Enantioselective total synthesis of (2S,3R,4R)-d-xylo-phytosphingosine from substituted azetidin-2-one

Article abstract of DOI:10.1016/j.tetlet.2009.02.050

Enantiomerically pure (2S,3R,4R)-d-xylo phytosphingosine is synthesized in 36% overall yield in seven steps from known β-lactam (8) derived from d-mannitol triacetonide.

Full text of DOI:10.1016/j.tetlet.2009.02.050

Tetrahedron Letters 50 (2009) 3296–3298
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Tetrahedron Letters
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Enantioselective total synthesis of (2S,3R,4R)-D-xylo-phytosphingosine
from substituted azetidin-2-one
*
Ganesh Pandey , Dharmendra Kumar Tiwari
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure (2S,3R,4R)-
steps from known b-lactam (8) derived from
D
-xylo phytosphingosine is synthesized in 36% overall yield in seven
-mannitol triacetonide.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 January 2009
Revised 2 February 2009
Accepted 9 February 2009
Available online 12 February 2009
D
Keywords:
Enantioselective synthesis
Sphingosine
b-Lactam
Wittig reaction
Sphingolipids which play crucial roles in many physiological
processes1 comprise sphingoid bases possessing long-chain ali-
phatic 2-amino-1,3-diol backbones. Sphingolipids such as Cera-
mide (1), sphingomyelins (2), and glycosphingolipids (3) are
important membrane components of all the eukaryotic cells, plas-
ma membranes, and intramolecular organelles playing vital roles
in a number of cellular events including cell growth, differentia-
tion, adhesion, and neuronal repair. They have also been proved
to play a prominent role in cell signaling (Fig. 1).2
ence as invaluable life-saving drugs. In addition to their medicinal
values, b-lactams have also proved to be invaluable precursors for
the syntheses of various natural products,15–17 owing to the flexi-
bility available for selective ring-cleavage reactions. Banik et al.18
have utilized this property of b-lactam for the synthesis of non-
natural (ꢀ)-polyoxamic acid. Furthermore, b-lactam skeletons
have also been used in the synthesis of sphingosines through their
ring-opening reaction using either long alkyl Grignard reagents14a
,
n-tetradecyl p-toluenesulfonate/n-BuLi19 or phosphonate-stabi-
Phytosphingosines, characterized by the 2-amino-1,3,4 triol
head group, are the most important naturally occurring sphingoli-
pids prevalent in microorganisms, plants, and many mammalian
tissues such as brain, hair, intestines,3 uterus,4 liver,5 skin,6 and
blood plasma.7 They are also found in human kidney cerebrosides
and some cancer cell types.8 In addition to being base components
of sphingolipids in membranes, phytosphingosines themselves are
found to be bioactive lipids. For example, phytosphingosine (5) is a
lized carbanion20 as nucleophiles.
OH
OH
NH2
CH2O
R
C11H23
C12H25
OH
NH
C14H29
potential heat stress signal in yeast cells9 and
D-erythro-sphingo-
OH
sine (6) shows promising protein kinase inhibitory activity.10 It
has also been established that various diastereomers of sphingo-
sines exhibit different activities and metabolism.11 This subtle var-
iation in biological activities over a range of diastereomers has led
to the synthesis of all the diastereomers of sphingosines. This fact
is very well reflected in the spurt of publications dealing with the
synthesis of sphingosines.8,12–14
O
R = H, Ceramide (1)
R = Phosphocholine, Sphingomyeline (2)
R = Sugars, Glycosphingolipid (3)
(2S,3R,4R)-xylo -phyto-
sphingosine (4)
NH2
OH
OH NH2
C13H27
OH
b-Lactams are part structures of the most widely used antibiot-
ics and remain unsurpassed in their contribution to medicinal sci-
C14H29
OH
OH
ribo-(2S,3S,4R)-phytosphingosine
5
( )
erythro-(2S,3R)-sphingosine (6
)
* Corresponding author. Tel.: +91 20 25902627; fax: +91 20 25902628.
E-mail address: gp.pandey@ncl.res.in (G. Pandey).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.050

G. Pandey, D. K. Tiwari / Tetrahedron Letters 50 (2009) 3296–3298
3297
ium aluminum hydride in THF, under reflux condition produced 11
in 93% yield having a vicinal diol moiety. N-Debenzylation of 11 by
catalytic hydrogenation (10%, Pd/C) at atmospheric pressure of
hydrogen followed by N-Boc protection gave 12 in 93% over two
steps. The oxidative cleavage of 12 using sodium periodate in eth-
anol/water (1:1) solvent at room temperature yielded 13 in 89%
yield. The subsequent reduction of 13 with sodium borohydride
gave compound 14 (92%). The treatment of 14 with TFA/water
(20:1) in dichloromethane at 0 °C led to the concomitant N-Boc
as well as acetonide deprotection affording 4 quantitatively. Since
it was difficult to purify 4 by column chromatography, this product
was acetylated using acetic anhydride/ pyridine with a catalytic
amount of DMAP to obtain 15. Compound 15 was easily purified
by silica gel column chromatography in 30% ethylacetate/petro-
leum ether as eluent.
O
O
H
O
H
O
O
CH
BnO
O
Ref-18
O
a
O
N
H
O
O
7
8
O
H
O
O
H
O
H
H
HO
O
BnO
O
C14H29
C12H25
b
N
N
The spectral data and specific rotation of 15 were in excellent
9
10
H
agreement with the reported values.22
In conclusion, an enantioselective synthesis of (2S,3R,4R)-
xylo-phytosphingosine is achieved from b-lactam derived from
mannitol triacetonide.
D
-
-
O
H
O
O
H
O
D
H
HO
HO
HO
C14H29
C14H29
c
d
HN
NHBoc
12
Acknowledgments
HO
11
The authors thank the Department of Science and Technology,
New Delhi, for financial support and CSIR, New Delhi, for a research
fellowship to D. K. Tiwari.
O
O
C14H29
O
O
C14H29
f
e
References and notes
HO
O
NHBoc
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14
13
g, h,
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OAc
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NHAcOAc
15
Scheme 1. Reagents and conditions: (a) PPh3BrC13H27, n-BuLi, dry THF, 0 °C, 1 h,
70%; (b) HCOONH4, Pd/C (10%), MeOH, reflux, 4 h; 80%; (c) LAH, dry THF, reflux, 4 h,
93%; (d) H2, Pd/C (10%), MeOH, (Boc)2O, rt 10 h, 93%; (e) NaIO4, EtOH:H2O (1:1) rt,
30 min, 89%; (f) NaBH4, dry. MeOH, 0 °C to rt, 10 h; 92%; (g) TFA/H2O (20:1), DCM,
0 °C, 3 h; (h) Ac2O, dry Py, DMAP (cat) 91%.
While all these reports present attractive approaches to
sphingosines, the installation of the tetradecyl chain has not been
easy and has often produced a mixture of different products.21
Therefore, it was felt that a route which introduces the long tetra-
decyl chain in sphingosines before the opening of the b-lactam ring
could be an attractive strategy. Toward this end, we have devised a
-xylo-phytosphingosine, starting from b-lac-
-mannitol triacetonide 7 and report herein
our successful preliminary endeavor (Scheme 1).
synthetic route for
tam 8 derived from
D
D
The required b-lactam 8 was synthesized in 70% yield using the
reported protocol from D
-mannitol triacetonide 7.18 Subjecting 8 to
Wittig olefination with a 13 carbon ylide in the presence of n-BuLi
at 0 °C produced 9 in 70% yield as a cis, trans mixture (55:45), con-
firmed by 1H NMR spectra. The geometrical isomers ratio was of no
relevance to the planned synthetic sequence as the double bond
was to be reduced in the immediate next step. It was also expected
that during the reduction of the olefinic double bond of 9, O-deb-
enzylation would occur. Accordingly, 9 upon transfer hydrogena-
tion using ammonium formate and Pd/C (10%) in methanol
furnished 10 in 80% yield. Compound 10 upon reduction with lith-

3298
G. Pandey, D. K. Tiwari / Tetrahedron Letters 50 (2009) 3296–3298
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ꢁ
6.5 (c 0.86, CHCl3), {lit
½ ꢁ 6.3 (c 0.86, CHCl3)}; IR (CHCl3) 3306, 1746, 1663, 1372, 1226, 1046,
18 a 2D7
954 cmꢀ1 1H NMR (500 MHz, CDCl3) d 5.77 (d, J = 9.5 Hz, 1H), 5.14 (dd, J = 6.6,
;
4.3 Hz, 1H), 5.03 (dd, J = 12.7, 6.8 Hz, 1H), 4.51 (m, 1H), 4.01 (m, 2H), 2.08 (s,
3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.00 (s, 3H) 152–1.60 (m, 2H), 1.22 (bs, 24H), 0.86
(t, J = 6.4 Hz, 3H), 13C NMR (75 MHz, CDCl3): 170.6, 170.1, 169.8, 72.2, 71.9,
62.9, 47.9, 31.9, 305.5, 29.7, 29.6, 29.3, 29.2, 24.8, 23.2, 22.7, 20.9, 20.7, 20.6,
14.1. MS (m/z): 486 (M++1).
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