Total synthesis of d - Lyxo -phytosphingosine and formal synthesis of pachastrissamine via a chiral 1,3-oxazine

Article abstract of DOI:10.1055/s-0031-1289813

Concise and efficient syntheses of d-lyxo-phytosphingosine and pachastrissamine were achieved utilizing a chiral oxazine. The key features in these strategies are the stereoselective intramolecular oxazine formation catalyzed by palladium(0), and intermolecular olefin cross-metathesis. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289813

2340▌
PAPER
paper
Total Synthesis of D-lyxo-Phytosphingosine and Formal Synthesis of
Pachastrissamine via a Chiral 1,3-Oxazine
Total Synthesis of D-lyxo-Phytosphingosine
Yu Mu,a Ji-Yeon Kim,a Xiangdan Jin,a Seok-Hwi Park,a Jae-Eun Joo,b Won-Hun Ham*a
a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b
Yonsung Fine Chemicals Co., Ltd., 129-9 Suchon-ri, Jangan-myeon, Hwaseong-si, Gyeonggi-do 445-944, Republic of Korea
Fax +82(31)2928800; E-mail: whham@skku.edu
Received: 27.03.2012; Accepted after revision: 14.05.2012
H2N
OH
OH
C14H29
Abstract: Concise and efficient syntheses of D-lyxo-phytosphingo-
sine and pachastrissamine were achieved utilizing a chiral oxazine.
The key features in these strategies are the stereoselective intramo-
lecular oxazine formation catalyzed by palladium(0), and intermo-
lecular olefin cross-metathesis.
C14H29
HO
NH2 OH
O
1
2
Figure 1 Structures of D-lyxo-phytosphingosine (1) and pachastrissa-
mine (2)
Key words: palladium catalysis, sphingolipids, stereoselective
synthesis, cross-coupling, natural products
same natural product from a different marine sponge, Jas-
pis sp., and named as jaspine B.8 Pachastrissamine 2 rep-
resents the first example of a cyclic anhydrosphingosine
structural feature as a natural product. It was reported to
possess the 2S,3S,4S absolute configuration and is struc-
turally similar to that of the open chain sphingolipid D-
The sphingolipids are distributed ubiquitously in the
membranes of eukaryotic cells and have been demonstrat-
ed to regulate biological processes.1 One of the most im-
portant sphingolipids, phytosphingosines, have been
widely distributed in plants, fungi, yeasts, mammalian tis-
sues, and marine organism. They consist of a base, bear-
ing a long aliphatic chain (an 18-carbon atom) and a polar
2-amino-1,3,4-triol head group. Phytosphingosines and
their glycosylated derivatives exhibit significant immuno-
stimulatory and antitumor properties.2,3 Phytosphingo-
sines with other chain lengths, as well as different
stereochemistries of the amino and hydroxy groups, are
also known and bioactive to various degrees.4 Because of
its promising biological activities and its three contiguous
stereocenters, much effort has been devoted to the devel-
opment of the syntheses of D-lyxo-phytosphingosine (1)
(see Figure 1) and other stereoisomers, such as D-lyxo-, D-
xylo- and D-arabino-phytosphingosine.5,6
ribo-phytosphingosine.
A
number of synthetic
approaches6a,9,10 have been reported due to its novel tetra-
hydrofuran structure and its promising biological activi-
ty.11
On the basis of our previous research,12 as shown in
Scheme 1, we anticipated that the palladium(0)-catalyzed
oxazine formation of a γ-allyl benzamide, having a benzo-
yl substituent as an N-protection group in the presence of
Pd(PPh3)4, NaH, and n-Bu4NI might proceed with high
stereoselectivity. The bulkiness of protecting group on the
secondary alcohols is responsible for controlling the dia-
stereoselectivity of oxazine ring formation. This process
efficiently adjusted stereochemistry and provided simul-
taneous protection for the nearly generated hydroxy
group.
(+)-Pachastrissamine (2) (see Figure 1), a potent cytotoxic
agent possessing a tetrahydrofuran skeleton, was isolated
from the Okinawa marine sponge, Pachastrissa sp. (fam-
ily calthropellidae), by Higa et al. in 2002.7 Subsequently,
the Debitus research group reported the isolation of the
As shown in Scheme 2, our retrosynthetic analysis sug-
gested that D-lyxo-phytosphingosine (1) and pachastrissa-
mine (2) could be easily synthesized from N-Boc triol 3.
OTBS
OTBS
R
OTBS
R
Pd(PPh3)4, NaH
R
Cl
+
N
O
N
O
n-Bu4NI, THF
0 °C
57–65%
12–30:1
NHBz
Ph
Ph
anti,syn-oxazines
anti,anti-oxazines
a R = Ph
b R = Bn
c R = i-Pr
d R = s-Bu
major
minor
Scheme 1 Oxazine formation from 1,2-anti-amino alcohol derivatives
SYNTHESIS 2012, 44, 2340–2346
Advanced online publication: 26.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289813; Art ID: SS-2012-F0314-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of D-lyxo-Phytosphingosine
Table 1 Cyclization Precursors Prepared
2341
N-Boc triol 3 could be synthesized by ring cleavage of ox-
azine under Schotten–Baumann reaction of 4e. We envi-
sioned that the intramolecular palladium(0)-catalyzed
oxazine formation of benzamide 5e would generate the
oxazine 4e, bearing a pendant vinyl group, that could be
elaborated to the alkene via an olefin cross-metathesis re-
action.
OH
OR
Cl
Cl
TBSO
TBSO
NHBz
NHBz
5a–e
Product R
Reagents
Temp Time Yield
(°C) (h) (%)a
OH
H2N
OH
OH
C14H29
OH
5a
5b
5c
5d
5e
Me
Bn
MeI, NaH, THF
BnBr, NaH, THF
0
2
2
73
70
80
76
93
C14H29
HO
BocHN
HO
C14H29
r.t.
NH2 OH
1
O
2
3
MeOCH2 MOMCl, Et3N, CH2Cl2 0–r.t. 24
OTBS
O
OTBS
BOM
TBS
BOMCl, Et3N, CH2Cl2
0
24
2
TBSO
Cl
TBSCl, imidazole, DMF r.t.
TBSO
N
NHBz
5e
a Yields refer to the isolated products.
Ph
4e
Scheme 2 Retrosyntheses of D-lyxo-phytosphingosine (1) and pa-
chastrissamine (2)
azine 4e as the major product along with a minor amount
of anti,anti-oxazine product 4e′. The diastereoselectivity
was improved to >30:1 with TBS protecting group on the
secondary alcohol. It is clear from this experiment that
steric bulkiness of the protecting group highly influences
the level of diastereoselectivity (Table 2).
In our laboratory, we have been exploring the utility of en-
antiopure oxazine, as a chiral building block, for the ste-
reocontrolled synthesis of natural products.12,13 As part of
this program, we have now developed a novel strategy for
concise syntheses of D-lyxo-phytosphingosine (1) and pa-
chastrissamine (2). Here we describe the novel asymmet-
ric syntheses of D-lyxo-phytosphingosine (1) and
pachastrissamine (2) that utilize an oxazine as a chiral
building block.
The stereochemistries of the oxazines obtained above
1
were elucidated by H NMR spectroscopy. The relative
configuration of each diastereomer of the oxazine prod-
ucts, obtained after the silica gel column separation, was
determined by a comparison of their coupling constants
(Figure 2). The small coupling constant of J5,6 = 4.0 Hz, as
in anti,syn-oxazine 4e, was caused by the axial-equatorial
relationship between the two adjacent protons in six-
membered rings. The large coupling constant of J5,6 = 8.8
Hz, as in anti,anti-oxazine 4e′, was typically due to the di-
axial relationship between the two adjacent protons in six-
membered rings.
The synthesis of 1 and 2, commenced with N-benzoyl-L-
serine methyl ester (6).12 Treatment of 6 with N,O-dimeth-
ylhydroxylamine in the presence of trimethylaluminum
readily converted the ester 6 into the corresponding
Weinreb amide in 94% yield. Reaction of this Weinreb
amide with vinyltin and MeLi in THF at –78 °C gave the
α,β-unsaturated ketone 7 in 86% yield (Scheme 3). Chela-
tion-controlled hydride reduction of amino ketone 7 with
lithium tri-tert-butoxyaluminum hydride in ethanol at
–78 °C gave anti-amino alcohol as the major compound in
good yield with excellent stereoselectivity (anti/syn =
J5,6 = 8.8 Hz
J4,5 = 6.0 Hz
J4,5 = 8.0 Hz
J
5,6 = 4.0 Hz
H
H
1
OTBS
OTBS
H
N
H
N
10:1, as determined by H NMR analysis). Protection of
H
H
TBSO
TBSO
anti-amino alcohol with TBSCl afforded the cyclization
precursor 5e in excellent yield (Scheme 3).
O
O
Different cyclization precursors 5a–e were simply pre-
pared under the reaction conditions shown in Table 1.
Ph
Ph
anti,syn-oxazine
anti,anti-oxazine
4e
4e'
The reaction of 5e, which has tert-butyldimethylsilyl as
the protecting group, with NaH and n-Bu4NI in the pres-
ence of Pd(PPh3)4 in THF at 0 °C afforded the anti,syn-ox-
Figure 2 1H NMR (CDCl3) coupling constants of oxazines
O
O
OTBS
1. LiAlH(Ot-Bu)3
EtOH, –78 °C, 87%
1. NH(OMe)Me, Me3Al
CH2Cl2, 94%
Cl
Cl
TBSO
OMe
TBSO
TBSO
2. TBSCl, imidazole
DMF, 93%
NHBz
NHBz
NHBz
n-Bu Sn
Cl
2.
3
6
7
5e
MeLi, THF, 86%
Scheme 3 Synthesis of 5 from l-serine
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2340–2346

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Y. Mu et al.
PAPER
Table 2 Oxazine Formation Catalyzed by Pd(0)a
OR2
OR2
OR2
R1
R1
Pd(PPh3)4, NaH
R1
Cl
+
n-Bu4NI, THF
N
O
N
O
NHBz
5a–e
R1 = TBSOCH2
Ph
Ph
anti,syn-oxazines
4a–e
anti,anti-oxazines
4a'–e'
R2
Substrate
Temp (°C)
Time (h)
Yield of 4 (%)b
Ratio (anti,syn/anti,anti)c
Me
5a
5b
5c
5d
5e
0
0
0
0
0
5
5
5
5
5
51
52
71
69
65
2:1
6:1
Bn
MOM
BOM
TBS
9:1
13:1
>30:1
a Reaction conditions: Pd(PPh3)4 (0.2 equiv), NaH (2 equiv), n-Bu4NI (1 equiv), and THF.
b Yield refers to the isolated and mixed products.
c Ratio was determined by 1H NMR analysis of anti,syn-oxazines and anti,anti-oxazines.
In addition, the coupling constant of the newly generated treatment with Pd(OH)2/C under 70 psi of H2 at ambient
chiral center (H5-H6) of 4e has similar values of 2.5–4.0 temperature in the presence of (Boc)2O in 75% yield. The
25
Hz, when compared to those of the previously reported optical rotation of N-Boc triol 3, [α]D –8.9 (c 0.9,
syn,syn-oxazine compounds.13 In contrast, the coupling CDCl3), compared to the reported value, [α]D25 –8.3 (c 1.0,
constant of the newly generated chiral center (H5-H6) of CDCl3),15 confirmed the identity of the absolute configu-
4e′ has the same values of 7.5–9.0 Hz, as the syn,anti-iso- ration. Since N-Boc-triol 3 was employed as an interme-
mer.
diate in the synthesis of pachastrissamine (2) by the
Marco group,15 this sequence represents a formal synthe-
sis of the 2.
The assignment of relative configuration was confirmed
by observation of the larger NOE enhancement for an-
ti,syn-oxazine 4e and anti,anti-oxazine 4e′ as shown in
Figure 3. In the anti,syn-oxazine case, for compound 4e:
there are 9.60% NOE between H5 and H6, 3.94% between
H5 and H4, but no NOE effects between H4 and H6. In the
anti,anti-oxazine case, for compound 4e′: there are 2.75%
NOE between H5 and H6, 2.00% between H5 and H4, and
5.99% between H4 and H6.
OTBS
tetradec-1-ene
Grubbs II cat.
C12H25
1. TBAF, THF, 90%
4e
TBSO
CH2Cl2
reflux, 12 h
94%
2. Pd(OH)2/C, H2
hexanes–MeOH
(3:2)
N
O
(E/Z >20:1)
Ph
Boc2O, 75%
8
H2N
OH
C14H29
ref.15
OH
O
C14H29
2
0%
HO
BocHN
5.99%
9.60%
2.75%
OTBS
TFA–H2O (20:1)
92%
OH
OH
3
3.94%
TBSO
2.00%
TBSO
H
H
C14H29
OH
OTBS
H
H
N
H
N
HO
H
NH2
1
O
O
Scheme 4 Syntheses of D-lyxo-phytosphingosine (1) and pachastris-
samine (2)
Ph
Ph
anti,syn-oxazine
anti,anti-oxazine
4e
4e'
Figure 3 Observed NOEs in oxazines
The final product 1 was easily obtained by a simple acid
hydrolysis with trifluoroacetic acid–water (20:1) of N-
Boc-triol 3. After vacuum evaporation of excess TFA,
neutralization with aqueous NaHCO3 and extraction with
EtOAc, D-lyxo-phytosphingosine (1) was isolated in 92%
yield, by flash chromatography on silica gel. Optical and
spectroscopic data were in excellent agreement with those
reported in the literature.6
The olefin cross-metathesis of 4e with tetradec-1-ene in
the presence of 5 mol% Grubbs II catalyst yielded com-
pound 8 in high yield (94%), with E/Z >20:1 regioseletiv-
ity (1H NMR).14 Deprotection of the disilyl ether of
oxazine 8 with tetrabutylammonium fluoride gave a diol.
The diol was converted into the known compound 3 by
Synthesis 2012, 44, 2340–2346
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of D-lyxo-Phytosphingosine
2343
A previous paper from our laboratory described12 a new
procedure for the highly stereoselective formation of an
oxazine ring. Further, the bulkiness of alcohol protecting
groups predominantly controls the diastereoselectivity of
oxazine ring formation. On the basis of these results, we
applied the asymmetric synthetic method of D-lyxo-phyto-
sphingosine (1) and pachastrissamine (2) utilizing the chi-
ral oxazine 4e. The key features in these strategies are the
stereoselective intramolecular oxazine formation cata-
lyzed by palladium(0) and intermolecular olefin cross-
metathesis. The net results were the syntheses from a lin-
ear sequence of five steps from 6 in 27.0% overall yield
for N-Boc triol 3, which has previously been transformed
to pachastrissamine (2) in three steps,15 and to D-lyxo-phy-
tosphingosine (1) in 24.8% overall yield in six steps .
Weinreb amide (0.50 g, 1.36 mmol) in anhyd THF (5 mL) was
added dropwise and the stirring was allowed to continue for 30 min,
after which time TLC analysis (eluent: EtOAc–hexanes, 1:2) indi-
cated completion of the reaction. The reaction was quenched by sat.
aq NH4Cl (10 mL) and then warmed to r.t. The layers were separat-
ed and the aqueous layer was extracted with EtOAc (2 × 20 mL).
The combined organic layers were washed with sat. aq NaHCO3 (20
mL), brine (20 mL), dried (MgSO4), and filtered. The filtrate was
concentrated in vacuo. The residue was purified by silica gel col-
umn chromatography to give the amino ketone 7 (447 mg, 86%) as
a colorless oil; Rf = 0.6 (EtOAc–hexanes, 1:2); [α]D25 +56.19 (c 1.6,
CHCl3).
IR (neat): 3412, 2932, 1643, 1521, 1255, 974 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.034–0.089 (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).
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.
HRMS-FAB: m/z [M + H]+ calcd for C19H29ClNO3Si: 382.1605;
found: 382.1602.
Optical rotations were measured on a polarimeter in the solvent
specified. 1H and 13C NMR spectra were obtained from Cooperative
Center for Research Facilities in Sungkyunkwan University on FT-
NMR 125 or 500 MHz spectrometers. Chemical shifts values are re-
ported in parts per million relative to TMS or CDCl3 as an internal
standard and coupling constants in hertz. IR spectra were recorded
on a FTIR spectrometer. Mass spectral data were obtained from the
Korea Basic Science Institute (Daegu) on Jeol JMS 700 high-reso-
lution mass spectrometer. Flash chromatography was carried out us-
ing mixtures of EtOAc and hexane as eluents. Unless otherwise
noted, all nonaqueous reactions were done under an argon atmo-
sphere with commercial grade reagents and solvents. THF was dis-
tilled over Na and benzophenone (indicator). CH2Cl2 was distilled
from CaH2.
N-{(5R,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)
Intermediate Amino Alcohol: To a solution of the amino ketone 7
(365 mg, 0.96 mmol) in EtOH (10 mL) was added LiAlH(Ot-Bu)3
(1 N solution in THF, 1.92 mL, 1.92 mmol) at –78 °C. After stirring
the reaction mixture at the same temperature for 2 h, 10% aq citric
acid (10.00 mL) was added. The resulting mixture was warmed to
r.t. and extracted with EtOAc (3 × 10 mL). The organic layers were
combined, washed with brine (10 mL), dried (MgSO4), filtered, and
concentrated in vacuo to give the crude product. Column chroma-
tography on silica gel gave the intermediate amino alcohol (323 mg,
0.84 mmol, 87% yield, ratio anti/syn >10:1 by 1H NMR) as a color-
less oil; Rf = 0.3 (EtOAc–hexanes, 1:1); [α]D25 +7.95 (c 1.0, CHCl3).
(S,E)-N-[1-(tert-Butyldimethylsilyloxy)-6-chloro-3-oxohex-4-
en-2-yl]benzamide (7)
Formation of Weinreb Amide: To a solution of N,O-dimethylhy-
droxylamine hydrochloride (867 mg, 8.89 mmol) in CH2Cl2 (10
mL) was added Me3Al (4.45 mL of a 2 M solution in hexane, 8.89
mmol) at 0 °C (Caution: CH4 evolution). The mixture was stirred
for 30 min at r.t. Subsequently, a solution of N-benzoyl-O-TBS-L-
serine methyl ester (6; 1.00 g, 2.96 mmol) in CH2Cl2 (5 mL) was
added dropwise. The mixture was stirred at r.t. for 1 h, after which
time TLC analysis (eluent: EtOAc–hexanes, 1:2) indicated comple-
tion of the reaction. The reaction mixture was cooled to 0 °C and
carefully quenched with aq 10% sodium potassium tartrate (2.20
mL). After stirring for 1 h at r.t., the resulting suspension was fil-
tered through a Celite pad and washed with CH2Cl2 (20 mL). The
filtrate was concentrated in vacuo to give the crude product, which
upon purification by column chromatography on silica gel gave the
corresponding Weinreb amide (987 mg, 91%) as a colorless oil; Rf =
0.30 (EtOAc–hexanes, 1:2); [α]D25 +41.15 (c 1.0, CHCl3).
IR (neat): 3346, 2953, 2858, 1639, 1534, 1487, 1253, 1076, 712
cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.076–0.13 (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).
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.
HRMS-FAB: m/z [M + H]+ calcd for C19H31ClNO3Si2: 384.1762;
found: 384.1759.
IR (neat): 3326, 2931, 2857, 1644, 1111 cm–1.
Formation of 5e: Imidazole (64 mg, 0.94 mmol) and tert-butyldi-
methylchlorosilane (141 mg, 0.94 mmol) were added to a stirred so-
lution of the above alcohol (300 mg, 0.78 mmol) in DMF (8.0 mL)
at r.t. And stirring for 6 h, the reaction mixture was quenched with
H2O (8 mL), and extracted with EtOAc (2 × 15 mL). The combined
organic layers were washed with brine (10 mL), dried (MgSO4), and
evaporated in vacuo. Purification by silica gel chromatography gave
5e (363 mg, 93%) as a colorless oil; Rf = 0.3 (EtOAc–hexanes, 1:8);
[α]D25 +13.61 (c 1.0, CHCl3) (Table 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).
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.
HRMS-FAB: m/z [M + H]+ calcd for C18H31N2O4Si: 367.2053;
found: 367.2050.
IR (neat): 3298, 2942, 2857, 1638, 1538, 1253, 1087, 838 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.06–0.11 (m, 12 H), 0.91–0.93
(m, 18 H), 3.71 (dd, J = 4.9, 10.2 Hz, 1 H), 3.98–4.07 (m, 2 H),
4.17–4.20 (m, 1 H), 4.44 (t, J = 6.4 Hz, 1 H), 5.83–5.87 (m, 1 H),
5.92 (dd, J = 6.5, 15.3 Hz, 1 H), 6.34 (d, J = 8.6 Hz, 1 H), 7.42–7.45
(m, 2 H), 7.49–7.52 (m, 1 H), 7.72–7.74 (m, 2 H).
Conversion of the Weinreb Amide into the Amino Ketone 7: Vinyltin
(1.50 g, 4.09 mmol) was dissolved in anhyd THF (10 mL) and
cooled to –78 °C. MeLi (1.6 M solution in hexane, 2.60 mL, 4.09
mmol) was added dropwise. The mixture was stirred for 30 min at
the same temperature. Subsequently, a solution of the above
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2340–2346

2344
Y. Mu et al.
PAPER
13C NMR (125 MHz, CDCl3): δ = –5.29, –5.09, –4.70, –3.84, 18.32,
18.42, 25.88, 26.05, 26.10, 31.17, 44.44, 55.46, 61.25, 72.20,
126.94, 128.18, 128.81, 131.63, 135.05, 135.45, 167.24.
(dd, J = 3.6, 9.9 Hz, 1 H), 4.17 (m, 1 H), 4.72–475 (m, 1 H), 5.41–
5.46 (m, 1 H), 5.69–5.86 (m, 2 H), 7.38–7.49 (m, 3 H), 7.98–8.03
(m, 2 H).
HRMS-FAB: m/z [M + H]+ calcd for C25H45ClNO3Si2: 498.2627;
found: 498.2624.
13C NMR (125 MHz, CDCl3): δ = –5.02, –4.99, –4.47, –4.33, 14.38,
18.30, 22.96, 26.03, 26.09, 26.14, 29.22, 29.44, 29.47, 29.64, 29.75
(several overlapped peaks), 29.81, 29.84, 29.88, 29.93, 29.97,
32.20, 32.70, 32.88, 59.86, 64.33, 65.76, 75.94, 125.53, 127.63,
128.12, 130.13, 130.48, 130.59, 133.98, 134.97, 154.88.
HRMS-FAB: m/z [M + H]+ calcd for C37H68NO3Si2: 630.4738;
found: 630.4734.
Oxazine Formation; (4S,5S,6S)-5-(tert-Butyldimethylsilyloxy)-
4-[(tert-butyldimethylsilyloxy)methyl]-2-phenyl-6-vinyl-5,6-di-
hydro-4H-1,3-oxazine (4e) and (4S,5S,6R)-5-(tert-Butyldimeth-
ylsilyloxy)-4-[(tert-butyldimethylsilyloxy)methyl]-2-phenyl-6-
vinyl-5,6-dihydro-4H-1,3-oxazine (4e′); Typical Procedure
NaH (321 mg, 8.03 mmol, 60% in mineral oil) and n-Bu4NI (1.48 g,
4.01 mmol) were added to a stirred solution of the silyl ether 5e
(2.00 g, 4.01 mmol) in anhyd THF (80 mL) at 0 °C. After stirring
for 5 min, Pd(PPh3)4 (928 mg, 0.80 mmol) was added to the mixture
and stirring was allowed to continue for 5 h at the same temperature.
The reaction mixture was filtered through a pad of silica gel and the
filtrate was evaporated under reduced pressure to give the crude
product. Purification by silica gel chromatography gave a mixture
of anti,syn/anti,anti 4e and 4e′ (1.20 g, 65%, ratio anti,syn/anti,anti
>30:1 by 1H NMR) as a colorless oil (Table 2).
tert-Butyl (2S,3S,4S)-1,3,4-Trihydroxyoctadecan-2-yl-carba-
mate (3)
Intermediate Diol: To a stirred solution of 8 (1.33 g, 2.10 mmol) in
THF (20 mL) at 0 °C was added n-Bu4NF (1.0 M solution in THF,
4.42 mL, 4.42 mmol). The reaction mixture was stirred at r.t. for 1
h. The reaction was quenched with sat. aq NH4Cl (15 mL) and ex-
tracted with EtOAc (3 × 15 mL). the combined organic layers were
washed with brine (20 mL), dried (MgSO4), and evaporated in vac-
uo. Purification of the residue by silica gel chromatography gave the
intermediate diol (0.79 g, 90%) as a white solid; Rf = 0.20 (EtOAc–
hexanes, 1:1); [α]D25 –42.19 (c 1.0, CHCl3).
4e
Rf = 0.5 (EtOAc–hexanes, 1:20); [α]D25 –37.24 (c 1.0, CHCl3).
IR (neat): 3327, 2198, 2851, 2357, 1639, 1246, 1059, 499 cm–1.
IR (neat): 2940, 2860, 1661, 1245, 1115, 836, 777 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.93 (t, J = 6.7 Hz, 3 H), 1.30–1.46
(m, 20 H), 2.13 (dt, J = 6.6, 14.0 Hz, 2 H), 3.58 (dd, J = 5.4, 11.7
Hz, 1 H), 3.83–3.99 (m, 3 H), 4.41–4.51 (m, 1 H), 4.82–4.85 (m, 1
H), 5.58–5.69 (m, 1 H), 5.80–5.96 (m, 1 H), 7.39–7.52 (m, 3 H),
7.93–8.01 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 14.33, 22.91, 29.31, 29.49, 29.58,
29.72, 29.83, 29.88, 29.90, 29.92, 32.15, 32.59, 68.56, 68.71, 73.76,
75.47, 127.22, 128.47, 128.57, 128.65, 128.71, 131.77, 135.49,
165.69.
1H NMR (500 MHz, CDCl3): δ = 0.08–0.20 (m, 12 H), 0.88–0.96
(m, 18 H), 3.47 (dd, J = 3.0, 5.0, 8.0 Hz, 1 H), 3.83 (dd, J = 5.0, 10.0
Hz, 1 H), 4.02 (dd, J = 3.0, 10.0 Hz, 1 H), 4.21 (dd, J = 4.0, 7.0 Hz,
1 H), 4.80 (ddd, J = 2.0, 4.0, 7.0 Hz, 1 H), 5.35 (ddd, J = 1.0, 2.0,
7.0 Hz, 1 H), 5.40 (ddd, J = 1.0, 2.0, 13.0 Hz, 1 H), 6.10 (ddd, J =
5.0, 10.5, 17.0 Hz, 1 H), 7.38–7.47 (m, 3 H), 8.01–8.04 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = –5.04, –4.99, –4.51, –4.35, 18.27,
18.55, 26.00, 26.13, 26.27, 59.62, 64.13, 65.35, 75.93, 117.54,
127.62, 128.21, 130.59, 133.72, 133.79, 154.43.
HRMS-FAB: m/z [M + H]+ calcd for C25H4NO3: 402.3008; found:
402.3008.
HRMS-FAB: m/z [M + H]+ calcd for C25H44NO3Si2: 462.2860;
found: 462.2862.
Conversion of the Diol into Carbamate 3: A solution of the above
diol (300 mg, 0.64 mmol) in a 3:2 mixture of hexane and MeOH (10
mL) was stirred at r.t. for 12 h under an atmosphere of H2 in the
presence of a catalytic quantity of 20% Pd(OH)2 on charcoal (60
mg) and Boc2O (562 mg, 2.58 mmol). The catalyst was then re-
moved by filtration through Celite, and the solvents were evaporat-
ed under reduced pressure. The resulting residue was purified by
silica gel chromatography to afford Boc-carbamate 3 (235 mg,
75%) as a white solid; mp 131–133 °C; Rf = 0.3 (EtOAc–hexanes,
2:1); [α]D25 –8.9 (c 0.9, CDCl3).
4e′
Rf = 0.5 (EtOAc–hexanes, 1:20); [α]D25 –28.41 (c 1.0, CHCl3).
IR (neat): 3356, 2946, 2833, 1663, 1451, 1030, 836, 780, 671 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.11 (s, 3 H), 0.12
(s, 3 H), 0.17 (s, 3 H), 0.87 (s, 9 H), 0.93 (s, 9 H), 3.43 (dd, J = 2.85,
2.85, 8.55 Hz, 1 H), 3.90 (t, J = 8.55 Hz, 1 H), 3.94–4.02 (m, 2 H),
4.40 (dd, J = 6.5, 8.5 Hz, 1 H), 5.38 (dt, J = 1.5, 10.5 Hz, 1 H), 5.53
(dt, J = 1.5, 17.5 Hz, 1 H), 6.03 (ddd, J = 6.5, 10.5, 17.5 Hz, 1 H),
7.33–7.42 (m, 3 H), 7.97–8.01 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = –5.05, –4.90, –4.20, –3.40, 18.39,
18.55, 26.05, 26.20, 62.80, 63.10, 66.28, 79.39, 119.10, 127.70,
128.19, 130.60, 133.21, 135.19, 154.70.
IR (neat): 3338, 2921, 2853, 1670, 1539, 1460, 1249, 1172, 1047
cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.20–1.40
(br m, 26 H), 1.47 (s, 9 H), 1.58–1.68 (m, 2 H), 2.59–2.64 (br s, 1
H, CH2OH), 3.39–3.41 (m, 1 H), 3.51–3.55 (m, 1 H), 3.62–3.63 (m,
1 H), 3.75 (dd, J = 4.0, 11.0 Hz, 1 H), 4.06 (d, J = 10.8 Hz, 1 H),
5.21 (br d, J = 8.7 Hz, 1 H).
HRMS-FAB: m/z [M + H]+ calcd for C25H44NO3Si2: 462.2860;
found: 462.2861.
(4S,5S,6S)-5-(tert-Butyldimethylsilyloxy)-4-[(tert-butyldimeth-
ylsilyloxy)methyl]-2-phenyl-6-[(E)-tetradec-1-enyl]-5,6-di-
hydro-4H-1,3-oxazine (8)
13C NMR (125 MHz, CDCl3): δ = 14.31, 22.90, 26.29, 28.54, 29.57,
29.76, 29.83, 29.87, 29.91, 32.14, 33.00, 53.72, 62.24, 69.91, 73.12,
80.63, 157.40.
HRMS-FAB: m/z [M + H]+ calcd for C23H48NO5: 418.3532; found:
418.3528.
To a solution of 4e (1.03 g, 2.24 mmol) in CH2Cl2 (50 mL) was add-
ed tetradec-1-ene (1.24 mL, 4.48 mmol) and Grubbs II catalyst (95
mg, 0.11 mmol) at r.t. After stirring the reaction mixture for 8 h un-
der reflux, the solvent was removed in vacuo to give the crude prod-
uct (E/Z >20:1 by 1H NMR). Column chromatography on silica gel
gave pure 8 (1.33 g, 94%) as a colorless oil; Rf = 0.5 (EtOAc–
hexanes, 1:20); [α]D25 –33.79 (c 1.0, CHCl3).
(2S,3S,4S)-2-Aminooctadecane-1,3,4-triol (D-lyxo-Phytosphin-
gosine, 1)
Triol 3 (26 mg, 0.06 mmol) was dissolved in CF3CO2H–H2O (20:1,
1.2 mL) and the solution was vigorously stirred at r.t. for 2 h. Excess
CF3CO2H was removed under reduced pressure, the aqueous layer
was neutralized with aq NaHCO3, and extracted with EtOAc (4 × 5
mL). The combined organic layers were dried (Na2SO4) and evapo-
rated at reduce pressure. The crude residue was purified by silica gel
IR (neat): 2927, 2857, 1657, 1462, 1115, 839, 776 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.07–0.18 (m, 12 H), 0.90–0.99
(m, 21 H), 1.33–1.45 (m, 20 H), 2.02–2.03 (m, 1 H), 2.14 (q, J = 6.9
Hz, 1 H), 3.50–3.55 (m, 1 H), 3.81 (dd, J = 5.1, 5.4 Hz, 1 H), 4.03
Synthesis 2012, 44, 2340–2346
© Georg Thieme Verlag Stuttgart · New York

PAPER
Total Synthesis of D-lyxo-Phytosphingosine
2345
chromatography eluting with CHCl3–MeOH–NH4OH, 40:10:1 to
afford 1 (18.2 mg, 92%) as a white solid; mp 104.5–105.5 °C; Rf =
0.27 (CHCl3–MeOH–NH4OH, 40:10:1); [α]D25 –6.4 (c 1.0, pyri-
dine) {Lit.11b [α]D25 –6.7 (c 0.9, pyridine)}.
(d) Ballereau, S.; Abadie, N. A.; Saffon, N.; Génisson, Y.
Tetrahedron 2011, 67, 2570. (e) Liu, Z.; Byun, H. S.;
Bittman, R. J. Org. Chem. 2010, 75, 4356. (f) Raghavan, S.;
Krishnaiah, V. J. Org. Chem. 2010, 75, 748. (g) Dubey, A.;
Kumar, P. Tetrahedron Lett. 2009, 50, 3425. (h) Pandey, G.;
Tiwari, D. K. Tetrahedron Lett. 2009, 50, 3296.
IR (neat): 3344, 2920, 2934, 2526, 1452, 1114, 1001, 693 cm–1.
1H NMR (500 MHz, pyridine-d5): δ = 0.81 (t, J = 7.0 Hz, 3 H), 1.20–
1.35 (m, 22 H), 1.48–1.58 (m, 1 H), 1.64–1.73 (m, 1 H), 1.82–1.90
(m, 1 H), 1.93–2.10 (m, 1 H), 3.84 (ddd, J = 4.5, 6.5, 11.0 Hz, 1 H),
4.15 (dd, J = 2.5, 6.5 Hz, 1 H), 4.26–4.29 (m, 1 H), 4.30–4.38 (m, 2
H).
13C NMR (125 MHz, pyridine-d5): δ = 14.22, 22.88, 26.64, 29.56,
29.87, 29.93, 30.01, 30.17, 32.07, 34.48, 56.65, 63.63, 72.02, 74.08.
(6) For recent syntheses of D-lyxo-phytosphingosine, see:
(a) Rao, G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52, 6076.
(b) Lee, Y. M.; Baek, D. J.; Kim, S. W.; Kim, D. J.; Kim, S.
H. J. Org. Chem. 2011, 76, 408. (c) Abraham, E.; Brock, E.
A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;
Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A.
J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 4668. (d) Kim,
S.; Lee, N.; Lee, S.; Lee, T.; Lee, Y. M. J. Org. Chem. 2008,
73, 1379.
HRMS-FAB: m/z [M + H]+ calcd for C18H40NO3: 318.3008; found:
318.3006.
(7) Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.;
Garcia Gravalos, D.; Higa, T. J. Nat. Prod. 2002, 65, 1505.
(8) Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G.
Tetrahedron Lett. 2003, 44, 225.
(9) For reviews on pachastrissamine syntheses, see:
(a) Ballereau, S.; Baltas, M.; Genisson, Y. Curr. Org. Chem.
2011, 15, 953. (b) Abraham, E.; Davies, S. G.; Roberts, P.
M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry
2008, 19, 1027.
Acknowledgment
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (S-2011-
0948-000) & Yonsung Fine Chemicals Corporations. The Global
Ph.D. Fellowship grant to S.H.P. is gratefully acknowledged.
(10) For recent syntheses of pachastrissamine, see: (a) Zhao, M.-
L.; Zhang, E.; Gao, J.; Zhang, Z.; Zhao, Y.-T.; Qu, W.; Liu,
H.-M. Carbohydr. Res. 2012, 351, 126. (b) Cruz-Gregorio,
S.; Espinoza-Rojas, C.; Quintero, L.; Sartillo-Piscil, F.
Tetrahedron Lett. 2011, 52, 6370. (c) Passiniemi, M.;
Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9, 1774.
(d) Lee, H. J.; Lim, C. M.; Hwang, S. H.; Jeong, B. S.; Kim,
S. H. Chem.–Asian J. 2011, 6, 1943. (e) Llaveria, J.; Diaz,
Y.; Matheu, M. I.; Castillon, S. Eur. J. Org. Chem. 2011,
1514. (f) Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.;
Ohno, H. J. Org. Chem. 2010, 75, 3843. (g) Vichare, P.;
Chattopadhyay, A. Tetrahedron: Asymmetry 2010, 21, 1983.
(h) Urano, H.; Enomoto, M.; Kuwahara, S. Biosci.
Biotechnol., Biochem. 2010, 74, 152. (i) Inuki, S.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
Primary Data for this article are available online and can be cited
using the following DOI: 10.4125/pd0031th. The primary data set
includes FIDs and associated files for the 1H and 13C NMR spectra
as well as NOE experiments.mPiDrayrmaPitDrayra
1
t
0.4125/pd0031th.mPirayrDaZtaheln101Chemyr
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2340–2346

2346
Y. Mu et al.
PAPER
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22.
1. TsCl, Et3N, DMAP
CH2Cl2, r.t.
2. K2CO3, MeOH, r.t.
70% for 2 steps
OH
H2N
OH
C14H29
OH
HO
BocHN
3. TFA, CH2Cl2
0 °C to r.t., 75%
C14H29
(15) The synthesis of pachastrissamine (2) was achieved in three
steps from N-Boc-triol 3: Ribes, C.; Falomir, E.; Carda, M.;
Marco, J. A. Tetrahedron 2006, 62, 5421.
O
3
pachastrissamine (2)
Scheme 5 Synthesis of pachastrissamine (2) from N-Boc-triol 3
Synthesis 2012, 44, 2340–2346
© Georg Thieme Verlag Stuttgart · New York