First asymmetric synthesis of 6-hydroxy-4-sphingenine-containing ceramides. Use of chiral propargylic alcohols to prepare a lipid found in human skin

Article abstract of DOI:10.1021/jo026240+

6-Hydroxy-(4E)-sphingenine-containing ceramides were found recently in human skin. We present here the first synthesis of the 6S and 6R diastereoisomers 2 and 3, which represent analogues of (2S,3R)-ceramide (1) having two allylic hydroxyl groups. Chiral propargylic alcohols 8 and 11, which were prepared by asymmetric dihydroxylation of α,β-unsaturated ester 13 and allylic chloride 22, respectively, were employed as precursors of 2 and 3. Nucleophilic addition of lithiated TBS-protected propargylic ethers 25 and 32 to L-serine-derived aldehyde 26, respectively, afforded oxazolidine intermediates 27 and 33. Acid-mediated deprotection of the oxazolidine, followed by N-acylation and Birch reduction, completed the syntheses of 2 and 3.

Full text of DOI:10.1021/jo026240+

F ir st Asym m etr ic Syn th esis of
6-Hyd r oxy-4-Sp h in gen in e-Con ta in in g Cer a m id es. Use of Ch ir a l
P r op a r gylic Alcoh ols To P r ep a r e a Lip id F ou n d in Hu m a n Sk in
J iong Chun, 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 J uly 25, 2002
6-Hydroxy-(4E)-sphingenine-containing ceramides were found recently in human skin. We present
here the first synthesis of the 6S and 6R diastereoisomers 2 and 3, which represent analogues of
(2S,3R)-ceramide (1) having two allylic hydroxyl groups. Chiral propargylic alcohols 8 and 11, which
were prepared by asymmetric dihydroxylation of R,â-unsaturated ester 13 and allylic chloride 22,
respectively, were employed as precursors of 2 and 3. Nucleophilic addition of lithiated TBS-protected
propargylic ethers 25 and 32 to L-serine-derived aldehyde 26, respectively, afforded oxazolidine
intermediates 27 and 33. Acid-mediated deprotection of the oxazolidine, followed by N-acylation
and Birch reduction, completed the syntheses of 2 and 3.
CHART 1. (2S,3R)-Cer a m id e (1), 2-Octa n oyla m id o-
(2S,3R,6S)-6-h yd r oxy-(4E)-sp h in gen in e (2), a n d
2-Octa n oyla m id o-(2S,3R,6R)-6-h yd r oxy-(4E)-
sp h in gen in e (3)
In tr od u ction
Ceramides (N-acylsphingosines) were reported to occur
in human epidermis in 1975,1 and ceramide (1) has since
been discovered to be a potent lipid mediator of many
cellular functions, including proliferation, differentiation,
and apoptosis.2 The role of ceramides in skin function,
particularly in the regulation of the water content of the
epidermis,3 has led to the development of synthetic
“pseudoceramides” as ceramide replacements in the
cosmetic industry.4 The sphingolipids in stratum corneum
are structurally heterogeneous. A substantial proportion
of skin ceramides are hydroxylated at various positions
of the sphingoid base or at the R and ω positions of
the N-linked fatty acyl chain.5 A novel sphingoid base,
(6R/6S)-6-hydroxy-(4E)-sphingenine, with predominately
18 and 20 carbon atoms, was identified in the ceramide
fraction of human stratum corneum; ∼25% of these
ceramides bear ω-hydroxy fatty acids,6a-c and ∼9%
have nonhydroxylated fatty acids.6d We report here
the first asymmetric synthesis of these diastereomeric
ceramides of human stratum corneum. The amide chain
of skin ceramides often contains as many as 30 carbons;5
however, for ease of handling, we synthesized model
ceramides 2 and 3 with an N-octanoyl chain (see Chart
1). The synthetic route to 2 and 3 described here can be
applied to the preparation of other 6-hydroxy-substituted
ceramides bearing longer N-acyl chains, thereby affording
homogeneous stratum corneum sphingolipids for bio-
physical investigations.
* To whom correspondence should be addressed. Phone: (718) 997-
3279. Fax: (718) 997-3349.
(1) (a) Gray, G. M.; Yardly, H. J . Lipid Res. 1975, 16, 434-440. (b)
Gray, G. M.; Yardly, H. J . Lipid Res. 1975, 16, 441-447.
(2) For reviews of ceramide biochemistry, see: (a) Perry, D. K.;
Hannun, Y. A. Biochim. Biophys. Acta 1998, 1436, 233-243. (b)
Kolesnick, R. N.; Goni, F. M.; Alonso, A. J . Cell Physiol. 2000, 184,
285-300. (c) Hannun, Y. A.; Obeid, L. M. J . Biol. Chem. 2002, 277,
25847-25850.
Resu lts a n d Discu ssion
Syn th etic P la n . As outlined in Scheme 1, our strategy
for the preparation of ceramide 2 involves the key
oxazolidine intermediate 27, which is obtained by the
addition of the acetylide ion derived from propargylic
alcohol 11 to N-Boc-N,O-isopropylidene-L-serinal ((S)-
(3) Together with other lipids (primarily cholesterol and free fatty
acids) in
a multilamellar matrix with a complex phase behavior,
ceramides are involved in providing skin with its barrier properties
and water-binding capacity: Downing, D. T.; Stewart, M. E.; Wertz,
P. W. J . Invest. Dermatol. 1987, 88, 2s-6s.
(4) (a) Suzuki, T. Fragrance J . 1993, 21, 23-33. (b) Mizushima, H.;
Fukasawa, J .; Suzuki, T. J . Colloid Interface Sci. 1997, 195, 156-163.
(c) Mo¨ller, H. The Chemistry of Natural and Synthetic Skin Barrier
Lipids. Cosmet. Sci. Technol. Ser. 2002, 24, 1-35.
(5) Koller, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532-
1568.
(6) (a) Robson, K. J .; Stewart, M. E.; Michelsen, S.; Lazo, N. D.;
Downing, D. T. J . Lipid Res. 1994, 35, 2060-2068. (b) Stewart, M. E.;
Downing, D. T. J . Invest. Dermatol. 1995, 105, 613-618. (c) Bouwstra,
J . A.; Gooris, G. S.; Dubbelaar, F. E. R.; Ponec, M. J . Lipid Res. 2001,
42, 1759-1770. (d) Stewart, M. E.; Downing, D. T. J . Lipid Res. 1999,
40, 1434-1439.
10.1021/jo026240+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/06/2002
348
J . Org. Chem. 2003, 68, 348-354

Asymmetric Synthesis of Ceramides
SCHEME 1. Retr osyn th etic P la n
SCHEME 2. Attem p ted P r ep a r a tion of Alcoh ol 8
via Asym m etr ic Red u ction a
a
Reagents and conditions: (a) PCC, CH2Cl2, rt; (b) LiAlH4,
Chirald, Et2O, -78 °C; (c) K2CO3, MeOH, rt; (d) (R)-Alpine-Borane,
0 °C to rt.
Garner aldehyde, 26).7 Similarly, diastereomer 3 arises
via intermediate 33, which is obtained by the reaction of
the acetylide ion derived from 8 with aldehyde 26. Thus,
the success of this synthetic plan depends on the ability
to prepare long-chain propargylic alcohols (R)-8 and (S)-
11 in high enantiomeric purity (see below).
SCHEME 3. Syn th esis of P r op a r gylic Alcoh ol
(R)-8a
Syn th esis of Ch ir a l P r op a r gylic Alcoh ols. Chiral
propargylic alcohols are important synthons. They have
been prepared by many methods, e.g., addition of an
organometallic compound to an acetylenic aldehyde in
the presence of chiral ligands,8 enantioselective aldol
addition to an R,â-ynal,9 asymmetric reduction of an R,â-
ynone,10 resolution via enzymatic techniques,11 Sharpless
asymmetric epoxidation of an allylic alcohol,12 and asym-
metric dihydroxylation (AD) of an allylic chloride.13
a
Attem p ted En a n tioselective Red u ction of Yn on es
6 a n d 10 (Sch em e 2). We first examined whether
the enantioenriched propargylic alcohols 8 and 11
could be prepared by asymmetric reduction of R,â-
ynones 6 and 10 (Scheme 2). Treatment of trimethyl-
silylacetylene with n-BuLi in THF at -78 °C followed
by reaction with tridecanal 4 provided alcohol 5 in 92%
yield. PCC oxidation of 5 afforded R,â-ynone 6 in 88%
yield. Asymmetric reduction of ynone 6 with LiAlH4 in
diethyl ether in the presence ofDarvon alcohol (Chirald)10,14
gave alcohol 7, but the resulting ee15 was low (43%). As
Reagents and conditions: (a) (i-PrO)2P(O)CH2CO2Et (12),
Et3N, LiBr, THF, rt; (b) AD-mix-â, MeSO2NH2, t-BuOH/H2O
(1:1), rt; (c) Me2C(OMe)2, p-TsOH, CH2Cl2, rt; (d) DIBAL-H, THF,
0 °C; (e) NCS, Ph3P, CH2Cl2, 0 °C to rt; (f) n-BuLi, HMPA, THF,
-42 °C to rt.
shown in Scheme 2, analogous treatment of ynone 10,
obtained by removal of the TBS group of 5 and PCC
oxidation of the resulting alcohol 9, also provided 8 in
poor enantiomeric purity (40%). Similarly, reduction of
ynone 10 with B-(3-pinanyl)-9-borabicyclo[3.3.1]nonane
((R)-Alpine-Borane)16 gave moderate enantioselectivity
(78% ee).
(7) For a review of the applications of the Garner aldehyde, see:
Liang, X.; Andersch, J .; Bols, M. J . Chem. Soc., Perkin Trans. 1 2001,
2136-2157.
(8) (a) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473-7484.
(b) BouzBouz, S.; Pradaux, F.; Cossy, J .; Ferroud, C.; Falguieres, A.
Tetrahedron Lett. 2000, 41, 8877-8880. (c) Lu, G.; Li, X.; Zhou, Z.;
Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 2147-
2152.
(9) Singer, R. A.; Shepard, M. S.; Carreira, E. M. Tetrahedron 1998,
54, 7025-7032.
(10) (a) Cohen, N.; Lopresti, R. J .; Neukom, C.; Saucy, G. J . Org.
Chem. 1980, 45, 582-588. (b) Marshall, J . A.; Wang, X.-J . J . Org.
Chem. 1991, 56, 4913-4918.
Therefore, we examined alternative routes for the
preparation of chiral propargylic alcohols 8 and 11. As
outlined in Schemes 3 and 4, the routes we chose involve
the AD reaction with an R,â-unsaturated ester17 or an
allylic chloride,13 and conversion of the resultant diol to
a 4-(chloromethyl)-1,3-dioxolane, followed by a double
elimination reaction.
Syn th esis of 8 via AD Rea ction of r,â-Un sa tu r -
a t ed E st er 13. On base-mediated double elimination,
chloromethyl-1,3-dioxolanes (+)-17 (Scheme 3) and (-)-
24 (Scheme 4) afforded alcohols 8 and 11, respectively.
R,â-Unsaturated ester 13 was prepared by Horner-
Wadsworth-Emmons (HWE) reaction of tridecanal 4
(11) (a) Takano, S.; Setoh, M.; Yamada, O.; Ogasawara, K. Synthesis
1993, 12, 1253-1256. (b) Waldinger, C.; Schneider, M.; Botta, M.;
Corelli, F.; Summa, V. Tetrahedron: Asymmetry 1996, 7, 1485-1488.
(12) Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. J . Chem.
Soc., Chem. Commun. 1989, 1344-1345.
(13) Takano, S.; Yoshimitsu, T.; Ogasawara, K. Synlett 1994, 119-
120.
(16) Alpine-Borane is a trademark of Aldrich Chemical Co. For the
preparation of (R)-Alpine-Borane and its use in the asymmetric
reduction of 1-octyn-3-one, see: (a) Midland, M. M.; Graham, R. S.
Org. Synth. 1985, 63, 57-65. (b) For a review of asymmetric reduction
of propargyl ketones with Alpine-Borane, see: Midland, M. M.;
Tramontano, A.; Kazubski, A.; Graham, R. S.; Tsai, D. J . S.; Cardin,
D. B. Tetrahedron 1984, 40, 1371-1380.
(17) (a) Kwong, H.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K.
B. Tetrahedron Lett. 1990, 31, 2999-3002. (b) Kolb, H. C.; Van-
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547.
(14) Chirald is a trademark for Darvon alcohol. Propargylic ketones
with a short-chain alkyl group were reduced with Chirald-LiAlH4 to
provide chiral alcohols in high ee;10b however, the enantiomeric purity
was decreased when a long-chain alkyl group was present.
(15) The % ee was determined by 1H and 19F NMR analysis of the
Mosher ester formed by the reaction of the alcohol with (S)-(+)-R-
methoxy-R-(trifluoromethyl)phenylacetic acid (MTPA) chloride in the
presence of DMAP: Guivisdalsky, P. N.; Bittman, R. J . Org. Chem.
1989, 54, 4637-4642.
J . Org. Chem, Vol. 68, No. 2, 2003 349

Chun et al.
SCHEME 5. Syn th esis of Cer a m id e An a logu e 2a
SCHEME 4. Syn th esis of P r op a r gylic Alcoh ol
(S)-11a
a
Reagents and conditions: (a) Li, NH3, Fe(NO3)3, C12H25Br (19),
THF, -78 °C; (b) LiAlH4, THF, reflux; (c) NCS, Ph3P, CH2Cl2,
0 °C to rt; (d) AD-mix-R, NaHCO3, MeSO2NH2, t-BuOH/H2O
(1:1), 0 °C; (e) Me2C(OMe)2, p-TsOH, CH2Cl2, rt; (f) n-BuLi, HMPA,
THF, -42 °C to rt.
with diisopropyl ester phosphonate 12 (Scheme 3).18
Reaction of 13 with AD-mix-â provided diol ester 14 in
90% yield and 96% ee. This result is consistent with
previous reports of very high ee values attained in AD
reactions of R,â-unsaturated esters.17b Treatment of diol
14 with 2,2-dimethoxypropane in the presence of p-TsOH
gave acetonide ester 15, which on reduction with DIBAL-H
gave alcohol 16. During the acetonide formation, a trace
of the methyl ester analogue of 15 was formed by
transesterification. However, subsequent reduction pro-
vided the same alcohol 16. The latter was converted
to chloride 17 in 88% yield by Mitsunobu reaction.19
Propargylic alcohol (R)-8 was obtained in good yield and
high ee20 by treatment of 17 with excess n-BuLi and
HMPA in THF at low temperature.
Syn th esis of 11 via Allylic Ch lor id e 22 (Sch em e
4). Takano et al. prepared short-chain propargylic alco-
hols from allylic chlorides.13 We applied this method to
the preparation of long-chain alcohol 11. Thus, alkylation
of propargyl alcohol (18) with dodecyl bromide (19) in
THF22a gave propargylic alcohol 20 in 95% yield (Scheme
4). The latter was converted to (E)-allylic alcohol 21 in
96% yield by LiAlH4 reduction23 and then to chloride 22
in 88% yield by Mitsunobu reaction of 21. Reaction of 22
with AD-mix-R23 provided diol 2324 in 88% yield and 93%
ee. To minimize epoxide formation, the AD reaction was
carried out under “buffered” conditions (with 3 equiv of
a
Reagents and conditions: (a) TBSCl, imidazole, DMF, rt;
(b) n-BuLi, THF, -78 °C to rt; (c) n-Bu4NF, THF, rt; (d) (i)
Li, EtNH2, -78 °C, (ii) HCl, dioxane, 100 °C, (iii)
1
M
p-O2NC6H4CO2C7H15-n, THF, rt; (e) (i) 1 M HCl, dioxane, 100 °C,
(ii) p-O2NC6H4CO2C7H15-n, THF, rt; (f) Li, EtNH2, -78 °C.
NaHCO3).25 Treatment of diol 23 with 2,2-dimethoxypro-
pane in the presence of p-TsOH gave acetonide 24, which
was treated with excess n-BuLi in the presence of HMPA
to provide alcohol (S)-11 in 80% yield (93% ee).
Syn t h esis of Cer a m id e An a logu e 2 (Sch em e 5).
Coupling of protected propargylic alcohols 8 and 11 with
(S)-aldehyde 267,26 led to ceramide analogues 2 and 3.
The C-2 and C-6 configurations in 2 and 3 are derived
from the stereogenic centers in serinaldehyde 26 and the
propargylic alcohols, respectively. The new stereocenter
at C-3 is generated by the asymmetric addition of the
lithium acetylide of 25 or 32 to the Boc-protected alde-
hyde. As shown in Scheme 5, protection of the hydroxy
group of 11 (TBSCl, Im) gave ether 25, which was
lithiated (n-BuLi, THF, -78 °C) and reacted with alde-
hyde 26 to give an 8:1 mixture of erythro-27 and threo-
28 in 80% overall yield.27 The diastereoselectivity was
improved significantly (ratio > 20:1) by the addition of 2
equiv of HMPA.28 After diastereomers 27 and 28 were
separated by chromatography, the TBS group of 27 was
removed by treatment with n-Bu4NF in THF to give diol
29, and Birch reduction was used to convert the triple
bond to a trans double bond. Acid hydrolysis (1 M HCl
in dioxane, 100 °C) followed by N-acylation with p-nitro-
phenyl octanoate provided target ceramide analogue 2
(18) Bonini, C.; Federici, C.; Rossi, L.; Righi, G. J . Org. Chem. 1995,
60, 4803-4812.
(19) For a review of the Mitsunobu reaction, see: Hughes, D. L. Org.
React. 1992, 42, 335-656.
(20) For a preliminary account of the preparation of both R and S
long-chain propargylic alcohols in high ee via AD reaction of R,â-
unsaturated esters with either AD-mix-R or AD-mix-â, see: Chun, J .;
Byun, H.-S.; Bittman, R. Tetrahedron Lett. 2002, 43, 8043-8045.
(21) Takano, S.; Sugihara, T.; Ogasawara, K.Heterocycles 1990, 31,
1721-1725.
(22) (a) van Aar, M. P. M.; Thijs, L.; Zwanenburg, B. Tetrahedron
1995, 51, 11223-11234. (b) Oppolzer, W.; Radinov, R. N.; El-Sayed,
E. J . Org. Chem. 2001, 66, 4766-4770.
(23) Zhang, Z.-B.; Wang, Z.-M.; Wang, Y.-X.; Liu, H.-Q.; Lei, G.-X.;
Shi, M. J . Chem. Soc., Perkin Trans. 1 2000, 53-57.
(24) Zhang et al.23 assigned the 2S,3S configuration to compound
23; however, it should be 2R,3S. Moreover, because of the discrepancy
between the mp and [R] values and those of ref 23, we prepared the
enantiomer of 23, (2S,3R)-1-chloropentadecane-2,3-diol, by the reaction
of 22 with AD-mix-â, and found no change in mp (64.5-65.5 °C) and
the same magnitude of specific rotation but opposite sign ([R]25D +8.9°
(c 1.0, MeOH)).
(25) For the “buffered” AD reaction of allylic halides, see: Van-
hessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron Lett.
1994, 35, 3469-3472.
(26) (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.
(27) The ratio of 27 to 28 was estimated by high-temperature 1H
NMR spectroscopy.
(28) For examples of high anti:syn ratios in the addition of alkynyl-
lithium reagents to 26 in the presence of HMPA, see: (a) Herold, P.
Helv. Chim. Acta 1988, 71, 354-362. (b) Gruza, H.; Kiciak, K.;
Krasinski, A.; J urczak, J . Tetrahedron: Asymmetry 1997, 8, 2627-
2631.
350 J . Org. Chem., Vol. 68, No. 2, 2003

Asymmetric Synthesis of Ceramides
SCHEME 6. Syn th esis of Cer a m id e An a logu e 3a
-78 °C and for 1 h at rt, the reaction was quenched by the
addition of aqueous saturated NH4Cl solution. The product was
extracted with EtOAc (3 × 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. Pentadecynyl alcohol 5
(0.77 g, 92%) was obtained by chromatography on silica gel
(hexane/EtOAc, 9:1): IR 3597, 3302, 2169 cm-1 1H NMR δ
;
0.14 (br s, 9H), 0.84 (t, 3H, J ) 6.7 Hz), 1.10-1.50 (m, 20H),
1.64 (m, 2H), 2.12 (br s, 1H), 4.31 (t, 1H, J ) 6.6 Hz); 13C NMR
δ -0.2, 14.1, 22.6, 22.7, 25.1, 27.8, 29.2, 29.3, 29.5, 29.61, 29.64,
+
31.9, 37.1, 37.6, 62.8, 89.1, 107.1; HR-MS [DCI/NH3, MNH4
]
m/z calcd for C18H14NOSi 314.1879, found 314.1879.
1-(Tr im eth ylsilyl)p en ta d ecyn -3-on e (6). To a solution of
0.30 g (1.0 mmol) of 5 in 10 mL of CH2Cl2 was added 0.43 g
(2.0 mmol) of PCC. The mixture was stirred at rt for 5 h and
then filtered through a pad of silica gel, which was washed
with CH2Cl2. The filtrate was concentrated to give a residue
that was purified by flash chromatography (hexane/EtOAc,
9:1), affording 0.26 g (88%) of ynone 6: IR 2172, 1665, 1256
a
Reagents and conditions: (a) TBSCl, imidazole, DMF, rt; (b)
cm-1; H NMR δ 0.16 (s, 9H), 0.82 (t, 3H, J ) 6.6 Hz), 1.10-
n-BuLi, HMPA, THF, -78 °C to rt; (c) (i) 1 M HCl, dioxane, 100
°C, (ii) p-O2NC6H4CO2C7H15-n, THF, rt; (d) Li, EtNH2, -78 °C.
1
1.60 (m, 18H), 1.57 (m, 2H), 2.46 (t, 1H, J ) 7.4 Hz); 13C NMR
δ -0.9, 14.0, 22.2, 22.6, 22.7, 23.7, 23.8, 28.8, 29.1, 29.2, 29.3,
29.4, 29.51, 29.52, 31.8, 42.3, 42.6, 45.1, 97.1, 102.0, 187.6; MS
[ESI] m/z 295.2 (M+), 312.2 (MNH4+), 317.1 (MNa+).
(route a). Unexpectedly, we found the yield of 2 to be only
42%; about 20% byproduct 30 was also formed. A much
better result (route b) was obtained when we changed
the sequence of these reactions: acid hydrolysis of 27
followed by N-acylation provided 4-alkynylceramide ana-
logue 31. In the last step, Birch reduction of 31 (Li,
EtNH2, THF, -78 °C) gave ceramide analogue 2 in 90%
yield.
Syn t h esis of Cer a m id e An a logu e 3 (Sch em e 6).
Protection of the hydroxy group of 8 as the TBS ether
followed by lithiation (n-BuLi, THF, -78 °C) and reaction
with aldehyde 26 in the presence of HMPA afforded 33
in 78% yield (Scheme 6). Acid hydrolysis (1 M HCl in
dioxane, 100 °C) of 33 followed by N-acylation with
p-nitrophenyl octanoate afforded 4-alkynylceramide ana-
logue 34, which on Birch reduction provided ceramide
analogue 3 in 88% yield.
In summary, we have reported the first synthesis of
naturally occurring sphingolipids with the 6(R/S)-hy-
droxysphing-(4E)-enine backbone, a novel long-chain base
bearing allylic hydroxy groups at C-3 and C-6. The key
precursors were the propargylic alcohols 8 and 11, which
were prepared by AD reactions with R,â-unsaturated
ester 13 and allylic chloride 22, respectively, followed by
acetonide formation and elimination. The target ceramide
analogues 2 and 3 were obtained with high stereoselec-
tivity and good yields.
1-(Tr im eth ylsilyl)p en ta d ecyn -3-ol (7). To a solution of
Chirald (1.70 g, 6.0 mmol) in 10 mL of dry Et2O was added
dropwise 2.8 mL (2.8 mmol) of LiAlH4 (a 1.0 M solution in
Et2O) at 0 °C. After being stirred for 5 min, the mixture was
chilled to -78 °C, and a solution of ketone 6 (590 mg, 2.0 mmol)
in 10 mL of Et2O was added over a 15 min period. The mixture
was stirred at -78 °C for 6 h. Saturated aqueous NH4Cl
solution was added to quench the reaction. The product was
extracted with EtOAc (3 × 30 mL), and the combined organic
layers were washed with brine (20 mL), dried (Na2SO4), and
concentrated. Purification of the residue by column chroma-
tography (hexane/EtOAc, 4:1) gave 275 mg (93%) of 7 as a
colorless oil: IR 3597, 2158 cm-1; MS [ESI] m/z 314.2 (MNH4+),
319.2 (MNa+).
r a c-1-P en ta d ecyn -3-ol (9). A mixture of 0.60 g (2.0 mmol)
of TMS acetylide 5 and 0.62 g (4.6 mmol) of K2CO3 in 4 mL of
MeOH was stirred at rt for 4 h. After the solvent was removed,
the residue was dissolved in 30 mL of Et2O, washed with
water, and dried (MgSO4). Concentration and purification of
the residue by column chromatography (hexane/EtOAc, 9:1)
gave 0.40 g (90%) of 9 as a white solid: mp 44.0-45.0 °C; IR
3597, 3302, 1457 cm-1 1H NMR δ 0.84 (t, 3H, J ) 6.6 Hz),
;
1.20-1.60 (m, 20H), 1.68 (m, 2H), 2.31 (br s, 1H), 2.42 (d, 1H,
J ) 3.7 Hz), 4.32 (dt, 1H, J ) 6.7, 2.1 Hz); 13C NMR δ 14.1,
22.6, 25.1, 29.3, 29.5, 29.62, 29.69, 29.7, 32.0, 37.6, 62.2, 72.7,
85.1; HR-MS [DCI/NH3, MNH4+] m/z calcd for C15H32NO
242.2484, found 242.2477.
1-P en ta d ecyn -3-on e (10). This compound was prepared
in 88% yield by using the same procedure as described for 6:
IR 3291, 2093, 1681 cm-1; 1H NMR δ 0.82 (t, 3H, J ) 6.6 Hz),
1.10-1.60 (m, 18H), 1.61 (m, 2H), 2.51 (t, 1H, J ) 7.4 Hz),
3.17 (s, 1H); 13C NMR δ 14.0, 22.6, 23.7, 28.8, 29.2, 29.3, 29.48,
29.53, 29.54, 31.8, 45.3, 78.2, 81.4, 187.3; HR-MS [DCI/NH3,
MNH4+] m/z calcd for C15H30NO 240.2327, found 240.2333.
Eth yl (2E)-P en ta d ecen oa te (13). To a nitrogen-flushed
solution of 10.5 g (122 mmol) of LiBr in 100 mL of dry THF
was injected 7.2 mL (7.6 g, 30 mmol) of (i-PrO)2P(O)CH2CO2-
Et (12) at rt. After the solution was stirred at rt for 10 min,
6.8 mL (49 mmol) of Et3N was added, and stirring was
continued for 10 min. A solution of 4.3 g (25 mmol) of 4 in 10
mL of dry THF was added. The reaction mixture was stirred
vigorously at rt until the full consumption of tridecanal was
observed (TLC). The precipitate was removed by passing the
reaction mixture through a pad of silica gel in a sintered glass
funnel. The pad was washed with hexane/EtOAc (10:1).
Concentration gave a pale yellow oil that was purified by
column chromatography (hexane/EtOAc, 20:1), providing 6.0
g (90%) of ester 13 as a colorless oil. The NMR data are in full
accord with the literature data.18
Exp er im en ta l Section
Gen er a l In for m a tion . See the previous paper for general
experimental details.29 (S)-Garner aldehyde (26) was prepared
from N-Boc-L-serine methyl ester as described previously.26b,c
Mosher esters were prepared as described previously.15 1H and
13C NMR spectra were recorded at 400 and 100 MHz, respec-
tively. The solvent was CDCl3 unless otherwise noted. IR
spectra were recorded in chloroform. The mobile phase used
in electrospray mass spectrometry contained ∼50 µM NH4OAc
and 0.1% HOAc.
r a c-1-(Tr im eth ylsilyl)p en ta d ecyn -3-ol (5). To a solution
of 0.43 mL (3.0 mmol) of (trimethylsilyl)acetylene in 15 mL of
dry THF was added 1.3 mL (3.2 mmol) of n-BuLi (2.5 M
solution in hexanes) at -78 °C under N2. After 30 min, a
solution of 0.48 g (2.8 mmol) of tridecanal (4) in 10 mL of THF
was added dropwise. After the mixture was stirred for 2 h at
(29) Chun, J .; He, L.; Byun, H.-S.; Bittman, R. J . Org. Chem. 2002,
67, 2600-2605.
J . Org. Chem, Vol. 68, No. 2, 2003 351

Chun et al.
Eth yl (2S,3R)-2,3-Dih yd r oxyp en ta d eca n oa te [(+)-14].
To a solution of 14.0 g of AD-mix-â in 200 mL of t-BuOH/H2O
(1:1) that had been stirred vigorously at rt for 30 min was
added 950 mg (10.0 mmol) of MeSO2NH2. Stirring was
continued for 10 min at rt. Then 2.7 g (10.0 mmol) of
R,â-unsaturated ester 13 was added. The reaction mixture was
stirred vigorously until the disappearance of ester 13 was
noted (TLC). Sodium sulfite (15.0 g, 14.6 mmol) was added to
quench the reaction, and stirring was continued for another
30 min. The product was extracted with EtOAc (3 × 80 mL),
and the combined extracts were dried (Na2SO4) and concen-
trated to give a yellow residue. Purification of the residue by
column chromatography (hexane/EtOAc, 2:1) gave 2.7 g (90%)
of diol ester 14 as a white solid: mp 69.0-70.0 °C; [R]25D +8.3°
washed with brine (20 mL), dried (Na2SO4), and concentrated.
Purification of the residue by column chromatography (hexane/
EtOAc, 7:1) gave 668 mg (80%) of 8 as a white solid: mp 40.0-
41.0 °C; [R]25D +2.60° (c 1.0, CHCl3); IR 3597, 3302, 1458 cm-1
;
1H NMR δ 0.88 (t, 3H, J ) 6.6 Hz), 1.20-1.60 (m, 20H), 1.72
(m, 2H), 2.41 (br s, 1H), 2.44 (d, 1H, J ) 3.7 Hz), 4.36 (m, 1H);
13C NMR δ 14.1, 22.7, 25.1, 29.3, 29.5, 29.62, 29.69, 29.7, 32.0,
37.6, 62.3, 72.8, 85.1; HR-MS [DCI/NH3, MNH4+] m/z calcd
for C15H32NO 242.2484, found 242.2489.
2-P en ta d ecyn -1-ol (20). This compound was prepared in
95% yield by a slight modification of the procedure of van Aar
et al.;22a we used 3 equiv of propargyl alcohol (18) rather than
1.5 equiv; mp 44.2-45.2 °C (lit.22a mp 38-41 °C, lit.22b mp
43-45 °C). The NMR data are in full accord with the literature
data.22a,b
(c 1.0, CHCl3); IR 3629, 3019, 2398, 1518, 1425, 1212 cm-1
;
1H NMR δ 0.88 (t, 3H, J ) 6.5 Hz), 1.10-1.70 (m, 25H), 3.06
(d, 1H, J ) 8.4 Hz), 3.86 (m, 2H), 4.06 (dd, 1H, J ) 6.5, 2.3
Hz), 4.24 (q, 2H, J ) 7.1 Hz); 13C NMR δ 14.15, 14.17, 22.8,
25.9, 29.5, 29.70, 29.72, 29.74, 29.76, 29.8, 32.0, 33.6, 61.8, 72.8,
73.6, 173.8; MS [ESI] m/z 320.2 (MNH4+), 325.2 (MNa+).
(4S,5R)-5-Dod ecyl-4-eth oxyca r bon yl-2,2-d im eth yl-1,3-
d ioxola n e (15). To a solution of 2.4 g (8.0 mmol) of diol ester
14 in 60 mL of dry CH2Cl2 were added 1.67 g (16.0 mmol) of
2,2-dimethoxypropane and 50 mg (0.26 mmol) of p-TsOH at
rt. The mixture was stirred at rt for 2 h and then passed
through a pad of silica gel in a sintered glass funnel. The pad
was washed with 50 mL of CH2Cl2. Concentration gave ester
15 as a colorless oil, which was used without further purifica-
tion in the subsequent reaction.
(2E)-P en ta d ecen -1-ol (21). This compound, which is a low-
melting-point white solid, was prepared in 96% yield as
described previously, and the NMR data are in full accord with
the literature data.23
(2E)-1-Ch lor op en ta d ecen e (22). To a solution of 5.0 g
(22.1 mmol) of alcohol 21 and 7.0 g (26.7 mmol) of Ph3P in 50
mL of dry CH2Cl2 was added 3.3 g (24.4 mmol) of NCS at 0 °C
under N2. The reaction mixture was stirred at 0 °C for 1 h,
then allowed to warm to rt, and stirred for 2 h. The mixture
was diluted with 150 mL of hexane and passed through a pad
of silica gel with suction to remove the precipitate of Ph3PO.
The filtrate was concentrated, and the resulting residue was
dissolved in 100 mL of hexane and passed through a pad of
silica gel to remove the precipitate of Ph3PO again. Concentra-
tion gave 4.79 g (88%) of allylic chloride 22 as a colorless oil.
This compound was used in the next step without further
purification.
(4R,5R)-5-Dod ecyl-4-h yd r oxym eth yl-2,2-d im eth yl-1,3-
d ioxola n e [(+)-16]. To a solution of ester 15 obtained above
in 15 mL of dry THF was added dropwise 10.7 mL (16.0 mmol)
of DIBAL-H (a 1.5 M solution in toluene) at 0 °C under N2.
The reaction mixture was stirred for 2 h at 0 °C until TLC
analysis showed the reaction to be complete. The reaction was
quenched by slow addition of 2 mL of MeOH followed by 15
mL of cold 5% aqueous potassium sodium tartrate solution.
The product was extracted with EtOAc (3 × 40 mL), and the
combined organic layers were washed with brine (15 mL),
dried (Na2SO4), and concentrated. Purification of the residue
by column chromatography (hexane/EtOAc, 4:1) gave 2.18 g
(2R,3S)-1-Ch lor op en ta d eca n e-2,3-d iol [(-)-23]. After a
solution of 14.0 g of AD-mix-R23,30 in 200 mL of t-BuOH/H2O
(1:1) was stirred vigorously at rt for 30 min, 2.52 g (30.0 mmol)
of NaHCO3 was added. After 15 min, 950 mg (10.0 mmol) of
MeSO2NH2 was added, and stirring was continued for 10 min
at rt. The reaction mixture was chilled to 0 °C, and 2.47 g (10.0
mmol) of allylic chloride 22 was added. The reaction mixture
was stirred vigorously for 8 h. Sodium sulfite (15.0 g, 14.6
mmol) was added to quench the reaction, and stirring was
continued for another 30 min. The product was extracted with
EtOAc (3 × 80 mL). The combined extracts were dried (Na2-
SO4) and concentrated to give a yellow solid residue, which
was purified by column chromatography (hexane/EtOAc, 2:1),
giving 2.45 g (88%) of diol 23 as a white solid: mp 64.5-65.5
°C (lit.23 mp 92-93 °C); [R]25 -9.6° (c 1.25, CHCl3); [R]25
(91%) of 16 as a colorless oil: [R]25 +18.8° (c 1.8, CHCl3); IR
D
1
3597, 1463, 1382, 1103 cm-1; H NMR δ 0.88 (t, 3H, J ) 6.6
Hz), 1.10-1.70 (m, 28H), 2.90 (t, 1H, J ) 6.0 Hz), 3.59 (m,
1H), 3.72 (m, 2H), 3.84 (m, 1H); 13C NMR δ 14.1, 22.7, 26.0,
27.1, 27.4, 29.4, 29.58, 29.63, 29.70, 29.73, 29.8, 32.0, 33.2, 62.2,
77.1, 81.8, 108.6; HR-MS [DCI, MH+] m/z calcd for C18H37O3
301.2743, found 301.2751.
D
D
-8.9° (c 1.0, MeOH) (lit.23 [R]25 -7.0° (c 1.0, MeOH)).24 The
D
NMR data are in full accord with the literature data.23
(4R,5S)-4-Ch lor om eth yl-5-d od ecyl-2,2-d im eth yl-1,3-d i-
oxola n e [(-)-24]. This compound was prepared in 98% yield
(4S,5R)-4-Ch lor om eth yl-5-d od ecyl-2,2-d im eth yl-1,3-d i-
oxola n e [(+)-17]. To a solution of 1.74 g (5.8 mmol) of alcohol
16 and 1.83 g (6.9 mmol) of Ph3P in 30 mL of dry CH2Cl2 was
added 930 mg (6.9 mmol) of NCS at 0 °C under N2. The
reaction mixture was stirred at 0 °C for 1 h, then allowed to
warm to rt, and stirred for 2 h. The mixture was diluted with
100 mL of hexane and passed through a pad of silica gel to
remove the precipitate of Ph3PO. Concentration and purifica-
tion of the residue by column chromatography (hexane/EtOAc,
by using the same procedure as described for 15: [R]25
D
-10.93° (c 2.1, CHCl3); IR and 1H and 13C NMR spectra
essentially identical to those of (+)-17; HR-MS [DCI, MH+]
m/z calcd for C18H36O2Cl 319.2404, found 319.2400.
(3S)-1-P en ta d ecyn -3-ol [(-)-11]. This compound was pre-
pared in 80% yield by using the same procedure as described
9:1) gave 1.59 g (86%) of 17 as a colorless oil: [R]25 +14.2° (c
for 8: mp 40.0-41.0 °C; [R]25 -2.59° (c 1.0, CHCl3); IR and
D
D
1
0.9, CHCl3); IR 1464, 1376, 1218, 1098 cm-1; H NMR δ 0.88
1H and 13C NMR spectra essentially identical to those of (+)-
8; HR-MS [DCI, MH+] m/z calcd for C15H29O 225.2218, found
225.2211.
(t, 3H, J ) 6.6 Hz), 1.20-1.70 (m, 28H), 3.58 (d, 2H, J ) 4.9
Hz), 3.88 (m, 2H); 13C NMR δ 14.1, 22.7, 26.0, 27.0, 27.5, 29.4,
29.5, 29.6, 29.7, 32.0, 33.5, 44.4, 79.4, 80.3, 109.1; HR-MS [DCI,
MH+] m/z calcd for C18H36O2Cl 319.2404, found 319.2407.
(3S)-3-(ter t-Bu tyldim eth ylsilyloxy)-1-pen tadecyn e [(-)-
25]. To a solution of 0.45 g (2.0 mmol) of 11 and 0.29 g (4.2
mmol) of imidazole in 4 mL of DMF under N2 was added 0.33
g (2.2 mmol) of tert-butylchlorodimethylsilane. After the solu-
tion was stirred at rt overnight, it was diluted with water (5
mL), and the product was extracted with Et2O (3 × 20 mL).
The combined extracts were washed with brine and water,
(3R)-1-P en ta d ecyn -3-ol [(+)-8]. To a stirred solution of
4.5 mL (26.1 mmol) of HMPA in 20 mL of dry THF was added
10.4 mL (26.1 mmol) of n-BuLi (a 2.5 M solution in hexane) at
-42 °C under N2. After 10 min, a solution of 1.19 g (3.73 mmol)
of chloride 17 in 10 mL of THF was added dropwise over 5
min. After 0.5 h, the reaction mixture was warmed to rt and
stirred for another 0.5 h. Saturated aqueous NH4Cl solution
was added to quench the reaction. The product was extracted
with EtOAc (3 × 30 mL), and the combined organic layers were
(30) 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.
352 J . Org. Chem., Vol. 68, No. 2, 2003

Asymmetric Synthesis of Ceramides
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by chromatography (hexane) to give 0.66
was dissolved in 6 mL of dry THF. After 108 mg (0.40 mmol)
of p-nitrophenyl octanoate was added at rt, the reaction
mixture was stirred for 24 h and concentrated. Purification
by flash chromatography (CHCl3/MeOH, 9:1) afforded 71 mg
(81%, two steps) of 4-alkynylceramide analogue 31 as a white
g (97%) of 25 as a colorless oil: [R]25 -26.9° (c 1.7, CHCl3);
D
1
IR 1714, 1463, 1256, 1093, 837 cm-1; H NMR δ 0.10 (s, 3H),
0.13 (s, 3H), 0.89 (m, 12H), 1.20-1.40 (m, 20H), 1.65 (m, 2H),
2.34 (d, 1H, J ) 2.1 Hz), 4.32 (dt, 1H, J ) 6.5, 2.1 Hz); 13C
NMR δ -5.1, -4.5, 14.1, 18.2, 22.7, 25.2, 25.8, 29.3, 29.4, 29.61,
29.64, 29.71, 29.74, 32.0, 38.6, 62.8, 71.8, 85.8; HR-MS [DCI,
MH+] m/z calcd for C21H43SiO 339.3083, found 339.3086.
N-ter t-Bu toxyca r bon yl-(4S,1′R,4′S)-4-[4′-(ter t-bu tyld i-
m eth ylsilyloxy)-1′-h ydr oxy-2′-h exadecyn yl]-2,2-dim eth yl-
1,3-oxa zolid in e [(-)-27]. To a solution of 1.01 g (3.0 mmol)
of alkyne 25 in 15 mL of dry THF was slowly added 1.3 mL
(3.2 mmol) of n-BuLi (2.5 M solution in hexanes) at -78 °C
under N2. The mixture was stirred for 30 min at -78 °C, and
a solution of 0.69 g (3.0 mmol) of 26 in 10 mL of THF was
added dropwise with stirring. The mixture was kept at -78
°C for 2 h and then allowed to warm to rt for 2 h. The reaction
was quenched with saturated aqueous NH4Cl solution, ex-
tracted with EtOAc (3 × 30 mL), dried (MgSO4), and concen-
trated under reduced pressure. The major diastereomer 27 was
isolated by chromatography on silica gel (hexane/EtOAc, 4:1):
solid: mp 95.2-96.2 °C; [R]25 -13.6° (c 1.1, CHCl3/MeOH,
D
4:1); IR 3426, 1659, 1509, 1052 cm-1;1H NMR (CDCl3/MeOD)
δ 0.88 (t, 6H, J ) 6.5 Hz), 1.20-1.70 (m, 32H), 2.24 (t, 2H, J
) 7.5 Hz), 3.67 (dd, 1H, J ) 11.5, 4.7 Hz), 3.90 (dd, 1H, J )
11.5, 4.6 Hz), 4.06 (d, 1H, J ) 4.7 Hz), 4.30 (m, 1H), 4.53 (dd,
1H, J ) 4.8, 1.3 Hz); 13C NMR (CDCl3/MeOD) δ 14.1, 22.7,
22.8, 25.4, 25.8, 29.1, 29.3, 29.5, 29.7, 31.8, 32.0, 36.66, 36.7,
37.6, 55.2, 61.5, 61.8, 62.8, 82.3, 87.8, 175.3; HR-MS [FAB,
MNa+] m/z calcd for C26H49NO4Na 462.3559, found 462.3552.
(2S,3R,6S)-2-Octa n oyla m id o-(4E)-octa d ecen e-1,3,6-tr i-
ol [(+)-2]. To the blue solution prepared by addition of 50 mg
(7.2 mmol) of lithium metal to 5 mL of liquid EtNH2 was added
a solution of 31 (44 mg, 0.10 mmol) in 5 mL of dry THF at
-78 °C. After the mixture was stirred for 1 h, the reaction
was quenched by addition of 400 mg (7.5 mmol) of NH4Cl. After
removal of EtNH2 by a stream of N2, the mixture was diluted
with 50 mL of CHCl3 and washed with water. The organic
layer was dried (Na2SO4) and concentrated. Purification by
column chromatography (CHCl3/MeOH, 9:1) gave 40 mg (90%)
[R]25 -41.1° (c 2.9, CHCl3); IR 3334, 3012, 1688, 1380, 1256,
D
1152 cm-1; 1H NMR (C6D6, 70 °C)31 δ 0.13 (s, 3H), 0.19 (s, 3H),
0.88 (t, 3H, J ) 6.1 Hz), 0.96 (s, 9H), 1.20-1.80 (m, 37H), 3.79
(t, 1H, J ) 7.5 Hz), 4.00 (br s, 2H), 4.41 (t, 1H, J ) 6.1 Hz),
4.70 (br s, 1H); 13C NMR (C6D6)32 δ -5.2, -4.9, 14.3, 18.1, 18.4,
18.5, 18.7, 23.1, 23.3, 25.7, 25.9, 26.0, 26.3, 28.3, 29.5, 29.7,
29.8, 30.00, 30.05, 30.07, 30.1, 32.3, 38.2, 39.2, (62.0) 63.3, 64.2
(64.6), 67.1, (79.9) 81.7, 83.0 (83.5), 87.6 (88.1), 101.0, (151.7)
154.3; HR-MS [FAB, MH+] m/z calcd for C32H62NO5Si 568.4397,
found 568.4366.
of 2 as a white solid: mp 119.5-121.0 °C; [R]25 +5.1° (c 1.1,
D
CHCl3/MeOH, 4:1); IR 3427, 1659, 1509, 1465, 1222 cm-1; 1H
NMR (CDCl3/MeOD) δ 0.88 (t, 6H, J ) 6.4 Hz), 1.20-1.70 (m,
32H), 2.21 (t, 2H, J ) 7.4 Hz), 3.63 (dd, 1H, J ) 10.9, 3.4 Hz),
3.84 (m, 2H), 4.06 (q, 1H, J ) 6.1 Hz), 4.20 (t, 1H, J ) 5.3
Hz), 5.65 (dd, 1H, J ) 15.5, 5.8 Hz), 5.73 (dd, 1H, J ) 16.7,
6.0 Hz); 13C NMR (CDCl3/MeOD) δ 14.1, 22.7, 22.8, 25.6, 25.9,
29.1, 29.4, 29.5, 29.7, 29.8, 31.8, 32.0, 36.7, 37.1, 54.7, 61.6,
71.9, 72.6, 129.5, 135.6, 174.9; HR-MS [FAB, MNa+] m/z calcd
for C26H51NO4Na 464.3716, found 464.3707.
Da ta for th e m in or d ia ster eom er 28: IR 3597, 3008,
1
1692, 1398, 1256, 1163, 1092 cm-1; H NMR (C6D6, 70 °C) δ
0.14 (s, 3H), 0.20 (s, 3H), 0.88 (t, 3H, J ) 6.1 Hz), 0.99 (s, 9H),
1.20-1.80 (m, 37H), 3.26 (br s, 1H), 3.49 (t, 1H, J ) 6.4 Hz),
3.83 (dd, 1H, J ) 9.5, 6.5 Hz), 4.13 (m, 2H), 4.46 (m, 1H), 4.76
Da t a for (3S,4S)-2-[(1′E)-1′-Tet r a d ecen yl]-3-h yd r oxy-
4-octa n oyla m id otetr a h yd r ofu r a n [(+)-30]: mp 142.0-
143.0 °C; [R]25 +12.9° (c 0.9, CHCl3/MeOH, 4:1); IR 1665,
D
(d, 1H, J ) 6.4 Hz); HR-MS [FAB, MNa+] m/z calcd for C32H61
-
1510, 1467, 1223 cm-1; 1H NMR (CDCl3/MeOD) δ 0.88 (t, 6H,
J ) 6.4 Hz), 1.20-1.70 (m, 30H), 2.08 (q, 2H, J ) 6.9 Hz),
2.21 (t, 2H, J ) 7.4 Hz), 3.62 (t, 1H, J ) 8.2 Hz), 3.79 (br s,
3H), 4.06 (m, 2H), 4.29 (q, 1H, J ) 3.0 Hz), 4.53 (m, 1H), 5.60
NO5SiNa 590.4217, found 590.4236.
N-ter t-Bu toxyca r bon yl-(4S,1′R,4′S)-4-[1′,4′-d ih yd r oxy-
2′-h exa d ecyn yl]-2,2-d im eth yl-1,3-oxa zolid in e [(-)-29]. To
a solution of 0.47 g (0.82 mmol) of 27 in 5.0 mL of THF was
added 1.64 mL (1.64 mmol) of a 1.0 M solution of n-Bu4NF in
THF at rt under N2. After the mixture was stirred for 1 h,
and the reaction was quenched with 5 mL of water. The
product was extracted with EtOAc (3 × 20 mL), dried (Na2-
SO4), and concentrated under reduced pressure. The residue
was purified by chromatography (EtOAc/hexane, 2:3) to give
(dd, 1H, J ) 15.4, 7.4 Hz), 5.83 (dt, 1H, J ) 15.4, 8.5 Hz); 13
C
NMR (CDCl3/ MeOD) δ 13.56, 13.6, 22.2, 22.3, 25.4, 28.6, 28.7,
28.8, 28.9, 29.2, 29.27, 29.3, 31.3, 31.6, 32.2, 36.0, 52.4, 69.4,
71.8, 83.1, 124.0, 136.4, 174.3; HR-MS [DCI, MH+ - H2O] m/z
calcd for C26H48NO2 406.3685, found 406.3669; MS [ESI, MH+]
m/z calcd for C26H50NO3 424.3, found 424.3. The configuration
at C-2 was not determined.
0.34 g (91%) of 29 as a colorless oil: [R]25 -41.1° (c 1.9,
D
(3R)-3-(ter t-Bu tyldim eth ylsilyloxy)-1-pen tadecyn e [(+)-
32]. This compound was prepared in 95% yield by using the
CHCl3); IR 1666, 1467, 1394, 1368, 1245, 1167, 1082 cm-1; 1H
NMR (C6D6, 70 °C) δ 0.89 (t, 3H, J ) 6.6 Hz), 0.96 (s, 9H),
1.20-1.80 (m, 37H), 2.22 (d, 1H, J ) 4.6 Hz), 3.78 (dd, 1H, J
) 9.0, 7.0 Hz), 3.96 (br s, 1H), 4.05 (br s, 1H), 4.31 (dd, 1H, J
) 11.1, 5.2 Hz), 4.69 (br s, 1H); 13C NMR (C6D6) δ 14.3, 14.8,
22.9, 23.0, 23.1, 23.3, 23.5, 25.3, 25.8, 26.1, 26.7, 28.3, 29.8,
30.09, 30.1, 30.2, 32.1, 32.3, 34.5, 38.2, (62.0) 62.3, 62.9, 63.7,
(64.8) 65.2, (79.9) 80.9, 83.6, 87.9 (88.4), 94.9 (95.4), (151.9)
154.2; HR-MS [FAB, MH+] m/z calcd for C26H48NO5 454.3532,
found 454.3517.
same procedure as described for 25: [R]25 +20.7° (c 0.7,
D
CHCl3); IR 1708, 1467, 1256, 1093, 837 cm-1; 1H NMR δ 0.10
(s, 3H), 0.13 (s, 3H), 0.89 (m, 12H), 1.20-1.40 (m, 20H), 1.65
(m, 2H), 2.34 (d, 1H, J ) 2.1 Hz), 4.32 (m, 1H); 13C NMR δ
-5.1, -4.5, 14.1, 18.2, 22.7, 25.2, 25.8, 29.3, 29.4, 29.61, 29.64,
29.71, 29.74, 32.0, 38.6, 62.8, 71.8, 85.8; MS [ESI] m/z 356.3
(MNH4+).
N-ter t-Bu toxyca r bon yl-(4S,1′R,4′R)-4-[4′-(ter t-bu tyld i-
m eth ylsilyloxy)-1′-h ydr oxy-2′-h exadecyn yl]-2,2-dim eth yl-
1,3-oxa zolid in e [(-)-33]. To a solution of 1.01 g (3.0 mmol)
of alkyne 32 in 15 mL of dry THF was slowly added 1.3 mL
(3.2 mmol) of n-BuLi (a 2.5 M solution in hexanes) at -78 °C
under N2. After the mixture was stirred for 30 min at -78 °C,
HMPA (1.05 mL, 6.0 mmol) was added, followed by a solution
of 0.69 g (3.0 mmol) of 26 in 10 mL of dry THF. The mixture
was kept at -78 °C for 2 h, and then allowed to warm to rt for
1 h. The reaction mixture was quenched with saturated
aqueous NH4Cl solution, extracted with EtOAc (3 × 30 mL),
dried (MgSO4), and concentrated under reduced pressure.
N-Boc-1,3-oxazolidine 33 was isolated by chromatography on
(2S,3R,6S)-2-Oct a n oyla m id o-4-oct a d ecyn e-1,3,6-t r iol
[(-)-31]. A solution of 113 mg (0.20 mmol) of 27 in 5 mL of 1
M HCl and 5 mL of dioxane was heated at 100 °C with stirring
for 1 h under N2. The reaction mixture was cooled to rt and
neutralized with 1 M NaOH (5 mL). The product was extracted
with EtOAc (3 × 20 mL), and the combined organic layers were
washed with brine and dried (Na2SO4). Removal of the solvent
provided a crude sphingosine analogue as a white solid, which
(31) The 1,3-oxazolidine carbamate system exists as
a pair of
rotamers, the interconversion of which is enhanced at high tempera-
ture; therefore, proton NMR spectra were recorded at 70 °C.
(32) Some of the signals in the ambient-temperature 13C NMR
spectra appear as a pair of singlets (denoted in parentheses).
silica gel (hexane/EtOAc, 4:1): [R]25 -4.3° (c 1.8, CDCl3); IR
D
1696, 1375, 1010 cm-1; H NMR (C6D6, 70 °C) δ 0.13 (s, 3H),
1
J . Org. Chem, Vol. 68, No. 2, 2003 353

Chun et al.
0.18 (s, 3H), 0.88 (t, 3H, J ) 6.1 Hz), 0.96 (s, 9H), 1.20-1.80
(m, 37H), 3.79 (t, 1H, J ) 7.1 Hz), 4.00 (br s, 2H), 4.41 (t, 1H,
J ) 5.0 Hz), 4.70 (br s, 1H); 13C NMR (C6D6) δ -4.8, -3.9,
14.4, 18.4, 23.1, 23.4, 24.0, 25.5, 25.7, 26.1, 26.3, 28.2, 28.4,
29.7, 29.8, 30.0, 30.1, 37.0, (63.1) 63.4, 64.2 (64.6), (65.0) 65.2,
(79.8) 80.8, 83.6 (83.7), 87.5 (88.0), 95.0, (151.7) 154.3; HR-
MS [FAB, MNa+] m/z calcd for C32H61NO5SiNa 590.4217, found
590.4231.
the same procedure as described for 2: mp 92.0-93.0 °C; [R]25
D
-10.0° (c 1.0, CHCl3); IR 3426, 1658, 1510, 1467, 1224 cm-1
;
1H NMR δ 0.88 (t, 6H, J ) 6.4 Hz), 1.20-1.70 (m, 32H), 2.23
(t, 2H, J ) 7.5 Hz), 3.70 (dd, 1H, J ) 10.9, 3.4 Hz), 3.94 (m,
2H), 4.13 (q, 1H, J ) 6.1 Hz), 4.37 (t, 1H, J ) 4.1 Hz), 5.79
(dd, 1H, J ) 15.5, 5.8 Hz), 5.81 (dd, 1H, J ) 16.7, 6.0 Hz),
6.38 (d, 1H, J ) 7.4 Hz); 13C NMR δ 14.1, 22.6, 22.7, 25.5,
25.7, 29.0, 29.2, 29.4, 29.6, 29.7, 31.7, 31.9, 36.8, 37.3, 54.4,
62.1, 71.9, 73.8, 129.4, 135.6, 174.2; HR-MS [FAB, MNa+] m/z
calcd for C26H51NO4Na 464.3716, found 464.3700.
(2S,3R,6R)-2-Oct a n oyla m id o-4-oct a d ecyn e-1,3,6-t r iol
[(-)-34]. This compound was prepared in 80% yield by using
the same procedure as described for 31: mp 82.5-83.5 °C;
[R]25 -1.56° (c 1.8, CDCl3); IR 3427, 1657, 1512, 1463, 1053
D
Ack n ow led gm en t. This work was supported by
National Institutes of Health Grant HL 16660.
cm-1;1H NMR δ 0.85 (t, 6H, J ) 6.4 Hz), 1.20-1.70 (m, 32H),
2.22 (t, 2H, J ) 7.5 Hz), 3.71 (dd, 1H, J ) 10.9, 3.4 Hz), 4.04
(m, 2H), 4.32 (t, 1H, J ) 6.5 Hz), 4.59 (d, 1H, J ) 3.6 Hz),
6.65 (d, 1H, J ) 7.9 Hz); 13C NMR δ 14.06, 14.1, 22.6, 22.7,
25.4, 25.7, 29.1, 29.3, 29.4, 29.67, 29.72, 31.7, 32.0, 36.7, 37.7,
54.9, 61.8, 62.0, 63.2, 82.5, 88.1, 174.9; HR-MS [DCI, MH+]
m/z calcd for C26H50NO4 440.3740, found 440.3742.
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, 5, 8, 10, 11, 14, 16, 17, 24,
25, 27, and 29-34. This material is available free of charge
via the Internet at http://pubs.acs.org.
(2S,3R,6R)-2-Octa n oyla m id o-(4E)-octa d ecen e-1,3,6-tr i-
ol [(-)-3]. This compound was prepared in 88% yield by using
J O026240+
354 J . Org. Chem., Vol. 68, No. 2, 2003