A flexible approach to construct three contiguous chiral centers of sphingolipids, and asymmetric synthesis of d-ribo-phytosphingosine and its derivatives

Article abstract of DOI:10.1016/j.tet.2012.05.120

An efficient approach to build the three contiguous stereogenic centers of sphingosine unit starting from cheap glutamic acid is described. The key step of this approach is the SmI₂-mediated cross-coupling of chiral N-tert-butanesulfinyl imine 11 with sterically hindered aliphatic aldehyde 9 or 21 to construct hydroxymethyl β-amino alcohol 10 or 22 in high diastereoselectivity (>99%, de). The utility of this flexible method has been demonstrated in the synthesis of d-ribo-phytosphingosine 1, its two derivatives 18 and 29. Moreover, a practicable synthetic route for synthesis of various sphingolipids, ceramides, α-galactosylceramides and their derivatives is also described.

Full text of DOI:10.1016/j.tet.2012.05.120

Tetrahedron 68 (2012) 6688e6695
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A flexible approach to construct three contiguous chiral centers of sphingolipids,
and asymmetric synthesis of
D-ribo-phytosphingosine and its derivatives
*
Cholmen Xarnod (Lu-Men Chao), Wei Huang, Rong-Guo Ren, Ru-Cheng Liu, Bang-Guo Wei
Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach to build the three contiguous stereogenic centers of sphingosine unit starting from
cheap glutamic acid is described. The key step of this approach is the SmI2-mediated cross-coupling of
chiral N-tert-butanesulfinyl imine 11 with sterically hindered aliphatic aldehyde 9 or 21 to construct
Received 28 March 2012
Received in revised form 21 May 2012
Accepted 29 May 2012
hydroxymethyl
b
-amino alcohol 10 or 22 in high diastereoselectivity (>99%, de). The utility of this
-ribo-phytosphingosine 1, its two derivatives
Available online 4 June 2012
flexible method has been demonstrated in the synthesis of
D
18 and 29. Moreover, a practicable synthetic route for synthesis of various sphingolipids, ceramides, a-
galactosylceramides and their derivatives is also described.
Keywords:
a
-Galactosylceramide
Ó 2012 Elsevier Ltd. All rights reserved.
Ceramide
Sphingolipid
Asymmetric synthesis
Phytosphingosine
1. Introduction
cancers, infection by microorganisms, Alzheimer’s disease, heart
disease of human body.9 In nature, among of eight possible
Sphingosine and phytosphingosine are two most important
long-chain constituents of cell members (Fig. 1).1 They are widely
distributed in mammalian cells, bacteria and fungi, yeasts, plants,
and marine organisms.2 Their structural function of a small positive
change at neutral pH as a consequence of intermolecular hydrogen
bonding enable them as an unusual class of sphingolipids, which
serve as an essential components of all eukaryotic cell membranes
together with glycerolipids and sterols.3 Sphingosine and phytos-
phingosine 1 play critical roles in many physiological processes,
which include cellular recognition, modulation of immune re-
sponse, adhesion and apoptosis.4 In addition, they can effectively
inhibit the protein kinase C, and their ceramide derivatives are also
potent stimulators of the mammalian immune system.5 Phytos-
phingosine or its derivatives are one essential core fragment of
several ceramides, which possess diverse bioactivities, such as
controlling cell growth, maturity, survival and death, and inhibiting
or activating certain enzymes, and lead to promising efficacies for
the control of cancer and other cell proliferation.6 As a prime in-
stance, modification of marine natural product agelasphine-9b 4
led to an anticancer drug candidate KRN7000,7 which can regulate
immune system through interaction with CD1d protein located on
the surface of antigen-presenting cells.8 Recent studies revealed
that some of sphingolipids analogues could inhibit the diabetes,
HO
O
OH
N
H
OH
OH
2 Cerebroside sphingolipid
C25H51
OH
OH
C14H29
O
NH OH
HO
O
HO
HO
O
NH2 OH
OH
OH C13H27
1 D-ribo-phytosphingosine
3 KRN-7000
HO
C21H43
OH
O
NH OH
O
HO
HO
O
(CH2)10CHMe2
OH
OH
4 Agelasphine-9b
* Corresponding author. E-mail address: bgwei1974@fudan.edu.cn (B.-G. Wei).
Fig. 1. The structure of several bioactive molecules.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.120

C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
6689
stereoisomers of phytosphingosines,
the most predominant one. Due to their biological activities and
intriguing structures, the -ribo-phytosphingosine 1, agelasphine-
D
-ribo-phytosphingosine 1 is
Hydrogenation (10% Pd/C, MeOH) of the olefin afforded the ester 8
in 95% yield. Treatment of ester 8 with DIBAL-H16 in toluene
at ꢀ78 ꢁC for 3 h gave aldehyde 9 in 85% yield. Although the cross-
coupling reaction of (S)-N-tert-butanesulfinyl imine with aromatic
D
9b 4 or their derivative KRN7000 3 have attracted more attention
of many chemists and several approaches to the asymmetric syn-
thesis of them have been reported recently.10 From the practical
point of view, the most challenging work is the construction of
three contiguous chiral centers in optically active sphingosine.
In continuation of our tremendous efforts to explore some
multifunctional building blocks based on the cheap resources and
utilizing them in the asymmetric synthesis of some natural prod-
ucts11 including asymmetric synthesis of ceramide sphingolipid 2,
a sex pheromone of hair crab, based on the chiral lactam derived
from the cheap glutamic acid.12 As part of this program, we focus on
developing efficient asymmetric methods to build the three chiral
centers unit of sphingosine and using them in the asymmetric
aldehydes is a robust method to build the unit of b-amino alcohol, it
often need 4 equiv amounts of aldehydes for the aliphatic reac-
tants.14a Considering the difficulty of preparation for 9 through the
multi-steps reaction, we started to screen the ratio of sterically
hindered aliphatic aldehyde 9 with (S)-N-tert-butanesulfinyl im-
ine17 11. Fortunately, when the equivalent amount aldehydes 9 was
used, the cross-coupling reaction was smoothly occurred in 5 h, and
generated protective hydroxymethyl b-amino alcohol 10 with high
diastereoselectivity (>99%, de) in 68% yield. Then, compound 10
was treated with dry HCl in MeOH for 4 h, the chiral auxiliary14a
and tert-butyldimethylsilyl group of secondary hydroxyl was re-
moved in one-pot. Then transfer hydrogenation18 (HCOOH/MeOH)
of the concentrated crude salt 11 in the presence of stoichiometric
catalyst (10% Pd/C) at room temperature for 12 h produced crude 1,
which was purified by chromatography on silica gel (DCM/MeOH)
synthesis of
actosylceramide derivatives. Herein we describe a flexible method
for the construction two chiral centers of the -ribo-phytos-
D-ribo-phytosphingosine 1 and its ceramides, a-gal-
D
phingosine 1 promoted by SmI2 and its utility in the diverse syn-
thesis of the derivatives.
Chiral N-tert-butanesulfinamide, as pioneered by Ellman and
Davis, is undoubtedly one of the most efficient auxiliaries occurring
in modern organic synthesis,13 and Lin group has achieved a pow-
to give
D
-ribo-phytosphingosine 1 {½a D25
ꢂ
þ7.9 (c 0.2, C6H5N); lit.19
½
a 2D3
ꢂ
þ7.0 (c 0.09, C6H5N); lit.10g
½
a 2D3
ꢂ
þ8.0 (c 0.8, C6H5N)} in 54%
overall yield. The spectroscopic and physical data of the synthetic
D
-ribo-phytosphingosine 1 were identical with the reported data.10g
erful method for the synthesis of unsymmetrical vicinal b-amino
O
H
alcohols based on it.14 Later, our group used it to study the chemical
selectivity of the imine15b with aldehydes in the presence of ester or
ketone, and those results have been applied in the total synthesis of
(ꢀ)-deoxoprosophylline 5 (Fig. 2).15a As shown in Fig. 2, in this work
our purpose is to study the stereoselective cross-coupling reaction
of imine with high sterically hindered long-chain aliphatic alde-
hydes derived from the glutamic acid, and to build a flexible
a
Ref. 11d
MeO
O
D-Glutamic acid
O
OTBS
6
OTBS
C14H29
b
c
O
C10H21
method for synthesis of bioactive
D
-ribo-phytosphingosine 1,
MeO
agelasphine-9b 4 and their analogues.
OMe
OTBS
7
8
5 (-)-deoxoprosophylline
3 KRN-7000
OH
OTBS
O
d
1 Phytosphingosine
BnO
(CH2)12CH3
4 Agelasphine-9b
(CH2)13CH3
NH OTBS
H
O S
OH
OH
R
R1
9
10
BnO
BnO
OH
NH2
O
NH2 OTBS
OH C13H27
e
HO
(CH2)12CH3
This work
SmI2
Glutamic Acid
BnO
Our previous work
SmI2
NH2 OH
NH2 OH
HCl
O
O
N
+
11
1 phytosphingosine
H
R1
OTBS
R
BnO
S
O
H
+
Scheme 1. Synthesis of D-ribo-phytosphingosine 1. a. n-C11H23PPh3Br, n-BuLi,
THF, ꢀ78 ꢁC, rt, 6 h, 89%; b. H2, 10% Pd/C, MeOH, rt, 1 h, 95%; c. DIBAL-H, toluene,
ꢀ78 ꢁC, 3 h, 88%; d. 2-benzoxyl ethyl (S)-N-tert-butanesulfinyl imine, SmI2, t-BuOH,
ꢀ78 ꢁC, 5 h, 68%; e. (i) HCl/MeOH, 4 h; (ii) 10% Pd/C, HOOH, MeOH, 12 h, 54%.
O
R1= n-C14H29, C10H20CHMe2
R = OMe, n-C12H25
Fig. 2. The synthetic strategy of this work.
ToexploreanefficientmethodforthesynthesisofKRN70003, The
crude salt 11 was treated with di-tert-butyl dicarbonate in the pres-
ence of 1 M NaOH to afford compound 12 in 75% yield (Scheme 2).
When compound 12 was treated with TBSOTf and 2,6-Lutidine in
DCM, the hydroxyl were protected, simultaneously, the deprotection
of amino group was occurred in one-pot to afford amine 13 in 78%
overall yield. Then compound 13 was treated with the commercial
active ester 14 in the presence of DMAP to afford amide 15 in 45%
yield. Hydrogenation (20% Pd(OH)2e10% Pd/C, H2) of amide 15 gave
2. Results and discussion
Firstly, -glutamic acid was selected as a starting material to
prepare the aldehyde R-6 for the cross-coupling reaction in our plan
according to our previous method.11d Then the unpurified aldehyde
6 was directly subjected to the Wittig reaction with undecane-
triphenylphosphonium bromide in the presence of n-BuLi to afford
the E and Z mixture of the olefin in 89% combined yield (Scheme 1).
D
alcohol 16 {½a 2D5
ꢂ
ꢀ9.2 (c 1.0, CHCl3);lit.20
½
a 1D6
ꢂ
ꢀ9.5 (c 6.2, CHCl3);lit.21

6690
C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
½
a 2D6
ꢂ
ꢀ10.9 (c 1.0, CHCl3)} in 82% yield, which can be easily converted
O
to KRN7000 3 by known method.20e22 Conveniently, when the al-
cohol 16 was treated with dry HCl in MeOH, a new derivative 17 of
a
OBn
5
b
6
MeO
OH
cerebroside was produced {½a D20
ꢀ5.3(c 1.0, CHCl3)} in 52% yield. The
ꢂ
OTBS
spectroscopic and physical data of the compound 1620,21 and 17 were
18a
identical with the reported data.
O
O
d
c
MeO
OH
MeO
O
OTBS
8
8
8
C13H27
OTBS
a
OTBS
C13H27
b
BnO
BocHN
11
BnO
18b
OH
19
NH2 OTBS
OTBS
O
12
13
e
O
(CH2)11CH(CH3)2
MeO
OTBS
C13H27
OTBS
H
OTBS
20
C13H27
NH OTBS
C25H51
c
BnO
O
HO
O
d
21
OR
10
NH OTBS
C25H51
OH
BnO
O
f
g
10
BnO
OTBS
NH
15
16
Ref.20-22
O
e
S
OR
NHR1
OH
24b R = H; R1=Boc
h
C13H27
OH
HO
HO
23 R = H; R1=H
HO
O
22
i
(CH2)24CH3
OH
HN
O
NH OH
C25H51
24a R = TBS; R1=H
Scheme 3. Reagents and conditions: a. BnOC7H14PPh3Br n-BuLi, THF, ꢀ78 ꢁC, rt, 6 h,
72%; b. H2, 10% Pd/C, 20% Pd(OH)2, MeOH, rt, 12 h, 78%; c. DMSO, (COCl)2, TEA, ꢀ78 ꢁC,
3.5 h, 82%; d. isobutanenetriphenylphosphonium bromide, n-BuLi, THF, ꢀ78 ꢁC, rt, 6 h,
84%; e. (i) H2, 10% Pd/C, MeOH, rt, 1 h, 96%; (ii) DIBAL-H, toluene, ꢀ78 ꢁC, 3 h, 85%; f. 2-
benzoxyl ethyl (S)-N-tert-butanesulfinyl imine, SmI2, t-BuOH, ꢀ78 ꢁC, 5 h, 67%; g. HCl/
MeOH, 4 h; h. Boc2O, 1M NaOH, dioxane/H2O (1:1), 48 h, 75%; i. TBSOTf, 2,6-Lutidine,
HO
O
(CH2)13CH3
OH
3 KRN7000
17
0
ꢁC, rt, 12 h, 78%.
Scheme 2. Reagents and conditions: a. Boc2O, 1 M NaOH, dioxane/H2O (1:1), 48 h,
75%; b: TBSOTf, 2,6-Lutidine, 0 ꢁC, rt, 12 h, 78%; c. (i) hexacosanoic acid, NMM, Ethyl
chloroformate, THF, ꢀ20 ꢁC, rt, 1 h; (ii) C2H5OCO2C26H53 14, NMM, DMAP, THF, 45%; d.
H2, 10% Pd/C, 20% Pd(OH)2, MeOH, rt, 12 h, 82%; e. HCl/MeOH, 4 h, 52%.
to afford the E and Z mixture of the olefin 25 in 85% combined yield.
Hydrogenation (10% Pd/C, H2) of the olefin 25 and subsequent re-
action with LiOH in mixture solvent of MeOH and water (MeOH/
THF/H2O¼5:3:3) generated crude intermediate acid, which was
directly treated with ethyl carbonochloridate in the presence of
NMM to give crude compound 26 in quantitative yield. When the
compound 24 was treated with the active ester 26 in the presence
of DMAP, amide 27 was produced in overall 27% yield from olefin
25. Although several conditions were conducted to improve the
yield of amide 27, all the results were not significantly improved.
Hydrogenation (20% Pd(OH)2e10% Pd/C, H2) of amide 27 generated
alcohol 28 in 65% yield. The compound 28, an important protective
isomer of cerebrosides, was easily converted to the epimer of
agelasphine-9b 4 by resemble reported method.7,20e22 Simulta-
neously, the alcohol 28 was treated with a solution of saturated
hydrogen chloride in 1,4-dioxane to afford an epimer of ceramide
Encouraged by the convenient method for synthesis of D-ribo-
phytosphingosine 1, we then started to investigate the synthesis of
agelasphine-9b 4 and its derivatives. The Wittig reaction of alde-
hyde
6
with 7-(benzyloxy)heptan-1-triphenylphosphonium
bromide in the presence of n-BuLi gave the mixture of E and
Z-olefin 18a in 72% yield (Scheme 3). Hydrogenation [20%
Pd(OH)2e10% Pd/C, H2] of a mixture of olefin 18a gave alcohol 19 in
78% yield. Upon Swern oxidation [(COCl)2, DMSO] of compound
18a, the resulting crude aldehyde 19 was directly treated with
2-methylpropanetriphenylphosphonium bromide in the presence
of n-BuLi to generate the mixture of E and Z-olefin 20 in 84% overall
yield. Reduction (10% Pd/C, H2) of the olefin 20 and subsequent
reaction with DIBAL-H in dry tetrahydrofuran at ꢀ78 ꢁC gave al-
dehyde 21 in 82% overall yield. Then the SmI2-induced cross-
coupling of 21 with (S)-N-tert-butanesulfinyl imine generated
29 {½a D
ꢂ
20 7.7 (c 0.2, CHCl3)} in 60% yield (Scheme 4). The structure of
29 was readily determined by all spectroscopic and physical data.
hydroxymethyl b-amino alcohol 22 with high diastereoselectivity
(>99%, de) in 67% yield. After removal (HCl/MeOH) of the chiral
auxiliary and protective group of secondary alcohol, the crude
amide 23 was obtained without further purification, which was
directly subject to react with di-tert-butyl dicarbonate and followed
by TBSOTf to produce the key intermediate amide 24a in 59%
overall yield from compound 22 (Scheme 3).
3. Conclusions
In summary, an efficient approach by SmI2-induced cross-
coupling of N-tert-butanesulfinyl imine with sterically hindered
aliphatic aldehydes derived from cheap glutamic acid for building
the three chiral centers of sphingosine unit has been developed.
To build an effective method for preparation of the side chain in
agelasphine-9b 4 and its derivatives, the numerous material S-18b
D-ribo-phytosphingosine 1 and its two derivatives 18 and 29 have
derived from
L
-glutamic acid was considered.12 Thus, Swern oxi-
been synthesized by this approach. Simultaneously, a practicable
approach for synthesis of agelasphine-9b 4 and its derivative
KRN7000 3 has also been achieved. Furthermore, this flexible ap-
proach might be generally applicable in the synthesis of various
dation [(COCl)2, DMSO] of compound S-18b and the resulted crude
aldehyde was directly subjected to the Wittig reaction with
dodecanetriphenylphosphonium bromide in the presence of n-BuLi

C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
6691
at room temperature. The reaction was quenched with an aqueous
solution of saturated NaHCO3 (10 mL) and diluted with water
(10 mL) and ethyl acetate (20 mL). The resulted mixture was sep-
arated and the aqueous phase was extracted with ethyl acetate for
three times. The combined organic layers were washed with brine
for three times and dried over anhydrous Na2SO4. Filtered and
concentrated, the residue was purified by chromatography on silica
O
OTBS
(CH2)21CH3
a
C2H5O2CO
b
S-19b
MeO
8
C11H23
OTBS
O
26
25
gel to give 7 (4.4 g, 89%) as a colorless oil. ½a D25
ꢂ
þ17.4 (c 1.0, CHCl3):
TBSO
TBSO
C21H43
C21H43
IR (film); nmax 2926, 1758, 1461, 1257, 1216, 1139, 1039 cmꢀ1
;
1H
O
d
O
c
NMR (400 MHz, CDCl3) d: 5.38e5.44 (m, 2H), 4.26e4.23 (m, 1H),
NH OTBS
NH OTBS
3.75 (s, 3H), 2.22e2.10 (m, 2H), 2.08e1.96 (m, 2H), 1.81e1.75 (m,
2H), 1.38e1.30 (m, 16H), 0.94 (s, 9H), 0.92 (t, J¼6.8 Hz, 3H), 0.11 (s,
HO
R
BnO
R
3H), 0.08 (s, 3H) ppm; 13C NMR (CDCl3, 100 Hz):
d
¼174.2, 131.0,
OTBS
28
OTBS
27
128.3, 71.9, 51.6, 35.4, 31.9, 29.7, 29.6, 29.5, 29.3, 27.3, 25.7, 22.8,
22.6, 18.3, 14.1, ꢀ4.9, ꢀ5.3 ppm; MS (ESI): 399 (MþHþ); HRMS (ESI)
calcd for (C23H46O3SiþHþ): 399.3294, found: 399.3276.
e
Ref.20-23
21H43
HO
HO
O
C
21H43
C
4.3. (S)-Methyl 2-(tert-butyldimethylsilyloxy)hexadecanoate (8)
OH
OH
O
NH OH
NH OH
O
To a suspension of 10% Pd/C (450 mg) in methanol (20 mL) was
dropped to a solution of 7 (4.3 g, 15.04 mmol) in methanol (100 mL)
under H2 atmosphere. After stirring for 1 h, the mixture was filtered
and concentrated under reduced pressure. The residue was purified
by chromatography on silica gel to give 8 (4.11 g, 95%), as a colorless
HO
R
HO
HO
O
R
OH
OH
R = C10H20CHMe2
oil. ½a 2D5
ꢂ
þ15.5 (c 1.0, CDCl3); IR (film): nmax 3416, 2927, 2855, 2283,
4 Epi-Agelasphine-9b
29
1591,1467,1216,1121 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 4.23e4.20
Scheme 4. Reagents and conditions: a. (i) DMSO, (COCl)2, TEA, ꢀ78 ꢁC, 3.5 h; (ii)
n-C12H25PPh3Br, n-BuLi, THF, ꢀ78 ꢁC, rt, 6 h, two steps 85%; b. (i) H2, 10% Pd/C, MeOH, rt,
(m, 1H), 3.74 (s, 3H),1.74e1.69 (m, 2H),1.46e1.38 (m, 2H),1.37e1.29
(m, 24H), 0.94 (s, 9H), 0.91e0.90 (m, 3H), 0.11 (s, 3H), 0.08 (s, 3H)
1
h, 95%; (ii) LiOH$H2O, MeOH, THF, H2O, 85%; (iii) NMM, Ethyl chloroformate,
THF, ꢀ20 ꢁC, rt, 1 h; c. 24a, NMM, DMAP, THF, in four steps 27%; d. H2, 10% Pd/C, 20%
ppm; 13C NMR (CDCl3, 100 Hz):
29.6, 29.5, 29.4, 29.3, 25.7, 25.1, 22.7, 18.3, 14.1, ꢀ5.0, ꢀ5.3 ppm; MS
(ESI): 401 (MþHþ); HRMS (ESI) calcd for (C23H48NO3SiþHþ):
401.3451, found: 401.3434.
d
¼174.5, 72.3, 51.7, 35.2, 31.9, 29.7,
Pd(OH)2, MeOH, rt, 12 h, 65%; e. HCl/MeOH, 4 h, 60%.
sphingolipids, ceramides,
a-galactosylceramides and their de-
rivatives with important structural and biological.
4.4. (S)-2-(tert-Butyldimethylsilyloxy)hexadecanal (9)
4. Experimental section
4.1. General
To a solution of compound 8 (4.0 g, 9.99 mmol) in dry toluene
(50 mL) was slowly dropped a solution of DIBAL-H (9.7 mL,
9.99 mmol, 20% in toluene) at ꢀ78 ꢁC under argon atmosphere.
After stirring for 3 h at the same temperature, the reaction mixture
was quenched with an aqueous solution of saturated potassium
sodium tartrate and stirred for another four 4 h at room tempera-
ture. The organic layer was separated and aqueous layer was
extracted with ethyl acetate for three times (40mLꢃ3). The com-
bined organic layers were washed with brine for three times
(20mLꢃ3) and dried over anhydrous Na2SO4. Filtered and concen-
trated under reduced pressure, the residue was purified by chro-
matography on silica gel to give 9 (3.36 g, 88%), as a colorless oil.
THF was distilled from sodium/benzophenone. All reactions
were monitored by thin layer chromatography (TLC) on glass plates
coated with silica gel with fluorescent indicator (Huanghai
HSGF254). Flash chromatography was performed on silica gel
(Huanghai 300e400) with Petroleum/EtOAc as eluent. Melting
points were recorded on a Mel-Temp apparatus and uncorrected.
Optical rotations were measured on a JASCO P-1030 polarimeter
with a sodium lamp. Mass spectra were recorded on a HP-5989
instrument and HRMS (MALDI/DHB) were measured on a LCMS-
IT-TOF (Shimazu Corporation) apparatus. IR spectra were recor-
ded using KBr disks or film, on a Fourier Transform Infrared Spec-
trometer, Type: Avatar 360 E.S.P, manufactured by Thermo Nicolet
Corporation, USA. NMR spectra were recorded on a Varian or
a Bruker spectrometer (300 or 400 MHz), and chemical shifts are
reported in d (parts per million) referenced to an internal TMS
standard for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR.
½
a 2D5
1467, 1468, 1115, 838, 778 cmꢀ1; 1H NMR (400 MHz, CDCl3)
ꢂ
þ10.8 (c 1.0, CDCl3); IR (film): nmax 3426, 2926, 2855, 1738,
d: 9.61
(d, J¼2.0 Hz, 1H), 4.00e3.97 (m, 1H), 1.69e1.61 (m, 2H), 1.45e1.36
(m, 2H), 1.35e1.29 (m, 22H), 0.95 (s, 9H), 0.91 (t, J¼6.8 Hz, 3H), 0.11
(s, 3H), 0.10 (s, 3H) ppm; 13C NMR (CDCl3, 100 Hz):
d
¼204.3, 77.7,
32.6, 31.9, 29.7, 29.6, 29.5, 29.4,29.3, 25.7, 24.6, 22.7, 18.2, 14.1, ꢀ4.6,
ꢀ4.9 ppm; MS (ESI): 371 (MþHþ); HRMS (ESI) calcd for
(C22H46NO2SiþHþ): 371.3345, found: 371.3321.
4.2. (R)-Methyl 2-(tert-butyldimethylsilyloxy)hexadec-5-
enoate (7)
4.5. N-((2S,3S,4R)-1-(Benzyloxy)-4-(tert-
butyldimethylsilyloxy)-3-hydroxyoctadecan-2-yl)-2-
methylpropane-2-sulfinamide (10)
To a solution of n-undecanetriphenylphosphonium bromide
(9.3 g, 18.7 mmol) in dry THF (60 mL) was treated with a solution of
n-BuLi (11.3 mL, 18.1 mmol, 1.6 in THF) to 0 ꢁC under argon atmo-
sphere for 2 h. Then, the resulted mixture was cooled to ꢀ78 ꢁC and
a solution of crude aldehyde 6 (3.24 g, 12.4 mmol) in dry THF was
slowly dropped. After being stirred for 1 h, the mixture was allowed
to worm to room temperature within 2 h and stirred for another 3 h
The mixture of compound 9 (3.10 g, 8.36 mmol), t-BuOH
(2.45 mL, 25.80 mmol) and 2-benzoxyl ethyl (S)-N-tert-butane-
sulfinyl imine (2.16 g, 8.36 mol) in the dry THF (30 mL) was stirred
at ꢀ78 ꢁC under argon atmosphere. Then a freshly solution of SmI2
(25.80 mmol, 20 mL) in dry THF was dropped. After stirred for 5 h,
the reaction mixture was quenched with an aqueous solution of

6692
C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
saturated Na2S2O3 (10 mL) and warmed to room temperature. The
mixture was diluted with ethyl acetate (30 mL) and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate for three times (40mLꢃ3) and the combined organic layers
were washed with brine for three times. Dried, filtered and con-
centrated, the residue was purified by chromatography on silica gel
28.3, 28.0, 27.4, 26.1, 22.7, 14.1 ppm: MS (ESI): 508 (MþHþ); HRMS
(ESI) calcd for (C30H53NO5þHþ): 508.4002, found: 508.4000.
4.8. (2S,3S,4R)-1-(Benzyloxy)-3,4-bis(tert-
butyldimethylsilyloxy)octadecan-2-amine (13)
to give 10 (3.36, 68%), as a colorless oil. ½a D25
ꢂ
þ1.2 (c 1.0, CDCl3); IR
To a solution of 12 (1.9 g, 3.85 mmol) and 2.6-luditine (1.31 mL,
11.24 mmol) in dry DCM (20 mL) was stirred for 15 min at 0 ꢁC
under argon atmosphere. Then, a solution of TBSOTf (2.58 mL,
11.24 mmol) was slowly dropped and the mixture was stirred for
over night at room temperature, the reaction mixture was
quenched with H2O, and the resulted mixture was extracted with
DCM for three times (50 mLꢃ3). The combined organic layers were
washed with saturated NaHCO3 aqueous solution (40 mL) and
brine (20 mLꢃ3), dried over anhydrous Na2SO4. Filtered and con-
centrated under reduced pressure, the residue was purified by
chromatography on silica gel to give to 13 (1.91 g, 78%), as a col-
(film): nmax 3409, 2924, 1739, 1598, 1467, 1119, 1077, 776 cmꢀ1
;
1H
NMR (400 MHz, CDCl3)
d
: 7.40e7.30 (m, 5H), 4.63 (d J¼11.6 Hz, H),
4.58 (d J¼11.6 Hz, H), 4.09e4.06 (m, 2H), 3.94 (dd, J¼4.2, 9.0 Hz,1H),
3.78 (dd, J¼3.2, 8.8 Hz, 1H), 3.46e3.44 (m, 1H), 3.28e3.23 (m, 1H),
2.63 (d, J¼9.2 Hz, 1H), 1.73e1.69 (m, 1H), 1.62e1.57 (m, 1H),
1.49e1.44 (m, 1H), 1.41e1.38 (m, 1H), 1.26 (s, 9H), 1.31e1.27 (m,
22H), 0.91 (s, 9H), 0.92e0.89 (m, 3H), 0.13 (m, 6H) ppm; 13C NMR
(CDCl3, 100 Hz):
d
¼138.3, 128.3, 127.8, 127.6, 73.3, 71.1, 70.8, 70.1,
58.0, 56.1, 34.6, 31.9, 29.7, 29.6, 29.3, 25.9, 25.3, 22.8, 22.7, 18.1,
14.1, ꢀ3.8, ꢀ4.1 ppm; MS (ESI): 626 (MþHþ); HRMS (ESI) calcd for
(C35H67NO4SSiþHþ): 626.4638, found: 626.4616.
orless oil. ½a 2D5
ꢂ
þ18.1 (c 1.0, CDCl3); IR (film): nmax 3379, 2928, 1702,
1502, 1464, 1377, 1179, 772 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d:
7.37e7.28 (m, 5H), 4.59 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz, 1H),
3.70 (dd, J¼2.6, 9.0 Hz, 1H), 3.66e3.65 (m, 1H), 3.64e3.63 (m, 1H),
3.54e3.50 (m, 1H), 3.21e3.17 (m, 1H), 2.09e2.04 (m, 2H), 1.77e1.69
(m, 1H), 1.57e1.50 (m, 1H), 1.42e1.28 (m, 24H), 0.93 (s, 9H),
0.92e0.90 (m, 3H), 0.89 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H), 0.09 (s,
4.6. (2S,3S,4R)-2-Aminooctadecane-1,3,4-triol
phytosphingosine (1)
To a solution of 10 (130 mg, 0.21 mmol) in absolute MeOH (3 mL)
was treated with a solution of HCl/MeOH (4 M, 3 mL) at room
temperature. After stirring for 4 h, the mixture was concentrated
under reduced pressure to afford crude intermediate salt 11 with-
out further purification. A suspension of 10% Pd/C (85 mg) in
methanol (3 mL) was dropped to a solution of above crude salt 11
(85 mg, 0.21 mmol) in methanol (4 mL) under argon atmosphere.
Then a solution of HCOOH (1 mL) was slowly dropped and the
mixture was stirred for 12 h. The mixture was directly concentrated
and the residue was purified by chromatography on silica gel to
3H), 0.06 (s, 3H) ppm; 13C NMR (CDCl3, 100 Hz):
d¼138.6, 128.3,
127.6, 127.4, 76.5, 74.5, 73.2, 72.6, 52.9, 31.2, 30.9, 29.7, 29.6, 29.4,
26.7, 26.0, 25.8, 22.7, 18.0, 14.1, ꢀ3.8, ꢀ4.1, ꢀ4.8, ꢀ4.9 ppm; MS
(ESI): 636 (MþHþ); HRMS (ESI) calcd for (C37H73NO3Si2þHþ):
636.5207, found: 636.5199.
4.9. (2S,3S,4R)-Benzyl-3,4-bis-tert-butyldimethylsilyloxy-2-
hexacosanoyl-amide-4-octadecanol (15)
give 1 (36 mg, 54% for two steps), as a white solid. {½a D25
ꢂ
þ7.9 (c 0.2,
To a solution of hexacosanoic acid (627 mg, 1.58 mmol) and
NMM (0.52 mL, 4.74 mmol) was stirred at ꢀ20 ꢁC under argon at-
mosphere. Then a solution of ethyl chloroformate (0.15 mL,
1.58 mmol) in dry THF was dropped and the reaction mixture was
stirred for 1 h at the same temperature to prepare a fresh solution
of 14. A mixture of NMM (0.52 mL, 4.74 mmol) and catalytic amount
of DMAP in THF (3 mL) was dropped, then, a solution of 13 (1 g,
1.58 mmol) in dry THF (8 mL) was dropped. The reaction mixture
was allowed to warm to room temperature and stirred for 5 h. The
reaction was quenched with water and extracted with ethyl acetate
for three times (50 mLꢃ3). The combined organic layers were
washed with saturated NaHCO3 aqueous solution (40 mL) and brine
(40 mLꢃ3), dried over anhydrous Na2SO4. Filtered and concen-
trated under reduced pressure, the residue was purified by chro-
matography on silica gel to give 15 (720 mg, 45%), as a colorless oil.
C6H5N); lit.19
½
a 2D3
ꢂ
þ7.0 (c 0.09, C6H5N); lit.10g
½
a 2D3
ꢂ
þ8.0 (c 0.8,
C6H5N)}; IR (film): nmax 3361, 2918, 2495, 1592, 1468, 1320, 1076,
1028 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
: 3.78 (dd, J¼4.2, 10.7 Hz,
1H), 3.60e3.53 (m, 2H), 3.39e3.34 (m, 1H), 3.67e3.66 (dd, J¼6.0,
10.4 Hz, 1H), 1.80e1.75 (m, 1H), 1.60e1.58 (m, 1H), 1.46e1.36 (m,
2H), 1.35e1.26 (m, 22H), 0.93 (t, J¼6.8 Hz, 3H), ppm; 13C NMR
(CDCl3, 100 Hz):
d
¼75.2, 73.1, 62.9, 54.5, 33.4, 31.7, 29.6, 29.4, 29.1,
25.3, 22.3, 13.0 ppm: MS (ESI): 308 (MþHþ); HRMS (ESI) calcd for
(C18H39NO3þHþ): 318.3008, found: 318.3008.
4.7. tert-Butyl (2S,3S,4R)-1-(benzyloxy)-3,4-
dihydroxyoctadecan-2-ylcarbamate (12)
To a solution of 11 (2.10 g, 5.43 mmol) in 1,4-dioxane and water
(30 mL, v/v¼1:1) was treated with a solution of 1 M NaOH (5 mL)
and stirred for 2 h. Then a solution of Boc2O (1.77 g, 8.16 mmol) in
1,4-dioxane (5 mL) was dropped and the resulted mixture was
stirred for 48 h at room temperature. The reaction mixture was
quenched with a solution of HCl (5 mL, 1 M), and the mixture was
extracted with ethyl acetate for three times (30 mLꢃ3). The com-
bined organic layers were washed with saturated NaHCO3 aqueous
solution (30 mL) and brine (20 mLꢃ3). Dried, filtered and con-
centrated, the residue was purified by chromatography on silica gel
½
a 2D5
1466, 1258, 1097, 836, 778 cmꢀ1
ꢂ
ꢀ12.1 (c 1.0, CDCl3); IR (film): nmax 3415, 2924, 2854, 1678,
;
1H NMR (400 MHz, CDCl3)
d:
7.34e7.28 (m, 5H), 6.78 (d, J¼5.6 Hz, 1H), 4.54 (d, J¼12.0 Hz, 1H),
4.48 (d, J¼12.0 Hz, 1H), 4.11 (dd, J¼2.8, 8.4 Hz, 1H), 3.99e3.92 (m,
1H), 3.78e3.72 (m, 2H), 3.70e3.67 (m, 1H), 2.15e2.11 (m, 2H),
1.73e1.70 (m, 2H), 1.66e1.62 (m, 2H), 1.30 (m, 68H), 0.96 (s, 9H),
0.90 (s, 9H), 0.94e0.92 (m, 6H), 0.14 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H),
0.07 (s, 3H) ppm; 13C NMR (CDCl3, 100 Hz):
d
¼172.6, 138.7, 128.2,
127.3, 76.3, 73.1, 70.2, 68.4, 53.4, 37.3, 31.9, 31.5, 31.4, 30.2, 29.7,
26.0, 25.8, 22.7, 18.0, ꢀ4.2, ꢀ4.9 ppm; MS (ESI): 1014 (MþHþ);
HRMS (ESI) calcd for (C63H123NO4Si2þHþ): 1014.9069, found:
1014.9066.
to give 12 (2.06, 75%), as a white solid. ½a D25
ꢀ6.4 (c 1.0, CDCl3); IR
ꢂ
(film): nmax 3378, 2928, 1710, 1502, 1463, 1377, 1169, cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
: 7.42e7.30 (m, 5H), 5.27 (d, J¼8.4 Hz, 1H), 4.59
(d, J¼11.6 Hz, 1H), 4.54 (d, J¼11.6 Hz, 2H), 3.9 (dd, J¼1.8, 9.0 Hz, 1H),
3.84 (d, J¼4.0 Hz, 1H), 3.68e3.66 (m, 1H), 3.64e3.58 (m, 2H),
3.49e3.45 (m, 1H), 2.34 (d, J¼10.0 Hz, 1H), 1.70e1.68 (m, 1H),
1.51e1.46 (m, 1H), 1.48 (s, 9H), 1.32e1.28 (m, 24H), 0.92 (t, J¼6.4 Hz,
4.10. (2S,3S,4R)-3,4-Bis-tert-butyldimethylsilyloxy-2-
hexacosanoyl-amide-4-octadecanol (16)
3H), ppm; 13C NMR (CDCl3, 100 Hz):
d¼157.2, 137.5, 128.5, 127.9,
To a suspension of 10% Pd/C (90 mg) and 20% Pd(OH)2 (90 mg) in
methanol (90 mL) was dropped a solution of 15 (600 mg,
127.8, 80.3, 73.6, 72.7, 69.5, 69.1, 52.5, 35.1, 32.7, 30.0, 29.7, 29.6,

C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
6693
0.59 mmol) in methanol (20 mL) under H2 atmosphere. After being
stirred for 12 h, the mixture was filtered and concentrated under
reduced pressure and the residue was purified by chromatography
4.13. (R)-2-(tert-Butyldimethylsilyloxy)-14-
methylpentadecanal (21)
on silica gel to give 16 (447 mg, 82%), as a colorless oil. {½a D25
ꢂ
ꢀ9.2 (c
To a suspension of 10% Pd/C (490 mg) in methanol (20 mL) was
dropped to a solution of 20 (4.9 g, 12.31 mmol) in methanol
(100 mL) under H2 atmosphere. After stirring for 1 h, the mixture
was filtered and concentrated to give 21 (4.68 g, 95%) without
further purification. To a solution of above crude compound (4.6 g,
11.5 mmol) in dry toluene (50 mL) was slowly dropped a solution of
DIBAL-H (11.2 ml, 11.5 mmol 0.73, 20%) at ꢀ78 ꢁC under argon at-
mosphere. After stirring for 3 h, the reaction mixture was quenched
with an aqueous solution of saturated potassium sodium tartrate
and stirred for another four 4 h at room temperature. The organic
layer was separated and aqueous layer was extracted with ethyl
acetate for three times (40mLꢃ3). The combined organic layers
were washed with brine for three times (20mLꢃ3) and dried over
anhydrous Na2SO4. Filtered and concentrated under reduced
pressure, the residue was purified by chromatography on silica gel
1.0, CHCl3); lit.20
½
a 1D6
ꢂ
ꢀ9.5 (c 6.2, CHCl3); lit.21
½
a 2D6
ꢂ
ꢀ10.9 (c 1.0,
CHCl3)}; IR (film): nmax 3415, 2925, 2853, 1655, 1529, 1467, 1256,
1095 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
: 7.22 (d, J¼4.0 Hz, 1H),
3.97e3.88 (m, 2H), 3.75e3.69 (m, 2H), 3.70e3.67 (m, 1H),
3.65e3.61 (m, 1H), 2.21e2.17 (m, 2H), 1.80e1.71 (m, 2H), 1.70e1.61
(m, 2H), 1.35e1.24 (m, 68H), 0.99 (s, 9H), 095 (s, 9H), 0.92e0.89 (m,
6H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H) ppm; 13C NMR
(CDCl3, 100 Hz):
d
¼174.9, 76.6, 71.8, 65.0, 56.9, 37.0, 31.9, 30.8, 29.7,
25.8, 22.7, 18.0, 14.1, ꢀ4.1, ꢀ4.5, ꢀ4.9 ppm; MS (ESI): 924 (MþHþ);
HRMS (ESI) calcd for (C56H117NO4Si2þHþ): 924.8599 found:
924.8596.
4.11. (2S,3S,4R)-3,4-Diol-2-hexacosanoyl-2-amino-4-
actadecanol (17)
to give 21 (3.62 g, 85%), as a colorless oil. ½a D25
þ3.4 (c 1.0, CDCl3); IR
ꢂ
(film): nmax 3451, 2926, 2855, 1738, 1467, 1468, 1115, 838, 778 cmꢀ1
;
To a solution of 16 (100 mg, 0.108 mmol) in MeOH (2 mL) was
dropped to solution of HCl/MeOH (4 M, 1 mL) at room temperature.
After stirring for 4 h, the mixture was concentrated under reduced
pressure to afford crude intermediate product, which was diluted
with water and extracted with ethyl acetate for three times
(10 mLꢃ5). The combined organic layers were washed with brine
(10mLꢃ2) and dried over anhydrous Na2SO4. Filtered and concen-
trated under reduced pressure, the residue was purified by chro-
matography on silica gel to give 17 (40 mg, 52%), as a white solid.
1H NMR (400 MHz, CDCl3)
1H), 1.66e1.63 (m, 2H), 1.62e1.61 (m, 1H), 1.44e1.36 (m, 2H),
1.33e1.26 (m, 16H), 1.19e1.17 (m, 2H), 0.93 (s, 9H), 0.90e0.88 (m,
6H), 0.11 (s, 3H), 0.10 (s, 3H) ppm; 13C NMR (CDCl3, 100 Hz):
d
: 9.62 (d, J¼2.0 Hz, 1H), 4.01e3.97 (m,
d
¼203.3, 77.7, 39.1, 32.6, 31.9, 29.7, 29.6, 29.5, 29.4, 25.7, 24.6, 22.7,
18.2, 14.1, ꢀ4.6, ꢀ4.9 ppm; MS (ESI): 371 (MþNaþ); HRMS (ESI)
calcd for (C22H46NO2SiþHþ): 371.3345, found: 371.3305.
4.14. N-((2S,3S,4R)-1-(Benzyloxy)-4-(tert-
butyldimethylsilyloxy)-3-hydroxy-16-methylheptadecan-2-
yl)-2-methylpropane-2-sulfinamide (22)
½
a 2D5
1216, 1164, 1107 cmꢀ1
ꢂ
ꢀ5.3 (c 1.0, CDCl3); IR (film): nmax 3500, 2956, 1739, 1456, 1261,
;
1H NMR (400 MHz, C6H5N)
d
; 8.01 (d,
J¼8.8 Hz, 1H), 5.10 (br s, 3H), 4.78e4.72 (m, 1H), 4.39e4.34 (m, 2H),
4.19e4.16 (m, 1H), 2.52e2.48 (m, 2H), 2.11e2.05 (m, 2H), 1.86e1.83
(m, 2H), 1.69e1.60 (m, 64H), 0.87e0.82 (m, 6H) ppm; 13C NMR
The mixture of compound 21 (3.5 g, 9.46 mmol), t-BuOH (3.6 ml,
28.4 mmol) and 2-benzoxyl ethyl (S)-N-tert-butanesulfinyl imine
(2.4 g, 9.46 mmol) was stirred in dry THF (30 mL) at ꢀ78 ꢁC under
argon atmosphere. Then a freshly solution of SmI2 (28.4 mmol,
20 mL) in dry THF was dropped and the resulted mixture was
stirred for 5 h the reaction was quenched with an aqueous solution
of saturated Na2S2O3 (10 mL) and warmed to room temperature.
The mixture was diluted with ethyl acetate (30 mL) and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate for three times (40mLꢃ3) and the combined organic layers
were washed with brine for three times. Dried, filtered and con-
centrated, the residue was purified by chromatography on silica gel
(CDCl3, 100 Hz):
d
¼176.1, 74.8, 72.3, 63.1, 55.9, 37.9, 36.4, 35.8, 35.2,
33.4, 32.7, 31.1, 30.3, 28.1, 27.5, 24.1, 20.5, 15.4, 14.8 ppm; MS (ESI):
696 (MþNaþ); HRMS (ESI) calcd for (C44H89NO4þNaþ): 696.6870,
found: 696.6843.
4.12. (R)-Methyl 2-(tert-butyldimethylsilyloxy)-7-methyloct-
5-enoate (20)
To a solution of isobutanenetriphenylphosphonium bromide
(9.29 g, 22.5 mmol) in dry THF (60 mL) was treated with a solution
of n-BuLi (13.4 mL, 18.1 mmol, 1.6 in THF) at 0 ꢁC under argon at-
mosphere. After stirring for 2 h, the mixture was cooled to ꢀ78 ꢁC
and a solution of crude aldehyde derived from compound 18b
(5.37 g, 15 mmol) in dry THF was slowly dropped. The reaction was
stirred for another 1 h at the same temperature and warmed to
room temperature within 2 h. After being stirred for 3 h at room
temperature. The mixture was quenched with an aqueous solution
of saturated NaHCO3 (10 mL) and diluted with water (10 mL) and
ethyl acetate (20 mL). The resulted mixture was separated and the
aqueous phase was extracted with ethyl acetate for there times. The
combined organic layers were washed with brine. Dried, filtered
and concentrated, the residue was purified by chromatography on
to give 22 (3.96, 67%), as a colorless oil. ½a D25
þ0.34 (c 1.0, CDCl3); IR
ꢂ
(film): nmax 3436, 2926, 1739, 1631, 1598, 1467,1119,1077, 776 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
: 7.40e7.29 (m, 5H), 4.63 (d, J¼11.6 Hz
1H), 4.58 (d, J¼11.6 Hz 1H), 4.08e4.06 (m, 2H), 3.94 (dd, J¼4.0,
8.6 Hz 1H), 3.79 (dd, J¼3.2, 8.8 Hz 1H), 3.50e3.45 (m, 1H),
3.28e3.24 (m, 1H), 2.62 (d, J¼9.6 Hz, 1H), 1.77e1.69 (m, 1H),
1.58e1.51 (m, 1H), 1.50e1.41 (m, 1H), 1.31e1.27 (m, 18H), 1.26 (s,
9H), 1.21e1.16 (m, 2H), 0.93 (s, 9H), 0.90 (d, J¼6.8 Hz, 6H), 0.13 (s,
6H) ppm; 13C NMR (CDCl3, 100 Hz):
d
¼138.3, 128.4, 127.9, 127.6,
73.4, 71.1, 70.8, 70.1, 58.0, 56.1, 39.1, 34.6, 31.9, 29.7, 29.6, 29.3, 25.9,
25.3, 22.8, 22.7, 22.6 18.1, ꢀ3.8, ꢀ4.1 ppm; MS (ESI): 626 (MþHþ);
HRMS (ESI) calcd for (C35H67NO4SSiþHþ): 626.4638, found:
626.4613.
silica gel to give 20 (5.0 g, 84%) as a colorless oil. ½a D25
þ17.5 (c 1.0,
ꢂ
CHCl3): IR (film): nmax 3416, 2926, 2283, 1758, 1590, 1467, 1257,
1216, 1120, 1039 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 5.39e5.20 (m,
4.15. tert-Butyl (2S,3S,4R)-1-(benzyloxy)-3,4-dihydroxy-16-
2H), 4.22 (t, J¼6.0 Hz, 1H), 3.74 (s, 3H), 2.59e2.47 (m, 1H),
2.08e2.03 (m, 2H), 1.75e1.69 (m, 2H), 1.43e1.30 (m, 14H),
1.00e0.96 (m, 6H), 0.96 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H) ppm;
methylheptadecan-2-ylcarbamate (24b)
To a solution of 12 (2.47 g, 6.07 mmol) in 1,4-dioxane and water
(30 mL, v/v¼1:1) was treated with a solution of 1 M NaOH (5 mL)
and stirred for 2 h at rt ꢁC. Then a solution of Boc2O (1.98 g,
9.11 mmol) in 1,4-dioxane (5 mL) was dropped and the resulted
mixture was stirred for 48 h at room temperature. The reaction was
13C NMR (CDCl3,100 Hz):
d
¼174.4, 137.5, 127.5, 72.3, 51.7,
35.3, 29.9, 29.5, 29.4, 29.3, 27.3, 25.7, 26.4, 25.7, 25.1, 23.2, 22.7,
18.3, ꢀ4.9, ꢀ5.3 ppm; MS (ESI): 399 (MþNaþ); HRMS (ESI) calcd for
(C23H46O3SiþHþ): 399.3294, found: 399.3270.

6694
C. Xarnod (Lu-Men Chao) et al. / Tetrahedron 68 (2012) 6688e6695
quenched with a solution of HCl (5 mL 1 M), and the mixture was
extracted with ethyl acetate for three times (30 mLꢃ3). The com-
bined organic layers were washed with saturated NaHCO3 aqueous
solution (30 mL) and brine (20 mLꢃ3). Dried, filtered and con-
centrated, the residue was purified by chromatography on silica gel
27.4, 26.5, 25.8, 22.7,18.0,14.6, ꢀ4.0, ꢀ4.3, ꢀ4.5, ꢀ4.9 ppm; MS (ESI):
1116 (MþHþ); HRMS (ESI) calcd for (C67H133NO5Si3þHþ): 1116.9570,
found: 1116.9541.
4.18. (R)-N-((2S,3S,4R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-
hydroxy-16-methylheptadecan-2-yl)-2-(tert-
butyldimethylsilyloxy)tetracosanamide (28)
to give 24b (2.31, 75%), as a white solid. ½a D25
ꢀ6.3 (c 1.0, CDCl3); IR
ꢂ
(film): nmax 3378, 2928, 1710, 1502, 1463, 1377, 1169, 722.3,
696.3 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d: 7.41e7.30 (m, 5H), 5.28 (d,
J¼8.0 Hz,1H), 4.60 (d, J¼11.6 Hz, 1H), 4.55 (d, J¼11.6 Hz, 1H), 3.97 (d,
J¼7.6 Hz, 1H), 3.84 (s, 1H), 3.67e3.64 (m, 1H), 3.62e3.59 (m, 2H),
3.49e3.44 (m, 1H), 2.46e2.40 (m, 1H), 1.73e1.65 (m, 1H), 1.60e1.52
(m, 1H), 1.48 (s, 9H), 1.34e1.27 (m, 18H), 1.20e1.16 (m, 2H), 0.90 (d,
To a suspension of 10% Pd/C (22.5 mg) and 20% Pd(OH)2
(22.5 mg) in methanol (20 mL) was dropped to a solution of 26
(150 mg, 0.14 mmol) in methanol (5 mL) under H2 atmosphere.
After being stirred for 12 h, the mixture was filtered and concen-
trated under reduced pressure, the residue was purified by chro-
matography on silica gel to give 28 (89 mg, 65%), as a colorless oil.
J¼6.8 Hz 6H) ppm; 13C NMR (CDCl3, 100 Hz):
¼157.2, 137.8, 128.5,
d
127.9, 127.8, 80.3, 73.6, 72.7, 69.5, 69.1,52.6,, 32.7, 32.0, 30.0, 29.7,
29.6, 29.3, 28.3, 26.1, 22.7, 14.1 ppm: MS (ESI): 508 (MþHþ); HRMS
(ESI) calcd for (C30H53NO5þHþ): 508.4002, found: 508.4000.
½
a 2D5
1377,1257, 1093, 836, 778 cmꢀ1
ꢂ
ꢀ0.9 (c 1.0, CDCl3); IR (film): nmax 3428, 2925, 2853, 1658, 1461,
;
1H NMR (400 MHz, CDCl3)
d: 7.27
(d, J¼8.8 Hz, 1H), 4.32e4.25 (m, 1H), 4.24e4.14 (m, 1H), 3.90e3.87
(m, 1H), 3.87e3.83 (m, 1H), 3.69e3.66 (m, 2H), 1.83e1.81 (m, 1H),
1.78e1.68 (m, 2H), 1.58e1.50 (m, 2H), 1.48e1.40 (m, 2H), 1.31e1.27
(m, 56H), 0.98e0.95 (m, 18H), 0.94e0.88 (m, 18H), 0.16e0.12 (m,
4.16. (2S,3S,4R)-1-(Benzyloxy)-3,4-bis(tert-
butyldimethylsilyloxy)-16-methylheptadecan-2-amine (24a)
18H) ppm; 13C NMR (CDCl3, 100 Hz):
d
¼174.9, 76.4, 76.2, 74.2, 71.8,
To a solution of 24b (2.2 g, 4.34 mmol) and 2.6-luditine (1.55 mL,
13.29 mmol) was stirred in dry DCM (20 mL) for 15 min at 0 ꢁC
under argon atmosphere, then a solution of TMSOTf (3.05 mL,
13.29 mmol) was slowly dropped and the mixture was stirred for
over night at room temperature. The reaction mixture was
quenched with H2O and extracted with CH2Cl2 for three times
(50 mLꢃ3). The combined organic layers were washed
with saturated NaHCO3 aqueous solution (40 mL) and brine
(20 mLꢃ3). Dried, filtered and concentrated, the residue was
purified by chromatography on silica gel to give to 24a (2.15 g, 78%),
65.0, 56.9, 37.0, 31.9, 30.8, 29.7, 25.8, 22.7, 18.0, 14.1, ꢀ4.1, ꢀ4.9 ppm;
MS
(ESI):
1048
(MþNaþ);
HRMS
(ESI)
calcd
for
(C60H127NO5Si3þNaþ): 1048.8920 found: 1048.8885.
4.19. (R)-2-Hydroxy-N-((2S,3S,4R)-1,3,4-trihydroxy-16-
methylheptadecan-2-yl)tetracosanamide (29)
To a solution of 28 (60 mg, 0.038 mmol) in MeOH (2 mL) was
dropped to solution of HCl/1.4-dioxane (4 M, 1 mL) at room tem-
perature. After stirring for 4 h, the mixture was concentrated under
reduced pressure to afford crude intermediate product, which was
diluted with water and extracted with ethyl acetate for three times
(10 mLꢃ5). The combined organic layers were washed with brine
(10mLꢃ2) and dried over anhydrous Na2SO4. Filtered and concen-
trated under reduced pressure, the residue was purified by chro-
matography on silica gel to give 29 (25 mg, 60%), as a white solid.
as a colorless oil. ½a D25
ꢂ
þ19.3 (c 1.0, CDCl3); IR (film): nmax
3379, 2928, 1702, 1502, 1464, 1377, 1179, 772 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
: 7.37e7.329 (m, 5H), 4.60 (d, J¼12.4 Hz, 1H),
4.51 (d, J¼12.4 Hz, 1H), 3.72e3.69 (m, 1H), 3.66e3.63 (m, 2H),
3.53e3.50 (m, 1H), 3.21e3.16 (m, 1H), 2.01 (s, 2H), 1.74e1.70 (m,
1H), 1.57e1.50 (m, 2H), 1.44e1.30 (m, 2H), 1.35e1.26 (m, 16H),
1.20e1.17 (m, 2H), 0.93 (s, 9H), 0.92e0.90 (m, 6H), 0.89 (s, 9H), 0.15
(s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H) ppm; 13C NMR (CDCl3,
½
a 2D5
1469, 1417, 1279, 1217, 1125, 1103 cmꢀ1; 1H NMR (400 MHz, CDCl3)
; 5.05e4.95 (m, 1H), 4.48e4.39 (m, 1H), 4.36e4.27 (m, 1H),
ꢂ
þ7.7 (c 0.2, CDCl3); IR (film): nmax 3338, 2953, 2850,1733,1650,
100 Hz):
d
¼138.6, 128.3, 127.6, 127.4, 76.5, 74.5, 73.2, 72.7, 52.9, 39.1,
30.9, 29.9, 29.7, 29.6, 29.5, 27.9, 27.4, 26.7, 25.9, 25.8, 22.7, 18.0,
14.1, ꢀ3.8, ꢀ4.1, ꢀ4.8, ꢀ4.9 ppm; MS (ESI): 635 (MþHþ); HRMS
(ESI) calcd for (C37H70NO3Si2þHþ): 635.5207, found: 635.5190.
d
4.03e3.88 (m, 1H), 3.82e3.70 (m, 1H), 1.83e1.70 (m, 1H), 1.55e1.51
(m, 2H),1.43e1.41 (m, 2H),1.37e1.25 (br m, 58H),1.24e1.19 (m, 2H),
0.93e0.89 (m, 9H) ppm; 13C NMR (CDCl3, 100 Hz):
75.2, 72.9, 60.3, 53.4, 38.9, 33.7, 31.8, 29.7, 27.8, 26.8, 22.7, 14.0 ppm;
MS (ESI): 684 (MþHþ); HRMS (ESI) calcd for (C42H85NO5þHþ):
684.6506, found: 684.6498.
d
¼173.9, 77.3,
4.17. (R)-N-((2S,3S,4R)-1-(Benzyloxy)-3,4-bis(tert-
butyldimethylsilyloxy)-16-methylheptadecan-2-yl)-2-(tert-
butyldimethylsilyloxy)tetracosanamide (27)
To a mixture of compound 26 (3.15 mmol, 10 mL), NMM (0.7 mL
6.31 mmol) and catalytic amount of DMAP was stirred in THF (3 mL),
then a solution of 24a (2.0 g, 3.15 mmol) in dry THF (4 mL) was
dropped. The reaction mixture was warmed to room temperature
and stirred for 5 h. The mixture was quenched with water and
extracted with ethyl acetate for three times (50 mLꢃ3). The com-
bined organic layers were washed with saturated NaHCO3 aqueous
solution (40 mL) and brine (40 mLꢃ3), dried overanhydrous Na2SO4.
Filtered and concentrated under reduced pressure, the residue was
purified by chromatography on silica gel to give 27 (912 mg, 27%).
Acknowledgements
We thank the National Natural Science Foundation of China
(20832005, 21072034, 20702007), and the National Basic Research
Program (973 program) of China (grant no. 2010CB912600) for fi-
nancial support. The authors also thank Dr. Xin-Sheng, Lei and Han-
Qing, Dong for helpful suggestions.
References and notes
½
a 2D5
1258, 1097, 836, 778 cmꢀ1; 1H NMR (400 MHz, CDCl3)
ꢂ
ꢀ8.5 (c 1.0, CDCl3); IR (film): nmax 3415, 2924, 2854,1678, 1466,
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