Enantioselective Synthesis of 3-Deoxy-(R)-sphingomyelin from (S)-1-(4′-Methoxyphenyl)glycerol

Article abstract of DOI:10.1021/jo971977y

(R)-3-Deoxysphingomyelin (2) was prepared from (S)-1-(4′-methoxyphenyl)-glycerol (3). The latter was converted into either p-methoxyphenyl (PMP) (S)-oxiranylmethyl ether (5) or (R)-1-(4′-methoxyphenyl)glycerol 2,3-cyclic sulfate (6). Opening of 5 with lithium pentadecyne in the presence of BF₃·Et₂O gave PMP (S)-2-hydroxy-4-octadecynyl ether (7) in 65percent yield. Alternatively, opening of cyclic sulfate 6 with excess lithium pentadecyne in the presence of catalytic cuprous iodide, followed by acidic workup, gave 7 in 90percent yield. After introduction of the amide group via azide displacement, reduction, and N-acylation, simultaneous reduction of the triple bond and deprotection of the PMP group by Birch reduction (Li, EtNH₂) provided 3-deoxy-N-palmitoyl-(A)-ceramide (9). Finally, phosphitylation of 9, oxidation of the cyclic phosphite with bromine, followed by in situ ring opening gave a (2-bromoethyl)phosphate ester, which on quaternization with aqueous trimethylamine afforded 3-deoxy-N-palmitoyl-(R)-sphingomyelin (2) in 49percent overall yield from PMP (S)-2-hydroxy-4-octadecynyl ether (7).

Full text of DOI:10.1021/jo971977y

2560
J . Org. Chem. 1998, 63, 2560-2563
En a n tioselective Syn th esis of 3-Deoxy-(R)-sp h in gom yelin fr om
(S)-1-(4′-Meth oxyp h en yl)glycer ol
Hoe-Sup Byun, J ason A. Sadlofsky, and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of the City University of New York,
Flushing, New York 11367-1597
Received October 28, 1997
(R)-3-Deoxysphingomyelin (2) was prepared from (S)-1-(4′-methoxyphenyl)-glycerol (3). The latter
was converted into either p-methoxyphenyl (PMP) (S)-oxiranylmethyl ether (5) or (R)-1-(4′-
methoxyphenyl)glycerol 2,3-cyclic sulfate (6). Opening of 5 with lithium pentadecyne in the presence
of BF3‚Et2O gave PMP (S)-2-hydroxy-4-octadecynyl ether (7) in 65% yield. Alternatively, opening
of cyclic sulfate 6 with excess lithium pentadecyne in the presence of catalytic cuprous iodide,
followed by acidic workup, gave 7 in 90% yield. After introduction of the amide group via azide
displacement, reduction, and N-acylation, simultaneous reduction of the triple bond and deprotection
of the PMP group by Birch reduction (Li, EtNH2) provided 3-deoxy-N-palmitoyl-(R)-ceramide (9).
Finally, phosphitylation of 9, oxidation of the cyclic phosphite with bromine, followed by in situ
ring opening gave a (2-bromoethyl)phosphate ester, which on quaternization with aqueous
trimethylamine afforded 3-deoxy-N-palmitoyl-(R)-sphingomyelin (2) in 49% overall yield from PMP
(S)-2-hydroxy-4-octadecynyl ether (7).
In tr od u ction
Sphingomyelin (1) is a major constituent of mam-
malian cell membranes, plasma lipoproteins, and the
myelin sheath. Sphingolipids formed intracellularly as
intermediates in the biosynthesis and catabolism of 1
evoke a wide range of stereospecific responses in cells.1
Many chiral syntheses of sphingolipids have been
reported,2 whereas methods for preparation of chiral
analogues have not yet received appreciable attention.
We reported previously the preparation of 3-deoxy-DL-
N-stearoylsphingomyelin3 and its use as an inhibitor of
neutral sphingomyelinase4 and as a probe of the role of
the 3-hydroxy group of sphingomyelin in the interaction
with cholesterol.3,5 Here, we report an enantioselective
synthesis of 3-deoxy-(R)-sphingomyelin (2) starting with
(S)-1-(4′-methoxyphenyl)glycerol (3), which can be pre-
pared conveniently on a large scale by asymmetric
dihydroxylation6 of allyl 4-methoxyphenyl ether using
AD-mix â supplemented with potassium persulfate.7 The
synthesis involves the following sequence of reactions:
(1) activation of the primary hydroxy group of glycerol 3
F igu r e 1.
either by conversion to glycidol 5 (Scheme 1) or to cyclic
sulfate 6 (Scheme 2); (2) preparation of PMP (S)-2-
hydroxy-4-octadecynyl ether (7) by opening of glycidol 5
with lithium pentadecyne in the presence of BF3‚Et2O
(Scheme 1) or by nucleophilic substitution of cyclic sulfate
6 with lithium pentadecyne in the presence of CuI
(Scheme 1); (3) conversion of the homopropargylic hy-
droxy group of 7 into an amide group by the sequence of
mesylation, azide substitution, reduction, and acylation;
(4) simultaneous reduction of the triple bond of amide 8
to an (E) double bond and deprotection of the PMP group
by Birch reduction; and (5) insertion of the phosphocho-
line moiety into 3-deoxyceramide 9 by phosphitylation,
followed by oxidation and opening of the cyclic phosphite
with bromine and quaternization with aqueous Me3N
solution.
* To whom correspondence should be addressed. Tel.: (718) 997-
3279. Fax: (718) 997-3349. E-mail: bittman@qcvaxa.qc.edu.
(1) For recent reviews, see: (a) Spiegel, S.; Merrill, A. H., J r. FASEB
J . 1996, 10, 1388-1397. (b) Hannun, Y. Science 1996, 274, 1855-1859.
(c) Spiegel, S.; Foster, D.; Kolesnick, R. N. Curr. Opin. Cell Biol. 1996,
8, 159-167. (d) Merrill, A. H., J r.; Sweeley, C. C. In Biochemistry of
Lipids, Lipoproteins, and Membranes, 2nd ed.; Vance, D. E., Vance,
J ., Eds.; Elsevier: Amsterdam, 1996; Vol. 31, pp 309-338. (e) Ghosh,
S.; Strum, J . C.; Bell, R. M. FASEB J . 1997, 11, 45-50.
(2) For a review, see: Byun, H.-S.; Bittman, R. In Phospholipids
Handbook; Cevc, G., Ed.; Marcel Dekker: New York, 1993; pp 97-
140.
Resu lts a n d Discu ssion
P r ep a r a tion of Glycid ol 5 fr om (S)-Glycer ol 3. It
is well known that 1,2-diols can be converted to epoxides
by the Mitsunobu reaction8 and by monotosylation of a
diol followed by base-induced cyclization.9 Scheme 1
shows the application of these two routes for the conver-
sion of protected diol 3 into glycidol 5. Mitsunobu
reaction of (S)-glycerol 3 in refluxing benzene gave only
(3) Kan, C.-C.; Ruan, Z.-S.; Bittman, R. Biochemistry 1991, 30,
7759-7766.
(4) Lister, M. D.; Ruan, Z.-S.; Bittman, R. Biochim. Biophys. Acta
1995, 1256, 25-30.
(5) Gro¨nberg, L.; Ruan, Z.-S.; Bittman, R.; Slotte, J . P. Biochemistry
1991, 30, 10746-10754.
(6) For a review, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1994, 94, 2483-2547.
(8) Takano, S.; Seya, K.; Goto, E.; Hirama, M.; Ogasawara, K.
Synthesis 1983, 116-117.
(9) Takano, S.; Moriya, M.; Suzuki, M.; Iwabuchi, Y.; Sugihara, T.;
Ogasawara, K. Heterocycles 1990, 31, 1555-1562.
(7) Byun, H.-S.; Kumar, E. R.; Bittman, R. J . Org. Chem. 1994, 59,
2630-2633.
S0022-3263(97)01977-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

Synthesis of Deoxysphingomyelin
Sch em e 1. Tw o Rou tes to P MP
J . Org. Chem., Vol. 63, No. 8, 1998 2561
Sch em e 3. Syn th esis of
(S)-2-Hyd r oxy-4-octa d ecyn yl Eth er (7) fr om 3 via
(S)-O-P MP -glycid ol (5)
3-Deoxy-(R)-sp h in gom yelin (2) fr om 7
for the preparation of diamido glycerolipids.11 The fol-
lowing three-step sequence of reactions, without purifica-
tion of the intermediates, was used (Scheme 3): (1)
mesylation of secondary alcohol 7 by reaction with MsCl
in the presence of pyridine in CH2Cl2, (2) SN2 substitution
of the mesylate group with lithium azide in the presence
of catalytic Bu4NHSO4 in DMF at 50 °C, and (3) reduction
of the azide with Ph3P-H2O and in-situ acylation of the
resulting amine with the 4-nitrophenyl ester of palmitic
acid. To minimize the possible elimination reaction, the
mesylation was carried out at -20 °C. For azide dis-
placement of the mesylate, lithium azide was used in the
presence of Bu4NHSO4 in DMF. Azide displacement,
followed by reduction of the azide with Ph3P-H2O in the
presence of 4-nitrophenyl palmitate, provided amide 8
in 82% overall yield. In contrast, the three-step overall
yield was only 35% when sodium azide was used at 90
°C in the absence of the phase-transfer catalyst, possibly
because at high-temperature elimination competes with
substitution.
Syn th esis of Deoxysp h in gom yelin (2) fr om Am id e
8. The E double bond was introduced into 8 by Birch
reduction of the triple bond. Under the reduction condi-
tions used, aryl ethers are also reduced to 1-alkoxy-1,4-
cyclohexadienes, with the addition of hydrogen taking
place at positions other than those occupied by the alkoxy
group.12 The resulting enol ether tends to undergo acid-
catalyzed hydrolysis and liberate the alcohol. Thus,
during the reduction of the triple bond, the PMP protect-
ing group of amide 8 can be removed also. Addition of a
solution of amide 8 in THF to a blue solution of lithium
metal in EtNH2 provided 3-deoxyceramide 9 in 74% yield.
Finally, insertion of the phosphocholine moiety into
3-deoxyceramide 9 was performed by the reported phos-
phitylation procedure13 to provide deoxysphingomyelin
(2) in 81% yield.
Sch em e 2. Syn th esis of 7 fr om 3 via Cyclic
Su lfa te 6
a moderate yield (69%) of glycidol 5. The yield of 5 was
improved markedly by using a route that involves the
formation of a cyclic stannylene intermediate in CHCl3-
MeOH (10:1); the latter was converted into the mono-
tosylate 4 by reaction with TsCl at room temperature in
CH2Cl2. After the byproduct (probably Ts2O) was re-
moved by filtration through a silica gel pad, treatment
of the monotosylate with K2CO3 in methanol at 0 °C
resulted in the formation of glycidol 5 in 98% yield. The
yield of the epoxide-forming step was reduced markedly
when the reaction was carried at room temperature
rather than at 0 °C, apparently because of opening of 5
by methanol.
Syn th esis of Eth er 7. Scheme 1 shows the regiose-
lective opening reaction of glycidol 5 with lithium pen-
tadecyne in the presence of BF3‚Et2O to give ether 7 in
65% yield. Scheme 2 shows an alternative route to PMP
(S)-2-hydroxy-4-octadecynyl ether (7). Previous work has
shown that 1,2-cyclic sulfates are opened under nucleo-
philic substitution conditions.10 (S)-Glycerol 3 was con-
verted to cyclic sulfate 6 with SOCl2 followed by oxidation
of the resulting sulfite with catalytic RuO4, giving 6 in
92% yield. Nucleophilic opening of 6 with 2.1 equiv of
lithium pentadecyne in the presence of catalytic CuI at
-23 °C and then overnight at room temperature, followed
by acidic workup, provided ether 7 in 90% yield.
Exp er im en ta l Section
Gen er a l In for m a tion . See refs 7 and 11 for general
experimental protocols.
4′-Meth oxyp h en yl (S)-2-Oxir a n ylm eth yl Eth er ((+)-5).
Meth od A (Sch em e 1). To a solution of 1.99 g (10.0 mmol)
of (S)-1-(4′-methoxyphenyl)glycerol (3) and 3.93 g (15.0 mmol)
of Ph3P in 100 mL of C6H6 was added 3.0 g (15.0 mmol) of
diisopropyl azodicarboxylate (DIAD). After the mixture was
refluxed for 24 h, the solvent was removed under reduced
Syn th esis of Am id e 8 fr om Eth er 7. The amide
group was introduced by a modification of our procedure
(11) Byun, H.-S.; Bittman, R. J . Org. Chem. 1996, 61, 8706-8708.
(12) For a review of Birch reductions of aromatic compounds, see:
Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.
(13) Erukulla, R. K.; Byun, H.-S.; Bittman, R. Tetrahedron Lett.
1994, 35, 5783-5784.
(10) (a) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538-
7539. (b) For a review, see: Lohary, B. B. Synthesis 1992, 1035-1052.

2562 J . Org. Chem., Vol. 63, No. 8, 1998
Byun et al.
pressure, and Et2O was added to the residue to precipitate
Ph3PO formed during the reaction. The precipitate was
removed by filtration, and the remaining light brown filtrate
was concentrated in a rotary evaporator. The residue was
purified by chromatography on silica gel (elution with 9:1
hexane/EtOAc) to give 1.25 g (69%) of glycidol 5 as a white
solid: mp 40.6-41.3 °C (lit.7 mp 42-43 °C); Rf 0.53 (3:1
hexane/EtOAc); [R]25D +9.13° (c 5.0, MeOH) [lit.7 [R]28D +11.04°
(c 1.08, MeOH) (lit.14 [R]30D +11.3° (c 0.98, MeOH))]. Meth od
B (Sch em e 1). A suspension of 1.99 g (10.0 mmol) of (S)-1-
(4′-methoxyphenyl)glycerol (3) and 2.49 g (10.0 mmol) of
dibutyltin oxide in 100 mL of 10:1 CHCl3/MeOH was refluxed
for 2 h (after 1 h it became a clear solution). After the solvents
were removed under reduced pressure, the residue was dis-
solved in 50 mL of CHCl3. The solvent was evaporated under
reduced pressure, and the residue was dried under high
vacuum for 5 h. To a solution of the residue in 25 mL of CH2-
Cl2 was added 2.48 g (13.0 mmol) of p-toluenesulfonyl chloride.
After the reaction mixture was stirred overnight, the reaction
was quenched with 0.2 mL (11.1 mmol) of H2O. After 2 h, the
mixture was diluted with 100 mL of hexane and filtered
through a pad of silica gel. The pad was washed with 200 mL
of 10:1 hexane/EtOAc in order to remove a nonpolar impurity
(probably p-toluenesulfonic anhydride). Monotosylate 4 was
eluted with 200 mL of 1:1 hexane/EtOAc. The filtrate was
concentrated to give 3.70 g (105%) of crude 4: Rf 0.19 (3:1
mmol) of 1-pentadecyne in 250 mL of dry THF was added 5.0
mL (12.5 mmol) of n-butyllithium (a 2.5 M solution in hexane)
at -23 °C. After the mixture had stirred for 2 h at -23 °C
and 2 h at room temperature, 0.75 g (4.2 mmol) of glycidol 5
was added. The mixture was cooled to -78 °C, and 1.9 mL
(15 mmol) of BF3‚Et2O was added. The reaction mixture was
stirred for 6 h and allowed to warm to -23 °C. After 24 h,
the reaction mixture was diluted with Et2O. The mixture was
washed with 1 N HCl solution and then with H2O. The organic
layer was dried over Na2SO4 and concentrated. The product
was purified by silica gel chromatography (elution with 6:1
hexane/EtOAc) to give 1.17 g (65%) of ether 7 as a white
solid: mp 55.0-55.1 °C; Rf 0.37 (5:1 hexane/EtOAc); [R]25
D
+12.0° (c 5.0, CHCl3). Meth od B (Sch em e 2). To a solution
of 4.40 g (21.1 mmol) of 1-pentadecyne in 250 mL of dry THF
was added 8.0 mL (20.0 mmol) of n-butyllithium (a 2.5 M
solution in hexane) at -23 °C. After the mixture was stirred
for 2 h at -23 °C and 2 h at room temperature, 2.60 g (10.0
mmol) of cyclic sulfate 6 and 95 mg (0.50 mmol) of CuI were
added at -23 °C. After 4 h, the mixture was warmed to room
temperature and stirred overnight. To the mixture were added
100 mL of 20% aqueous H2SO4 and 100 mL of ether. After
the biphasic mixture was stirred overnight, the product was
extracted with ether. The organic layer was washed with 10%
aqueous ammonium hydroxide solution, water, and brine and
dried (MgSO4). After concentration, the crude product was
purified by column chromatography on silica gel, eluting with
6:1 hexane-EtOAc, to give 3.50 g (90%) of ether 7 as a white
1
hexane/EtOAc); H NMR (CDCl3) δ 7.78 (d, 2H, J ) 8.2 Hz),
7.31 (d, 2H, J ) 8.2 Hz), 6.74-6.84 (m, 4H), 4.12-4.23 (m,
3H), 3.93 (d, 2H, J ) 4.8 Hz), 3.76 (s, 3H), 2.61 (br s, 1H), 2.42
(s, 3H). To a suspension of the crude 4 in 25 mL of MeOH
was added 6.82 g (49.3 mmol) of powdered K2CO3 at 0 °C. After
the reaction mixture was stirred for 2.5 h at 0 °C, it was diluted
with 100 mL of Et2O. The mixture was filtered through a pad
of silica gel, which was washed with 200 mL of Et2O. The
filtrate was concentrated to give 1.77 g (98%) of glycidol 5 as
a white solid: mp 40.0-40.8 °C; Rf 0.53 (3:1 hexane/EtOAc);
solid: mp 55.1-55.5 °C; Rf 0.37 (5:1 hexane/EtOAc); [R]25
D
+11.8° (c 5.0, CHCl3); IR (NaCl) 3355, 1025 cm-1
;
1H NMR
(CDCl3) δ 6.82-6.88 (m, 4H), 4.08-4.10 (m, 1H), 4.02 and 4.05
(ABq, 1H, J ) 4.1 Hz, ∆ν ) 8.3 Hz), 3.92 and 3.96 (ABq, 1H,
J ) 6.5 Hz, ∆ν ) 6.6 Hz), 3.77 (s, 3H), 2.52-2.54 (m, 2H),
2.13-2.18 (m, 2H), 1.93 (br s, 1H), 1.44-1.49 (m, 2H), 1.30-
1.37 (m, 2H), 1.25 (s, 18H), 0.88 (t, 3H, J ) 6.5 Hz); 13C NMR
(CDCl3) δ 154.53, 153.10, 115.98, 115.07, 71.79, 56.15, 32.36,
30.12, 30.10, 30.00, 29.78, 29.60, 29.36, 24.36, 23.13, 19.18;
HRMS [FAB, M+] calcd for C25H40O3 m/z 388.2977, found
388.2976.
[R]25 +10.5° (c 5.0, MeOH); IR (NaCl) 1232, 1031 cm-1 1H
;
D
NMR (CDCl3) δ 6.81-6.91 (m, 4H), 4.15 and 4.19 (ABq, 1H, J
) 3.2 Hz, ∆ν ) 10.6 Hz), 3.90 and 3.94 (ABq, 1H, J ) 5.6 Hz,
∆ν ) 9.24 Hz), 3.77 (s, 3H), 3.31-3.35 (m, 1H), 2.89 (t, 1H, J
) 4.6 Hz), 2.73 and 2.75 (ABq, 1H, J ) 2.6 Hz, ∆ν ) 4.2 Hz);
13C NMR (CDCl3) δ 154.17, 152.64, 115.71, 114.64, 69.51,
55.69, 50.26, 44.72; HRMS [FAB, MH+] calcd for C10H13O3 m/z
180.0786, found 180.0780.
4′-Meth oxyp h en yl (R)-2-(Hexa d eca n a m id o)-4-octa d e-
cyn yl Eth er ((+)-8). To a solution of 1.00 g (2.57 mmol) of 7
in 20 mL of CH2Cl2 and 0.60 mL (7.4 mmol) of pyridine was
added 0.25 mL (3.2 mmol) of methanesulfonyl chloride at -20
°C, and the mixture was allowed to stand for 24 h. The
reaction mixture was diluted with Et2O and washed with a
10% aqueous CuSO4 solution, a saturated aqueous NaHCO3
solution, and finally with H2O. The Et2O layer was dried (Na2-
SO4), filtered, and concentrated to give 1.30 g (108%) of the
crude mesylate: Rf 0.66 (CHCl3); 1H NMR (CDCl3) δ 6.84-
6.89 (s, 4H), 4.93-4.99 (m, 1H), 4.22 and 4.25 (ABq, 1H, J )
3.5 Hz, ∆ν ) 10.1 Hz), 4.13 and 4.17 (ABq, 1H, J ) 6.8 Hz, ∆ν
) 8.2 Hz), 3.77 (s, 3H), 3.07 (s, 3H), 2.73-2.78 (m, 2H), 2.12-
2.16 (m, 2H), 1.43-1.50 (m, 2H), 1.30-1.37 (m, 2H), 1.25 (s,
18H), 0.88 (t, 3H, J ) 6.9 Hz). After the crude mesylate was
dissolved in 10 mL of DMF, 0.63 g (12.9 mmol) of LiN3 and
340 mg (1.0 mmol) of Bu4NHSO4 were added. The mixture
was heated at 50 °C for 24 h. The resulting viscous, caramel-
colored reaction mixture was diluted with Et2O and washed
with H2O. The Et2O layer was dried (Na2SO4), filtered, and
concentrated. To remove the color, the residue was dissolved
in hexane/EtOAc 10:1 and filtered through a pad of silica gel,
which was washed with 100 mL of hexane/EtOAc 10:1. The
filtrate was concentrated to give 0.95 g (88%) of crude azide
as a colorless liquid: Rf 0.81 (4:1 hexane/EtOAc); 1H NMR
(CDCl3) δ 6.80-6.87 (m, 4H), 3.92-3.95 (m, 1H), 3.79-3.84
(m, 2H), 3.60 (s, 3H), 2.74-2.87 (m, 2H), 2.12-2.16 (m, 2H),
1.53-1.67 (m, 2H), 1.30-1.37 (m, 2H), 1.26 (s, 18H), 0.88 (t,
3H, J ) 6.9 Hz). To a solution of the azide in 25 mL of THF-
H2O (10:1) were added 0.67 g (2.55 mmol) of Ph3P and 0.96 g
(2.55 mmol) of p-nitrophenyl hexadecanoate. After 24 h, the
reaction mixture was diluted with 100 mL of CH2Cl2 and
washed with 1 N NaOH solution and H2O. The organic layer
was dried (Na2SO4) and concentrated in a rotary evaporator.
The residue was purified by column chromatography (elution
with 8:1 hexane/EtOAc) to give 1.33 g (82% overall yield from
(R)-1-(4′-Met h oxyp h en yl)glycer ol 2,3-Cyclic Su lfa t e
((+)-6). To a solution of 3.0 g (15.1 mmol) of (S)-1-(4′-
methoxyphenyl)glycerol (3) and 2.40 g (30.3 mmol) of pyridine
in 25 mL of CH2Cl2 was added 1.4 mL (19.2 mmol) of SOCl2.
After the mixture was stirred for 2 h at 0 °C, 50 mL of EtOAc
was added. The mixture was filtered through a pad of silica
gel, which was washed with 100 mL of EtOAc. After the
filtrate was concentrated, the residue was dissolved in 25 mL
of CH3CN. To the solution of the cyclic sulfite (diastereomeric
ratio 1:1, Rf 0.50 and 0.60, developed with hexane/EtOAc 2:1)
were added 4.90 g (22.9 mmol) of NaIO4 and 8 mg (0.03 mmol)
of RuCl3‚3H2O, followed by 25 mL of water at room temper-
ature. After 2 h, the mixture was diluted with EtOAc, the
two phases were separated, and the organic layer was washed
with water, saturated aqueous NaHCO3, and brine. The
solution was dried (MgSO4) and then filtered through a pad
of silica gel to remove the brown color. The filtrate was
concentrated to give 3.53 g (92%) of cyclic sulfate 6 as a white
solid: mp 90.1-90.8 °C; Rf 0.46 (2:1 hexane/EtOAc); [R]25
D
+2.88° (c 5.6, CHCl3); IR (NaCl) 1237, 1202, 1031 cm-1 1H
;
NMR (CDCl3) δ 6.84 (m, 4H), 5.18-5.24 (m, 1H), 4.81 and 4.83
(ABq, 1H, J ) 6.6 Hz, ∆ν ) 6.0 Hz), 4.70 and 4.72 (ABq, 1H,
J ) 8.9 Hz, ∆ν ) 6.0 Hz), 4.18-4.26 (m, 2H), 3.77 (s, 3H); 13
C
NMR (CDCl3) δ 154.88, 151.60, 115.87, 115.64, 115.04, 114.84,
78.93, 69.71, 66.60, 55.70; HRMS [FAB, M+] calcd for C10H12O6S
m/z 260.0355, found 260.0348.
4′-Meth oxyp h en yl (S)-2-Hyd r oxy-4-octa d ecyn yl Eth er
((+)-7). Meth od A (Sch em e 1). To a solution of 2.70 g (13.0
(14) Takano, S.; Setoh, M.; Ogasawara, K. Heterocycles 1992, 34,
173-180.

Synthesis of Deoxysphingomyelin
J . Org. Chem., Vol. 63, No. 8, 1998 2563
7) of amide 8 as a white solid: mp 81.0-82.2 °C; Rf 0.47 (4:1
-23 °C. After the reaction mixture was stirred for 2 h at -23
°C, 29 µL (0.57 mmol) of Br2 was added. After 5 min, the P-Br
bond was hydrolyzed by the addition of 10 mL of H2O. After
the reaction mixture was warmed to room temperature, the
solvents were removed in a rotary evaporator. The residue
was dissolved in 10 mL of CH3CN-2-PrOH-CHCl3 (5:5:3), and
10 mL of 45% aqueous Me3N was added. The mixture was
stirred overnight at room temperature. The solvents were
removed in a rotary evaporator, and the residue was dissolved
in a minimal amount of 9:1 THF-H2O. The solution was
passed through a column of TMD-8 exchange resin (elution
with 9:1 THF/H2O), and the product was concentrated in a
rotary evaporator. The resulting residue was lyophilized from
C6H6 to give crude deoxysphingomyelin (2) as a white solid.
Final purification by column chromatography on silica gel
(elution with 9:1 CHCl3/MeOH and then with 65:25:4 CHCl3/
MeOH/H2O) gave 106 mg (81%) of 3-deoxysphingomyelin 2 as
hexane/EtOAc); [R]25 +6.35° (c 5.0, CHCl3); IR (NaCl) 3295,
D
1
1637, 1043 cm-1; H NMR (CDCl3) δ 6.81-6.88 (m, 4H), 5.81
(d, 1H, J ) 8.4 Hz), 4.35 (s, 1H), 4.08 and 4.12 (ABq, 1H, J )
3.8 Hz, ∆ν ) 8.5 Hz), 3.91 and 3.94 (ABq, 1H, J ) 5.7 Hz, ∆ν
) 7.4 Hz), 3.77 (s, 3H), 2.58-2.63 (m, 1H), 2.49 and 2.54 (ABq,
1H, J ) 7.8 Hz, ∆ν ) 14.9 Hz), 2.20 (t, 2H, J ) 7.6 Hz), 2.14
(t, 2H, J ) 6.9 Hz), 1.63 (t, 2H, J ) 6.9 Hz), 1.43-1.50 (m,
2H), 1.25 (s, 44H), 0.88 (t, 6H, J ) 6.8 Hz); 13C NMR (CDCl3)
δ 173.18, 154.53, 153.10, 115.96, 115.04, 68.60, 56.09, 47.65,
37.23, 32.31, 30.05, 29.89, 29.75, 29.64, 29.56, 29.34, 26.11,
23.08, 21.75, 19.10, 14.51; HRMS [FAB, MH+] calcd for
C
41H72O3N m/z 626.5512, found 626.5515.
(R)-N-(Hexa d eca n a m id o)-4-octa d ecen -1-ol ((+)-9). To
a blue solution of 102 mg (147 mmol) of lithium metal in 75
mL of EtNH2 was added dropwise a solution of 1.01 g (1.61
mmol) of amide 8 in 40 mL of THF at -78 °C. During the
addition of the amide solution, the blue color of the reaction
mixture was maintained by adjusting the speed of the addition.
After all of the amide solution had been added, the reaction
mixture was stirred for 6 h at -78 °C. The reaction was
quenched by adding 7.86 g (147 mmol) of NH4Cl, and the
mixture was warmed to room temperature overnight, during
which time the EtNH2 evaporated. The mixture was then
diluted with water and neutralized by the addition of 1 N HCl.
The product was extracted with CH2Cl2, and the organic layer
was dried (Na2SO4). Concentration of the organic layer gave
a brown residue, which was purified by column chromatogra-
phy on silica gel (elution with 1:1 hexane/EtOAc) followed by
recrystallization from hexane to give 630 mg (75%) of (R)-3-
deoxyceramide 9 as a white solid: mp 76.8-79.0 °C; Rf 0.37
a white solid: Rf 0.28 (65:25:4 CHCl3/MeOH/H2O); [R]25
D
-7.46° (c 1.0, 1:1 CHCl3/MeOH); IR (NaCl) 3293, 1637, 1237,
1
1084, 1055 cm-1; H NMR (CDCl3-CD3OD) δ 5.47-5.53 (m,
1H), 5.31-5.36 (m, 1H), 3.23-4.26 (m, 7H), 3.18 (s, 9H), 2.14-
2.31 (m, 4H), 1.97-2.02 (m, 2H), 1.60-1.64 (m, 2H), 1.25 (s,
46 H), 0.88 (t, 6H, J ) 6.6 Hz); 13C NMR (CDCl3) δ 174.30,
133.94, 124.68, 66.71, 66.02, 59.01, 53.91, 36.31, 33.91, 32.40,
31.64, 29.43, 29.38, 29.31, 29.26, 29.19, 29.08, 29.05, 25.81,
22.39, 13.71; HRMS [FAB, MH+] calcd for C39H80O5N2P m/z
687.5805, found 687.5774.
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 facility at Michigan State
University for the HR-FAB MS. We gratefully acknowl-
edge support from the National Science Foundation
(CHE-9408535) for funds for the purchase of the 400-
MHz NMR spectrometer.
(1:1 hexane/EtOAc); [R]25 +3.06° (c 5.0, CHCl3); IR (NaCl)
D
3355, 3296, 1637 cm-1
;
1H NMR (CDCl3) δ 5.92 (br s, 1H),
5.50-5.57 (m, 1H), 5.31-5.38 (m, 1H), 3.93 (br s, 1H), 3.66
and 3.70 (ABq, 1H, J ) 3.1 Hz, ∆ν ) 10.7 Hz), 3.58 and 3.62
(ABq, 1H, J ) 6.2 Hz, ∆ν ) 9.1 Hz), 3.00 (s, 1H), 2.14-2.31
(m, 6H), 1.97-2.02 (m, 2H), 1.60-1.64 (m, 2H), 1.25 (s, 44 H),
0.88 (t, 6H, J ) 6.6 Hz); 13C NMR (CDCl3) δ 174.67, 134.95,
125.00, 65.74, 52.02, 36.68, 34.37, 32.59, 31.94, 29.72, 29.68,
29.55, 29.47, 29.38, 29.26, 25.86, 22.70, 14.13; HRMS [FAB,
MH+] calcd for C34H68O2N m/z 522.5250, found 522.5251.
(R)-N-Hexadecan oyl-3-deoxysph in gom yelin ((-)-2). To
a solution of 100 mg (0.19 mmol) of 9 in 20 mL of THF were
added 96 mg (130 µL, 0.74 mmol) of N,N-diisopropylethyl-
amine and 51 µL (0.57 mmol) of ethylene chlorophosphite at
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 2 and 5-9 (12 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O971977Y