Total syntheses of D -xylo- and D -arabino-phytosphingosine based on the syntheses of chiral 1,3-oxazines

Article abstract of DOI:10.1002/ejoc.201200064

An efficient, stereocontrolled, and short synthetic method for the preparation D-xylo- and D-arabino-phytosphingsine was achieved utilizing chiral oxazines. The key features of this strategy are the stereoselective intramolecular oxazine formation catalyzed by palladium(0) and an intermolecular olefin cross-metathesis reaction.

Full text of DOI:10.1002/ejoc.201200064

FULL PAPER
DOI: 10.1002/ejoc.201200064
Total Syntheses of
D
-xylo- and
D
-arabino-Phytosphingosine Based on the
Syntheses of Chiral 1,3-Oxazines
Yu Mu,[a] Tian Jin,[a] Gun-Woo Kim,[a] Jin-Seok Kim,[a] Sung-Soo Kim,[a]
Yong-Shou Tian,[a] Chang-Young Oh,[b] and Won-Hun Ham*[a]
Keywords: Total synthesis / Natural products / Nitrogen heterocycles / Sphingolipids / Palladium / Diastereoselectivity /
C–C coupling
An efficient, stereocontrolled, and short synthetic method for
the preparation -xylo- and -arabino-phytosphingsine was
achieved utilizing chiral oxazines. The key features of this
strategy are the stereoselective intramolecular oxazine for-
mation catalyzed by palladium(0) and an intermolecular ole-
fin cross-metathesis reaction.
D
D
Introduction
Phytosphingosines, one of the most important sphingoli-
pids, are widely distributed in plants, fungi, yeasts, mamma-
lian tissues, and marine organisms.[1,2] They consist of a
base bearing a long aliphatic chain (18 carbon atoms) and
a polar 2-amino-1,3,4-triol head group. d-ribo-Phytosphin-
gosine (1) is a potential heat stress signal in yeast cells and
a cytotoxic agent against human leukemic cell lines.[3,4]
Some of its derivatives exhibit significant immunostimula-
tory, antitumor, and antiviral activities.[5–7]
The subtle variations in biological activities throughout
the diastereomers of the phytosphingosines have inevitably
led to their syntheses as well as the syntheses of more than
one stereoisomer. Both the wide spectrum of biological ac-
tivity for these molecules and their three contiguous stereo-
centers justify the efforts towards the syntheses of them as
well as their stereoisomers, as shown in Figure 1.[8–10]
On the basis of our previous research, we anticipated
that the palladium(0)-catalyzed oxazine formation of a γ-
allyl benzamide with a benzoyl substituent as the N-protect-
ing group in the presence of Pd(PPh3)4, NaH, and nBu4NI
might proceed with high stereoselectivity. Unlike other pal-
ladium-catalyzed reactions, the diastereoselectivity of the
oxazine ring formation is predominantly controlled by tem-
perature. Our study of intramolecular oxazine formation
starting from 5a–d shows that the stereoselectivity of these
cyclizations is critically dependent upon the reaction tem-
Figure 1. Structures of d-ribo-phytosphingosine (1), d-lyxo-phyto-
sphingosine (2), d-xylo-phytosphingosine (3), and d-arabino-phyto-
sphingosine (4).
perature, resulting in kinetic or thermodynamic control of
the products (Scheme 1). Starting from allyl chlorides 5a–d,
both syn,syn-6a–d and syn,anti-6aЈ–dЈ isomers were stereo-
selectively prepared by changing the reaction temperature,
syn,syn-6a–d under kinetic control (0 °C) and syn,anti-
6aЈ–dЈ under thermodynamic control (40 °C).[11]
[a] School of Pharmacy, Sungkyunkwan University,
Suwon 440-746, Republic of Korea
Fax: +82-31-292-8800
E-mail: whham@skku.edu
Scheme 1. Palladium-catalyzed oxazine formation.
[b] Yonsung Fine Chemicals Co., Ltd.,
129-9 Suchon-ri, Hangan-myeon, Hwaseong-si, Gyeonggi-do
445-944, Republic of Korea
We have also explored the utility of enantiopure oxazine
as a chiral building block for use in the stereocontrolled
syntheses of natural products. As part of this program, we
have developed a new strategy for stereoselective syntheses
Fax: +82-31-351-6624
E-mail: yonsungfc@yonsungchem.co.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200064.
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Total Syntheses of d-xylo- and d-arabino-Phytosphingosine
Scheme 2. Retrosyntheses of d-xylo-phytosphingosine (3) and d-arabino-phytosphingosine (4).
of 3 and 4. Herein, we describe new asymmetric syntheses
of 3 and 4 utilizing oxazines 6e and 6eЈ as chiral building
blocks. We envision that this method could be utilized to
set the three contiguous stereocenters in 3 and 4. The pen-
dant vinyl group of oxazines could be converted into alk-
enes 7 and 7Ј through an olefin cross-metathesis reaction.
We now report the efficient and concise syntheses of 3 and
4 in accordance with these strategies. Our retrosynthetic
analysis is displayed in Scheme 2.
Results and Discussion
Scheme 3. Reagents and conditions: (a) MeNHOMe·HCl, Me3Al,
As shown in Scheme 3, N-Benzoyl-l-serine methyl ester
8 was readily converted into the Weinreb amide in 95%
yield by treatment with N,O-dimethylhydroxylamine in the
presence of trimethylaluminium. The reaction of the Wein-
reb amide with vinyltin 9[12] and MeLi in THF (tetra-
hydrofuran) at –78 °C gave α,β-unsaturated ketone 10 in
86% yield. The chelation-controlled hydride reduction of
10 using lithium tri-tert-butoxyaluminohydride yielded anti-
amino alcohol with excellent stereoselectivity (anti/syn, 10:1
CH2Cl2, 0 °C to r.t., 95%; (b) 9, MeLi, THF, –78 °C, 86%; (c) Li-
AlH(OtBu)3, EtOH, –78 °C, 87% (anti/syn, 10:1); (d) DEAD (di-
ethyl azodicarboxylate), PPh3, p-nitrobenzoic acid (catalytic), THF,
room temp., 89%; (e) HCl (1 n), THF, MeOH then NaHCO3;
(f) TBSCl, imidazole, DMF (dimethylformamide), 89% (2 steps).
1
determined by H NMR). A p-nitrobenzoic acid-catalyzed
Mitsunobu-type reaction of anti-amino alcohol gave trans-
oxazoline 11 in a good yield (89%). The subsequent acid-
catalyzed hydrolysis of the oxazoline followed by the ad-
dition of sodium hydrogen carbonate to increase the pH of
Scheme 4. Oxazine formation catalyzed by Pd0.
the reaction mixture to 9.0 furnished the syn-amino stereochemistry of the major diastereomer 6eЈ was assumed
alcohol. The protection of the resulting alcohol by TBSCl to be anti, in the light of our previous results, and was con-
(t-butyldimethylsilyl chloride) afforded the cyclization pre- firmed by its conversion into d-arabino-phytosphingosine
cursor 5e in 89% yield.
(4).
To verify the stereochemical outcome at the newly gener-
Under the conditions of Pd(PPh3)4, NaH, and nBu4NI
in THF at 0 °C, the stereoselective intramolecular cycliza- ated stereocenter at C-6, the NOE spectroscopic data of the
tion of the allyl chloride 5e afforded syn,syn-oxazine 6e and oxazine was studied under the assumption that there must
syn,anti-oxazine 6eЈ as a 9.5:1 mixture (1H NMR) in good be NOE differences between the two isomers 6e and 6eЈ.
yield (see Scheme 4). However, when the reaction tempera- The assignment of relative configuration was confirmed by
ture was increased to 50 °C, the diastereoselectivity of the observation of the larger NOE enhancements for syn,syn-
reaction changed. The major isomer was syn,anti-oxazine oxazine 6e compared to syn,anti-oxazine 6eЈ as shown in
6eЈ (1:9 mixture), which was obtained in 73% yield.
Figure 2. In the case of syn,syn-oxazine 6e, there is a NOE
It is interesting that the palladium-catalyzed reaction is of 5.28% between H-5 and H-6, 3.94% between H-5 and H-
strongly temperature-dependent. At 0 °C, the stereochemis- 4, and 3.69% between H-4 and H-6. In the case of syn,anti-
try of the major diastereomer 6e was assumed to be syn, in oxazine 6eЈ, there is a NOE of 5.46% between H-5 and H-
the light of our previous results, and was confirmed by its 6, 8.24% between H-5 and H-4, but no NOE effect between
conversion into d-xylo-phytosphingosine (3). At 50 °C, the H-4 and H-6.
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W.-H. Ham et al.
FULL PAPER
+12.9 (c = 0.5, pyridine),[10a] confirmed the absolute config-
uration of 3.
In the same manner, d-arabino-phytosphingosine (4) was
synthesized from oxazine 6eЈ (see Scheme 6). The optical
rotation of 4, [α]2D5 = –3.79 (c = 0.6, pyridine), compared to
the reported value, [α]2D5 = –2.76 (c = 1.0, pyridine),[10d] con-
firmed the absolute configuration of 4.
Figure 2. NOE spectroscopic data of 6e and 6eЈ.
After the silica gel column separation, the relative config-
uration of each of the oxazine diastereomers was deter-
mined by comparing their coupling constants. Small cou-
pling constants, like J5,6 = 1.5 Hz as for syn,syn-oxazine 6e,
are caused by the axial–equatorial relationship between the
two adjacent protons in six-membered rings. Large cou-
pling constants, like J5,6 = 4.0 Hz as for syn,anti-oxazine
6eЈ, are typically because of the diequatorial relationship
between the two adjacent protons in six-membered rings.
Scheme 6. Reagents and conditions: (a) 1-tetradecene, Grubbs’ sec-
ond-generation catalyst, CH2Cl2, 90%, E/Z Ͼ 20:1; (b) TBAF,
THF, 90%; (c) Pd(OH)2/C, (Boc)2O, H2, hexane/MeOH, 3:2, 72%;
(d) HCl (6 n), MeOH, 79%.
1
Compound 6e and 6eЈ have almost similar TLC and H
NMR patterns as previously reported benzyl oxazine com-
pounds. In the 1H NMR for syn,syn-oxazine 6e, the protons
of the terminal olefin and H-5 have peaks at δ = 6.0 and
4.2 ppm, respectively. In the H NMR for syn,anti-oxazine
6eЈ, the protons of the terminal olefin and H-5 have peaks
at δ = 5.9 and 4.0 ppm, respectively.
The spectroscopic (1H and 13C NMR) data for synthetic
3 and 4 were fully identical with those of the natural prod-
ucts, and the properties of 3 and 4 showed good agreement
with those reported.[10]
1
The olefin cross-metathesis reaction of oxazine with 1-
tetradecene in the presence of 3 mol-% of the Grubbs’ sec-
ond-generation catalyst yielded the desired alkene 7 in a
high yield (92%) with a stereoselectivity of E/Z Ͼ 20:1.[13]
After removal of the TBS groups with TBAF (tetra-n-butyl-
ammonium fluoride, 88%), the oxazine ring was cleaved by
treatment with Pd(OH)2/C under hydrogen in the presence
of (Boc)2O (di-tert-butyl dicarbonate) to give triol 12 in
69% yield (Scheme 5). Finally, the Boc protecting group
was removed by treatment with 6 n HCl in methanol, and
the crude product was purified by column chromatography
over silica gel to give d-xylo-phytosphingosine (3) as a white
solid in 74% yield. The optical rotation of 3, [α]2D5 = +11.15
Conclusions
We have described a new Pd0-catalyzed procedure for the
stereoselective formation of an oxazine ring. The diastereo-
selectivity of the oxazine ring formation is predominantly
controlled by temperature. On the basis of these results, we
applied the asymmetric synthetic method to d-xylo-phyto-
sphingosine (3) and d-arabino-phytosphingsine (4), utilizing
chiral oxazines 6 and 6eЈ. The key features of these strate-
gies are the stereoselective intramolecular oxazine forma-
tion catalyzed by palladium(0) and an intermolecular olefin
cross-metathesis reaction. The main advantage of this strat-
egy is its high versatility, allowing the syntheses of not only
3 and 4, but also a range of structural analogues from a
common precursor oxazine. The net results are syntheses
from a linear sequence starting from 8 in 7 steps and 19%
overall yield for d-xylo-phytosphingosine (3) and 7 steps
and 18.9% overall yield for d-arabino-phytosphingosine (4).
(c = 0.7, pyridine), compared to the reported value, [α]D25
=
Experimental Section
General Methods: Optical rotations were measured with a polari-
meter in the solvent specified. 1H and 13C NMR spectroscopic data
were recorded with FT-NMR 125 or 500 MHz spectrometers at
the Cooperative Center for Research Facilities in Sungkyunkwan
University. Chemical shift values are reported in parts per million
relative to TMS or CDCl3, as the internal standard, and coupling
constants are reported in Hertz. IR spectra were measured with a
FTIR spectrometer. Mass spectroscopic data were obtained from
Scheme 5. Reagents and conditions: (a) 1-tetradecene, Grubbs’ sec-
ond-generation catalyst, CH2Cl2, 92%, E/Z Ͼ 20:1; (b) TBAF,
THF, 88%; (c) Pd(OH)2/C, (Boc)2O, H2, hexane/MeOH, 3:2, 69%;
(d) HCl (6 n), MeOH, 74%.
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Total Syntheses of d-xylo- and d-arabino-Phytosphingosine
the Korea Basic Science Institute (Daegu) with a Jeol JMS 700 high
resolution mass spectrometer. Flash chromatography was executed
using mixtures of ethyl acetate and hexane as the eluents. Unless
otherwise noted, all nonaqueous reactions were carried out under
an argon atmosphere with commercial grade reagents and solvents.
Tetrahydrofuran was distilled from sodium and benzophenone (in-
dicator). Methylene chloride was distilled from calcium hydride.
3.45 mL, 3.45 mmol) at –78 °C. After the reaction mixture was
stirred at the same temperature for 4 h, citric acid (10% aqueous
solution, 20.0 mL) was added. The resulting mixture was warmed
to room temperature and extracted with ethyl acetate (3ϫ20 mL).
The organic layers were combined, washed with brine (50 mL),
dried with MgSO4, filtered, and concentrated in vacuo to give the
crude product. Column chromatography on silica gel gave the
1
amino alcohol (517 mg, 87%, anti/syn, 10:1 by H NMR) as a col-
(S,E)-N-[1-(tert-Butyldimethylsilyloxy)-6-chloro-3-oxohex-4-en-2-yl-
]benzamide (10): To a solution of N,O-dimethylhydroxylamine hy-
drochloride (6.32 g, 64.83 mmol) in CH2Cl2 (200 mL) was added
trimethylaluminum (2.0 m solution in hexane, 32.40 mL,
64.83 mmol) at 0 °C (caution: CH4 evolution). The mixture was
stirred for 30 min at room temperature. Subsequently, a solution of
methyl ester 8 (7.12 g, 21.61 mmol) in CH2Cl2 (200 mL) was added
dropwise. The mixture was stirred at room temperature for 1 h,
after which time, TLC analysis indicated that the reaction was com-
plete. The reaction mixture was cooled to 0 °C and carefully
quenched with sodium potassium tartrate (10% solution, 25 mL).
After stirring for 1 h at room temperature, the resulting suspension
was filtered through a pad of Celite that was then washed with
CH2Cl2. The filtrate was concentrated in vacuo to give the crude
product which upon purification by column chromatography on
silica gel gave the Weinreb amide (5.40 g, 95%) as a colorless oil;
Rf = 0.3 (ethyl acetate/hexane, 1:2). [α]2D5 = +41.15 (c = 1.0, CHCl3).
orless oil; Rf = 0.3 (ethyl acetate/hexane, 1:1). [α]2D5 = +7.95 (c =
1.0, CHCl ). IR (neat): ν
= 3346, 2953, 1639, 1534, 1487, 1253,
˜
3
max
1
1076, 712 cm–1. H NMR (500 MHz, CDCl3): δ = 0.08–0.13 (m, 6
H), 0.92–0.95 (m, 9 H), 3.91 (dd, J = 3.0, 10.5 Hz, 1 H), 3.99–4.03
(m, 1 H), 4.05 (d, J = 3.0, 5.4 Hz, 1 H), 4.12 (d, J = 6.0 Hz, 2 H),
4.15–4.25 (m, 1 H), 4.47–4.44 (m, 2 H), 5.87–6.10 (m, 2 H), 6.97
(d, J = 8.1 Hz, 1 H), 7.42–7.59 (m, 3 H), 7.78–7.85 (m, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = –5.38, –5.35, 18.30, 54.03, 63.38,
73.74, 127.17, 127.99, 128.80, 128.91, 131.98, 134.32, 134.41,
167.86 ppm. HRMS (FAB+): calcd. for C19H30NO3SiCl [M + H]+
384.1762; found 384.1764. To a stirred solution of the anti-amino
alcohol (133 mg, 0.37 mmol), p-nitrobenzoic acid (12 mg,
0.074 mmol), and triphenylphosphane (145 mg, 0.55 mmol) in dry
THF (4.0 mL) was added dropwise diethyl azodicarboxylate (40%
in toluene, 0.24 mL, 0.55 mmol) at room temperature. The stirring
was continued for 15 min, after which time, TLC analysis indicated
that the reaction was complete. The reaction mixture was added
to an aqueous saturated solution of sodium hydrogen carbonate
(3.0 mL), and the mixture was extracted with diethyl ether
(2ϫ5.0 mL). The extracts were washed with brine (10 mL) and
dried with MgSO4, and the solvents were evaporated in vacuo. The
residue was purified by silica gel column chromatography to give
oxazoline 11 (105 mg, 0.31 mmol, 89%) as a colorless oil; Rf = 0.30
(ethyl acetate/hexane, 1:8). [α]2D5 = +3.62 (c = 0.29, CHCl3). IR
IR (neat): νmax = 3326, 2931, 2857, 1644, 1111, 838 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 0.02–0.05 (m, 6 H), 0.92 (s, 9 H), 3.29 (s,
3 H), 3.83 (s, 3 H), 3.96 (dd, J = 4.5, 10.0 Hz, 1 H), 4.06 (dd, J =
4.5, 10.0 Hz, 1 H), 5.25 (m, 1 H), 7.09 (d, J = 7.5 Hz, 1 H), 7.44–
7.52 (m, 3 H), 7.83–7.85 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 0.02, 0.05, 23.76, 31.31, 57.48, 67.06, 68.73, 132.62,
134.07, 137.13, 139.26, 172.43 ppm. HRMS (FAB+): calcd. for
C18H31N2O4Si [M + H]+ 367.2053; found 367.2050. Vinyltin 9
(4.83 g, 13.22 mmol) was dissolved in dry THF (40 mL), and the
resulting solution was cooled to –78 °C. MeLi (1.6 m solution in
hexane, 8.27 mL, 13.22 mmol) was added dropwise, and the mix-
ture was stirred for 30 min at the same temperature. Subsequently,
a solution of the Weinreb amide (1.58 g, 4.41 mmol) in dry THF
(30 mL) was added dropwise, and the stirring was continued for
30 min. After this time, TLC analysis indicated that the reaction
was complete. The reaction mixture was quenched by the addition
of aqueous saturated NH4Cl (50 mL), and the resulting mixture
was then warmed to room temperature. The layers were separated,
and the aqueous layer was extracted with ethyl acetate (2ϫ50 mL).
The combined organic layers were washed with a saturated solution
of NaHCO3 (50 mL) and brine (50 mL), dried with MgSO4, and
filtered. The filtrate was concentrated in vacuo. The resulting sub-
stance was purified by silica gel column chromatography to give
amino ketone 10 (1.51 g, 86%) as a colorless oil; Rf = 0.6 (ethyl
acetate/hexane, 1:2). [α]2D5 = +56.19 (c = 1.6, CHCl3). IR (neat):
(neat): ν
= 1649, 1494, 1450, 1328, 1061 cm–1 1H NMR
.
˜
max
(500 MHz, CDCl3): δ = 0.07–0.13 (m, 6 H), 0.89–0.91 (m, 9 H),
3.67 (dd, J = 6.6, 10.2 Hz, 1 H), 3.99 (dd, J = 3.6, 10.2 Hz, 1 H),
4.08–4.14 (m, 3 H), 5.10 (dd, J = 5.4, 6.6 Hz, 1 H), 5.95–6.00 (m,
2 H), 7.42–7.53 (m, 3 H), 7.98–8.01 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.10, 18.44, 26.04, 44.14, 64.93, 74.40,
81.97, 127.84, 128.01, 128.54, 128.57, 131.69, 133.18, 164.03 ppm.
HRMS (FAB+): calcd. for C19H29O2NSiCl [M + H]+ 366.1656;
found 366.1658.
N-{(5S,6S)-5-[(E)-3-Chloroprop-1-enyl]-2,2,3,3,9,9,10,10-octa-
methyl-4,8-dioxa-3,9-disilaundecan-6-yl}benzamide (5e): HCl (1 n
aqueous solution, 14 mL, 14 mmol) was added to a stirred solution
of allyl chloride 11 (1.03 g, 2.81 mmol) in THF (28 mL) and MeOH
(28 mL) at room temperature, and the reaction mixture was stirred
for 12 h. A saturated aqueous solution of NaHCO3 (70 mL) was
added, and the stirring was continued for 3 h. The reaction mixture
was extracted with ethyl acetate (4ϫ50 mL), and the combined
organic layers were washed with brine (50 mL) and dried with
MgSO4. The solvents were evaporated in vacuo. Purification by
silica gel chromatography (ethyl acetate/hexane, 5:1) gave the
alcohol (728 mg) as a colorless oil. Imidazole (0.92 g, 13.46 mmol)
and tert-butylchlorodimethylsilane (2.03 g, 13.46 mmol) were
added to a stirred solution of the alcohol (605 mg, 2.24 mmol) in
DMF (25 mL) at room temperature, and the stirring was continued
for 2 h. The reaction mixture was quenched with H2O (100 mL),
and the resulting mixture was extracted with EtOAc (5ϫ20 mL).
The combined organic layers were washed with brine and dried
with MgSO4, and the solvents were evaporated in vacuo. Purifica-
ν
=
3412, 2932, 1643, 1521, 1255, 974 cm–1. 1H NMR
˜
max
(500 MHz, CDCl3): δ = 0.03–0.09 (m, 6 H), 0.87–0.91 (m, 9 H),
4.02 (dd, J = 4.5, 10.2 Hz, 1 H), 4.26 (dd, J = 3.0, 4.5 Hz, 1 H),
4.27 (dd, J = 1.8, 5.7 Hz, 2 H), 5.06–5.11 (m, 1 H), 6.67 (ddd, J =
1.5, 1.8, 15.3 Hz, 1 H), 7.03–7.08 (m, 1 H), 7.11 (d, J = 3.0 Hz, 1
H), 7.47–7.60 (m, 3 H), 7.86–7.89 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.34, –5.32, 18.28, 25.95, 42.97, 59.67,
63.28, 127.29, 127.46, 128.36, 128.88, 132.02, 134.16, 141.50,
167.13, 195.89 ppm. HRMS (FAB+): calcd. for C19H29NO3SiCl [M
+ H]+ 382.1605; found 382.1602.
(4S,5S)-4-[(tert-Butyldimethylsilyloxy)methyl]-5-[(E)-3-chloroprop-
1-enyl]-2-phenyl-4,5-dihydrooxazole (11): To a solution of amino tion by silica gel chromatography gave silyl ether 5e (1.04 g, 89%)
ketone 10 (644 mg, 1.72 mmol) in ethanol (20 mL) was added lith-
ium tri-tert-butoxyaluminium hydride (1.0 m solution in THF,
as a colorless oil; Rf = 0.20 (ethyl acetate/hexane, 1:8). [α]2D5 = –5.37
(c = 1.3, CHCl ). IR (neat): ν = 2953, 2929, 2857, 1651, 1508,
˜
3
max
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2617

W.-H. Ham et al.
FULL PAPER
1472, 1254, 1123, 965, 837, 694 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 0.07–0.15 (m, 12 H), 0.92 (s, 9 H), 0.95 (s, 9 H), 3.57 (dd, J =
10.0, 9.0 Hz, 1 H), 3.82 (dd, J = 10.0, 4.5 Hz, 1 H), 3.99 (m, 2 H),
4.09 (m, 1 H), 4.66 (dd, J = 3.5, 3.5 Hz, 1 H), 5.81 (m, 2 H), 6.53
(d, J = 9.0 Hz, 1 H), 7.41 (m, 2 H), 7.47 (m, 1 H), 7.74 (m, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.20, –5.07, –4.79,
–3.91, 18.37, 18.84, 26.03, 26.05, 26.09, 26.10, 26.15, 28.27, 44.52,
2 H), 3.53 (m, 1 H), 3.69 (dd, J = 10.0, 10.5 Hz, 1 H), 3.84 (dd, J
= 5.5, 10.0 Hz, 1 H), 4.11 (dd, J = 1.5, 2.0 Hz, 1 H), 4.62 (m, 1 H),
5.67 (dd, J = 7.0, 15.5 Hz, 1 H), 5.84 (dt, J = 7.0, 15.0 Hz, 1 H),
7.32–7.38 (m, 3 H), 7.88–7.93 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3) δ = –5.02, –4.89, –3.99, –3.85, 14.32, 18.51, 22.91, 25.94,
26.15, 26.26, 29.11, 29.57 (several overlapped peaks), 29.88, 29.92,
32.14, 32.70, 60.17, 63.51, 65.29, 80.13, 127.32, 127.45, 128.11,
55.17, 60.76, 69.88, 127.01, 127.39, 128.12, 128.86, 130.01, 131.73, 130.27, 134.21, 135.10, 155.86 ppm. HRMS (FAB+): calcd. for
134.75, 135.53, 167.13 ppm. HRMS (FAB+): calcd. for C37H68NO3Si2 [M + H]+ 630.4738; found 630.4740.
C25H45O3NSi2Cl [M + H]+ 498.2627; found 498.2625.
(4S,5R,6S)-5-(tert-Butyldimethylsilyloxy)-4-[(tert-butyldimethyl-
General Procedure for Oxazine Formation: NaH (60% in mineral
oil, 1.61 mmol) and nBu4NI (0.80 mmol) were added to a stirred
solution of allyl chloride 5e (0.80 mmol) in THF (30 mL) at 0 °C
or 50 °C. After stirring for 5 min, Pd(PPh3)4 (0.16 mmol) was
added to the mixture, and the stirring was continued for 12 h at
the same temperature. The reaction mixture was filtered through a
pad of silica, and the filtrate was evaporated under reduced pres-
sure to give the crude product. Purification by silica gel chromatog-
raphy gave the oxazine as a colorless oil.
silyloxy)methyl]-2-phenyl-6-(tetradec-1-enyl)-5,6-dihydro-4H-1,3-
oxazine (7Ј): Rf = 0.30 (ethyl acetate/hexane, 1:20). [α]2D5 = –34.84
(c = 0.1, CHCl ). IR (neat): ν
= 2942, 2845, 1658, 1464, 1255,
˜
3
max
1
1115, 839, 777, 694 cm–1. H NMR (500 MHz, CDCl3): δ = 0.03–
0.10 (m, 12 H), 0.81–0.88 (m, 21 H), 1.26–1.38 (m, 20 H), 2.06 (m,
2 H), 3.50 (m, 1 H), 3.80 (dd, J = 13.5, 16.0 Hz, 1 H), 3.95 (m, 2
H), 4.81 (m, 1 H), 5.48 (dd, J = 6.0, 15.5 Hz, 1 H), 5.76 (dt, J =
6.5, 13.5 Hz, 1 H), 7.33–7.43 (m, 3 H), 7.92–7.95 (m, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = –5.04, –5.01, –4.43, –4.38, 14.32,
18.43, 22.90, 25.94, 26.15, 29.12, 29.41 (several overlapped peaks),
29.87, 29.91, 32.14, 32.54, 55.24, 62.74, 66.08, 79.61, 127.07,
127.45, 128.09, 128.12, 130.28, 134.37, 134.73, 154.67 ppm. HRMS
(FAB+): calcd. for C37H68NO3Si2 [M + H]+ 630.4738; found
630.4741.
(4S,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-[(tert-butyldimethyl-
silyloxy)methyl]-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine (6e):
Rf = 0.30 (ethyl acetate/hexane, 1:20). [α]2D5 = –6.53 (c = 1.6,
CHCl ). IR (neat): νmax = 2954, 2885, 1660, 1472, 1255, 1115, 836,
˜
3
776, 696 cm–1. H NMR (500 MHz, CDCl3): δ = 0.07–0.14 (m, 12
1
H), 0.83–0.97 (m, 18 H), 3.59 (m, 1 H), 3.71 (t, J = 10.0 Hz, 1 H),
3.91 (dd, J = 10.0, 5.0 Hz, 1 H), 4.20 (dd, J = 2.0, 1.5 Hz, 1 H),
4.71 (dd, J = 6.0, 1.5 Hz, 1 H), 5.35 (d, J = 10.0 Hz, 1 H), 5.48 (d,
J = 18.0 Hz, 1 H), 6.00–6.07 (ddd, J = 18.0, 10.0, 6.0 Hz, 1 H),
7.28–7.42 (m, 3 H), 7.93–7.95 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –4.90, –4.88, –4.01, –3.57, 18.28, 18.44, 18.52, 18.56,
25.95, 26.16, 26.26, 26.27, 60.22, 63.47, 64.84, 79.93, 118.05,
127.46, 128.17, 130.41, 133.90, 135.53, 155.56 ppm. HRMS
(FAB+): calcd. for C25H44NO3Si2 [M + H]+ 462.2860; found
462.2858.
General Procedure for the Preparation of Triols 12 and 12Ј: To a
stirred solution of 7 or 7Ј (0.1 m solution in dry THF, 1.0 equiv.)
at 0 °C was added tetrabutylammonium fluoride (1.0 m solution in
THF, 2.0 equiv.). The reaction mixture was stirred at room tem-
perature for 1 h. Then, the reaction was quenched with a saturated
aqueous solution of NaHCO3, and the resulting mixture was ex-
tracted with ethyl acetate. The organic layer was washed with brine
and dried with MgSO4, and the solvents were evaporated in vacuo.
Purification by silica gel chromatography gave the diol as a white
solid. Data for (4S,5R,6R)-4-(Hydroxymethyl)-2-phenyl-6-(tetradec-
1-enyl)-5,6-dihydro-4H-1,3-oxazin-5-ol: Rf = 0.15 (ethyl acetate/hex-
(4S,5R,6S)-5-(tert-Butyldimethylsilyloxy)-4-[(tert-butyldimethyl-
silyloxy)methyl]-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine (6eЈ):
Rf = 0.30 (ethyl acetate/hexane, 1:20). [α]2D5 = –29.3 (c = 0.22,
ane, 1:1). [α]2D5 = –1.66 (c = 0.28, CHCl ). IR (neat): ν
= 3327,
˜
3
max
2980, 2851, 1650, 1246, 1059, 840, 777, 693 cm–1 1H NMR
.
(500 MHz, CDCl3): δ = 0.88 (t, J = 6.5 Hz, 3 H), 1.25–1.39 (m, 18
H), 1.44 (m, 2 H), 2.08 (dt, J = 7.5, 14.5 Hz, 2 H), 2.63–2.73 (m,
2 OH), 3.69 (m, 1 H), 3.99 (dd, J = 5.5, 10.5 Hz, 1 H), 4.03 (dd, J
= 4.5, 10.0 Hz, 1 H), 4.11 (dd, J = 1.5, 3.0 Hz, 1 H), 4.68 (dd, J =
1.0, 7.0 Hz, 1 H) 5.72 (ddd, J = 1.5, 6.0, 15.5 Hz, 1 H), 5.98 (ddd,
J = 5.5, 7.0, 9.5 Hz, 1 H), 7.36–7.45 (m, 3 H), 7.98–8.00 (m, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.32, 2290, 29.20,
29.45 (several overlapped peaks), 29.88, 29.90, 32.14, 32.68, 57.35,
64.77, 66.60, 78.31, 124.87, 127.55, 128.25, 128.59, 130.99, 133.24,
136.58, 156.85 ppm. HRMS (FAB+): calcd. for C25H40NO3 [M +
H]+ 402.3008; found 402.3010. Data for (4S,5R,6S)-4-(hy-
droxymethyl)-2-phenyl-6-(tetradec-1-enyl)-5,6-dihydro-4H-1,3-
oxazin-5-ol: Rf = 0.15 (ethyl acetate/hexane, 1:1). [α]2D5 = –8.55 (c =
CHCl ). IR (neat): νmax = 2960, 2857, 1660, 1464, 1254, 1114, 840,
˜
3
776, 692 cm–1. H NMR (500 MHz, CDCl3): δ = 0.08–0.10 (m, 12
1
H), 0.86–0.90 (m, 18 H), 3.47 (m, 1 H), 3.77 (t, J = 9.5 Hz, 1 H),
3.94 (dd, J = 4.0, 9.5 Hz, 1 H), 4.00 (dd, J = 3.5, 4.0 Hz, 1 H), 4.87
(dd, J = 4.5, 5.5 Hz, 1 H), 5.28 (d, J = 10.0 Hz, 1 H), 5.35 (d, J =
17.5 Hz, 1 H), 5.86 (ddd, J = 5.0, 10.5, 17.5 Hz, 1 H), 7.26–7.40
(m, 3 H), 7.93–7.95 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = –5.02, –4.44, –4.37, –4.01, 18.26, 18.43, 25.93, 26.14, 62.66,
65.65, 79.55, 117.39, 127.44, 128.17, 130.38, 134.18, 135.14,
154.35 ppm. HRMS (FAB+): calcd. for C25H44NO3Si2 [M + H]+
462.2860; found 462.2856.
General Procedure for Olefin Cross-Metathesis Reaction: To a solu-
tion of oxazine 6e or 6eЈ (1.0 equiv.) in CH2Cl2 (0.1 m) were added
1-tetradecene (2.0 equiv.) and Grubbs’ second-generation catalyst
(0.05 equiv.) at room temperature. After the reaction mixture was
stirred and heated at reflux for 8 h, the solvent was removed in
1.9, CHCl ). IR (neat): ν
= 3340, 2960, 2845, 1657, 1246, 1067,
˜
3
max
1
840, 776, 692 cm–1. H NMR (500 MHz, CDCl3): δ = 0.88 (t, J =
7.0 Hz, 3 H), 1.25–1.39 (m, 18 H), 1.40 (m, 2 H), 2.08 (dt, J = 6.5,
13.5 Hz, 2 H), 2.69 (m, OH), 3.55 (m, 1 H), 4.08 (m, OH), 4.35
(dd, J = 4.5, 9.0 Hz, 1 H), 4.45 (m, 2 H), 4.57 (m, 1 H), 5.62 (ddd,
J = 1.5, 5.0, 14.5 Hz, 1 H), 5.87 (ddd, J = 1.5, 5.0, 12.0 Hz, 1 H),
7.36–7.45 (m, 3 H), 7.98–8.00 (m, 2 H) ppm. 13C NMR (125 MHz,
1
vacuo to give the crude products (E/Z Ͼ 20:1 by H NMR). The
product was purified by silica gel chromatography to give the de-
sired alkene.
(4S,5R,6R)-5-(tert-Butyldimethylsiloxy)-4-[(tert-butyldimethyl- CDCl3): δ = 14.32, 22.90, 29.32, 29.34 (several overlapped peaks),
silyloxy)methyl]-2-phenyl-6-(tetradec-1-enyl)-5,6-dihydro-4H-1,3-
29.88, 29.90, 32.13, 32.59, 67.41, 69.93, 74.13, 75.69, 127.14,
128.60, 128.68, 129.12, 132.04, 133.74, 165.66 ppm. HRMS
oxazine (7): Rf = 0.30 (ethyl acetate/hexane, 1:20). [α]2D5 = +40.51
(c = 1.3, CHCl ). IR (neat): ν
= 2927, 2858, 1657, 1463, 1253, (FAB+): calcd. for C25H40NO3 [M + H]+ 402.3008; found
˜
3
max
1115, 839, 776, 694 cm–1. H NMR (500 MHz, CDCl3) δ = 0.04–
402.3011. A solution of the diol (0.1 m solution in hexane/meth-
1
0.11 (m, 12 H), 0.82–0.93 (m, 21 H), 1.25–1.46 (m, 20 H), 2.11 (m, anol, 3:2, 1.0 equiv.) was stirred at room temperature for 12 h under
2618
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2614–2620

Total Syntheses of d-xylo- and d-arabino-Phytosphingosine
a hydrogen atmosphere in the presence of 20% palladium hydrox-
ide on charcoal (catalytic amount, 4.0 equiv.) and di-tert-butyl di-
carbonate (4.0 equiv.). The catalyst was removed by filtration
through a pad of Celite, and the solvents were evaporated under
reduced pressure. The resulting residue was purified by silica gel
chromatography to afford the triol as a white solid.
1.87 (m, 2 H), 2.01–2.07 (m, 1 H), 3.83 (t, J = 5.5 Hz, 1 H), 4.06
(m, 1 H), 4.08–4.12 (m, 1 H), 4.17–4.25 (m, 2 H) ppm. 13C NMR
(125 MHz, [D5]pyridine): δ = 14.22, 22.88, 26.50, 29.56, 29.87,
30.06, 30.27, 32.08, 35.22, 54.47, 65.66, 73.79, 74.00 ppm. HRMS
(FAB+): calcd. for C18H40NO3 [M
318.3004.
+
H]+ 318.3008; found
tert-Butyl [(2S,3R,4R)-1,3,4-Trihydroxyoctadecan-2-yl]carbamate Supporting Information (see footnote on the first page of this arti-
(12): 69%, m.p. 66–67 °C. Rf = 0.10 (ethyl acetate/hexane, 1:1).
cle): Compound characterization data.
[α]2D5 = +4.21 (c = 0.5, CDCl ). IR (neat): νmax = 3338, 2920, 2857,
˜
3
1670, 1540, 1460, 1250, 1173, 1035 cm–1. 1H NMR (500 MHz,
CDCl3 + 1 drop D2O): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.20–1.39 (m.
26 H), 1.45 (s, 9 H), 3.01 (m, 1 H), 3.59 (m, 1 H), 3.69–3.79 (m, 2
H), 3.81–3.90 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3 + 1 drop
D2O): δ = 14.22, 22.91, 25.80, 28.46, 29.57, 29.80, 29.89, 29.91,
32.14, 32.64, 52.58, 64.02, 71.67, 74.46, 80.00, 157.50 ppm. HRMS
Acknowledgments
This research was supported by the National Research Foundation
of Korea (NRF) through the Basic Science Research Program. Fur-
ther support by the South Korean Ministry of Education, Science
and Technology (S-2011-0948-000) and Yonsung Fine Chemicals
Corporation is appreciated.
(FAB+): calcd. for C23H48NO5 [M
418.3536.
+
H]+ 418.3532; found
tert-Butyl [(2S,3R,4S)-1,3,4-Trihydroxyoctadecan-2-yl]carbamate
(12Ј): 72%, m.p. 80 °C. Rf = 0.10 (ethyl acetate/hexane, 1:1). [α]2D5
[1] A. H. Merrill Jr, K. Sandhoff, Sphingolipid Metabolism and
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= –8.04 (c = 0.53, CDCl ). IR (neat): ν
= 3340, 2925, 2850,
˜
3
max
1670, 1510, 1462, 1246, 1172, 1047 cm–1. 1H NMR (500 MHz,
CDCl3 + 1 drop D2O): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.20–1.35 (m.
24 H), 1.45 (s, 9 H), 1.55 (m, 1 H), 1.66 (m, 1 H), 3.32 (m, 1 H),
3.60 (m, 1 H), 3.85 (m, 1 H), 3.93–3.96 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3 + 1 drop D2O): δ = 14.32, 22.90, 25.86, 28.50,
29.57, 29.77, 29.87, 29.11, 32.14, 32.74, 52.59, 65.93, 71.17, 78.20,
80.77, 157.76 ppm. HRMS (FAB+): calcd. for C23H48NO5 [M +
H]+ 418.3532; found 418.3529.
(2S,3R,4R)-2-Aminooctadecane-1,3,4-triol (3): To triol 12 (26 mg,
0.06 mmol) in MeOH (0.6 mL) was added HCl (6 n solution,
0.1 mL), and the mixture was kept at room temperature for 5 h.
The excess amounts of HCl and MeOH were removed under re-
duced pressure, and the aqueous layer was neutralized with ammo-
nium hydroxide (0.6 m aqueous solution). The resulting mixture
was extracted with ethyl acetate (4ϫ5 mL). The combined organic
layers were dried with Na2SO4 and evaporated under reduced pres-
sure. The crude residue was purified by silica gel chromatography
(CHCl3/CH3OH/NH4OH, 40:10:1) to afford d-xylo-phytosphingo-
[4] K. Tamiya-Koizumi, T. Murate, M. Suzuki, C. M. G. Simbu-
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sine (3, 11.2 mg, 74%) as a white solid; m.p. 95–96 °C. [α]2D5
=
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[9] For a more recent synthesis of phytosphingosines, see: a) R. S.
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9290; b) G. S. Rao, B. V. Rao, Tetrahedron Lett. 2011, 52, 6076–
6079; c) G. S. Rao, B. V. Rao, Tetrahedron Lett. 2011, 52, 4861–
4864; d) M. Martinkova, J. Gonda, K. Pomikalova, J. Kozisek,
J. Kuchar, Carbohydr. Res. 2011, 346, 1728–1738; e) S. Bal-
lereau, N. A. Abadie, N. Saffon, Y. Génisson, Tetrahedron
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+11.15 (c = 0.7, pyridine). IR (neat): νmax = 3360, 2927, 2857, 1672,
˜
1
1470, 1120 cm–1. H NMR (500 MHz, [D5]pyridine): δ = 0.83 (t, J
= 6.5 Hz, 3 H), 1.24–1.40 (m, 22 H), 1.49–1.54 (m, 1 H), 1.66–1.70
(m, 1 H), 1.78–1.84 (m, 1 H), 1.91–1.97 (m, 1 H), 3.46 (dt, J = 3.0,
5.5 Hz, 1 H), 4.04–4.07 (m, 2 H), 4.08–4.10 (m, 1 H), 4.11–4.18 (m,
1 H) ppm. 13C NMR (125 MHz, [D5]pyridine): δ = 14.21, 22.88,
26.48, 29.55, 29.86, 29.92, 29.98, 30.16, 32.07, 34.74, 57.57, 65.09,
72.01, 74.05 ppm. HRMS (FAB+): calcd. for C18H40NO3
[M + H]+ 318.3008; found 318.3005.
(2S,3R,4S)-2-Aminooctadecane-1,3,4-triol (4): To triol 12Ј (20 mg,
0.047 mmol) in MeOH (0.5 mL) was added HCl (6 n solution,
0.07 mL), and the mixture was kept at room temperature for 5 h.
The excess amounts of HCl and MeOH were removed under re-
duced pressure, and the aqueous layer was neutralized with ammo-
nium hydroxide (0.6 m aqueous solution). The resulting mixture
was extracted with ethyl acetate (4ϫ5.0 mL). The combined or-
ganic layers were dried with Na2SO4 and evaporated under reduced
pressure. The crude residue was purified by silica gel chromatog-
raphy (CHCl3/CH3OH/NH4OH, 40:10:1) to afford d-arabino-phy-
tosphingosine (4, 15.63 mg, 79%) as a white solid; m.p. 82–83 °C.
[α]2D5 = –3.79 (c = 0.6, pyridine). IR (neat): νmax = 3340, 2950, 2854,
˜
1620, 1456, 1095 cm–1. 1H NMR (500 MHz, [D5]pyridine): δ = 0.83
(t, J = 6.5 Hz, 3 H), 1.24–1.40 (m, 22 H), 1.58–1.64 (m, 1 H), 1.80–
Eur. J. Org. Chem. 2012, 2614–2620
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: January 18, 2012
Published Online: March 19, 2012
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Eur. J. Org. Chem. 2012, 2614–2620