Efficient enantioselective total synthesis of arabino-phytosphingosine

Article abstract of DOI:10.1055/s-2005-872242

Enantioselective total synthesis of arabino-phytosphingosine has been achieved in 8 steps employing Claisen rearrangement and Fleming-Tamao oxidation as key steps. Installation of all chiral centers present in arabino- phytosphingosine was achieved throug

Full text of DOI:10.1055/s-2005-872242

LETTER
2183
Efficient Enantioselective Total Synthesis of arabino-Phytosphingosine
Total
S
ynthesis of
o
arabino-Phy
o
tosphingosine Young Jung, Sol Kang, Suk Bok Chang, Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, Korea Advanced Institute of Science and Technology,
Daejon, 305-701, Korea
Fax +82(42)8695818; E-mail: kimyh@kaist.ac.kr
Received 22 June 2005
oxidation13 which occurs under acidic conditions and will
result in the formation of fully deprotected arabino-
phytosphingosine. In turn, the epoxide 2 can be prepared
from the allyl silane 3, which may result from the Claisen
Abstract: Enantioselective total synthesis of arabino-phytosphin-
gosine has been achieved in 8 steps employing Claisen rearrange-
ment and Fleming–Tamao oxidation as key steps. Installation of all
chiral centers present in arabino-phytosphingosine was achieved
through the use of asymmetric catalysis. This synthesis provides rearrangement of allylic ester 4.
one of the most efficient routes to prepare 2-amino-1,3,4-triol moi-
ety.
To prepare 4, we started from tetradecanal (Scheme 2).
According to our retrosynthetic analysis and preceding
experimental evidences about the stereochemistry of
Claisen rearrangement, to prepare natural enantiomer of
arabino-phytosphingosine, R-form of E-allylic alcohol 6
should be prepared. Enantio-enriched allylic alcohol 6 can
be prepared by many ways, including kinetic resolution
with Sharpless procedure, chromatographic separation of
diastereomeric derivatives of rac-6, and probably enzy-
matic resolution of rac-6.14 However, it is important that
for an asymmetric synthesis to be practical, the stereo-
chemistry should be installed by asymmetric catalysis
involving carbon–carbon bond formation. Thus, tetrade-
canal was reacted with dimethylphenylsilyl acetylene un-
der the conditions of Pu.15 Treatment of tetradecanal with
(S)-BINOL, Ti(Oi-Pr)4, Et2Zn and dimethylphenylsilyl
acetylene gave the corresponding propargyl alcohol 5 in
85% yield with 98% ee. It was partially reduced with Red-
Al to give allylic alcohol 6 in high yield in an almost enan-
tiomerically pure form (98% ee). The coupling of 6 with
Boc-glycine gave 4 in good yield. Allylic alcohol like 6
has been prepared in many ways, however to our knowl-
edge, it is the first time to employ asymmetric catalysis to
establish the stereochemistry of 6.
Key words: amino alcohol, enantioselective synthesis, total syn-
thesis, sphingolipids, Claisen rearrangement
Sphingolipids and glycosphingolipids are important ele-
ments of eukaryotic cell membranes and are known to
regulate several biological processes, such as cell prolifer-
ation, differentiation, adhesion, neuronal repair, and sig-
nal transduction.1 Additionally, many glycosphingolipids
from marine organisms display remarkable antitumor,2
antiviral,3 antifungal,4 antiinflammatory,5 immunosup-
pressive,6 immunostimulatory,2 neuritogenic,7 and cyto-
toxic activities.8 Phytosphingosines are one of the major
long chain components of glycosphingolipids with an 18-
carbon chain and a terminal 2-amino-1,3,4-triol moiety.
Like many members of sphingolipids, phytosphingosine
itself is a bioactive lipid and its analogues also show sig-
nificant bioactivities. Due to these biochemical impor-
tance, along with the fact that natural supply of
phytosphingosines are fairly limited, there is a continuing
interests in developing efficient methods for the synthesis
of phytosphingosines.
Many methods have been reported for the synthesis of
phytosphingosines.9–11 Most of them, however, are based
SiMe2Ph
on
a chiral pool strategy that usually employs
OAc
carbohydrates9 or amino acid10 derived starting material to
install chiral centers present in the final product. Also,
very few methods employing asymmetric synthesis to in-
stall chiral centers are reported.11 However, except for
some cases,9a they often suffer from the drawbacks of
being a multistep synthesis with a poor overall yield. To
overcome the problems inherent in the previous synthetic
routes, new retrosynthetic analysis of arabino-phyto-
sphingosine was made (Scheme 1).
C13H27
O
C13H27
OAc
O
BocN
OAc NHAc
1
2
O
SiMe2Ph
CO2Me
NHBoc
O
C13H27
NHBoc
C13H27
SiMe2Ph
3
4
Scheme 1 Retrosynthetic analysis for arabino-phytosphingosine.
The arabino-phytosphingosine 1 can be thought to derive
from the epoxide 2 through regioselective reduction of
epoxide10b,c,12
and
subsequent
Fleming–Tamao
The Claisen rearrangement of amino acid derived allylic
ester is known.16 However, only one report17 has been
written regarding the Claisen rearrangement of allylic es-
ter in which the allylic component is vinyl silane. To in-
vestigate the key rearrangement step, we first employed
SYNLETT 2005, No. 14, pp 2183–2186
0
2
.0
9
.2
0
0
5
Advanced online publication: 22.07.2005
DOI: 10.1055/s-2005-872242; Art ID: U19105ST
© Georg Thieme Verlag Stuttgart · New York

2184
D. Y. Jung et al.
LETTER
OH
SiMe2Ph
OH
H
(a)
+
C13H27
SiMe2Ph
C13H27
NHBoc
C13H27
O
SiMe2Ph
5
O
O
O
7
OH
(d)
NHBoc
(b)
(c)
O
C13H27
SiMe2Ph
O
C13H27
SiMe2Ph
6
4
SiMe2Ph
CO2Me
NHBoc
(a) or (b)
O
Scheme 2 Reagents and conditions: (a) Et2Zn (6 equiv), dimethyl-
phenylsilyl acetylene (6 equiv), toluene, reflux, 1 h; then, (S)-BINOL
(0.5 equiv), Ti(Oi-Pr)4 (1.5 equiv), tetradecanal in Et2O, 75%, 98%
ee; (b) Red-Al (2.1 equiv), Et2O, 0 °C to r.t., 87%, 98% ee; (c) EDCI
(1.1 equiv), Boc-Gly-OH (1.1 equiv), DMAP (0.3 equiv), 95%.
C13H27
C13H27
SiMe2Ph
NHBoc
4
3
(c)
(e)
SiMe2Ph
conditions reported by Kazmaier et al. (Scheme 3).16 In
the presence of LDA and ZnCl2, 3 can be obtained in mod-
erate yield with excellent stereoselectivity [ca. 60% yield,
syn:anti > 95:5, (S,S):(R,R) > 95:5]. To improve the yield,
the conditions of Brook was employed.17 Thus, by treating
lithium enolate, generated from 4 by treatment with LDA,
with TMSCl, we could induce the more efficient Claisen
rearrangement with the same degree of stereoselectivity
[77% yield, syn:anti > 95: 5, (S,S): (R,R) > 95:5]. The syn-
relation of amino- and silyl-groups have been established
by transforming the allyl silane to the lactone 7 and taking
NOE spectra.18 To adjust the oxidation state of C-1 car-
bon, the ester 3 was reduced to give amino alcohol 8. We
also tried the one pot reaction of 4 to 8. The completion of
the rearrangement was confirmed by TLC, the reaction
mixture was treated with excess amount of LiAlH4 to give
8. The yield improved significantly compared with the
two-step procedure one-step reaction (77%).
C13H27
OH
NHBoc
8
Scheme 3 Reagents and conditions: (a) LDA (2.5 equiv), ZnCl2
(1.3 equiv), THF, –78 °C to r.t., 60%; (b) LDA (2.1 equiv), TMSCl (3
equiv), THF, –78 °C to r.t., 77%; (c) LiAlH4 (2 equiv), THF, 0 °C,
80%; (d) OsO4 (5 mol%), NMO (2.1 equiv), acetone–H2O = 20:1, r.t.;
(e) LDA (2.1 equiv), TMSCl (3 equiv), THF, –78 °C to r.t., then,
LiAlH4 (2 equiv), THF, 0 °C, 78%.
SiMe2Ph
SiMe2Ph
(a)
C13H27
O
C
13H27
OH
NHBoc
BocN
8
9
SiMe2Ph
BocN
(b)
C13H27
O
O
O
The deoxygenation of lactone 7 could be a possible option
for introducing C-4 hydroxyl group though, it would re-
quire two additional steps and in view of atom economy,
it should be avoided. Thus, instead we chose to epoxidize
the double bond in 8 and then make a reductive cleavage
of the epoxide to synthesize the key intermediate
(Scheme 4). Thus, 8 was protected as the corresponding
acetonide 9.19 Treatment of 9 with four equivalents of
MCPBA followed by reduction by lithium triethylborohy-
dride (super-hydride) gave 10 as a sole diastereomer, pre-
2
SiMe2Ph
BocN
OAc
(c)
C13H27
C13H27
OAc
HO
OAc NHAc
10
1
Scheme 4 Reagents and conditions: (a) 2,2-dimethoxypropane,
acetone, BF3·OEt2, r.t., ca. 100%;19 (b) MCPBA (4 equiv), NaHCO3
sumably through the key epoxide 2. In spite of the effort (6 equiv), CH2Cl2, 0 °C, then, LiEt3BH (2 equiv), THF, 0 °C, 81%; (c)
Hg(TFA)2 (1.1 equiv), TFA–HOAc = 1:1, 25 °C, then, peracetic acid
(3 equiv); then, Ac2O (6 equiv), pyridine (10 equiv), 70%.
to isolate the epoxide 2, it decomposed readily and has to
be employed directly in the next reaction. The 10 was then
subjected to the Fleming–Tamao oxidation, under which
the Boc- and acetonide protection of 10 were also depro-
tected.14 The crude arabino-phytosphingosine was then
acetylated to give the known tetra-acetyl arabino-
phytosphingosine 1.22
made B unfavorable and oxidation reaction would pro-
ceed through the transition state A. This kind of stereose-
lection has well-established precedents.
In conclusion, we have developed a short, efficient, and
conceptually novel synthesis of arabino-phytosphin-
gosines starting from easily obtainable starting materials.
This synthesis provides phytosphingosines in only eight
steps starting from tetradecanal. The overall yield of
synthesis reaches nearly 30% and the all the stereocenters
of arabino-phytosphingosine are derived from the stereo-
The high diastereoselectivity of epoxidation step could be
rationalized by the following model, suggested by Flem-
ing et al. (Scheme 5).20 The dimethylphenylsilyl group of
allyl silane should take the position vertical to the plane of
olefin double bond to ensure maximum overlap of orbit-
als. Theoretically, two transition states A and B are possi-
ble. However, the presence of bulky R group in this case
Synlett 2005, No. 14, 2183–2186 © Thieme Stuttgart · New York

LETTER
Total Synthesis of arabino-Phytosphingosine
2185
SiMe2Ph
BocN
(9) (a) Chiu, H.-Y.; Tzou, D.-L. M.; Patkar, L. N.; Lin, C.-C. J.
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C13H27
O
(10) (a) Ndakala, A. J.; Hashemzadeh, M.; So, R. C.; Howell, A.
R. Org. Lett. 2002, 4, 1719. (b) Azuma, H.; Tamagaki, S.;
Ogino, K. J. Org. Chem. 2000, 65, 3538. (c) Takikawa, H.;
Muto, S.-E.; Mori, K. Tetrahedron 1998, 54, 3141.
(11) (a) Kang, S. H.; Hwang, Y. S.; Lee, H. S. Bull. Korean
Chem. Soc. 2002, 23, 1195. (b) Ayad, T.; Genisson, Y.;
Verdu, A.; Baltas, M.; Gorrichon, L. Tetrahedron Lett. 2003,
44, 579. (c) Nakamura, T.; Shiozaki, M. Tetrahedron 2001,
57, 9087. (d) Martin, C.; Prunck, W.; Bortolussi, M.; Bloch,
R. Tetrahedron: Asymmetry 2000, 11, 1585.
R
H
R
H
SiMe2Ph
PhMe2Si
Ox
C13H27
C13H27
Ox
R
R
H
H
H
H
C13H27
C
13H27
(12) (a) Brown, H. C.; Narasimhan, S.; Somayaji, V. J. Org.
Chem. 1983, 48, 3091. (b) Corey, E. J.; Tius, M. A.; Das, J.
J. Am. Chem. Soc. 1980, 102, 7612.
SiMe2Ph
SiMe2Ph
A
B
(13) (a) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987,
28, 4229. (b) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada,
M. Organometallics 1983, 2, 1694. (c) Kolb, H. C.; Ley, S.
V.; Slawin, A. M. Z.; Williams, D. J. J. Chem. Soc., Perkin
Trans. 1 1992, 2735. (d) Heo, J.-N.; Holson, E. B.; Roush,
W. R. Org. Lett. 2003, 5, 1697.
SiMe2Ph
SiMe2Ph
C13H27
C13H27
O
O
O
O
BocN
BocN
(14) (a) Panek, J. S.; Sparks, M. A. Tetrahedron: Asymmetry
1990, 1, 801. (b) Panek, J. S.; Yang, M.; Solomon, J. S. J.
Org. Chem. 1993, 58, 1003.
(15) Gao, G.; Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4,
4143.
(not observed)
(only product)
Scheme 5 Stereochemical model for epoxidation.
(16) (a) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33,
998. (b) Kazmaier, U. J. Org. Chem. 1996, 61, 3694.
(17) Mohamed, M.; Brook, M. A. Helv. Chim. Acta 2002, 85,
4165.
(18) Panek, J. S.; Zhang, J. J. Org. Chem. 1993, 58, 294.
(19) Dondoni, A.; Perrone, D. Org. Synth. 2000, 77, 64.
(20) (a) Fleming, I.; Sarkar, A. K.; Thomas, A. P. J. Chem. Soc.,
Chem. Commun. 1987, 157. (b) Murphy, P. J.; Russel, A. T.;
Procter, G. Tetrahedron Lett. 1990, 31, 1055.
chemistry of the propargyl alcohol 5, prepared through an
asymmetric catalysis. Also, it is the first time to synthe-
size allyl silane such as 321 without depending on chiral
resolution.
Acknowledgment
This work was financially supported by grant No. R02-2002-000-
00097-0 from the Korea Science & Engineering Foundation and
Center for Molecular Design and Synthesis.
(21) Experimental Procedure for the Synthesis of Allylsilane
3.
A freshly prepared solution of LDA (2.1 equiv) in THF
under argon was cooled down to –78 °C. To the above
solution, the allylic ester 4 was added rapidly. The resulting
mixture was left to stir for 3 min and then treated with 3.0
equiv of TMSCl. This solution was allowed to warm to r.t.
and stirred for further 2 h. The reaction was quenched with
dilute aq HCl and extracted with EtOAc. The extract was
dried over MgSO4, filtered and concentrated under reduced
pressure to give crude carboxylic acid. The crude product
was dissolved in the mixed solvent of MeOH–benzene (1:1)
and treated with TMS-diazomethane (2.0 equiv). The
mixture was stirred for 30 min at r.t. and concentrated in
vacuo to give crude g,d-unsaturated methyl ester 3. The
crude ester 3 was purified by silica gel column
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chromatography using EtOAc–n-hexane = 1:8 as eluents. 1H
NMR (300 MHz, CDCl3): d = 7.45–7.48 (m, 2 H), 7.24–7.33
(m, 3 H), 5.29 (m, 1 H), 5.14 (m, 1 H), 4.87 (br d, 1 H), 4.31
(br t, 1 H), 3.52 (s, 3 H), 2.05 (m, 1 H), 1.95 (m, 2 H), 1.38
(s, 9 H), 1.24 (br s, 24 H), 0.86 (t, 3 H), 0.31 (d, 6 H). 13
C
NMR (75 MHz, CDCl3): d = 0.3, 1.1, 12.9, 22.8, 23.1, 28.4,
30.1, 30.6, 30.7, 32.5, 33.7, 50.4, 53.5, 71.0, 127.8, 128.4,
128.9, 133.6, 133.9, 140.4, 158.1, 170.9. MS (EI): m/z calcd
for C31H53NO4Si: 544.29; found: 545.3900.
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(22) Experimental Procedure for the Synthesis of arabino-
Phytosphingosine.
To a solution of acetonide 9 in CH2Cl2, 8 equiv of NaHCO3
was added. The resulting mixture was cooled to 0 °C and
Synlett 2005, No. 14, 2183–2186 © Thieme Stuttgart · New York

2186
D. Y. Jung et al.
LETTER
then, 4 equiv of MCPBA were added in one portion. The
resulting mixture was allowed to warm to r.t. over 6 h. The
reaction was quenched by the addition of sat. aq Na2SO3
solution and extracted with CH2Cl2. The resulting organic
layer was washed twice with sat. aq NaHCO3 solution, dried
over anhyd MgSO4, filtered and concentrated in vacuo. The
crude epoxide 2 was dissolved in anhyd THF and cooled to
0 °C. It was treated with 2 equiv of lithium triethylboro-
hydride and allowed to stir for additional 2 h. The reaction
was quenched with dilute aq HCl and extracted with EtOAc.
The extract was dried over MgSO4, filtered and concentrated
under reduced pressure to give crude alcohol 10. The
resulting crude alcohol 10 was purified by silica gel column
chromatography using EtOAc–n-hexane = 1:4 as eluents.
The alcohol 10 was placed in a round-bottom flask and the
mixture of TFA–HOAc (1: 1) was added. To the above
mixture was added 2.0 equiv of mercury trifluoroacetate.
After 15 min of stirring, 4 equiv of peracetic acid (40 wt% in
acetic acid) were added and stirring was continued overnight
with exclusion of light. The reaction mixture was diluted
with Et2O and washed successively with excess amount of
aq NaHCO3 solution and aq Na2SO3 solution. The combined
aqueous layer was again extracted with Et2O several times.
The resulting organic layer was washed with sat. aq
NaHCO3 solution twice, dried over anhyd MgSO4, filtered
and concentrated in vacuo. To the resulting crude arabino-
phytosphingosine was added THF and it was treated with
excess pyridine and Ac2O. The reaction was quenched with
dilute aq HCl and extracted with EtOAc. The extract was
dried over MgSO4, filtered and concentrated under reduced
pressure to give crude tetraacetyl arabino-phytosphingosine
(1). The resulting crude 1 was purified by silica gel column
chromatography using EtOAc–n-hexane = 1:5 as eluents to
give pure tetraacetyl arabino-phytosphingosine whose
spectral data are identical with those reported in literature.10b
1H NMR (300 MHz, CDCl3): d = 5.63 (d, 1 H), 5.19 (dd,
1 H), 5.00 (dt, 1 H), 4.60 (m, 1 H), 4.00 (d, 2 H), 2.11 (s,
3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.99 (s, 3 H), 1.54 (br s,
2 H), 1.24 (br s, 24 H), 0.88 (t, 3 H). [a]D25 –24.7 (c 1.0,
CHCl3); lit. [a]D25 –25.1 (c 1.5, CHCl3).
Synlett 2005, No. 14, 2183–2186 © Thieme Stuttgart · New York