7.76
(d, 2H, J ) 7.0 Hz), 8.15 (d, 2H, J ) 7.0 Hz); 13C NMR δ 13.74,
14.02, 22.58, 29.24, 29.28, 29.37, 29.49, 29.53, 29.56, 31.42,
31.80, 35.70, 62.41, 73.34, 82.51, 123.27, 123.95, 125.93,
128.36, 128.38, 128.87, 137.37, 141.21, 143.31, 150.32, 166.50;
HR-MS (DCI, MNH4+) calcd for m/z C29H45N2O8S 581.2897,
found 581.2872.
Eth yl (2R,3R)-3-(3′-Dod ecylp h en yl)-2-a zid o-3-h yd r oxy-
p r op ion a te [(+)-19]. A mixture of 0.37 g (0.66 mmol) of
nosylate 18 and 0.46 g (7.1 mmol) of NaN3 in 12 mL of dry
DMF was stirred vigorously under argon at 55 °C until TLC
analysis indicated that no nosylate was still present. After
addition of 30 mL of H2O, the product was extracted with Et2O
(3 × 20 mL). The combined extracts were dried (Na2SO4) and
concentrated, and the residue was purified by column chro-
matography (hexane/EtOAc 3:1) to give 0.20 g (75%) of 2-azido
2-Br om o-6-(1′-br om od od ecyl)p yr id in e (24). To a solu-
tion of 0.34 g (1.0 mmol) of alcohol 23 and 0.31 g (1.2 mmol) of
Ph3P in 15 mL of dry CH2Cl2 was added 0.20 g (1.1 mmol) of
NBS at 0 °C under argon atmosphere. The mixture was stirred
at 0 °C for 1 h, then allowed to warm to room temperature
and stirred for 1 h. The mixture was diluted with 30 mL of
hexane and passed through a pad of silica gel to remove the
derivative 19 as a colorless oil: [R]25 +6.4° (c 1.6, CHCl3); IR
D
3602, 2116, 1736 cm-1
;
1H NMR δ 0.86 (t, 3H, J ) 7.0 Hz),
1.23 (m, 21H), 1.57 (m, 2H), 2.59 (t, 2H, J ) 7.9 Hz), 2.82 (br
s, 1H), 4.06 (d, 1H, J ) 7.1 Hz), 4.22 (q, 2H, J ) 7.1 Hz), 4.97
(d, 1H, J ) 7.0 Hz), 7.16 (m, 3H), 7.26 (m, 1H); 13C NMR δ
(30) Kunesch, G. Tetrahedron Lett. 1983, 24, 5211-5214.

7640 J . Org. Chem., Vol. 65, No. 22, 2000
Chun et al.
precipitate of Ph3PO. Concentration gave 0.38 g (93%) of 24
as a colorless oil. A small sample was purified by flash
chromatography (hexane/EtOAc 9:1): 1H NMR δ 0.85 (t, 3H,
J ) 7.0 Hz), 1.00-1.60 (m, 18H), 2.00-2.30 (m, 2H), 4.93 (dd,
1H, J ) 8.2, 6.8 Hz), 7.38 (m, 2H), 7.52 (t, 1H, J ) 7.7 Hz);13C
NMR δ 14.09, 22.65, 27.85, 28.83, 29.30, 29.32, 29.46, 29.56,
31.87, 38.09, 54.16, 120.96, 127.30, 139.15, 141.16, 161.98.
2-Br om o-6-d od ecylp yr id in e (25). To a solution of 1.12 g
(2.77 mmol) of crude 24 in 10 mL of dry DMSO was added
0.63 g (16.6 mmol) of NaBH4 at room temperature under argon
atmosphere. After the mixture was stirred at room tempera-
ture overnight, the mixture was diluted with 50 mL of Et2O
and washed with brine (10 mL). The organic layer was dried
(MgSO4) and concentrated. The residue was purified by flash
chromatography (hexane/EtOAc 9:1) to give 0.81 g (90%) of
25 as a colorless oil: 1H NMR δ 0.83 (t, 3H, J ) 7.0 Hz), 1.10-
1.40 (m, 18H), 1.60-1.90 (m, 2H), 2.71 (t, 2H, J ) 7.9 Hz),
7.05 (d, 1H, J ) 7.4 Hz), 7.25 (d, 1H, J ) 7.7 Hz), 7.39 (t, 1H,
J ) 7.7 Hz);13C NMR δ 14.05, 22.62, 29.25, 29.29, 29.37, 29.47,
29.56, 29.60, 29.73, 31.85, 37.97, 121.36, 125.08, 138.48,
141.36, 164.22.
N-ter t-Bu toxylca r bon yl (4S)-4-[1′-(6′′-Dod ecylp yr id in -
2′′-yl)-h yd r oxym eth yl]-2,2-d im eth yl-1,3-oxa zolid in e (26,
27). To a solution of 0.39 g (1.2 mmol) of 25 in 10 mL of dry
THF was added 0.5 mL (1.25 mmol) of n-BuLi (a 2.5 M solution
in hexane) dropwise at -78 °C under argon atmosphere. After
the mixture was stirred for 1 h, a solution of 0.23 g (1.0 mmol)
of aldehyde 4 in 5 mL of dry THF was added dropwise over a
5-min period. The mixture was stirred at -78 °C for 3 h. The
reaction was quenched with aqueous saturated NaHCO3
solution (5 mL). The organic phase was separated and the
aqueous phase was extracted with Et2O (3 × 15 mL). The
combined organic phases were washed twice with brine, dried
(MgSO4), and evaporated. Column chromatography (hexane/
EtOAc 4:1) gave 0.26 g (55%) of diastereoisomers 26 and 27,
which have very similar Rf values (0.56, hexane/EtOAc 4:1).
1H NMR (C6D6, 60 °C) δ 0.90 (t, 3H, J ) 7.0 Hz), 1.10-1.93
(m, 37H), 2.68 and 2.69 (two sets of t, 2H, J ) 7.0 Hz), 3.66
(dd, 0.83H, J ) 9.7, 6.4 Hz), 3.73 (dd, 0.17H, J ) 9.3, 6.7 Hz),
4.19-4.40 (m, 1.67H), 4.36 (m, 0.34H), 4.18-5.22 (m, 1H), 6.72
(m, 1H), 6.90-7.20 (m, 2H).
28 in 3 mL of dry THF was added 35 mg (0.18 mmol) of
p-nitrophenyl butyrate at room temperature. The reaction was
stirred for 48 h and then concentrated under reduced pressure.
TLC analysis (CHCl3/MeOH 9:1) showed the formation of (-)-3
(Rf 0.52) and its diastereoisomer (Rf 0.45). Purification by
column chromatography (by gravity, CHCl3/MeOH 9:1) af-
forded 24 mg (70%) of (-)-3 as a white solid: mp 52.2-53.5
°C; [R]25 -100.5° (c 2.1, CHCl3); IR 3425, 3305, 1644, 1507,
D
1
1096 cm-1; H NMR δ 0.74 (t, 3H, J ) 7.4 Hz), 0.85 (t, 3H, J
) 7.0 Hz), 0.90-1.40 (m, 18H), 1.40-1.60 (m, 2H), 1.60-1.80
(m, 2H), 1.90-2.20 (m, 2H), 2.60-2.90 (t, 2H, J ) 7.9 Hz),
3.66 (dd, 1H, J ) 11.8 Hz, 4.5 Hz), 4.00 (dd, 1H, J ) 11.8, 2.2
Hz), 4.30 (m, 1H), 4.98 (s, 1H), 5.89 (br s, 1H), 6.46 (d, 1H, J
) 6.3 Hz), 7.07 (d, 1H, J ) 7.7 Hz), 7.46 (d, 1H, J ) 7.8 Hz),
7.66 (t, 1H, J ) 7.8 Hz);13C NMR δ 13.43, 14.08, 19.02, 22.65,
29.26, 29.31, 29.40, 29.54, 29.62, 29.72, 31.88, 37.51, 38.07,
57.33, 62.62, 77.25, 119.07, 121.78, 138.28, 150.78, 160.52,
174.94; HR-MS (FAB, MH+) calcd for m/z C24H43N2O3 407.3274,
found 407.3269.
(2S,3S)-3-(6′-Dod ecylp yr id in -2′-yl)-2-ter t-bu tyloxyca r -
bon yla m in op r op a n e-1,3-d iol [(-)-29]. Amberlyst 15 (0.15
g) was added to a solution of 26 and 27 (0.10 g, 0.21 mmol) in
MeOH (5 mL). The mixture was stirred at room temperature
for 48 h, filtered through Celite, and concentrated. The residue
was purified by column chromatography (by gravity, CHCl3/
MeOH 9:1). Unreacted starting material was recovered, re-
treated with Amberlyst, and the product was purified as above.
There was obtained 59 mg (65%) of diol 29 as a colorless oil:
[R]25 -46.2° (c 3.4, CHCl3); IR 3025, 1701, 1496, 1454, 1167
D
cm-1
;
1H NMR (C6D6) δ 0.75 (t, 3H, J ) 6.9 Hz), 1.10-1.50
(m, 27H), 1.60 (m, 2H), 2.57 (t, 2H, J ) 7.6 Hz), 3.47 (m, 1H),
3.80 (dd, 1H, J ) 11.3, 4.4 Hz), 4.11 (br s, 1H), 4.59 (br s, 1H),
5.02 (s, 1H), 5.55 (m, 2H), 6.55 (d, 1H, J ) 7.6 Hz), 7.07 (t,
1H, J ) 7.7 Hz), 7.28 (d, 1H, J ) 7.7 Hz);13C NMR δ 14.35,
23.09, 28.24, 29.57, 29.79, 29.83, 29.88, 29.99, 30.08, 30.11,
32.30, 38.00, 58.10, 62.71, 77.12, 79.41, 119.05, 121.43, 137.43,
157.36, 159.96, 160.93.
(4S,5S)-4-(6′-Dod ecylp yr id in -2′-yl)-5-ter t-bu tyloxyca r -
bon yla m in o-2,2-d im eth yl-1,3-d ioxa n e [(-)-31]. This com-
pound was prepared in 66% yield by using the same procedure
as described for (+)-13: [R]25 -25.0° (c 3.4, CHCl3); IR 1713,
D
3-(6′-Dodecylpyr idin -2′-yl)-2-am in opr opan e-1,3-diol (28).
A solution of 48 mg (1.0 mmol) of 26 and 27 in 3 mL of 1 M
HCl and 3 mL of THF was heated at 70 °C under argon with
stirring for 5 h. The reaction mixture was cooled to room
temperature, and neutralized with 1 M NaOH (3 mL). The
mixture was extracted with EtOAc (3 × 10 mL), and the
combined organic layers were washed with brine and dried
(Na2SO4). Flash chromatography (CHCl3/MeOH/concd NH4OH
130:25:4) gave 28 mg (84%) of diastereomeric sphingosine
analogue 28 as a white solid: mp 54.0-56.0 °C; Rf 0.52 (CHCl3/
MeOH/concd NH4OH 130:25:4); 1H NMR δ 0.84 (t, 3H, J )
7.0 Hz), 1.10-1.50 (m, 18H), 1.64 (t, 2H, J ) 7.3 Hz), 2.71 (t,
2H, J ) 7.9 Hz), 3.18 (m, 5H), 3.34 (dd, 1H, J ) 11.2, 5.3 Hz),
3.58 (dd, 1H, J ) 11.2, 6.2 Hz), 4.74 (d, 0.17H, J ) 3.8 Hz),
4.78 (d, 0.83H, J ) 4.8 Hz), 7.03 (d, 1H, J ) 7.6 Hz), 7.16 (d,
0.17H, J ) 7.7 Hz), 7.18 (d, 0.83H, J ) 7.7 Hz), 7.58 (t, 1H, J
) 7.7 Hz); 13C NMR31 δ 14.08, 22.65, 29.31, 29.43, 29.55, 29.61,
29.63, 31.88, 37.95, 57.20, (57.67), 63.42, (64.69), (73.49), 74.72,
(117.77), 118.41, (121.53), 121.63, 137.16, (137.29), 158.77,
(158.91), (161.17), 161.37.
1214, 1161 cm-1; 1H NMR (C6D6, 60 °C) δ 0.88 (t, 3H, J ) 6.8
Hz), 1.10-1.50 (m, 35H), 1.81 (m, 2H), 2.76 (t, 2H, J ) 7.8
Hz), 3.71 (t, 1H, J ) 10.2 Hz), 3.81 (br s, 1H), 4.40 (dd, 1H, J
) 10.8, 4.8 Hz), 4.96 (d, 1H, J 4,5 ) 9.6 Hz), 5.73 (s, 1H), 6.68
(d, 1H, J ) 7.5 Hz), 7.18 (1H, overlap with C6H6), 7.35 (d, 1H,
J ) 7.6 Hz);13C NMR δ 14.34, 19.06, 23.09, 28.36, 29.40, 29.79,
29.87, 29.95, 30.05, 30.08, 30.12, 32.30, 38.46, 51.51, 64.09,
74.71, 78.69, 99.09, 118.05, 121.78, 137.26, 155.58, 159.48,
160.69.
Ack n ow led gm en t. This work was supported by
National Institutes of Health Grant No. HL 16660. We
thank the mass spectrometry facilities at the University
of California at Riverside and Michigan State University
for the HR-MS. We gratefully acknowledge support from
the National Science Foundation (CHE-9408535) for
funds for the purchase of the 400-MHz NMR spectrom-
eter.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 2, 3, 6-8, 10, 11, 13, 16-21, and
23-25. This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S,3S)-3-(6′-Dodecylpyr idin -2′-yl)-2-bu tan oylam idopr o-
p a n e-1,3-d iol [(-)-3]. To a solution of 31 mg (0.92 mmol) of
(31) The values in parentheses represent the diastereoisomeric
peaks.
J O001227F