An efficient and convenient approach to the total synthesis of sphingofungin

Article abstract of DOI:10.1021/jo005612g

As a new member of the sphingofungin family, sphingofungin F exhibits interesting physiological activities with a structural unit of an α-substituted alanine. Described herein is an efficient and convenient stereoselective synthesis of sphingofungin F from L-(+)-tartaric acid, which utilizes Sharpless asymmetric epoxidation of allylic alcohol and Lewis acid-catalyzed intramolecular epoxideopening reaction with an N-nucleophile, to introduce the other two desired stereogenic centers. Side chain functionality was incorporated into the chiral segment using a Wittig reaction.

Full text of DOI:10.1021/jo005612g

9114
J . Org. Chem. 2000, 65, 9114-9119
An Efficien t a n d Con ven ien t Ap p r oa ch to th e Tota l Syn th esis of
Sp h in gofu n gin
Ding-Guo Liu, Bing Wang, and Guo-Qiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai, 200032, China
lingq@pub.sioc.ac.cn
Received August 15, 2000
As a new member of the sphingofungin family, sphingofungin F exhibits interesting physiological
activities with a structural unit of an R-substituted alanine. Described herein is an efficient and
convenient stereoselective synthesis of sphingofungin F from L-(+)-tartaric acid, which utilizes
Sharpless asymmetric epoxidation of allylic alcohol and Lewis acid-catalyzed intramolecular epoxide-
opening reaction with an N-nucleophile, to introduce the other two desired stereogenic centers.
Side chain functionality was incorporated into the chiral segment using a Wittig reaction.
In tr od u ction
In recent years, more and more sphingosine-like com-
pounds including sphingofungins A-F have been isolated
from various natural resources. Due to their interesting
physiological properties, the syntheses of these com-
pounds have attracted considerable attention of synthetic
chemists. Sphingofungin E and F (Figure 1), two new
members of the sphingofungin family, were first isolated
from the fermentation broth of Poecilomyces variotii by
a Merck group in 1992.1 Similar to sphingofungin A, B,
C, and D,2 these two compounds exhibit inhibitory effects
toward Serinepalmitoyl transferase, an enzyme playing
an important role in the biosynthesis of sphingolipids.
Bearing a structural unit of a R-substituted serine or
alanine, they have structural resemblance to myriocin.3
Up to now, two groups4,5 have reported preparations of
sphingofungin F, basing their syntheses on either aldol
or palladium-catalyzed alkylation reactions as key steps.
As part of our continuing efforts to study the syntheses
of sphingosine-like compounds, we describe herein an
alternative approach to sphingofungin F, which utilizes
Lewis acid-catalyzed intramolecular epoxide-opening
reaction with an N-nucleophile as a key step.
F igu r e 1. Structure of sphingofungins.
according to literature procedures.6 Swern oxidation7 of
3 afforded an aldehyde, which was subjected to Wittig
reaction with ylide 4 by refluxing the reaction mixture
in benzene, to afford R,â-unsaturated ester 5. The E/Z
ratio of 5 was only 11:1. To improve stereoselectivity, we
attempted to optimize the reaction condition. Conse-
quently, a ratio of 17:1 (E/Z) was obtained when the
reaction was performed at 0 °C in CH2Cl2. While optimiz-
ing the reaction conditions, occasionally, we used crude
aldehyde stored in a refrigerator (-30 °C) overnight. To
our surprise, an enhancement to 23:1(E/Z) was observed.
Regarding this unexpected good stereogenic outcome, we
surmised that it could potentially be attributed to self-
polymerization of aldehyde at low temperature. Accord-
ingly, depolymerization would be needed to release the
aldehyde prior to reacting with ylide 4. This could result
in a slowed reaction rate, leading to remarkable elevation
in stereoselectivity. Reduction of ester 5 with DIBAL-H
afforded alcohol 6 in 91% yield. The next step required
stereoselective epoxidation of compound 6. Initially, using
m-CPBA as oxidant, epoxide 7 was expected to predomi-
nate according to the transition state supposed by S.
Takano et al.8 However, the stereogenic outcome (7:8 )
1:10) was opposite to this prediction. We envisioned that
the different stereogenic outcome in their case might be
due to steric factors arisen from a methyl group in their
Resu lts a n d Discu ssion
As shown in Scheme 1, the known alcohol 3 could be
readily prepared in four steps from L-(+)-tartaric acid
* To whom correspondence should be addressed. Fax: 86-21-
64166263.
(1) Horn, W. S.; Smith, J . L.; Bills, G. F.; Raghoobar, S. L.; Helms,
G. L.; Kurtz, M. B.;Marrinan, J . A.; Frommer, B. R.; Thornton, R. A.;
Mandala, S. M. J . Antibiot. 1992, 45, 1693.
(2) (a) VanMiddlesworth, F.; Giacobbe, R. A.; Lopez, M.; Garrity,
G.; Bland, J . A.; Bartizal, K.;Fromtling, R. A.; Wilson, K. E.; Monaghan,
R. L. J . Antibiot. 1992, 45, 861. (b) VanMiddlesworth, F.; Dufresne,
C.; Wincott, F. E.; Mosley,R. T.; Wilson, K. E. Tetrahedron Lett. 1992,
33, 297.
(3) Kluepfel, D.; Bagli, J .; Baker, H.; Charest, M.-P.; Kudelsk, A.;
Sehgal, S. N.; Vezina, C. J . Antibiot. 1972, 25, 109.
(4) (a) Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.;
Iwamoto, S. Synlett 1997, 301. (b) Kobayshi, S.; Furuta, T.; Hayashi,
T.; Nishijima, M.; Hanada, K. J . Am. Chem. Soc. 1998, 120, 908. (c)
Kobayashi, S.; Furuta, T. Tetrahedron 1998, 54, 10275.
(5) Trost, B. M.; Lee, C. B. J . Am. Chem. Soc. 1998, 120, 6818.
(6) Hungerbuhler, E.; Seebach, D. Helv. Chim. Acta. 1981, 64, 687.
(7) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978, 43,
2480.
(8) Hatakeyama, S.; Matsui, Y.; Suzuki, M.; Sakurai, K.; Takano,
S. Tetrahedron Lett. 1985, 26, 6485.
10.1021/jo005612g CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/30/2000

Total Synthesis of Sphingofungin
J . Org. Chem., Vol. 65, No. 26, 2000 9115
Sch em e 1a
Sch em e 2a
a
(a) I(CH2)6OTHP (12), K2CO3, DMF, acetone, reflux, 77%; (b)
3% KOH (aq), CH3OH, reflux, 100%; (c) PTS, CH3OH, 99%; (d)
PPh3, CBr4, CH2Cl2, 100%; (e) ethylene glycol, PTS, benzene,
reflux, 98%; (f) PPh3, Na2CO3, acetonitrile, reflux, 100%.
smoothly in 85% yield. Treatment of 17 with TBAF in
THF, yielded alcohol 18. To introduce the amino group
regioselectively at C2, Hatakeyama’s method12 was em-
ployed. Thus, treatment of 18 with trichloroacetonitrile
and DBU was followed by intramolecular epoxide-open-
ing reaction catalyzed by BF3‚OEt2, to afford oxazoline
19 in 70% yield over two steps, in addition to a 20% yield
of the hydrolysis product. According to Hatakeyama’s
report, AlEt2Cl is superior to BF3‚OEt2 in inhibiting
oxazoline hydrolysis. However, in our case, a complex
result was obtained. Subsequently, we found that oxazo-
line hydrolysis took place predominantly at workup stage.
Therefore, the workup was modified by diluting the
mixture with ethyl acetate prior to the addition of
saturated NaHCO3, resulting in the yield of 19 being
improved to 80%. Treatment of 19 with triphosgene and
pyridine,13 followed by removal of the trichloroacetyl
group with K2CO3, gave alcohol 20 in 83% yield over two
steps. Oxidation of 20 with PDC in DMF, followed by
methylation of the resulting carboxylic acid with CH2N2,
yielded ester 21. The stereochemistry of 21 was confirmed
to be consistent with that of sphingofungin F by NOE
experiments on γ-lactone 22, which was obtained by
refluxing 21 with PTS in EtOH (Scheme 3).
a
(a) i. (COCl)2, DMSO, -78 ˚C, NEt3, CH2Cl2; ii. 4, CH2Cl2, 0
˚C, 85% (two steps); (b) DIBAL-H, CH2Cl2, -78 °C, 90%; (c) TBHP,
L-(+)-DIPT, Ti(OPri)4, 4 Å MS, CH2Cl2, -20 °C, 73%; (d) i. TBSCl,
NEt3, DMAP (cat.), CH2Cl2, 80%; ii. Pd(OH)2/C (20%), H2, EtOAc/
CH3OH (4:1), 97%; (e) (COCl)2, DMSO, -78 °C, NEt3, CH2Cl2, 87%.
substrate, rather than a hydrogen bonding entity. We
therefore turned our attention to the Sharpless assymet-
ric epoxidation (AE) reaction.9 When this reaction was
conducted at -20 °C, epoxide 7 was obtained as the main
product in a ratio of 3:1 (7:8). Protection of the hydroxy
group of 7 as its TBS ether, followed by catalytic
hydrogenation over 20% Pd(OH)2/C, afforded alcohol 9,
which was subjected to Swern oxidation to give crude
aldehyde 10.
Our synthesis of phosphonium salt 16 was achieved
from â-keto ester (11)10 (Scheme 2). Treatment of 11 with
iodide 12 and K2CO3 under reflux afforded the alkylation
product 13 in 77% yield. Ketone 14 was obtained by
refluxing 13 with 3% aqueous KOH. Treatment of 14
with PTS afforded alcohol 15, which could be easily
converted to phosphonium salt 16 in three known steps.11
With the two required segments in hand, Wittig
reaction was conducted at -78 °C, to provide Z-17
Finally, compound 21 was smoothly converted to
sphingofungin F (2) in three sequential steps. Photo-
isomerization of Z-21 with phenyl disulfide resulted in a
mixture of E- and Z-21 (E/Z ) 5:1), which could be
separated by flash chromatography on silica gel. Reflux-
ing E-21 with PTS afforded γ-lactone 23, which was
saponified with 1 N NaOH in EtOH-H2O to give 2 after
purification by chromatograph on Dowex-50 H+ resin
(elution with l N NH3) (Scheme 4).
(9) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5974.
(10) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J . Org. Chem. 1978, 43,
2087.
(11) (a) Payette, D. R.; J ust, G. Can. J . Chem. 1981, 59, 269. (b)
Sano. S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.;
Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097.
(12) Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.; Mukugi, Y.;
Irie, H. J . Org. Chem. 1997, 62, 2275.
(13) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J .;
Fischer, P. Synthesis 1989, 256.

9116 J . Org. Chem., Vol. 65, No. 26, 2000
Liu et al.
lit.4: [R]D20 ) +0.80 (c 0.33, CH3OH, 89% e.e.), mp 142-
144 °C}. Since the stereochemistry of our intermediate
21 was confirmed by NOE experiments on its derivative
22, we concluded that the discrepancy could only arise
from the different purification procedure in the last step.
As reported in the literature,14 amino acid could come
out as its ammonium salt after chromatography on
Dowex-50 H+ resin. Therefore, we surmised that the
above sample might be a mixture of sphingofungin F and
its ammonium salt. To verify this conjecture, 2 was
treated with a weak acid resin (IRC-76) in CH3OH to
release the free amino acid and purified by silica gel flash
chromatography to afford a white solid, which was
observed with specific rotation of [R]2D0 ) + 0.91 (c 0.22,
CH3OH) and mp of 145-147 °C. In this manner, all
spectral data of our final product were consistent with
literature values.
Sch em e 3a
In conclusion, we have demonstrated an alternative
and convenient approach to the synthesis of sphingofun-
gin F from L-(+)-tartaric acid, which was achieved in 3.7%
yield over 22 steps. In this route, Lewis acid-catalyzed
intramolecular epoxide-opening reaction with an N-
nucleophile has been successfully utilized to construct the
R-substituted alanine structural unit. With the same
protocol, our synthesis of sphingofungin E is in progress.
Exp er im en ta l Section
Gen er a l. All melting points are uncorrected. IR spectra
1
were recorded with FT-IR apparatus. H NMR and 13C NMR
spectra were recorded at 300 and 75 MHz in CDC13 and CD3-
OD, respectively. Chemical shifts are reported in ppm relative
to TMS as internal standard. Mass spectra were recorded by
EI methods. Flash column chromatography was carried out
with silica gel (200-300 mesh). Solvent THF was distilled over
sodium, with dichloromethane and DMF being distilled over
CaH2.
(2E,4S,5S)-2-Meth yl-4,5-O-isop r op ylid en e-6-ben zyloxy-
4,5-d iol-2-en e-1-h exa n oic Acid Eth yl Ester (5). To a solu-
tion of oxalyl chloride (0.69 mL, 7.94 mmol) in CH2Cl2 (8 mL)
was added DMSO (1.13 mL, 15.88 mmol) at -78 °C under N2.
The mixture was stirred for 10 min, and then a solution of 3
(1.00 g, 3.97 mmol) in CH2Cl2 (1 mL) was added. The mixture
was stirred for 1 h, triethylamine (5.5 mL, 39.7 mmol) was
added, and the stirring was allowed to continue for 20 min.
The mixture was allowed to warm to 0 °C and then quenched
with saturated NaH2PO4 (5 mL). The mixture was extracted
with CH2Cl2 (3 × 10 mL), and the combined extract was
washed with water and brine, dried over anhydrous Na2SO4,
and evaporated. The residue was filtered through silica gel
column to give 0.90 g of crude aldehyde. To a solution of the
above aldehyde (stored at -30 °C overnight) in CH2Cl2 (15 mL)
was added ylide 4 (1.95 g, 5.4 mmol) at 0 °C. After being stirred
for 30 min, the mixture was evaporated to give a residue,
which was purified by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ) 1:10) to afford 5 (1.12
g, 85%) as a colorless oil with a E/Z ratio of 23:1 (determined
by GC-MS). [R]1D9 ) -32.7 (c 2.20, CHCl3); IR (film) ν: 2987,
2935, 1715, 1660, 1455, 1370, 1255 cm-1; 1H NMR (CDCl3, 300
MHz) δ: 1.29 (3H, t, J ) 7.1 Hz), 1.46 (6H, s), 1.86 (3H, d, J
) 1.5 Hz), 3.56 (1H, dd, J ) 4.8, 10.7 Hz), 3.63 (1H, dd, J )
3.6, 10.7 Hz), 3.97 (1H, ddd, J ) 3.6, 4.8, 8.2 Hz), 4.20 (1H, q,
J ) 7.1 Hz), 4.21 (1H, q, J ) 7.1 Hz), 4.56, 4.62 (2H, AB, J AB
) 12.1 Hz), 4.72 (1H, t, J ) 8.5 Hz), 6.65 (1H, dt, J ) 1.5, 8.7
Hz), 7.20-7.40 (5H, m) ppm; MS (m/z, %): 319 (M+ - CH3,
1.32), 126 (36.37), 98 (30.19), 91 (100); HRMS calcd for
C18H2305 (M+ - CH3): 319.1545, Found: 319.1537.
a
(a) 16, n-BuLi, then -78 °C, 10, THF, 85%; (b) n-Bu4NF, THF,
95%; (c) i. Cl3CCN, DBU, CH2Cl2, 0 °C; ii. BF3‚OEt2, CH2Cl2, -23
°C, 80% (two steps); (d) i. CO(OCCl3)2, pyr, CH2Cl2, -35 °C to room
temperature, 4 h; ii. K2CO3, CH3OH, 82% (two steps); (e) i. PDC,
DMF; ii. CH2N2, Et2O, 78% (two steps); (f) PTS, 70% EtOH (aq),
reflux, 80%.
Sch em e 4a
a
(a) PhSSPh, hν, cyclohexane, 1,4-dioxane, 95%; (b) PTS, 70%
EtOH (aq), reflux, 81%; (c) 2 N NaOH, EtOH, reflux, 51%.
1
The sample 2 obtained by this route provided H NMR,
13C NMR, and IR spectra and MS identical with the
natural product. However, the specific rotation and mp
were different from those reported in the literature {our
sample: [R]2D0 ) -11 (c 0.59, CH3OH), mp: 123-125 °C;
(14) Ohfune, Y.; Shimamoto, K.; Ishida, M.; Shinozaki, H. Bioorg.
Med. Chem. Lett. 1993, 3, 15.

Total Synthesis of Sphingofungin
J . Org. Chem., Vol. 65, No. 26, 2000 9117
(2E,4S,5S)-l-Hyd r oxy-2-m eth yl-4,5-O-isop r op ylid en e-6-
ben zyloxy-2-en e-4,5-h exa n ed iol (6). To a solution of 5 (1.2
g, 3.6 mmol) in dry CH2Cl2 (15 mL) was added 9.0 mL of
DIBAL-H (1 M in hexane, 9.0 mmol) at -78 °C under argon.
After being stirred for 2.5 h, the mixture was quenched with
saturated NH4Cl (10 mL). The mixture was allowed to warm
to room temperature and stirred for 30 min. After filtration
through Celite, the filtrate was extracted with CH2Cl2 (3 ×
15 mL). The combined extract was washed with brine, dried
over anhydrous Na2SO4, and evaporated to give a residue,
which was purified by flash chromatography (eluent: ethyl
acetate/petroleum ether ) 2:1) to afford 6 (0.94 g, 90%) as a
colorless oil. [R]1D8 ) -14.0 (c 1.29, CHCl3); IR (film) ν: 3439,
g, 43.6 mmol) and K2CO3 (11.0 g, 79.6 mmol), the mixture was
refluxed for 12 h. After being cooled to room temperature, the
solvent was evaporated, and water (50 mL) was added. The
mixture was extracted with EtOAc (3 × 70 mL). The combined
organic layer was washed with water and brine, dried over
anhydrous Na2SO4, filtered, and evaporated to give a residue,
which was purified by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ) 1:12) to afford
compound 13 (11.4 g, 77%) as a colorless oil. IR (film) ν: 2936,
2860, 1748, 1717, 1439, 1353, 1201 cm-1; 1H NMR (CDCl3, 300
MHz) 8: 0.88 (3H, t, J ) 7.0 Hz), 1.20-1.90 (24H, m), 2.50
(2H, m), 3.37 (1H, dt, J ) 6.6, 9.7 Hz), 3.41 (1H, t, J ) 7.6
Hz), 3.46-3.52 (1H, m), 3.72 (3H, s), 3.68-3.76 (1H, m), 3.83-
3.95 (1H, m), 4.554.58 (1H, m) ppm; 13C NMR (CDCl3, 75 MHz)
δ: 13.96, 19.67, 22.43, 23.40, 25.49, 25.95, 27.41, 28.19, 28.67,
29.16, 29.60, 30.76, 31.52, 41.84, 52.18, 58.95, 62.29, 67.46,
98.83, 170.37, 205.33 ppm; MS (m/z, %): 370 (1.54), 287 (100),
85 (61.44). Anal. Calcd for C21H38O5: C, 68.07; H, 10.34.
Found: C, 67.81; H, 10.61.
1-Tetr a h yd r op yr a n yloxy-8-tetr a d eca n on e (14). To a
solution of 13 (10.76 g, 29.0 mmol) in methanol (75 mL) was
added 3% aqueous KOH (90 mL), the mixture was refluxed
for 4 h. After being cooled to room temperature, methanol was
evaporated and water (50 mL) was added. The mixture was
extracted with EtOAc (3 × 70 mL). The combined organic layer
was washed with water and brine, dried over anhydrous Na2-
SO4, filtered, and evaporated to give a residue, which was
purified by flash chromatography on silica gel (eluent: ethyl
acetate/petroleum ether ) 1:10) to afford compound 14 (9.07
g, 100%) as a colorless oil. IR (film) ν: 2933, 2857, 1714, 1465,
1368 cm-1; 1H NMR (CDCl3, 300 MHz) δ: 0.88 (3H, t, J ) 6.6
Hz), 1.20-1.90 (24H, m), 2.38 (2H, t, J ) 7.5 Hz), 3.38 (1H,
dt, J ) 6.6, 9.5 Hz), 3.48-3.54 (1H, m), 3.73 (1H, dt, J ) 6.7,
9.5 Hz), 3.83-3.90 (1H, m), 4.46-4.58 (1H, m) ppm; 13C NMR
(CDCl3, 75 MHz) δ: 14.08, 19.78, 22.56, 23.90, 23.94, 25.59,
26.17, 29.02, 29.29, 29.33, 29.78, 30.87, 31.68, 42.85, 42.91,
62.43, 67.68, 98.95, 211.68 ppm; MS (m/z, %): 313 (3.33), 229
(88.17), 85 (100), 43 (15.21). Anal.-Calcd for C19H36O3: C, 73.03;
H, 11.61. Found: C, 72.58; H, 11.90.
1
2987, 1454, 1370, 1243 cm-1; H NMR (CDCl3, 300 MHz) δ:
1.45 (6H, s), 1.67 (3H, s), 1.74 (1H, s.b), 3.55 (1H, dd, J ) 5.2,
10.7 Hz), 3.60 (1H, dd, J ) 3.4, 10.7 Hz), 3.90 (1H, ddd, J )
3.4, 5.2, 8.7 Hz), 4.00 (2H, s), 4.56, 4.61 (2H, AB, J AB ) 12.1
Hz), 4.63 8 (1H, t, J ) 8.7 Hz), 5.47 (1H, d, J ) 8.7 Hz), 7.25-
7.41 (5H, m) ppm; MS (m/z, %): 277 (0.85), 217 (15.77), 91
(100), 43 (36.39). Anal. Calcd for C17H24O4: C, 69.84; H, 8.27.
Found: C, 69.62; H, 8.47.
(2S,3S,4R,5S)-l-Hyd r oxy-2,3-ep oxy-2-m eth yl-4,5-O-iso-
p r op ylid en e-6-ben zyloxy-4,5-h exa n ed iol (7). To a suspen-
sion of 4 Å MS (1.5 g) in dry CH2Cl2 (40 mL) were added L-(+)-
DIPT (0.13 mL, 0.61 mmol), Ti(OPri)4 (0.15 mL, 0.51 mmol),
and TBHP (1.1 mL, 6.78 M in CH2Cl2, 7.46 mmol) at -20 °C
under argon. The mixture was stirred for 30 min, and then a
solution of 6 (1.50 g, 5.14 mmol) in CH2Cl2 (5 mL) was added.
After being stirred at -20 °C for 24 h, the reaction was
quenched with acetone (50 mL) containing 2% (v/v) water at
room temperature. The mixture was stirred for 3 h, filtered
through Celite, dried over anhydrous Na2SO4, filtered, and
evaporated to give a residue, which was purified by flash
chromatography on silica gel (eluent: ethyl acetate/petroleum
ether ) 1: 2) to afford compound 7 (1.15 g, 73%) as a colorless
oil and compound 8 (0.38 g, 24%). Compound 7: [R]1D7 ) -20.5
(c 1.09, CHCl3); IR (film) ν: 3460, 2988, 2935, 1455, 1372 cm-1
;
1H NMR (CDCl3, 300 MHz) δ: 1.24 (3H, s), 1.43 (3H, s), 1.46
(3H, s), 1.70-1.80 (1H, m), 3.14 (1H, d, J ) 8.0 Hz), 3.50 (1H,
dd, J ) 8.5, 12.3 Hz), 3.58 (1H, dd, J ) 3.3, 12.3 Hz), 3.62
(2H, d, J ) 4.7 Hz), 3.89 (1H, t, J ) 8.0 Hz), 4.08 (1H, dt, J )
4.7, 8.0 Hz), 4.55, 4.59 (2H, AB, J AB ) 11.9 Hz), 7.30-7.35
(5H, m) ppm; MS (m/z, %): 293 (M+ - CH3, 1.68), 221 (3.08),
149 (9.03), 91 (100), 43 (13.82); HRMS calcd for C17H2405
(M+): 308.1624, Found: 308.1646.
1-Hyd r oxy-8-tetr a d eca n on e (15). To a solution of 14 (9.07
g, 29.0 mmol) in methanol (100 mL) was added PTS‚H2O (20
mg), the mixture was stirred at room temperature for 4 h. The
solvent was evaporated to give a residue, which was purified
by flash chromatography on silica gel (eluent: ethyl acetate/
petroleum ether ) 1:2) to afford compound 15 (6.60 g, 99%)
1
as a white solid. mp: 51-52 °C (lit.:11a 52-53 °C); H NMR
(2S,3S,4R,5S)-1-ter t-Bu tyld im eth ylsilyloxy-2,3-ep oxy-
2-m e t h yl-4,5-O-isop r op yid e n e -6-h yd r oxy-4,5-h e xa n e -
d iol (9). To a solution of 7 (610 mg, 1.98 mmol) in CH2Cl2 (10
mL) were added DMAP (10 mg, 0.078 mmol), TBDMSCl (600
mg, 3.98 mmol), and triethylamine (0.68 mL, 4.88 mmol). After
being stirred at room temperature for 24 h, the reaction
mixture was diluted with ethyl acetate (50 mL), washed with
1 N HCl, water, and brine, dried over anhydrous Na2SO4,
filtered, and evaporated to give a residue, which was purified
by flash chromatography on silica gel (eluent: ethyl acetate/
petroleum ether ) 1:10) to afford a TBS-protected product (671
mg, 80%) as a colorless oil. The above product was hydroge-
nated over 20% Pd(OH)2/C (67 mg) in ethyl acetate/methanol
(4:1, 50 mL) at room temperature for 4 h. The mixture was
filtered and evaporated to give a residue, which was purified
by flash chromatography on silica gel (eluent: ethyl acetate/
petroleum ether ) 1:2) to afford compound 9 (410 mg, 97%)
as a colorless oil. [R]2D0 ) -14.9 (c 1.75, CHCl3); IR (film) ν:
3485, 2956, 2932, 1464, 1373, 1255 cm-1; 1H NMR (CDCl3, 300
MHz) 8: 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.35 (3H, s),
1.43 (3H, s), 1.47 (3H, s), 2.00 (1H, b), 2.95 (1H, d, J ) 7.8
Hz), 3.51, 3.63 (2H, AB, J AB ) 11.2 Hz), 3.55-3.65 (1H, m),
3.85-3.90 (1H, m), 3.89 (1H, dd, J ) 7.8, 8.3 Hz), 3.98 (1H,
dt, J ) 3.3, 8.3 Hz) ppm; MS (m/z, %): 317 (M+ - CH3, 4.47),
145 (70.96), 131 (94.31), 75 (100), 59 (78.14), 43 (58.96); HRMS
calcd for C15H29O5Si (M+ - CH3): 317.1784, Found: 317.1771.
(CDCl3, 300 MHz) δ: 0.87 (3H, t, J ) 7.0 Hz), 1.26-1.60 (18H,
m), 2.37 (2H, t, J ) 7.3 Hz), 3.62 (2H, t, J ) 6.6 Hz) ppm.
(2S,3S,4R,5S,6Z)-1-ter t-Bu tyldim eth ylsilyloxy-2,3-epoxy-
2-m eth yl-4,5-O-isop r op ylid en e-13-(2′-h exyl-1′,3′-d ioxola n -
2′-yl)-6-en e-4,5-tr id eca n ed iol (17). To a solution of oxalyl
chloride (1.1 mL, 12.65 mmol) in CH2Cl2 (50 mL) was added
DMSO (1.8 mL, 25.30 mmol) at -78 °C under argon. The
mixture was stirred at -78 °C for 10 min, and then a solution
of 9 (2.1 g, 6.32 mmol) in CH2Cl2 (15 mL) was added. The
mixture was stirred at -78 °C for 1 h, triethylamine (8.8 mL,
63.2 mmol) was added, and the stirring was allowed to
continue for 20 min. The reaction was quenched with saturated
NaH2PO4 (25 mL), and the mixture was allowed to warm to
room temperature and then extracted with CH2Cl2 (3 × 30
mL). The combined organic layer was washed with water and
brine, dried over anhydrous Na2SO4, filtered, and evaporated
to give crude aldehyde (1.82 g), which was used directly in
the next step without purification. To a solution of 16 (4.0 g,
6.7 mmol) in dry THF (40 mL) was added 2.2 mL of n-BuLi
(4.4 mmol, 2.0 M in hexane) at room temperature under argon.
The mixture was stirred for 10 min, and then a solution of
the above crude aldehyde (1.0 g, -3.0 mmol) in THF (10 mL)
was added to the mixture at -78 °C. After being stirred for 1
h at -78 °C, the mixture was allowed to warm to room
temperature and stirred overnight. The reaction was quenched
with saturated NH4Cl (30 mL), and the mixture was extracted
with ethyl acetate (3 × 20 mL). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered,
and evaporated to give a residue, which was purified by flash
2-(6′-Tet r a h yd r op yr a n yloxyh exyl)-3-k et o-l-n on a n oic
Acid Meth yl Ester (13). To a solution of 11 (7.4 g, 39.8 mmol)
in acetone (210 mL) and DMF (9.45 mL) were added 12 (13.6

9118 J . Org. Chem., Vol. 65, No. 26, 2000
Liu et al.
chromatography on silica gel (eluent: ethyl acetate/petroleum
ether ) 1:20) to afford compound 17 (1.46 g, 85%) as a colorless
oil. [R]2D0 ) +15.1 (c 1.39, CHCl3); IR (film) ν: 2932, 1464,
was diluted with ethyl acetate, dried over anhydrous Na2SO4,
filtered, and evaporated. The residue was stirred with K2CO3
(120 mg, 0.87 mmol) in methanol (20 mL) at room temperature
for 20 min. The mixture was filtered through Celite, and the
filtrate was evaporated to give a residue, which was purified
by flash chromatography on silica gel (eluent: ethyl acetate/
petroleum ether ) 1:1) to afford compound 20 (406 mg, 82%)
as a colorless oil. [R]2D0 ) -22.4 (c 1.02, CHCl3); IR (film) ν:
1
1372, 1252 cm-1; H NMR (CDCl3, 300 MHz) δ: 0.05 (3H, s),
0.06 (3H, s), 0.88 (3H, t, J ) 7.0 Hz), 0.89 (9H, s), 1.25 (3H, s),
1.25-1.43 (16H, m), 1.43 (3H, s), 1.47 (3H, s), 1.56-1.63 (4H,
m), 1.95-2.25 (2H, m), 2.97 (1H, d, J ) 7.8 Hz), 3.53, 3.60
(2H, AB, J AB ) 11.4 Hz), 3.62 (1H, t-like, J ) 8.3 Hz), 3.92
(4H, s), 4.65 (1H, t-like, J ) 8.8 Hz), 5.37 (1H, dd, J ) 9.2,
10.8 Hz), 5.67-5.75 (1H, m) ppm; 13C NMR (CDCl3, 75 MHz)
δ: -5.39, -5.35, 14.10, 15.37, 18.39, 22.62, 23.79, 23.85, 25.91,
27.05, 27.10, 27.74, 29.24, 29.59, 29.64, 29.81, 31.86, 37.15,
37.19, 59.87, 60.53, 64.90, 67.18, 73.99, 80.13, 109.83, 111.85,
125.68, 136.49 ppm; MS (m/z, %): 553 (M+ - CH3), 409 (1.58),
215 (34.09), 157 (100), 127 (18.21). Anal. Calcd for C32H60O6-
Si: C, 67.56; H, 10.63. Found: C, 67.48; H, 10.87.
(2S,3S,4R,5S,6Z)-l-Hyd r oxy-2,3-ep oxy-2-m eth yl-4,5-O-
isop r op ylid en e-13-(2′-h exyl-1′,3′-d ioxola n -2′-yl)-6-en e-4,5-
tr id eca n ed iol (18). To a solution of 17 (2.70 g, 4.75 mmol) in
THF (60 mL) was added 7.20 mL of n-Bu4NF (7.20 mmol, 1 M
in THF). After being stirred at room temperature for 10 min,
the mixture was diluted with ethyl acetate, washed with water
and brine, dried over anhydrous Na2SO4, filtered, and evapo-
rated to give a residue, which was purified by flash chroma-
tography on silica gel (eluent: ethyl acetate/petroleum ether
) 1:4) to afford compound 18 (2.05 g, 95%) as a colorless oil.
[R]2D0 ) +15.4 (c 1.02, CHCl3); IR (film) ν: 3473, 2931, 1458,
1373 cm-1; 1H NMR (CDCl3, 300 MHz) δ: 0.88 (3H, t, J ) 7.0
Hz), 1.27 (3H, s), 1.20-1.50 (16H, m), 1.45 (3H, s), 1.48 (3H,
s), 1.50-1.70 (4H, m), 1.75-1.95 (1H, b), 2.00-2.20 (2H, m),
3.17 (1H, d, J ) 7.9 Hz), 3.55, 3.66 (2H, AB, J AB ) 12.4 Hz),
3.64 (1H, t-like, J ) 8.4 Hz), 3.93 (4H, s), 4.67 (1H, t-like, J )
9.0 Hz), 5.38 (1H, dd, J ) 9.3, 10.8 Hz), 5.70-5.78 (1H, m)
ppm; MS (m/z, %): 397 (1.24), 311 (18.11), 157 (100), 43 (28.95).
Anal. Calcd for C26H46O6: C, 68.69; H, 10.20. Found: C, 68.23;
H, 10.62.
3314, 2932, 1757, 1714, 1459, 1374, 1246 cm-1 1H NMR
;
(CDCl3, 300 MHz) 6: 0.86 (3H, t, J ) 6.8 Hz), 1.20-1.45 (15H,
m), 1.47 (6H, s), 1.51-1.56 (4H, m), 2.04-2.25 (2H, m), 2.37
(4H, t, J ) 7.2 Hz), 3.46, 3.73 (2H, AB, J AB ) 12.6 Hz), 3.73
(1H, d, J ) 9.0 Hz), 3.99 (1H, s), 4.79 (1H, b), 4.93 (1H, t, J )
9.0 Hz), 5.34 (1H, dd, J ) 9.0, 10.8 Hz), 5.73 (1H, dt, J ) 7.7,
10.8 Hz) ppm; 13C NMR (CDCl3, 75 MHz) δ: 14.03, 22.44,
22.49, 23.72, 23.86, 26.14, 27.41, 27.77, 28.87, 28.93, 29.03,
29.32, 31.61, 42.68, 42.85, 61.49, 65.91, 73.46, 76.70, 80.72,
110.53, 124.24, 138.63, 158.77, 211.69 ppm; MS (m/z, %): 454
(3.31), 452 (3.43), 438 (18.30), 395 (32.98), 113(56.05), 100
(100), 43 (88.43); HRMS calcd for C24H40NO6 (M+ - CH3):
438.2856, Found: 438.2855.
(1R,2S,3Z,4′S,5′R)-1-(4′-Meth yl-4′-m eth oxyca r bon yl-2′-
oxa zolid in on -5′-yl)-1,2-O-isop r op ylid en e-11-k et o-3-en e-
1,2-h ep ta d eca n ed iol (21). To a solution of 20 (100 mg, 0.22
mmol) in DMF (1.2 mL) was added PDC (615 mg, 1.63 mmol)
slowly. After being stirred at room temperature for 30 h, the
reaction was quenched with water (3 mL). The mixture was
extracted with ether (3 × 10 mL). The combined organic layer
was washed with water and brine, dried over anhydrous Na2-
SO4, filtered, and evaporated. The residue was dissolved in
ether (2 mL), and a solution of CH2N2 in ether (3.5 mL, - 1.0
mmol) was added at 0 °C. After being stirred for 5 min, the
reaction was quenched with acetic acid. The mixture was
diluted with ethyl acetate, washed with saturated NaHCO3,
water, and brine, dried over anhydrous Na2SO4, filtered, and
evaporated to give a residue, which was purified by flash
chromatography on silica gel (eluent: ethyl acetate/petroleum
ether ) 1:2) to afford compound 21 (83 mg, 78%) as a colorless
oil. [R]2D0 ) -53.4 (c 1.16, CHCl3); IR (film) ν: 3321, 2931,
1778, 1713, 1459, 1372, 1252 cm-1; 1H NMR (CDCl3, 300 MHz)
δ: 0.88 (3H, t, J ) 7.0 Hz), 1.20-1.40 (12H, m), 1.36 (3H, s),
1.39 (3H, s), 1.52-1.60 (4H, m), 1.62 (3H, s), 2.00-2.25 (2H,
m), 2.38 (2H, t, J ) 7.4 Hz), 2.39 (2H, t, J ) 7.4 Hz), 3.77 (3H,
s), 3.89 (1H, dd, J ) 0.7, 8.3 Hz), 4.16 (1H, d, J ) 0.7 Hz),
4.88 (1H, dd, J ) 8.3, 9.1 Hz), 5.37 (1H, dd, J ) 9.1, 10.8 Hz),
5.76 (1H, dt, J ) 7.7, 10.8 Hz), 5.86 (1H, s) ppm; 13C NMR
(CDC13, 75 MHz) 8: 14.07, 22.54, 23.76, 23.91, 26.25, 26.95,
27.21, 27.76, 28.91, 28.98, 29.08, 29.41, 31.66, 42.73, 42.90,
53.01, 62.58, 72.42, 78.10, 80.87, 109.77, 124.78, 137.94,
157.28, 171.25, 211.68 ppm; MS (m/z, %): 482 (2.27), 424
(18.01), 361 (44.30), 97 (45.44), 43 (100); HRMS calcd for
(1R,2R,3S,4Z,4′′)-1-(4′-Meth yl-2′-tr ich lor om eth yl-2′-ox-
azolin -4′-yl)-1-h ydr oxy- 2,3-O-isopr opyliden e-11-(2′′-h exyl-
1′,3′′-d ioxola n -2 -yl)-4-en e-2,3-u n d eca n ed iol (19). To a
solution of 18 (500 mg, 1.10 mmol) in CH2Cl2 (10 mL) were
added trichloroacetonitrile (0.15 mL, 1.49 mmol) and DBU
(0.030 mL, 0.20 mmol) at 0 °C under N2. After being stirred
at 0 °C for 30 min, the mixture was diluted with ethyl acetate,
washed with water and brine, dried over anhydrous Na2SO4,
filtered, and evaporated. The residue was filtered through a
short silica gel column to afford crude epoxytrichloroacet-
imidate (633 mg), which was used immediately in the next
step. To a stirred solution of the above epoxytrichloroacet-
imidate in CH2Cl2 (15 mL) was added BF3‚OEt2 (0.067 mL,
0.53 mmol) at -23 °C under argon. After being stirred at -23
°C for 30 min, the mixture was diluted with ethyl acetate,
washed with saturated NaHCO3, water, and brine, dried over
anhydrous Na2SO4, filtered, and evaporated to give a residue,
which was purified by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ) 1:5) to afford com-
pound 19 (524 mg, 80%) as a colorless oil. [R]2D0 ) 2.0 (c 1.04,
C
26H43NO7 (M+): 481.3040, Found: 481.3029.
(4S,5R,1′R,2′S,3′Z)-4-Meth yl-5-(1′,2′-d ih yd r oxy-11′-k eto-
3′-en e-l′-h ep ta d ecyl)-2-oxa zolid in on e-1-ca r boxylic a cid
γ-la cton e (22). A mixture of 21 (35 mg, 0.073 mmol) and
PTS-H2O (33 mg, 0.174 mmol) in 70% aqueous ethanol (3 mL)
was refluxed for 2 h under N2. After being cooled to room
temperature, the mixture was diluted with ether, dried over
anhydrous Na2SO4, filtered, and evaporated to give a residue,
which was purified by flash chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ) 1:1) to afford com-
pound 22 (22 mg, 74%) as a colorless oil. [R]2D0 ) +2.6 (c 0.97,
CHCl3); IR (film) ν: 3516, 3242, 2932, 1761, 1736, 1708, 1467,
1369 cm-1; 1H NMR (CDCl3, 300 MHz) δ: 0.88 (3H, t, J ) 6.9
Hz), 1.20-1.45 (12H, m), 1.51-1.60 (4H, m), 1.60 (3H, s), 2.16-
2.22 (2H, m), 2.39 (4H, t, J ) 7.4 Hz), 2.94 (1H, s.b), 4.55 (1H,
dd, J ) 4.7, 6.9 Hz), 4.77 (1H, d, J ) 4.7 Hz), 4.85 (1H, t-like,
J ) 7.9 Hz), 5.43 (1H, t-like, J ) 10.0 Hz), 5.72 (1H, dt, J )
7.3, 10.8 Hz), 6.62 (1H, s) ppm; MS (m/z, %): 409 (M+, 15.63),
391 (M+ - H2O, 8.35), 347 (84.61), 113 (67.64), 57 (52.83), 43
(100).
CHCl3); IR (film) ν: 3466, 2933, 1660, 1457, 1373, 1240 cm-1
;
1H NMR (CDCl3, 300 MHz) δ: 0.88 (3H, t, J ) 7.0 Hz), 1.20-
1.42 (16H, m), 1.37 (3H, s), 1.43 (3H, s), 1.44 (3H, s), 1.56-
1.62 (4H, m), 2.04-2.25 (2H, m), 2.41 (lH, d, J ) 6.9 Hz), 3.57
(1H, d-like, J ) 6.2 Hz), 3.81 (1H, dd, J ) 8.5, 1.1 Hz), 3.92
(4H, s), 4.21, 4.88 (2H, AB, J AB ) 9.0 Hz), 4.88 (1H, t-like, J )
9.2 Hz), 5.35 (1H, ddt, J 1.4, 9.2, 10.8 Hz), 5.73 (1H, dt, J )
7.2, 10.8 Hz) ppm; MS (m/z, %): 598 (M+), 540 (4.10), 454
(6.95), 157 (100), 43 (21.02).
(1R,2S,3Z,4′R,5′R)-1-(4′-Meth yl-4′-h yd r oxym eth yl-2′-ox-
a zolid in on -5′-yl)-1,2-O-isop r op ylid en e-11-k eto-3-en e-1,2-
h ep ta d eca n ed iol (20). To a solution of 19 (655 mg, 1.10
mmol) in CH2Cl2 (8 mL) was added pyridine (0.113 mL, 1.40
mmol). The mixture was cooled to -35 °C, and then a solution
of triphosgene (138 mg, 0.47 mmol) in CH2Cl2 (2 mL) was
added dropwise. The mixture was allowed to warm to room
temperature slowly (∼4 h), and then water (0.060 mL, 3.30
mmol) was added. After being stirred for 30 min, the mixture
(4S,5R,1′R,2′S,3′E)-4-Meth yl-5-(1′,2′-d ih yd r oxy-11′-k eto-
3′-en e-1′-h eptadecyl)-2-oxazolidin on e-1-car boxylic Acidγ-
la cton e (23). A mixture of 21 (78 mg, 0.162 mmol) and phenyl

Total Synthesis of Sphingofungin
J . Org. Chem., Vol. 65, No. 26, 2000 9119
disulfide (68 mg, 0.31 mmol) in cyclohexane (15 mL) and 1,4-
dioxane (0.9 mL) was irradiated with a 75 W Hg bulb for 24 h
under N2. Evaporation was followed by purification by flash
chromatography on silica gel (eluent: ethyl acetate/petroleum
ether ) 1:2) to afford E-21 (62 mg, 79%) as a colorless oil, and
Z-21 (13 mg, 17%) was recovered. A mixture of E-21 (52 mg,
0.108 mmol) and PTS‚H2O (50 mg, 0.263 mmol) in 70%
aqueous ethanol (3 mL) was refluxed for 2 h under N2. After
being cooled to room temperature, the mixture was diluted
with ether, dried over anhydrous Na2SO4, filtered, and evapo-
rated to give a residue, which was purified by flash chroma-
tography on silica gel (eluent: ethyl acetate/petroleum ether
) 3:5) to afford compound 23 (36 mg, 81%) as a colorless oil.
[R]2D0 ) -27.4 (c 1.59, CHCl3); IR (film) ν: 3307, 2930, 1771,
acid and evaporated. The residue was purified by chromatog-
raphy on Dowex-50 H+ resin (eluent: 1 N NH3) to give a white
solid, which was dissolved in methanol (1 mL). To the mixture
was added IRC-76 H+ resin (50 mg), and the mixture was
stirred for 30 min, filtered, and evaporated to give a residue,
which was purified by flash chromatography on silica gel
(eluent: methanol/chloroform/H2O ) 3:10:1, lower layer) to
afford compound 2 (4 mg, 51%) as a white solid. mp: 145-
147 °C; [R]2D0 ) + 0.91 (c 0.22, CH3OH); IR (film) ν: 3369,
3209, 2930, 2855, 1710, 1630, 1497, 1466, 1404, 1368, 1106,
972 cm-1; 1H NMR (CD3OD, 300 MHz) 5: 0.89 (3H, t, J ) 6.9
Hz), 1.20-1.43 (12H, m), 1.49 (3H, s), 1.45-1.59 (4H, m), 2.02-
2.09 (2H, m), 2.43 (4H, t, J ) 7.5 Hz), 3.67 (1H, d, J ) 7.2
Hz), 3.87 (1H, s), 4.10 (1H, dd, J ) 7.2, 7.6 Hz), 5.46 (1H, dd,
J ) 7.6, 15.4 Hz), 5.77 (1H, dt, J ) 6.6, 15.4 Hz) ppm; 13C
NMR (CD3OD, 75 MHz) δ: 14.65, 22.07, 23.86, 25.17, 25.18,
30.29, 30.32, 30.44, 30.47, 33.10, 33.72, 43.78, 43.80, 67.06,
72.81, 75.99, 76.48, 130.50, 135.95, 170.50, 214.67 ppm; MS
(m/z, %): 383 (M+ - H2O, 0.52), 366 (1.94), 295 (2.13), 256
(14.41), 131 (16.78), 86 (88.42), 85 (100), 73 (36.77), 43 (56.56).
HRMS calcd for C21H37NO5 (M+ - H2O): 383.2671, Found:
383.2678.
1709, 1459, 1382 cm-1 1H NMR (CDCl3, 300 MHz) δ: 0.88
;
(3H, t, J ) 7.0 Hz), 1.23-1.45 (12H, m), 1.51-1.60 (4H, m),
1.61 (3H, s), 2.07 (2H, q, J ) 6.8 Hz), 2.39 (4H, t, J ) 7.9 Hz),
2.81 (1H, b), 4.47 (1H, dd, J ) 4.4, 7.6 Hz), 4.54-4.59 (1H,
m), 4.80 (1H, d, J ) 4.4 Hz), 5.53 (1H, ddt, J ) 1.3, 6.4, 15.5
Hz), 6.01 (1H, dt, J ) 6.8, 15.5 Hz), 6.52 (1H, s) ppm; 13C NMR
(CDCl3, 75 MHz) 6: 14.03, 18.98, 22.50, 23.75, 23.88, 28.50,
28.81, 28.94, 28.95, 31.61, 32.23, 42.70, 42.88, 62.03, 70.40,
81.04, 83.09, 125.00, 137.03, 156.12, 174.79, 211.97 ppm; MS
(m/z, %): 409 (M+, 1.14), 348 (13.74), 131 (30.16), 113 (61.56),
43 (100); HRMS calcd for C22H35NO6 (M+): 409.2465, Found:
409.2491
Ack n ow led gm en t. This work was supported by the
National Natural Science Foundation of China. The
authors thank Prof. Wei-Shan Zhou for helpful
discussion.
Sp h in gofu n gin F (2). To a solution of 23 (8 mg, 0.020
mmol) in ethanol (1 mL) was added 2 N aqueous NaOH (1
mL). The mixture was refluxed for 5 h. After being cooled to
room temperature, the mixture was neutralized with acetic
J O005612G