Stereoselective synthesis of D-erythro-sphingosine and L-lyxo-phytosphingosine

Article abstract of DOI:10.1016/S0040-4020(01)00915-2

An alternative synthetic route to D-erythro-sphingosine and L-lyxo-phytosphingosine was developed, utilizing chiral β-lactam 3 obtained from D-(-)-tartaric acid as a starting material.

Full text of DOI:10.1016/S0040-4020(01)00915-2

TETRAHEDRON
Pergamon
Tetrahedron 57 '2001) 9087±9092
Stereoselective synthesis of d-erythro-sphingosine
and l-lyxo-phytosphingosine
Tsuyoshi Nakamura and Masao Shiozakip
Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140-8710, Japan
Received 13 July 2001; accepted 13 September 2001
AbstractÐAn alternative synthetic route to d-erythro-sphingosine and l-lyxo-phytosphingosine was developed, utilizing chiral b-lactam 3
obtained from d-'2)-tartaric acid as a starting material. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
reduction of the enol tri¯ate 10, which is obtained by
Z-selective enolization of the ketone 9. On the other hand,
the C4 hydroxy group of phytosphingosine could be intro-
duced by the stereoselective hydride reduction of the
carbonyl moiety of the ketone 9. The disconnection of the
C4±C5 bond of the ketone 9 leads to the alkyl sulfone 7 and
the chiral b-lactam 6. The b-lactam 6 is easily derived from
chiral b-lactam 3 obtained from d-'2)-tartaric acid accord-
ing to the reported method.6
Sphingolipids are ubiquitous membrane components of
eukaryotic cells. d-erythro-Sphingosine is a structural unit
common to almost all sphingolipids in eukaryotic cells,1
and a lipophilic component of glycosphingolipids and cera-
mides. It exhibits potent inhibitory activity against protein
kinase C, and blocks human polymorphonuclear leukocyte
phagocytosis through inhibition of mitogen-activated
protein kinase activation.2 On the other hand, it is a
novel activator of 3-phosphoinositide-dependent kinase.3
Sphingosines, ceramides, and glycosphingolipids have been
shown to play a role in inter- and intracellular signaling
along with other secondary messenger molecules.4 Simul-
taneously, they play key roles in the regulation of cell
growth, differentiation and apoptosis. Phytosphingosines5
constitute the major base component of higher plants,
protozoa, yeast, and fungi, and are found in human kidney
cerebrosides 'Fig. 1).
2. Results and discussion
The synthesis of the ketone 9 was performed by conversion
24
of the chiral b-lactam 3 '[a]D ˆ229.58, c 1.2, CHCl3)
obtained from d-'2)-tartaric acid according to a previously
reported method 'Scheme 1). Compound 3 was converted to
alcohol 4 by sodium borohydride reduction, and was then
treated with triisopropylsilyl chloride in DMF using
imidazole as a base to give the silyl ether 5. Treatment of
a solution of 5 in CH2Cl2 with di-tert-butyl dicarbonate and
triethyl amine gave N-Boc-protected b-lactam 6. Treatment
of 6 with 4-tolyl tetradecylsulfone 7 and n-butyllithium in
THF at 2788C yielded a-sulfonyl ketone 8 as a 1:1 mixture
Due to the importance of these compounds, a great deal of
effort has been devoted to the synthesis of the chiral
sphingosines and various synthetic routes are still being
investigated to produce them more effectively. Here we
report an alternative stereoselective route for the syn-
thesis of d-erythro-sphingosine and l-lyxo-phytosphingo-
sine.
Our synthesis is shown by retroanalysis in Fig. 2.
Thus, we designed the ketone 9 as a key intermediate of the
alternative synthesis of both d-erythro-sphingosine and
l-lyxo-phytosphingosine. The C4±C5 E-double bond
moiety in sphingosine should be constructed by hydride
Keywords: stereoselective synthesis; d-erythro-sphingosine; l-lyxo-phyto-
sphingosine.
p
Corresponding author. Tel.: 181-3-3491-3131; fax: 181-3-5436-8570;
e-mail: shioza@shina.sankyo.co.jp
Figure 1. Structures of d-erythro-sphingosine, ceramide and l-lyxo-phyto-
sphingosine.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)00915-2

9088
T. Nakamura, M. Shiozaki / Tetrahedron 57 .2001) 9087±9092
Figure 2. Retrosynthesis of d-erythro-sphingosine and l-lyxo-phytosphingosine.
Scheme 1. Reagents and conditions: 'a) NaBH4, EtOH, rt, 1 h; 'b) TIPSCl, imidazole, DMF, rt, 4 h; 'c) 'Boc)2O, Et3N, cat. DMAP, CH2Cl2, rt, 1 h; 'd) n-
C14H29SO2C6H4Me '7), n-BuLi, THF, 2788C, 1 h; 'e) lithium naphthalenide, THF, 2788C, 20 min.
of two diastereomers at the C5 position.7 The p-toluene-
sulfonyl moiety of 8 was eliminated with lithium naph-
thalenide in THF to give 9 in good yield.8
The synthesis of the N-Boc sphingosine 11 is depicted in
Scheme 2. Deprotonation of 9 with potassium bis'trimethyl-
silyl)amide and successive sulfonylation with N-phenyl-
tri¯uoromethanesulfonimide gave enol tri¯ate 10, exclu-
sively.9 At this stage, the geometry of 10 was not clear.
The reductive elimination of the tri¯uoromethanesulfonate
group from the enol tri¯ate by formic acid and triethylamine
using bis'acetato)bis'triphenylphosphine)palladium'II) as a
catalyst10 and successive deprotection of the two silyl
Scheme 2. Reagents and conditions: 'a) KN'TMS)2, THF, 2788C, 1 h then
PhN'Tf)2, THF, 2238C, 20 min; 'b) HCO2H, Et3N, cat. Pd'OAc)2'PPh3)2,
DMF, 608C, 7 h; 'c) TBAF, THF, rt, 2 h.
Table 1. Hydride reduction of ketone 9
Entry
Conditions
Resultsa '12S/12R, % yield)
1
2
3
DIBAL, toluene
LiEt3BH, THF
Li's-Bu)3BH, THF
54:46, 86
92:8, 86
No reaction
a
The diastereomeric ratio was determined by 1H NMR.

T. Nakamura, M. Shiozaki / Tetrahedron 57 .2001) 9087±9092
9089
4.1.1. *3S,4S)-3-tert-Butyldiphenylsilyloxy-4-hydroxy-
methylazetidin-2-one *4). To a solution of 3 '1.6 g,
3.5 mmol) in EtOH '8.0 ml) was added NaBH4 '0.26 g,
7.0 mmol). After stirring for 1 h at room temperature, the
reaction mixture was quenched with 10% AcOH aqueous
solution. After removal of solvents under reduced pressure,
the mixture was added to H2O '20 ml) and extracted with
ether. The organic layer was washed with brine, dried over
anhydrous MgSO4 and concentrated to give a residue, which
was puri®ed by silica gel column chromatography. Elution
with EtOAc/hexane '1:1, then 7:3) afforded 4 '0.90 g, 73%)
Scheme 3. Reagents and conditions: 'a) LiEt3BH, THF, 2788C, 2 h;
'b) TBAF, THF, rt, 2 h; 'c) 10% HCl in MeOH 'w/v), 408C, 9 h.
as a colorless oil. [a]24 ˆ245.28 'c 0.37, CHCl3). IR
D
1
'CHCl3) 3623, 3417, 1770 cm21. H NMR 'CDCl3) d 1.08
's, 9H), 3.02 'dd, 1H, Jˆ11.8, 6.3 Hz), 3.27 'dd, 1H, Jˆ
11.8, 3.5 Hz), 3.52±3.60 'm, 1H), 4.51±4.57 'm, 1H), 6.40±
6.50 'brs, 1H), 7.30±7.50 'm, 6H), 7.62±7.80 'm, 4H). 13C
NMR 'CDCl3) d 19.09, 26.62 '3C), 60.54, 61.62, 78.17,
127.95 '4C), 130.14, 130.26, 131.99, 133.02, 135.57 '2C),
135.69 '2C), 169.15. HRMS 'FAB, positive), calcd for
C20H25NNaO3Si: 'M1Na)1 378.1501; found 378.1521.
Anal. calcd for C20H25NO3Si; C, 67.57; H, 7.09; N, 3.94.
Found; C, 67.17; H, 6.91; N, 3.73.
groups with tetrabutylammonium ¯uoride in THF exclu-
sively gave trans-ole®nated N-Boc sphingosine 11, and
conversion into d-erythro-sphingosine by deprotection
have already been reported.11
Hydride reduction of the ketone 9 to introduce the C4
hydroxy group of phytosphingosine 2 is summarized in
Table 1. The hydride reduction using DIBAL in toluene
gave no selective results 'entry 1). The reduction using
LiEt3BH in THF at 2788C gave satisfactory results in
yield and stereoselectivity 'entry 2). The reduction using
l-selectride gave no reducing products, which may have
been due to the bulkiness of the reducing agent 'entry 3).
The diastereomeric ratio of these compounds was deter-
4.1.2. *3S,4S)-3-tert-Butyldiphenylsilyloxy-4-triisopropyl-
silyloxymethylazetidin-2-one *5). To a solution of 4
'0.49 g, 1.4 mmol) and imidazole '0.28 g, 4.1 mmol) in
DMF '3.0 ml) was added TIPSCl '0.45 ml, 2.1 mmol).
After stirring for 4 h at room temperature, the reaction
mixture was treated with sat. NaHCO3 '0.5 ml) and poured
into H2O '20 ml). After extraction with ether, the organic
layer was washed with brine and dried over anhydrous
MgSO4. The crude product was concentrated in vacuo and
puri®ed by silica gel column chromatography. Elution with
EtOAc/hexane '1:9, then 1:4) afforded 5 '0.67 g, 95%) as a
1
mined by H NMR. However, the stereochemistry was not
identi®ed at this stage. Therefore, we converted the major
compound 12 obtained in this reduction to a deprotected
compound by treatment with TBAF, and then 10% HCl in
MeOH 'Scheme 3). That compound was the same as the one
in the reported data of 2.12 It then became clear that the
con®guration of the major product obtained from LiEt3BH
reduction of 9 was the compound 12S.
colorless oil. [a]24 ˆ253.18 'c 0.35, CHCl3). IR 'CHCl3)
D
3237, 3072, 3051, 1767 cm21. 1H NMR 'CDCl3) d 0.92 's,
21H), 1.08 's, 9H), 3.16 'dd, 1H, Jˆ11.9, 8.2 Hz), 3.31 'dd,
1H, Jˆ11.9, 3.8 Hz), 3.59 'ddd, 1H, Jˆ8.2, 3.8, 3.1 Hz),
4.56 't, 1H, Jˆ3.1 Hz), 5.95 'brs, 1H), 7.32±7.50 'm, 6H),
7.65±7.80 'm, 4H). 13C NMR 'CDCl3) d 11.72 '3C),
17.85 '6C), 19.13, 26.63 '3C), 60.63, 63.27, 78.46,
127.88 '4C), 130.03, 130.03, 130.14, 132.03, 133.21,
135.58 '2C), 135.75 '2C), 168.09. HRMS 'FAB, positive),
calcd for C29H45NNaO3Si2: 'M1Na)1 534.2836; found
534.2832.
3. Summary
In summary, we have developed an alternative method,
which allows the total synthesis of d-erythro sphingosine
and l-lyxo phytosphingosine from the same precursor
ketone 9. Thus, the C4±C5 E-double bond moiety of
sphingosine could be constructed by hydride reduction of
the enol tri¯ate 10, which is obtained by Z-selective
enolization of the ketone 9. The C4 hydroxy group of
phytosphingosine was also constructed by stereoselective
reduction of the carbonyl moiety of the ketone 9.
4.1.3. *3S,4S)-N-tert-Butoxycarbonyl-3-tert-butyldiphenyl-
silyloxy-4-*triisopropylsilyloxy)methylazetidin-2-one *6).
To a solution of 5 '0.63 g, 1.23 mmol), DMAP '10 mg,
0.082 mmol) and Et3N '0.52 ml, 3.7 mmol) in CH2Cl2
'3.0 ml) was added di-tert-butyl dicarbonate '0.32 ml,
1.8 mmol). After stirring for 1 h at room temperature, the
reaction mixture was treated with sat. NaHCO3 '0.50 ml)
and poured into H2O '20 ml). After extraction with ether,
the organic layer was washed with brine and dried over
anhydrous MgSO4. The crude product was concentrated in
vacuo and puri®ed by silica gel column chromatography.
Elution with EtOAc/hexane '1:9) afforded 6 '0.77 g,
4. Experimental
4.1. General
1H NMR spectra were recorded on a JEOL JNM-EX270 at
270 MHz using tetramethylsilane as an internal reference.
13C NMR spectra were recorded on a JEOL JNM-GSX400
at 100 MHz. IR absorption spectra were recorded on a Jasco
IR A-2 spectrophotometer, and mass spectra were obtained
with a JMS-O1SG mass spectrometer. Separation of the
compounds by column chromatography was carried out
with Silica Gel 60 'Merck, 230±400 mesh ASTM).
100%) as a colorless oil. [a]24 ˆ11.28 'c 0.35, CHCl3).
D
1
IR 'CHCl3) 1805, 1719 cm21. H NMR 'CDCl3) d 0.77±
0.90 'm, 21H), 1.08 's, 9H), 1.51 's, 9H), 3.38 'dd, 1H,
Jˆ11.4, 1.6 Hz), 3.85 'ddd, 1H, Jˆ1.8, 1.6, 2.3 Hz), 4.96
'd, 1H, Jˆ2.3 Hz), 7.33±7.50 'm, 6H), 7.63±7.80 'm, 4H).

9090
T. Nakamura, M. Shiozaki / Tetrahedron 57 .2001) 9087±9092
13C NMR 'CDCl3) d 11.73 '3C), 17.78 '6C), 19.24, 26.62
'3C), 28.05 '3C), 58.53, 60.38, 63.29, 76.47, 83.15, 127.91
'4C), 130.09, 130.14, 131.90, 133.06, 135.51 '2C), 135.76
'2C), 148.60, 165.36. HRMS 'FAB, positive), calcd for
C34H53NNaO5Si2: 'M1Na)1 612.3541; found 612.3565.
Anal. calcd for C34H53NO5Si2; C, 66.73; H, 8.73; N, 2.29.
Found; C, 66.33; H, 8.33; N, 2.24.
layer was diluted with brine and dried over anhydrous
MgSO4 and concentrated to give a residue, which was puri-
®ed by silica gel column chromatography. Elution with
EtOAc/hexane '0:100, then 5:95) afforded 9 '93 mg, 93%)
as a colorless oil. [a]24 ˆ14.98 'c 1.0, CHCl3). IR 'CHCl3)
D
1
3445, 1709, 1501 cm21. H NMR 'CDCl3) d 0.88 't, 3H,
Jˆ6.5 Hz), 0.94±1.32 'm, 63H), 2.08 'dt, 1H, Jˆ17.6,
5.8 Hz), 2.30 'dt, 1H, Jˆ17.6, 6.4 Hz), 3.69 'dd, 1H, Jˆ
9.9, 8.0 Hz), 3.77 'dd, 1H, Jˆ9.9, 5.8 Hz), 4.08 'm, 1H),
4.39 'd, 1H, Jˆ4.8 Hz), 4.82 'd, 1H, Jˆ9.0 Hz), 7.30±7.66
'm, 10H). 13C NMR 'CDCl3) d 11.92 '3C), 14.13, 17.96
'6C), 19.60, 22.72 '2C), 27.06 '3C), 28.33 '3C), 29.00,
29.40 '3C), 29.69 '3C), 31.61, 31.95 '3C), 39.29, 55.01,
61.96, 77.87, 79.25, 127.61 '2C), 127.73 '2C), 129.86,
129.90, 133.04, 133.09, 135.91 '2C), 136.04 '2C), 155.38,
209.40. HRMS 'FAB, positive), calcd for C48H83NNaO5Si2:
'M1Na)1 832.5708; found 832.5697. Anal. calcd for
C48H85NO5Si2; C, 70.97; H, 10.55; N, 1.72. Found; C,
71.37; H, 10.15; N, 1.58.
4.1.4. 4-Tolyl tetradecylsulfone *7). To a solution of
p-toluenesul®nic acid sodium salt '1.1 g, 6.0 mmol) in
MeOH '7 ml) was added 1-bromotetradecane '1.5 ml,
5.0 mmol). The reaction mixture was re¯uxed for 24 h and
cooled and the solvent evaporated. The crude mixture was
added to H2O '5.0 ml), and extracted with AcOEt. The
organic layer was washed with brine and dried over
anhydrous MgSO4. After the removal of solvents, recrystal-
lization from hexane gave 7 '1.0 g, 73%) as a white crystal-
line solid. mp 61±638C. IR 'CHCl3) 1316, 1303, 1288,
1144 cm21
.
1H NMR 'CDCl3) d 0.87 't, 3H, Jˆ
5.7 Hz),1.20±1.40 'm, 22H), 1.60±1.75 'm, 2H), 2.45 's,
3H), 3.00±3.09 'm, 2H), 7.36 'd, 2H, Jˆ8.7 Hz), 7.79 'd,
2H, Jˆ8.7 Hz). 13C NMR 'CDCl3) d 14.12, 21.62, 22.73
'2C), 28.29, 29.02, 29.26, 29.36, 29.48, 29.58, 29.66 '2C),
31.94, 56.46, 77.05, 128.11 '2C), 129.87 '2C), 136.40,
144.51. HRMS 'FAB, positive), calcd for C21H37O2S:
'M1H)1 353.2514; found 353.2534. Anal. calcd for
C21H36O2S; C, 71.54; H, 10.29; S, 9.09. Found; C, 71.14;
H, 10.39; S, 9.07.
4.1.7.
*2S,3S,4Z)-2-tert-Butoxycarbonylamino-3-tert-
butyldiphenylsilyloxy-4-tri¯uoromethanesulfonyloxy-1-
triisopropylsilyloxyoctadec-4-ene *10). A solution of 9
'93 mg, 0.11 mmol) in THF '0.3 ml) was cooled to
2788C, treated with 0.5 M KHMDS/toluene solution
'0.70 ml, 0.35 mmol) and stirred for 1 h. The reaction
mixture was warmed up to 2238C, and N-phenylbistri-
¯uoromethanesulfonamide '0.10 g, 0.34 mmol) was added.
After stirring for 20 min, the reaction mixture was treated
with sat. NH4Cl '0.10 ml) and poured into H2O '10 ml).
After extraction with ether, the organic layer was diluted
with brine and dried over anhydrous MgSO4 and concen-
trated to give a residue, which was puri®ed by silica gel
column chromatography. Elution with EtOAc/hexane
'0:10, then 1:49) afforded 10 '107 mg, 99%) as a colorless
4.1.5. *2S,3S,5RS)-2-tert-Butoxycarbonylamino-3-tert-
butyldiphenylsilyloxy-5-p-tolylsulfonyl-1-triisopropyl-
silyloxyoctadecan-4-one *8). To a solution of 7 '33.8 mg,
0.096 mmol) in THF '0.80 ml) cooled to 08C was added
1.5 M n-BuLi/hexane solution '0.12 ml, 0.19 mmol). After
stirring for 5 min, the reaction mixture was cooled to
2788C, and added to a solution of 6 '30 mg, 0.048 mmol)
in THF '0.50 ml) via cannula. After stirring for 1 h at
2788C, the reaction mixture was treated with sat. NH4Cl
'0.10 ml) and poured into H2O '10 ml). After extraction
with ether, the organic layer was washed with brine and
dried over anhydrous MgSO4. The solvents were removed
under reduced pressure and puri®ed by silica gel column
chromatography. Elution with EtOAc/hexane '3:97, then
oil. [a]24 ˆ21.18 'c 1.0, CHCl3). IR 'CHCl3) 3447, 1712,
D
1
1503 cm21. H NMR 'CDCl3) d 0.82±1.43 'm, 64H), 1.60
'm, 1H), 2.04 'm, 1H), 3.57±3.92 'm, 3H), 4.52 'd, 1H, Jˆ
5.3 Hz), 4.65 'd, 1H, Jˆ8.4 Hz), 5.51 't, 1H, Jˆ8.0 Hz),
7.23±7.80 'm, 10H). 13C NMR 'CDCl3) d 11.87 '3C),
14.14, 17.97 '6C), 19.40, 22.68, 22.73, 25.59, 29.63,
27.01 '3C), 28.30 '3C), 28.44, 28.90, 29.26, 29.37, 29.54,
29.70 '2C), 31.63, 31.97, 55.43, 62.28, 72.84, 78.82, 125.30,
127.59 '2C), 127.81 '2C), 129.91, 130.02, 132.84 '2C),
136.02 '2C), 136.13 '2C), 146.30, 155.14. HRMS
'FAB, positive), calcd for C49H82F3NNaO7SSi2:
'M1Na)1 964.5200; found 964.5198. Anal. calcd for
C49H82F3NO7SSi2; C, 62.45; H, 8.77; N, 1.49; S, 3.40.
Found; C, 62.85; H, 8.73; N, 1.49; S, 3.03.
5:95) afforded 8 '40 mg, 86%) as a colorless oil. [a]24
ˆ
D
17.58 'c 1.0, CHCl3). IR 'CHCl3) 3420, 1712, 1598, 1319,
1
1305, 1290 cm21. H NMR 'CDCl3) '1:1 diastereomeric
mixture) d 0.80±1.50 'm, 66H), 2.42 's, 3H), 3.62±3.71
'm, 1H), 3.77±3.87 'm, 1H), 4.10±4.50 'm, 1.5H), 4.71 't,
0.5H, Jˆ7.2 Hz), 4.80±5.05 'm, 2H), 7.20±7.80 'm, 14H).
HRMS 'FAB, positive), calcd for C55H89KNO7Si2:
'M1K)1 1002.5535; found 1002.5539. Anal. calcd for
C55H91NO7SSi2; C, 68.35; H, 9.49; N, 1.45; S, 3.32.
Found; C, 68.75; H, 9.70; N, 1.50; S, 3.40.
4.1.8. *2S,3R,4E)-2-tert-Butoxycarbonylaminooctadec-4-
ene-1,3-diol *11). To a stirred solution of 10 '53 mg,
0.056 mmol) and tributylamine '41 ml, 0.17 mmol), bis-
'acetato)bis'triphenylphosphine)palladium '4.5 mg, 0.006
mmol) in DMF '0.3 ml) was added formic acid '4.3 ml,
0.11 mmol) at room temperature. After stirring for 7 h at
608C, the reaction mixture was treated with sat. NaHCO3
'0.20 ml) and extracted with ether. The ether layer was
evaporated in vacuo. The crude mixture was dissolved in
THF '0.10 ml) and added to 1.0 M TBAF/THF solution
'0.12 ml, 0.12 mmol). After stirring for 2 h at room
temperature, the reaction mixture was treated with sat.
NaHCO3 '0.20 ml) and poured into H2O '10 ml). After
4.1.6. *2S,3S)-2-tert-Butoxycarbonylamino-3-tert-butyl-
diphenylsilyloxy-1-triisopropylsilyloxyoctadecan-4-one
*9). To a solution of lithium-naphthalenide, prepared from
naphthalene '64 mg, 0.50 mmol) in THF '1.0 ml) and Li
wire '4.3 mg, 0.62 mmol) was added a solution of 7
'0.12 g, 0.12 mmol) in THF '0.50 ml) via cannula. The
mixture was stirred for 20 min at 2788C. The reaction
mixture was treated with sat. NH4Cl '0.50 ml) and poured
into H2O '10 ml). After extraction with ether, the organic

T. Nakamura, M. Shiozaki / Tetrahedron 57 .2001) 9087±9092
9091
extraction with ether, the organic layer was washed with
References
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chromatography. Elution with EtOAc/hexane '3:7±2:3)
afforded 11 '14 mg, 63%) as a white crystalline solid. Mp
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61±648C; [a]24 ˆ21.48 'c 1.0, CHCl3). IR 'KBr) 3364,
D
1
1687, 1668, 1533 cm21. H NMR 'CDCl3) d 0.88 't, 3H,
Jˆ5.5 Hz), 1.20±1.54 'm, 33H), 2.05 'q, 2H, Jˆ7.5 Hz),
3.5±3.67 'm, 1H), 3.72 'dd, 1H, Jˆ8.3, 4.5 Hz), 4.32 't,
1H, Jˆ6.7 Hz), 5.30 'brs, 1H), 5.53 'dd, 1H, Jˆ16.3,
6.7 Hz), 5.78 'dt, 1H, Jˆ16.3, 7.2 Hz). 13C NMR 'CDCl3)
d 14.13, 22.71 '2C), 27.72, 28.11, 28.41 '3C), 28.56, 29.14,
29.24, 29.39, 29.51, 29.71, 31.95, 32.33, 55.49, 62.66,
74.77, 79.81, 128.98, 134.15, 156.28. HRMS 'FAB,
positive), calcd for C23H46NO4: 'M1H)1 400.3427;
found 400.3432. Anal. calcd for C23H45NO4; C, 69.13;
H, 11.35; N, 3.51; S, 3.32. Found; C, 68.73; H, 10.95; N,
3.44.
4.1.9. *2S,3S,4S)-2-tert-Butoxycarbonylaminooctadecane-
1,3,4-triol *13). To a solution of 9 '55 mg, 0.068 mmol) in
THF '0.30 ml) cooled to 2788C was added 1.0 M lithium
triethylborohydride '0.21 ml, 0.21 mmol). After stirring for
2 h, the reaction mixture was treated with sat. Na2CO3
'0.20 ml) and 30% aqueous H2O2 '0.10 ml) and warmed
to room temperature. The aqueous layer was extracted
with ether, and the ether layer was evaporated in vacuo.
The crude mixture was dissolved in THF '0.20 ml) and
treated with 1.0 M TBAF/THF solution '0.13 ml, 0.13
mmol). After stirring for 2 h at room temperature, the reac-
tion mixture was treated with sat. NaHCO3 '0.20 ml). After
extraction with ether, the organic layer was washed with
brine and dried over anhydrous MgSO4 and concentrated
to give a residue, which was puri®ed by silica gel column
chromatography. Elution with EtOAc/hexane '1:1±3:2)
afforded 13 '24 mg, 85%) as a white crystalline solid. Mp
4. Reviews: 'a) Merrill Jr., A. H.; Sweeley, C. C. In Biochemistry
of Lipids, Lipoproteins and Membranes, Vance, D. E., Vance,
J. E., Eds.; Elsevier: Amsterdam, 1996; pp. 309±339 Chapter
12. 'b) Ref. 1a. 'c) Kolter, T.; Sandhoff, K. Angew. Chem., Int.
Ed. 1999, 38, 1532±1568.
5. For recent studies on synthesis of phytosphingosine and its
derivatives, see: 'a) Sugiyama, S.; Honda, M.; Komori, T.
Liebigs Ann. Chem. 1990, 1069±1078. 'b) Dondoni, A.;
Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990,
55, 1439±1446. 'c) Wild, R.; Schmidt, R. R. Tetrahedron:
Asymmetry 1994, 5, 2195±2208. 'd) Murakami, T.;
Minamikawa, H.; Hato, M. Tetrahedron Lett. 1994, 35,
745±748. 'e) Nakashima, H.; Hirata, N.; Iwamura, T.;
Yamagiwa, Y.; Kamikawa, T. J. Chem. Soc., Perkin Trans.
1 1994, 2849±2857. 'f) Kobayashi, S.; Hayashi, T.; Kawasuji,
T. Tetrahedron Lett. 1994, 35, 9573±9576. 'g) Matsumoto,
K.; Ebatu, T.; Matsushita, H. Carbohydr. Res. 1995, 279,
93±106. 'h) Wild, R.; Schmidt, R. R. Liebigs Ann. Chem.
1995, 755±764. 'i) Li, Y. L.; Mao, X. H.; Wu, Y. L.
J. Chem. Soc., Perkin Trans. 1 1995, 1559±1563. 'j) Kemp,
S. J.; Bao, J.; Pedersen, S. F. J. Org. Chem. 1996, 61, 7162±
7167. 'k) Lin, G. Q.; Shi, Z. C. Tetrahedron 1996, 52, 2187±
2192. 'l) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron:
Asymmetry 1996, 7, 2113±2116. 'm) Murakami, M.; Ito, H.;
Ito, Y. Chem. Lett. 1996, 185±186. 'n) Wee, A. G. H.; Tang, F.
Tetrahedron Lett. 1996, 37, 6677±6688. 'o) Shimizu, M.;
Wakioka, I.; Fujisawa, T. Tetrahedron Lett. 1997, 38, 6027±
6030. 'p) Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa,
H. Tetrahedron 1998, 54, 10657±10670. 'q) Takikawa, H.;
Muto, S.; Mori, K. Tetrahedron 1998, 54, 3141±3150.
'r) Li, S.; Pang, J.; Wilson, W. K.; Schroepfer Jr., J.
Tetrahedron: Asymmetry 1999, 10, 1697±1707. 's) Murakami,
T.; Toguchi, K. Tetrahedron 1999, 55, 989±1004. 't) Shirota,
O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55, 13643±
13658. 'u) Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R.
Tetrahedron: Asymmetry 2000, 11, 1585±1592 and references
cited therein.
142±1458C. [a]24 ˆ27.78 'c 0.10, CHCl3). IR 'KBr) 3351,
D
1
3255, 1672, 1544 cm21. H NMR 'CDCl3) d 0.88 't, 3H,
Jˆ6.9 Hz), 1.19±1.75 'm, 35H), 3.40 'd, 1H, Jˆ9.5 Hz),
3.48±3.70 'm, 2H), 3.75 'dd, 1H, Jˆ11.0, 4.0 Hz),
4.06 'dd, 1H, Jˆ11.0, 2.6 Hz), 5.24 'd, 1H, Jˆ8.6 Hz).
14.14, 22.71, 26.10, 28.35
13C NMR 'CDCl3)
d
'3C), 29.38 '2C), 29.57, 29.70 '5C), 31.96, 32.81, 53.51,
62.04, 69.68, 72.91, 77.62, 80.42, 157.20. HRMS 'FAB,
positive), calcd for C23H48NO5: 'M1H)1 418.3532; found
418.3525.
4.1.10. *2S,3S,4S)-2-Aminooctadecane-1,3,4-triol *2). To
a solution of 13 '6.6 mg, 0.016 mmol) in MeOH '0.1 ml)
was added 10% 'w/v) HCl/MeOH '0.1 ml) and the mixture
was stirred for 9 h at 408C. The reaction mixture was
concentrated in vacuo and puri®ed by silica gel column
chromatography. Elution with CHCl3/MeOH/aq. NH3
'40:10:1) afforded 2 '4.8 mg, 96%) as a white crystalline
solid. Mp 92±958C. [a]24 ˆ22.68 'c 0.21, pyridine). IR
D
1
'KBr) 3374, 3318, 3267, 3054 cm21. H NMR 'CD3OD) d
0.90 't, 3H, Jˆ7.4 Hz), 1.20±1.60 'm, 26H), 3.20±3.33 'm,
1H), 3.54±3.67 'm, 2H), 3.70 'dd, 1H, Jˆ11.6, 7.4 Hz), 3.84
6. Barrett, A. G. M.; Sakadarat, S. J. Org. Chem. 1990, 55,
5110±5177.
1
'dd, 1H, Jˆ11.6, 5.0 Hz); H NMR 'DMSO-d6) d 0.86 't,
3H, Jˆ6.5 Hz), 1.15±1.35 'm, 24H), 1.35±1.50 'm, 2H),
3.06±3.08 'm, 1H), 3.40±3.51 'm, 6H), 3.68 'dd, 1H, Jˆ
3.9, 11.4 Hz). HRMS 'FAB, positive), calcd for C18H40NO3:
'M1H)1 318.3008; found 318.3026.
7. Baldwin, J. E.; Adlighton, R. M.; Russell, A. T.; Smith, M. L.
Tetrahedron 1995, 51, 4733±4762.
8. Jones, A. B.; Villarobos, A.; Linde II, R. G.; Danishefsky, S. J.
J. Org. Chem. 1990, 55, 2786±2797.

9092
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11. Herold, P. Helv. Chim. Acta 1988, 71, 354±362 and Ref. 1e.
9. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979±
982.
12. Refs. 5a,i,t and Schmidt, R. R.; Maier, T. Carbohydr. Res.
1988, 174, 169±179.
10. Cacchi, S.; Morera, A.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821±4824.