Stereoselective Preparation of Ceramide and Its Skeleton Backbone Modified Analogues via Cyclic Thionocarbonate Intermediates Derived by Catalytic Asymmetric Dihydroxylation of α,β-Unsaturated Ester Precursors

Article abstract of DOI:10.1021/jo001226n

A novel and efficient synthetic route to ceramide 1a and skeleton backbone modified ceramide analogues 1b,c is reported. The syntheses utilize osmium-catalyzed asymmetric dihydroxylation of (E)-α,β-unsaturated ester 5a-c as the chiral induction step, with the desired configurations in the products 1a-c, 2a, and 13 being generated by regioselective azide substitution at the α position of α,β-dihydroxyesters 6a-c via a cyclic thionocarbonate intermediate. Azido esters 10a-c are converted to the corresponding ceramides 1a-c by a sequence of azide reduction, N-acylation, ester reduction (NaBH₄/LiBr), and Birch reduction of the triple bond (Li, EtNH₂). These seven- to eight-step syntheses afford the target compounds 1a-c with excellent stereocontrol and in 30-42% overall yields. Furthermore, propargylic α-azido-β-hydroxyester 10a is converted to D-erythro-sphingosine 2a via simultaneous reduction of the triple bond, azido, and ester functional groups with LiAlH₄, providing a highly concise and practical four-step synthesis of this key naturally occurring sphingolipid. The L-erythro stereoisomers are also available in high enantiomeric purity by the method described herein.

Full text of DOI:10.1021/jo001226n

J . Org. Chem. 2000, 65, 7627-7633
7627
Ster eoselective P r ep a r a tion of Cer a m id e a n d Its Sk eleton
Ba ck bon e Mod ified An a logu es via Cyclic Th ion oca r bon a te
In ter m ed ia tes Der ived by Ca ta lytic Asym m etr ic Dih yd r oxyla tion
of r,â-Un sa tu r a ted Ester P r ecu r sor s
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
A novel and efficient synthetic route to ceramide 1a and skeleton backbone modified ceramide
analogues 1b,c is reported. The syntheses utilize osmium-catalyzed asymmetric dihydroxylation
of (E)-R,â-unsaturated ester 5a -c as the chiral induction step, with the desired configurations in
the products 1a -c, 2a , and 13 being generated by regioselective azide substitution at the R position
of R,â-dihydroxyesters 6a -c via a cyclic thionocarbonate intermediate. Azido esters 10a -c are
converted to the corresponding ceramides 1a -c by a sequence of azide reduction, N-acylation, ester
reduction (NaBH4/LiBr), and Birch reduction of the triple bond (Li, EtNH2). These seven- to eight-
step syntheses afford the target compounds 1a -c with excellent stereocontrol and in 30-42% overall
yields. Furthermore, propargylic R-azido-â-hydroxyester 10a is converted to D-erythro-sphingosine
2a via simultaneous reduction of the triple bond, azido, and ester functional groups with LiAlH4,
providing a highly concise and practical four-step synthesis of this key naturally occurring
sphingolipid. The L-erythro stereoisomers are also available in high enantiomeric purity by the
method described herein.
In tr od u ction
activities are not well understood. Potential targets for
ceramide action include protein phosphatases, protein
kinases, and other membrane-associated enzymes.2b,c,3,4
In view of their biological importance, sphingolipids
have attracted the attention of many synthetic chemists.
Many routes to enantiomerically pure sphingolipids have
been described; L-serine and carbohydrates have been
used extensively as the chiral synthons, and approaches
involving asymmetric induction to control the stereo-
chemistry are also available.54,5 Unnatural ceramide
analogues may be useful in the investigation of cer-
amide’s modes of action and also may provide opportuni-
ties for modulating the cellular responses mediated by
ceramide. As an extension of our work on the syntheses
of phytosphingolipids6 and of ceramides bearing a C(5)-
C(6) double bond,7 we describe here an efficient, stereo-
controlled synthesis of ∆4-ceramide 1a and analogues
1b,c, which are modified in the sphingolipid backbone
by having the trans double bond positioned at C(7)-C(8)
Sphingolipids are distributed ubiquitously in the mem-
branes of eukaryotic cells,1 where they were previously
thought to play only a structural role. In recent years,
however, a great deal of attention has been devoted to
studies of the biological processes regulated by sphin-
golipids, and evidence of newly discovered roles of these
compounds in cell functions is continually being demon-
strated. In response to stress stimuli such as inflamma-
tory cytokines, chemotherapeutic agents, heat shock, and
UV-C and ionizing radiation, a cell-line dependent (e.g.,
endothelial, lymphoid, and hematopoietic) increase in
sphingosine and ceramide (N-acylsphingosine, 1a ) levels
takes place, leading to cell growth arrest and initiation
of programmed cell death (apoptosis).2 Ceramide, which
is produced by stimulation of sphingomyelinases or by
de novo synthesis, is a second messenger that triggers
multiple receptor-mediated cell signaling pathways.3 In
contrast to the wealth of information available concerning
the functions of ceramide in various cell types, the
molecular mechanisms by which ceramide exerts its
(4) (a) Dobrowsky, R. T.; Hannun, Y. A. J . Biol. Chem. 1992, 267,
5048-5051. (b) J oseph, C. K.; Byun, H.-S.; Bittman, R.; Kolesnick, R.
N. J . Biol. Chem. 1993, 268, 20002-20006. (c) J arvis, W. D.; Fornari,
F. A. J r.; Auer, K. L.; Freemerman, A. J .; Szabo, E.; Birrer, M. J .;
J ohnson, C. R.; Barbour, S. E.; Dent, P.; Grant, S. Mol. Pharmacol.
1997, 52, 935-947. (d) Kro¨nke, M. Chem. Phys. Lipids 1999, 101, 109-
121.
(5) For recent reviews, see: (a) J ung, K.-H.; Schmidt, R. R. In Lipid
Synthesis and Manufacture; Gunstone, F. D., Ed.; Sheffield Academic
Press: Sheffield, U. K.; CRC Press: Boca Raton, FL, 1999; pp 208-
249. (b) Curfman, C.; Liotta, D. Methods Enzymol. 2000, 311, 391-
457. (c) Koskinen, P. M.; Koskinen, A. M. P. Methods Enzymol. 2000,
311, 458-479.
* To whom correspondence should be addressed. Tel: (718) 997-
3279. Fax: (718) 997-3349.
(1) Sweeley, C. C. In Biochemistry of Lipids, Lipoproteins, and
Membranes; Vance, D. E., Vance, J . E., Eds.; Elsevier: Amsterdam,
1991; pp 327-361.
(2) For reviews, see: (a) Spiegel, S.; Merrill, A. H., J r. FASEB J .
1996, 10, 1388-1397. (b) Hannun, Y. A. Science 1996, 224, 1855-
1859. (c) Kolesnick, R. N.; Kro¨nke, M. Annu. Rev. Physiol. 1998, 60,
643-645. (d) J arvis, W. D.; Grant, S. Curr. Opin. Oncol. 1998, 10, 552-
559.
(3) For reviews, see: (a) Perry, D. K.; Hannun, Y. A. Biochim.
Biophys. Acta 1998, 1436, 233-243. (b) Mathias, S.; Pen˜a, L. A.;
Kolesnick, R. N. Biochem. J . 1998, 335, 465-480.
(6) He, L.; Byun, H.-S.; Bittman, R. J . Org. Chem. 2000, 65, 7618-
7626.
(7) He, L.; Byun, H.-S.; Smit, J .; Wilschut, J .; Bittman, R. J . Am.
Chem. Soc. 1999, 121, 3897-3903.
10.1021/jo001226n CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

7628 J . Org. Chem., Vol. 65, No. 22, 2000
He et al.
Sch em e 1. Retr osyn th etic P la n
Sch em e 2. Syn th esis of r,â-Un sa tu r a ted Ester s
5a -ca
and C(15)-C(16), respectively. We also now report a
practical synthesis of D-erythro-(2S,3R)-sphingosine (2a ),
the backbone component of various sphingolipids, from
1-pentadecyne.
Resu lts a n d Discu ssion
Syn th etic P la n . As outlined in Scheme 1, the strategy
for the preparation of ceramides 1a -c involves three
major reactions: (1) asymmetric dihydroxylation of an
(E)-R,â-unsaturated ester as the chiral induction stage,8
(2) regioselective introduction of the azido group at the
R position, with inversion, via a cyclic thionocarbonate
intermediate, and (3) selective reduction of the ester
functional group after the azido group has been converted
to a long-chain amido group. The synthetic route has the
advantage of being simple, efficient, and highly enantio-
selective.
a
Reagents and conditions: (a) (i) n-BuLi, THF, -23 to 0 °C,
Syn th esis of (E)-R,â-Un sa tu r a ted Ester s 5a -c.
Since an isolated double bond is more reactive in the
asymmetric dihydroxylation reaction than the C(2)-C(3)
double bond in conjugation with an ester functional
group,9 a synthon with a triple bond was chosen for the
construction of (E)-R,â-unsaturated esters 5a -c (Scheme
2). The required trans geometry was generated subse-
quently by Birch reduction of the triple bond. The
Horner-Wadsworth-Emmons (HWE)10 reaction was
employed for the construction of the R,â-unsaturated
ester via coupling of the corresponding aldehyde with a
phosphonate reagent.11 As shown in Scheme 2, the
required precursors 5-hexadecyn-1-ol (4b) and 13-hexa-
decyn-1-ol (4c) were obtained in 90% and 75% yields,
respectively, via ring opening of cyclic sulfate 312 with
lithium 1-dodecyne and 9-dodecynylmagnesium bromide,
respectively, in the presence of a catalytic amount of
CuI.13 During the preparation of 9-dodecynylmagnesium
bromide, a small amount of 9-dodecyn-1-ol was repro-
(ii) 1-formylpiperidine; (b) (i-PrO)2P(O)CH2CO2Et, LiBr, Et3N,
THF, rt; (c) (i) 1-dodecyne, n-BuLi, THF, -23 °C, then CuI (cat.),
3, rt; (d) 1-bromododec-9-yne, Mg, THF, reflux; then CuI (cat.), 3,
rt; (e) (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to -42 °C, (ii)
(EtO)2P(O)CH2CO2Et, LiBr, Et3N, THF, rt.
ducibly formed, which made it difficult to purify the
desired product 4b. Fortunately, the directly obtained
ring-opened product is a sulfate salt, which is insoluble
in hexane-THF mixtures, whereas the byproduct (9-
dodecyn-1-ol) is soluble. Therefore, the latter could be
removed by simply adding hexane to the reaction mixture
when the reaction was completed and separating the solid
and liquid phases. Ynols 4b,c were converted to the
corresponding aldehydes in almost quantitative yield via
Swern oxidation.14 Although hexadec-2-yn-1-ol (4a ) can
be prepared by coupling of propargyl alcohol with 1-bro-
motridecane using lithium amide,15 we found that Swern
and PCC oxidation of alcohol 4a provided the desired
aldehyde in only moderate yield. Alternatively, formyl-
ation of lithium 1-pentadecyne with 1-formylpiperidine
provided the desired hexadec-2-ynal in almost quantita-
tive yield. HWE olefination of hexadec-2-ynal and of the
aldehydes derived from alcohols 4b ,c with triethyl
phosphonoacetate provided enyne esters 5a -c in high
yield and good E/ Z ratio (10:1-15:1). Use of diisopropyl
(ethoxycarbonylmethyl)phosphonate in the HWE reaction
improved the E/Z ratio significantly; for example, E-5a
was formed (in 91% yield) exclusively.16
(8) The Sharpless asymmetric aminohydroxylation (AA) reaction of
olefins, such as (E)-R,â-unsaturated esters 5, is a powerful reaction
for the stereocontrolled construction of a vicinal hydroxyamido moiety.
For AA reactions of olefins, see: Bruncko, M.; Schlingloff, G.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 1483-1486, and
references therein. However, the AA reaction produces a 3-amido-2-
hydroxyester instead of the desired 2-amido-3-hydroxyester. Although
Morgan et al. (Morgan, A. J .; Masse, C. E.; Panek, J . S. Org. Lett. 1999,
1, 1949-1952) demonstrated recently that the AA reaction of 4-haloaryl
esters provided a 2-amido-3-hydroxyester as the major product, the
chemical yield and the % ee are generally unsatisfying. Furthermore,
the AA reaction produces the threo instead of the desired erythro
stereochemistry.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(10) For a review of the HWE reaction, see: Maryanoff, B. E.; Reitz,
A. B. Chem. Rev. 1989, 89, 863-927.
(11) (a) Rathke, M. W.; Nowak, M. J . Org. Chem. 1985, 50, 2624-
2626. (b) The Z and E stereoisomers were separated by column
chromatography (elution with hexane/EtOAc 25:1) and characterized
by 1H NMR.
Asym m etr ic Dih yd r oxyla tion of (2E)-R,â-Un sa tu -
r a ted Ester s 5a -c. Asymmetric dihydroxylation of
(13) For recent reviews of cyclic sulfate chemistry, see: (a) Lohray,
B. B.; Bhushan, V. Adv. Heterocycl. Chem. 1997, 68, 89-180. (b) Byun,
H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-7091.
(14) For reviews of the Swern oxidation, see: (a) Tidwell, T. T.
Synthesis 1990, 857-870. (b) Tidwell, T. T. Org. React. 1990, 39, 297-
572.
(12) Cyclic sulfate 3 was prepared from 1,4-butanediol in 72% yield
by using the Gao and Sharpless procedure (ref 19).
(15) Ruan, Z.-S. Ph.D. Thesis, The City University of New York,
1990.

Asymmetric Synthesis of Ceramide and Its Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7629
Sch em e 3. Syn th esis of
enyne esters 5b,c proceeded smoothly, affording the
desired 2,3-diol esters in excellent yield and chiral purity.
However, under the optimized conditions reported by
Sharpless and co-workers in 1992,17 asymmetric dihy-
droxylation of enyne ester 5a was unsuccessful. In view
of the electron deficiency of the double bond, it is not
surprising that the reaction using commercial AD-mix
(both R and â) proceeded very slowly and was incomplete.
Thus, only a very low yield (∼20%) of diol ester 6a was
obtained initially, even after prolonged reaction. The yield
was not improved by changing the solvent system, e.g.,
by varying the t-BuOH/H2O ratio or by using other
solvents such as MeCN/H2O or MeCN/H2O/EtOAc. This
problem was overcome by the addition of more osmium
reagent (K2OsO4‚2H2O) and chiral ligand [(DHDQ)2-
PHAL or (DHQ)2-PHAL] to the commercial AD-mix-â/
R. The desired diol ester 6a was obtained in 90% yield
and 98% ee.18 Although asymmetric dihydroxylation of
both conjugated enynes and R,â-unsaturated esters has
been well documented,9 to the best of our knowledge this
is the first reported example of the asymmetric dihy-
droxylation reaction at a conjugated olefin located be-
tween a triple bond and an ester functional group.
Regioselective R-Azid a tion of Diol Ester s 6a -c
(Sch em e 3). Regioselective R-azidation of diol esters
6a -c via a cyclic sulfate intermediate was attempted.
However, the desired cyclic sulfate intermediate 8a -c
of all three diols 6a -c could not be formed, since under
the oxidation conditions (NaIO4, cat. RuCl3, MeCN, H2O)
required for the conversion of a cyclic sulfite to the
corresponding cyclic sulfate,19 the triple bond was also
oxidized.20 Attempts to achieve a kinetic differentiation
of the triple bond and cyclic sulfite also failed. The triple
bond became oxidized just as quickly as the sulfite group
in the same molecule. Several other oxidants were also
tried for the oxidation of cyclic sulfite 7 to cyclic sulfate
8.21 Direct azidation of cyclic sulfite 7a -c13 at high
temperature (e.g., 90-120 °C) was also unsuccessful.
Regioselective monoazidation of 6a via Mitsunobu reac-
(2S,3R)-r-Azid o-â-h yd r oxyester s 10a -c via Cyclic
Th ion oca r bon a te In ter m ed ia tes 9a -ca
a
Reagents and conditions: (a) AD-mix-â, MeSO2NH2, t-BuOH/
H2O 1:1, rt; (b) SOCl2, py, CH2Cl2, 0 °C; (c) Cl2CdS, py, DMAP
(cat.), CH2Cl2, 0 °C; (d) NaN3, DMF, PPTS, 0 °C.
R-nosylate intermediates of diol 6a in only low yield (due
to the formation of R,â-bissulfonate and R-sulfonyloxy-
R,â-unsaturated ester). Finally, cyclic thionocarbonate
chemistry24 was found to be the best choice (Scheme 3).
Thus, diols 6a -c were quantitatively converted to the
corresponding cyclic thionocarbonates 9a -c by reaction
with thiophosgene in the presence of a catalytic amount
of DMAP; then the crude cyclic thionocarbonate was
22
tion using Ph3P, DIAD, and TMSN3 in CH2Cl2 fur-
nished â-azido ester 10a ′ instead of the desired R-azido
ester 10a as the major product. Although R-azido esters
10b,c could be obtained in moderate yields (∼60%) via
nucleophilic azide substitution of ethyl R-(p-nitrophenyl-
sulfonyloxy)-â-hydroxyoctadec-7/15-ynoate (derived from
the regioselective reaction of diol ester 6b or 6c
with p-nitrophenylsulfonyl chloride in the presence of
Et3N),23 the same reaction conditions provided the
subjected to a ring-opening reaction with NaN3. In the
ring opening of cyclic thionocarbonates 9b,c with N3
-
,
the nucleophile attacked the R position exclusively,
providing 10b,c in high yield (85% and 87%, respec-
tively). Although the overall monoazidation of diol 6a was
also achieved in 89% yield (10a + 10a ′) via cyclic
thionocarbonate 9a , only a moderate degree of regio-
selectivity (R/â 2.4/1) was achieved. Presumably, the
triple bond in cyclic thionocarbonate 9a activates the â
position toward nucleophilic substitution.
Syn th esis of Cer a m id es 1a -c. As shown in Scheme
4, R-azido-â-hydroxyesters 10a -c were converted to
ceramide 1a and ceramide analogues 1b,c in high yields
via Staudinger reduction followed by in situ N-acylation,
selective reduction of the ester functional group with
NaBH4/LiBr/THF, and Birch reduction using Li/EtNH2.
(16) Generally, use of a larger phosphonoester reagent in the HWE
reaction gives a higher E/Z ratio (Nagaoka, H.; Kishi, Y. Tetrahedron
1981, 37, 3873-3888).
(17) 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.
(18) The ee of diols 6a -c was determined by 1H NMR analysis of
the corresponding bis-Mosher esters derived from these diols and their
enantiomers.
(19) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 1538-
1539.
(20) (a) Carlsen, P. H. J .; Katsuki, T.; Mart´ın, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936-3938. (b) Mart´ın, V. S.; Palazo´n, J .
M.; Rodr´ıguez, C. M. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, U.K., 1995; pp 4415-4422.
(c) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2607-
2624.
(21) Attempts to oxidize cyclic sulfite 7 to 8 by using K3[Fe(CN)6],
NaIO4, CrO3, or CrO3 on silica gel were unsuccessful.
(22) He, L.; Wanunu, M.; Byun, H.-S.; Bittman, R. J . Org. Chem.
1999, 64, 6049-6055.
(23) Regioselective R-nosylation of an R,â-dihydroxyester may result
from the acidity difference of the two hydroxyl groups or from
intramolecular hydrogen bonding of the â-hydroxy group with the
carboxylate oxygen: (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. (c) Hoffman, R. V.; Kim, H.-O. J .
Org. Chem. 1991, 56, 6759-6764.
(24) Ko, S. Y. J . Org. Chem. 1995, 60, 6250-6251.

7630 J . Org. Chem., Vol. 65, No. 22, 2000
He et al.
As noted previously,7 there are several examples of
biological processes that are affected differentially by the
double-bond position in substrates, inhibitors, and other
ligands. Thus it will be of interest to examine the
biological properties of trans double-bond regioisomers
of sphingolipids.
Sch em e 4. Syn th eses of D-er yth r o-tr a n s-∆4-, ∆7-,
a n d ∆15-Cer a m id es 1a -ca
Con clu sion s
A novel and efficient synthetic route has been devel-
oped for the synthesis of D-erythro-ceramide 1a . The
requisite chirality was introduced in two key steps:
asymmetric dihydroxylation of an R,â-unsaturated ester
and regioselective introduction of azide ion to the R
position of a cyclic thionocarbonate intermediate. Using
a similar synthetic strategy, ceramide analogues bearing
a E double bond at different positions along the sphingoid
backbone (e.g., 1b and 1c) were synthesized in high yield
and chiral purity. Simultaneous reduction of the triple
bond, azido, and ester functional groups in 10a by LiAlH4
furnished D-erythro-sphingosine 2a (four steps, 23%
overall yield), completing a practical and concise route
to this important sphingolipid.
a
Reagents and conditions: (a) Ph3P, n-C15H31CO2C6H4NO2-p,
THF/H2O 9:1, rt; (b) NaBH4, LiBr, THF, rt; (c) Li, EtNH2, THF,
-78 °C.
Sch em e 5. On e-P ot Con ver sion of Azid o Ester
10a to Sp h in gosin e An a logu e 13 a n d Sp h in gosin e
2a
Exp er im en ta l Section
Gen er a l In for m a tion . See the previous reports for general
experimental details.6,7 Thiophosgene was purchased from
Acros. NMR spectra were recorded in CDCl3 unless otherwise
noted.
5-Hexa d ecyn -1-ol (4b). To a stirred solution of 5.9 g (34.2
mmol) of 1-dodecyne in 200 mL of freshly distilled THF at -23
°C was injected 13.7 mL (34.2 mmol) of n-BuLi (a 2.5 M
solution in hexane). The reaction mixture was stirred for 4.5
h at this temperature under nitrogen, during which time a
milk-like suspension was obtained. After 300 mg (1.6 mmol)
of CuI was added, the cold bath was removed. Stirring was
continued, and 15 min later a solution of 2.6 g (17.1 mmol) of
cyclic sulfate 3 in 20 mL of THF was injected. The reaction
mixture was stirred overnight under nitrogen at room tem-
perature. After most of the THF was blown out by using a
gentle stream of air, 200 mL of Et2O and 80 mL of 20%
aqueous H2SO4 were added. The heterogeneous solution was
stirred vigorously at room temperature for 24 h. The two layers
were separated, and the aqueous layer was extracted with
Et2O (2 × 100 mL). The combined organic layer was treated
with anhydrous K2CO3 to remove the dissolved sulfuric acid,
dried (Na2SO4), and concentrated. The liquid residue was
purified by column chromatography (elution with hexane/
EtOAc 4:1), affording 3.2 g (75%) of alkynol 4b as a pink oil:
This seven-step synthesis provided ceramide 1a in 30%
overall yield25 and ceramide analogues 1b and 1c in 38%
and 42% yields. Moreover, the triple bond, azido, and
ester functional groups in azido ester 10a were reduced
simultaneously by LiAlH4 in THF at reflux, furnishing
D-erythro-sphingosine 2a in 50% yield (Scheme 5). (The
triple-bond analogue of sphingosine 13 was obtained in
85% yield when the reduction was carried out at 0 °C.
Selective N-acylation of 13 provided the triple-bond
ceramide analogue 12a .) Thus, starting from the inex-
pensive precursor 1-pentadecyne, we developed a practi-
cal four-step synthesis of D-erythro-sphingosine 2a in 23%
overall yield. The structure of 2a was confirmed by the
identity of its physical data (1H and 13C NMR, IR, [R]25
,
D
mp) with those reported in the literature.26
L-erythro-Sphingosine and L-erythro-ceramide were
prepared in similar yields by the same reaction sequence
by simply using AD-mix-R rather than AD-mix-â in the
dihydroxylation step.
The strategy used for the efficient syntheses of 1b and
1c represents a versatile methodology for moving the
trans double bond (which is between C(4) and C(5) in
ceramide 1a ) to other positions in the long-chain base.
IR 3563 cm-1 1H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.24 (m,
;
15H), 1.45 (m, 2H), 1.54 (m, 2H), 1.66 (m, 2H), 2.10 (tt, 2H, J
) 7.1, 2.3 Hz), 2.17 (tt, 2H, J ) 7.0, 2.3 Hz), 3.65 (t, 2H, J )
6.5 Hz); 13C NMR δ 14.11, 18.53, 18.73, 22.68, 25.35, 28.89,
29.13, 29.16, 29.32, 29.55, 29.58, 31.88, 31.90, 62.54, 79.69,
80.77.
Hexa d ec-13-yn -1-ol (4c). To a solution of 8.9 g (36.5 mmol)
of 1-bromo-9-dodecyne in 140 mL of freshly distilled THF in a
500-mL three-neck round-bottomed flask was added 1.6 g (65.8
mmol) of magnesium turnings and two drops of 1,2-dibromo-
ethane. After being flushed with nitrogen, the reaction mixture
was stirred vigorously under reflux until the shiny magnesium
metal became dark or gray (1.5-2 h). After the reaction
mixture was cooled to about room temperature, a catalytic
amount of CuI (250 mg, 1.3 mmol) was added, which made
the light yellow solution turn to purple. After stirring was
continued for another 10 min, the reaction mixture was chilled
to -23 °C, and a solution of 3.7 g (24.3 mmol) of cyclic sulfate
3 in 30 mL of dry THF was injected. The reaction mixture was
stirred at this temperature until cyclic sulfate 3 was completely
consumed (TLC). After most of the THF was removed by using
a gentle stream of air, 300 mL of hexane was added to the
(25) The 1H NMR spectra, IR, specific rotation, and melting point
of 1a were in accord with those reported in the literature.26a,g The 13C
NMR spectrum was consistent with that reported in ref 26a; Ohashi
et al.26g did not report the 13C NMR spectrum.
(26) (a) Shibuya, H.; Kawashima, K.; Narita, N.; Ikeda, M.; Kita-
gawa, I. Chem. Pharm. Bull. 1992, 40, 1154-1165. (b) Nugent, T. C.;
Hudlicky, T. J . Org. Chem. 1998, 63, 510-520. (c) Murakami, T.; Hato,
M. J . Chem. Soc., Perkin Trans. 1 1996, 823-827. (d) Enders, D.;
Whitehouse, D. L.; Runsink, J . Chem. Eur. J . 1995, 5, 382-388. (e)
Katsumara, S.; Yamamoto, N.; Fukuda, E.; Iwama, S. Chem. Lett.
1995, 393-394. (f) Solladie´-Cavallo, A.; Koessler, J . L. J . Org. Chem.
1994, 59, 3240-3242. (g) Ohashi, K.; Kosai, S.; Arizuka, M.; Watanabe,
T.; Yamagiwa, Y.; Kamikawa, T.; Kates, M. Tetrahedron 1989, 45,
2557-2570. (h) Boutin, R. H.; Rapoport, H. J . Org. Chem. 1986, 51,
5320-5327. (i) Groth, U.; Scho¨llkopf, U.; Tiller, T. Tetrahedron 1991,
47, 2835-2842. (j) Zimmermann, P.; Schmidt, R. R. Liebigs Ann. Chem.
1988, 633-667.

Asymmetric Synthesis of Ceramide and Its Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7631
slurry. The heterogeneous solution was stirred vigorously for
10 min and then allowed to stand for precipitation. The clear
top solution was separated. The precipitate (i.e., slurry) was
washed again with another 300 mL of hexane. After separa-
tion, Et2O (200 mL) and 20% aqueous H2SO4 (80 mL) were
added to the precipitate. The heterogeneous solution was
stirred vigorously at room temperature for 24 h. The layers
were separated, and the aqueous layer was extracted with
Et2O (2 × 150 mL). The combined ether layers were treated
with anhydrous K2CO3 to remove the dissolved H2SO4, dried
(Na2SO4), and concentrated. Purification of the light yellow
residue by flash chromatography (elution with hexane/EtOAc
4:1) provided 5.2 g (90%) of the desired alcohol 4c as a white
solid: mp 40.8-41.2 °C; IR 3560 cm-1; 1H NMR δ (t, 3H, J )
7.4 Hz), 1.24 (m, 14H), 1.49 (m, 6H), 2.12 (m, 4H), 3.61 (t, 2H,
J ) 6.6 Hz); 13C NMR δ 12.41, 14.37, 18.71, 25.72, 28.85, 29.13,
29.41, 29.50, 29.58, 32.76, 63.06, 79.57, 81.56.
reaction mixture through a pad of silica gel in a sintered glass
funnel. The pad was washed with 400 mL of hexane/EtOAc
6:1. Concentration gave a pale yellow oil that was purified by
column chromatography (elution with a gradient of hexane/
EtOAc 100:1-25:1).
1
5b: IR 2220, 1715, 1650 cm-1; H NMR δ 0.86 (t, 3H, J )
7.0 Hz), 1.29 (m, 17H), 1.45 (m, 2H), 1.62 (m, 2H), 2.11 (tt,
2H, J ) 7.1, 2.2 Hz), 2.17 (tt, 2H, J ) 7.0, 2.3 Hz), 2.29 (ddt,
2H, J ) 6.7, 6.6, 0.9 Hz), 4.17 (q, 2H, J ) 7.1 Hz), 5.82 (dt,
1H, J ) 15.6, 1.3 Hz), 6.94 (dt, 1H, J ) 15.6, 7.0 Hz); 13C NMR
δ 14.11, 14.26, 18.25, 18.71, 22.67, 27.39, 28.88, 29.09, 29.15,
29.32, 29.55, 29.58, 31.12, 31.90, 60.16, 79.02, 81.21, 121.79,
148.38, 166.63; HR-MS (FAB, MH+) m/z calcd for C20H35O2
307.2637, found 307.2629.
5c: IR 1707, 1648 cm-1; 1H NMR δ 1.09 (t, 3H, J ) 7.5 Hz),
1.08-1.51 (m, 21H), 2.05-2.21 (m, 6H), 4.15 (q, 2H, J ) 7.1
Hz), 5.78 (dt, 1H, J ) 15.6, 1.3 Hz), 6.94 (dt, 1H, J ) 15.6, 7.0
Hz); 13C NMR δ 12.39, 14.26, 14.37, 18.71, 28.00, 28.84, 29.13,
29.37, 29.48, 29.54, 32.18, 60.10, 79.57, 81.56, 121.17, 149.50,
166.80; HR-MS (DEI, M+) m/z calcd for C20H34O2 306.2559,
found 306.2551.
Eth yl (2E)-Octa d ec-2-en -4-yn oa te (5a ). Hexadec-2-ynal
(Scheme 2) was prepared by formylation of 1-pentadecyne as
follows. To a solution of 1-pentadecyne (5.21 g, 25.0 mmol) in
100 mL of dry THF was added 11 mL (27.5 mmol) of n-BuLi
(a 2.5 M solution in hexane) at -23 °C. The mixture was
stirred at -23 °C for 2 h, then at room temperature for another
2 h. To the pentadecynyllithium suspension was added 3.1 mL
(27.9 mmol) of 1-formylpiperidine at 0 °C. The reaction mixture
was stirred for 2 h at room temperature. The reaction was then
quenched by the addition of 100 mL of 10% aqueous NaHSO4
solution. The product was extracted with Et2O (4 × 100 mL).
The organic layer was washed with 10% aqueous NaHSO4
solution (3 × 100 mL), dried (Na2SO4), and concentrated under
reduced pressure. The product, 2-hexadecynal, was obtained
as a pale yellow liquid, which was thoroughly dried under high
vacuum (0.7 Torr) and used without further purification in the
subsequent HWE reaction (see the general procedure outlined
below for the preparation of 5b,c). 5a : IR 2215, 1711, 1620
Gen er a l P r oced u r es for Asym m etr ic Dih yd r oxyla tion
of a n r,â-Un sa tu r a ted Ester . After a solution of 14.0 g of
AD-mix-â (or AD-mix-R) in 300 mL of t-BuOH/H2O 1:1 was
stirred vigorously at room temperature for 1 h, 950 mg (10.0
mmol) of methanesulfonamide was added, and stirring was
continued for an additional 10 min at room temperature. After
the reaction mixture was chilled with an ice-water bath, 10.0
mmol of the R,â-unsaturated ester (5a , 5b, or 5c) was added,
and the reaction mixture was stirred vigorously at this
temperature until the disappearance of the R,â-unsaturated
ester was noticed (TLC). After sodium sulfite (15.0 g, 146.0
mmol) was added to quench the reaction, stirring was contin-
ued for another 30 min while the reaction mixture was allowed
to warm to room temperature. The product was extracted with
EtOAc or CHCl3 (3 × 150 mL). The combined extracts were
dried (Na2SO4) and concentrated to give a yellow solid residue,
which was dissolved in a minimum volume of CHCl3 and
passed through a pad of silica gel in a sintered glass funnel to
remove the ligand. The pad was washed with hexane/EtOAc
3:1 to collect the product. Concentration of the eluent provided
an almost pure product. The % ee of diols 6a -c was deter-
1
cm-1; H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.24 (m, 20H), 1.28
(t, 3H, J ) 7.2 Hz), 1.49-1.56 (m, 2H), 2.34 (t, 2H, J ) 6.7
Hz), 4.19 (q, 2H, J ) 7.2 Hz), 6.12 (d, 1H, J ) 15.9 Hz), 6.73
(d, 1H, J ) 15.9 Hz); 13C NMR δ 14.11, 14.20, 19.75, 22.68,
28.30, 28.86, 29.08, 29.35, 29.48, 29.60, 29.64, 29.67, 31.91,
60.55, 77.91, 100.87, 126.13, 129.21, 166.17; HR-MS (FAB,
MH+) m/z calcd for C20H35O2 307.2637, found 307.2644.
Eth yl (2E)-Octa d ec-2-en -7-yn oa te (5b) a n d Eth yl (2E)-
Oct a d ec-2-en -15-yn oa t e (5c). These two compounds were
prepared from alkynols (4b,c, respectively) via Swern oxidation
and subsequent HWE olefination as follows. a . Sw er n Oxid a -
tion . To a solution of 780 mg (10.0 mmol) of DMSO in 40 mL
of dry CH2Cl2 at -78 °C was injected 0.44 mL (5.0 mmol) of
oxalyl chloride under nitrogen. The reaction mixture was
stirred at this temperature for 10 min, followed by the injection
of 2.0 mmol of alcohol 4b or 4c in 5-8 mL of dry CH2Cl2. The
reaction temperature was then changed from -78 to -42 °C,
and the reaction mixture was stirred at the latter temperature
until the complete consumption of alcohol was noticed by TLC
(<3 h). After 3 mL (28.0 mmol) of Et3N was injected, the cold
bath was removed and stirring was continued while the
reaction mixture was allowed to warm to room temperature.
The reaction mixture was transferred to a separatory funnel
containing 50 mL of saturated aqueous NaHCO3 solution, and
the product was extracted with CH2Cl2 (3 × 40 mL). The
combined extracts were dried (Na2SO4) and concentrated. The
crude aldehyde was dried thoroughly under high vacuum (0.7
Torr) and used without further purification in the subsequent
reaction. b. HWE Rea ction . To a nitrogen-flushed solution
of 870 mg (10.0 mmol) of LiBr in 50 mL of freshly distilled
THF was injected 2.4 mmol of (EtO)2P(O)CH2CO2Et or (i-
PrO)2P(O)CH2CO2Et at room temperature. After the solution
was stirred at room temperature for 10 min, 0.42 mL (4.0
mmol) of Et3N was injected, and stirring was continued for
another 15 min. A solution of the thoroughly dried crude
aldehyde in 10 mL of dry THF was injected. A white precipi-
tate was formed several minutes after the addition of the
aldehyde. The reaction mixture was stirred vigorously at room
temperature until the full consumption of the aldehyde was
observed (TLC). The precipitate was removed by passing the
1
mined by H NMR or 19F NMR analysis of the corresponding
bis-Mosher esters derived from both enantiomers.
Eth yl (2S,3R)-2,3-d ih yd r oxyocta d ec-4-yn oa te [(-)-6a ]:
27
90% yield (98% ee); mp 57.3-57.9 °C; [R]25 -3.81° (c 3.15,
D
CHCl3); IR 3560, 2228, 1735 cm-1; 1H NMR δ 0.86 (t, 3H, J )
7.0 Hz), 1.24 (m, 20H), 1.30 (t, 3H, J ) 7.1 Hz), 1.48 (m, 2H),
2.20 (dt, 2H, J ) 7.26, 2.0 Hz), 2.73 (br s, 2H), 4.22 (d, 1H, J
) 2.8 Hz), 4.28 (q, 2H, J ) 7.1 Hz), 4.62 (dt, 1H, J ) 2.4, 2.0
Hz); 13C NMR δ 14.10, 14.14, 18.68, 22.67, 28.46, 28.86, 29.11,
29.34, 29.49, 29.61, 29.63, 31.90, 62.40, 64.05, 73.80, 87.36,
171.82; HR-MS (FAB, MH+) m/z calcd for C20H37O4 341.2692,
found 341.2693.
Eth yl (2S,3R)-2,3-d ih yd r oxyocta d ec-7-yn oa te [(+)-6b]:
94% yield (96% ee); mp 52.6-53.2 °C; [R]25 +12.63° (c 1.18,
D
CHCl3); IR 3563, 1732 cm-1; H NMR δ 0.86 (t, 3H, J ) 7.0
1
Hz), 1.24 (m, 14H), 1.30 (t, 3H, J ) 7.0 Hz), 1.43-1.72 (m,
6H), 2.10 (tt, 2H, J ) 7.1, 2.2 Hz), 2.20 (m, 2H), 3.90 (dt, 1H,
J ) 6.5, 1.9 Hz), 4.06 (d, 1H, J ) 1.9 Hz), 4.27 (q, 2H, J ) 7.1
Hz); 13C NMR δ 14.15, 18.73, 25.28, 29.12, 29.31, 29.54, 31.89,
32.95, 62.17, 72.10, 73.11, 79.43, 80.91, 173.53; HR-MS [FAB,
MH+] m/z calcd for C20H37O4 341.2692, found 341.2699.
Eth yl (2S,3R)-2,3-d ih yd r oxyocta d ec-15-yn oa te [(+)-6c]:
95% yield (96% ee); mp 62.0-62.5 °C; [R]25 +8.8° (c 1.72,
D
CHCl3); IR 3560, 1731 cm-1; H NMR δ 1.09 (t, 3H, J ) 7.4
1
Hz), 1.24 (m, 15H), 1.30 (t, 3H, J ) 7.2 Hz), 1.45 (m, 3H), 1.59
(m, 2H), 2.12 (m, 4H), 3.86 (dt, 1H, J ) 7.5, 1.9 Hz), 4.05 (d,
1H, J ) 1.9 Hz), 4.27 (q, 2H, J ) 7.1 Hz); 13C NMR δ 12.41,
14.16, 14.38, 18.72, 25.71, 28.86, 19.14, 29.50, 29.53, 29.57,
(27) For asymmetric dihydroxylation of 3.07 g (10.0 mmol) of enyne
ester 5a (Scheme 3), 160 mg of (DHQ)2-PHAL/(DHQD)2-PHAL and
30 mg of K2OsO4‚(H2O)2 were added to 15 g of commercial AD-mix-
R/â before the reaction.

7632 J . Org. Chem., Vol. 65, No. 22, 2000
He et al.
33.83, 62.13, 72.51, 72.98, 79.59, 81.57, 173.69; HR-MS [FAB,
phase was dried (Na2SO4) and concentrated. The residue was
purified by column chromatography (elution with hexane/
EtOAc 5:1).
MH+] m/z calcd for C20H37O4 341.2692, found 341.2693.
Gen er a l P r oced u r e for th e R-Azid a tion of a Diol Ester
via a Cyclic Th ion oca r bon a te In ter m ed ia te. a . P r ep a r a -
tion of a Cyclic Th ion oca r bon a te. To a solution of 1.0 mmol
of diol ester (6a , 6b, or 6c) in 18 mL of dry CH2Cl2 was added
sequentially 325 mL (4.0 mmol) of pyridine, 10 mg (0.05 mmol)
of DMAP, and 103 µL (1.3 mmol) of thiophosgene at 0 °C. The
reaction mixture was stirred at this temperature under
nitrogen until the total consumption of the diol ester was noted
by TLC (<2 h). The reaction mixture was filtered through a
pad of silica gel in a sintered glass funnel to remove the salts.
The pad was washed with hexane/EtOAc 6:1, and the filtrate
was concentrated under reduced pressure and dried under
high vacuum (0.7 Torr, 3 h). The cyclic thionocarbonate was
used directly in the subsequent azidation reaction without
further purification. b. Nu cleop h ilic Rin g Op en in g. To a
solution of the crude cyclic thionocarbonate in 8 mL of dry
DMF was added 277 mg (1.1 mmol) of PPTS and 195 mg (3.0
mmol) of NaN3 at 0 °C. The reaction mixture was stirred at
this temperature under nitrogen until the disappearance of
the cyclic thionocarbonate was noticed by TLC. [Alternatively,
to a solution of 232 mg of crude cyclic thionocarbonate derived
from diol 6a in 12 mL of THF/DMF 5:1 were added 90 µL (0.68
mmol) of TMSN3 and 2 mg (0.036 mmol) of NaN3 at 0 °C. The
reaction mixture was stirred at this temperature under
nitrogen. n-Bu4NF (1 mL, 1.0 M solution in THF) was added
at 0 °C after the ring-opening reaction was completed.] The
reaction mixture was diluted with 30 mL of H2O and extracted
with Et2O (3 × 60 mL). The combined extracts were dried
(Na2SO4) and concentrated. The product was purified on silica
gel (elution with hexane/EtOAc 20:1).
Eth yl (2R,3R)-2-p a lm itoyla m id o-3-h yd r oxyocta d ec-4-
yn oa te [(-)-11a ]: mp 82.4-83.1 °C; [R]25 -41.2° (c 1.5,
D
CHCl3); IR 3419, 2229, 1736, 1655, 1505 cm-1; 1H NMR δ 0.84
(t, 6H, J ) 6.9 Hz), 1.23 (m, 44H), 1.28 (t, 3H, J ) 7.3 Hz),
1.40 (tt, 2H, J ) 7.6, 7.2 Hz), 1.60 (tt, 2H, J ) 7.4, 6.8 Hz),
2.09 (dt, 2H, J ) 7.1, 2.1 Hz), 2.17 (t, 2H, J ) 7.4 Hz), 3.04 (br
s, 1H), 4.23 (m, 2H), 4.81 (m, 2H), 6.03 (d, 1H, J ) 8.8 Hz);
13C NMR δ 14.06, 14.11, 18.47, 22.64, 25.49, 28.45, 28.73,
29.07, 29.19, 29.31, 29.45, 29.49, 29.57, 29.61, 29.64, 31.71,
31.88, 36.50, 44.93, 62.19, 72.28, 73.72, 86.01, 171.32, 172.26;
HR-MS (DCI, MH+) m/z calcd for C36H68NO4 578.5148, found
578.5127.
Eth yl (2R,3R)-2-p a lm itoyla m id o-3-h yd r oxyocta d ec-7-
yn oa te [(-)-11b]: mp 60.8-61.3 °C; [R]25 -23.3° (c 1.05,
D
1
CHCl3); IR 3426, 1731, 1668, 1508 cm-1; H NMR δ 0.85 (t,
6H, J ) 7.0 Hz), 1.23 (m, 38H), 1.28 (t, 3H, J ) 7.1 Hz), 1.41-
1.64 (m, 8H), 2.08 (tt, 2H, J ) 7.2, 2.2 Hz), 2.14 (m, 2H), 2.25
(t, 2H, J ) 7.5 Hz), 2.92 (br s, 1H), 3.96 (m, 1H), 4.22 (m, 2H),
4.65 (dd, 1H, J ) 6.6, 3.0 Hz), 6.45 (d, 1H, J ) 6.6 Hz); 13C
NMR δ 14.11, 18.49, 18.72, 22.67, 25.16, 25.56, 28.92, 29.16,
29.21, 29.30, 29.34, 29.46, 29.54, 29.59, 29.64, 29.67, 31.89,
32.09, 36.38, 57.91, 61.98, 72.79, 79.32, 80.84, 170.31, 174.35;
HR-MS (FAB, MH+) calcd for m/z C36H68NO4 578.5148, found
578.5175.
Eth yl (2R,3R)-2-p a lm itoyla m id o-3-h yd r oxyocta d ec-15-
yn oa te [(-)-11c]: mp 70.5-71.2 °C; [R]25 -25.1° (c 0.95,
D
1
CHCl3); IR 3421, 1732, 1669, 1507 cm-1; H NMR δ 0.86 (t,
3H, J ) 7.0 Hz), 1.09 (t, 3H, J ) 7.4 Hz), 1.23 (m, 42H), 1.28
(t, 3H, J ) 7.2 Hz), 1.44 (m, 2H), 1.62 (m, 2H), 2.14 (m, 5H),
2.25 (t, 2H, J ) 7.8 Hz), 3.92 (m, 1H), 4.22 (m, 2H), 4.65 (dd,
1H, J ) 6.6, 3.0 Hz), 6.41 (d, 1H, J ) 6.6 Hz); 13C NMR δ
12.40, 14.11, 14.12, 14.37, 18.71, 22.67, 25.57, 25.65, 28.85,
29.14, 29.20, 29.30, 29.34, 29.47, 29.51, 29.54, 29.57, 29.59,
29.64, 29.67, 31.90, 33.20, 36.40, 57.88, 61.94, 73.23, 79.58,
Eth yl (2R,3R)-2-a zid o-3-h yd r oxyocta d ec-4-yn oa te [(+)-
10a ]: [R]25 +17.4° (c 1.9, CHCl3); IR 3575, 2227, 2111, 1740
D
1
cm-1; H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.22 (m, 20H), 1.30
(t, 3H, J ) 7.1 Hz), 1.46 (tt, 2H, J ) 7.4, 7.1 Hz), 2.17 (dt, 2H,
J ) 7.1, 1.9 Hz), 2.65 (br s, 1H), 3.99 (d, 1H, J ) 5.1 Hz), 4.27
(m, 2H), 4.72 (dt, 1H, J ) 5.1, 2.6 Hz); 13C NMR δ 14.07, 18.60,
22.64, 28.18, 28.76, 29.05, 29.30, 29.46, 29.58, 29.60, 29.63,
31.87, 62.19, 63.35, 65.87, 75.97, 88.85, 167.59; HR-MS (FAB)
m/z calcd for C20H36O3N3 366.2757, found 366.2756. 10a ′: 1H
NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.15-1.40 (m, 24H), 1.49 (tt,
2H, J ) 7.4, 7.1 Hz), 2.23 (dt, 2H, J ) 7.0, 2.0 Hz), 3.08 (br s,
1H), 4.20-4.34 (m, 4H); 13C NMR δ 14.10, 18.53, 22.65, 28.46,
28.67, 29.04, 29.32, 29.46, 29.58, 29.61, 29.64, 31.88, 55.70,
62.35, 69.98, 73.56, 91.34, 170.66.
81.57, 170.44, 174.28; HR-MS (FAB, MH+) calcd for m/z C36H68
-
NO4 578.5148, found 578.5162.
Gen er a l P r oced u r e for Selective Red u ction of a n
Ester w ith Na BH4-LiBr in th e P r esen ce of a n Am id e.
To a heterogeneous mixture of 1.0 mmol of R-amido ester (11a ,
11b, or 11c) and 868 mg (10.0 mmol) of LiBr in 40 mL of
freshly distilled THF was added 454 mg (12.0 mmol) of NaBH4
at 0 °C. The suspension was stirred vigorously at room
temperature under nitrogen until the full consumption of
starting ester was noticed (TLC). The reaction mixture was
transferred to a sintered glass funnel containing a pad of silica
gel with a Pasteur pipet. The pad was washed with 400 mL of
CHCl3/MeOH 15:1 by gravity to collect the product. The filtrate
was concentrated, and the residue was purified by column
chromatography (elution with CHCl3/MeOH 50:1). The product
was dissolved in CHCl3 (15-25 mL) and passed through a
Cameo filter (Fisher Scientific) to remove the dissolved silica
gel.
Eth yl (2R,3R)-2-a zid o-3-h yd r oxyocta d ec-7-yn oa te [(+)-
10b]: [R]25 +45.3° (c 2.38, CHCl3); IR 3605, 2113, 1732 cm-1
;
D
1H NMR δ 0.85 (t, 3H, J ) 7.0 Hz), 1.24 (m, 16H), 1.32 (t, 5H,
J ) 7.1 Hz), 1.42-1.69 (m, 6H), 2.10 (tt, 3H, J ) 7.0, 2.3 Hz),
2.18 (m, 2H), 3.94 (m, 2H), 4.28 (q, 2H, J ) 7.0 Hz); 13C NMR
δ 14.11, 14.15, 18.49, 18.72, 22.67, 24.93, 28.90, 29.10, 29.17,
29.32, 29.54, 29.59, 31.90, 32.09, 62.11, 66.17, 71.49, 79.28,
81.09, 168.95; HR-MS (FAB) m/z calcd for C20H35O3N3 365.2678,
found 365.2693.
(2S,3R)-2-P a lm it oyla m id o-4-oct a d ecyn -1,3-d iol [(-)-
12a ]: mp 102.0-102.5 °C; [R]25 -8.2° (c 2.0, CHCl3/MeOH
Eth yl (2R,3R)-2-azido-3-h ydr oxyoctadec-15-yn oate [(+)-
10c]: [R]25D +43.54° (c 1.3, CHCl3); IR (CHCl3) 3590, 2113, 1735
D
9:1); IR 3609, 3429, 2229, 1660, 1500 cm-1; 1H NMR δ 0.86 (t,
6H, J ) 7.0 Hz), 1.24 (m, 44H), 1.48 (m, 2H), 1.61 (m, 2H),
2.20 (m, 4H), 2.30 (br s, 2H), 3.74 (dd, 1H, J ) 11.3, 3.9 Hz),
4.02 (m, 1H), 4.11 (dd, 1H, J ) 11.4, 3.8 Hz), 4.58 (m, 1H),
6.27 (d, 1H, J ) 7.5 Hz); 13C NMR (CDCl3/CD3OD) δ 13.92,
18.53, 22.53, 25.60, 28.46, 28.82, 29.02, 29.13, 29.21, 29.24,
29.37, 29.41, 29.52, 29.54, 31.77, 36.50, 55.01, 61.68, 63.19,
1
cm-1; H NMR δ 1.09 (t, 3H, J ) 7.5 Hz), 1.24 (m, 18H), 1.32
(t, 3H, J ) 7.1 Hz), 1.47 (m, 6H), 1.82 (br s, 1H), 2.12 (m, 4H),
3.92 (m, 2H), 4.27 (q, 2H, J ) 7.1 Hz); 13C NMR δ 12.41, 14.17,
14.39, 18.72, 25.35, 28.86, 29.15, 29.37, 29.47, 29.52, 29.56,
33.02, 62.09, 66.18, 71.90, 79.59, 81.57, 168.99; HR-MS [FAB,
M+] m/z calcd for C20H35O3N3 365.2678, found 365.2654.
77.62, 87.28, 174.71; HR-MS (DCI, MH+) m/z calcd for C34H66
-
Gen er a l P r oced u r e for th e On e-P ot Con ver sion of a n
Azid o to a n Am id o Gr ou p . To a solution of 1.0 mmol of
R-azidoester (10a , 10b, or 10c) and 944 mg (2.5 mmol) of
p-nitrophenyl palmitate in 30 mL of THF/H2O 9:1 was added
314 mg (1.2 mmol) of Ph3P. The reaction mixture was stirred
at room temperature under nitrogen for 48 h. After the
solvents were removed in vacuo (2-PrOH was used to remove
the H2O residue), the light yellow residue was dissolved in 100
mL of Et2O and washed with 1% aqueous Na2CO3 solution (4
× 20 mL) to remove the 4-nitrophenol byproduct. The organic
NO3 536.5043, found 536.5046.
(2R,3R)-2-P a lm it oyla m id o-7-oct a d ecyn -1,3-d iol [(+)-
12b]: mp 88.2-88.9 °C; [R]25 +5.4° (c 1.3, CHCl3); IR 3453,
D
1663, 1510 cm-1; 1H NMR δ 0.85 (t, 6H, J ) 7.0 Hz), 1.23 (m,
38H), 1.44 (m, 2H), 1.63 (m, 6H), 2.10 (t, 2H, J ) 7.1 Hz), 2.19
(m, 4H), 2.54 (br s, 2H), 3.72-3.83 (m, 3H), 3.99 (dd, 1H, J )
11.3, 3.1 Hz), 6.43 (d, 1H, J ) 7.0 Hz); 13C NMR δ 14.11, 18.59,
18.73, 22.67, 25.44, 25.76, 28.93, 29.13, 29.17, 29.32, 29.35,
29.50, 29.56, 29.65, 29.68, 31.90, 33.46, 36.83, 53.87, 62.44,

Asymmetric Synthesis of Ceramide and Its Analogues
J . Org. Chem., Vol. 65, No. 22, 2000 7633
73.63, 79.42, 81.06, 173.72; HR-MS (FAB, MH+) calcd for m/z
δ 0.86 (t, 3H, J ) 7.0 Hz), 0.94 (t, 3H, J ) 7.5 Hz), 1.23 (m,
42H), 1.50 (m, 2H), 1.62 (m, 2H), 1.95 (m, 4H), 2.21 (t, 2H, J
) 7.3 Hz), 2.38 (br s, 2H), 3.74 (m, 2H), 3.81 (m, 1H), 3.98 (d,
1H, J ) 10.6 Hz), 5.39 (m, 2H), 6.43 (d, 1H, J ) 6.5 Hz); 13C
NMR δ 13.99, 14.11, 22.68, 25.59, 25.77, 25.97, 29.18, 29.29,
29.35, 29.52, 29.57, 29.65, 29.68, 31.91, 32.56, 34.49, 36.86,
53.71, 62.48, 74.20, 129.36, 131.82, 173.61; HR-MS (FAB,
MH+) calcd for m/z C34H68NO3 538.5199, found 538.5182.
D-er yth r o-Sp h in gosin e [(-)-2a ]. To an ice-cooled suspen-
sion of 83 mg (2.2 mmol) of LiAlH4 in 15 mL of freshly distilled
THF under nitrogen was injected a solution of 80 mg (0.22
mmol) of azido ester 10a in 4 mL of THF. The reaction mixture
was stirred at room temperature for 2 h and then refluxed
overnight. After the addition of 10 mL dry THF, the reaction
mixture was chilled with an ice-water bath and filtered
through a pad of silica gel (∼7 g) slurry in hexane in a sintered
glass funnel (3 cm × 6 cm) to remove the salt and the excess
LiAlH4 by gentle suction. Note: It was found that this workup
procedure was very efficient for small-scale reactions. The pad
was washed with CHCl3/MeOH/concd NH4OH 130:25:4 to
collect the product. After concentration, the residue was
purified by column chromatography (elution with CHCl3/
MeOH/concd NH4OH 130:25:4), providing 33 mg (50%) of
sphingosine 2a as a white solid. The product was dissolved in
a minimum volume of CHCl3 and passed through a Cameo
filter to remove dissolved silica gel. 2a : mp 80.7-82.1 °C [lit.26a
mp 81-82 °C, lit.26f mp 76-77 °C, lit.26h mp 72-75 °C, lit.26i
mp 75-80 °C]; [R]25 -2.7° (c 1.2, CHCl3) [lit.26a [R]28 -2.8°
C
34H66NO3 536.5043, found 536.5021.
(2S,3R)-2-P a lm itoyla m id o-15-octa d ecyn -1,3-d iol [(+)-
12c]: mp 90.5-91.5 °C; [R]25 +6.4° (c 1.54, CHCl3); IR 3440,
D
1664, 1510 cm-1; H NMR δ 0.86 (t, 3H, J ) 7.0 Hz), 1.09 (t,
1
3H, J ) 7.5 Hz), 1.23 (m, 40H), 1.46 (m, 4H), 1.61 (m, 2H),
2.11 (m, 4H), 2.26 (t, 2H, J ) 7.8 Hz), 2.87 (br s, 2H), 3.72 (m,
2H), 3.80 (m, 1H), 3.95 (dd, 1H, J ) 11.4, 3.5 Hz), 6.47 (d, 1H,
J ) 7.8 Hz); 13C NMR δ 12.39, 14.10, 14.36, 18.70, 22.66, 25.77,
25.98, 28.86, 29.13, 29.15, 29.29, 29.34, 29.36, 29.51, 29.58,
29.64, 29.68, 31.90, 34.42, 36.83, 53.81, 62.35, 73.99, 79.56,
81.54, 173.78; HR-MS (FAB, MH+) m/z calcd for C34H66NO3
536.5043, found 536.5016.
Gen er a l P r oced u r e for Red u ction of a n Alk yn e to a n
(E)-Alk en e by Li/EtNH2. In a 100-mL, two-necked round-
bottomed flask was collected 20 mL of EtNH2 at -78 °C. Then
small pieces of lithium metal were added (100 mg, 14.4 mmol;
the lithium bar was pretreated first with hexane, then with
Et2O, and finally with MeOH until it was shiny). The reaction
mixture was stirred under nitrogen at -78 °C until the deep
blue color was sustained for at least 30 min. At this moment
an yne-diol solution (250 mg of 12a , 12b, or 12c in 10 mL of
dry THF) was injected slowly. The reduction was run for 40
min and then quenched by MeOH (added dropwise until the
blue color completely disappeared) at -78 °C. Stirring was
continued while the reaction mixture was allowed to warm to
room temperature. After most of the solvents were blown out
by air, H2O (30 mL) and Et2O (30 mL) were added. The layers
were separated, and the aqueous layer was extracted with
Et2O (3 × 30 mL). The combined organic layers were dried
(Na2SO4) and concentrated (2-PrOH was used to remove the
residual H2O). The white solid residue was purified by column
chromatography (elution with CHCl3/MeOH 100:1). The prod-
uct was dissolved in a minimum volume of CHCl3 and passed
through a Cameo filter to remove dissolved silica gel. Finally,
the product was lyophilized from benzene to give a white
powder.
D
D
(c 1.0, CHCl3), lit.26h [R]21 -1.3° (c 3.5, CHCl3), lit.26i [R]20
D
D
-6° (c 0.84, CHCl3), lit.26j [R]22 -2.5° (c 6, CHCl3)]; IR 3616,
D
3412, 1587, 1463, 1040, 970 cm-1; 1H NMR δ 0.85 (t, 3H, J )
7.0 Hz), 1.23 (m, 20H), 1.35 (m, 2H), 2.02 (q, 2H, J ) 7.0 Hz),
2.64 (br s, 4H), 2.84 (q, 1H, J ) 5.2 Hz), 3.64 (m, 2H), 4.04 (t,
1H, J ) 6.0 Hz), 5.44 (dd, 1H, J ) 15.4, 7.2 Hz), 5.71 (dt, 1H,
J ) 15.4, 7.2 Hz); 13C NMR δ 14.11, 22.67, 29.17, 29.26, 29.35,
29.48, 29.62, 29.65, 29.68, 31.91, 32.35, 56.15, 63.66, 75.06,
129.11, 134.67.
D-er yth r o-∆4-Cer a m id e [(2S,3R)-N-p a lm it oylsp h in go-
(2S,3R)-2-Am in o-1,3-d ih yd r oxyocta d ec-4-yn e [(+)-13]:
sin e, (-)-1a ]: mp 96.5-97.4 °C [lit.26a mp 95-96 °C, lit.26g mp
mp 58.6-59.4 °C; [R]25 -5.4° (c 1.0, CHCl3); IR 3605, 3390,
D
95.0-96.0 °C]; [R]25 -5.4° (c 1.5, CHCl3/MeOH 9:1) [lit.26a
2214, 1581, 1463, 1029, 834 cm-1; 1H NMR δ 0.86 (t, 3H, J )
7.0 Hz), 1.23 (m, 15H), 1.48 (tt, 2H, J ) 7.6, 7.1 Hz), 2.18 (dt,
2H, J ) 7.1, 1.6 Hz), 2.83 (br s, 4H), 2.92 (m, 1H), 3.67 (m,
2H), 4.37 (br s, 1H); 13C NMR δ 14.10, 18.69, 22.67, 28.66,
28.97, 29.12, 29.34, 29.52, 29.64, 29.67, 29.86, 31.90, 56.85,
63.56, 64.56, 78.14, 87.70.
D
[R]23 -5.4° (c 0.9, CHCl3/MeOH 9:1), lit.26g [R]25 -5.82° (c
D
D
0.98, CHCl3/MeOH 9:1)]; IR 3433, 1653 cm-1; 1H NMR δ 0.85
(t, 6H, J ) 7.0 Hz), 1.23 (m, 46H), 1.61 (m, 2H), 2.02 (dt, 2H,
J ) 7.1, 7.1 Hz), 2.21 (t, 2H, J ) 7.8 Hz), 2.46 (br s, 2H), 3.67
(dd, 1H, J ) 11.1, 3.1 Hz), 3.84-3.95 (m, 2H), 4.29 (t, 1H, J )
5.4 Hz), 5.49 (dd, 1H, J ) 15.5, 6.4 Hz), 5.76 (dt, 1H, J ) 15.5,
6.5 Hz), 6.29 (d, 1H, J ) 7.3 Hz); 13C NMR δ 14.12, 22.68,
25.76, 28.93, 29.12, 29.23, 29.28, 29.36, 29.50, 29.51, 29.66,
29.69, 31.92, 32.29, 36.82, 54.50, 62.45, 74.57, 128.72, 134.29,
174.03.
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.
D-er yth r o-∆7-Cer a m id e [(+)-1b]: mp 92.5-94.3 °C; [R]25
D
+5.8° (c 1.4, CHCl3); IR 3430, 1654 cm-1; H NMR δ 0.83 (t,
1
6H, J ) 7.0 Hz), 1.21 (m, 42H), 1.46-1.62 (m, 4H), 1.86-2.16
(m, 4H), 2.18 (t, 2H, J ) 7.5 Hz), 2.98 (br s, 2H), 3.68 (m, 2H),
3.80 (m, 1H), 3.95 (dd, 1H, J ) 11.5, 3.6 Hz), 5.35 (m, 2H),
6.60 (d, 1H, J ) 7.9 Hz); 13C NMR δ 14.10, 18.73, 22.67, 25.77,
25.91, 28.93, 29.17, 29.23, 29.31, 29.34, 29.37, 29.52, 29.64,
29.69, 31.90, 32.36, 32.60, 33.81, 36.84, 53.90, 62.34, 73.61,
129.53, 130.94, 173.62; HR-MS (FAB, MH+) calcd for m/z
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 1a -c, 3, 4b-c, 5a -c, 6a -c,
10a -c, 10a ′, 11a -c, 12a -c, 13, and 2a . This material is
available free of charge via the Internet at http://pubs.acs.org.
C
34H68NO3 538.5199, found 538.5180.
D-er yth r o-∆15-Cer a m id e [(+)-1c]: mp 97.8-99.0 °C; [R]25
D
+7.12° (c 1.93, CHCl3/MeOH 9:1); IR 3427, 1654 cm-1; 1H NMR
J O001226N