Synthesis of sphingosine relatives, XXI. - Synthesis of sphingofungin D and its three diastereomers

Article abstract of DOI:10.1002/(SICI)1099-0690(199908)1999:8<1795::AID-EJOC1795>3.0.CO;2-Y

Sphingofungin D [(2S,3R,4R,5S,14R)-1] and its three diastereomers were synthesized by starting from (R)-1,2 epoxyoctane [(R)-7], 1-heptyne (8) and N-acetyl-D-mannosamine (9).

Full text of DOI:10.1002/(SICI)1099-0690(199908)1999:8<1795::AID-EJOC1795>3.0.CO;2-Y

FULL PAPER
Synthesis of Sphingosine Relatives, XXI[°]
Synthesis of Sphingofungin D and Its Three Diastereomers
Ken Otaka,[a,b] and Kenji Mori*[a,c]
Keywords: Antifungal agents / Aspergillus fumigatus / Enzyme inhibitors / Sphingofungins / Sphingosines
Sphingofungin D [(2S,3R,4R,5S,14R)-1] and its three dia-
stereomers were synthesized by starting from (R)-1,2-
epoxyoctane [(R)-7], 1-heptyne (8) and N-acetyl-D-
mannosamine (9).
In 1992 VanMiddlesworth et al. reported the isolation[1]
and structure elucidation[2] of sphingofungins, a new family
of antifungal metabolites produced by Aspergillus fumigatus
ATCC 20857. These compounds are potent and specific in-
hibitors of serine palmitoyl transferase. The structures 1, 2
and 3 assigned to sphingofungins D, B and A, respectively,
show their similarity to sphingolipids. Their stereochem-
istry at C-14 was not reported initially,[2] but in 1995, Chida
et al. elucidated it to be (R) by examining the ozonolysis
product of natural sphingofungin C (2, OAc instead of OH
at C-5).[3]
In continuation of our synthetic studies on sphingosine
relatives, we undertook a synthesis of both the (14R) and
(14S) isomers of 4. Because 4 derived from the natural
sphingofungin C has been converted into sphingofungin D
(1), B (2) and A (3),[2] the synthesis of 4 implies that of
these three sphingofungins. In this paper, we will report the
synthesis of four diastereomers of 4, and their conversion
into sphingofungin D and its three diastereomers.[4] In
1996, a synthesis of sphingofungin B was reported by Ko-
bayashi et al.[5][6]
Our retrosynthetic analysis as shown in Scheme 1 sug-
gests that 4 may be synthesized by the coupling reaction of
5 (nonpolar part) and 6 (polar part). Optically active 5 will
be derived from (R)-1,2-epoxyoctane (7) and 1-heptyne (8).
On the other hand, preparation of 6 will be possible from
N-acetyl--mannosamine (9).
Scheme 2 summarizes the preparation of the nonpolar
building block 15. Cleavage of (R)-7 (91% ee; purchased
from Japan Energy Co.) with the acetylide from 8 yielded
10 and 11. After separation by column chromatography, 10
was subjected to the acetylene zipper reaction[7] to give
crystalline (R)-12, m.p. 42Ϫ43°C, [α]D ϭ Ϫ0.86 (c ϭ 1.7
in Et2O). The corresponding TBS ether (R)-13 was metal-
23
Scheme 1. Structures of sphingofungins and their retrosynthetic
analysis
[°] Part XX: H. Takikawa, S. Muto, K. Mori, Tetrahedron 1998,
54, 3141Ϫ3150.
lated with tri(n-butyl)tin hydride[8] to give the alkenylstan-
nane (R)-14, which furnished the alkenyl iodide (R)-15 by
treatment with iodine in diethyl ether.[9] The overall yield
of (R)-15 based on 7 was 61% after 5 steps. Mitsunobu in-
version[10] smoothly converted (R)-12 into (S)-12, m.p.
41Ϫ42°C, [α]D ϭ ϩ0.88 (c ϭ 1.7 in Et2O). Similarly, (S)-
12 was converted into (S)-15 in 49% overall yield based on
7 (7 steps).
[a]
Department of Agricultural Chemistry, The University of
Tokyo,
Yayoi 1-1-1, Bunkyo-ku, Tokyo 113Ϫ8657, Japan
[b]
Research fellow on leave from Sumitomo Chemical Co.
(1993Ϫ1995). Present address: 2Ϫ1, Takatsukasa 4-chome,
Takarazuka, Hyogo 665Ϫ8555, Japan
22
[c]
New address: Department of Chemistry, Faculty of Science,
Science University of Tokyo, Kagurazaka 1Ϫ3, Shinjuku-ku,
Tokyo 162-8601, Japan; Fax: (internat.) ϩ 81-3/3235-2214
Eur. J. Org. Chem. 1999, 1795Ϫ1802
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0808Ϫ1795 $ 17.50ϩ.50/0
1795

K. Otaka, K. Mori
FULL PAPER
Synthesis of the polar building block 6 is shown in
Scheme 3. N-Acetyl--mannosamine (9) was oxidized with
bromine in water to give 16.[11] Protection of the vic-diol
system of 16 as benzylideneacetal 17[12] was followed by
further protection of the remaining hydroxy group of 17 as
TBS ether to yield 18.[13] Hydrogenolytic removal of the
benzylidene protective group of 18 by transfer hydrogen-
ation with cyclohexene and the Pearlman palladium[14] gave
19. In the case of acetonide group instead of benzylidene
one for the vic-diol protection, the selective deprotection of
acetonide group did not proceed very smoothly under sev-
eral conditions so far examined. The diol 19 was oxidized
with sodium periodate to give the aldehyde 6 as a crude
gum. The overall yield of 6 was 21% based on 9 (5 steps).
Coupling of 6 with (R)-15 or its equivalent was examined
under several different conditions. The best result was ob-
tained when the coupling was carried out with chro-
mium(II) chloride and nickel chloride in DMSO[15][16] to
give in 41% yield the desired product 20 as a diastereomeric
mixture as shown in Scheme 4. In the case of lithium or
Scheme 2. Synthesis of the nonpolar building block 15; reagents:
(a) 1) 1-heptyne (8), nBuLi, BF3·OEt2, THF; 2) (R)-7 (80%); (b)
Li, tBuOK, H2N[CH2]3NH2 (88%); (c) TBSCl, imidazole, DMF
(quant.); (d) (nBu)3SnH, AIBN (92%); (e) I2, Et2O (95%); (f) 1)
EtO2CNϭNCO2Et, Ph3P, PhCO2H; 2) K2CO3, MeOH (80%)
Scheme 4. Synthesis of the four stereoisomers of 4; reagents: (a)
CrCl2 (6.0 equiv.), NiCl2 (0.04 equiv.), DMSO (41%); (b) HF aq.,
MeCN; (c) Me2C(OMe)2, TsOH, DMF, chromatog. sepn. [28% of
(2S,3R,4R,5S,14R)-4 based on 20, 46% of (2S,3R,4R,5R,14R)-4 ba-
sed on 20]
Scheme 3. Synthesis of the polar building block 6; reagents: (a)
Br2, H2O (41%); (b) PhCH(OMe)2, HBF4·OEt2, DMF (98%); (c)
TBSOTf, 2,6-lutidine, CH2Cl2 (65%); (d) Pd(OH)2, cyclohexene,
EtOH (85%); (e) NaIO4, H2O, CH2Cl2 (crude 95%)
1796
Eur. J. Org. Chem. 1999, 1795Ϫ1802

Synthesis of Sphingosine Relatives, XXI
FULL PAPER
distinction between the diastereomers (see Experimental
Section).
The four diastereomers of 4 were then converted into
sphingofungin D (1) and its three diastereomers as shown
in Scheme 5. The (2S,3R,4R,5S,14R) isomer of 4 was re-
fluxed in aqueous acetic acid and then in aqueous methanol
to give (2S,3R,4R,5S,14R)-1 (sphingofungin D). Under
these conditions only the (5S)-trihydroxylactone intermedi-
ate 21 was hydrolyzed even in the presence of a small
amount of the (5R) isomer. In the same manner,
(2S,3R,4R,5S,14S)-1 was derived from the corresponding
isomer of 4. In the case of the (5R) isomer of 4, the trihy-
droxylactone intermediate 21 could be purified by recrysral-
lization, which furnished (5R)-1 after hydrolysis with LiOH.
Figure 1. Determination of the stereochemistry of 4 by 300-MHz
1H-NMR analysis (CDCl3)
aluminium as a metal of 5 (see Scheme 1), the yield of 20
was very low. Removal of the TBS protective group of 20
afforded 21. The corresponding diastereomeric mixture of
the acetonide 4 could be separated by silica gel chromatog-
raphy to give a more polar compound (28% yield based on
20) and a less polar one (46% yield based on 20). Careful
1
examination of their 300-MHz H-NMR spectra (see Fig-
ure 1) revealed the spectrum of the more polar product to
be identical with that of (2S,3R,4R,5S)-4 derived from
sphingofungin C.[3] Especially the magnitude of the coup-
ling constants J2,3, J3,4 and J4,5 of the more polar product
were in good agreement with the values reported for
(2S,3R,4R,5S)-4.[3]
Scheme 5. Synthesis of sphingofungin D and its three stereoiso-
mers; reagents: (a) 1) AcOH, THF, H2O; 2) MeOH, H2O (59%);
(b) AcOH, THF, H2O (95%); (c) LiOH, THF, H2O (78%)
The
more
polar
material
was
therefore
(2S,3R,4R,5S,14R)-4, while the less polar one must be
For the determination of the stereochemistry at C-14, we
(2S,3R,4R,5R,14R)-4. The coupling of 6 with (S)-15, fol- prepared both the enantiomers of 1,8-tetradecanediol (23)
lowed by deprotection-protection and diastereomer separ- as shown in Scheme 6. The alkenylstannane (R)-14 was
ation by chromatography, yielded (2S,3R,4R,5S,14S)-4 and hydrodestannylated to (R)-22 by contact with silica gel. Re-
its (5R) isomer. It was impossible to find out any notable ductive work up of the ozonide of (R)-22, followed by re-
differences between the 1H-NMR spectrum of moval of the silyl protective group, gave the diol (R)-23. In
(2S,3R,4R,5S,14R)-4 and that of the (14S) isomer. Their the same manner (S)-23 was prepared from (S)-14. Both
[α]D values were also quite similar and did not allow the the enantiomers of 23 were converted into bis{O-[(S)-(ϩ)-
Eur. J. Org. Chem. 1999, 1795Ϫ1802
1797

K. Otaka, K. Mori
FULL PAPER
1
was chromatographed on silica gel (700 g). Elution with n-hexane/
ethyl acetate (25:1) gave 29.5 g (80%) of 10; nD20 ϭ 1.4595, [α]D20 ϭ
Ϫ2.50 (c ϭ 1.22 in CHCl3). Ϫ IR (film): ν˜ ϭ 3360 cmϪ1 (m, OH),
O-acetylmandelyl]} derivatives 24, and their 300-MHz H-
NMR spectra were examined. As reported by Chida et al.[3]
the methylene signals at C-1 were clearly different between
the enantiomers, and those of the (8R) isomer were iden-
tical with the reported data of 24 derived from sphingofun-
gin C.
1
1050 (m, CϪO). Ϫ H NMR (90 MHz in CDCl3): δ ϭ 0.40Ϫ1.00
(m, 6 H), 1.00Ϫ1.80 (m, 16 H), 1.91 (br. s, 1 H, OH), 2.00Ϫ2.70
(m, 4 H, CH2CCCH2), 3.69 (tt, J ϭ 5.7, 5.7 Hz, 1 H, 7-H). Ϫ
C15H28O (224.4): calcd. C 80.29, H 12.58; found C 80.54, H 12.74.
In conclusion, we synthesized the sphingofungin D (1)
and its three diastereomers at C-5 and C-14 by coupling
reaction of the polar part 6 and the nonpolar part (R)-[or
(S)-]15 as the key step. Thanks to the previous conversion
of 1 to spingofungin B (2) and A (3),[3] the present synthesis
of 1 can be regarded as a formal total synthesis of 2 and 3.
The less polar fractions gave 1.88 g (5%) of (R)-8-hydroxymethyl-
6-tetradecyne (11). Ϫ 1H NMR (90 MHz in CDCl3): δ ϭ 0.50Ϫ1.00
(m, 6 H), 1.00Ϫ1.80 (m, 16 H), 1.90Ϫ2.60 (m, 2 H, 5-H), 2.70Ϫ3.00
(m, 4 H, OCH2, OH, 8-H).
(R)-14-Pentadecyn-7-ol [(R)-12]: Under a slightly positive pressure
of argon, lithium (4.07 g, 0.586 mol, washed free of mineral oil
with n-hexane) was added to dry 1,3-diaminopropane (300 mL).
The mixture was heated and stirred at 70°C for approximately 2 h
until the blue color had discharged, and a milky white suspension
of the lithium salt was obtained. The mixture was cooled to 10°C
and potassium tert-butoxide (38.1 g, 0.339 mol) was added all at
once, affording a pale yellow solution. After stirring for 15 min at
room temp., addition of 10 (18.6 g, 82.8 mmol) in one portion re-
sulted in the reaction mixture turning orange with a suspended
white solid. Stirring was continued for a further 5 h and the mixture
was poured into a mixture of ice water (800 mL) and diethyl ether
(400 mL). The organic layer was separated and the aqueous layer
was extracted with diethyl ether (3 times). The combined organic
layers were washed successively with water, saturated aqueous am-
monium chloride and brine, dried with anhydrous magnesium sul-
fate and concentrated in vacuo. The residue was purified by chro-
matography on silica gel [400 g, eluent: n-hexane/ethyl acetate
(12:1)] followed by recrystallization from n-hexane to give 16.3 g
(88%) of (R)-12; m.p. 42Ϫ43°C, [α]D23 ϭ Ϫ0.86 (c ϭ 1.70 in Et2O).
Ϫ IR (KBr): ν˜ ϭ 3300 cmϪ1 (s, OH), 2120 (w, CϵCH), 1290 (w).
Ϫ
1H NMR (90 MHz in CDCl3): δ ϭ 0.88 (t, J ϭ 5.0 Hz, 3 H,
Scheme 6. Synthesis of optically active tetradecane-1,8-diol (23);
reagents: (a) silica gel, n-hexane (quant.); (b) 1) O3, MeOH then
NaBH4, EtOH, H2O; 2) HF aq., MeCN (85%); (c) (S)-(ϩ)-O-ace-
tylmandelic acid, DCC, DMAP, CH2Cl2 (89%)
Me), 1.00Ϫ1.85 (m, 20 H), 1.94 (t, J ϭ 2.4 Hz, 1 H, CϵCH),
2.00Ϫ2.30 (m, 3 H, CϵCϪCH2, OH), 3.35Ϫ3.80 (m, 1 H, 7-H). Ϫ
C15H28O (224.4): calcd. C 80.29, H 12.58; found C 80.03, H 12.50.
(S)-14-Pentadecyn-7-ol [(S)-12]: A solution of (R)-12 (6.36 g,
28.3 mmol), triphenylphosphane (11.2 g, 42.5 mmol) and benzoic
acid (5.19 g, 42.5 mmol) in dry THF (200 mL) was stirred at 0°C.
To this was added dropwise a solution of 7.40 g (42.5 mmol) of
diethyl azodicarboxylate in 40 mL of THF over 1.5 h. The contents
were stirred for 30 h at room temp. Removal of THF under reduced
pressure afforded a syrupy product, which was chromatographed
on silica gel (400 g). Elution with n-hexane/ethyl acetate
(40:1Ϫ20:1) gave 8.37 g of (S)-1-hexyl-8-nonynyl benzoate, which
was dissolved in 40 mL of MeOH. To this was added potassium
carbonate (6.36 g, 46.0 mmol) at 0°C, and the mixture was stirred
for 8 h at room temp. The mixture was poured into water and ex-
tracted with chloroform (4 times). The combined organic layers
were washed with saturated aqueous ammonium chloride and
brine, dried with anhydrous magnesium sulfate and concentrated
in vacuo. The residue was chromatographed on silica gel (100 g).
Elution with n-hexane/ethyl acetate (20:1Ϫ9:1) gave (S)-12 (5.59 g,
Experimental Section
General: IR spectra: Jasco A-102 spectrometer. Ϫ H-NMR spec-
1
tra: JNM JEOL EX 90 spectrometer (90 MHz), Bruker AC-300
spectrometer (300 MHz). Ϫ 13C-NMR spectra: Bruker AC-300
spectrometer (75.5 MHz). ϪOptical rotations: Jasco DIP-371
polarimeter. Ϫ Refractive indices: Atago 1T. Ϫ Column chroma-
tography: Merck Kieselgel 60, Art. Nr. 7734. Ϫ Melting points:
uncorrected values.
(R)-9-Pentadecyn-7-ol (10): A 1.71  solution of nBuLi in n-hexane
(115 mL, 0.197 mol) was added dropwise to a solution of 1-heptyne
(8) (19.0 g, 0.197 mol) in dry THF (300 mL) at Ϫ50 to Ϫ70°C
under argon. After stirring for 1 h at Ϫ70°C, BF3·OEt2 (24 mL,
0.196 mol) was added and the mixture was stirred for 10 min at
Ϫ70°C. To this was added dropwise a solution of (R)-1, 2-epoxy-
octane (7) (91% ee; 21.0 g, 0.164 mol) in dry THF (40 mL) over
15 min at Ϫ60 to Ϫ70°C, and the stirring was continued at Ϫ70°C
for 3 h. The mixture was then allowed to warm to room temp., and
poured into a mixture of 10% aqueous ammonium chloride solu-
tion (800 mL) and diethyl ether (600 mL). The organic layer was
separated, and the aqueous layer was extracted with diethyl ether
(3 times). The combined organic layers were washed with saturated
aqueous sodium hydrogen carbonate and brine, dried with anhy-
drous magnesium sulfate and concentrated in vacuo. The residue
23
88%); m.p. 41Ϫ42°C, [α]D ϭ ϩ0.88 (c ϭ 1.70 in Et2O). Ϫ The
IR and 1H-NMR spectra were identical with those of (R)-12. Ϫ
C15H28O (224.4): calcd. C 80.29, H 12.58; found C 80.25, H 12.66.
(R)-7-(tert-Butyldimethylsilyloxy)-14-pentadecyne [(R)-13]: To
a
solution of (R)-12 (6.00 g, 26.7 mmol) and tert-butyldimethylchlo-
rosilane (4.44 g, 29.5 mmol) in dry DMF (30 mL) was added imi-
dazole (2.37 g, 34.8 mmol) in one portion at 0°C. After stirring for
10 h at 0°C to room temp., the mixture was poured into a mixture
of water (100 mL) and ethyl acetate (60 mL). The organic layer was
1798
Eur. J. Org. Chem. 1999, 1795Ϫ1802

Synthesis of Sphingosine Relatives, XXI
FULL PAPER
separated, and the aqueous layer was extracted with ethyl acetate
(3 times). The combined organic layers were washed with water
(twice) and brine, dried with anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatographed on silica
gel (150 g). Elution with n-hexane, then n-hexane/ethyl acetate
(20:1) gave 9.05 g (quant.) of (R)-13; nD19 ϭ 1.4499, [α]D25 ϭ Ϫ0.17
(c ϭ 1.20 in CHCl3). Ϫ IR (film): ν˜ ϭ 3320 cmϪ1 (m, CϵCH),
NMR spectra were identical with those of (R)-15. Ϫ C21H43ISiO
(466.6): calcd. C 54.06, H 9.29; found C 54.43, H 9.35.
2-Acetamido-2-deoxy-D-mannono-1,4-lactone (16): This compound
was prepared from N-acetyl--monnosamine (9) according to
[11]
´
Pravdıc et al.
A solution of the monohydrate of 9 (50.0 g, 0.209
mol) in water (1 l) was treated with bromine (30 mL), and the mix-
ture was kept in the dark overnight and stirred for 3 d. The excess
of bromine was removed in vacuo without heating, and the solution
was treated with silver carbonate (125 g). After filtration, the re-
sulting solution was treated with hydrogen sulfide to remove silver
ions, and the precipitate was removed by filtration through a layer
of decolorizing carbon. The colorless filtrate was concentrated in
vacuo (40°C bath), and the syrupy residue was dried in a desiccator
over phosphorus pentaoxide, then the crystallization was spon-
taneous. The product was triturated with methanol (100 mL), and
collected by filtration: 14.2 g (31%). Upon concentration, the
mother liquor yielded a second crop (4.6 g), raising the total yield
to 41%. After recrystallization from methanol, the pure 16 had a
1
2120 (w, CϵCH), 1255 (s, SiMe), 1100Ϫ1020 (br. s, SiϪO). Ϫ H
NMR (90 MHz in CDCl3): δ ϭ 0.03 (s, 6 H, SiMe), 0.88 (br. s, 12
H, tBu, Me), 1.00Ϫ1.80 (m, 20 H), 1.93 (t, J ϭ 2.4 Hz, 1 H,
CϵCH), 2.00Ϫ2.35 (m, 2 H, CϵCϪCH2), 3.45Ϫ3.80 (m, 1 H,
7-H). Ϫ C21H42SiO (338.6): calcd. C 74.48, H 12.50; found C 74.54,
H 12.61.
(S)-7-(tert-Butyldimethylsilyloxy)-14-pentadecyne [(S)-13]: In the
same manner as described for (R)-13, (S)-12 (4.40 g, 19.6 mmol)
19
was converted into 6.64 g (quant.) of (S)-13; nD ϭ 1.4500,
25
[α]D ϭ ϩ0.17 (c ϭ 1.18 in CHCl3). Ϫ The IR and 1H-NMR
spectra were identical with those of (R)-13. Ϫ C21H42SiO (328.6):
calcd. C 74.48, H 12.50; found C 74.42, H 12.37.
19
m.p. of 174Ϫ177°C, [α]D ϭ ϩ76.5 (c ϭ 1.11 in H2O). Ϫ IR
(KBr): ν˜ ϭ 3500 cmϪ1 (s, OH), 3400 (s, NH), 1770 (s, OϪCϭO),
(R)-7-(tert-Butyldimethylisilyloxy)-15-(tri-n-butylstannyl)-14-
pentadecene [(R)-14]: A mixture of (R)-13 (9.05 g, 26.7 mmol), tri-
n-butyltin hydride (8.54 g, 29.3 mmol) and azobis(isobutyronitrile)
(0.14 g, 0.85 mmol) was heated slowly to 90°C and then kept at
that temp. for 40 h. The reaction mixture was cooled, a white pre-
cipitate was removed by filtration through a Celite pad, and the
liquid was chromatographed on aluminium oxide 90 active neutral
(Merck 1077, Activity 3, 400 g). Elution with n-hexane gave 16.8 g
1
1650 (s, HNϪCϭO), 1540 (s, HNϪCϭO). Ϫ H NMR (90 MHz
in [D6]DMSO): δ ϭ 1.93 (s, 3 H, Ac), 3.30Ϫ4.00 (m, 3 H),
4.20Ϫ4.40 (m, 2 H), 4.61 (t, J ϭ 5.8 Hz, 1 H, OH), 4.83 (d, J ϭ
5.9 Hz, 1 H, OH), 4.96 (dd, J ϭ 9.0, 4.2 Hz, 1 H, H-2), 5.64 (d,
J ϭ 5.9 Hz, 1 H, OH), 8.14 (d, J ϭ 9.0 Hz, 1 H, NH). Ϫ C8H13NO6
(219.2); calcd. C 43.84, H 5.98, N 6.39; found C 43.72, H 5.89,
N 6.39.
22
20
(quant.) of (R)-14; nD ϭ 1.4733, [α]D ϭ ϩ0.33 (c ϭ 1.17 in
2-Acetamido-2-deoxy-5,6-O-benzylidene-D-mannono-1,4-lactone
CHCl3). Ϫ IR (film): ν˜ ϭ 1250 cmϪ1 (s, SiMe), 1120Ϫ1020 (br. s,
SiϪO). Ϫ H NMR (90 MHz in CDCl3): δ ϭ 0.04 (s, 6 H, SiMe),
(17): To a solution of 16 (7.50 g, 34.2 mmol) in dry DMF (150 mL)
were added benzaldehyde dimethylacetal (6.00 g, 39.4 mmol) and
tetrafluoroboric acidϪdiethyl ether (85% in diethyl ether, 5.93 mL,
34.2 mmol). After stirring at room temp. for 10 h, triethylamine
(48 g) was added, and the solvent was evaporated in vacuo. The
residue was chromatographed on silica gel (300 g). Elution with
diethyl ether, and then diethyl ether/methanol (50:1Ϫ25:1Ϫ15:1)
gave 10.3 g (98%) of 17 as a 1:1 diastereomeric mixture; m.p.
1
0.30Ϫ1.70 (m, 59 H), 1.80Ϫ2.30 (m, 2 H, 13-H), 3.45Ϫ3.75 (m, 1
H, 7-H), 5.80Ϫ6.00 (m, 2 H, vinyl). Ϫ C33H70SiSnO (629.7): calcd.
C 62.95, H 11.20; found C 63.19, H 11.33.
(S)-7-(tert-Butyldimethylsilyoxy)-15-(tri-n-butylstannyl)-14-
pentadecene [(S)-14]: In the same manner as described for (R)-14,
(S)-13, (6.64 g, 19.6 mmol) was converted into 11.9 g (96%) of (S)-
17
18
19
14; nD ϭ 1.4749, [α]D ϭ Ϫ0.27 (c ϭ 1.18 in CHCl3). Ϫ The IR
and 1H-NMR spectra were identical with those of (R)-14. Ϫ
C33H70SiSnO (629.7): calcd. C 62.95, H 11.20; found C 63.27, H
11.31.
165Ϫ170°C, [α]D ϭ ϩ109 (c ϭ 1.09, CH3OH). Ϫ IR (KBr): ν˜ ϭ
3370 cmϪ1 (s, NH, OH), 1775 (s, OϪCϭO), 1650 (s, HNϪCϭO),
1530 (s, NHϪCϭO), 1100 (s, CϪO). Ϫ 1H NMR (90 MHz in
[D6]DMSO): δ ϭ 1.94 (s, 3 H, Ac), 3.80Ϫ4.70 (m, 4 H), 4.86 (dd,
J ϭ 3.9, 5.0 Hz, 1 H), 5.05 (dd, J ϭ 8.3, 4.8 Hz, 1 H, 2-H), 5.72
and 5.87 (each s, total 1 H, benzyl), 5.99 (d, J ϭ 5.3 Hz, 1 H, OH),
7.43 (br. s, 5 H, Ph), 8.25 (d, J ϭ 7.9 Hz, 1 H, NH). Ϫ C15H17NO6
(307.3): calcd. C 58.63, H 5.58, N 4.56; found C 58.35, H 5.53,
N 4.57.
(R)-7-(tert-Butyldimethylsilyloxy)-15-iodo-14-pentadecene [(R)-15]:
To a solution of (R)-14 (14.6 g, 23.1 mmol) in diethyl ether (54 mL)
was added dropwise at 0°C a 0.2  solution of iodine in diethyl
ether (75 mL) until the color of iodine persisted. After stirring for
1 h at 0°C, a 5% aqueous sodium hydrogen sulfite solution was
added. The organic layer was separated, and the aqueous layer was
extracted with diethyl ether (3 times). The combined organic layers
were washed with saturated aqueous sodium hydrogen carbonate
and brine, dried with anhydrous magnesium sulfate and concen-
trated in vacuo. The residue was chromatographed on silica gel
(200 g). Elution with n-hexane, then n-hexane/ethyl acetate (60:1)
2-Acetamido-5,6-O-benzylidene-3-O-(tert-butyldimethylsilyl)-2-
deoxy-D-mannono-1,4-lactone (18): To a solution of 17 (11.3 g,
36.8 mmol) and 2,6-lutidine (11.8 g, 0.111 mol) in dry dichloro-
methane (70 mL) was added tert-butyldimethylsilyl trifluorometh-
anesulfonate (24.4 g, 92.1 mmol) dropwise at 0°C under argon.
After stirring at 0°C for 2.5 h, iced water (200 g) was added. The
organic layer was separated and the aqueous layer was extracted
with dichloromethane (3 times). The combined organic layers were
washed successively with water (3 times) and brine, dried with an-
hydrous magnesium sulfate and concentrated in vacuo. The residue
was purified by chromatography on silica gel (380 g). Elution with
n-hexane/diethyl ether (1:4), diethyl ether, then diethyl ether/meth-
anol (19:1Ϫ9:1) gave 9.36 g (60.3%) of 18 as a 1:1 diastereomeric
17
19
gave 10.6 g (98%) of (R)-15; nD ϭ 1.4803, [α]D ϭ Ϫ0.02 (c ϭ
1.1 in CHCl3). Ϫ IR (film): ν˜ ϭ 1605 cmϪ1 (w, CϭC), 1255 (m,
SiMe), 1120Ϫ1020 (br. m, SiϪO), 945 (m). Ϫ H NMR (90 MHz
1
in CDCl3): δ ϭ 0.04 (s, 6H, SiMe), 0.65Ϫ1.70 (m, 32 H), 2.05 (dt,
J ϭ 6.1, 7.1 Hz, 2 H, 13-H), 3.45Ϫ3.70 (m, 1 H, 7-H), 5.96 (d, J ϭ
14.5 Hz, 1 H, 15-H), 6.52 (dt, J ϭ 14.5, 7.1 Hz, 1 H, 14-H). Ϫ
C21H43ISiO (466.6): calcd. C 54.06, H 9.29; found C 53.94, H, 9.31.
(S)-7-(tert-Butyldimethylsiliyloxy)-15-iodo-14-pentadecene [(S)-15]: mixture [further elution gave 0.80 g (7.1%) of the recovered 17];
19
In the same manner as described for (R)-15, (S)-14 (11.4 g,
m.p. 44Ϫ46°C, [α]D ϭ ϩ55.1 (c ϭ 1.62 in CHCl3). Ϫ IR (KBr):
ν˜ ϭ 3340 cmϪ1 (m, NH), 1785 (s, OϪCϭO), 1665 (s, HNϪCϭO).
Ϫ 1H NMR (90 MHz in CDCl3): δ ϭ 0.04 (s, 3 H, SiMe), 0.09 and
17
18.1 mmol) was converted into 8.16 g (97%) of (S)-15; nD
ϭ
19
1.4801, [α]D ϭ ϩ0.04 (c ϭ 1.6 in CHCl3). Ϫ The IR and 1H-
Eur. J. Org. Chem. 1999, 1795Ϫ1802
1799

K. Otaka, K. Mori
FULL PAPER
0.10 (each s, total 3 H, SiMe), 0.89 and 0.91 (each s, total 9 H,
tBu), 2.05 (s, 3 H, Ac), 3.93Ϫ4.70 (m, 5 H), 4.92 and 4.97 (each
dd, J ϭ 7.5, 4.5 Hz, total 1 H, 2-H), 5.79 and 5.97 (each s, total 1
H, benzyl), 6.28 (d, J ϭ 7.5 Hz, 1 H, NH), 7.40 (br. s, 5 H, Ph). Ϫ
C21H31NSiO6 (421.6): calcd. C 59.83, H 7.41, N 3.32; found C
59.68, H 7.46, N 3.18.
(m, 3 H, vinyl, NH). Ϫ C34H67NSi2O6 (642.1): calcd. C 63.60, H
10.52, N 2.18; found C 63.28, H 10.71, N 2.07.
(2S,3R,4R,5RS,14S)-2-Acetylamino-3,14-bis(tert-butyldimeth-
ylsilyloxy)-5-hydroxyicos-6-en-4-olide [(14S)-20]: In the same man-
ner as described for (14R)-20, crude 6 (595 mg, 1.97 mmol) and
(S)-15 (2.27 g, 5.94 mmol) were converted into 381 mg (30%) of
19
19
(14S)-20 as a diastereomeric mixture; nD ϭ 1.4778, [α]D
ϭ
2-Acetamido-3-O-(tert-butyldimethylsilyl)-2-deoxy-D-mannono-
ϩ39.4 (c ϭ 1.03 in CHCl3). There was no notable difference be-
tween the IR and 1H-NMR spectra of (14S)-20 and those of (14R)-
20. Ϫ C34H67NSi2O6 (642.1): calcd. C 63.60, H 10.52, N 2.18;
found C 63.32, H 10.52, N 2.15.
1,4-lactone (19): Palladium hydroxide on carbon (20%, 1.54 g) was
added to a solution of 18 (2.96 g, 7.02 mmol) in ethanol (56 mL)
and cyclohexene (50 mL), and the suspension was stirred under
reflux for 21 h. The catalyst was removed by filtration and the fil-
trate was concentrated in vacuo. The residue was purified by chro-
matography on silica gel (100 g). Elution with diethyl ether, then
diethyl ether/methanol (30:1Ϫ15:1) gave 1.67 g (71%) of 19 [the less
polar fractions gave 0.63 g (21%) of the recovered 18]; m.p.
(2S,3R,4R,5S,14R)-2-Acetylamino-14-hydroxy-3,5-isopropylidene-
dioxyicos-6-en-4-olide [(2S,3R,4R,5S,14R)-4] and Its C-5 Dia-
stereomer (2S,3R,4R,5R,14R)-4: To a solution of (14R)-20 (390 mg,
0.607 mmol) in acetonitrile (7 mL) was added 46% aqueous hydro-
fluoric acid (1.32 g, 30.4 mmol) at room temp. After stirring for
20 h at this temp., 2.81 g of sodium hydrogen carbonate was added
to the solution, and the mixture was stirred for 10 min. The reac-
tion mixture was chromatographed directly on silica gel (50 g). Elu-
tion with chloroform, then chloroform/methanol (9:1Ϫ4:1) gave
239 mg of crude triol (5RS,14R)-21. This was then dissolved in
DMF (4 mL), and 2,2-dimethoxypropane (9.0 mL, 73.2 mmol) and
p-toluenesulfonic acid monohydrate (30 mg) were added at room
temp. After stirring for 50 h at room temp., the reaction mixture
was poured into a mixture of saturated aqueous sodium hydrogen
carbonate (30 mL) and ethyl acetate (30 mL). The organic layer
was separated, and the aqueous layer was extracted with ethyl acet-
ate (3 times). The combined organic layers were washed with water
and brine, dried with anhydrous magnesium sulfate and concen-
trated in vacuo. The residue was chromatographed on silica gel
(15 g). Elution with n-hexane/ethyl acetate (1:1Ϫ1:2) gave 127 mg
[46% based on (14R)-20] of (2S,3R,4R,5R,14R)-4 (less polar) and
77 mg [28.0% based on (14R)-20] of (2S, 3R, 4R, 5S, 14R)-4.
19
70Ϫ72°C, [α]D ϭ ϩ78.4 (c ϭ 1.12 in CHCl3). Ϫ IR (KBr): ν˜ ϭ
3390 cmϪ1 (br. s, OH), 3100 (w, NH), 1780 (s, OϪCϭO), 1660 (s,
HNϪCϭO). Ϫ 1H NMR (90 MHz in CDCl3): δ ϭ 0.06 (s, 3H,
SiMe), 0.15 (s, 3H, SiMe), 0.90 (s, 9H, tBu), 2.08 (s, 3H, Ac), 2.94
(br. s, 2H, OH), 3.60Ϫ4.10 (m, 3H, 4-H and 6-H), 4.20Ϫ4.50 (m,
1H, 5-H), 4.68 (dd, J ϭ 2.6, 4.0 Hz, 1H, 3-H), 4.92 (dd, J ϭ 7.4,
4.1 Hz, 1H, 2-H), 6.09 (d, J ϭ 7.4 Hz, 1H, NH). Ϫ C14H27NSiO6
(333.5): calcd. C 50.43, H 8.16, N 4.20; found C 49.93, H 8.01,
N 4.13.
(2S,3R,4S)-2-Acetylamino-3-(tert-butyldimethylsilyloxy)-4-
formyl-4-butanolide (6): To a solution of 19 (500 mg, 1.50 mmol)
in dichloromethane (12 mL) and water (8 mL) was added sodium
periodate (963 mg, 4.50 mmol) at room temp. After stirring for
4.5 h, the reaction mixture was poured into a mixture of dichloro-
methane (40 mL) and water (30 mL). The organic layer was sepa-
rated, and the aqueous layer was extracted with dichloromethane
(4 times). The combined organic layers were dried with anhydrous
magnesium sulfate and concentrated in vacuo to give 452 mg
24
19
(quant.) of crude 6; [α]D ϭ ϩ40.6 (c ϭ 0.57 in CHCl3). Ϫ IR
Physical Data of (2S,3R,4R,5S,14R)-4: M.p. 60Ϫ62°C, [α]D
ϭ
ϩ87.2 (c ϭ 0.36 in CHCl3). Ϫ IR (KBr): ν˜ ϭ 3250 cmϪ1 (br. m,
OH), 1780 (s, OϪCϭO), 1645 (s, HNϪCϭO), 1370 (m), 1160 (s,
CϪO). Ϫ 1H NMR (300 MHz in CDCl3): δ ϭ 0.88 (t, J ϭ 6.5 Hz,
3 H, 20-H), 1.15Ϫ1.75 (m, 21 H, ϪCH2Ϫ, OH), 1.43 (s, 3 H, ace-
tonide Me), 1.49 (s, 3 H, acetonide Me), 2.00Ϫ2.15 (m, 2 H, 8-H),
2.10 (s, 3 H, Ac), 3.50Ϫ3.65 (m, 1 H, 14-H), 4.13 (dd, J ϭ 2.1,
1.7 Hz, 1 H, 4-H), 4.47 (dd, J ϭ 7.3, 1.7 Hz, 1 H, 5-H), 4.61 (dd,
J ϭ 3.9, 2.1 Hz, 1 H, 3-H), 5.05 (dd, J ϭ 8.2, 3.9 Hz, 1 H, 2-H),
5.64 (dd, J ϭ 15.5, 7.2 Hz, 1 H, 6-H), 5.86 (dt, J ϭ 15.5, 6.6 Hz, 1
H, 7-H), 6.00 (d, J ϭ 8.2 Hz, 1 H, NH). Ϫ13C NMR (in CDCl3):
δ ϭ 14.1, 19.4, 22.6, 23.0, 25.5, 25.6, 28.6, 29.1, 29.2, 29.4, 29.5,
31.8, 32.2, 37.4, 37.5, 53.8, 67.8, 69.8, 72.0, 73.2, 98.8, 124.5, 136.7,
170.4, 173.5. Ϫ C25H43NO6 (453.6): calcd. C 66.20, H 9.53, N 3.09;
found C 66.01, H 9.47, N 2.97.
(KBr): ν˜ ϭ 3370 (m, NH), 1780 (s, OϪCϭO), 1745 (m, HϪCϭO),
1660 (s, HNϪCϭO), 1130 (s). Ϫ 1H NMR (90 MHz in CDCl3):
δ ϭ 0.01 (s, 6 H, SiMe), 0.84 (s, 9 H, tBu), 2.08 (s, 3 H, Ac),
3.35Ϫ3.40 (m, 1 H), 4.60Ϫ5.10 (m, 2 H), 5.97 (br. d, J ϭ 8.0 Hz,
1 H, NH), 9.63 (d, J ϭ 1.8 Hz, 1 H, CHO). Ϫ This crude 6 was
employed in the next step without further purification.
(2S,3R,4R,5RS,14R)-2-Acetylamino-3,14-bis(tert-butyl-
dimethylsilyloxy)-5-hydroxyicos-6-en-4-olide [(14R)-20]: A mixture
of anhydrous CrCl2 (300 mg, 2.44 mmol) and a catalytic amount
of NiCl2 (2.0 mg, 0.015 mmol) in dry and oxygen-free DMSO
(5 mL) was stirred at room temp. for 10 min under argon. To the
reagent at room temp. was added a solution of crude 6 (122 mg,
0.405 mmol) in DMSO (3 mL) and a solution of (R)-15 (567 mg,
1.22 mmol) in DMSO (2 mL) successively. After stirring at room
temp. for 33 h, the reaction mixture was quenched by stirring with
saturated ammonium chloride and chloroform. The organic layer
was separated, and the aqueous layer was extracted with ethyl acet-
ate (3 times). The combined organic layers were washed with brine,
dried with anhydrous magnesium sulfate and concentrated in
vacuo. The residue was chromatographed on silica gel (15 g). Elu-
19
Physical Data of (2S,3R,4R,5R,14R)-4: M.p. 64Ϫ66°C, [α]D
ϭ
ϩ48.3 (c ϭ 0.87 in CHCl3). ϪIR (KBr): ν˜ ϭ 3300 cmϪ1 (br. m,
OH), 1780 (s, OϪCϭO), 1645 (s, HNϪCϭO), 1215 (m), 1170 (s,
CϪO). Ϫ 1H NMR (300 MHz in CDCl3): δ ϭ 0.88 (t, J ϭ 6.6 Hz,
3 H, 20-H), 1.15Ϫ1.75 (m, 21 H, ϪCH2Ϫ, OH), 1.39 (s, 6 H, ace-
tonide Me), 2.00Ϫ2.20 (m, 2 H, 8-H), 2.10 (s, 3 H, Ac), 3.50Ϫ3.65
tion with n-hexane/ethyl acetate (10:1Ϫ5:1) gave 107 mg (41%) of (m, 1 H, 14-H), 4.06 (dd, J ϭ 6.8, 6.5 Hz, 1 H, 5-H), 4.40Ϫ4.55
19
19
(14R)-20 as a diastereomeric mixture; nD ϭ 1.4779, [α]D
ϭ
(m, 2 H, 3-H, 4-H), 5.08 (dd, J ϭ 8.4, 5.5 Hz, 1H, 2-H), 5.52 (dd,
ϩ41.7 (c ϭ 0.60 in CHCl3). Ϫ IR (film): ν˜ ϭ 3390 cmϪ1 (br. m, J ϭ 15.4, 6.5 Hz, 1H, 6-H), 5.85 (ddt, J ϭ 15.4, 0.8, 6.8 Hz, 1H,
OH), 1780 (s, OϪCϭO), 1660 (s, HNϪCϭO), 1250 (s, SiMe), 7-H), 5.95 (d, J ϭ 8.4 Hz, 1 H, NH). Ϫ 13C NMR (in CDCl3): δ ϭ
1190Ϫ1000 (br. s, SiϪO). Ϫ 1H NMR (90 MHz in CDCl3): δ ϭ
14.0, 22.6, 22.9, 23.9, 24.0, 25.5, 25.6, 28.7, 29.1, 29.4, 29.5, 31.8,
0.00Ϫ0.15 (m, 12 H, SiMe), 0.50Ϫ1.50 (m, 41 H), 1.60Ϫ2.20 (m, 32.3, 37.4, 37.5, 50.7, 66.3, 71.96, 72.02, 81.1, 101.8, 125.8, 135.6,
3 H, 8-H, OH), 2.03 and 2.08 (each s, total 3 H, Ac), 3.45Ϫ3.75 170.2, 173.5. Ϫ- C25H43NO6 (453.6): calcd. C 66.20, H 9.53, N
(m, 1 H, 14-H), 4.00Ϫ5.20 (m, 4 H, 2-H, 3-H, 4-H, 5-H), 5.35Ϫ6.25 3.09; found C 66.15, H 9.48, N 3.11.
1800
Eur. J. Org. Chem. 1999, 1795Ϫ1802

Synthesis of Sphingosine Relatives, XXI
FULL PAPER
( 2 S, 3 R , 4R , 5 S, 14 S) - 2 - A c e t y la m i no - 1 4- hydrox y - 3 , 5 -
s, OH), 1760 (s, OϪCϭO), 1640 (s, HNϪCϭO). Ϫ 1H NMR
isopropylidenedioxyicos-6-en-4-olide [(2S,3R,4R,5S,14S)-4] and Its (300 MHz in CD3OD): δ ϭ 0.90 (t, J ϭ 6.5 Hz, 3 H, Me),
C-5 Diastereomer (2S,3R,4R,5R,14S)-4: In the same manner as de-
scribed for (2S,3R,4R,5S,14R)-4 and (2S,3R,4R,5R,14R)-4, (14S)-
20 (360 mg, 0.561 mmol) was converted into 125 mg [49% based on
1.20Ϫ1.60 (m, 20 H, ϪCH2Ϫ), 2.00Ϫ2.20 (m, 2 H, 8-H), 2.06 (s,
3 H, Ac), 3.45Ϫ3.55 (m, 1 H, 14-H), 4.22 (dd, J ϭ 8.3, 2.5 Hz, 1
H, 3-H), 4.37 (dd, J ϭ 8.3, 6.8 Hz, 1 H, 5-H), 4.50Ϫ4.55 (m, 1 H,
(14S)-20] of (2S,3R,4R,5R,14S)-4 (less polar) and 70 mg [28% 4-H), 4.97 (d, J ϭ 4.4 Hz, 1 H, 2-H), 5.59 (dd, J ϭ 15.4, 6.8 Hz, 1
based on (14S)-20] of (2S,3R,4R,5S,14S)-4.
H, 6-H), 5.82 (dt, J ϭ 15.4, 6.5 Hz, 1 H, 7-H). Ϫ 13C NMR (in
CD3OD): δ ϭ 14.4, 22.3, 23.7, 26.7, 26.8, 30.16, 30.19, 30.5, 30.7,
33.0, 33.4, 38.4 (2 ϫ), 55.6, 70.0, 70.1, 72.5, 84.1, 130.4, 135.1,
173.8, 176.0. Ϫ C22H39NO6 (413.6): calcd. C 63.90, H 9.51, N 3.39;
found C 64.06, H 9.47, N 3.36.
20
Physical Data of (2S,3R,4R,5S,14S)-4: M.p. 60Ϫ62°C, [α]D
ϭ
ϩ88.5 (c ϭ 0.48 in CHCl3). There was no notable difference be-
tween the IR, 1H-NMR and 13C-NMR spectra of
(2S,3R,4R,5S,14S)-4 and those of (2S,3R,4R,5S,14R)-4.
Ϫ
C25H43NO6 (453.6): calcd. C 66.20, H 9.53, N 3.09; found C 65.98,
H 9.49, N 2.99.
(2S,3R,4R,5R,14S)-2-Acetylamino-3,5,14-trihydoxyicos-6-en-4-
olide [(2S,3R,4R,5R,14S)-21]: In the same manner as described for
24
(2S,3R,4R,5R,14R)-21,
(2S,3R,4R,5R,14S)-4
(43.0 mg,
Physical Data of (2S,3R,4R,5R,14S)-4: M.p. 63Ϫ65°C, [α]D
ϭ
0.0948 mmol) was converted into 35.5 mg (91%) of
(2S,3R,4R,5R,14S)-21; m.p. 177Ϫ179°C, [α]D18 ϭ ϩ71.1 (c ϭ 0.37
in MeOH). Ϫ There was no notable difference between the IR, 1H-
NMR and 13C-NMR spectra of (2S,3R,4R,5R,14S)-21 and those
of (2S,3R,4R,5R,14R)-21. Ϫ C22H39NO6 (413.6): calcd. C 63.90, H
9.51, N 3.39; found C 63.64, H 9.22, N 3.28.
ϩ44.8 (c ϭ 1.15 in CHCl3). There was no notable difference be-
tween the IR, 1H-NMR and 13C-NMR spectra of
(2S,3R,4R,5R,14S)-4 and those of (2S,3R,4R,5R,14R)-4.
Ϫ
C25H43NO6 (453.6): calcd. C 66.20, H 9.53, N 3.09; found C 65.83,
H 9.61, N 3.02.
(2S,3R,4R,5S,14R)-2-Acetylamino-3,4,5,14-tetrahydroxyicos-6-
enoic Acid [(2S,3R,4R,5S,14R)-1]; Sphingofungin D: To a solution
of (2S,3R,4R,5S,14R)-4 (71.5 mg, 0.158 mmol) in THF (3 mL) and
water (3 mL) was added acetic acid (3 mL) at room temp. The mix-
ture was then heated to reflux temp. and stirred for 4 h. The reac-
tion mixture was concentrated in vacuo, and the residue was thor-
oughly dried in vacuo. The resulting crude products were dissolved
in methanol (2 mL) and water (2 mL), and then heated to reflux
temp. After stirring for 3.5 h at this temp., the reaction mixture was
concentrated in vacuo and the residue was chromatographed on
silica gel (3 g). Elution with chloroform/methanol (3:1Ϫ1:1Ϫ1:2)
gave 40.1 mg [59% based on (2S,3R,4R,5S,14R)-4] of sphingofun-
gin D [(2S,3R,4R,5S,14R)-1]; m.p. 151Ϫ162°C (decomp.), [α]D26 ϭ
ϩ2.91 (c ϭ 1.10 in MeOH). Ϫ IR (KBr): ν˜ ϭ 3700Ϫ2900 cmϪ1
(br. s, OH), 1570 (br. s), 1410 (br. s). Ϫ 1H NMR (300 MHz in
CD3OD): δ ϭ 0.90 (t, J ϭ 6.6 Hz, 3 H, 20-H), 1.25Ϫ1.55 (m, 20
H, ϪCH2Ϫ), 1.90Ϫ2.20 (m, 2 H, 8-H), 2.02 (s, 3 H, Ac), 3.40Ϫ3.55
(m, 1 H, 4-H), 3.55Ϫ3.65 (m, 1 H, 14-H), 3.87 (bd, J ϭ 4.2 Hz, 1
H, 3-H), 4.21 (br. t, J ϭ 7.3 Hz, 1 H, 5-H), 4.40 (br. d, J ϭ 4.2 Hz,
1 H, 2-H), 5.55 (dd, J ϭ 14.9, 7.3 Hz, 1 H, 6-H), 5.79 (dt, J ϭ
14.9, 7.0 Hz, 1 H, 7-H). Ϫ 13C NMR (in CD3OD): 14.4, 22.9, 23.7,
26.8 (2 ϫ), 30.2, 30.4, 30.6, 30.8, 33.1, 33.5, 38.5 (2 ϫ), 58.2, 72.5
(2 ϫ), 75.2, 75.7, 130.5, 135.7, 173.4, 178.2. Ϫ C22H41NO7 (431.6):
calcd. C 61.23, H 9.58, N 3.25; found C 61.16, H 9.38, N 3.22.
(2S,3R,4R,5R,14R)-2-Acetylamino-3,4,5,14-tetrahydroxyicos-6-
enoic Acid [(2S,3R,4R,5R,14R)-1]: To
a
solution of
(2S,3R,4R,5R,14R)-21 (33.0 mg, 0.0798 mmol) in a mixture of
THF (2 mL) and water (2 mL) was added at 0°C lithium hydroxide
monohydrate (10.0 mg, 0.238 mmol). After stirring for 30 min at
this temp., water (2 mL) was added and then the mixture was neu-
tralized with 0.5  hydrochloric acid (pH ϭ 7). The aqueous layer
was saturated with ammonium sulfate and extracted with THF (6
times). The combined organic layers were dried with anhydrous
magnesium sulfate and concentrated in vacuo. The residue was
chromatographed on silica gel (3 g). Elution with chloroform/meth-
anol (3:1Ϫ1:1Ϫ1:2) gave 26.9 mg (78.1%) of (2S,3R,4R,5R,14R)-1;
25
m.p. 195Ϫ205°C (decomp), [α]D ϭ ϩ1.40 (c ϭ 0.11 in MeOH).
Ϫ IR (KBr): ν˜ ϭ 3450 cmϪ1 (br. s, OH), 3350 (s, NH), 1660 (s),
1590 (s). Ϫ 1H NMR (300 MHz in CD3OD): δ ϭ 0.90 (t, J ϭ
6.7 Hz, 3 H, 20-H), 1.20Ϫ1.65 (m, 20 H), 1.90Ϫ2.20 (m, 2 H,
8-H), 2.01 (s, 3 H, Ac), 3.41 (dd, J ϭ 7.1, 1.4 Hz, 1 H, 4-H),
3.45Ϫ3.55 (m, 1 H, 14-H), 4.02 (dd, J ϭ 6.8, 1.4 Hz, 1 H, 3-H),
4.12 (dd, J ϭ 7.1, 6.0 Hz, 1 H, 5-H), 4.37 (d, J ϭ 6.8 Hz, 1 H,
2-H), 5.58 (dd, J ϭ 15.3, 6.0 Hz, 1 H, 6-H), 5.75 (dt, J ϭ 15.3,
6.2 Hz, 1 H, 7-H). Ϫ 13C NMR (in CD3OD): δ ϭ 14.5, 22.9, 23.7,
26.8 (2 ϫ), 30.4 (2 ϫ), 30.6, 30.8, 33.1, 33.6, 38.5 (2 ϫ), 57.5, 71.9,
72.4 (2 ϫ), 74.2, 130.8, 134.5, 173.5, 178.2. Ϫ C22H41NO7 (431.6):
calcd. C 61.23, H 9.58, N 3.25; found C 60.95, H 9.39, N 3.32.
(2S,3R,4R,5S,14S)-2-Acetylamino-3,4,5,14-tetrahydroxyicos-6-
enoic Acid [(2S,3R,4R,5S,14S)-1]: In the same manner as described
for sphingofungin D [(2S,3R,4R,5S,14R)-1], (2S,3R,4R,5S,14S)-4
(37.0 mg, 0.0816 mmol) was converted into 15.5 mg (44%) of
(2S,3R,4R,5R,14S)-2-Acetylamino-3,4,5,14-tetrahydroxyicos-6-
enoic Acid [(2S,3R,4R,5R,14S)-1]: In the same manner as described
for [(2S,3R,4R,5R,14R)-1], (2S,3R,4R,5R,14S)-21 (18.9 mg,
0.0457 mmol) was converted into 15.5 mg (79%) of
23
(2S,3R,4R,5S,14S)-1; m.p. 151Ϫ162°C (decomp.), [α]D ϭ ϩ2.83
22
(2S,3R,4R,5R,14S)-1; m.p. 182Ϫ202°C (decomp.), [α]D ϭ ϩ1.31
(c ϭ 0.73 in MeOH). Ϫ There was no notable difference between
the IR, 1H-NMR and 13C-NMR spectra of (2S,3R,4R,5S,14S)-1
(c ϭ 0.35 in MeOH). Ϫ There was no notable difference between
the IR, 1H-NMR and 13C-NMR spectra of (2S,3R,4R,5R,14S)-1
and those of [(2S,3R,4R,5R,14R)-1]. Ϫ C22H41NO7 (431.6): calcd.
C 61.23, H 9.58, N 3.25; found C 61.11, H 9.45, N 3.41.
and those of sphingofungin
D
[(2S,3R,4R,5S,14R)-1].
Ϫ
C22H41NO7 (431.6): calcd. C 61.23, H 9.58, N 3.25; found C 61.25,
H 9.42, N 3.17.
(2S,3R,4R,5R,14R)-2-Acetylamino-3,5,14-trihydroxyicos-6-en-4-
olide [(2S,3R,4R,5R,14R)-21]: To a solution of (2S,3R,4R,5R,14R)-
(R)-7-(tert-Butyldimethylsilyloxy)-14-pentadecene [(R)-22]: A mix-
ture of (R)-14 (630 mg, 1.00 mmol) and silica gel (3 g) in n-hexane
4 (47.0 mg, 0.104 mmol) in THF (2 mL) and water (2 mL) was ad- (30 mL) was stirred at room temp. for 1 h, then the whole was sub-
ded acetic acid (2 mL) at room temp. The reaction mixture was
then heated to reflux temp. and stirred for 4 h. The reaction mix-
jected to silica gel chromatography (15 g) directly. Elution with n-
25
20
hexane gave 341 mg (quant.) of (R)-22; nD ϭ 1.4462, [α]D
ϭ
ture was concentrated in vacuo, and the residue was chromato- Ϫ0.10 (c ϭ 0.46 in CHCl3). Ϫ IR (film): ν˜ ϭ 1645 cmϪ1 (w, CHϭ
graphed on silica gel (10 g). Elution with chloroform gave 41.0 mg
CH2), 1255 (m, SiMe), 1160Ϫ980 (br. m, SiϪO). Ϫ 1H NMR
19
(95%) of (2S,3R,4R,5R,14R)-21; m.p. 175Ϫ177°C, [α]D ϭ ϩ67.1 (300 MHz in CDCl3): δ ϭ 0.04 (s, 6 H, SiMe), 0.85Ϫ0.95 (m, 12
(c ϭ 0.32 in MeOH). Ϫ IR (KBr): ν˜ ϭ 3540 cmϪ1 (m), 3350 (br. H, tBu, Me), 0.55Ϫ1.70 (m, 20 H, ϪCH2Ϫ), 2.04 (dt, J ϭ 6.7,
Eur. J. Org. Chem. 1999, 1795Ϫ1802
1801

K. Otaka, K. Mori
FULL PAPER
6.6 Hz, 2 H, 13-H), 3.55Ϫ3.65 (m, 1 H, 7-H), 4.85Ϫ5.05 (m, 2 H,
and saturated aqueous sodium hydrogen carbonate, dried with an-
15-H), 5.81 (ddt, J ϭ 17.3, 10.0, 6.7 Hz, 1 H, 14-H). Ϫ C21H44SiO hydrous sodium sulfate, and concentrated in vacuo. The residue
(340.7): calcd. C 74.04, H 13.02; found C 74.08, H 13.18.
was chromatographed on silica gel (2 g). Elution with n-hexane and
then n-hexane/ethyl acetate (25:1Ϫ10:1) gave 110 mg (87%) of (8R)-
(S)-7-(tert-Butyldimethylsilyloxy)-14-pentadecene [(S)-22]: In the
same manner as described for (R)-22, (S)-14 (630 mg, 1.00 mmol)
19
22
24; nD ϭ 1.5012, [α]D ϭ ϩ81.3 (c ϭ 0.55 in CHCl3). Ϫ IR
(film): ν˜ ϭ 1740 cmϪ1 (br. s, CϭO), 1230 (br. s), 1050 (br. s). Ϫ 1H
NMR (300 MHz in CDCl3): δ ϭ 0.82 (t, J ϭ 7.1 Hz, 3 H, Me),
0.95Ϫ1.60 (m, 22 H, ϪCH2Ϫ), 2.19 (s, 3 H, Ac), 2.20 (s, 3 H, Ac),
4.11 (t, J ϭ 6.7 Hz, 2 H, 1-H), 4.87 (tt, J ϭ 6.2, 6.2 Hz, 1 H, 8-H),
5.86 (s, 1 H, benzyl), 5.91 (s, 1 H, benzyl), 7.25Ϫ7.50 (m, 10 H,
Ph). Ϫ C34H46O8 (582.7): calcd. C 70.08, H 7.96; found C 69.93,
H 7.88.
22
was converted into 342 mg (quant.) of (S)-22; nD ϭ 1.4463,
[α]D22 ϭ ϩ0.11 (c ϭ 0.31 in CHCl3). The IR and 1H NMR spectra
were identical with those of (R)-22. Ϫ C21H44SiO (340.7): calcd. C
74.04, H 13.02; found C 74.31, H 12.90.
(R)-Tetradecane-1,8-diol [(R)-23]: A 50-mL, two-necked, round-
bottomed flask was fitted with a glass tube to admit ozone, a cal-
cium chloride drying tube, and a magnetic stirring bar and was
charged with 715 mg (2.10 mmol) of (R)-22 and methanol (15 mL).
The flask was cooled to ca. Ϫ60°C, and ozone was bubbled
through the solution with stirring. When the solution turned blue,
the ozone addition was stopped. Nitrogen was passed through the
solution until the blue color was discharged and then the cold bath
was removed. The ozone inlet was replaced with a rubber septum,
and a solution of sodium tetrahydroborate (640 mg, 16.9 mmol) in
ethanol (4 mL) and water (4 mL) was added. The solution was al-
lowed to warm to room temp. and stirred for 10 h. The reaction
mixture was poured into an ice-cold mixture of 1  hydrochloric
acid (30 mL) and chloroform (40 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with chloroform (4
times). The combined organic layers were washed with brine, dried
with anhydrous magnesium sulfate, concentrated in vacuo and
dried thoroughly in vacuo. The crude products were dissolved in
acetonitrile (10 mL) and stirred, followed by dropwise addition of
46% aqueous hydrofluoric acid at room temp. After stirring for 2 h
at room temp., aqueous sodium hydrogen carbonate (20 mL) was
added and stirring continued. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate (5 times). The
combined organic layers were washed with brine, dried with anhy-
drous magnesium sulfate and concentrated in vacuo. The residue
was chromatographed on silica gel (15 g). Elution with n-hexane/
ethyl acetate (3:2Ϫ1:1) gave 409 mg (85% for 2 steps) of (R)-23;
(8S)-Tetradecane-1,8-diyl Bis[(S)-(؉)-O-acetylmandelate] [(8S)-24]:
In the same manner as described for (R)-24, (S)-23 (45 mg,
23
0.195 mmol) was converted into 101 mg (89%) of (S)-24; nD
ϭ
1.4849, [α]D23 ϭ ϩ80.2 (c ϭ 3.17 in CHCl3). Ϫ IR (film): ν˜ ϭ 1740
cmϪ1 (s, CϭO), 1230 (br. s), 1050 (s). Ϫ 1H NMR (300 MHz in
CDCl3): δ ϭ 0.87 (t, J ϭ 6.9 Hz, 3 H, Me), 0.95Ϫ1.65 (m, 22 H,
ϪCH2Ϫ), 2.195 (s, 3 H, Ac), 2.203 (s, 3 H, Ac), 4.08 (dt, J ϭ 4.0,
6.7 Hz, 2 H, 1-H), 4.87 (tt, J ϭ 6.2, 6.2 Hz, 1 H, 8-H), 5.87 (s, 1
H, benzyl), 5.91 (s, 1 H, benzyl), 7.25Ϫ7.50 (m, 10 H, Ph). Ϫ
C34H46O8 (582.7): calcd. C 70.08, H 7.96; found C 70.03, H 7.89.
Acknowledgments
We thank Dr. N. Chida (Keio University, Yokohama) for dis-
cussion. Financial support of this work by Sumitomo Chemical
Co. is acknowledged with thanks.
[1]
F. VanMiddlesworth, R. A. Giacobbe, M. Lopez, G. Garrity, J.
A. Bland, K. Bartizal, R. A. Fromtling, J. Polishook, M. Zwee-
rink, A. M. Edison, W. Rozdilsky, K. E. Wilson, R. L. Mon-
aghan, J. Antibiot. 1992, 45, 861Ϫ867.
[2]
F. VanMiddlesworth, C. Dufresne, F. E. Wincott, R. T. Mosley,
K. E. Wilson, Tetrahedron Lett. 1992, 33, 297Ϫ300.
[3]
N. Chida, H. Ikemoto, A. Noguchi, S. Amano, S. Ogawa, Nat.
19
Prod. Lett. 1995, 6, 295Ϫ302.
m.p. 57Ϫ58°C, [α]D ϭ Ϫ0.48 (c ϭ 1.1 in CHCl3). Ϫ IR (KBr):
[4]
Preliminary communication: K. Mori, K. Otaka, Tetrahedron
1
ν˜ ϭ 3310 (br. m, OH), 1065 (m, CϪO). Ϫ H NMR (90 MHz in
Lett. 1994, 35, 9207Ϫ9210.
[5]
CDCl3): δ ϭ 0.88 (t, J ϭ 5.6 Hz, 3 H, Me), 0.80Ϫ1.80 (m, 22 H,
ϪCH2Ϫ), 1.40 (s, 2 H, 2 OH), 3.75Ϫ3.40 (m, 3 H, 1-H, 8-H). Ϫ
C14H30O2 (230.4): calcd. C 72.99, H 13.12; found C 72.85, H 13.28.
S. Kobayashi, T. Hayashi, S. Iwamoto, T. Furuta, M. Matsu-
mura, Synlett 1996, 672- 674.
[6]
S. Kobayashi, T. Furuta, T. Hayashi M. Nishijima, K. Hanada,
J. Am. Chem. Soc. 1998, 120, 908Ϫ919.
[7]
S. R. Abrams, Can. J. Chem. 1984, 62, 1333Ϫ1334.
(S)-Tetradecane-1,8-diol [(S)-23]: In the same manner as described
for (R)-23, (S)-22 (325 mg, 0.954 mmol) was converted into 193 mg
[8]
J. W. Labadie, J. K. Stille, J. Am. Chem. Soc. 1983, 105,
6129Ϫ6137.
19
(88% for 2 steps) of (S)-23; m.p. 57Ϫ58°C, [α]D ϭ ϩ0.52 (c ϭ
[9]
S. Okamoto, T. Shimazaki, Y. Kobayashi, F. Sato, Tetrahedron
1.03 in CHCl3). Ϫ The IR and 1H-NMR spectra were identical
with those of (R)-23. Ϫ C14H30O2 (230.4): calcd. C 72.99, H 13.12;
found C 72.77, H 13.31.
Lett. 1987, 28, 2033Ϫ2036.
[10]
O. Mitsunobu, Synthesis 1981, 1Ϫ28.
[11]
´
N. Pravdıc, H. G. Fletcher, Jr., Carbohydr. Res. 1971, 19,
339Ϫ352.
[12]
[13]
(8R)-Tetradecane-1,8-diyl Bis[(S)-(؉)-O-acetylmandelate] [(8R)-24]:
To a solution of (R)-23 (50.0 mg, 0.217 mmol) and (S)-(ϩ)-O-ace-
tylmandelic acid (92.9 mg, 0.478 mmol) in dichloromethane (2 mL)
was added 4-(dimethylamino)pyridine (46.9 mg, 0.384 mmol) at
room temp. After cooling with an ice bath to 0°C, dicyclohexylcar-
bodiimide (103 mg, 0.499 mmol) was added and then the reaction
mixture was stirred at room temp. for 24 h. The white precipitates
were removed by filtration through a Celite pad, and the filtrate
was washed successively with 0.5  hydrochloric acid (twice), water
R. Albert, K. Dax, R. Pleschko, E. Stutz, Carbohydr. Res. 1985,
137, 282Ϫ290.
E. J. Corey, H. Cho, C. Rucker, D. H. Hua, Tetrahedron Lett.
1981, 22, 3455Ϫ3458.
[14]
[15]
S. Hanessian, T. J. Liak, B. Vanasse, Synthesis 1981, 396Ϫ397.
K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K. Utimoto,
H. Nozaki, J. Am. Chem. Soc. 1986, 108, 6048Ϫ6050.
H. Jin, J. Uenishi, W. J. Christ, Y. Kishi, J. Am. Chem. Soc.
1986, 108, 5644Ϫ5646.
[16]
Received March 22, 1999
[O99170]
1802
Eur. J. Org. Chem. 1999, 1795Ϫ1802